Severe Asthma (Fatal Asthma) 1

Bronchial
Asthma

Bronchial
Asthma
Second Edition

D Behera
MD (Medicine) FCCP FNCCP FICP FICA MNAMS (Medicine)
Dip. NBE (Respiratory Medicine)

Professor
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh (India)

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Bronchial Asthma
2005, D Behera
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Dedicated to
the loving memory of
my distinguished teacher
late Dr SK Malik

VALLABHBHAI PATEL CHEST INSTITUTE

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July 8, 2004
Date: ...........................

Foreword
The prevalence of bronchial asthma, a major public health problem is increasing worldwide.
Several studies have demonstrated that there is an increase in morbidity and mortality from
bronchial asthma. Over and under treatment of asthma may be responsible for high mortality
rates. Until recently bronchospasm that results from hyperresponsiveness of the airways to
multiplicity of stimuli has been regarded as the main cause of airway dysfunction in asthma.
Bronchial asthma is now considered as a chronic inflammatory disease of the airways. This
realization that inflammation is the key factor in the pathogenesis of asthma is reflected in the
change in asthma therapy with emphasis on inhaled anti-inflammatory drugs. There are
many controversies in the management of bronchial asthma especially the role of
immunotherapy. Many new drugs are under development and yet there is no cure for asthma.
In a country like India with different socio-cultural diversities and beliefs, the treatment of
asthma varies and the existence of different systems of medicine in our country complicates
the treatment issues. Prof D Behera, a renowned Pulmonologist of our country and Professor
of Pulmonary Medicine at the Postgraduate Institute of Medical Education and Research,
Chandigarh has taken up the challenge of bringing out the updated second edition of his
book, Bronchial asthma. The tremendous response to the first edition of his book is a
testimony to the academic excellence of this book. The second edition has 21 chapters including
epidemiology, pathophysiology, clinical presentation, complications, management and
various guidelines. This revised edition is a comprehensive review of bronchial asthma and
provides practical information for Physicians and Pulmonologists who have to take
appropriate diagnostic and therapeutic decisions in patients with bronchial asthma.
I congratulate Dr Behera for his tireless efforts to bring out the second edition of this book.

Dr VK Vijayan
Director

Preface to the Second Edition

Bronchial asthma is a common respiratory disorder affecting approximately
3-5 percent of the population, although there is a wide variation in its
prevalence in the world, even in the same country at different parts. Over the
years our understanding about the disease has changed. One of the major
changes in our thinking about the pathophysiology of the disease is that the
disease is inflammatory in nature rather than the earlier simplistic view of it
being a simple bronchospastic disorder. A number of cytokines and mediators
take part in its causation. Accordingly the approach to management of
asthma has also changed. A number of guidelines have come up in recent
years and there is a constant renewal in some of the concepts. Although
there is no guideline for adult Indian patients, the same is given for children.
The chapter on bronchial asthma in children is not complete in all aspects,
but it will give a brief account of the same for the pulmonary physician. This
edition has brought out some of these changes. Further, the references are
updated with Vancouver style.
D Behera

Preface to the First Edition

Bronchial asthma is a common disease affecting nearly 3 to 5 percent of the
population. Although incidence- and prevalence-wise the disease is not more
common than tuberculosis in this country, the major difference is its recurring
nature with periods of remissions and exacerbation. In some cases life long,
and in many cases most of the times, medications with anti-asthma drugs
will be required for symptom-free life. This is a major contrast to tuberculosis
where treatment for 6 to 9 months will cure the disease. Earlier concepts
about bronchial asthma, that it is a bronchospastic disease, have changed in
recent years, wherein it is proved that it is an inflammatory disease. A wide
array of cells with a number of cytokines take active role in the pathophysiology of the disease.
The idea of writing this book came to my mind while I was preparing for
the second edition of my textbook entitled Pulmonary Medicine. I thought a
chapter on Bronchial Asthma in a textbook may not give sufficient justification
to cover the explosion of recent knowledge acquired about the disease,
particularly our understanding of its pathophysiology and approach to
management.
D Behera

Contents
1. Epidemiology ........................................................................................................................ 1
2. Aetiology ............................................................................................................................... 14
3. Pathophysiology of Bronchial Asthma ............................................................................ 40
4. Pathology .............................................................................................................................. 86
5. Clinical Presentation of Bronchial Asthma ..................................................................... 92
6. Diagnosis of Bronchial Asthma ........................................................................................ 98
7. Prognosis of Bronchial Asthma ...................................................................................... 114
8. Complications of Bronchial Asthma .............................................................................. 117
9. Management of Bronchial Asthma ................................................................................ 127
10. Pharmacologic Management of Asthma ....................................................................... 134
11. Inhalation Therapy ........................................................................................................... 176
12. Therapeutic Approach in Patients with Asthma
I. Chronic Bronchial Asthma ........................................................................................... 183
13. Therapeutic Approach in Patients with Asthma
II. Acute Severe Asthma (SA) ......................................................................................... 208
14. Management of Asthma with Special Problems ......................................................... 235
15. New Treatment Modalities/Newer Drugs for Bronchial Asthma ............................ 247
16. New Guidelines for Asthma Management
(Non-pharmacological Management) ............................................................................ 256
17. New Guidelines for Asthma Management (Pharmacological Management) ........ 265
18. New Guidelines for Asthma Management (Acute Asthma) ..................................... 276
19. Alternate Treatments in Asthma .................................................................................... 293
20. Severe Asthma (Fatal Asthma, Refractory Asthma) .................................................... 306
21. Asthma in Children .......................................................................................................... 314
Index ..................................................................................................................................... 337

1
Epidemiology
DEFINITION
Asthma is a disease whose presence dates back to at least the time of Hippocrates who
noted a condition of deep and heavy breathing. The Greeks had labelled this condition as
asthma, the meaning of which was panting. Bronchial asthma is difficult to define since it
is not one homogenous condition and because there is no one objective measurement or
series of measurements that can be used to make the diagnosis of asthma. A widely
acceptable definition still remains elusive ever since it was first defined in 1959 by an expert
study group during the CIBA Foundation Guest Symposium.1 The Global Initiative for
Asthma (1995) defines asthma on the basis of its pathogenesis (vide infra). The clinician,
immunologist, physiologist, and pathologist all have their own perspective of asthma, and
all these perspectives are difficult to merge into a comprehensive definition sufficiently
specific to exclude other diseases. Earlier definitions were non-specific and therefore the
condition was both under and over-diagnosed.2,3 However, during the past one-decade
there have been major changes in the concepts of pathophysiology of asthma. Whereas the
condition was previously considered as a bronchospastic disorder only, it is now recognised
that asthma is primarily an inflammatory disease. The current definition incorporates both
of these components and a generally agreed-on working definition of asthma is as follows:4
Bronchial asthma is a disease characterised by (i) airway obstruction (airway narrowing)
that is reversible (but not completely so in some patients) either spontaneously or with
treatment; (ii) airway inflammation; and (iii) airway hyperresponsiveness to a variety of
stimuli.
Subsequently, the Consensus Report5 describes asthma as a Chronic inflammatory
disorder of the airways in susceptible individuals, inflammatory symptoms are usually
associated with widespread but variable airflow obstruction and an increase in airway
response to a variety of stimuli. Obstruction is often reversible, either spontaneously or
with treatment.
PREVALENCE
The prevalence of asthma is not exactly known. This is because the precise way how to
define asthma in population studies is defined differently. Questionnaires are the most
practical tools to use in screening population for asthma. Such questionnaires have been
validated to assess the ability of individual questions and combination of questions to predict
which individuals in the population have either clinical diagnoses of asthma or non-specific
bronchial hyperreactivity to agents like methacholine or histamine.6 Unfortunately,

Bronchial Asthma

physician-diagnosis of asthma and bronchial hyperreactivity are not particularly good gold
standards for identifying asthma. While the former can miss milder forms of asthma, the
later is present in many people without asthma.6-8 To avoid these limitations, many studies
now use questionnaires.6,9-11 In general, questions about ever having asthma, ever having
asthma diagnosed by a physician, and having wheezing during the previous 12 months
have been the questions with best sensitivity and specificity for prediction of the flawed
gold standards. These questionnaires, of course are being used most often in recent studies.
However, earlier surveys will have flaws as mentioned, and the difference prevalence rates
in different studies in the past can be explained in part due to these methodological
difficulties. Nonetheless, in many countries, the prevalence of asthma has increased in recent
decades.12,13
The disease has reached epidemic proportions affecting 155 million individuals in the
world. About 15% (one out of seven) of children in United Kingdom wheeze and similar
number suffers from the related disorders of atopic dermatitis. The prevalence has risen
over the past 30 years all over the world particularly in all Westernised societies perhaps as
a result of the loss of childhood infections.14 While asthma is one of the less common causes
of death, the magnitude of the problem is evident from the fact that during a 10 years
period from 1978 to 1987, there were 1,87,000 deaths in USA, Canada, England, Wales,
France, West Germany, and Japan.15,16 Since the definition of asthma was varying, the
available statistics is viewed with some skepticism. In general, it seems that asthma remains
under diagnosed especially during childhood. There is some evidence that bronchial asthma
is increasing in a number of countries particularly New Zealand, UK and USA.15,17 An
estimated 10 million persons in the USA had asthma. In the general population, asthma
prevalence rates increased 29% from 1980 to 1987.
Bronchial asthma is the most common chronic respiratory disorder among all age groups
with a reported prevalence of 5 to 10%.18 During the last decade, studies from different
countries keeping appropriate statistics have reported a significant rise in asthma morbidity
and mortality.18-28 In the United States, approximately 17 million people have asthma (and
asthma related symptoms) account for 10 million missed school days, > 1.5 million
emergency department visits, approximately 500,000 hospitalisations and > 5000 deaths
annually. In 1998, the direct and indirect expenditures for the treatment of asthma in the
United States were approximately $11.3 billion.29 The overall 1988 asthma death rate was
1.9/100,000 persons with much lower rates in persons younger than 45 years, rising
dramatically with increasing age.18-30 Asthma is the most common chronic disease of children
in USA.31,32 About 6 million children in the United States have asthma compared to 3.1 million
in 1984, an increase of 80%. Annually, asthma accounts for 12 million primary care visits,
1.6 million emergency department visits, 11 million missed school days, 200,000 hospital
admissions, and 150 paediatric deaths.33 Improved personal behaviour and medical care
have a limited sustained impact on childhood asthma until basic environmental issues are
modified.34 Various other statistics also prove that both asthma and allergic rhinitis have
increased in recent years. The effect of these disorders on children and adults is considerable
in terms of morbidity and lost productivity resulting from the disease and its treatment .35,36
In addition, hospitalisation due to asthma and deaths attributed to asthma are increasing,
despite the availability of effective drugs.37 From 1982 to 1992, the overall annual age-adjusted
prevalence rate of self reported asthma increased 42% (from 34.7 per 1,000 people to 49.4

Epidemiology 3
per 1,000 people). Even more alarming is the observation that during this period, the overall
annual age-adjusted death rate for asthma increased 40%.38
One disadvantage with these statistics is that these are based on informations obtained
by questionnaire and in most cases identical questions were not used at each survey.39
However, from available data, both morbidity and mortality from asthma in New Zealand
are amongst the highest in the world.40 A survey of 12-year-old school children carried out
in New Zealand and South Wales41 revealed a higher prevalence in the former (17%) than
in the later (12%). New Zealand children were also more likely than the Wales children to
have a history of wheeze ever (27% vs. 22%) and wheeze brought on by running (15% vs.
10.5%). The sex ratio of asthmatic and wheezy children was very similar in the two countries.
The overall prevalence of asthma is estimated at 13.7%, bronchial hyperresponsiveness at
13.4%, and atopy at 31.1% in the age range of 13 to 18 years. The prevalence of bronchial
hyperresponsiveness in those without asthma symptoms is 3%. Both current asthma
symptoms and bronchial hyperresponsiveness are more common among females. In a study
to determine the prevalence of asthma in cohorts of Finnish young men in the period 19261989, Haahtela et al42 found that during 1926-1961 the prevalence was steady at between
0.02 and 0.08%. Between 1961 and 1966, however, a continuous, linear rise began, the
prevalence increasing from 0.29% in 1966 to 1.79% in 1989, that is, representing a six-fold
increase. The rise is 20 folds compared with that in 1961. Much of this increase appears real
and not merely due to an improvement in the methods of diagnosis over these years. A
review of the available published figures for children in United Kingdom revealed
prevalence for wheeze in the previous year of between 4.9 and 15% and wheeze ever
between 9.9 and 24.9%. Figures for asthma ever varied between 1.2 and 5%.
A simple flow diagram of the natural history of asthma17 based on the prevalence of
childhood wheeze in Australia is shown in Figure 1.1.

Fig.1:1. Natural history of bronchial asthma in Australian children. The

hatching represents the approximate percentages in each group who are
atopic and who have bronchial hyperresponsiveness. The top line indicates
the group who are atopic and who wheeze while the bottom line represents
those without evidence of (a) allergy; (b) wheeze; (c) and persistent wheeze

Bronchial Asthma

The Figure 1.1 also shows the approximate number of people entering adult life with
persistent wheeze. This study showing natural history of asthma is based on the prevalence
of atopy as measured by skin tests and the prevalence of childhood wheeze in Australia. A
number of studies from around the world show that the prevalence of atopy is between 3050% in children.43-46 In addition, the number of children who have wheezed at sometime is
around 25-30%.47-49 Most children with persistent wheeze are atopic.50,51 About 7% of the
patients have persistent asthma as reported from Australia by Woolcock et al.18
Adequate prevalence data from most developing countries is not available either for children
or adults. Although it is a general perception that bronchial asthma is a very common problem
in India, apart from tuberculosis, authentic information is not available regarding its
prevalence or incidence. Whatever data is available, it lacks the uniformity of definition,
problems of sample size, and analytical methodology used. From different studies, the
prevalence of asthma has been reported to be 1.2 to 6.2% in adults in the western world.
In a survey of respiratory symptoms in India, the prevalence of asthma has been reported
to be 0.6 and 3.2% in rural and urban women respectively. The same in urban males has been
4%.52-55 The prevalence was reported to be 1.76% in an urban population in the mid sixties.56
It was also reported by the same investigators that the prevalence in the morbidity surveys of
government employees and their families in Delhi was 1.8%.56 However, in recent years two
studies from Mumbai and Northern India are available.57,58 The study from Greater Mumbai
revealed a prevalence of 3.5% by physician diagnosis and 17% using a very broad definition
including those with asymptomatic bronchial reactivity. Prevalence of asthma in Mumbai
was similar in males and females (3.8 and 3.4% respectively). In the North Indian survey, a
validated questionnaire was used tested against physiciandiagnosed asthma and the
prevalence in the population was assessed.58 The true population prevalence was reported as
3.94% in urban and 3.99% in rural males and 1.27% in both urban and rural females. A recent
study from Delhi59 estimated the risk of asthma in children to be very high.59 Prevalence of
asthma symptoms in children was determined in the International Study of Asthma and
Allergies in Childhood (ISAAC) in the age groups of 6-7 and 13-14 years using a standardised
sample survey.60,61 Prevalence of ever asthma varied from 1.8 to 12.4% with an overall figure
of 4.5%. The figure of ever asthma in 12 months is not strictly same as prevalence of asthma
in adults. The overall prevalence of asthma in children of 10-18 years age at Chandigarh was
2%, using the same methodology as in adults.58,62
Since morbidity depends, at least partly, on prevalence, the trends should be similar.
Other indices of morbidity such as days lost from work and restriction in lifestyle, nocturnal
disturbances with symptoms and hospital admission rates confirm the trends and extent of
problem due to asthma. It is clear that the most dramatic increase in admission to hospitals
has been in children. All the data collected on the basis of above informations indicate
continuing extensive morbidity from asthma, although more effective treatment may be
modifying this.
MORTALITY
Statistics for deaths from asthma yield widely variable mortality rates between countries.15
Increasing asthma mortality was first highlighted in the early-mid 1960s63,64 when there
was a dramatic increase in asthma deaths in England and Wales, Australia and New Zealand.
This was most apparent in children 10-14 years, but was also apparent for all age groups,

Epidemiology 5
particularly in 5-34 age group. The range of such mortality between 1985-1987 in 20 different
countries has been depicted in Figure 1.2.15
The intriguing points about asthma mortality are that there are sizeable differences
between countries and that death rates from asthma are gradually increasing in most western
countries. An analysis of asthma mortality rates in Western countries as well as developed
nations such as the United States, Canada, New Zealand, France, Denmark, and Germany
has revealed a distinct rise in rates during the 20 years period prior to 1990. Recent trends,
however, suggest a stabilisation of mortality rates due to asthma in United States. From
1977 to 1996, there was a rise in deaths due to asthma in the USA from 1,674 (0.8 per
100,000) to 5,667 (2.1 per 100,000).65 The mortality rate increased by 6.2% annually during
the 1980s and faster among subjects aged 5 to 14 years than those aged 15 to 34 years.
Among Whites, the mortality has increased more in female subjects than male subjects. The
death rates for asthma among African Americans is three times higher than among White
Americans. The trend in other countries is less apparent.66-72 In some countries, the rates
have doubled over the past 10 years. Two countries, the UK and New Zealand, have
experienced epidemics of asthma deaths; one epidemic in 1960s in the UK and two in
New Zealand; one in the 1960s and the other in the 1970s. At the peak of the New Zealand
epidemic in the 1970s, the mortality rate for asthma was approximately 10 times the rate in
the USA. However, the rate has shown a declining trend since 1979. However, this trend is
less apparent in other countries.73,74 For example, asthma mortality rate in Israel during the
years 1980 to 1997 was low and stable. Most of the patients still died outside the hospital.
There was no difference in the asthma death rate and place of death between Jews and
Arabs, suggesting that the population genetic predisposition is not likely to be a risk factor
for mortality.75

Fig. 1.2: Asthma mortality in 20 different countries of the world.

The rate is per 100,000 population (1985-1987)

Bronchial Asthma

All statistics shown are derived from published population and mortality data available
from the national statistics centres in each country. West Germany reported over 9 deaths
per 100,000 followed by Norway, New Zealand, and Sweden. Netherlands, USA, and Hong
Kong reported asthma mortality rates less than 2/100,000.
The reasons for the trends in mortality due to asthma and for the sizeable differences
between countries are not clear.76-79 The increase in mortality in most countries cannot be
primarily due to an increase in the prevalence of asthma as the rise in mortality is
disproportionately greater than that of the prevalence.80 In the last decade, though, the
stabilisation of mortality, and even a decrease in mortality, from asthma has been reported.81-84
A number of reasons have been proposed including: (i) Partial contribution from the shift
of International code of death (ICD-8 to ICD-9). Due to this, the term asthmatic bronchitis
was coded as asthma rather than bronchitis; (ii) Shifts in physician diagnosis patterns,
especially from bronchitis to asthma in the 0-5 years age group and from COPD to asthma
in smokers past middle life. There is clearly some misclassification of asthma deaths with
over-reporting over age 50 and under-reporting in the younger age groups; (iii) An increase
in the prevalence and or severity of asthma; (iv) Increased diagnosis of asthma; and
(v) Adverse drug effects. In the 60s overuse of adrenaline in Europe and currently the use
of fenoterol have been postulated to be contributory to the mortality due to asthma. However,
these postulates have not been confirmed.85-89 Other possible contributors are delay in care,
poor compliance, lack of access to health care, theophylline toxicity, besides the overuse of
-agonists.90-92 Most likely cause of the recent decline in asthma deaths is the more judicious
use of prophylactic treatment, particularly inhaled steroids, as a possible factor.93,94 Race
and socioeconomic status may influence the outcome of an asthma attack.95,96 Hospital
admission rates for asthma are high and have increased in the last few decades.97,98 However,
some patients die before they can receive medical care.98-100 The exact proportion of deaths
occurring outside the hospital and its association with genetic, environmental or social
factors is not clear. An estimated 15 million persons in the United States have bronchial
asthma, and the number is increasing. Although asthma is generally treated in an outpatient
basis, increased hospitalisation rates have been observed. Hospitalisation rates and episodes
of asthma have increased in all age groups particularly in boys up to 4 years old.101
Hospitalisation rates are twice as common in African Americans as White Americans.102
Causes for the Increase in Asthma Mortality
Besides the above mentioned reasons, many other causes have been advocated for the
increase in asthma mortality and morbidity and they include allergen exposure, air pollution,
medication use, inadequate access to health care, increased incidence of viral infections,
and physician management of asthma (Discussed subsequently).
The risk of death due to asthma appears to predominate in large urban areas with high
rates of poverty. Risk of hospitalisation for children with asthma is 8.4 times greater in
areas with population of lower socioeconomic status and 5.3 times greater in areas with a
larger African American population.103 Lower socioeconomic status and African American
race are strong risk factors for hospitalisation and mortality from asthma.
NATURAL HISTORY OF BRONCHIAL ASTHMA
Over the last few decades the natural evolution of asthma from childhood to adulthood has
been the subject of many reviews and studies and more than 50 such well-designed

Epidemiology 7
publications highlight the subject.104 It was long believed that the prognosis for asthma
originating in infancy or childhood was good, and that in most patients the symptoms would
resolve by the age of puberty. However, a review of literature shows that not all patients
become asymptomatic in adulthood. In fact, asthma symptoms persist in 30-80% of adult
patients. Although epidemiological studies have shown a fair chance of either remission or
a reduction in asthma symptoms between the ages of 10 and 20 years,105-108 and most population
based and clinical studies have also shown a reduction in asthma symptoms with age, the
relapse rates after a symptom-free interval is also high.107,109 It has also been shown that, even
in the absence of asthma symptoms, subjects may still have obstructive lung functions and
increased bronchial hyperresponsiveness.110-116
No definite information is available about the progression of asthma through childhood
and adolescence.117 Martinez118 studied the natural history of wheezing in children aged
0-6 years and found that approximately half of the children experienced wheezing illness at
sometime during the study period. In some of them wheezing occurred early in life but resolved
by the age of three years (transient early wheezing), some experienced wheezing illness between
the ages of three and six years (late onset wheezing) and others had wheezing illness throughout
the entire study period (persistent wheezing). Different risk factors were associated with these
results. Children with transient early wheezing had reduced pulmonary function, as measured
by functional residual capacity shortly after birth and before any lower respiratory tract
illness had occurred. The risk was also increased in children whose mothers smoked during
pregnancy. Congenitally smaller airways may therefore predispose children to wheezing
illness early in life. Children with late and persistent wheezing are more likely to be atopic as
assessed by elevated serum IgE levels and skin test reactivity, asthmatic mothers, and their
lung function decreased after the age of one till they are six years of age. This study suggests
the presence of two distinct wheezing illnesses up to the age of six years. As discussed above,
there are varying reports about the persistence/disappearance of asthma symptoms in
adolescence. However, some reports suggest that up to 80% of asthmatics may become
asymptomatic during puberty.119,120 In a cohort study of Australian school children121 tested
initially at the age of 8-10 years and then again at 12-14 years of age, the persistence of
bronchial hyperresponsiveness at 12-14 years of age was found to be related to the severity of
disease at 8-10 years of age, the atopic status of the child, and parental history of bronchial
asthma. Most of the children who had a slight or mild degree of bronchial hyperresponsiveness
at 8-10 years of age lost their increased response by the age of 12-14 years. Only 15.4% of
children with severe or moderate bronchial hyperresponsiveness at the initial assessment
had normal levels of bronchial responsiveness at the later assessment. Whether the decline in
reported symptoms is real or the result of the children increasingly denying their illness as
they reach puberty remains to be clarified. The reduced bronchial responsiveness may favour
the hypothesis of a real reduction in the activity of the disease or higher doses of the provocative
agents like histamine or methacholine may be needed to provoke hyperresponsiveness in
larger airways of rapidly growing children.
As against the above figures, the prevalence of bronchial asthma in adolescents in 4 different
countries 122 varied from 2.8 to 38% at different ages and is summarised in
Table 1.1.123-126 This shows a significant number still will have asthma in adolescence.

Bronchial Asthma
Table 1.1: Prevalence of bronchial asthma in adolescents

Country
New Zealand
Australia
Netherland
Finland

Year of study
1991
1992
1989
1991

Age (years)

Prevalence (%)

12-15
12-15
10-23
15-16

32-38
16.5
19
2.8

Several other prospective studies,127-130 which separately examined subjects aged 10 to 19,
20 to 40, and over 60 years, revealed that asthma was frequently preceded by lower respiratory
tract symptoms, sometimes for years. Among subjects who were diagnosed with asthma after
age 60, one-third reported respiratory symptoms before age 16.130 Similarly 82.7% with asthma
diagnosed between the ages of 5 and 11 years had lower respiratory tract symptoms before the
age of 5 years.127
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1. CIBA Foundation Guest Symposium: Terminology, definitions, and classification of chronic
pulmonary emphysema and related conditions. Thorax 1959;14:286-99.
2. American Thoracic Society: Standards for the diagnosis and care of patients with chronic
obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225-44.
3. American College of Chest Physicians, American Thoracic Society: Pulmonary terms and symbols.
Chest 1975;67:583.
4. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and
management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health,
Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991.
5. International Consensus Report on the diagnosis and treatment of asthma. National Heart, Lung,
and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, 20892. Publication
No. 92-3091, March, 1992. Eur Respir J 1992;5:601-841.
6. Toren K, Brisman J, Jarvholm B. Asthma and asthma like symptoms in adults assessed by
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Epidemiology 9
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40. Shaw RA, Crane J, ODonnell TV. Asthma symptoms, bronchial hyperresponsiveness and atopy
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43. Hurry VM, Peak JK, Woolcock AJ. Prevalence of respiratory symptoms, bronchial hyperresponsiveness and atopy in school going children living in the Villawood area of Sydney. Austr NZ
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10

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45. Clifford RD, Howell JB, Radford M, Holgate ST. Association between respiratory symptoms,
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50. McNichol KH, Williams HE. Spectrum of asthma in children-II. Allergic components. Br Med J
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51. Van Asperen PP, Kemp AS, Mukhi A. Atopy in infancy predicts the severity of bronchial
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52. Behera D, Jindal SK. Respiratory symptoms in Indian women using domestic cooking fuels.
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54. Behera D, Malik SK. Chronic respiratory disease and ventilatory function in adult rural Oriya
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in India. Lung India 1989; 7: 119-21.
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57. Chougule R, Shetye VM, Parmer JR et al. Prevalence of respiratory symptoms, bronchial
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58. Jindal SK, Gupta D, Aggarwal AN, Jindal RC, Singh V. Study of prevalence of asthma in adults
in North India using a standardised questionnaire. J Asthma 2000;37:345-51.
59. Chhabra SK, Epidemiology of childhood asthma. Indian J Chest Dis Allied SS 1998; 40:179-94.
60. The International Study of Asthma and Allergies in Childhood (ISAAC)Steering Committee:
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and atopic eczema: ISAAC. Lancet 1998;351:1225-32.
61. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee:
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(ISAAC). Eur Respir J 1998;12:315-35.
62. Jindal SK. Asthma epidemiology in India. Chest2001; 2(Indian Edition):115.
63. Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. Br Med J
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64. Fraser PM, Speizer FE, Water SDM, Doll R, Mann NM. The circumstances preceding death from
asthma in young people in 1968-1969. Br J Dis Chest 1971;65:71-84.
65. Sly R. decreases in asthma mortality in the United States. Ann Allergy Asthma Immunol
2000;85:121-27.
66. Evans R, Mullally DI, Wilson RW et al. National trends in the morbidity and mortality of asthma
in the US prevalence, hospitalisation, and mortality of asthma over two decades; 1965-1984.
Chest 1987;91:65S-74S.
67. Buist AS. Asthma mortality: What have we learnt? J Allergy Clin Immunol 1989;84:275-83.
68. Sheffer AI, Buist AS. Proceedings of the asthma mortality task force. J Allergy Clin Immunol
1987;80:361-62.

Epidemiology 11
69. Khanna PM, Linger J. Asthma mortality and hospitalisation among children and young adults;
United States, 1980-1993. JAMA 1996;275:1535-37.
70. Buist AS, Vollmer WM. Reflections in the rise in asthma morbidity and mortality. JAMA
19990;264:1719-20.
71. Burney P. Asthma deaths in England and Wales 1931-85: Evidence for a true increase in asthma
mortality. J Epidemiol Community Health 1988;42:316-20.
72. Weiss KB, Wagener DK. Changing pattern of asthma mortality. JAMA 1990;264:1683-87.
73. Salas-Ramirez M, Sagura N, Martinez C. Trends in asthma mortality in Mexico. Bol Oficina
Sanit Panam 1994, 116:298-306.
74. Molinari J, Chatkin J. Tendencia da mortalidade por asthma bronnquica no Rio Grande do Sul.
J Pneumonol 1995;21:103-06.
75. Picard E, Barmeir M, Schwartz S et al. Rate and place of death from asthma among different
ethnic groups in Israel. National trends 1980 to 1997. Chest 2002;122:1222-27.
76. Sears MR, Rea HH, De Boer G et al. Accuracy of certification of death due to asthmaA national
study. Am J Epidemiol 1986;124:1004-11.
77. Hunt LW, Mair JE, Laplante JM et al. Causes of death in a population with asthma. Am Rev
Respir Dis. 1989;139:A486.
78. Riou B, Barriot P. Accuracy of asthma mortality in France. Chest 1990;97:507-08.
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injuries and causes of death: Based on the recommendation of the ninth revision conference,
1975. WHO, Geneva, 1979, Vol 1.
80. Garrett J, Kolbe J, Richards G et al. Major reduction in asthma morbidity and continued reduction
in asthma mortality in New Zealand: What lessons have been learned? Thorax 1995;50:303-11.
81. Sly RM. Changing asthma mortality. Ann Allergy 1994;73:259-68.
82. Vergara C, Caraballo L. Asthma mortality in Colombia. Ann Allergy Asthma Immunol 1998;80:5560.
83. Pearce N, Beasley R, Crane J et al. End of the New Zealand asthma mortality epidemic. Lancet
1995;345:41-44.
84. Sly RM, ODonnell R. Stabilisation of asthma mortality. Ann Allergy Asthma Immunol
1997;48:347-54.
85. Stolley PD, Schinnar R. Association between asthma mortality and isoprenol aerosols: A review.
Preventive Med 1978;7:519-38.
86. Esdaile JM, Feinstein AR, Horwitz RI. Can general mortality data implicate a therapeutic agent?
Arch Intern Med 1987;147:543-49.
87. Crane J, Flatt A, Jackson R et al. Prescribed fenoterol and death from asthma in New Zealand.
Lancet 1989;1:917-22.
88. Poole C, Lanes SF, Walker AM et al. Fenoterol and fatal asthma. Lancet 1990;335:920.
89. Beasley R, Smith K, Pearce N et al. Trends in asthma mortality in New Zealand, 1908-1986. Med
J Aust 1990;152:570-73.
90. Sly RM. Mortality from asthma. J Allergy Clin Immunol 1989;84:421-34.
91. Spitzer WO, Suissa S, Ernst P et al. The use of beta-agonists and the risk of death and near-death
from asthma. New Engl J Med 1992;326:501-06.
92. Sly RM. ODonnell R. Regional distribution of deaths from asthma. Ann Allergy 1989;62:347-54.
93. Goldman M, Rachmiel M,Gendler M et al. Decrease in asthma mortality rate in Israel from
19991-1995: Is it related to increased use of inhaled corticosteroids? J allergy Clin Immunol
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94. Campbell MJ, Gogman GR, Holgate ST et al. Age, specific trends in asthma mortality in England
and Wales, 1983-1995; Results of an observational study. BMJ 1997;314:1439-41.
95. Respiratory diseases disproportionately affecting minorities. The NHLBI Working Group. Chest
1995;108:1380-92.

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96. Lang D. Trends in US asthma mortality: Good news and bad news. Ann Allergy Asthma Immunol
1997;78:333-36.
97. Gergen PJ, Weiss KB. Changing patterns of asthma hospitalisation among children. 1979 to
1987. JAMA 1990;264:1688-92.
98. To T, Dick P, Feldman W et al. A cohort study in childhood asthma admissions and readmissions.
Paediatrics 1996;98:191-95.
99. Jones AP, Bentham G. Health service accessibility and death from asthma in 401 local authority
districts in England and Wales. 1988-92. Thorax 1997;52:218-22.
100. Capewell S. The continuing rise in emergency admissions. BMJ 1996;312:991-992.
101. Vollmer et al. Am Rev Respir Dis 1993;147:347
102. Osborne M. Clinical asthma: Will NAEP guidelines help? Pulm Perspectives 1994;11(1):1-3.
103. Castro M, Halstead J, Schechtman K et al. Risk factors for asthma morbidity and mortality in a
large metropolitan city. J Asthma 2001;38:625-36.
104. Roorda RJ. Prognostic factors for the outcome of childhood asthma in adolescence. Thorax
1996;51(Suppl 1):S7-S12.
105. Peckham C, Butler N. A national study of asthma in childhood. J Epidemiol Community Health
1978;32:79-85.
106. Anderson HR, Bland JM, Patel S, Pekham C. The natural history of asthma in childhood. J
Epidemiol Community Health 1986;40:121-29.
107. Bronniman S, Burros B. A prospective study of the natural history of asthma. Remissions and
relapse rates. Chest 1986;90:480-84.
108. Aberg N, Engstrom I. Natural history of allergic diseases in children. Acta Paediatr Scand
1990;79:206-11.
109. Radford PG, Hopp RJ, Biven RE et al. Longitudinal changes in bronchial hyperresponsiveness
in asthmatic and previously normal children. Chest 1992;101:624-29.
110. Friberg S, Bevegard S, Graff-Lonnevig V, Hallback I. Asthma from childhood to adulthood. A
follow-up study of 20 subjects with special reference to work capacity and pulmonary gas
exchange. J Allergy Clin Immunol 1989;84:183-90.
111. Ferguson AC. Persisting airway obstruction in asymptomatic children with asthma with normal
peak expiratory flow rates. J Allergy Clin Immunol 1988;82:19-22.
112. Cooper DM, Cutz E, Levison H. Occult pulmonary abnormalities in asymptomatic asthmatic
children. Chest 1977;71:361-65.
113. Blackhall M. Ventilatory function in subjects with childhood asthma who have become symptom
free. Arch Dis Child 1970;45:363-65.
114. Cade JF, Pain MCF. Pulmonary function during clinical remission of asthma. How reversible is
asthma? Aust NZ J Med 1973;3:545-51.
115. Strachan DP. The prevalence and natural history of wheezing in early childhood. J Royal Coll
Gen Pract 1985;35:182-84.
116. Peat JK. Salome CM, Toelle BG, Bauman A, Woolcock AJ. Reliability of a respiratory history
questionnaire and effect of mode of administration on classification of asthma in children. Chest
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1996;51(Suppl 1):S3-S6.
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N Engl J Med 1995;332:133-38.
119. Park Es, Golding J, Carswell F, Stewart-Brown S. Pre-school wheezing and prognosis at 10.
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Clin Exp Allergy 1989;19:299-306.

Epidemiology 13
122. Price JF. Issues in adolescent asthma: What are the needs? Thorax 1996;51(Suppl 1):S13-S17.
123. Robson B, Woodman K, Burgess C et al. Prevalence of asthma symptoms among adolescents in
the Wellington region by area and ethnicity. NZ Med J 1993;106:239-41.
124. Forero R, Bauman A, Young L, Larkin P. Asthma prevalence and management in Australian
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develops during the second decade of life. J Allergy Clin Immunol 1993;92:744-49.
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1991;88:870-77.

14

Bronchial Asthma

2
Aetiology
A number of factors are responsible either in the causation or exacerbation of bronchial
asthma. A brief account of each of these factors will be discussed.
ATOPY AND ALLERGY
The association between asthma and allergy has long been recognised. It has been reported
that 75-85% of patients with asthma have positive immediate skin reactions to common
inhalant allergens. There are at least 6 major evidences to prove that most asthma in young
people is due to exposure to allergens or to sensitisers. They are summarised below.
i. Most people with asthma are atopic, which can be measured by skin tests or with
measurements of specific IgE. In population studies and in clinical practice, it is clear
that majority of young people are atopic. Furthermore, in most population studies of
asthma, atopy has been found to be the most important single risk factor. House dust
mite allergens appear to be the most common one associated with asthma.
ii. Challenge with allergens in atopic asthmatics increases the severity of the disease. The
stimulus is capable of increasing this for days and sometimes for weeks. This implies
that allergens play a role in maintaining the disease.
iii. Occupational asthma occurs due to allergens and sensitisers. In some healthy people,
who are exposed to these agents, sensitisation occurs and is followed by episodic wheeze.
Unless the subject is removed from the source, episodic symptoms continue, and with
time become persistent.
iv. It has been shown that subjects with apparently intrinsic asthma (normal skin tests),
have higher levels of circulating IgE than the non-asthmatic population.
v. Improvement in the symptomatology occurs on allergen withdrawal, which proves
the causal relationship between the two.
vi. Population studies have clearly demonstrated the association between atopy and
asthma.
It has been shown that in Indonesian children, there is less atopy and less asthma.
Similarly studies from France have reported a lower prevalence of asthma where mites
are less in number. There is a strong co-relation between allergic sensitisation to common
aeroallergens and the subsequent development of asthma. There is also a strong
association between allergen exposure in early life and sensitisation to these allergens,
although it has not been possible to demonstrate an association between allergen
exposure and the development of asthma.1

Aetiology 15
Some studies, however, challenged the assumption that childhood asthma is largely of
allergic etiology.2 Pearce et al 3 reviewed the epidemiological evidence implicating
aeroallergen exposure in the primary causation of asthma, and concluded that the available
data do not indicate that aeroallergen exposure is a major risk factor. In a further study,
they reported that atopy attributes only 38% to the causation of asthma.2 Some investigators
have observed a weak and inconsistent association between atopy and asthma prevalence.
On the contrary, recent studies suggest that among those reporting wheezing in the previous
months have a stronger relationship with atopy for those reporting > 12 episodes of wheezing
in the past 12 months compared to those reporting 1 to 3 episodes in the last 12 months.4
The proportion of asthma-ever attributable to atopy was 33%, while the proportion was
89% for those who were attending hospitals (indicating more severe form). Based on these
findings, it is suggested that atopy contributes more to the frequent or severe asthma than
to mild or infrequent asthma.4 These findings are consistent with other studies. The important
association of atopy with childhood asthma is well recognised.5 A review of studies relating
atopy to asthma notes that in cross-sectional studies conducted exclusively or predominantly
in children, the proportion of cases attributable to atopy varied from 25 to 63%, with a
weighted mean of 38%.6 Relationship of atopy and severity of asthma is a well-known fact.6
Atopy is also related to degree of bronchial hyperreactivity.7,8 Conversely, in patients having
wheeze in the previous 12 months, bronchial hyperactivity is related to both atopy and
measures of disease severity such as peak expiratory flow variability.9
Taken together these facts are strong evidence for the role of atopy in asthma. Even
though not all asthmas are associated with or perpetuated by exposure to common airborne
allergens, exposure to these agents plays a major role. Both indoor and outdoor allergen
exposures have increased asthma morbidity. People now spend a substantial proportion of
the time indoors. Most of the responsible allergens are probably prevalent inside the houses
since this is where human beings spend most of their lives. The most important ones
throughout the world appear to be the house dust mites, grass pollens, animal proteins, and
moulds. Recent changes in housing styles in many western countries may have led to
increased allergens levels. Houses tend to have less ventilation, making them more humid,
and there has been widespread introduction of carpeted floors and pets living in the houses.
Whereas house dust mite is the most important and common indoor allergen linked to
asthma,10 Outdoor allergens such as grass pollen, soyabean dust and Alternaria alternate
have been specifically linked to severe asthma exacerbations.11,12 There has also been spread
of plants, cockroaches and perhaps mites. Moreover, the climate of a particular area may
favour the availability of various allergens, which in part may be responsible for the
difference in the prevalence of asthma in various countries. Another important factor is the
way the allergen is handled. Pollutions add to the allergenicity of aeroallergens. The
predominance of these allergens will of course depend upon various factors, particularly
local. Studies in asthmatics of allergen skin reactivity, IgE antibody levels, and bronchial
provocation have all helped establish the important role of allergens in many asthma
exacerbations.13 Further, reducing the patients exposure to allergens can help bring asthma
symptoms under control. A growing number of uncontrolled and controlled studies suggest
that allergen eradication and avoidance measures lead to improvement in bronchial
hyperresponsiveness, severity of symptoms, and requirements of asthma medications.14
Recent research suggests that for many allergic disorders associated with aeroallergens,
the process of IgE sensitisation begins right early in life while the immune response is still

16

Bronchial Asthma

developing. It has been shown that the level of dust mite allergen present in the home
during the first year of life is a major factor in determining whether an infant born of an
allergic mother who is genetically susceptible, did in fact develop allergy or asthma by the
time they are 11 years of age. Moreover, the density of allergen (per gram of dust) is an
important factor in determining the age of onset of first symptoms. Higher is the
concentration of allergen earlier is the onset of disease.
Allergenic pollens vary at different places. The predominant offending allergen will
vary with locality, lifestyle, season, and climate. For example, in Delhi, Amarantus pollen is
the most common offending allergen followed by Cassia siamea, Ricinus, Brassica, Imperata,
Prosopis, Cenchrus, Cassia occidentalis, etc.15 Prosopis is the commonest antigenic pollen in
Bikaner, Lucknow, and Varanasi.16-18 Brassica is the commonest pollen in Bhopal and
Kanpur.19,20 On the other hand Parthenium is the commonest offending agent in Kolhapur .21
In the United kingdom, 50-75% of atopic asthmatics react to house dust mite, similar number
to grass pollens, 35-55% to cat dander, 10-20% to dog dander, 10-20% to tree pollens,
10-15% to moulds, and fewer than 10% to food allergens.13 In contrast, keeping cats as pets,
unlike in many western countries is not a common practice in India. Therefore, cat or dog
dander allergy may not be that important in this country. On the other hand because of
tropical climates, and peculiar habit of storage of food articles, cockroaches grow plenty in
this country. Therefore, these might be an important allergen for people of India.
The importance of allergy is different for different age groups. In infants, allergens play
a less important role than other ages and viral respiratory infections are the principal triggers.
Although allergic reactions to food can occur in infants, foods are not the common triggers.
Studies in children suggest that allergy influences the persistence and severity of asthma. It
is reported by several authors that severity of childhood asthma corelates with the number
of positive immediate skin tests. Children with multiple positive skin tests are more likely
to have daily rather than intermittent symptoms of asthma. The important allergens in
children after infancy appear to be inhalants. Aeroallergens are important in patients whose
disease has started before the age of 30 years or who are exposed to occupational allergens.
Patient can also have allergy for the first time after the age of 30. However, in adults the
intensity of allergic skin tests does not appear to be associated with increased severity of
asthma. Food allergies are not common triggers for asthma in adults. The patient may have
aspirin sensitivity, but it has no immunological basis.
Different Allergens (Figs 2.1a to 2.1h)
i. Important outdoor allergens include pollens and moulds.
Pollen Particles greater than 10 micron in diameter are usually cleared in the nose and
mouth and do not penetrate the lower respiratory tract. However, there are some plants,
which produce allergen-containing particles that are less than 10 microns. Ragweed
and grass pollination are definitely associated with asthma. Pollen allergy is usually
season-related and is more closely linked to hay fever and allergic conjunctivitis.
Mould Mould spores are generally smaller than pollen grains and are more likely to
penetrate the lower respiratory tract. Mould spores exist primarily outdoors and tend
to be seasonal. Some fungi sporulate on warm, dry summer days and others prefer the
rainy season. The species of the fungus vary with the geographic distribution according
to climatic conditions.

Aetiology 17

Fig. 2.1a: Dust during cleaning

Fig. 2.1c: Smoke

Fig. 2.1e: House dust mite in the bedding

Fig. 2.1b: Pollen

Fig. 2.1d: Domestic fuel

Fig. 2.1f: Perfumes

18

Bronchial Asthma

Fig. 2.1g: Pets (Animal dander)

Fig. 2.1h: Mould in the wall

ii. Although house dust itself is not an allergen, there are allergic components in it. The
most important ones are mites, animal danders, and cockroaches.
House dust mite plays a major role in the causation of asthma, although it does not leave
any immediately perceptible sting or bite. This is the agent most widely implicated in
the pathogenesis and provocation of allergic asthma. They are arachnoids distantly
related to ticks and spiders. They are ubiquitous, living in the house dust that provides
both their shelter and food (scales of skin shed by humans). They occur in environments
with sufficient humidity since they are quite dependent for survival on moisture from
the atmosphere. Loss of water from the mite body constrains their growth, but mites
are capable of extracting water vapour even from air that is only 50% saturated. Live
mites are equipped with suckers at the tips of their legs, which make them difficult to
remove by vacuuming. The commonest mite is Dermatophagoides pteronyssinus. Other
species may also exist in small numbers. Mite antigen is found throughout the home,
wherever human dander, the food for the mite, is found.
High levels are found in mattresses, pillows, carpets, upholstered furnitures, bed
covers, clothes, and soft toys. The principal allergen of the house dust mite is found in
its faeces. A gram of dust may contain 1,000 mites and 250,000 faecal pellets. These
pellets are quite large and 10-40 microns in size, similar to pollen grains and share
some of the aerodynamic properties with them. Like larger pollen grains, they do not
easily enter the lower respiratory tract and are rapidly cleared from the airway by

Aetiology 19
gravity. Mite antigen is readily demonstrated in the air during cleaning. Some mite
allergens may be smaller that may be in the respirable range for the lower respiratory
tract. The major allergens of house dust mites are probably digestive enzymes,
collectively designated as group I allergens or Der p I, and there are now tests available
to quantitate this.
The improvement of asthma in children residing in high altitude where low humidity
constrains dust mite growth or in patients admitted to the relatively dust-free environment of a hospital14 indicates the contribution of the house dust mite to asthma
exacerbation. A study of children requiring hospitalisation for asthma found that the
risk of re-admission was associated with continued exposure to high concentrations of
mite allergen.22-28
Animal allergens Dogs, cats, and other pet animals including rodents are commonly
kept in homes. Danders from these animals contribute greatly to the allergenic
components of house dust. All warm-blooded pets can cause allergic reactions, including
the birds and small rodents. Products made from feathers retain the allergens from
bird. All breeds of cats produce common allergens, and cat saliva and cat danders are
potent allergens. Dogs also produce common allergens, although minor breed
differences may exist. For several reasons cat allergen is more likely to cause sensitisation
than that of dogs. The major cat allergen is Fel d I, which is a protein secreted by the
cats salivary, sebaceous, and lacrimal glands. The protein is very stable and loses none
of its antigenic potency for at least a month. It is coated on to the fur by the usual
grooming, and at the rate cats shed their fur and dander, a reservoir of the antigen
rapidly accumulates in household furnishings. In addition, Fel d I, particles are less
than 2.5 mm in diameter and flake-shaped, making them easily airborne and easily
respirable. While air filtration can remove some of the allergens, little permanent
reduction occurs unless carpets, furnishings, and other reservoirs of coated fur (the cat
itself) are removed. It takes several months before the concentration of allergens in
domestic dust falls after removal of the pet.
A number of epidemiological studies suggest that close contact with a cat or dog in
very early infancy reduces subsequent prevalence of allergy and asthma. This may be
a consequence of high allergen exposure inducing tolerance.29-31
Cockroach allergen The cockroach appears to be important, particularly in warmer
climates and inner side of the house in cooler climates. Cockroach allergy has been
identified as an important cause of asthma. This form of asthmaThe cockroach
asthmais a more severe form of the disease, having perennial symptoms, and high
levels of IgE. Cockroaches produce several allergens, which produce sensitisation.
Usually there is exposure to high levels of this allergen at homes. The important domestic
species are Blattella germanica and Periplaneta American.
Kinds of Allergens
The allergens are Bla g 2 (inactive aspartic protease), Bla g 4 (calycin), Bla g 5 (glutathione
S-transferase), Bla g 6 (troponin), the Group I cross-reactive allergen Bla g 1 and Per a 1,
Per a 3 (arylphorin), and Per a 7 (tropomyosin). Although elimination of cockroaches totally
is difficult, development of cockroach allergens as recombinant proteins has led to better
control of this form of asthma.32 Indoor moulds are prominent in environments with
increased humidity. Bathrooms, kitchens, basement areas, and perspiration on pillows are

20

Bronchial Asthma

the common sites of mould growth. Cockroach sensitivity in children has been associated
with greater symptom frequency and more emergency department visits due to
asthma.33-36 Similar observations are made for elderly patients with asthma also.37
Risk Allergens: Responsible for Acute Attacks
Threshold concentrations of allergens that can be regarded as risk factors for acute attacks
include:
10 g/g dust of group I mite allergen
8 g/g dust of Fel d I, the major cat allergen
10 g/g dust of Can f I, the major dog allergen
8 g/g dust of cockroach allergen
FOOD ALLERGEN AND BREASTFEEDING
In the first 1 or 2 years of life, food sensitivity is an important factor in the development of
allergies. Breastfeeding has been advocated as a method of preventing allergy and asthma.
With breastfeeding there is a decreased risk (about 20%) for development of asthma.38 Impact
of exclusive breastfeeding in children at 6 years of age has shown that the introduction of
milk other than breast milk before the age of 4 months of age is a significant risk factor for
increased likelihood of bronchial asthma.39 However, another study has shown an increased
risk of wheezing, particularly in asthmatic mothers and if the child is also atopic.40
There are some reports that regular consumption of oily fish is associated with a reduced
risk for asthma in children, although subsequent studies have not shown clinical benefits of
supplemental 3 fatty acids over a 6 months period.41,42 Further, it has been hypothesised that
decreased dietary antioxidant vitamin intake is associated with increased asthma.43 Higher
concentrations of vitamin intake are associated with a decreased serum levels if IgE and a
significant decrease of atopy.44 Recent experimental data showed a reduced risk with intake
of lectins (wheat germ agglutinin from whole wheat products).45
INFECTION
It has long been recognised that viral respiratory infections provoke and alter asthmatic
responses. Over 80% of acute asthma exacerbations in school children and about 60% in
adults result from viral infections, mostly common cold viruses. These observations have
suggested that viral infections may be intimately involved in the development of asthma
and allergy. The susceptibility of the asthmatic airway to viral inflammation is due to
persistent allergic mast cell and eosinophil-derived inflammation stimulates the release of
cytokines such as tumour necrosis factor-alpha, which cause an increase in the expression
of receptors for human respiratory viruses on the airway lining epithelium. In case of most
rhinoviruses, the receptor is an adhesion molecule (intracellular adhesion molecule-1). The
Viral respiratory illnesses may produce their effect by causing epithelial damage, producing
specific immunoglobulin IgE antibodies directed against respiratory viral antigens and
enhancing mediator release. Once the virus enters the epithelial cells, it replicates and
generates a wide variety of proinflammatory cytokines, which further enhance eosinophil
and mast cell inflammation. Apart from aggravating clinical asthma, viral upper respiratory

Aetiology 21
infections increase airway responsiveness, which may persist for many weeks after the
infection.
Provocateurs of Asthma
The principal infection provocateurs of asthma in childhood during the first 2 years of
life are respiratory syncytial virus (RSV), parainfluenza virus, and rhinovirus. Influenza
virus is much more common in older children and adults. Early hospitalisation for respiratory
syncytial virus, croup, or bronchiolitis is associated with greater airway responsiveness and
more frequent history of wheezing.46 Other microorganisms that can exacerbate bronchial
asthma include Mycoplasma pneumoniae. Although bacterial infection i s no t a cause of
such exacerbations, it has been reported recently that H.influenzae and other Gram-negative
bacteria can synthesise histamine both in vivo and in vitro.47 The presence of this mediator
may contribute to the bronchoconstriction and other effects of histamine that can accompany
bronchial infection. Pseudomonas infection in cystic fibrosis is responsible for a hyperreactivity
reaction in these patients. A recent study in 101 nonsmoking severe asthmatics shows
association between accelerated loss of lung function and seropositivity to Chlamydia
pneumoniae.48
Interestingly, in recent years it is also observed that some infections are protective of
bronchial asthma. While viral infections can undoubtedly cause deterioration of established
asthma, viral or bacterial infections during the first three years of life may serve a protective
function against the development of allergic diseases. Possibly they evoke a Th1-like protective
response with the generation of IFN-gamma and IL-2. Thus, if multiple infections occur during
the first few years of life, high concentrations of these Th1 cytokines could inhibit the release
of Th2 cytokines, thereby tuning the mucosal immune response away from allergen
sensitisation. This hypothesis is supported from observations from an African study, where
children infected with measles during the first year of life had a 63% lesser chance of developing
positive skin tests to common aeroallergens. Similarly repeated vaccination with BCG exerted
a protective effect against the development of allergy in young Japanese children. Both measles
and BCG are potent stimulators of the Th1 cytokine response. Another support of this protective
infection comes from observations comes from the fact that the increase in asthma and allergy
with movement to urban areas may be related to a decrease in early exposure to parasitic
infections. One study from slum are of Caracas, Venezuela showed that antihelminthic
treatment causes a decrease in IgE level, but was accompanied by an increase in skin test
reactivity to house dust mite. In contrast, in the untreated children, the parasitic colonisation
continued, IgE levels increased but the dust mite sensitisation fell. It indirectly means that
eradication of parasites or reduced opportunities for infection could, in part, explain the rural
to urban differences in the prevalence of allergic diseases. These observations led to the
Hygiene hypothesis of bronchial asthma. This suggests that early exposure to microbial
products will switch off allergic responses preventing allergic disorders like asthma.49
Epidemiological studies comparing large populations who have or have not had such
exposures support the hypothesis.50 The hygiene hypothesis explains that allergic diseases
were prevented by infections in early childhood, transmitted by unhygienic contact with
older siblings or acquired prenatally. Over the past century declining family size, improved
household amenities, and higher standards of personal cleanliness may have resulted in
more atopic diseases.49 It is further proposed that modern vaccinations, fears of germs and

22

Bronchial Asthma

obsession with hygiene are depriving the immune system of input on which it is dependent.
Recent data suggest that exposure of young children to older children at home or to children
at day-care protects against the development of asthma and frequent wheezing later in
childhood. A double blind placebo controlled trial using the probiotic.
Lactobacillus CG, observed a reduced incidence of atopic eczema but no effect on IgE antibody
sensitisation, important for bronchial asthma. However, this study has the limitation of small
sample size and early age limit of interpretation.51
DRUGS
About 5 to 20 per cent of adults with asthma will experience severe and even fatal exacerbations of bronchoconstriction after ingestion of aspirin or certain non-steroidal antiinflammatory drugs (NSAIDs). These drugs are as follows:52-58
Aspirin
Ibuprofen
Indomethacin
Piroxicam
Sulindac
Tolmetin
Naproxen
Fenoprofen
Meclofanamate
Mefenamic acid
Diclofenac sodium
The list is not complete and aspirin sensitivity implies cross-reactivity with other nonsteroidal medications. The prevalence increases with increasing severity of asthma. In these
individuals, ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm,
which may be accompanied by rhinitis and/or urticaria. An association between aspirin
sensitivity in people with asthma and the presence of sinusitis and nasal polyps is often
stressed. Although there is a statistical relation, many patients with nasal polyps are not
aspirin sensitive, and many patients with asthma and aspirin sensitivity have not been
found to have nasal polyps. It is likely that sinusitis, nasal polyps, and aspirin sensitivity all
increase in prevalence with increasing severity of asthma and they are not causally related.
Although the exact mechanism is not known, it is nonimmunologic and probably depends
on inhibition of cyclo-oxygenase. Accordingly, the arachidonic acid metabolism proceeds via
the lipo-oxygenase pathway producing leukotrienes (see pathogenesis). Although the exact
pathogenesis of aspirin-induced asthma is unclear, studies have demonstrated that
leukotrienes play an important role in airway narrowing and other signs in these patients.
These observations are derived from the fact that urinary LTE4 is two-folds to ten-folds higher
in these patients than in aspirin tolerant patients.59-61 Several leukotriene modifiers inhibit the
asthma response in oral or inhaled bronchial provocation tests, such as aspirin and
nonsteroidal anti-inflammatory drugs,62-64 and improve respiratory function by expanding
the airway in patients with aspirin induced asthma.65 An additional hypothesis for the
mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to
leukotrienes. The inhibition of cyclo-oxygenase is a property common to all of the drugs
producing this adverse reaction. Although analgesics not inhibiting this enzyme are generally
considered to be safe, the most frequently employed alternative, acetaminophen, has been
reported to cause asthma exacerbations in a few aspirin-sensitive patients.
Other drugs that are known to exacerbate asthma include beta-blocker drugs (i.e. propranolol and nadolol). Eye drop preparations of this class of drugs also can induce asthma.
Recently, inhaled verapamil, a calcium channel blocker, has been reported to induce severe
bronchospasm in mild asthma.

Aetiology 23
EXERCISE-INDUCED ASTHMA66-71
Exercise-induced asthma (EIA) is often used to describe the asthma of persons in whom
exercise is the predominant or even the only identified trigger to airflow obstruction. No
available data support the concept that exercise-induced asthma represents a distinct
pathologic or pathophysiologic entity. Exercise-induced bronchoconstriction is one
manifestation of the asthmatic diathesis. Most, virtually all, people with asthma have airway
hyperirritability that leads to exercise-induced asthma if the provocative stimulus - eucapnic
voluntary hyperventilation- is appropriately intensified. Accordingly, this condition should
be anticipated in all asthma patients. For some asthmatics, exercise is the only trigger. In
addition, most patients in whom exercise is the predominant trigger, will have other
additional sensitivities that either can be found in the clinical history or will evolve over
time. It is estimated that approximately 40 per cent of children with allergic rhinitis, but
without clinical asthma, have EIA. This situation probably holds true for adults. Untreated
EIA can limit and disrupt normal life. Although individual episodes of EIA are short lived,
the severity and impact is striking.
During short (few minutes) periods of exercise, airways actually dilate. Exercise-induced
asthma is the airway narrowing that occurs minutes after the onset of vigorous activity.
Airway narrowing develops within 2-3 minutes after cessation of exercise. It generally
reaches its peak about 5-10 minutes after cessation of activity and usually resolves
spontaneously in the next 30-90 minutes or within a few minutes of administration of an
inhaled beta-adrenergic bronchodilator. There are some reports now that a late phase of
EIA exists.72,73 However, this phase is uncommon (EIA is a nonimmunologic form of asthma)
and not severe unlike the late phase of allergen-induced asthma. Ambient air conditions
during the post-exercise period also influence the degree of bronchoconstriction that
develops. A rapid change to warm, moist air post-exercise tends to worsen the development
of airflow obstruction.74 Some patients who engage in continuous, repetitive exercise periods,
EIA diminishes or is completely abated during a refractory period that usually lasts 2 hours
after an exercise challenge. This is referred to as refractory period. Because of this
phenomenon, many asthmatic athletes report that a warm-up period of sub-maximal exercise
helps to minimise exercise-induced symptoms.75 During sustained exercise they are often
able to work through initial respiratory symptoms, i.e. experience resolution of initial
symptoms despite continued exercise.
In contrast to asthma in general, which is characterised by both smooth muscle contraction
and airway inflammation, exercise-induced asthma is due mainly to smooth muscle
contraction. Therefore some investigators call this as airflow-induced bronchoconstriction
(AIB) or exercise-induced bronchospasm (EIB). Although the exact mechanism of asthma
is debated, it is generally established that EIA is due to loss of heat or water or both, from
the lung during exercise resulting from hyperventilation of air that is cooler and dryer than
that of the bronchial tree. The key aspects of the triggering stimulus are the level of ventilation
during exercise and the temperature/water content of the inspired air.70 The higher the
minute ventilation during exercise and the colder and drier the inspired air, the greater is
the stimulus for bronchoconstriction. How this airway cooling causes bronchoconstriction,
is not exactly clear. It has been suggested that heat and water loss leads to changes in airway
fluid osmolarity which initiates mediator release that cause constriction in the smooth
muscle. Some investigators believe that airway cooling triggers bronchoconstriction in
asthmatic subjects, and a rewarming-induced hyperaemia and oedema results in airway

24

Bronchial Asthma

obstruction. Another hypothesis put forth is that exercise-induced bronchoconstriction results

from an imbalance between two opposing mechanisms: an excitatory pathway stimulated by
airway drying and an inhibitory pathway initiated by airway cooling. It is speculated that
cooling attenuates hypocapnia, hypertonic aerosol- and dry air-induced bronchospasm via a
cold induced reduction in neuronal activity or mediator production and release.
Effects of Exercise
An athletes minute ventilation during exercise is determined in part by the workload
undertaken as measured by oxygen consumption and in part by the degree of deconditioning
as measured by minute ventilation. Thus, for all asthmatics, regular exercise that improves
cardiovascular fitness and thereby increased oxygen extraction from the blood by exercising
muscle can help reduce exercise-induced bronchoconstriction by lowering the level of
ventilation needed during any given exercise task. Rate, depth, and pattern (I:E ratio) of
breathing at a given level of ventilation during eucapnic voluntary hyperventilation are not
important determinants of bronchoconstriction.71 To reduce/avoid EIA, avoidance of a cold/
dry environment is preferable. Swimming is the preferred exercise for persons with asthma
because of this mechanism. Other inhaled irritants in the ambient air including high levels of
air pollutants and smoke can also trigger asthma especially during exercise when larger than
normal volumes of these irritants are inhaled.
OCCUPATION AND ASTHMA
Occupational asthma is the commonest industrial lung disease in the developed world with
over 400 causes.76-78 It may account for about 10% of adult onset asthma.79 Environmental
agents related to work place have been recognised as the causative agents for respiratory
diseases for many centuries. Bernardino Ramazzini had recognised the importance of
occupation in the causation of asthma as early as 1713 particularly in grain workers, bakers,
millers, sulphur workers, and other occupations. With increased industrialisation, simple
chemicals and organic compounds have been used more often with a consequent increase in
new respiratory hazards, particularly occupational asthma. Occupational asthma may account
for about 10% of adult onset asthma.79 It is now the commonest industrial lung disease in the
developed world with over 400 causes.80-86
Agents causing occupational asthma are usually encountered in an industrial setting,
but it is also possible for persons outside the working area to develop disease after
contamination of their environment by a point source industrial chemical irritant or allergen.
Industries in which asthma occurs include plastics and paint manufacturing, electronics,
welding, metal refining, photography, health-related industries, antibiotics and cosmetic
manufacturing, dyeing, forestry, and food processing. Asthma can also result from massive
pollution due to transportation accidents or gross contamination of the local environment
by manufacturing industries. It can also occur in more unrecognised ways like materials
contaminating air conditioning system inlets from near by factories, or by contamination of
workers or of their clothing. Thus the strict definition of occupational asthma as reversible
obstructive airways disease contracted in the work place may underestimate the real extent of the
problem.

Aetiology 25
Prevalence of Asthma in Workers
Although the exact prevalence of occupational asthma is not known and will vary according
to the setting in which it occurs, on the industrial agent involved, on the intensity of exposure,
and on working conditions, industrial hygiene, and engineering factors; it is reported that
between 5 to 15% of all cases of asthma in Japan are occupational. Bakers exposed to flour
dust develop asthma at a rate of 10-30%, in washing powder industry, up to 60% of the
workers become sensitised to Bacillus subtilis, and in the cotton industry the prevalence of
byssinosis is 25-29% in workers exposed in the carding process and 10-29% in those exposed
in the spinning process. Similarly 5% of the western red cedar workers, 6% of the animal
handlers, 5% of the workers in plastics industry (volatile isocyanates), and 30-50% of those
working in the metal industry using soluble platinum salts develop the disease.
Agents capable of inducing occupational asthma can be vapours, gases, aerosols, or
particulate matters and can range from very low molecular weight inorganic chemicals to
complex organic macromolecules. Some of these agents are shown in Table 2.1.
Table 2.1: Selective agents known to cause occupational asthma

Agents

Occupation

1. Natural organic environmental agents.

Animal proteins (urine, danders)
Shellfish, egg proteins, pancreatic enzymes papain, amylase
B.subtilis enzymes
Poultry mites, droppings, feathers
Flour grain
Storage mites, soyabean, wheat
Midges
Silk-worm moths and larvae
Castor beans, Coffee seeds bean
Colophony
Wood dusts (red cedar, oak,mahogany, etc)
Grain dust (moulds, insects, grain)
Cotton dust
Storage mites, fungi, ragweed, pollen

Laboratory workers/Veterinarians
Food processing
Detergent factory
Poultry farmers
Bakers
Farmers
Fish food manufacturing
Silk workers
Farmers
Electric soldering
Carpenters and Saw mill workers
Shipping workers
Cotton mill workers
Granary workers

2. Organic chemicals.
Isocyanates (TDI, MDI, HDI)
Antibiotics, piperazine, methyl dopa
Disinfectants
Paraphenylene diamine
Formaldehyde, ethylene diamine
Furfuryl alcohol resin
Dimethyl ethanolamine toluene di-isocyanate

Plastic and foam

Manufacturing
Hospital workers
Fur dyeing
Rubber processing
Foundry workers
Automobile painting

3. Inorganic chemicals.
Platinum salts
Nickel salts
Cobalt salts
Chromium salts
Aluminium fluoride
Persulphate
Vanadium
Stainless fumes

Refining
Plating
Diamond polishing
Stainless steel welding
Manufacturing
Beauty shop
Refinery workers
Welding

26

Bronchial Asthma

Occupational asthma can be mediated by any of the several, mechanisms. They include,
reflex vagal bronchoconstriction in response to an irritant effect on specific receptors;
inflammatory bronchoconstriction secondary to toxic concentration of gases (nonspecific
complement activation, neuro-peptide release, disrupted cell membrane releasing arachidonic
acid products); direct pharmacological reaction by agents such as organic insecticides
(parasympathetic agonists) and beta-adrenergic blocking agents; or by immunologic
mechanisms. Some agents also act via alternative path way of complement activation through
an antibody-independent mechanism.
TARTRAZINE AND SULPHITE SENSITIVITY
Tartrazine is a yellow dye commonly employed in food and medications. Beginning in 1958,
a number of reports appeared linking this agent with the occurrence of acute
bronchoconstriction. The reaction is particularly noted in those with aspirin sensitivity.
Although the exact prevalence is not known, there are reports of positive challenge in up to
22% of unselected asthma patients and 25-50% of those with aspirin sensitivity. It is not an
inhibitor of cyclo-oxygenase. However, the incidence of tartrazine-induced asthma is very
low and perhaps is limited to those rare individuals who appear to have an immunologically
mediated sensitivity to the dye.87
Sulphiting agents88-90 have been used to preserve foods and beverages since ancient times.
They maintain the crisp and fresh appearance of the foods, prevent browning, and control
microbial growth and spoilage. The agents used include sulphur dioxide as well as the
sodium and potassium salts of sulphite, bisulphite, and metabisulphite. All these agents
release sulphur dioxide gas under suitable conditions of warmth and acidity. Major sources
of exposure to sulphites are processed potatoes, shrimp, dried fruits, beer and wine. Another
source of sulphite exposure for patients with asthma is medication. Sulphites are used to
prevent oxidation of beta-adrenergic agonists. For this purpose, sulphites are contained in
some nebuliser solutions, injected epinephrine, and injected local anaesthetics containing
epinephrine. Except in vary rare individuals with true allergy to sulphites, the amount of
injected solutions is inconsequential. However, the amount in the nebuliser solutions is
sufficient to cause paradoxical bronchoconstriction or a blunted bronchodilator response
in these subjects.
Exposure to sulphites, particularly in restaurant salad bars in western countries, or after
drinking wine or beer, has been reported to be responsible for fatal attacks of asthma and
its use has been banned in many countries. Sulphur dioxide released in the mouth and
stomach from sulphites has been incriminated as the cause of precipitation of asthma in a
vast majority of patients. Sulphur dioxide is a known irritant and asthmatics are particularly
susceptible. The levels released from food and beverages may be sufficient to account for
the bronchoconstriction. However, all patients with asthma do not react adversely to
sulphites. This may be due to varying extent of inhalation of liberated sulphur dioxide by
different patients or there may be a subset of asthmatics, which have low levels of the
enzyme sulphite oxidase. These patients will be able to metabolise sulphites to harmless
sulphates. A small number of asthma patients may have true allergy to sulphites, in whom
an immediate skin test reactivity can be demonstrated.

Aetiology 27
RHINITIS AND SINUSITIS
A possible relation between sinusitis and activation of asthma has been postulated recently.
A high incidence of radiographic evidence of sinusitis on the order of 40 to 60 % has been
demonstrated in asthmatic patients. However, the question is, does this association represent
an epiphenomenon? There is suggestive clinical evidence that sinusitis not only occurs in
association with asthma but may also play some role in its pathogenesis. Studies of children
and adults after medical or surgical therapy indicate that the asthmatic state may improve
with proper management of the underlying sinusitis. It is also likely that nasal and sinus
pathology can aggravate asthma, particularly if there is uncontrolled drainage of mucoid
or mucopurulent material down the nasopharynx where it can contribute to cough and
irritability of larynx. This material may also be aspirated into the lower respiratory tract,
especially during sleep. It is also possible, but not proven, that sinus infection may aggravate
asthma through reflex mechanisms.91-93
Although historically, it was believed that structurally and functionally there are
differences within the respiratory tract which have been used as the basis for separating the
airway into upper and lower respiratory tracts, it is now being appreciated that allergic
rhinitis and bronchial asthma are considered as one airway, and one disease.94 The
prevalence of asthma and allergic rhinitis is increasing in the general population, and a
high proportion of new patients have coexisting upper and lower respiratory tract disease.
It is estimated that 60 to 70% of patients who have asthma have also coexisting allergic
rhinitis. During the past decade with increased understanding, current thinking is emerging
that they should better be described as a continuum of inflammation involving one common
airway. Traditional therapies originally indicated for allergic rhinitis and asthma are being
reassessed to explore their potential utility in both these conditions. Recently, there has
been a renewed interest in the role that histamine plays in lower airway disease, and interest
in increasing in the theory that leukotrienes, which are more potent inflammatory mediators
than histamine, play a role in upper airway disease as well. Because its important role in
the pathogenesis of both airways disease, leukotriene receptor antagonists are recently have
emerged as important therapeutic advances that have potential clinical utility in both asthma
and allergic rhinitis.
GASTRO-OESOPHAGEAL REFLUX (GER)
A number of reports are available in the medical literature on the relationship between gastrooesophageal reflux (GER) and pulmonary disease. Since the late seventies, numerous
investigators have reported on epidemiology, mechanisms and clinical trials in an effort to
piece together the gastro-oesophageal reflux and asthma. Epidemiological evidence for the
association suggest that about three-fourth of the asthmatics, independent of the use of
bronchodilators, have acid gastro-oesophageal reflux, increased frequency of reflux episodes,
or heart burn, and about 40 per cent have reflux oesophagitis. As early as 1967, Urschel and
Paulson reported that of 636 patients scheduled for an operative treatment for GER, 60%
also had pulmonary symptoms.95 Since then, many studies have shown a high prevalence
of GER among patients with asthma.96,97 A recent report says that even asthmatics without
having reflux symptoms have a high prevalence (62%) of abnormal results for 24-hours
oesophageal tests.98 The simultaneous occurrence of GER and asthma suggests a causal

28

Bronchial Asthma

relationship. The occurrence of GER after bedtime is strongly associated with asthma,
respiratory symptoms, and obstructive sleep apnoea syndrome.99
Two separate mechanisms are involved in the gastro-oesophageal reflux and asthma
relationship.99,100
i. Reflex vagal bronchoconstriction occurs secondary to stimulation of sensory nerve fibres
in the lower oesophagus. This mechanism is supported by the findings that acid infusion
of the oesophagus in asthmatic patients leads to increased airway resistance that rapidly
reverses with antacids and infusion of acid into the lower oesophagus of asthmatic
children during sleep induces bronchoconstriction.
ii. The second proposed mechanism is micro-aspiration, particularly during sleep. This is
supported by the findings of (a) a large vagally mediated increase in airway resistance
with minute quantities of hydrochloric acid infused into the trachea of cats; (b) a high
prevalence rate of hiatus hernia and gastro-oesophageal reflux in patients with bronchial
asthma and (c) an incidence of gastro-oesophageal reflux in 63 per cent of children
with asthma. The prevalence of gastro-oesophageal reflux is increased at least threefolds in both children and adults with bronchial asthma. The evidence for the relationship
also has gained support from the results of clinical trials.
iii. The partial narrowing or occlusion of the upper airway during sleep, followed by an
increase in intrathoracic pressure, might predispose the patient to nocturnal GER and,
consequently, to respiratory symptoms.99 Both medical treatment with antacids and
postural therapy and surgical management of gastro-oesophageal reflux have resulted
in improvement of asthma symptoms. However, other studies have not demonstrated
such a beneficial effect.101-105
Prevalence of gastro-oesophageal reflux in asthmatics can be summarised as follows:106
57% of asthmatics have heartburn
41% of asthmatics note reflux-associated respiratory symptoms
82% of asthmatics have abnormal oesophageal acid contact times
43% of asthmatics have oesophagitis
Heartburn is more prevalent in asthmatics over 65 years of age (35%) compared with
asthmatics 18-34 years of age (23%)
Heartburn is associated with a higher rate of future asthma hospitalisation
Subjects reporting nocturnal GER have higher asthma prevalence rates and symptoms
of obstructive sleep apnoea
Proximal oesophageal acid exposure is present in 48% of asthmatics
In children : abnormal oesophageal pH tests are present in 62% and GER is a risk
factor for asthma (OR 1.9).
PSYCHOLOGICAL FACTORS
There has been a great deal of controversy regarding the cause and effect relationship of
asthma and psychological factors. Many patients with asthma acknowledge that
exacerbations are provoked by psychological events, such as shock, bereavement, or
excitement. However, such factors are rarely the dominant cause of disease. Suggestion
and hypnosis may have some beneficial effect in modifying the asthmatic reactions.
Depression most often associated with asthma may be secondary to a chronic disease. In
rare instances, patients commit suicide. Although the information linking depression and

Aetiology 29
increased death from asthma is derived from clinical reports, the association, however, is
striking. In a review of cases in which children died suddenly and unexpectedly of asthma,
there is clinical evidence that the children had expressed despair, hopelessness, a wish to
die, and other evidence of depression. Other psychological problems that are documented
as associated with those at increased risk of mortality include alcohol abuse, documented
depression, recent family loss and disruption, recent unemployment, and schizophrenia.
The severe asthmatic attack is very frightening and such patients are understandably
anxious. Occasionally, psychological illness, family disputes or marital disharmony may
be major factors in the aetiology of intractable asthma.107-109
POLLUTION
Pollution with particulate matter adds to the allergenicity of aeroallergens. Passive smoking
is known to be a risk factor110 and there is evidence that diesel fumes are associated with
increased allergic responses. Similarly smokers have increased bronchial hyperreactivity
to a variety of stimuli. A small increase in allergen exposure will make the airway more
reactive, which will result in a large increase in severity and potential deaths. Ozone and
other oxidants contained in photochemical smog which occurs in areas of high traffic density,
high sunlight and temperature inversions as in Los Angeles and Athens, act as respiratory
irritants and can exacerbate asthma. Similarly other atmospheric pollutants as in highly
industrialised area containing sulphur dioxide and other smoke particulates can provoke
asthma. Indoor air pollution due to cooking fuels such as gas, biomass, and kerosene contain
oxides of nitrogen and are responsible for increased respiratory symptoms as reported in
some studies.111
Other environmental pollutants such as diesel particulates, and noxious gases like ozone,
sulphur dioxide, and nitrous oxides may be important in the development in young
children.112
Air pollution is partly being incriminated as a possible contributing factor in the recent
rise in the prevalence, morbidity and mortality of asthma globally.113 Although recent studies
have not established a direct causal relation of air pollution and bronchial asthma, there is
now substantial evidence that air pollution can contribute significantly to asthma morbidity
and mortality. Ambient levels of air pollutants exacerbate mucosal inflammation in asthmatic
airways, can affect lung function, and potentiate inhaled response to aeroallergens. Emissions
from motor vehicles are a major source of these pollutants. Retrospective analysis of pollution
episodes in the world history (Meuse Valley, Belgium -1930; Donnora, Pennsylvania-1948;
London 1952) have identified a link between respiratory morbidity and mortality and high
levels of sulphur dioxide and black smoke, although these studies were not primarily
focussed to study the association between asthma and air pollution.114-116 Reports from the
Tokyo-Yokohama area of Japan where USA soldiers were based, revealed many cases of
asthmatic bronchitis characterised by cough, wheeze, and breathlessness associated with
eosinophilia and positive skin prick tests. This area experienced smog as it was highly
industrialised and surrounded by hills. These individuals experienced relief of their
symptoms when they moved out to less polluted areas. This entity is known as TokyoYokohama asthma. However, since the levels of pollutants were not measured, this could
not be attributed to any specific pollutant.117-119 Other studies from Yokkaichi, Japan,120
Birmingham, UK,121 Seattle,122 Utah valley,123 Southern Ontario and Toranto124-126 have shown

30

Bronchial Asthma

positive correlations between asthma exacerbations and SO2, ozone, fine particulate matter,
and sulphates.127-129 Indoor air pollution is a contributory factor in exacerbation of bronchial
asthma.130
Environmental tobacco smoke is important in the development of childhood asthma
and in the worsening of asthma in children and adults.131 The earlier and the greater the
degree of environmental tobacco smoke, the greater the likelihood of asthma developing in
children. In infants exposed to prenatal and postnatal cigarette smoking, have altered lung
function.130,132,133 These limitations in lung functions may be secondary to smaller lung size,
and less maturity of lungs secondary to in utero lung growth retardation because of persistent
exposure of lungs to nicotine.134-136 Increased bronchial responsiveness after birth occurs in
infants exposed to maternal smoking.137 Infants exposed to smoking are at increased risk of
developing asthma later in life.138-146 It is, however, not clear whether increased bronchial
reactivity after birth plays a role, if any, in the development of asthma. It is also not clear
whether the increased bronchial reactivity in these infants is purely genetic, or whether it is
the result of lung injury from exposure to cigarette smoke.
Asthmatic smokers have increased hyperresponsiveness to methacholine.147 Asthmatic
smokers have higher sputum total cell and neutrophil numbers and IL-8 concentrations
compared to asthmatic nonsmokers. In contrast, sputum eosinophils and eosinophil-cationprotein levels are higher in nonsmoking than smoking asthmatics, suggesting a normalising
effect of smoking on the Th1/Th2 balance. Thus upon the eosinophils inflammation, smoking
induces neutrophilic airway inflammation in asthma.147 Further, smoking asthmatics show
no improvement in lung function, airway hyperresponsiveness, and sputum eosinophilia
on treatment with steroid inhalation.148 This decreased steroid responsiveness is responsible
for the faster decline in FEV1 seen in smoking asthmatics.
ENDOCRINAL FACTORS
Although the exact role of hormones in asthma has not been defined, a number of patients
complain of exacerbation of their symptoms during or preceding menstruation.
Retrospective studies suggest that in approximately one-third of women, asthma becomes
worse during pregnancy; in one-third, it becomes better; and in one-third, it remains
unchanged. In women in whom asthma becomes worse during pregnancy, peak severity
occurs at 29-36 weeks of gestation. Asthma becomes less severe during the last 4 weeks of
pregnancy. The change in the severity of asthma during pregnancy is sometimes dramatic
and tends to be consistent in subsequent pregnancies. Most patients return to a prepregnancy level of severity by 3 months of postpartum.149-152 There may be an improvement
in airway responsiveness during pregnancy that is greatest in those with the most
hyperresponsive airway initially. It is also reported that improvements in responsiveness
are associated with improvements in clinical asthma severity. However, progesterone alone
did not appear to be the sole contributor to these improvements. It is also suggested that
oestrogen plays a role in the pathophysiology of asthma and long-term use and/or high
doses of postmenopausal hormone therapy increase subsequent risk of asthma.153
Several observations have been made on the influence of thyroid hormones on asthma.
Hyperthyroidism is accompanied by many manifestations suggesting over stimulation of
the sympathetic system and this condition is a contraindication for use of -2 agonists. One,
therefore would expect that patients of bronchial asthma, who in addition develop hyperthyroidism, should either have a decreased requirements of bronchodilators or amelioration
of their symptoms. However, the reverse has been observed. Asthmatics who develop

Aetiology 31
hyperthyroidism, do far worse than euthyroid asthmatics. In some hyperthyroid asthmatics
following treatment of hyperthyroidism, not only asthma improves, but in rare instances
they become completely asymptomatic. Similar discrepancies have also been observed in
hypothyroidism. Various mechanisms such as changes in beta adrenoceptor activity and
altered prostaglandin metabolism have been proposed to explain these observations.
Bronchodilator response is impaired in the presence of excess thyroid hormones, which
improves after euthyroid state is achieved.154
GENETICS AND ASTHMA
Genetic factors play a contributing role in the pathogenesis of asthma.155 There are several
studies indicating familial aggregation of asthma. It is a frequent clinical observation that
asthma runs in families. Moreover, other atopic conditions like allergic rhinitis and atopic
dermatitis are common among the family members of the asthma patients. The concordance
of asthma in monozygotic (MZ) twins is reported to be significantly greater than that in
dizygotic (DZ) twins. Though the dosage of inhaled antigens and other factors influence
the likelihood of clinical disease, recent family studies suggest that atopy is dominantly
inherited. Molecular genetic linkage studies indicate that the atopy gene locus is on
chromosome 11.156-159
Cytokines are important components in the pathogenesis of asthma (see below). The
genes for these cytokines are encoded in a small region in the long arm of chromosome 5
and a number of them are coordinately regulated. T cells that differentiate along this route
and preferentially release cytokines of the IL-4 gene cluster are called Th2-like. These Th2like lymphocytes and their cytokines are over represented in tissue biopsy studies in patients
with allergic diseases. The chromosome 5 contains an IL-4 gene cluster which encodes the
allergic cytokines IL-3,4,5,9,13 and GM-CSF (granulocyte macrophage colony-stimulating
factor). This gene is closely linked to inheritance of an increased IgE response and to increased
bronchial hyperresponsiveness. Further, human genome studies have revealed that allergic
diathesis is linked with a region on the long arm of chromosome 12 which contains the
gene encoding interferon-) (INF-), which is a powerful suppressor of Th2 responses. It is
established that there is a reciprocal relationship between Th2 and Th1 responses with
IL-10 derived from Th2 cells inhibiting Th1 responses while INF- generated by Th1 cells
inhibits Th2 responses. It is possible that, in allergic diseases like asthma, there is an increase
in the expression of genes, which regulates Th2 cytokines, a decrease in expression of genes
that regulate INF- production, or a combination of both.160
The other genetic component that plays an important role is the ability of a susceptible
individual to recognise an environmental allergen as foreign and starts an allergic immune
response. This component operates through the human lymphocyte antigen (HLA, or MHC
class II) molecules HLA-DR, HLA-DP, HLA-DQ, which provide the mechanism for antigen
recognition and presentation to and by T and B lymphocytes.160
Many candidate genes and positional cloning have recently been identified.161 The first
genome-wide screen for linkages to asthma identifies linkages on chromosomes 4q,6 (near
the major histocompatibility complex, (MHC), 7,11q containing FcR1-, 13q and 16.
Linkages have been confirmed to chromosomes 4,11,13 and 16. Suggestive evidences are
also found for linkages and replication for loci on chromosomes 5q, 12q, 19q, and 21q.
Different linkages have been reported from different ethnic groups. The loci most consistently
and robustly identified are on chromosomes 5, 6, 12 and 13.

32

Bronchial Asthma

Various candidate genes those have been implicated in atopy and asthma are summarised
in Table 2.2.162
Several studies have shown that polymorphisms in the 2 adrenergic receptor gene
influences responsiveness to -agonists. Similarly polymorphisms in the 5-lipoxygenase gene
and the leukotriene C4 synthase gene have been associated with response to medications that
target leukotriene metabolism. These findings suggest the potential for pharmacogenetic
tailoring of therapy in individual asthmatic patients.163
Environmental risk factors for development of asthma are summarised in Table 2.3.
Table 2.2: Candidate genes for asthma

Chromosome
1
5

6
11
12
13
14
16

Gene
IL-10
IL-4 promoter
IL-5
IL-9
IL-12B
IL-13
GM-CSF
CD 14
2 adrenergic receptor
TNF-
Human leukocyte antigens
FcR1-,
CC16
Interferon
STAT 5
T-cell receptor / complex
IL-4 receptor (IL-4)

Table 2:3: Environmental risk factors for the development of bronchial asthma
Allergens
Pollutants

Infections

Dietary modifications

Food allergens
Inhalant allergens
Environmental tobacco smoke
Diesel particulates
Noxious gases (ozone, SO2, NO2)
Viral
Respiratory syncytial virus
Parainfluenza virus
Human rhinovirus
Bacterial
Mycobacterium
Chlamydia
Mycoplasma
Lactobacillus
3 fatty acids
Vitamins
Antioxidants
Lectins

Aetiology 33
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117. Phleps HW, Koike S. Tokyo-Yokohama asthma. The rapid development of respiratory distress
presumably due air pollution. Am rev Respir Dis 1962;86:55-63.
118. Oshima Y, Ishizaka T, Miyamato T, Kabe J, Makino S. A study of Tokyo-Yokohama asthma
among Japanese. Am Rev Respir Dis 1964;90:632-34.
119. Tremonti LP. Tokyo-Yokohama asthma. Ann Allergy 1970;28:590-95.
120. Kitagawa T. Cause analysis of Yokkaichi asthma episode in Japan. JAPCA 1984;34:743-46.
121. Walters S, Griffiths RK, Ayers J. Temporal association between hospital admissions for asthma
in Birmingham and ambient levels of sulphur dioxide and smoke. Thorax 1994;49:79-83.
122. Schwartz J, Slater D, Larson TV, Pierson WE, Koenig JQ. Particulate air pollution and hospital
emergency room visits for asthma in Seattle. Am Rev Respir Dis 1993;147:826-31.
123. Pope CA. Respiratory disease associated with community air pollution and a steel mill, Utah
Valley. Am J Public Health 1989;79:623-28.
124. Bates DV, Sitzo R. Relationship between air pollutant levels and hospital admissions in Southern
Ontario. Can J Public Health 1983;74:117-22.
125. Bates DV, Sitzo R. Air pollutant levels and hospital admissions in Southern Ontario: The acid
summer haze effect. Environ Res 1987;43:317-31.
126. Bates DV, Sits R. The Ontario air pollution study; Identification of the causal agent. Environ
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127. Committe of the Environmental and occupational health Assembly of the American Thoracic
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128. Pande JN, Bhatta N, Biswas D, Pandey RM, Ahluwalia G, Siddaramaiah NH, Khilnani GC.
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129. Cunningham J, OConnor GT, Dockery DW, Speizer FE. Environmental tobacco smoke, wheezing,
and asthma in children in 24 communities. Am J Respir Crit Care Med 1996;153:218-24.
130. Martinez FD, Wright AL, Tausig LM et al. Asthma and wheezing in the first six years of life.
New Engl J Med 1995;332:133-38.
131. Committee of the Environmental and occupational Health Assembly of the American Thoracic
Society: Health of outdoor air pollution. Am J Respir Crit Care Med 1996;153:3-50.
132. Stick SM, Burton PR, Gurrin L et al. Effect of maternal smoking during pregnancy and a family
history of asthma on respiratory function in newborn infants. Lancet 1996;348:1060-64.
133. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy: effects on lung function
during the first 18 months of life. Am J Respir Crit Care Med 1995;152:977-83.
134. Chen MF, Kimizuka G, Wang NS. Human fetal lung changes associated with maternal smoking
during pregnancy. Pediatr Pneumonol 1987;3:51-58.
135. Lieberman E, Torday J, Barbieri R et al. Association of intrauterine cigarette smoke exposure
with indices of fetal lung maturation. Obstet Gynecol 1992;79:564-70.
136. Sheikh S, Goldsmith LJ, Howell L et al. Comparison of lung function in infants exposed to
maternal smoking and in infants with a family history of asthma. Chest 2002;116:52-58.
137. Young S, Le Souef PN, Greelhoed GC et al. The influence of family history of asthma and parental
smoking on airway responsiveness in early infancy. New Engl J Med 1991;324:1168-73.
138. Infante-Rivard C. Childhood asthma and indoor environmental risk factors. Am J Epidemiol
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139. Arshad SH, hide DW. Effects of environmental factors on the development of allergic disorders
in infancy. J Allergy Clin Immunol 1992;90:235-41.
140. Weitzman M, Gortmaker S, walker DK et al. Maternal smoking and childhood asthma. Pediatrics
1990;85:505-11.
141. Stoddard JJ, Miller T. Impact parental smoking on the prevalence of wheezing respiratory illness
in children. Am J Epidemiol 1995;141:96-102.
142. Lewis S, Richards D, Bynner J et al. Prospective study of risk factors for early and persistent
wheezing in childhood. Eur Respir J 1995;8:349-56.
143. Weiss ST. Environmental tobacco smoke and asthma. Chest 1993;104:991-92.
144. Martinez FD, Cline M, Burrows B. Increased incidence of asthma in children of smoking mothers.
Pediatrics 1992;89:21-26.
145. Ehrlich RL, Tott DD, Jordan E et al. Risk factor for childhood asthma and wheezing: Importance
of maternal and household smoking. Am J Respir Crit Care Med 1996;154:681-85.
146. Wright AL, Holberg C, Martinez FD et al. Relationship of parental smoking to wheezing and
non-wheezing lower respiratory tract illness in infancy. J Pediatr 1991;118:207-14.
147. Chalmers DW, MacLeod KJ, Thomson L et al. Smoking and airway inflammation in patients
with mild asthma. Chest 2001;120:1917-22.
148. Chalmers DW, MacLeod KJ, Little SA et al. Influence of cigarette smoking on inhaled
corticosteroid treatment in mild asthma. Thorax 2002;57:226-30.
149. Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy; a prospective study of 198
pregnancies. Thorax 1988;43:12-18.
150. Editorial. Pregnancy and the asthmatic. Respir Med 1991;85:451.
151. Schatz M, Harden KM, Forsythe A et al. The course of asthma during pregnancy, postpartum,
and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;81:509.
152. Schatz M, Zeiger RS, Harden KM et al. The safety of inhaled -agonist bronchodilators during
pregnancy. J Allergy Clin Immunol 1988;82:686.
153. Troisi RJ, Speizer FE, Willett WC, trichopoulos D, Rosner B. Menopause, postmenopausal
estrogen preparations, and the risk of adult-onset asthma: A prospective cohort study. Am J
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154. Behera D, Roy R, Dash RJ, Jindal SK: Airway response to inhaled fenoterol in hyperthyroid
patients before and after treatment. J Asthma 1992; 29:307, 369-74.
155. Meyers DA, Bleecker ER. Approaches to mapping genes for allergy and asthma. Am J Crit Care
Med 1995;152:411-13.
156. Hopkin J. Genetics and lung disease. Advances in our understanding of emphysema, cystic
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157. Cookson WOCM, Hopkin JM. Dominant inheritance of atopic immunoglobulin-E responsiveness.
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158. Cookson WOCM, Sharp P, Faux J, Hopkin JM. Linkage between immunoglobulin-E responsiveness underlying asthma and rhinitis and chromosome 11q. Lancet 1989;i:1292.
159. Nieminen MM, Kaprio J, Koskenvuo M. A population-based study of bronchial asthma in adult
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160. Holgate ST. Asthma and allergy: Interaction of immunology and environment. Pulmonary
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161. Cookson WOC. Asthma genetics. Chest 2002;121:7S-13S.
162. Sandford A, Pare P. The genetics of asthma: The important questions. Am J Respir Crit Care
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163. Joos L, Sandford AJ. Genotype predictors of response to asthma medications. Curr Opin Pulm
Med 2002;8:9-15.

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Bronchial Asthma

3
Pathophysiology of
Bronchial Asthma
Bronchial asthma is a disease characterised by wide variation over short periods of time in
the resistance to flow in the airways. The hallmark of the disease is the airflow obstruction.
Most asthma is of allergic origin. In this form, it is viewed as a sum of three features: the
early asthmatic reaction (EAR); the late asthmatic reaction (LAR); and bronchial
hyperresponsiveness, with varying contribution from each. The cellular response in LAR
in non-allergic asthma is similar, but little is known of the underlying aetiology. Three
factors narrow airway caliber to limit the flow:
Airway smooth muscle contraction;
Gland and epithelial secretions and exudation into the airway lumen; and
Inflammatory oedema and vasodilatation (hyperaemia).
Early Asthmatic Reaction (EAR)
In atopic individuals, bronchial challenge/inhalation of appropriate antigens will elicit an
early response, which is maximum at 15 minutes and characterised by smooth muscle
contraction, exudation of plasma, and mucus production. This reaches its peak in about
thirty minutes and resolves within 90-180 minutes. This early reaction is IgE dependent
and is the result of IgE binding to mast cells by its Fc portion and to specific antigens by its
F(ab) portion. When IgE-sensitised mast cells are exposed to antigen against which the IgE
molecule is directed, pre-formed and newly generated mediators are released.1 These can be
detected in the blood as they overflow into the circulation, in bronchoalveolar lavage fluid,
and as metabolites in the urine and include histamine, prostaglandin D2, and leukotriene C4
from airway mast cells.2 This early response is due to the release of histamine. This reaction
can be prevented by pre-medication with sodium cromoglycate and nedocromil sodium and
-2 agonists,3 but not with steroids.
Late Asthmatic Reaction (LAR) and Bronchial Hyperreactivity (BHR)
The EAR is followed by a complete or partial recovery period over the next 1 to 2 hours and
then by a further progressive fall in respiratory function, which is maximal between 6 to 12
hours. A further recovery occurs by 24 to 36 hours. This response can only be partially
reversed by -2 agonist, but pre-medication with cromolyn and corticosteroids inhibits this
response. The LAR is also characterised by the release of inflammatory mediators into the
same fluids. However, during this phase there is a striking infiltration of inflammatory

Pathophysiology of Bronchial Asthma 41

cells with activation of these cells which include eosinophils, neutrophils, and lymphocytes.
This LAR is thought to be a primary mechanism responsible for airway (bronchial)
hyperresponsiveness (BHR). The BHR is an exaggerated bronchoconstriction of smooth
muscles and airway narrowing on exposure to small quantity of non-allergic stimulant
that usually does not provoke such a reaction in normal subjects.4 The BHR usually precedes
the onset of LAR.5 This may last for several days or occasionally weeks.6 The BAL fluid
from these subjects contains increased eosinophils, eosinophilic cationic protein, CD4+ T
lymphocytes, macrophages, monocytes, basophils, and neutrophils.3,6 The selective
recruitment of these leucocytes into the airways during the LAR are probably due to the
release of local and circulating messengers, i.e. cytokines from the cells in the airway mucosa
in relation to allergen exposure with the subsequent effect of recruiting mature and precursor
cells from the bone marrow and other sites of leucocyte sequestration.7 Mucosal oedema
and vasodilatation are the important components of airway obstruction during the LAR
and contraction of airway smooth muscle contribute substantially to the EAR.
It is clear from studies in human and animals that the two phases of bronchoconstriction
response to inhaled antigen have distinct characteristics. The immediate response to antigen
occurs before airway inflammation is established histologically, is abolished or attenuated
by prior bronchodilator drugs like -2 adrenergic agonist, is sensitive to the effects of antiinflammatory drugs, and is not associated with an increased bronchial hyperreactivity. In
contrast, the LAR is associated with histologic evidence of airway inflammation, is relatively
resistant to bronchodilator drugs, is lessened by corticosteroids, and is associated with
bronchial hyperreactivity. Rabbit experiments showed that if they are depleted of neutrophils
and then exposed to inhaled antigen, there will be an immediate bronchoconstrictor response,
but there will be no late bronchoconstriction, neither they develop bronchial hyperreactivity.
These findings suggest that airway inflammation underlines the bronchial hyperreactivity
characteristic of LAR. Non-immunologic causes of airway inflammation are also associated
with the development of bronchial reactivity. Inhaled ozone and viral infections damage
the bronchial epithelium, leading to an inflammatory response in the bronchial walls and
bronchial hyperreactivity develops once airway inflammation become evident. Similarly
neutropenic dogs do not develop hyperreactivity after exposure to ozone. All these support
the hypothesis that inflammatory processes are important in the pathogenesis of bronchial
hyperreactivity.8
The results of skin testing of allergic subjects indicate that isolated immediate
hypersensitivity reactions occur in about 20% of positive challenges, isolated late phase
reactions in 6-14%, and both reactions in 66 to 85%.
Thus, it is apparent that both inflammation and bronchial hyperreactivity are important
to bring about these changes. A series of events including cellular elements, mediators, and
neuropeptides in a coordinated manner are responsible for the ultimate airway obstruction.
A number of cells and chemical by-products take part in the pathogenesis of bronchial
asthma to bring about changes outlined above. The stimulus/stimuli in a susceptible host
starts the ball rolling so that a number of cells with their products cause various changes
that are characteristic of bronchial asthma. The understanding and concept of pathogenesis
of bronchial asthma has changed considerably over the past decade. Bronchial asthma is
now considered as a heterogeneous disorder with multiple triggers. However, certain
features are common to all asthmatics: Airway inflammation and hyperresponsiveness to a
broad range of stimuli. It is also known over the last few years that there is a close relationship

42

Bronchial Asthma

between airway inflammation and hyperresponsiveness. Exposure to oxidants, pollutants,

viral infections, chemicals, and allergens are all associated with inflammation and these
inflammatory stimuli are associated with airway hyperresponsiveness. Most studies have
shown that airway inflammation precedes hyperresponsiveness and may be a prerequisite
for the development of hyperresponsiveness and clinical bronchospasm. On the other hand,
airway inflammation as in purulent bronchitis may be present without hyperresponsiveness
or bronchospasm. Thus, airway inflammation, a hallmark of bronchial asthma is of a specific
nature that differs from other types of inflammation.
Bronchial asthma is now established as an inflammatory disease of the airways associated
with inflammatory cell infiltration, epithelial damage, and subepithelial fibrosis. Bronchoalveolar lavage studies from patients with bronchial asthma have shown increased number
of eosinophils, mast cells, epithelial cells, and various humoral and chemical mediators of
asthma.9-15 Histopathological studies also have shown epithelial shedding and influx of
eosinophils into the airway mucosa.16-18 Fresh biopsies from asthmatics of varying severity
have shown epithelial changes, deposition of collagens, and influx of inflammatory cells
even in patients with mild asthma.19 Further, presence of increased number of eosinophils
in the sputum and peripheral blood of patients with bronchial asthma has been known for
many years. It is also reported subsequently that eosinophils and mast cells increase
quantitatively during exacerbations of asthma. Substantial data also support the role for
both neutrophils and macrophages.20 Specific subtypes of lymphocytes (T-helpers2 [Th2])
may orchestrate a unique inflammatory response in the asthmatic lung and may significantly
modulate the function not only of the inflammatory cells, but also non-inflammatory cells
which include endothelial cells, platelets, sensory nerves, and airway epithelial cells.21 These
non-inflammatory cells may contribute to the inflammatory response and may also directly
participate in the regulation of normal airway tone. The function of these cells can be
modulated in asthmatics and they may produce mediators with effects on airway
function.22-31
INFLAMMATORY CELLS IN ASTHMA
Mast Cells
Mast cells have been recognised since a long time as the main effectors cells in early asthma
reaction.32,33 Normal human respiratory tract contains large numbers of mast cells beneath
the bronchial epithelium and alveolar walls. Increased numbers of mast cells and histamine
(a product of mast cells) have been found in the bronchoalveolar lavage fluid obtained
from patients with bronchial asthma.34,35 These calls are derived from CD34+ cells in the
bone marrow.36 Based on the production of proteases, a number of subtypes of mast cells
exist in human beings.37 A large number of biologically active molecules, both preformed,
i.e. histamine, proteases38 and newly synthesised,39 are released from the mast cell during
the allergic reaction when its high affinity, IgE receptors are cross-linked with antigen.40
After immunological activation, some populations of mast cells metabolise arachidonic
acid, primarily through the cyclooxygenase pathway to prostaglandin (PGD2), and
thromboxane A2, whereas other populations of mast cells metabolize arachidonic acid
primarily through the 5'-lipooxygenase pathway to LTB4 and LTC4 (Fig. 3.1). All mast cells
have secretory granules that contain large amounts of histamine, proteoglycans, heparin,
and proteases. These preformed substances are exocytosed from the cell after immunologic

Pathophysiology of Bronchial Asthma 43

Fig. 3.1: Arachidonic acid metabolism and mediator release (LT- Leukotriene)

activation. It has been shown recently in experimental animals that certain activated mast
cells also release transiently a large number of cytokines affect the tissue microenvironment
during inflammation. These substances are GM-CSF, INF-, IL-1, IL-3-6, PAF, transforming
growth factor, JE, and M1P1. These cytokines are capable of recruiting, priming and
activating other cells involved in inflammation. Through the release of cytokines similar to
those released from TH2 lymphocytes, it is possible that mast cells also play an important
role in the development of LAR in addition to its primary role in EAR.
It has been suggested that mast cells also possess anti-inflammatory properties through
release of heparin and related proteolysis. The tissue damaging properties of cationic protein
mediators released from eosinophils (see later) are neutralised by the highly anionic heparin.
It has also been shown that heparin inhibits the increased vascular permeability induced
by a wide range of agonists, can inhibit lymphocyte activation and trafficking and like
glucocorticoids is capable of inhibiting delayed hypersensitivity responses. Thus, it is
hypothesised that an imbalance between these inflammatory and anti-inflammatory
substances will decide the final outcome. However, this has not yet been proven.
Although mast cells are primary cells in EAR through IgE dependent release of
spasmogenic mediators, they also have an important role in LAR as they also produce

44

Bronchial Asthma

GM-CSF, interleukins, etc.41 although some other reports indicate that they are less likely to be
involved in the chronic inflammatory response.42,43
Eosinophils44-47
The importance of eosinophils in the causation of bronchial asthma is evident in view of
extensive tissue, blood and sputum eosinophilia in this disease. Biopsy studies both
postmortem and during life have shown the presence of excess eosinophils in the bronchial
mucosa of these patients. They also play a key role in asthma, and their presence in the
airways characterises the inflammation of asthma, which has been termed as chronic
eosinophilic bronchitis. The number of activated eosinophils is closely related to asthma
severity and may be associated with epithelial shedding. Their development is dependent
on T cell function. The IL-5 specifically stimulates eosinophil differentiation. They have
receptors for IgG, IgA, and IgE on their cell surface.
These cells are able to produce many mediators that are responsible for the disordered
airway function characteristic of asthma. These substances include:
Platelet activating factor
LTB4
LTC4
PGE2
15-HETE
Oxygen radicals and
Four cytotoxic proteins48-51
i. Major basic protein (MBP)
ii. Eosinophil cationic protein (ECP)
iii. Eosinophil-derived neurotoxin (EDN) and
iv. Eosinophil peroxidase (EPO).
All these mediators are released by activated eosinophils. The release of these mediators
results in bronchoconstriction, epithelial damage, and recruitment and priming of other
inflammatory cells. Eosinophil maturation and priming are under the control of IL-3, IL-4,
IL-5, and GM-CSF (Granulocyte macrophage-colony stimulating factor), cytokines released
from a number of cell types in the airways including activated T cells of the TH2 type, and
mast cells. Another molecule present in the eosinophils is the Charcot-Leydon crystal protein
that possesses lysophospholipase activity.
Eosinophils have characteristic granules and granule proteins. The granule is composed
of a crystalloid core and a matrix. The above four proteins are present in the granules. The
genes of these proteins are cloned and the cDNA for MBP specifies the existence of a proMBP molecule that is composed of an acid-rich portion and a basic MBP portion. EDN and
ECP are both ribonucleases. In addition, ECP is a potent helminthotoxin. EPO is a member
of the peroxidase multigene family that is composed of myeloperoxidase, thyroid peroxidase,
and lactoperoxidase. The MBP is toxic to respiratory epithelium and is elevated in the sputum
of patients with asthma. It has also been shown that MBP is deposited in the damaged areas
in the epithelium. Not only MBP, but also ECP and EPO alone, as well as EPO in the presence
of halide and hydrogen peroxidase, damage bronchial epithelium. Experimental studies
have shown that eosinophil proteins, particularly MBP applied to respiratory epithelium
stimulates smooth muscle contraction and also can increase the sensitivity of the smooth

Pathophysiology of Bronchial Asthma 45

muscle to acetylcholine, which suggests that eosinophil is an effector of the changes of
bronchial hyperreactivity in vivo.
Lymphocytes52-70
Although production of IgE by B lymphocytes is well known, the role of T lymphocytes in
bronchial asthma had received little attention till recently.52,53 Chronic asthma, at least in
part, represents a form of delayed-type hypersensitivity involving interactions between
activated lymphocytes and eosinophils. There are a number of evidences to prove that
these cells play important roles in this disease.
i. T lymphocytes secrete lymphokines, IL-4, and interferon-, that closely regulate IgE
production by B lymphocytes. While IL-4 stimulates, interferon- inhibits IgE synthesis.
ii. IL-3, and IL-5, and GM-CSF regulate eosinophil production, and IL-3, and IL-4 are
important regulators of mast cell and basophil production.
iii. T cells are attracted to the bronchial mucosal surface to the site of inflammation by
specific receptors both on themselves and on the mucosal capillary and endothelial
venules.
iv. Local accumulation of CD8+ cells in early phase reactions recovered in BAL fluid
suggests that the subsequent late phase reaction may be in part, under the control of
T cells. Although CD8+ cells are not a part of this reaction, it has been found that
substantial infiltration of CD4 IL-2R+ lymphocytes, and activated (EG2+) eosinophils
occurs in allergen-induced late phase reaction in atopic subjects. Recently it has been
reported that a high percentage of these CD4+ cells are UCLH-1 or memory cells, that
respond to recall antigens.
v. Patients with acute severe asthma have activated CD4+ lymphocytes in their blood,
the number of which returns to baseline value after successful treatment. The elevation
is associated with increased serum concentration of IL-2 soluble receptors and INF-.
These changes corelate well with the severity of disease.
vi. Corticosteroid resistant asthmatics have chronically activated circulating T cells (IL-2R
and HLA-DR positive).
vii. More recently, direct evidence of T cell involvement in bronchial asthma is acquired by
the study of mucosal biopsy specimens from volunteers. Electron microscopy has
revealed elevated numbers of activated irregular lymphocytes in the bronchial
mucosa. There is a significant increase in the number of IL-2R+ (CD25) cells both at the
central and subsegmental airways.
It is now well established that there are two types of T cells.54 They are Th1 and Th2,
divided on the basis of lymphokines they secrete. While the Th1 cells secrete IL-2, interferonalpha and tumour necrosis factor-beta, the Th2 cells secrete IL-4,IL-5, IL-6, and IL-10, and
IL-3 and GM-CSF are secreted by both. While INF- inhibits the development of Th2 cells,55
IL-10 inhibits Th1 proliferation.56 Details of such interaction are being discussed above under
genetics and asthma. More recently, another stable phenotype among T-helper clones has
been recognised both in mouse and man, which is called Th0. This subtype is characterised
by an ability to generate a large variety of cytokines, including IL-4 and INF-, which are
characteristic of either the Th1 or Th2 subset.
Therefore, activated CD4+ cells are a feature of both active and chronic asthma, more so
for the later, and their presence is associated with actively secreting eosinophils. T cells
may be directly involved in eosinophil recruitment and activation by secreting various

46

Bronchial Asthma

interleukins which favour the synthesis of IgE and activation of eosinophils and mast cells.
There is a preferential expansion of type Th2 T cells secreting IL-3, IL-4, IL-5 and GM-CSF with
fewer Th1 cells whose cytokine profile includes IL-2 and interferon-. Such a mechanism
would explain the peculiarities of allergic inflammation involving isotype switching to IgE
synthesis, and the preferential recruitment of eosinophils and mast cells.
Lymphokines and various other cytokines that are relevant to airway inflammation in
asthma are shown subsequently.57-68 Two important cytokines , that are particularly important
in bronchial asthma are IL-4 and NF-KB.69,70 IL-4 is essential for IgE production. INF-
diminishes cell processing necessary for IL-4 production.69 Thus, interplay of these cytokines
will decide whether IL-4 producing cells will be produced, and, thus, whether IgE will be
produced in response to various allergic stimuli. The role of transcription-factor NF-KB is
emerging recently to play a key role in the pathogenesis of bronchial asthma. It is postulated
that inflammatory signals activate transcription factors such as NF-KB and this in turn will
switch on the inflammatory genes, which will lead on to the increased expression of
inflammatory proteins. Corticosteroids are potent inhibitors of NF-KB and their antiinflammatory action is believed to be mediated through this mechanism.70
Thus, it may be summarised that T cell participation is an important event in allergic
diseases and asthma. Th2 cells are more important by the way of production of various
cytokines which are necessary for allergic responses. In contrast, Th1 cells are primarily
responsible for classic delayed hypersensitivity. Products of Th1 type cells, principally
INF-, inhibit or antagonize Th2 effector function. IL-4 induces IgE synthesis, and INF- is
a strong inhibitor of this process. Such control establishes a model of how IgE can be tightly
regulated in vitro. The Th2 pathway is also involved in regulation of eosinophilia, mast cell
activity and IgE synthesis. The differentiation into Th1 and Th2 cells are again regulated by
cytokines. While IL-4 may act directly on the precursor T cell to induce Th2 differentiation,
interferon and transforming growth factor-beta TGF-.71 While T cell sensitisation is an
important factor in the development of IgE production to a particular antigen and T cell
subsets are important in establishing the process of airway hyperresponsiveness.
Experimental data have shown that the transfer of antigen-specific IgE, immediate cutaneous
hypersensitivity, and increased airway responsiveness may be mediated, depending on
the antigen, by specific V expressing T cell subsets.
While the precise mechanisms by which inflammatory cells are recruited into the lungs
are not fully understood, increasingly available evidence suggest that the activation of
antigen-specific CD4+ T cells of the type 2 T-helper (Th2) subset in the lungs, which results
in IL-5 secretion, plays a major role in asthmatic airway inflammation.72 CD4+ T cell
activation leading to cytokine production and effector function requires two signals from
the antigen-presenting cell (APC). The first signal is triggered by the interaction between
antigen-specific T cell receptor and peptide-major histocompatibility complex II complexes
on APCs. The second signal or co-stimulatory signal is triggered by CD80 (B7-1) and CD86
(B7-2) of the APC binding to the CD28 and cytotoxic T lymphocyte antigen (CTLA-4) of the
T lymphocytes.73-76 In the absence of co-stimulatory signals, the T cell-dependent immune
response is greatly diminished, or even eliminated.77 Thus, costimulatory signals may fulfill
a valuable role in T lymphocyte activation, Type 1 T-helper (Th1) or Th2 cell differentiation,
and the production of different cytokines.78
CTLA-4 is a second co-stimulatory molecule and is a homologue of CD28. It is expressed
only on activated T cells, binds to accessory molecule B7,79 and mediates T cell-dependent

Pathophysiology of Bronchial Asthma 47

immune response. Signalling through CTLA-4 may down regulate Th1 cell proliferation
by inhibiting the production of IL-2 and IL-2 receptor expression.80,81 However, the role of
CTLA-4 remains uncertain, with some studies79 the CTLA-4 might also deliver a positive
signal to Th2 cell activation. Disruption of this delicate balance of immune regulation could
lead to autoimmune diseases or atopic diseases. Therefore, CTLA-4 is considered to be
important in the development of many of the immunologic and physiologic features of
asthma.
Polymorphisms of the CLTA-4 gene, located on chromosome 2q33, could thus have effects
on immune response. Three CTLA-4 genes are known at present.82-86 The CTLA-4 promoter
(-318 C/T) T allele may serve as a clinically useful marker of severe asthma. This promoter
polymorphism is associated with asthma severity, but not with asthma, atopy, or bronchial
hyperresponsiveness. A significant association is found between severe asthma and
bronchial hyperresponsiveness.85
Monocytes and Macrophages
Several findings favour a role for macrophages in bronchial asthma.86-94 Firstly, after in vivo
and in vitro contact with specific allergen or non-specific stimulus, alveolar macrophages
from asthmatics have been shown to release lysosomal enzymes, prostaglandin (TxB2),
leukotrienes, and platelet-activating factor (PAF). They are also able to generate oxygen
free radicals, neutral proteases, and -glucuronidase after non-specific stimulation. Some
of these studies also have shown that macrophages from asthmatics are hyperactive and
release more lipid-derived mediators than those from the normal subjects.
Secondly, a subpopulation of peripheral blood monocytes and alveolar macrophages
are IgE receptor positive.95,96 Whereas in normal healthy humans, only 5 to 10% of the alveolar
macrophages and 10-15% of the peripheral monocytes are IgE Fc positive, these numbers
increase dramatically in asthmatics. As many as 80% of the monocytes and up to 30% of the
macrophages recovered from BAL fluid in mild asthmatics will be IgE receptor positive.
The percentage may be still higher in severe forms of asthma. The macrophage IgE receptors
(IgE FcR) has a low affinity for IgE compared to that of the mast cell. This lower affinity
binding suggests that IgE immune complexes may be more important in activation of these
cells compared to mast cells and basophils that are sensitised by monomeric IgE, because of
their greater strength of binding to this FcR.
Thirdly, it has been demonstrated that active macrophages are present at the air-surface
interface of human airways as well as in alveoli. Therefore it is possible that these cells
interact with any inhaled allergen.
Fourthly, macrophages are capable of releasing several potent neutrophil chemotaxins.
These include complement fragments, fibronectins, neutrophil attractant/activating protein1 (IL-8), and LTB4. IL-8 is also chemotactic for lymphocytes. The production of LTB4 from
macrophages is greater on a nanogram per cell basis than other cells. LTB4 and PAF are
chemo attractants for eosinophils. Macrophages produce histamine-releasing factor(s) that
induce the release of histamine from basophils.
Fifthly, macrophage function is altered by lymphokines, such as INF-. It is reasonable
to hypothesize that this lymphokine and/or others, such as IL-4, may regulate the number
of IgE FcRs on lung macrophages.

48

Bronchial Asthma

Basophils
Basophils are histamine releasing cells in the late phase reaction of asthma unlike mast
cells, which release histamine in the early phase reaction. The spontaneous release of
histamine is quite high by these activated basophils (20-40% of total). This release process
has slow kinetics and is temperature dependent. Various cytokines (IL-1, IL-3, and histamine
releasing factor) and PAF have an up regulatory/stimulatory effect on blood basophils.
Any or all of these cytokines could prime the basophils such that they become responsive
to very low concentrations of stimuli or some could directly trigger basophil mediator release.
Epithelial Cells and Adhesion Molecules
The infiltration of inflammatory cells into the airways is dependent on the expression of
adhesion molecules on inflammatory cells and endothelial cells of the bronchial circulation.97
One consequence of inflammation is epithelial injury. Morphological studies have shown
that asthma is associated with epithelial injury. These changes range from minor disruption
of the epithelium with loss of ciliated cells to complete denudation of the epithelium. These
structural changes in the epithelial barrier can lead to increased permeability to inhaled
allergens, irritants, and inflammatory mediators. In addition, transudation of fluids and
reduced clearance of inflammatory substances and respiratory secretions occur with
disruption of epithelial mucociliary mechanisms. The epithelium also participates in
mediator release and metabolism.98-101 They have the capacity to produce PGE2, PGF2,
12-and 15-hydroxy eicosatetraenoic acid, GM-CSF, etc. The bronchial hyperresponsiveness
in asthma is attributed to the epithelial cell damage. The airway epithelial cells have a
protective role against various tachykinins.
Currently, adhesion molecules are considered to be important in the causation of airway
inflammation, although the specific mechanism is still under investigation.102-109 Adhesion
of various inflammatory cells to the bronchial vascular endothelium is a key step in the
initiation and propagation of inflammation. This is effected by the interaction of various
adhesion molecules expressed on endothelial cells, epithelial cells, platelets, and leucocytes.
These molecules are specific glycoproteins that are grouped into different families depending
upon their molecular structure. These include integrins, immunoglobulin super gene family
(intracellular adhesion molecule-ICAM, vascular cell adhesion molecule-VCAM; platelet
endothelial adhesion molecule-PCAM), selectins (E-selectin like ELAM-1, and ECAM-1,
P-selectin, L-selectin) and carbohydrates are important for lung inflammation. Expression
of various adhesion molecules is regulated by various mediators of inflammation.
Neutrophils
Although neutrophils are found in large proportions in the bronchial wall and
bronchoalveolar lavage fluid in bronchial asthma, it is not clear if they have any definite
role to play in bronchial asthma. However, such neutrophils in bronchial asthma show
increased expression of membrane complement receptors and enhanced toxicity for
complement coated antigens. They also have ability to alter airway function. These finding
suggest that neutrophils probably participate in inflammation of bronchial asthma.

Pathophysiology of Bronchial Asthma 49

CYTOKINES IN BRONCHIAL ASTHMA
Cytokines are extracellular signalling proteins, usually less than 80 KD in size, and many are
glycosylated. They are produced by different cell types. A detailed discussion on the role of
different cytokines is given below.
Various cytokines and their function are shown in Table 3.1.

Cytokines
IL-1
IL-2
IL-3
IL-4
IL-5

IL-6
IL-8
IL-10

Table 3.1: Various cytokines, their source and function in

the pathogenesis of bronchial asthma110
Origin
Function
Various cells
Th2-cells
Th2 cell, mast cells
eosinophils
T cell, mast cell
T cell, mast cells,

Increased expression of endothelial adhesion molecules

Eosinophil activation
Eosinophil and neutrophil differentiation, activation,
and eosinophils survival, eosinophil chemotaxis
IgE synthesis, T cell growth, endothelial adhesion
Eosinophil differentiation, maturation, activation,
eosinophils, adhesion, priming and chemotaxis,
basophil differentiation and priming, cofactor in IgE
synthesis
T cells
T cell growth factor, eosinophil chemo-attractant
Monocytes, T cells Neutrophil chemo-attractant and activator,
fibroblasts
inhibits IgE synthesis
T cell
Inhibition of Th1 cytokine, stimulates monocytes
production
T cells
NK cell and T cell growth, IgE synthesis inhibition
T cells
Critical regulator of allergic response
T cells, mast cells Granulocyte differentiation, activation, survival,
macrophages, eosinophils, epithelial cells
T cells
Eosinophil and macrophage activation
T cell and macrophage activation,

IL-12
IL-13
GM-CSF
chemotaxis
IFN-
Tumour necrosis
factor
Platelet derived
Monocytes,
growth factor (PDGF) Macrophages

Fibrosis, Th2 cytokine inhibition

INFLAMMATORY MEDIATORS IN ASTHMA

From the foregoing paragraphs it is apparent that a number of mediators released by different
cells are important for various changes observed in bronchial asthma.111-116 They are generated
by recruited cells and resident cells of the airways. These mediators cause contraction of
airway smooth muscle, increased mucus secretion, microvascular leak, further recruitment
and activation of various inflammatory cells, all essential changes in bronchial asthma.
LEUKOTRIENES
Of the many mediators that have been implicated in the asthmatic response, the
sulphidopeptide leukotrienes are of interest because they have the potential of involvement
in both aspects of the asthma syndrome, i.e. hyperresponsiveness, and inflammation. The
original discovery of a slow-reacting substance was that of smooth muscle contractile activity
distinct from histamine; it was distinguished from histamine on the basis that its effects
were slow in onset and prolonged in duration.117 The subsequent isolation and elucidation

50

Bronchial Asthma

of the structure of slow-reacting substance was identified as cysteinyl leukotrienes (LTC4,

LTD4, LTE4) which are synthesised and exported into the microenvironment by a number of
the above mentioned inflammatory cells, including mast cells and eosinophils.118-127
Furthermore, since plasma leakage is prominent in more severe asthma, it is likely that the
vascular endothelium will be exposed to cells capable of donating LTA4. It is well established
that the cysteinyl leukotrienes are formed when LTA4 exporting cells, such as polymorphonuclear leucocytes (neutrophils and eosinophils) provide LTA4 for effector cells such
as vascular endothelial cells or platelets.
As shown in Figure 3.2 arachidonic acid (AA) released from membrane phospholipids
during cell activation may be oxidatively metabolised by the enzymes of the cyclooxygenase
or lipooxygenase pathways.109 Arachidonate is presented to the 5-lipooxygenase enzyme
by 5-lipooxygenase-activating protein (FLAP).120 This FLAP is a cofactor resident in the
nuclear membrane. While cyclooxygenase pathway produces prostaglandins and
thromboxane, the 5-lipooxygenase pathway generates 5-hydroperoxy-eicosatetraenoic acid
(5-HPETE) or is converted enzymatically to the unstable intermediate LTA4. LTA4 is
metabolised by an epoxide hydrolase to LTB4, or by a glutathion-S-transferase (LTC4
synthase) to LTC4.128 LTC4 is cleaved by glutamyl-transpeptidase to LTD4, which is converted
by a peptidase to LTE4, these enzymes being ubiquitous in the tissues and circulation
(Fig. 3.2). LTB4 is a potent chemo attractant for neutrophils, and the sulphidopeptide
leukotrienes (LTC4, LTD4, and LTE4) are potent spasmogens for non-vascular smooth muscle
and comprise the activity previously known as slow-reacting substance of anaphylaxis
(SRS-A).
The leukotrienes have profound biochemical and physiologic effects, even in Pico molar
concentrations. The importance of leukotrienes has been suggested in a wide variety of
disorders that include hepatorenal syndromes, myocardial ischaemia, and inflammatory
conditions of bowel, skin and joints,122 besides their involvement principally in bronchial
asthma.123 These include severe airway obstruction, i.e. bronchoconstriction,129 oedema,130
and increased secretion of bronchial mucus from submucosal gland secretion.131 The most

Fig. 3.2: Synthesis of leukotrienes and their function

Pathophysiology of Bronchial Asthma 51

prominent effect is their ability to mediate airway narrowing in normal subjects as well as
in subjects with asthma. The airway obstruction is prolonged compared to that induced by
histamine. LTC4 and LTD4 are approximately 3000 times more potent in contracting the
airway compared to histamine in normal subjects. LT4 is also a potent bronchoconstrictor
although 30-100 times less potent than the above two. LTE4 induces a state of enhanced
airway responsiveness in asthmatics, but not in normal subjects. Inhalation of LTE4at doses
that induce a small but significant contractile response enhances the response to subsequent
administration of inhaled histamine. This enhancement is on the order of a four-fold shift
in the histamine dose-response curve with the effect lasting approximately 24 hours with
small effects persisting for up to a week. Thus a state of airway hyperresponsiveness is
maintained.
Leukotriene B4 (LTB4) is a potent chemotactic factor and is responsible, in part, for the
recruitment of inflammatory cells to the airway and stimulation of secretion of inflammatory
products. Their role in the smooth muscle contraction is controversial, although some studies
suggest that they may increase airway smooth muscle responsiveness to subsequent
stimulation. This can also modulate the immune response by inhibiting the capacity to
mount a delayed hypersensitivity response.132
The cells producing leukotrienes are only macrophages, neutrophils, eosinophils, and
mast cells that can synthesise them from the substrate arachidonic acid. However, subsequent
enzymes like LTA4 hydrolase, and LTC4 synthase are more broadly distributed including
non-inflammatory cells, airway epithelial cells and in the lung lining fluids. It is also now
recognised that synthesis of leukotrienes in the lung may involve a single inflammatory
cell type or an interaction between inflammatory and non-inflammatory cells termed
transcellular metabolism. Some reports suggest that even transcellular metabolism may
be the principal source of LTC4 in the lungs.133,134
These leukotrienes are recovered from nasal lavage fluid after inhalation challenge.
Significantly larger quantities are also recovered from the BAL fluid from subjects with
symptomatic asthma. Sulphidopeptide leukotrienes have been detected in the plasma during
asthma attacks. Larger quantities of these substances have been recovered from the urine
of asthma patients during acute spontaneous attacks than found in normal subjects.
The recent development and usefulness of leukotriene receptor antagonists and synthesis
inhibitors in bronchial asthma further emphasizes the role of these leukotrienes in the
pathogenesis of this condition.135-138
Leukotrienes are important in asthma, and leukotriene modifiers modulate antigeninduced asthma. Leukotrienes participate in the pathogenesis of bronchial asthma besides
the involvement eosinophilic airway inflammation.139 Overproduction of leukotrienes not
only occurs in house dust mite provoked asthma, but also in aspirin induced bronchial
asthma, although the mechanisms of such overproduction are different. While in the former
the overproduction occurs with an antigen-antibody reaction, in aspirin-induced asthma,
the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate
cascade.140 Pranleukast, a leukotriene inhibitor suppresses the increased values of sputum
eosinophil count and eosinophil cationic protein during house dust mite-induced asthma
are suppressed by further, this drug increases FEV1 that falls during such provocation.140
The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact
that airway narrowing and other signs in these patients are associated with 2-10 fold higher
values of LTE4 in the urine of these patients compared to aspirin tolerant patients.141-143

52

Bronchial Asthma

Further, several leukotriene modifiers inhibit the asthma response in oral or inhaled
bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144,145 and
improve respiratory function by bronchodilatation.146
Mast Cell Proteases
As much as 70% of the weight of a mast cell consists of proteases that are enzymatically active
at neutral pH. These cells express a complex array of proteases, which consist of serine
proteases, tryptases, and chymase. These enzymes regulate neuropeptide regulation in the
airways, smooth muscle contraction, and submucosal gland secretion.147-149 Histamine, another
mast cell product has a well-established role in the pathogenesis of asthma. It induces
bronchospasm, increases vascular and epithelial permeability, and increases the mucous
glycoprotein secretion.150
Histamine
The role of histamine in the pathogenesis of bronchial asthma is well established for a long
time. Histamine induces bronchoconstriction, increases epithelial and vascular permeability,
and increases the secretion of mucus glycoproteins.150 In patients of bronchial asthma, the
levels of histamine are increased in blood and bronchoalveolar lavage fluid.151,152
Prostaglandins
PGD2 and PGF2- A are very potent bronchoconstrictor agents. The former has greater
bronchoconstrictor activity compared to that of the later or histamine.153 Both these
prostaglandins also potentiates the bronchoconstricting activity of histamine and
methacholine.155,156 On the other hand, PGE1 and PGE2 has bronchodilating effect. While
Thromboxane A2 (TXA2) is a bronchoconstrictor, vasoconstrictor, and platelet aggregator,
PGI2 is a bronchodilator, vasodilator and prevents platelet aggregation.156,157
Platelet-activating Factor (PAF)
PAF has attracted attention as an important mediator of bronchial asthma.158-161 Recovery of
this substance from bronchoaveolar lavage fluid in antigen exposed individuals supports
such a role.162,163 It is an important mediator involved in the bronchial hyperresponsiveness
in addition to having action of bronchoconstriction, stimulation of eosinophil and eosinophil
accumulation in the airway, induction of airway microvascular leakage and oedema, and
increased airway secretions and epithelial permeability.
Bradykinin
Bradykinin is another important inflammatory mediator in asthma and asthmatics have
increased responsiveness to bradykinin,164 and the levels are found to be high in bronchoalveolar lavage fluid from these patients165 The substance causes bronchoconstriction,
increases vascular permeability, has vasodilator activity, increases mucus secretion, activates
C-fibre nerve endings, enhances neuropeptide release from sensory nerves, and increases
cholinergic reflex.164, 166,167 Bradykinin mediates its effects through BK1 and BK2 receptors,166
although the effects on airways are primarily mediated via BK2 receptors. It also releases
tachykinins from airway sensory nerves.

Pathophysiology of Bronchial Asthma 53

Cytokines
Cytokines are extracellular signalling proteins, usually less than 80 kD in size and many
are glycosylated. They are produced by different cell types involved in cell-to-cell interactions,
having an effect on closely adjacent cells, and therefore function in a predominantly paracrine
fashion. They may also act at a distance (endocrine) and may have effects on the cell of origin
(autocrine). A classification according to function is proposed in Table 3.2.
Table 3.2: Classification of cytokines and cytokine receptors

Cytokines
Pro-inflammatory cytokines

IL-1/, TNF/, IL-6, IL-11, IFN-

Cytokines involved in atopy

IL-4, IL-13 (promoters); IFN-, IL-12 (inhibitors)

Cytokines of eosinophil chemo-attraction

and activation

IL-2, IL-3, IL-4, IL-5, GM-CSF, RANTES, eotaxin,

MCP-3, MCP-4

Th2 cytokines

IL-4, IL-5, IL-10, IL-13

Cytokines involved in T cell

chemo-attraction

IL-16, RANTES, MIP-1/

Cytokines of neutrophil chemo-attraction

and activation

IL-8, IL-1/, TNF/

Anti-inflammatory cytokines

IL-10, IL-4, IL-13, IL-12, IL-1ra

Growth factors

PDGF, TGF-, FGF, EGF, TNF-, SCF

Cytokine receptors
Cytokine receptor super family

IL-2R-and -chains, IL-4R, IL-3R -and -chains,

IL-5 -and -chains, IL-6R, gp130, IL-12R,
GM-CSFR; soluble forms by alternative splicing
(e.g. IL-4R)

Immunoglobulin super family

IL-1R, IL-6R, PDGFR, M-CSFR

Protein kinase receptor super family

PDGFR, EGFR, FGFR

Interferon receptor super family

IFN-/ receptor, IFN- receptor and IL-10 receptor

Never growth factor super family

NGFR, TNFR-1(p55), TNFR-II(p75)

Seven-transmembrane G-protein
coupled receptor super family

Chemokine receptors

The effects of an individual cytokine may be influenced by other cytokines released

simultaneously from the same cell or from target cells following activation by the cytokine,
and are mediated by binding to cell surface high-affinity receptors usually present in low
numbers, which can be up regulated with cell activation. The receptors for many cytokines
have been regrouped into super families based on the presence of common homology regions
(Table 3.3). Cytokines themselves may induce the expression of receptors which may change
the responsiveness of both source and target cells. Some cytokines may stimulate their own
production in an autocrine manner, where as others stimulate the synthesis of difference
cytokines that have a feedback stimulatory effect on the first cytokine, resulting in an increase
in its effects. The effects of cytokines are summarised in Table 3.3.168

54

Bronchial Asthma
Table 3.3: Summary of effects of cytokines

Cytokines
Lymphokines
IL-2
IL-3
IL-4

IL-5

IL-13

IL-15
IL-16
IL-17

Pro- inflammatory
IL-1

TNF-

IL-6

IL-9

IL-11

GM-CSF

Important cellular and mediator effects

Eosinophilia in vivo
Growth and differentiation of T cells
Eosinophilia in vivo
Pluripotent haematopoietic factor
Eosinophil growth
Th2; Th1
IgE
Mucin expression and goblet cells
eosinophil maturation
Apoptosis
Th2 cells
BHR
Activates eosinophils
apoptosis
IgE
mucin expression and goblet cells
As for IL-2
Growth and differentiation of T cells
Eosinophil migration
Growth factor and chemotaxis of T cells (CD4+)
T cell proliferation
Activates epithelia, endothelial cells, fibroblasts

adhesion to vascular endothelium; cosinophil accumulation in vivo

Growth factor for Th2 cells
B cell growth factor; neutrophil chemo-attractant; T cell and
epithelial activation
BHR
Activation epithelium, endothelium, antigen-presenting cells;
monocytes/macrophages
BHR
IL-8 from epithelial cells
MMPs from macrophages
T cell growth factor
B cell growth factor
IgE
Activated T cells and IgE from B cells
Mast cell growth and differentiation
Mucin expression and goblet cells
Causes eosinophilic inflammation and BHR
B cell growth factor
Activates fibroblast
BHR
Eosinophil apoptosis and activation; induces release of leukotrienes

Contd...

Pathophysiology of Bronchial Asthma 55

Contd...
Cytokines

SCF

Important cellular and mediator effects

Proliferation and maturation of haematopoietic cells; endothelial cell
migration
BHR
VCAM-1 on eosinophils
Growth factor for mast cells

Inhibitory cytokines
IL-10

IL-1ra

IFN-g

IL-18

Growth factors
PDGF

TGF-

Eosinophil survival
Th1 and Th2
Monocyte/macrophage activation; B cell; mast cell growth
BHR
Th2 proliferation
BHR
Eosinophil influx after allergen
Th2 cells
Activates endothelial cell, epithelial cells, alveolar macrophages/monocytes
IgE
BHR
Via IFN- release
Releases IFN- from Th1 cells
Activates NK cells, monocytes
IgE
Fibroblast and airway smooth muscle proliferation
Release of collagen
T cell proliferation
Blocks IL-2 effects
Fibroblast proliferation
Chemo-attractant for monocytes, fibroblasts, mast cells
Airway smooth muscle proliferation

Inflammation and Cytokines in Asthma

Asthmatic Inflammation
The chronic airway inflammation of asthma is characterised by an infiltration of T lymphocytes,
eosinophils, macrophages/monocytes and mast cells, and sometimes neutrophils. An acute
or chronic inflammation may be observed with acute exacerbations, with an increase in
eosinophils and neutrophils in the airway submucosa and release of mediators, such as
histamine and cysteinyl-leukotrienes, from eosinophils and mast cells to induce
bronchoconstriction, airway oedema and mucus secretion. Changes in the resident cells are
also observed, such as an increase in the thickness of the airway smooth muscle with
hypertrophy and hyperplasia, more myofibroblasts with an increase in collagen deposition
in the lamina reticularis, more vessels and an increase in goblet cell numbers in the airway
epithelium.
Cytokines play an integral role in the coordination and persistence of the inflammatory
process in the chronic inflammation of the airways (Table 3.3).

56

Bronchial Asthma

Th2-associated Cytokines
CD4+ T lymphocytes of the asthmatic airways express Th2 cytokines including IL-3, IL-4, IL5, IL-10, IL-13 and GM-CSF. The primary signals that activate Th2 cells may be related to the
presentation of a restricted panel of antigens in the presence of appropriate cytokines. Dendritic
cells are ideally suited to being the primary contact between the immune system and external
allergens. Co-stimulatory molecules on the surface of antigen-presenting cells, in particular
B7.2/ CD28 interaction, may lead to proliferation of Th2 cells.169 With the expression of IL-4,
synthesis of IgE by B lymphocytes on immunoglobulin isotype switching occurs.170 IgE
produced in asthmatic airways binds to FcRI receptors (high-affinity IgE receptors) on mast
cells priming them for activation by antigen. The maturation and expansion of mast cells from
bone marrow cells involve growth factors and cytokines such as SCF and IL-3 derived from
structural cells. Bronchoalveolar mast cells from asthmatics show enhanced release of
mediators such as histamine. Mast cells also elaborate IL-4 and IL-5.171 IL-4 also increases the
expression of an inducible form of the low-affinity receptor for IgE (FcRII or CD23) on B
lymphocytes and macrophages.172 IL-4 drives the differentiation of CD4+ Th precursors to
Th2- like cells.
IL-18 is a cytokine with potent interferon (IFN)- -inducing activity. It is predominantly
produced by activated macrophages and synthesised with IL-12 to induce (IFN)- synthesis
from T lymphocytes, promoting differentiation of T cells to the Th1 subsets. The IL-18 levels
are low in the BAL fluid of patients with bronchial asthma. This inherently low levels of IL18 may be associated with pathogenesis of asthmatic airway inflammation.173

Antigen presentation Cytokines may play an important role in antigen presentation

(Fig. 3.3). Airway macrophages are usually poor at antigen presentation and suppress
T cell proliferative responses (possible via release of cytokines such as IL-1 receptor
antagonist), but in asthma there is reduced suppression after exposure to allergen.174 Both
GM-CSF and IFN- increase the ability of macrophages to present allergen and express
HLA-DR.175 IL-1 is important in activating T lymphocytes and is an important co-stimulator
of the expansion of Th2 cells after antigen presentation.176 Airway macrophages may be an
important source of first-wave cytokines, such as IL-1, TNF- and IL-6, which may be
released on exposure to inhaled allergens via FcRI receptors. These cytokines, may then act
on epithelial cells to release a second wave of cytokines, including GM-CSF, IL-8 and RANTES
which then leads to influx of secondary cells, such as eosinophils, which themselves may
release multiple cytokines.
Eosinophil-associated cytokines The differentiation, migration and pathobiological effects
of eosinophils may occur through the effects of GM-CSF, IL-3, IL-5 and certain chemokines
such as eotaxin.177,178 IL-5 and eotaxin also induce the mobilisation of eosinophils and
eosinophil precursors into the circulation.179 Mature eosinophils may show increase survival
in bronchial tissue.180 Eosinophils themselves may also generate other cytokines such as
IL-3, IL-5 and GM-CSF.181
Cytokines such as IL-4 may also exert an important regulatory effect on the expression
of adhesion molecules such as VCAM-1, both on endothelial cells of the bronchial circulation
and on airway epithelial cells. IL-1 and TNF- increase the expression of ICAM-1 in both
vascular endothelium and airway epithelium.182 Cytokines also play an important role in
recruiting inflammatory cells to the airways.

Pathophysiology of Bronchial Asthma 57

Fig. 3.3: Cytokines and cell interaction in bronchial asthma

Airway wall remodelling cytokines Proliferation of myofibroblasts and the hyperplasia of

airway smooth muscle may occur through the action of several growth factors such as
PDGF and TGF-. They may be released from inflammatory cells in the airways, such as
macrophages and eosinophils, but also by structural cells, such as airway epithelium,
endothelial cells and fibroblasts. These growth factors may stimulate fibrogenesis by
recruiting and activating fibroblasts or transforming myofibroblasts. Epithelial cells may
release growth factors, since collagen deposition occurs underneath the basement membrane
of the airway epithelium.183 Growth factors may also stimulate the proliferation and growth
of airway smooth muscle cells. PDGF and EGF are potent stimulants of human airway
smooth muscle proliferation184 and these effects are mediated via activation of tyrosine
kinase and protein kinase C. Cytokines, such as TNF- and FGF may also play an important
role in angiogenesis of chronic asthma.
Oxygen Radicals
Oxygen radicals have been indirectly implicated in the development of hyperresponsiveness.
They are produced by neutrophils, eosinophils, and macrophages in the lungs. The relative
importance of these substances in bronchial asthma is poorly defined.

58

Bronchial Asthma

Nitric Oxide
Although it is now well established that normal subjects have measurable concentrations of
nitric oxide (NO.) in their expired air, in patients with bronchial asthma the peak or mixed
expired NO are about 50% higher.185-187 Furthermore, compared with normal subjects, the
airways of patients with asthma have up regulated expression of type II nitric oxide synthase,
NOS.188 Taken together, these findings have led to the speculation that expired concentrations
of NO reflect the inflammatory microenvironment of the asthmatic airway wall.189
Neurotrophins
The neurotrophins are a family of peptides that promote survival, growth, and differentiation
of neurons. They may also influence the function of non-neuronal cell types, including
immune cells. The development and maintenance of asthma are thought to involve nervous
system and the immune system, but the exact role that the neurotrophins play is unclear.
The cellular sources of neurotrophins include mast cells, lymphocytes, macrophages,
epithelial cells, smooth muscle cells, and eosinophils. The action of neurotrophin receptors
like Trk (tyrosine kinase) acts possibly act in concert with known immune regulating factors
to modulate the maturation, accumulation, proliferation, and activation of immune cells.
Neurotrophins also can modulate afferent nerve function by stimulating the production of
neuropeptides within airway afferent neurons. These neuropeptides may be released from
the central terminals of airway afferent neurons, which leads to increased autonomic reflex
activity, and increased reactivity in the airways.190
The role of different mediators is summarised in Table 3.4.
Table 3.4: Role of mediators causing pathological changes in asthma
Pathological changes
Mediator implicated
Bronchospasm
Histamine (H1response)
LTC4, LTD4, LTE4
Prostaglandins and TXA2
Bradykinin
Platelet activating factor
Acetylcholin
Mucosal oedema
Histamine (H1response)
LTC4, LTD4, LTE4
Prostaglandin E
Bradykinin
Platelet activating factor
Cellular infiltration
Eosinophil chemotactic factor
(airway hyperreactivity)
Neutrophil chemotactic factor
HETEs
LTB4
Mucus secretion
Histamine (H1response)
LTC4, LTD4, LTE4
Prostaglandins generating
Factor of anaphylaxis
Prostaglandins
HETEs
Acetylcholin
Macrophage mucus secretagauge
Desquamation
O2, H2O2, OH
Proteolytic enzymes
Basement membrane thickening
O2, Proteolytic enzymes

Pathophysiology of Bronchial Asthma 59

NEUROPEPTIDES IN ASTHMA
There is increasing evidence that abnormal neurogenic mechanisms and neuropeptides
contributing in the pathophysiology of bronchial asthma.191-197 Autonomic nerves regulate
airways smooth muscle tone, mucous secretion, blood flow, vascular permeability, and
migration and release of inflammatory cells.198,199 Neuropeptides are small amino acid
components that are localised to neurons. Originally described in the gastrointestinal tract,
neuropeptides were first termed gut hormones. Upon their discovery subsequently in
brains, they were termed as gut-brain hormones. However, now it is established that
these peptides are present throughout the body and may be produced by, localised to, cells
other than cells of the nervous system. In the respiratory tract, they are located in neurons,
neuroendocrine cells, and inflammatory cells. Neuroendocrine cells are granulated epithelial
cells found throughout the conducting airways. They contain a number of peptides, including
calcitonin, katacalcin, CGRP (calcitonin gene-related peptide), and bombesin. Neuropeptides
such as VIP (vasoactive intestinal peptide) has been identified in various inflammatory
cells including eosinophils, mast cells, and mononuclear and polymorphonuclear leucocytes.
Once released these peptides act as either neurotransmitters, hormones, or mediators. They
modulate airway caliber, vascular tone, mucus secretion, and vascular permeability. They
are also capable of affecting inflammatory cell function by modulating mediator release
and chemotactic responses. Their wide spread distribution and different physiological effects
make neuropeptides excellent candidates to play important roles in asthma.
The neural control of the airways is mediated by three pathways: cholinergic (parasympathetic); adrenergic (sympathetic); and the nonadrenergic noncholinergic (NANC)
pathways.191 The cholinergic nervous system is considered excitatory in nature because it
plays an important role in maintaining bronchial smooth muscle tone and in mediating
acute bronchospastic responses. The system consists of vagal afferent fibres in and around
the airway lumen that travels to the central nervous system and then terminate in efferent
fibres. The later innervate airway smooth muscle. There are three types of pharmacologically
defined muscarinic receptors, which are important in regulating the smooth muscle tone.
The M1 receptor is located in the parasympathetic ganglia and facilitates vagal transmission.
The M3 receptors are present in large airways and in some peripheral airways and are
largely responsible for smooth muscle contraction. The M2 receptor functions as an
autoreceptor in airway tissue, acting as a feedback-inhibitory receptor to reduce neurotransmission. Acetylcholin is the cholinergic messenger. Acetylcholin normally binds to the
cholinergic receptor and causes release of cyclic 3',5'-guanosine monophosphate (cyclicGMP). This causes bronchoconstriction. Cholinergic nerves are the dominant neural
bronchoconstrictor pathways for human lungs. Triggers like sulphur dioxide, prostaglandins, histamine, and cold air stimulate afferent receptors causing reflex bronchoconstriction. Inflammatory mediators like histamine, prostaglandins, and bradykinin
stimulate irritant receptors and C-fibre endings in the airway leading to a reflex
bronchoconstriction.200 Neurotransmitters like TxA2, PGD2, and tachykinins enhance Acetylcholine release from the postganglionic nerves in the airways. It is suggested that M2
autoreceptors are dysfunctional in bronchial asthma.201
The sympathetic nervous system in the bronchial tree is inhibitory because of its prominent
airway relaxant effect. This is mediated by -receptor stimulation and by cAMP. Adrenergic

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Bronchial Asthma

fibres represent only a minor component of the total nerve fibres in human airways. Although
there is little or no direct sympathetic innervations of human airways, there are many and -adrenergic receptors that are important in regulating bronchomotor tone. Earlier it
was believed the imbalance between cGMP and cAMP production was the underlying
mechanism of bronchial asthma, (Yin-Yang hypothesis).
The neurotransmitters for the NANC nervous system were initially thought to be purine
nucleotides, such as adenosine and adenosine triphosphate and accordingly the NANC
nerves were termed purinergic. However, now it is believed that the neurotransmitters
are not purines, but peptides, and thus the nerves are peptidergic. Although a number of
neurotransmitters have been identified, only VIP, peptide histidine methionine (PHM),
and nitric oxide may be the neurotransmitters of the nonadrenergic inhibitory nervous system
and thus are important endogenous bronchodilators.202,203 They also decrease mucus secretion
and manifest anti-inflammatory actions. Deficiency of this system has been postulated to
contribute to the development of bronchial hyperreactivity. Functional deficiencies of the
system can result from blockade of nonadrenergic pathways at the level of ganglia or nerve
endings; from deficiency of airway VIP or PHM receptors, or from enhanced breakdown of
neuropeptides by peptidases released from inflammatory cells in the asthmatic airway. It
has been demonstrated recently that there is a loss of VIP from pulmonary nerve fibres in
asthmatics. Immunoreactive VIP is observed within nerves in more than 90% of lung sections
from normal subjects but is not identified in any lung sections from patients with asthma.
However, it is not clear whether it is a primary or secondary event.
Other peptides such as substance P, neurokinin A (substance K, neuromodulin L) and
calcitonin gene-related peptide (CGRP) are believed to be neurotransmitters of the
noncholinergic excitatory system and thus act as endogenous bronchoconstrictors.204-209 These
peptides also play a role in regulating mucus production, pulmonary vasomotor tone,
mucosal permeability, and inflammatory cell function. A number of substances are known
to release neuropeptides from these nerves include capsaicin (most potent), irritant gases,
antigen, and various inflammatory mediators, including histamine, bradykinin, and
prostaglandins. These neuropeptides have the remarkable ability to affect multiple cells in
the airways and to provoke many responses including cough, mucus secretion, smooth
muscle contraction, plasma extravasations, and neutrophil adhesion. This series of effects
is termed as neurogenic inflammation.210-215 An enzyme neutral endopeptidase (NEP)
exists on the surfaces of all lung cells. The enzyme inactivates the neuropeptides limiting
their concentration. Angiotensin converting enzyme (ACE) also helps in the degradation of
these neuropeptides. Thus neurogenic inflammatory responses are normally mild and
probably protective in nature. It is proposed that in asthma, a decrease in the normal
degradation process of substance P occurs by NEP or ACE. Cigarette smoke, respiratory
viral infections, and inhalation of industrial pollutant toluene diisocyanate inhibit NEP
and exaggerate neurogenic inflammation. In addition, there are reports that there are more
substance P immunoreactive nerves in the lungs of patients with asthma compared to that
in normal subjects.
Therefore, in addition to the proposed changes in the cholinergic and adrenergic nervous
systems, subjects with asthma have now been revealed to potentially have changes in their
nonadrenergic inhibitory and noncholinergic excitatory nervous system. These changes
will lead to an imbalance in the autonomic nervous system and predispose subjects with
asthma towards bronchospasm (Fig. 3.4).

Pathophysiology of Bronchial Asthma 61

Fig. 3.4: Autonomic imbalance postulated for bronchial asthma

It is suggested that abnormal control of the airway is the underlying mechanism of

bronchial hyperreactivity, with a preponderance of excitatory (cholinergic and -adrenergic)
or a deficiency of inhibitory (-adrenergic) control.
Bronchial Hyperreactivity
Airway hyperresponsiveness to a large number of stimuli is a characteristic feature of asthma
in humans. Various components of the tracheobronchial tree might contribute to this
phenomenon, such as smooth muscle, the bronchial epithelium, various neurohumoral
mechanisms and the mechanical linkage between the lung parenchyma and the airways
including the baseline airflow obstruction. The degree of responsiveness can be further
increased by a series of stimuli associated with inflammation in the periphery of the lung.
Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics,
making them more prone to overt attacks in response to minor stimuli that would be
ordinarily tolerated. Depending upon the inciting stimulus, different cells and mediators
may be playing a role in producing and perpetuating the inflammatory state and producing
further increases in responsiveness. The level of airway responsiveness usually correlates
with the clinical severity of asthma and medication requirement. The airways of asthmatic
subjects are 14-fold, 15-fold, 5-fold, 9-fold, and 194-fold more responsive than were the
airways of normal subjects to histamine, methacholine, LTC4, LTD4, and LTE4 respectively
in a direct comparison of the potencies of these substances in six asthmatics and six controls.112
Further, cumulative data suggest that hyperresponsiveness to the leukotrienes may be more
marked in the central rather than the peripheral airways of asthmatic subjects. Bisgard
reported that the airways of 8 asthmatic subjects were more responsive to LTD4 than were
those of 9 nonasthmatic controls; the relative differences in potencies between asthmatic
and controls were 100- to 1000-fold when measured in terms of FEV1 but they were only 15fold differences in V30.216 Similarly Smith et al reported a 30% fall in V30 in response to LTD4

62

Bronchial Asthma

was accompanied by a 60% fall in sGaw in asthmatic subjects but only a 30% fall in sGaw in
normal controls.217 In another study Davidson et al reported a 30% fall in V30 induced by
inhaled histamine was accompanied by a 10 and 13% fall in FEV1 in asthmatic and normal
subjects, respectively. But when the same individuals inhaled LTE4, a 30% fall in V was
accompanied by a 17% fall in FEV1 in asthmatic subjects and a 3% fall in FEV1 in normal
controls.218 While FEV1 represents the central airway function, V30 represents small or
peripheral airways function. The interaction of various factors and the pathophysiology of
bronchial asthma is summarised in Figure 3.5.
AR) and Asthma
Beta-adrenergic Receptors (
ARs belong to the family of adrenergic receptors that use the endogenous catecholamines
epinephrine and norepinephrine (and, to a lesser extent dopamine) as agonists. Nine different
adrenergic receptor subtypes have been cloned.219 There are three AR subtypes (1, 2, 3)
and they couple to the stimulatory G-protein, Gs, which results in activation of adenyl
cyclase and increases in intracellular cAMP. The 2 AR is expressed to some extent in virtually
every tissue in the body. In the lung, this is present in epithelium, smooth muscle of bronchi
and bronchioles, submucosal glands, the endothelium and smooth muscle of pulmonary
arteries, alveolar walls, immune cells including mast cells, macrophages, eosinophils,
neutrophils, and lymphocytes. There are reports that 3AR also regulates bronchial smooth
muscle tone in pharmacological in vivo studies. 2 AR has been studied extensively and
thought to have important therapeutic implications. Recent genetic polymorphisms of the
2 AR have been identified in the population, which may be the basis of a more severe form
of the disease or the basis of the heterogeneity of receptor expression and response to betaagonists observed clinically.220 Some of the important molecular domains that have been
found to be important for receptor function have also been identified. Although a number
of studies have addressed whether 2 AR are dysfunctional in asthma, there appears to be
no consensus in this matter.221 It seems that beta-receptor dysfunction may not be the primary
lesion in asthma. Perhaps this occurs as a secondary phenomenon in asthma either because
of the drugs used and thus acquired or there may be a receptor mutation or polymorphism.
Szentivanyi proposed in 1968 that asthma may be due to an inherited or acquired deficit
in -adrenoceptor function.222 Several lines of evidence suggest that the 2-adrenoceptor
may be abnormal in asthma, making the 2-adrenoceptor gene an attractive candidate
gene in this disease. Administration of 2-adrenoceptor agonists increases airway tone and
responsiveness in patients with asthma.223 Bronchial or tracheal smooth muscle obtained at
either autopsy or surgery from asthmatic patients show a deficit in -adrenoceptor
function.224-227 A large number of polymorphisms or point mutations have been described
in the human 2-adrenoceptor gene. A restriction fragment length polymorphism (RFLP)
of this gene has been reported using the restriction enzyme Ban I.228 Another biallelic
polymorphism is reported using the restriction enzyme Fnu4HI,229 while subsequent
investigations reported nine different point mutations within the coding region, four of
which result in changes in amino acid residues 16, 27, 34 and 164.230
Moreover, cells transferred with 2-adrenoceptor complimentary DNA containing the
mutations at amino acid positions 27 or 164 showed altered -adrenoceptor function. Studies
on the distribution of Ban I polymorphisms in South African asthmatics showed the presence
of both these alleles in this group, but the genotypes were found with similar frequencies in

Pathophysiology of Bronchial Asthma 63

Fig. 3.5: Interaction of various factors in the causation of asthma

allergic and nonallergic subjects. Further studies on sequencing of the 2-adrenoceptor gene
identified nine separate point mutations or polymorphisms, but there was no significant
difference in the frequency of alleles between the asthmatic and nonasthmatic patients.230
Japanese investigation on family members of asthmatics found a higher prevalence of asthma
in family members who lacked the 3.1 kb Ban I RFLP, but the findings were not sufficient to
exclude genetic linkage to either methacholine responsiveness or allergy.231 Subsequent

64

Bronchial Asthma

studies also showed that distribution of these alleles was not different between asthmatics
and nonasthmatics,232 although it was not possible to exclude an association. In a more
recent study to exclude genetic linkage between the 2-adrenoceptor gene and asthma,
allergy, and methacholine airway hyperresponsiveness, indicated that these are not linked
to a dominant 2-adrenoceptor gene with strong effect in families with an inherited pattern
of asthma.233
Nitric Oxide (NO) and Bronchial Asthma185-188
Nitric oxide is synthesised from L-arginine by the enzyme NO synthase (NOS). Two forms
of NO is known; iNOS (independent of Ca++) and cNOS (Ca++/calmodiulin-dependent,
constitutive form). While the former is induced by TNF-alpha and beta, interferon gamma,
endotoxins, interleukin-1 and other cytokines, stimulation of the later occurs through
mediators like bradykinin, histamine, PAF, acetylcholine, and leukotrienes. Thus, it is
obvious that NO has the potential to affect a number of cells critical for normal lung function
and NO possibly plays a key role in the pathogenesis of asthma and its inhibitors may be
useful therapeutically to treat asthma.221 Nitric oxide is present in the expired air of healthy
individuals.234 It is a known bronchial smooth muscle relaxant. Thus its level should be
reduced in bronchial asthma. But on the contrary, NO is higher in the expired air of
asthmatics,185,235 and epithelial NOS is higher in the epithelial cells in them.236 This implies
that NO may increase in asthma as a compensatory response to other factors, such as those
that cause bronchoconstriction or inflammation. Further, elevated NO might exacerbate
bronchial obstruction because NO relaxes vascular smooth muscle and thus, vascular
engorgement which is an important pathogenetic mechanism. In addition, elevated NO
may result in elevated NO reaction products, such as superoxides, particularly peroxynitrite,
which may cause airway damage if excess. However, it is not clear whether elevated NO is
part of the primary pathologic process in asthma or is a compensatory response.
SUMMARY OF EVENTS LEADING TO AIRWAYS INFLAMMATION
The pathogenesis of bronchial asthma is more clearly understood in extrinsic or allergic
asthma and is summarised in Figure 3.6.237 Although the terms intrinsic and extrinsic
no longer adequately reflect our knowledge of the clinical syndrome of asthma, recent
advances in the understanding of its pathophysiology indicate that it is a heterogenous
disorder with multiple triggers. There are, however, features, which are virtually common
to all asthmatics. These include airways inflammation and hyperreactivity to a broad range
of stimuli. The chronic allergic response is a continuous process of IgE generation, mast cell
activation, and eosinophil recruitment. These processes are orchestrated by T lymphocytes.
In atopic individuals, T lymphocytes receive an allergen-specific signal from highly
specialised antigen presenting cells, called dendritic cells, at mucosal surfaces. Presentation
of allergen peptides to the T cell usually occurs in local lymphoid tissue along with the
essential engagement of co-stimulatory molecules (B7 and CD28) and results in the
differentiation of the naive T cell to one that generates a range of cytokines which upregulate
cells and antibodies involved in the allergic response. CD4+ lymphocytes of the Th2-type
are activated and clonally expand after capture and processing of inhaled allergens like
cigarette smoke, house dust mites, pollen, viral infection, fungi, etc. by the dendritic cells

Pathophysiology of Bronchial Asthma 65

Fig. 3.6: Pathogenesis of bronchial asthma

which migrate to the regional lymph nodes and present allergens, together with major
histocompatibility antigen II, to lymphocytes.237,238
A number of cytokines are then released. The genes for these cytokines are encoded in a
small region on the long arm of chromosome 5 and a number of them (IL-4, IL-5, and GMCSF) are coordinately regulated. While Th2 lymphocytes produce these cytokines, Th1
lymphocytes are involved in cell-mediated immunity. A number of Th2-derived cytokines
are involved in mast cell, basophil, and eosinophil recruitment and maturation, IL-4 and
IL-3 play a particularly important role in this arm of the immune process by interacting
with B lymphocytes, they change the immunoglobulin isotope being secreted from the shortterm protective antibody IgM to the allergic antibody IgE. As with dendritic T cell
interactions, effective signalling to cells requires an interaction with the Th2 cell and

66

Bronchial Asthma

involves antigen presentation and engagement of a second set of co-stimulatory molecules

(CD40 and its ligand, CD40L). If T and B cell interact in the presence of antigen, IL-4 or IL-13,
and co-stimulatory molecules, allergen-specific IgE is generated. If IL-4 or IL-3 is present, but
cell-cell contact does not occur, only non-specific IgE is generated. Thus IgE has the important
role of linking allergen recognition to cell signalling in a variety of cells, which release a range
of active mediators. IL-4 produced by Th2 lymphocytes fuels the inflammatory reactions in
the airways and leads to production of further Th2 lymphocytes and to differentiation and
maturation of IgE producing B lymphocytes. A strong genetic component plays important
role in the form of an ability of a susceptible individual to recognise an environmental allergen
as foreign and mounts an allergic immune response through the human lymphocyte antigen
(HLA or MHC class II) molecules. The second component of the gene involves the genes
responsible for cytokine response.
Allergen specific IgE binds to IgE receptors on several inflammatory cell types such as
eosinophils, mast cells, and macrophages. High affinity IgE receptors are an important link
between the presence of specific antigen in the microenvironment and activation of mast cells
and other cells. Antigen-specific IgE binds to effector cells via specific IgE receptors; when
antigen binds an adequate number of these receptors to initiate receptor clustering, signal
transduction occurs. The molecular nature of the IgE receptor has now been clearly defined;221
it is composed of four chains: an alpha chain, a beta chain, and two gamma chains. While the
alpha chain binds IgE, it is thought that the gamma chains are the units that initiates
intracellular signal transduction; however, the specific mechanisms of transduction are not
established.
The inflammatory cells then release various inflammatory mediators outlined above, which
accentuates airways inflammation including the release of 5-lipooxygenase products and
proteases. Leukotrienes along with other products cause bronchoconstriction and other
changes characteristic of bronchial asthma. Mast cell proteases are also important players in
the inflammatory process. Neutral endopeptidase (NEP) is a major enzyme of importance in
limiting the biologic activity of small peptide mediators such as substance P or neurokinin A.
The beta-adrenergic receptor and nitric oxide represent two effector mechanisms that are
important in modifying the biology of an asthmatic response.
Although smooth muscle constriction can lead to airways obstruction, it is now understood
that nonmuscular airway obstruction is not less important. The importance of airway wall
remodelling with thickening of the airway wall due to infiltration with inflammatory cells
and alteration in the amount and type of collagen deposited in the airway is reflected in the
enhanced degree of obstruction that is observed for a given level of smooth muscle activation
in the remodelled wall. The wall is also thickened and obstructed due to the engorgement of
the bronchial blood vessels. Such engorgement could account for a significant component of
asthmatic airway narrowing under certain circumstances. The presence of intraluminal fluids
including mucosubstances further obstruct airways and could make it more difficult for
individuals to clear secretions from their airways.
The relationship between airway inflammation and the development of airway
hyperresponsiveness and clinical asthma has been well established during the last decade.
Exposure to oxidant pollutants, some chemicals, antigens, and viral respiratory tract infections
are all associated with inflammatory cell infiltration into the airway and these inflammatory
stimuli are also associated with the development of airway hyperresponsiveness. Most studies
have shown that airway inflammation precedes the development of hyperresponsiveness

Pathophysiology of Bronchial Asthma 67

and may be the prerequisite feature necessary for the development of both hyperresponsiveness
and clinical bronchospasm. The relationship between airway inflammation, bronchial
hyperreactivity and airway obstruction in asthma is shown in Figure 3.7.
Although, approximately one-half of the children with wheezing in infancy and young
childhood will no longer be wheezing at 6 years of age,239 a different type of observation has
been noted in children with wheezing in their bronchoalveolar lavage fluid. Increased numbers
of cells and increased neutrophils in BAL samples have been reported in children having
wheezing.240-244 In contrast, BAL eosinophilia is a common finding in adults with asthma.
Eosinophilia and elevated IgE levels have also been found in infants who subsequently
develop asthma. It is possible that neutrophil-induced inflammation is important in the early
stages of wheezing in infants. It is also possible that this neutrophil response may be a
response to an unrecognised infection.
While the pathogenesis of occupational asthma, intrinsic asthma and other forms of asthma
is less clearly understood, these conditions are thought to involve a cytokine cascade similar
to that involved in extrinsic or allergic asthma.237
The mechanisms of allergy in causing episodic and chronic asthma are shown in
Figure 3.8.
Aspirin Induced Asthma
Patients with bronchial asthma and sensitivity to aspirin (ASA) and other nonsteroidal antiinflammatory drugs are often corticosteroid-dependent and have the accompanying symptoms
of rhinosinusitis, rhinorrhoea, nasal congestion, anosmia, loss of taste, and recurrent severe
nasal polyposis.245 Upon challenge with aspirin or other cyclooxygenase inhibitors these
patients have increased cysteinyl leukotriene release as detected in urine,246,247 in nasal
lavage,248,249 and in bronchial lavage fluids,250 in contrast to aspirin-tolerant subjects. These

Fig. 3.7: Interaction of various factors

68

Bronchial Asthma

Fig. 3.8: Mechanisms of episodic and chronic asthma.

(TH-:T-lymphocyte; MC-; Mast cell ; Ag-; Antigen)

observations conclude that cysteinyl leukotrienes are involved in aspirin-induced asthma

(AIA). The mechanism of AIA is due to the inhibition of cyclooxygenase and bronchospasm is
because of an increased generation of spasmogenic leukotrienes via lipooxygenase pathway.
In patients with AIA, ingestion of aspirin is followed within 1 to 2 hours by the onset of
bronchospasm, which may be accompanied by rhinitis and/or urticaria. Majority of these
subjects can be desensitised by the administration of aspirin orally, which may lead to an
improvement in the severity of asthma and of rhinitis. Further, inflammatory cell population
in bronchial biopsies from aspirin-sensitive asthmatic patients demonstrates significantly
greater numbers of mast cells and eosinophils per square millimetre of tissue than do similar
biopsies from asthmatic subjects without aspirin sensitivity.251 Furthermore, the percentage of
cells that immunostained for lipooxygenase and that are identified as eosinophils and mast
cells are significantly increased in aspirin-sensitive patients.
An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is
increased target organ sensitivity to leukotrienes.112 The recent development and usefulness
of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma including
that of aspirin-induced asthma further emphasizes the role of these leukotrienes in the
pathogenesis of this condition.135-138
Leukotrienes are important in asthma, and leukotriene modifiers modulate antigen-induced
asthma. Leukotrienes participate in the pathogenesis of bronchial asthma besides the
involvement eosinophilic airway inflammation.139 Overproduction of leukotrienes not only
occurs in house dust mite provoked asthma, but also in aspirin induced bronchial asthma,
although the mechanisms of such overproduction are different. While in the former, the
overproduction occurs with an antigen-antibody reaction, in aspirin-induced asthma, the
overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade.140
Pranleukast a leukotriene inhibitor suppresses the increased values of sputum eosinophil
count and eosinophil cationic protein during house dust mite-induced asthma are suppressed
by further, this drug increases FEV1 that falls during such provocation.140 The role of
leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway

Pathophysiology of Bronchial Asthma 69

narrowing and other signs in these patients are associated with 2-10 fold higher values of
LTE4 in the urine of these patients compared to aspirin tolerant patients.142-144 Further, several
leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by
aspirin and other non-steroidal anti-inflammatory agents144,145 and improve respiratory
function by bronchodilatation.146
Virus-induced Asthma
Viral infections have been considered to play a significant role in the development and
consolidation of obstructive airway disease. This may occur by amplification of the response
to cigarette smoke, induction of steroid resistance,252 enhanced sensitisation to inhaled
allergens due to increased permeability and recruitment of dendritic cells,253 or reactivation of
latent but persistent virus due to insufficient T-helper-1-type immune response and/or
administration of corticosteroids.254 Viral respiratory infections increase symptoms of bronchial
asthma in many patients.255 Rhinovirus increases airway responsiveness and also promotes
the likelihood of a late allergic reaction to allergen.256,257 Enhanced airway responsiveness
and the late allergic reaction persist for weeks beyond the viral infection. Lymphocytes are
activated during incubation with rhinovirus and secrete cytokines, like -interferon. Although
-interferon does not have any proinflammatory activity like those of Il-4 and 5, it does affect
eosinophil function, including promotion of survival. Furthermore, -interferon can augment
basophil mediator release. Thus, lymphocyte activation by virus may provide a very different
cytokine profile and in this manner selectively enhances inflammation.71,258
Exercise-induced Asthma (EIA)
Exercise-induced asthma is a temporary increase in the airway resistance following vigorous
physical activity. Obstruction to airflow begins soon after cessation of exercise and peaks in
5-10 minutes.259 Most patients will recover completely in the next 30-60 minutes, but in few
this EAR will be followed by a LAR several hours after the initial response subsides.260,261
Two major hypotheses have been put forward to explain the mechanism whereby water
and heat loss by hyperventilation with exercise causes airway narrowing.
i. The EIA is a consequence of thermodynamic events that occur within the tracheobronchial
tree during or after hyperventilation that is associated with exercise.262 Because of this
hyperventilation during exercise, there is a fall in the airway temperature and respiratory
water loss, i.e. evaporation causes cooling.263 Mouth breathing to meet increased demand
of oxygen further aggravates this factor because air bypasses the nasal air-conditioning
mechanism. Thus, during re-warming of the airways by reactive hyperaemia of the
bronchial circulation with subsequent airway oedema of the bronchial wall during the
post-exercise period.264 Further, the event precipitates bronchoconstriction. The magnitude
of bronchospasm is directly proportional to the heat loss from the respiratory tract required
to bring the inspired air to alveolar conditions.265 Oedema due to hyperaemia of
microcirculation may be the cause of bronchial obstruction developing after exercise. It is
also possible that patients with EIA may have hyperplastic capillary bed that develop
exaggerated hyperaemia and airway oedema leading on to bronchial obstruction.262
ii. The other mechanism of EIA may be as a result of water loss from mucosal surface and
resulting increase in osmolarity of the fluid interface of the mucosal surface in the airways,

70

Bronchial Asthma
which may lead to mast cell and basophil degranulation and precipitating EIA.266,267
Exercise-induced bronchoconstriction, a feature of 70-80% of asthmatics,268 is triggered
by drying of the bronchial epithelium due to airway water loss from the tracheobronchial
tree.269-273 During exercise, the ventilation rate increases, and thus the respiratory tract
needs to condition much larger volumes of air over a much shorter time during exercise
compared with rest, and airway dehydration occurs with subsequent exercise-induced
bronchoconstriction. The findings that269 inhaling fully humidified air at body conditions
could prevent exercise-induced bronchoconstriction demonstrated the importance of water
loss from the airway. It is also been recommended swimming as the exercise least
troublesome to asthmatic patients because of the humidity of the inspired air, a phenomenon
that is supported by comparative studies of diverse sporting activities.274,275

Since mast cell-derived mediators, such as histamine and leukotrienes, may cause not only
airway smooth-muscle contraction, but also airway oedema, it is possible that both of these
hypotheses are related to the airway narrowing following exercise in asthmatics. Exerciseinduced bronchospasm is, at least in part, due to bronchial microvascular phenomena such
as vascular engorgement and plasma leakage that could thicken the mucosa and thereby
narrow airway diameters, which could in turn amplify the effects of airway smooth muscle
contraction.
Various reports give conflicting results concerning the role of inflammation in EIA.276,277
However, some believe that EIA, to a larger extent, is mediated through the release of
bronchoconstrictor substances from inflammatory cells in the airway wall. Leukotrienes seem
to play a particularly important role in this response. This conclusion is arrived from
observations made in antileukotriene drug studies in EIA.278,279 Similarly antileukotrienes are
helpful in cold air-induced bronchial asthma280 highlighting the role of cold air in causing
EIA. Further, eucapnic voluntary hyperventilation manoeuvres designed to simulate exerciseinduced bronchoconstriction in the laboratory, demonstrate that airway fluid-loss has a similar
bronchoconstrictor effect to histamine.281-284 It is also demonstrated that the release of histamine,
a potent bronchoconstrictor, and other pro-inflammatory bronchoconstrictor mediators,
including cysteinyl-leukotrienes,285 from mast cells and other airway cells under hyperosmolar
conditions.286-288 These findings underline the bronchoconstrictor potential of airway
dehydration. Presence of thermally sensitive neural receptors in the airways of patients
susceptible to EIA may be responsible for bronchoconstriction in response to cold air.267
Recently another hypothesis suggests that increased excessive production of nitric oxide
during exercise289,290 increases airway vascular permeability, that co-relates with the severity
of exercise-induced bronchoconstriction in asthmatics. Assessment of albumin flux in airway
lining fluid stimulated by hypertonic saline solution is a sensitive predictor of the severity of
this phenomenon.291
Occupational Asthma
Bronchial hyperreactivity is a characteristic feature of occupational asthma.292 Specific
inhalation challenge tests may induce any of the five types of reactions: (i) isolated early;
(ii) isolated late; (iii) biphasic; (iv) continuous; or (v) atypical asthmatic reactions.293 An early
reaction occurs within a few minutes after an inhalation challenge, reaches maximal intensity
within 30 minutes, and ends within 60-90 minutes. An isolated late asthma reaction occurs
4-6 hours after the challenge, reaches maximal intensity within 8-10 hours, and ends after

Pathophysiology of Bronchial Asthma 71

24-48 hours. A biphasic reaction is an early reaction with spontaneous recovery followed by
a late asthma reaction. In a continuous type of asthma reaction there will be no remission
between the early and late reactions. Atypical reactions usually start 2 hours after a challenge
and last for a few hours.294 Generally, IgE-dependent agents induce isolated early reactions or
biphasic reactions, and IgE-independent agents will induce isolated late, biphasic or atypical
asthma reactions.
Occupational asthma induced by IgE-dependent agents is similar to allergic asthma.295
Most high-molecular-weight compounds (5000 or more daltons) induce asthma by producing
specific IgE antibodies. These molecules such as proteins, glycoproteins and polysaccharides
are usually complete antigens. Some low-molecular-weight molecules (<5000 daltons) like
acid anhydrides and platinum salts act as haptens and induce specific IgE antibodies by
combining with a body protein. The specific reaction between antigen and IgE gives rise to a
cascade of events that is responsible for the activation of inflammatory cells. Both preformed
and newly formed inflammatory mediators are released, and they orchestrate the inflammatory
events already outlined above. However, for many low-molecular-weight molecules, such as
isocyanates, specific IgE antibodies have not been identified or are found only in a small
proportion of cases.296 Presence of these antibodies does not necessarily mean the cause of the
disease, but may be the markers of exposure .297 In addition to IgE-mediated reactions,
immunoglobulins of the IgG class, possibly IgG4, may be involved in immediate-type reaction.
T lymphocytes may be directly involved in the inflammatory process.297,298 Pathologic airway
changes are similar to those in patients with other forms asthma. Some of them include
accumulation of inflammatory cells, mostly eosinophils, oedema, hypertrophy of smooth
muscle, subepithelial fibrosis, and exudation of fluid and mucus.299-301 An increase in the
activated eosinophils and T lymphocytes has been found in the mucosa and sub-mucosa,
and mast cells increase in the epithelium.302 Animal models for pathogenic and immunologic
mechanisms of bronchial asthma have also confirmed these observations.303
Some other mechanisms that are responsible for occupational asthma are as follows; (i)
reflex vagal bronchoconstriction in response to an irritant-effect on specific receptors; (ii)
inflammatory bronchoconstriction secondary to toxic concentrations of gases (nonspecific
complement activation, neuropeptide release, perturbation of cell membrane releasing
arachidonic acid products); (iii) a direct pharmacological reactions by agents like organic
insecticides with anticholinergic activity (parasympathetic agonists) and beta-adrenergic
blocking agents; (iv) or immunologic mechanism leading to allergic tissue injury.304
Irritant induced occupational asthma (Reactive airways dysfunction syndrome, RADS) is
persistent asthma and airway hyperresponsiveness, which develops after acute inhalation of
a respiratory irritant in toxic concentrations.305 The onset of respiratory symptoms and the
presence of airway hyperresponsiveness within a few hours of exposure to an identifiable
irritant distinguish this entity from hypersensitivity induced occupational asthma. This form
of asthma is associated with the workplace, in which wheezing illness starts within 24 hours
or less of a single large exposure to an irritant. The condition is inflammatory, but does not
involve immunological recognition of the irritant, so that continued low-level exposure to the
causative agent can be tolerated without problem. Bronchial biopsy studies in these
individuals have shown bronchial epithelial cell injury with desquamation, and bronchial
wall inflammation, with infiltration of plasma cells and lymphocytes, but not eosinophils.306307
The diagnosis is made by the presence of non-specific responsiveness and a compatible
history. The prognosis varies, but most often the condition improves.

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Bronchial Asthma

Nocturnal Asthma
Diurnal variations (circadian rhythm) is normally seen in healthy normal individuals as well
as in patients with bronchial asthma. Lowest airways function during early in the morning
and best during the mid-day and evening has been shown by various investigators.308-310
Frequent occurrence of nocturnal symptoms has been shown in many reports.311-313 Patients of
bronchial asthma show a greater bronchial reactivity at 4 AM when compared to at 4 PM.314 It
is also seen that majority of asthma deaths occur most often at night.315,316
Although mechanisms involved in nocturnal asthma are not clearly understood, multiple
factors seem to be involved. In allergic individuals, allergen exposure during evening hours
initiates a cascade of events to produce a LAR. Further, exposure to house-dust mite may
precipitate an EAR, and these factors precipitate bronchoconstriction.317 Lowest levels of
serum adrenaline and cortisol, and highest levels of histamine during night hours could be
responsible for nocturnal episodes in asthmatic individuals318 The BAL fluid recovered from
patients having nocturnal asthma shows greater number of eosinophils and neutrophils at
4 AM compared to that at 4 PM. This indirectly suggests worsening of inflammation during
night319 Increased vagal tone at night or gastro-oesophageal reflux leading to increased vagal
tone may further be contributory to increased bronchial reactivity and bronchial asthma at
night. Changes of body temperature, i.e. lowering of temperature, and increased accumulation
of secretions in the respiratory tract during sleep may be additional factors.320-321
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4
Pathology
The earlier descriptions of histological changes in bronchial asthma relied on postmortem
specimens taken from people dying in status asthmaticus. Since the 1960s, epithelial
shedding and influx of eosinophils into the airway mucosa have been associated with
bronchial asthma.1,2 Large segments of the airway from the major bronchi to the periphery
are occluded with a mixture of tenacious secretion containing serum protein mixed with
mucus and cellular debris. Crystalline material consisting largely of major basic protein
derived from eosinophil granules (Charcot-Leyden crystals) may be present. There is
oedema, dense eosinophilic infiltration, and epithelial denudation in the bronchial wall.
Airway samples obtained at open lung biopsy show goblet cell hyperplasia, peribronchial
smooth muscle hypertrophy and apparent basement membrane thickening. Further evidence
of epithelial shedding in asthmatics is provided by the findings of clumps of epithelial cells
in the sputum of such patients during acute attacks. The strips of epithelial cells are called
Curschmanns spirals. Clumps of cells (Creola bodies) or isolate metaplastic cells are
common. However, no detailed pathological changes were available in milder forms of
asthma before the use of fibreoptic bronchoscope (Fig 4.1a-c)
Fibreoptic bronchoscopy has helped in sampling the bronchial mucosa as well as the
submucosa from the subcarinal levels in asthmatics at various stages of their disease. In
1985, fresh biopsies were taken from eight asthmatics, with two of them having mild asthma,
three having moderate and three with severe asthma.3 All of them showed virtual destruction
and shedding of epithelium at the three airway levels studied. This was in contrast to
perfectly intact epithelium found in a control subject. The most important observation was
that epithelial changes and influx of inflammatory cells also existed in the two untreated
patients who had mild disease both clinically and functionally. The existence of severe
inflammatory changes is well known from necropsy studies on patients died of bronchial
asthma. However, significant inflammation is also present in early asthma in patients with
only a short duration of symptoms, or with mild disease.4-6 These bronchial mucosal biopsy
findings resulted in surprising results. Biopsies taken from mild asthmatics requiring only
occasional bronchodilators, showed them to be always abnormal compared to that from
nonatopic normal individuals. Such changes included the presence of mast cells at various
stages of degranulation, and a wide spread infiltration of eosinophils. Most of the eosinophils
revealed the ultrastructural features of activation and degranulation. Eosinophils,
neutrophils, and mononuclear cells were present in increased numbers in the postcapillary
venules, and were frequently in close contact with the vascular endothelium.
Another important observation was the presence of apparent thickening of the subepithelial basement membrane.7-9 Although the basement membrane is of normal thickness,

Pathology 87

Fig. 4.1a: Normal airway

Fig. 4.1b: Airway during an attack of bronchial asthma

Fig. 4.1c: Schematic representation of the airway in

patients with bronchial asthma

88

Bronchial Asthma

the subepithelial band consists of dense cross-linked collagen fibrils. Monoclonal antibody
studies suggest that the sub-basement membrane band consists of types III and V collagen,
together with fibronectin but not laminin. This suggests the fibroblastic origin of the band.
Recent data further revealed an expanded network of subepithelial myofibroblasts with both
contractile and collagen secreting properties. The number of myofibroblasts correlates with
the degree of subepithelial thickening, suggesting a repair response secondary to chronic
inflammation. Extensive collagen deposition within the bronchial mucosa might influence
the mechanical properties of the airways and contribute towards bronchial
hyperresponsiveness and irreversible airflow obstruction. The thickness of the reticular
basement is increased even in mild asthma and is correlated with airway obstruction and
hyperresponsiveness. It is therefore, suggested that anti-inflammatory treatment with inhaled
steroids should be started in the early stage of bronchial asthma to prevent structural changes
from occurring in the airway wall.10
Similar changes have been described in the asthmatic airway in childhood. Bronchial
biopsy specimens from children show thickening and hyalinization of the basement membrane.
The ciliated epithelial cells showed loss of cilia in some cases. Overactive fibroblasts are
constant findings. There is submucosal infiltration with degranulating mast cells and
lymphocytes. Eosinophils are present in some cases.11
AIRWAY REMODELLING
Chronic inflammation in the airways leads to structural changes, including hypertrophy and
hyperplasia of airway smooth muscle and thickening of the reticular layer of basement
membrane. This later thickening is due to the deposition of collagen from activated
myofibroblasts in response to cytokines and growth factors released during the inflammatory
response.12 There is extensive deposition of collagen beneath the true basement membrane.
Using immunostaining this collagen is identified as predominantly types III and V, but not
type IV (basement membrane)13 collagen. Thus, the increased subepithelial collagen in asthma
does not represent a thickening of the true basement membrane but rather collagen laid down
by fibroblasts with the lamina propria. Although the factor(s) controlling the proliferation
and collagen-secreting activities of the myofibroblasts is not known, these structural changes
may underlie the progressive and irreversible airflow obstruction that is seen in patients with
poorly controlled asthma over a period of time.
The remodelling of airways in bronchial asthma involves structural changes in the
epithelium, the myofibroblasts, and extracellular matrix including the basement membrane,
and smooth muscle. This remodelling process is mainly caused by a complex interaction of
inflammatory cells that are central to the pathogenesis of asthma with structural tissue cells.
The inflammatory cells such as eosinophils, T cells, mast cells and macrophages together
with structural tissue cells, play important effector role through the release of a number of
cytokines, mediators, and chemokines.
Remodelling of the airways in asthma involves structural changes in the epithelium, the
myofibroblasts and extracellular matrix including basement membrane, and smooth muscle.
This remodelling process is mainly orchestrated by a complex interaction of inflammatory
cells that are central in the pathogenesis of asthma with structural tissue cells. Epithelial
injury plays an important role in asthma airway remodelling.14 An intrinsically aberrant
epithelium when injured by toxic mediators, cause the epithelium to be in a chronic state of

Pathology 89
increased injury and repair. Pro-fibrotic stimuli cause subsequent subepithelial basement
membrane and submucosal alterations of collagen, elastin, and smooth muscle fibres. This
interaction is called the epithelial mesenchymal trophic unit. Patients of asthma have increased
goblet cell hyperplasia, and increased stored mucin in the airway epithelium.
Airway inflammation and remodelling contribute significantly to the decline in lung
function in bronchial asthma. Generally, lung function increases during childhood, levels
off around 25-35 years of age, and declines after the age of 35 years. However, in asthmatic
children the observation is different. A girl developing asthma at age of 7 years would have
5% reduction in FEV1 by age of 10 years and a 7% deficit by age of 15 years compared with
children without asthma.15,16 Similar observations are made for adult asthmatics that may
also have increased decline in lung function during their life.17 This enhanced decline in
lung function is present in both sexes and is further enhanced by smoking. On this logic a
175 cm tall, nonsmoker, nonasthmatic man had an average FEV1 of 3.05 L, compared with
the FEV1 of 1.99 L for a man of the same age and height who smoked and had asthma.
Further, there may be a subset of nonsmoking asthmatics those have an excess overall decline
in lung function. This may lead to severe, potentially life-threatening, irreversible airway
obstruction without the presence of emphysema.18
Further, ongoing inflammation results in more severe airway hyperreactivity, and lower
lung function as well as accelerated loss of FEV1.
Airway Pathology during Asthma Remission
Spirometric abnormalities and bronchial hyperresponsiveness to methacholine or cold air
challenge during clinical remission of asthma are often observed.19,20 It is unclear whether
these functional abnormalities reflect persistent activity of the airways inflammatory process
or merely indicates structural changes of the airways as a consequence of childhood asthma.
These structural changes (airway remodelling) are probably early events in the course of
the disease that appear to progress. The process of remodelling leads to thickening of the
airway wall.21-24 The exact physiologic consequences of airway wall thickening are not
completely understood.25 If airway wall thickening is present in subjects in clinical remission
of asthma, it could at least partly account for the functional abnormalities including bronchial
hyperreactivity observed during remission. On the other hand, ongoing active airway
inflammation will have substantial impact on the risk of relapse later in life. Therefore,
subjects with subclinical airway inflammation could benefit from anti-inflammatory
treatment.26-28 Elevated exhaled nitric oxide (eNO) levels and bronchial hyperreactivity during
clinical remission have been demonstrated recently implying ongoing inflammation.29 Recent
studies have shown that eosinophils, T cells, mast cells, and IL-5 are significantly elevated in
the airway mucosa of subjects with bronchial asthma in remission compared with control
subjects.13 Also blood eosinophil cell counts were higher in subjects with clinical remission.
Blood eosinophil cell counts, exhaled nitric oxide (eNO) levels, and bronchial response to
adenosine-5-monophosphate correlated significantly with the quantity of tissue eosinophils.
Significant airway remodelling was found in subjects in clinical remission. Matrix
metalloproteinase-9 concentrations are increased in severe, persistent asthma and following
airway challenge.30 These results indicate ongoing airway inflammation and airway
remodelling in adolescents in clinical remission of atopic asthma. Subclinical airway
inflammation may well determine the risk of an asthma relapse later in life.

90

Bronchial Asthma
REFERENCES

1. Glynn AA, Michaels L. Bronchial biopsy in chronic bronchitis and asthma. Thorax 1960;15:14253.
2. Dunhill MS, Massarella GR, Anderson JA. A comparison of the quantitative anatomy of the
bronchi in normal subjects, status asthmaticus, in chronic bronchitis and emphysema. Thorax
1969;24:176-79.
3. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and
bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985;131:599-606.
4. Laitinen LA, Laitinen A, Heino M, Haahtela T. Eosinophilic airway inflammation during
exacerbation of asthma and its treatment with inhaled corticosteroid. Am Rev Respir Dis
1992;42:423-27.
5. Laitinen LA, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly
diagnosed asthma. Am Rev Respir Dis 1993;147:697-704.
6. Jeffrey PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural quantitative study and correlation with hyperreactivity. Am Rev Respir Dis
1989;140:1745-53.
7. Brewster CE, Howarth PH, Djukanovic R et al. Myofibroblast and subepithelial fibrosis in
bronchial asthma. Am J Respir Cell Mol Biol 1990;3:507.
8. Reid LM. Workshop on pathology; summary of workshop manuscripts and discussion with
recommendation from the panel. J Allergy Clin Immunol 1987;80(Suppl):403.
9. Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology 1978:2:407.
10. Shiba K, Kasahara K, Nakajima H, Adachi M. Structural changes of the airway wall impair
respiratory function, even in mild asthma. Chest 2002;122:1622-26.
11. Cokugras H, Akcakaya N, Seckin I, Camcroglu Y, Sarmurat M, Aksoy F. Ultrastructural
examination of bronchial biopsy specimens from children with moderate asthma. Thorax
2001;56:25-29.
12. Djuknovie R, Roche WR, Wilson JW et al. Mucosal inflammation in asthma. Am Rev Respir Dis
1990;142:437-52.
13. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics.
Lancet 1989;i:520-23.
14. Holgate ST, Davies DE, Lackie PM et al. Epithelial mesenchymal interactions in the pathogenesis
of bronchial asthma. J Allergy Clin Immunol 2000;105: 193-204.
15. Weiss ST, Tosteson TD, Segal MR et al. Effect of asthma on pulmonary function in children. A
longitudinal population based study. Am Rev Respir Dis 1992;145:58-64.
16. Roorda RJ, Germitsen J, van Aalderen WM et al. Follow up of asthma from childhood to
adulthood: Influence of potential childhood risk factors on the outcome of pulmonary function
and bronchial responsiveness in adulthood. J Allergy Clin Immunol 1994;93:575-84.
17. Lange P, Parmer J, Vestbo J et al. A 15-year follow up study of ventilatory function in adults
with asthma. New Engl J Med 1998;339:1194-1200.
18. Nick HT, Hacken T, Postma Ds, Timens W. Airway remodelling and long-term decline in lung
function in asthma. Curr Opin Pulm Med 2003;9;9-14.
19. Kerrebijn KF, Fioole AC, van Bentveld RD. Lung function in asthmatic children after year or
more without symptom or treatment. Br Med J 1978;I:886-88.
20. Gruber W, Eber E, Steinbrugger B, Modl M, Weinhandle E, Zach MS. Atopy, lung function,
and bronchial responsiveness in symptom-free pediatric asthma patients. Eur Respir J
1997;10:1041-45.
21. Sears MR. Consequences of long-term inflammation. The natural history of asthma. Clin Chest
Med 2000;21:315-29.

Pathology 91
22. Gillis HL, Lutchen KR,. Airway remodelling in asthma amplifies heterogeneities in smooth
muscle shortening causing hyperresponsiveness. J Appl Physiol 1999;86:2001-12.
23. Djukanovic R. Asthma: a disease of inflammation and repair. J Allergy Clin Immunology
2000;105:522-26.
24. Vignola AM, Chanez P, Bonsignore G, Godard P, Bousquet J. Structural consequences of airway
inflammation in asthma. J Allergy Clin Immunol 2000;105:514-17.
25. Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodelling in asthma. Curr Opin
Pulm Med 2000;6:15-20.
26. Hodshino M, Takahashi M, Takai Y, Sim J. Inhaled corticosteroids decrease subepithelial collagen
deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor
of metalloproteinase-1 expression in asthma. J Allergy ClinImmunol 1999;104:356-63.
27. Laitinen A, Altraza A, Kampe M, linden M, Virtanen I, Laitinen LA. Tenascin in airway basement
membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med
1997;156:951-58.
28. Van den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC, de Jongste JC. Adolescents in clinical
remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162;953-57.
29. Van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway
inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med
2001;164:2107-13.
30. Mattos W, Lam S, Russell R et al. Matrix metalloproteinase-9 expression in asthma. Effect of
asthma severity, allergen challenge, and inhaled corticosteroids. Chest 2002;122:1543-52.

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Bronchial Asthma

5
Clinical Presentation of
Bronchial Asthma
The clinical presentations of bronchial asthma are heterogeneous, falling into every age
group from infancy to old age, and the spectrum of signs and symptoms varies in degree of
severity from patient to patient, as well as within each patient, over time. Detailed clinical
history taking is very important in the clinical diagnosis of bronchial asthma. The usual
symptoms include cough, wheezing, shortness of breath, chest tightness, and modest degree
of sputum production. The sputum is usually white or clear, and the patient may sometimes
notice more solid or greenish streaks in it. Dry cough may be the only manifestation of
asthma in some (cough variant asthma). It is estimated that about 10% of the population,
i.e. double the number having overt asthma symptoms experience asthma-like symptoms.1
Conditions known to be associated with bronchial asthma include rhinitis, sinusitis, nasal
polyposis, or atopic dermatitis. Between 60-78% of patients, who have asthma have
coexisting allergic rhinitis.2 Further, allergic rhinitis has been recognised as a risk factor for
asthma and between 20-38% of patients who have allergic rhinitis have coexisting asthma.
Most patients will complain of the onset of an attack of bronchial asthma following allergic
pharyngitis, in the form of sore throat, pain in the throat, itching, sneezing, running nose or
a blocked nose. Viral infection of the upper airways is another important preceding event
in many patients.3 The pattern of symptoms may be perennial, seasonal, or perennial with
seasonal exacerbations. The symptomatology is generally episodic, although may be
continuous or continuous with acute exacerbations. There is usually a circadian variation
with more nocturnal symptoms.4 These nocturnal attacks wake the patient in early hours of
morning and the patient feel the need to get out of bed and want to open the window for
air. Exacerbation of symptoms, may occur after several minutes of usually unaccustomed
exertion, increase in severity over a minute or two and wane over about half an hour. The
precipitating event (discussed above under etiology) may or may not be evident from history.
The incidence of IgE mediated allergy (allergic rhinitis, atopic dermatitis, hay fever)
and bronchial asthma in close relatives is very high. The detailed medical history of the
patient including other allergic disorders and in children history of early life injury to airways
(bronchopulmonary dysplasia, history of pulmonary infiltrates, documented pneumonia,
viral bronchiolitis, recurrent croup, symptoms of gastro-oesophageal reflux and passive
exposure to smoking) may be rewarding.5 Many other risk factors discussed above like
domestic dust mite, pollens, mould, furred animals, airborne irritants, tobacco smoke, are
also capable of aggravating asthma and are known as asthma triggers as they can provoke

Clinical Presentation of Bronchial Asthma 93

asthma attacks. Other triggers include smoke from domestic cooking fuels, physical activity
(running and other exercises), extreme emotional expressions (laughing or crying hard),
cold air or weather changes, food additives, cold drinks, and drugs like aspirin. People with
asthma may have one or more triggers, and different individuals have different triggers.
Physical examination of chronic asthma (for acute attacks see later) should focus on the
upper respiratory tract, the skin and the chest. The findings may reveal the presence of
rhinitis and/or sinusitis in the form of purulent nasal discharge, pale nasal mucosa, postnasal
drip, and nasal polyps. Flexural eczema may indicate the presence of atopic dermatitis. In
children, there will be evidence of hyperinflation of the lungs with use of accessory muscles
and appearance of hunched shoulders and pigeon chest. The intensity of the breath sounds
in symptomatic asthma will be reduced and the expiratory phase is prolonged. Presence of
rhonchi is a characteristic finding in asthma and will be present in most patients. However,
neither its presence nor its absence will confirm or exclude bronchial asthma. Rhonchi may
be heard in many other conditions including chronic bronchitis, pulmonary oedema,
bronchial stenosis, foreign body aspiration, upper airway obstruction, aspiration pneumonia
and pulmonary embolism, etc. It is often said that all that wheezes is not asthma.
Moreover, wheezing is not a reliable sign of severity. Crepitations are not the findings of
asthma unless there is secondary infection or a complication like allergic bronchopulmonary
mycosis.
CLASSIFICATION
Intrinsic and Extrinsic Asthma
Some investigators try to classify bronchial asthma into the intrinsic and extrinsic types.
The intrinsic asthma usually has late onset with no history of atopy or allergy and is nonseasonal. The skin test for allergens is usually negative and the serum IgE level is often
normal. The symptoms are generally severe, they do not respond well to conventional
therapy and a greater likelihood that the patient will need maintenance oral steroids, to
which the response is dramatic. A great majority of these patients have auto-antibodies to
smooth muscle and among women, thyroid and gastric antibodies and antinuclear factor.
Asthma associated with polyarteritis nodosa and aspirin-sensitive bronchial asthma are
usually of intrinsic type. However, many do not agree with this classification in view of the
recent understanding of the underlying pathogenesis of asthma. Moreover, history of allergy
or the responsible allergen is not easy to find out always.
Late Onset Asthma
Late onset asthma is a much used but poorly defined term. The difficulty arises because of
the lack of appreciation of the difference between truly late onset asthma and asthma that is
recognised late.6,7 This is important because the missed asthmatic patient with long-standing
under treated asthma is more likely to develop irreversible airflow obstruction. Although
there is no agreeable definition of this entity, a reasonable definition would be asthma
with onset of symptoms in adult life in a patient with no pre-existing, persistent respiratory
symptoms. True onset of asthma is perhaps more common than it was appreciated and
may affect one in 50 of the adult population, assuming a 5% prevalence of asthma overall.
Asthma perhaps occurs more frequently in the elderly than is usually appreciated and

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Bronchial Asthma

may, therefore, be under diagnosed and under treated.8 Although several studies report
the characteristics of older patients with asthma, few have described patients with onset of
asthma after the age of 65 years. Available studies are limited by small number of patients.9,10
In a recent population based study, the incidence of asthma was found to be more common
in the elderly.11 The age-and sex-adjusted incidence was 95/100,000 at or after the age of
65 years.
Late onset asthma has sometimes been equated with intrinsic asthma, but in some patients
there will be other important causes that must be recognised. Asthma induced by drugs,
and occupational asthma may belong to this category. Asthma of adult onset may be the
first sign of the development of polyarteritis nodosa. Women, who develop adult onset
asthma more often than men, often give a history of asthma beginning at the menopause.
Many patients report that their symptoms started after a respiratory tract infection.
Occupational Asthma
Occupational asthma is the most common occupational lung disease in developed world
and accounts for 26-52% of all occupational lung diseases in UK, and Canada.12 About 15%
of bronchial asthma are due to occupational exposure as reported from USA.13 About 250
agents have been identified that can cause occupational asthma and some of them are
indicated in earlier in the section under aetiology. Isocyanates that are widely used in many
industries are responsible for the most common form of the disease and the prevalence of
isocyanate-induced asthma in exposed workers is close to 10%.14
There can be two categories of asthma related to the workplace. They are: occupational
asthma and work-aggravated asthma. Occupational asthma is characterised by variable
airflow limitation, bronchial hyperresponsiveness, or both, due to conditions in particular
work environment, not to stimuli outside the workplace.15 On the other hand, workaggravated asthma is preexisting or concurrent asthma that is aggravated by irritants or
physical stimuli in the workplace. Occupational asthma may develop in a person with
preexisting asthma or concurrent asthma after workplace exposure. There is usually a latent
period between the first exposure to the offending agent and the onset of asthma. This
period may vary from a few weeks to over 20 years. Occupational asthma with latency
includes all instances of immunologic asthma, although the immunologic mechanism has
not been identified for all agents. The other type of occupational asthma is without a latent
period and the worker develops symptoms immediately upon working with the same
substance. This is usually due to exposure to high concentrations of irritant gases, fumes,
or chemicals on one or several occasions-reactive airway dysfunction syndrome.16
Exposure is the most important determinant whether occupational asthma develops.
Higher the degree of exposure to an agent, higher is the prevalence of occupational asthma.
History of atopy and smoking are important determinants to induce occupational asthma
that occurs through an IgE-dependent mechanism. The duration of exposure is not important.
About 40% of patients with occupational asthma have symptoms within 2 years of exposure
and in 20%, symptoms develop after 10 years of exposure.17 HLA class II alleles are involved
in some cases of isocyanate-induced asthma. The patient usually complains of chest
symptoms after working hours, in the evenings and at nights, but not during working
hours at the onset of the illness. Improvement in symptoms occurs at weekends or during
longer periods away from work and worsening on return to work suggests but does not

Clinical Presentation of Bronchial Asthma 95

confirm occupational asthma. Runny and itchy eyes and nose and sneezing often accompany
respiratory symptoms. Peak flow monitoring is important to recognize this problem.
Diagnosis of occupational asthma includes:
a. Diagnosis of asthma and
b. Establishment of a relation between asthma and work.
The diagnosis of asthma is based on compatible history and the presence of variable
airflow obstruction or, in the absence of airflow limitation, the presence of pharmacologically
induced bronchial hyperresponsiveness. The number of criteria required to establish the
relation to work depends on the purpose for which the diagnosis is made. They are more
stringent if the diagnosis is required for medical purposes, and the relation to work should
be objectively demonstrated. But for screening examinations in the workplace or for field
epidemiological surveys, less stringent diagnostic requirements can increase the sensitivity
of case detection. An occupational cause should be sought for all new onset asthma in
adults. The disease should be suspected in a person exposed at work to agents known to
cause occupational asthma. History of both past and current exposures is required to be
obtained since previous exposure to such agents may have induced permanent asthma.
Such list of agents is available.18 However, the inability to identify an agent should not rule
out the diagnosis of occupational asthma. Detailed assessment of workplace exposure may
help determine the specific type of occupational asthma. The history should include specific
job duties and work processes for both the patient and the coworkers. A visit of the site by
the physician may help to understand the work situation better.
The diagnosis should always be confirmed by objective measurements. Various methods
used to diagnose occupational asthma include questionnaire, immunological testing,
bronchial responsiveness to methacholin or histamine, measurement of FEV1 before and
after work, peak expiratory flow monitoring, specific inhalation challenges in a hospital
laboratory, and serial FEV1 measurements at work under supervision. There are many
advantages and disadvantages of all these tests. While questionnaire is simple and sensitive,
it has a low specificity. Although immunological tests are simple and sensitive, they can
only be used for high-molecular weight and some low-molecular weight agents. The test
only identifies sensitisation, but not disease. Further, most of the allergens are not available
commercially.
Nocturnal Asthma
Nocturnal asthma symptoms are frequent and about 39% of asthmatics awaken nightly,
and 94% have nocturnal awakenings at least once a month. A number of mechanisms have
been hypothesised to explain the phenomenon of nocturnal asthma including exposure to
dust mite allergen, late-phase allergic reactions, effects of posture and sleep stages on airway
tone, gastro-oesophageal reflux, impaired mucociliary clearance, airway cooling, and
changes in circadian rhythms of circulating hormones (adrenaline and steroids). While no
single mechanism can explain these changes, circadian rhythms may be particularly relevant.
Normal airway tone increases during sleep and is magnified in asthmatics. Normally there
is a rhythm city in the lung function parameters with maximum readings between 3-4 PM
and the lowest being at 3-4 AM. This is exaggerated in asthmatics. Bronchial responsiveness
to histamine and allergen challenge increases during sleep and mast cell mediator release

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Bronchial Asthma

is enhanced. Circulating eosinophils increase, which may allow their ingress into pulmonary
tissue. Together with a decreased plasma catecholamine and cortisol levels all these factors
may influence airway tone, inflammation, and responsiveness during sleep and produce
the observed clinical picture.
The characteristic symptomatology is described above.
PATTERNS OF AIRFLOW OBSTRUCTION IN CHRONIC ASTHMA
Chronic asthma may be classified according to patterns of variations in their airflow
obstruction.18
1. Brittle asthma
2. The morning dipper
3. The irreversible asthma
a. A group never achieving a normal peak flow, but showing a reversible component,
either spontaneously or after specific drug therapy.
b. A subgroup having a reversible FVC, but irreversible FEV1 and PEFR.
c. The drifter, having irreversible airflow obstruction gradually improving over
weeks of intensive therapy.
Brittle Asthma
This is a form of intractable and persistent asthma resistant to all conventional therapy.
There will be no wheeze at one moment, but gross wheezing may be present over a short
period of time. Most often they are misunderstood to have deliberate or emotional asthma.
Serial measurements of PEFR show a chaotic pattern, with normal to grossly abnormal
patterns of airflow obstruction. They occur randomly throughout 24 hours. Low readings
may reverse to normal with small doses of bronchodilators, but stabilisation is difficult.
The salient feature of this asthma is their response to sympathomimetic drugs but without
stabilisation. The patient may be atopic or non-atopic. Cromoglycate and steroid therapy
will not be able to stabilize. These patients usually need frequent bronchodilators. However,
not all patients are resistant to conventional therapy.
Morning Dippers
These are the patients who have worsening of their symptoms during early hours of the
night and is discussed above. The rhythm city is maintained during the day and reduction
occurs early in the morning. During day times, the patient may be completely normal and
stable, so that no abnormality may be detected during the visit to the doctor. In children,
the attack is usually worse around 2 AM and in adults it is variable increasing slowly and
rapidly from midnight. Waking does not change the attack. It is observed in sleep workers
that the attack is worse towards the end of sleeping hours.
REFERENCES
1. National Asthma Programme in Finland 1994-2004. Ministry of Health and Social Welfare,
Helsinki, 1994; quoted in Haahtela T. The importance of inflammation in early asthma. Respiratory
Med 1995;89:461-62.
2. Braman SS, Barrows AA, deCotiis BA et al. Airway hyperresponsiveness in allergic rhinitis: A
risk factor for asthma. Chest 1987;91:671-74.

Clinical Presentation of Bronchial Asthma 97

3. Steinium-Aarniale B. The role of infection in asthma. Chest 1987;91:157S.
4. Clark TJV. Diurnal rhythm of asthma. Chest 1987;91:137S.
5. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway
disease in children. Paediatrics 1984;73:526.
6. Ayres JG. Late onset asthma. Br Med J 1990;300:1602.
7. Lee HY, Stretton TB. Asthma in the elderly. Br Med J 1972;4:93-95.
8. Banerjee DK, Lee GS, Malik SK, et al. Under diagnosis of asthma in the elderly. Br J Dis Chest
1987;81:23-29.
9. Burr ML, Charles TJ, Roy K et al. Asthma in the elderly: an epidemiological survey. BMJ
1979;1:1041-44.
10. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly: a comparison between patients
with recently acquired and long-standing disease. Am Rev Respir Dis 1991;143:336-40.
11. Bauer BA, Reed CE, Yunginger JW, Wollan PC, Silverstein MD. Incidence and outcomes of
asthma in the elderly. A population based study in Rochester, Minnesota. Chest 1997;111:
303-10.
12. Chan-Yeung M, Malo JL. Occupational asthma. New Engl J Med 1995;333:107-12.
13. Blane P. Occupational asthma in national disability survey. Chest 1987;92:613-17.
14. Chan-Yeung M, Malo JL. Epidemiology of occupational asthma. In: Busse WW, Holgate ST
(Eds). Asthma and rhinitis. Boston; Blackwell Scientific Publications. 1995;44-57.
15. Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI. Definition and classification of asthma. In:
Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI (Eds). Asthma in the workplace. New York:
Marcel Dekker, 1993;1-4.
16. Brooks SM, Weiss MA, Bernstein IL. Reactive airway dysfunction syndrome (RADS): persistent
asthma syndrome after high level irritant exposures. Chest 1985;88:376-84.
17. Malo JL, Ghezzo H, DAquino C, LArcheveque J, Cartier A, Chan-Yeung M. Natural history of
occupational asthma; relevance of type of agent and other factors in the rate of development of
symptoms in affected subjects. J Allergy Clin Immunol 1992;90:937-44.
18. Turner Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis
Chest 1977;71:73-86.

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Bronchial Asthma

6
Diagnosis of
Bronchial Asthma
The diagnosis of asthma is a clinical one; there is no confirmatory diagnostic blood test,
radiographic or histopathological investigation. In some people, the diagnosis can be
corroborated by suggestive changes in lung function tests. The clinical diagnosis of asthma
is not always simple and the absence of an agreed definition of the disease is a problem,
with many descriptions existing. However, while making a diagnosis of bronchial asthma
The International Consensus Report definition of asthma should be kept in mind which
states that it is a chronic inflammatory disorder of the airways..in susceptible individuals,
inflammatory symptoms are usually associated with widespread but variable airflow
obstruction and an increase in airway response to a variety of stimuli. Obstruction is often
reversible, either spontaneously or with treatment.
Some of the symptoms of asthma are shared with diseases of other systems. Even when
the symptom of breathlessness is thought to be due to lung disease, there are numerous
relatively common lung diseases and differentiation of an airway disorder needs to be
made from both infections, and pulmonary thromboembolic disease and restrictive lung
disorders. Features of an airway disorder such as cough, wheeze and breathlessness should
be corroborated where possible by measurement of airflow limitation. They may be due
either to a localised airway obstruction (e.g. tumour, foreign body, vocal cord dysfunction
or post-tracheostomy stenosis), or to a generalised problem (such as asthma, chronic
obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis or obliterative
bronchiolitis).
Symptoms of Asthma
To avoid misdiagnosis it is essential to remember that people with asthma may suffer from
a variety of symptoms, none of which is specific for asthma:
Wheeze
Shortness of breath
Chest tightness
Cough
The hallmark of asthma is that these symptoms tend to be:
Variable
Intermittent
Worse at night
Provoked by triggers including exercise

Diagnosis of Bronchial Asthma 99

When cough is the predominant symptom without wheeze, this is often refered to as
cough variant asthma.
Signs of Asthma
During exacerbations, the patient will often have wheeze and reduced lung function, either
reduced peak flow or an obstructive pattern on spirometry. The presence of wheeze (usually
diffuse, polyphonic, bilateral and particularly expiratory) is a cardinal sign of asthma and,
if present, should be documented in clinical notes. Outside acute episodes, there may be no
objective signs of asthma. Patients who present with chronic asthma may have signs of
hyperinflation with or without wheeze.
Additional information which may contribute towards a clinical suspicion of asthma
includes: personal or family history of asthma or other atopic condition (eczema, allergic
rhinitis); worsening of symptoms after exposure to recognised triggers such as pollens,
dust, feathered or furry animals, exercise, viral infections, chemicals, and environmental
tobacco smoke; and worsening of symptoms after taking aspirin/non-steroidal antiinflammatory medication or use of blockers. A good medical history is enough in most of
the time to diagnose bronchial asthma. Particular attention should be paid to the precipitating
and/or aggravating factors. Pattern of symptoms may be perennial, seasonal, or perennial
with seasonal exacerbations. The symptoms may also be continuous, episodic, or continuous
with acute exacerbations. The onset, duration, and frequency of symptoms like number of
days per week or month are also important to note. Day-night (circadian) variation with
special reference to nocturnal symptoms should be asked for in each case. This should also
include the age of onset and age of diagnosis, progress of the disease, previous and present
evaluation of the disease, treatment, and response to such therapy, living situation with
home age, location, cooling, and heating (central with gas, oil, electric, or kerosene), wood
burning fire place, type of domestic cooking fuel used, carpeting, and humidifier. Special
attention should be paid in enquiring about the patients living room with particular
reference to pillow, bed, floor covering, and dust collectors. Information regarding animals
in home and exposure to cigarette smoke, direct or side stream, is important. The impact of
disease on the patient including number of emergency department visits, hospitalisation,
history of life-threatening acute exacerbations, ventilatory support, requirement of oral
steroid therapy, number of school or work days missed, limitation of activity especially
sports, nocturnal awakening and the effect on growth, development, behaviour, school or
work achievements and lifestyles need to be assessed. Similarly, the impact on family including
disruption of family life, effect on spouse and children, and economic impact needs assessment.
Patient, parental, and spouse knowledge of asthma and belief in the chronicity of asthma and
in the efficacy of treatment, ability of the patient and the family to cope with disease, level of
family support and economic resources are helpful in planning out a management programme
for the patient which is to be evaluated at the time of diagnosis. Any precipitating and/or
aggravating factors like viral respiratory tract infections,1 exposure to environmental allergens,
exposure to occupational chemicals or allergens, impact of environmental changes like moving
into a new home, going on a vacation, and/or alterations in workplace, work process, or
material used, exposure to irritants like tobacco smoke, strong odour, air pollutants like ozone,
oxides of sulphur, occupational chemicals, vapors, gases and aerosols, emotional expressions
like anger, laughter, frustrations, crying, fear, drugs like aspirin, beta blockers, nonsteroidal

100 Bronchial Asthma

anti-inflammatory drugs, food additives like sulphites, change in weather, particularly
exposure to cold air, exercise, endocrinal factors like menstruation, pregnancy, thyroid disease,
etc. are very important to evaluate since they will be very helpful in identifying the possible
agent/factor(s) that care responsible in causing the disease.
Family history of allergic diseases, asthma in close relatives is important pointers. In the
personal and past history, any previous allergic disease like chronic rhinitis, repeated throat
infections, sneezing, dermatitis, gastrointestinal disturbances, adverse reaction to foods, history
of pulmonary infiltrates, and history of smoking or passive smoking are important points to
note.
Diagnosis of allergy in an asthma patient requires a thorough history taking. For example,
if the asthma worsens in certain months and other symptoms of allergy like allergic rhinitis,
sneezing, itching, running nose and nasal obstruction occur at the same time, pollens and
outdoor moulds are the responsible allergens. If symptoms appear when visiting a house
where there are indoor pets or if the symptoms improve when the patient is away from home
for a week or longer, animal dander is the offending agent. Further evidence of animal dander
comes from the fact that eyes may itch and become red after handling the pet. If the pet licks the
patient, a red, itchy welt develops. If symptoms are more where a carpet is being vacuumed
and bed making makes asthma worse, most likely mites are the responsible antigens. Mould
allergy is usual if symptoms develop around hay and on being exposed into a damp
environment. If symptoms are related to certain job activities, either at work and they improve
when away from work for a few days will indicate occupational asthma.
Physical findings of bronchial asthma are already discussed above. Although recurrent
episodes of cough and wheezing with breathlessness are almost always due to bronchial
asthma in both children and adults, there are other causes of airways obstruction leading to
wheezing. The diagnosis may be little more difficult in children and infants rather in adults.
Laboratory Studies
Spirometry should be undertaken to document severity of airflow obstruction and to establish
acute bronchodilator responsiveness for all patients in whom the diagnosis of asthma is
being considered. All patients suspected to have bronchial Asthma should have spirometry
done at least for initial assessment. However, it is important to use an accurate spirometer
and the procedure being done correctly.2 In bronchial asthma, typically one gets an obstructive
pattern. Usually there will be a normal vital capacity with either impaired FEV1 or impaired
MMEF.3 When the FEV1 is severely reduced with clear evidence of obstruction (FEV1/FVC
ratio less than 75% predicted), the vital capacity can also be reduced due to severe obstruction
alone which prevents all the air to be emptied out during forced expiration. The mid-expiratory
flow rate is useful as a screening test but it is too sensitive to assess the severity of obstruction.
The FEV1 is the single best measure of pulmonary function for assessing severity, although
PEFR when measured accurately correlated well with FEV1. Bronchial asthma has a significant
impact on lung function decline, although not as great as COPD. Decline in FEV1 in patients
with bronchial asthma is significantly influenced by baseline FEV1, disease duration, and
FEV1 variability. Moreover, the rate of FEV1 decline seems to increase in younger subjects only
when the baseline function is poorer.4
The low FEV1 in bronchial asthma is due to increased resistance because of bronchoconstriction and remodelled airway walls. However, recently it is reported that measurement

Diagnosis of Bronchial Asthma 101

of maximum static pleural pressure at different lung volumes showed marked loss of lung
recoil in patients with moderate and severe asthma.5 Loss of this elastic recoil accounted for
more than half of the reduction in total maximum airflow in these patients. This low elastic
recoil in patients of asthma is due to long-term corticosteroid therapy, which has known
detrimental effect on connective tissue, smoking, mechanical fatigue due to the persistent
stretch in over inflation, and altered surfactant levels. Further accumulation of inflammatory
cells has been reported in the alveolar tissue of these patients.6
While complete spirometry can be done in a laboratory only, the patient can measure the
peak expiratory flow rate (PEFR) himself. Such measurement has many benefits. It provides a
simple, quantitative, reproducible measure of airway obstruction that can be obtained using
inexpensive, portable peak flow meters. PEFR has a very good correlation with FEV1. This is
almost analogous to measuring blood pressure with a sphygmomanometer. This simple
objective measurement of lung function helps detecting early deterioration of lung function.7,8
The most common strategy employed to support a clinical diagnosis of asthma is to demonstrate
the presence of an abnormal, short-term variable airflow obstruction. Spontaneous variable
airflow obstruction can be assessed by using peak expiratory flow monitoring at home9 or
treatment induced variable airflow obstruction can be assessed in the laboratory by measuring
the bronchodilator response to 2-agonists or the bronchoconstrictor response to short-acting
airway smooth muscle spasmogens like methacholine.
Patients with stable asthma should be encouraged to measure their peak expiratory flow
rates at least one or two days a week to detect any slow deterioration and to start recording it
regularly if they develop a respiratory tract infection, increase in wheeze, or other symptoms
of increasing airway obstruction. They should normally measure their PEFR twice daily, on
waking and in the evening, before using a bronchodilator, and perhaps four times a day
during exacerbations. On each occasion, three readings should be taken and the best recorded
graphically for easy inspection. Patients at increased risk, who are those recently admitted to
hospitals with acute asthma, brittle asthmatics, unstable asthma, those requiring varying
doses of systemic steroids to control their symptoms, and those using home nebulizers should
record their PEFR more often.
Home recordings of PEFR should improve the detection of under treated asthma. Patients
thought to overuse their 2-agonist inhalers may show previously unrecognised nocturnal
asthma or pronounced morning dipping. Recordings may also allow unnecessary drugs to
be withdrawn, thus reducing morbidity and cost of treatment. High dose corticosteroids
required initially may not be necessary subsequently. Thus in summary, measurement of
PEFR is valuable in medical care settings to:
Assess the severity of asthma as a basis for making treatment decisions, such as admission
to or release from the hospital or initiation of oral steroids.
Monitor response to therapy during an acute exacerbation.
Monitor response to chronic therapy and provide objective justification for therapy to
patients.
Diagnose exercise-induced asthma.
Detect asymptomatic deterioration in lung function in the office and intervene before it
becomes more serious.
Monitor degree of airflow obstruction during a series of office visits to assess the overall
success of therapy.

102 Bronchial Asthma

The primary limitation of PEFR measurement is that it is effort dependent and valid
measurements depend upon the patients willingness and ability to exhale as hard as
possible. Adequate training and periodic checkups are necessary to verify the accuracy. In
addition, PEFR measures only large airway function; therefore, patients with mild asthma
whose pathophysiologic abnormalities are linked to the small airways may be under
diagnosed if spirometry, which measures flow rates at low lung volumes (i.e., FEF50,
FEF25-75), is not performed.
Other laboratory investigations for bronchial asthma include:
Complete and differential blood counts; chest X-ray (to rule out other causes of airway
obstruction, and to detect associated complications);
Sputum examination and stain for eosinophils (sputum eosinophils are highly characteristic of asthma and neutrophils predominate in bronchitic sputum); nasal secretions and
stain for eosinophils (neutrophilic nasal discharge indicates sinusitis); sputum differential
eosinophil count is one of the most useful objective tests in patients with bronchial asthma10
and
Complete pulmonary function studies including flow-volume loops which may reveal the
presence of upper airway obstruction.
Determination of specific IgE antibodies to common inhalant allergens with skin tests or
with in vitro test is useful to find out the role of allergy in the patients asthma. Incorporating
a skin prick test using commonly inhaled allergens is a simple, safe, inexpensive, rapid, and
most common way of assessing the contribution of atopy.11 The incidence of positive skin
prick test result, at least to one aeroallergen in asthmatic adults residing in the UK, age range
18-50 years, was 90%,12 whereas a positive result has been found in 15-40% of normal
individuals.13-15 Inclusion of this test in suspected asthma cases can reduce the cost of this
process significantly, and the test can be used as a reliable method to predict the absence of
asthma in young adults.16
OBJECTIVE TESTS
Obstructive airways disease produces a decrease in peak expiratory flow (PEF) and forced
expiratory volume in one second (FEV1). One or both of these should be measured, but may be
normal if the measurement is made between episodes of bronchospasm. If they are repeatedly
normal in the presence of symptoms, then a diagnosis of asthma must be in doubt. Variability
of PEF and FEV1, either spontaneously over time or in response to therapy is a characteristic
feature of asthma. Although the normal level of diurnal variability is open to question, sequential
measurement of PEF may be useful in the diagnosis of asthma. Calculating variability may be
done in one of several ways. A 20% or greater variability in amplitude % best with a minimum
change of at least 60L/min, ideally for three days in a week for two weeks seen over a period
of time, is highly suggestive of asthma.17-23
Many patients with asthma will demonstrate variability below 20%, making this a
reasonably specific but insensitive diagnostic test. That is, marked variability of peak flow
and easily demonstrated reversibility confirms a diagnosis of asthma, but smaller changes do
not necessarily exclude the diagnosis.

Diagnosis of Bronchial Asthma 103

Diagnosis of Asthma Using PEF
Amplitude % best
Highest PEF
Lowest PEF
Amplitude
Percentage PEF variability

=
=
=
=
=

(highestlowest)/highest 100
400 1/min
300 l/min
400 l/min 300 l/min = 100 l/min
(400-300)/400 100 = 25%

The objective measurements helpful in the diagnosis of asthma include:

> 20% diurnal variation on > 3 days in a week for two weeks (to be maintained in a
diary)
or FEV1 > 15% (and 200 ml) increase after short acting 2-agonist (salbutamol 400 g
by metered dose inhaler (pMDI) +spacer or 2.5 mg by nebuliser)
or FEV1 > 15% (and 200 ml) increase after trial of steroid tablets (prednisolone 30 mg/
day for 14 days)
or FEV1 > 15% decrease after six minutes of exercise (running)
Histamine or methacholine challenge in difficult cases
Methods for Measuring Reversibility
An increase after inhalation of a short acting 2-agonist (e.g. salbutamol 400 mg by metered
dose inhaler (pMDI) +spacer or 2.5 mg by nebuliser)
An increase after a trial of steroid tablets (prednisolone 30 mg/day for 14 days)
A decrease after six minutes of exercise, e.g. running. A resting measurement is to be
taken first and then the patient is to be asked to exercise for six minutes, a further reading
is to be taken and then every 10 minutes for 30 minutes. As this procedure may rarely
induce significant asthma, facilities for immediate treatment should be available.
Objective tests should be used to try to confirm a diagnosis of asthma before long-term
therapy is started. Each of the above methods can be used, measuring either PEF (a 20%
change from baseline and at least 60 l/min) or FEV1 (15% change and at least 200 ml).24
Bronchodilators reduce hyperinflation. Measurements of lung volumes before and after
bronchodilators add sensitivity when examining for bronchodilator responsiveness.25
Other investigations that may be helpful include rhinoscopy, sinus X-ray and bronchoprovocation tests,26,27 provocative challenge with occupational allergens and evaluation of
pH for gastro-oesophageal reflux.
Bronchoprovocation Test
Bronchoprovocation test is indicated to assess the airway hyperresponsiveness in the form
of increased bronchoconstrictor response to a variety of physical, chemical, or pharmacological stimuli.28-30 This can better be assessed in a specialised pulmonary testing facility
using bronchial challenge or provocation techniques. The most commonly employed
methods used to evaluate airway hyperresponsiveness include inhalation provocation with
methacholine or histamine and exercise challenge. During such a test changes in pulmonary
function are measured with serial spirometry after inhaling incremental doses of an agonist
such as methacholine or histamine or after exercise.31 The results are then expressed either
as the cumulative dose or the concentration of agonist that produces a 20% fall in FEV1
(PD20). Methacholine bronchoprovocation testing is frequently used to diagnose airway

104 Bronchial Asthma

hyperresponsiveness and asthma. A > 20% reduction in FEV1 following methacholine
administration is a common parameter used to determine airway hyperresponsiveness. Some
observed that the slope of the decline of FEV1 with increasing dose of methacholine is a better
way of measuring responsiveness because a value can be assigned to all subjects. Alternatively,
a > 40% reduction in specific airway conductance (sGaw) can be used to determine airway
hyperresponsiveness.32,33 Regardless of which test is selected, according to the American
Thoracic Society guidelines, the changes in the test parameter following methacholine
challenge must exceed 2 SDs or coefficients of variation for repeated measures in the same
individual before a statistically significant change can be established.33 Although either of the
two measurements is good enough, a substantial number of patients have a reduction in
SGaw alone in response to methacholine, and this response is seen in patients with a higher
FEF25-75 / FVC ratio.34 Large, central airway obstruction is best detected by SGaw measurements,
while both large and small airway narrowing will affect measurements of FEV1.
Methacholine responsiveness is often used to confirm asthma status in patients, and as a
predictor of later development of respiratory disease.35,36 It is widely used in epidemiological
studies, where a standardised tool for measurements of bronchial responsiveness to
methacholine has been developed to estimate variation in prevalence of increased bronchial
responsiveness and predictors of asthma in different groups.37 Various such predictors are
the FEV1 and symptom status, female sex, smoking, atopy, occupational exposure, and
geographical regions are associated with increased responsiveness. Smaller airways are more
responsive than larger ones, and the reduction in responsiveness diminishes with each
increase of lung size.38
Methacholine challenge testing may cause an acute episode of vocal cord adduction and
thus, positive results may not reflect underlying reactive airways disease. However, a flattening
or truncation of the inspiratory flow-volume loop after the patient undergoes methacholine
testing is not diagnostic for the presence of inspiratory vocal cord adduction.39
Results of exercise provocation are expressed as the peak fall in FEV1 after exercise.
Asthmatics respond to bronchoprovocation with greater degree of airflow obstruction than
normal subjects.40 Other conditions that are associated with an increased bronchial hyperreactivity include allergic rhinitis, cystic fibrosis, COPD, normal persons after a viral upper
respiratory tract infection or oxidant exposure, and smokers.40,41 Diurnal variation in the
measurement of PEFR is an indirect but clinically useful way of the degree of bronchial
hyperreactivity even if there may be some variation.42
Bronchial provocation test is helpful in the differential diagnosis of asthma when the
respiratory history, physical findings, and PEFR variations are not adequate to confirm the
clinical diagnosis. These situations include cough variant asthma and exercise-induced
dyspnoea.28,43
There is no one test or set of tests that should be ordered for every patient. Selection of tests
should be individualised. However, with careful attention to the history, physical examination,
and laboratory results, a correct diagnosis of asthma will be made in virtually all instances.
Asthma may be under diagnosed particularly in young children, if they only wheeze
when they have respiratory infections which may be dismissed as wheezy bronchitis,
asthmatic bronchitis, bronchitis, or pneumonia. Although recurrent episodes of cough and
wheezing are almost always due to asthma in both children and adults, there are other

Diagnosis of Bronchial Asthma 105

causes of airway obstruction which produce similar symptoms that need to be excluded. In
adults, such conditions include mechanical obstruction of the airways, laryngeal
dysfunction, chronic bronchitis, pulmonary emphysema, congestive cardiac failure,
pulmonary embolism, pulmonary infiltration with eosinophilia, and cough secondary to
drugs. Of particular interest is the confusion with chronic bronchitis more so in elderly
smokers. Presence of crepitations; absence of eosinophils in the nasal secretion, sputum,
and blood eosinophilia; lack of good reversibility after bronchodilators; and an abnormal
diffusion capacity favours chronic bronchitis with emphysema. Occasionally, it is not
possible to differentiate the two conditions.
Of all the battery of tests utilised to diagnose asthma (methacholine challenge testing, peak
expiratory flow variability over a 2-week period, the FEV1/FVC ratio, the reversibility testing,
and the differential count of eosinophils in blood and sputum), methacholine airway
responsiveness and the sputum differential eosinophil count seems to be the most useful
objective tests in patients with mild asthma. The sensitivity of these two tests are 91 and 72%
respectively, and the specificity is 90 and 80% respectively.44
Increase bronchial responsiveness demonstrated by methacholine or histamine challenge
is associated with symptomatic asthma, but is also common in the general population and in
patients with COPD. However, failure to demonstrate hyperresponsiveness in an untreated
person with suspected asthma should prompt reconsideration of the diagnosis.
Other Tests
Lung function tests may show changes suggestive of an alternative lung disease. For example,
COPD may be suspected in the presence of obstructive spirometry, reduced diffusing capacity
(CO uptake) and pressure dependent airway collapse on flow volume curves, but these changes
are not diagnostic and do not exclude asthma, which may anyway coexist with other
conditions. Failure to respond to asthma treatment should prompt a search for an alternative,
or additional, diagnosis. Chest X-rays in all patients with atypical symptoms should be done.
The differential diagnosis of bronchial asthma includes: COPD, cardiac diseases, laryngeal
tumours, tracheal tumours, bronchogenic carcinoma, bronchiectasis, foreign body, interstitial
lung disease, pulmonary embolism, aspirations, vocal cord dysfunction, pulmonary
infiltrations with eosinophilia, cough due to drugs (beta blockers, ACE inhibitors) and
hyperventilation. A detailed clinical history as well as investigations as outlined will be
helpful in differentiating these conditions.
In spite of a cautious and careful approach, there may be situations when one has to refer
the case to a specialist for opinion and further investigations. These situations include:
Diagnosis unclear or in doubt
Unexpected clinical findings (like crepitations, collapse, effusion, cardiac murmur, clubbing,
heart failure, cyanosis, etc.)
Spirometry or PEFR does not fit the diagnosis (like restrictive defect)
Suspected occupational asthma
Persistent shortness of breath (non-episodic, or without wheeze)
Unilateral or fixed wheeze
Stridor
Persistent chest pain or atypical features

106 Bronchial Asthma

Weight loss
Persistent cough or sputum production
Non-resolving pneumonia
A suggested algorithm for the diagnostic work up in younger subjects with suspected
asthma is shown in Figure 6.1.
Cough, Wheezing, Dyspnoea

Spirometry with bronchodilators (Reversibility testing)

Positive

Negative

Skin testing

Positive

Exercise/Methacholine

Positive

Negative

Consider other diagnosis

Negative

Bronchial asthma
Fig. 6.1: Diagnostic work-up for bronchial asthma

COPD and Bronchial Asthma

Most often there is a confusion whether the patient is having bronchial asthma or COPD as
both the conditions has similar symptoms like cough, wheezing and breathlessness. There
are some similarities also between the two conditions. Tissue eosinophilia, sputum
eosinophilia, increased bronchial hyperreactivity, inflammatory cells, cytokines, etc. can
be similar in COPD, but the types of cells and degree of involvement differ. Because the
overall prognosis and course of the disease are entirely different in both the conditions.
Hence, the differentiation should always be made. It must, however, be possible that both
conditions may coexist.
The important differentiating points between the two are shown in Table 6.1.45
Diagnosis of Occupational Asthma
Careful history and temporal relationship of symptoms with work place will clinch the
diagnosis. However, it is important to establish objectively a relationship between work
and asthma symptoms. Specific challenge tests of occupational exposure tests are often
considered a reference standard for the diagnosis of occupational asthma. The various tests
used are:

Diagnosis of Bronchial Asthma 107

Table 6:1: Important differentiating points between bronchial asthma and COPD

Parameter

Bronchial asthma

Clinical

Young age of onset

Associated history of allergy
(rhinitis, urticaria, eczema etc)
Episodic wheezing
Signs of hyperinflation unusual
Crepitationsunusual findings
Evidence of cor
pulmonaleabsent
Cyanosisunusual except in
acute severe asthma
Signs of hypercarbia unusual
Chest skiagramfrequently
normal

Airflow obstruction

Postmortem

Sputum

Surface epithelium
Bronchiolar mucus cells
Reticular basement
membrane
Congestion/oedema
Bronchial smooth
muscle
Bronchial glands
Cellular infiltrates

Cytokines

COPD

More older people

History of smoking,
exposure to pollution
No history of allergy
Signs of hyperinflation (hyperresonant notes on percussion,
obliteration of cardiac dullness,
low, diaphragm)
Air entry diminished
Rhonchi and crepitation present
Cor pulmonale is a frequent
complication
Cyanosis may be a finding
Signs of hypercarbia, frequent
Chest skiagram will show changes of
COPD like increased lung volumes,
tubular heart, low, flat diaphragms,
attenuation of peripheral vessels,
emphysematous bullae etc.
Variable (irreversible component Progressive deterioration of
may be there in late stages)
lung function
Hyperinflation, mucus plugs
Excessive mucus (mucoid/ purulent)
(exudates + mucus),
Small airway disease, Emphysema
No or little emphysema
Eosinophilia, metachromatic
Neutrophils (infective exacerbations)
cells, creola bodies
Fragility undetermined
Fragility loss
Mucus metaplasia debated
Metaplasia/hyperplasia definite
Homogenously thickened and
Variable or normal
hyaline present
Present
Variable/fibrotic
Enlarged mass (large airways)
Enlarged (Small airways)

Enlarged mass, but no change in

mucin histochemistry
Predominantly CD3, CD4, CD25
(IL-2R)+,
Marked eosinophilia (activation)
Mast cells increase (Decrease in
severe/fatal cases)
IL-4, IL-5, eotaxin, and RANTES
gene expression

Enlarged mass, increased acidic

glycoprotein
Predominantly CD3, CD8, CD68,
CD25, HLA-1 and HLA-DR+,
Mild eosinophilia except during
exacerbations,
Mast cells increase in smokers
IL-4 and IL-5 gene expression
RANTES only in exacerbations

108 Bronchial Asthma

i. Measurement of lung function before and after a work shift. This is not very helpful in
establishing a causal relationship between symptoms and work exposure.
ii. Measurements of lung function (FVC and FEV1) when the patient has been away from the
work environment for a period of time and again when he returns to work. An improvement
in symptoms and lung functions away from work and recurrence of symptoms and
deterioration in lung function after returning to work, confirms that the symptoms are
related to the work environment.
iii. Prolonged recording of PEFR by the patient at work and at home is a good method of
establishing the causal relationship. The patient is asked to measure and record the
PEFR every 2 hours from waking to sleep for at least 2 to 3 weeks at work, followed by
at least 10 days off work. Different patterns of PEFR are described. The method has the
disadvantage of falsification of data and inaccurate readings.
iv. Serial measurements of nonspecific airway responsiveness in conjunction with
prolonged recording of PEFR has been proposed as an additional test to provide objective
evidence of sensitisation. Significant increases in airway responsiveness when away
from work, associated with appropriate changes in PEFR, suggest an occupational
relationship. Specific challenge tests are required to identify the substances in the work
place causing the symptoms. However, this is time consuming and not devoid of danger.
They should be performed by experienced personnel in hospital settings where
resuscitation facilities are available and frequent observations can be made.
Allergy skin tests with high molecular weight compounds may be useful in identifying
the responsible agent. Animal products, flour, coffee, and castor bean produce immediate
positive reactions on skin testing in sensitised subjects.
Specific IgE antibodies to various occupational allergens may be demonstrated by RAST
or by ELISA. Such specific antibodies against low molecular weight compounds conjugated
to a protein like trimellite anhydride and isocyanate have been demonstrated in some
exposed subjects. However, positive skin tests and the presence of IgE antibodies indicate
sensitisation and may occur in exposed workers without asthma.
The clinical investigation of occupational asthma is shown in Figure 6.2.46
Classification of Asthma
Bronchial asthma can be defined as mild, moderate, and severe on severity of disease.47
This enables the clinician to categorize the overall assessment of a patients asthma and
select appropriate therapy. The characteristics are shown in Table 6.2 and are recommended
by the Expert Panel of the National Asthma Education Program by the National Heart,
Lung, and Blood Institute, USA.47 The characteristics are general, and because asthma is
highly variable, these characteristics may overlap. Furthermore, an individual may switch
into different categories over time.
Thus, severity of bronchial asthma, as defined by the National Asthma Education
Programme (NAEP) Expert Panel of 1991, can be summarised as:

Mild: It is characterised by intermittent daytime symptoms up to two times in a week, brief

wheezing, cough, or breathlessness with activity, and infrequent nocturnal cough or
wheezing less than two times in a month. The FEV1 or PEFR is expected to be greater than
80% when asymptomatic and to vary 20% with symptoms.

Diagnosis of Bronchial Asthma 109

Fig. 6.2: Diagnostic work-up of occupational asthma

110 Bronchial Asthma

Table 6.2: Classification of bronchial asthma

Characteristics
Pretreatment
Frequency of
exacerbations

Mild
Exacerbation of
cough and wheezing
no more often than
1-2 times/week

Moderate

Severe

Virtually daily. Exacerbations frequent.

Often severe. Tends to
have sudden severe
urgent visits to emergency department or
doctors office > 3/year
Hospitalization > 2/yr
Frequency of
Few clinical
Cough and low grade wheezing Continuous symptoms
symptoms
signs/symptoms
between acute exacerbations of cough and wheezing
between exacerbations almost often present
always present
Degree of
Good. May not tolerate Diminished
Very poor. Marked
exercise
vigorous exercise
activity limitation
tolerance
like prolonged running
Frequency of
Not more than 1-2
2-3 times/week
Considerable. Almost
nocturnal
times per month
nightly sleep interrupasthma
tion. Early morning
chest tightness
School or work Good
May be affected
Poor attendance
Attendance
> 80% predicted.
60-80% predicted.
< 60% predicted.
Pulmonary function
PEFR
Normal or minimal
Airway obstruction
Substantial degree of
Spirometry
airway obstruction.
evident. Flow
airway obstruction.
Normal expiratory
volume curve shows
Flow volume
flow volume curve.
reduced expiratory flow
curve shows
Lung volumes
at low lung volumes.
marked concavity.
not increased.
Lung volumes often
Spirometry may not be
Usually a > 15%
increased. Usually a
normalised even with
response to acute
> 15% response to
steroids. May have
aerosol bronchoaerosol bronchosubstantial increase in
dilator even with near
dilator
lung volumes and
normal baseline
marked unevenness
values.
of ventilation. Incomplete
reversibility to acute
aerosol bronchodilator
Methacholine
> 20 mg/ml
Between 2-20 mg/ml
< 2 mg/ml
sensitivity (PC20)

After optimal treatment is established

Response to
Exacerbations respond
and duration of to bronchodilators
therapy.
without the use of
systemic steroids
Regular therapy
not required except
for exacerbations

Exacerbations of cough and

wheezing more frequent.
Severe exacerbations infrequent. Urgent care treatment < 3/year

Periodic use of bronchodilators required

during exacerbations
for a week or more
Steroids needed
for short periods

Requires continuous
multiple round-theclock drug therapy
including daily steroids
either aerosol or
systemic in high doses

Diagnosis of Bronchial Asthma 111

Moderate: Moderate asthma is characterised by symptoms more than 1-2 times weekly affecting
sleep and activity levels, exacerbations lasting several days, and occasional emergency care.
The FEV1 or PEFR is expected to be 60-80% at baseline and vary between 20-30% with
symptoms.
Severe: This is characterised by continuous symptoms including nocturnal symptoms,
limited activity levels, frequent exacerbations, and occasional hospitalisation, and emergency
treatment. The FEV1 or PEFR is less than 60% at baseline and highly variable.
The British Guidelines are parallel to the NAEP guidelines. However, the Global Strategy
for Asthma Management and Prevention Workshop, a joint effort of the National Heart,
Lung, and Blood Institute and the WHO, 1995 (NIH Publication No. 96-3659A) classifies
severity of asthma into different (discussed subsequently).
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1. Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel A. Mechanisms of bronchial hyperreactivity
in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131.
2. Behera D. Normal values of Pulmonary Function Tests. In: Pulmonary functions tests in Health
and Disease (Ed). PS Shankar. Indian College of Physicians, 1998; 150-59.
3. Wagner EM, Liu MC, Weinnman GG, Permutt S, Bleecker ER. Peripheral lung resistance in
normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584.
4. Cibella F, Cuttitta G, Bella V et al. Lung function decline in bronchial asthma. Chest 2002;122:
1944-48.
5. Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic
persistent asthma. Hest 2002;121:715-21.
6. Wassermann K. Is asthma another interstitial lung disease? Chest 2002;121:673-74.
7. Gupta ML, Behera D: Pattern of airflow obstruction in Bronchial AsthmaAn observation on
Home-Monitoring of Peak Expiratory Flow Rate. J Ass Phy India, 1997;45:94-96.
8. Clark TJH, Hetzel MR. Diurnal variation of asthma. Br J Dis Chest 1977;71:87-92.
9. Jamison JP, McKinley RK. Validity of peak expiratory flow rate variability for the diagnosis of
asthma. Clin Sci 1993;85:367-71.
10. Hunter CJ, Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. A comparison of the validity
of different diagnostic tests in adults with asthma. Chest 2002;121:1051-57.
11. Allergy skin testing. Board of Directors,; American Academy of Allergy and Immunology
J Allergy Clin Immunol 1993;92:636-37.
12. Corne J, Smith S, Schreiber J et al. Prevalence of atopy in asthma. Lancet 1994;344:344-45.
13. Holt PG, Macaubas C, Stumbles PA et al. The role of allergy in the development of asthma.
Nature 1999;402:B12-B17,
14. Holgate ST. The epidemic of allergy and asthma. Nature 1999;402:B2-B4.
15. Busse WW, Lemanske RF. Advances in immunology: Asthma. N Engl J Med 2001;344:350-62.
16. Graif Y, Yigla M, Tov N, Kramer MR. Value of a negative aeroallergen skin-prick test result in
the diagnosis of asthma in young adults. Co-relative study with methacholine challenge testing.
Chest 2002;122:821-25.
17. Higgins BG, Britton JR, Chinn S et al. The distribution of peak flow variability in a population
sample. Am Rev Respir Dis 1989;140:1368-72.
18. Kesten S, Rebuck AS. Is the short-term response to inhaled beta-adrenergic agonist sensitive or
specific for distinguishing between asthma and COPD! Chest 1994;105:1042-1045.
19. Thiadens HA, De Bock GH, Dekker FW et al. Value of measuring diurnal peak flow variability
in the recognition of asthma: a study in general practice. Eur Respir J 1998;12:842-47.

112 Bronchial Asthma

20. Kunzli N, Stutz EZ, Perruchaoud AP et al. Peak flow variability in the SAPALDIA study and its
validity in screening for asthma-related conditions. The SAPALDIA Team. Am J Respir Crit
Care Med 1999;160:427-34.
21. Siersted HC, Mostgaard G, Hyldebrandt N et al. Interrelationships between diagnosed asthma,
asthma like symptoms, and abnormal airway behaviour in adolescence. The Odense Schoolchild
Study. Thorax 1996;51:503-09.
22. Quackenboss JL, Libowitz MD, Krzyzanoski M. The normal range of diurnal changes in peak
expiratory flow rates. Relationship to symptoms, and respiratory disease. Am Rev Respir Dis
1991;143:323-30.
23. Reddel HK, Salome CM, Peat JK et al. Which index of peak expiratory flow is most useful in the
management of stable asthma? Am J Respir Crit Care Med 1995;151:1320-25.
24. Tweeddale PM,Alexander F, McHardy GJ. Short-term variability in FEV1 and bronchodilator
responsiveness in patients with obstructive ventilatory defects. Thorax 1987;42:487-90.
25. Newton MF, ODonnell E, Forkert L. Response of lung volumes to inhaled salbutamol in a large
population of patients with severe hyperinflation. Chest 2002;121:1042-50.
26. Anderson SD. Nonisotonic aerosol challenge in the evaluation of bronchial hyper-responsiveness.
Allergy Proc 1991;12:143.
27. Boulet LP, Legris C, Thibault L, Turcotte H. Comparative bronchial response to hyperosmolar
saline and methacholine in asthma. thorax 1987;42:953-58.
28. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyper-reactivity. Am Rev Respir
Dis 1980;121:389-414.
29. Hopp RJ, Townley RG, Biven RE, Bewtra AK, Nair NM. The presence of airway reactivity before
the development of asthma. Am Rev Respir Dis 1990;141;2-8.
30. Jones A. Asymptomatic bronchial hyper-reactivity and the development of asthma and other
respiratory tract illnesses. Thorax 1994;49;757-61.
31. Chatham M, Bleecker ER, Smith PL, Rosenthal RR, Mason P, Norman PS. A comparison of
histamine, methacholine, and exercise airway reactivity in normal and asthmatic subjects. Am
Rev Respir Dis 1982;126:235-40.
32. American Thoracic Society Guidelines for methacholine and exercise challenge testing, 1999.
Am J Respir Crit Care Med 2000;161:309-329.
33. American Thoracic Society Guidelines for bronchial inhalation challenges with pharmacologic
and antigenic agents. ATS News 1980 (Spring).
34. Parker AL, McCool FD. Pulmonary function characteristics in patients with different patterns of
methacholine airway hyper-responsiveness. Chest 2002;121:1818-23.
35. Laprise C, Boulet LP. Asymptomatic airway hyper-responsiveness: A three year follow-up. Am
J Respir Crit Care Med 1997;156:403-409.
36. Pattemore PK, Asher MH, Harrison AC et al. The interrelationship among bronchial hyperresponsiveness, the diagnosis of asthma, and asthma symptoms. Am Rev Respir Dis 1990;142:
549-554.
37. Burney PGJ, Luczynska G, Chinn S et al. The European Community Respiratory Health Survey.
Eur Respir J 1994;7:954-60.
38. Schwartz J, Schindler C, Zemp E et al. Predictors of methacholine responsiveness in a general
population. Chest 2002;122:812-20.
39. Perkins PJ, Morris MJ. Vocal cord dysfunction induced by methacholine challenge testing. Chest
2002;122:1988-93.
40. Hargreave FE, Ryan G, Thomson NC et al. Bronchial responsiveness to histamine or methacholine
in asthma: Measurement and clinical significance. J Allergy Clin Immunol 1981;68:347-55.
41. Chatham M, Bleecker ER, Norman P, Smith PL, Mason P. A Screening test for airways reactivity.
Chest 1982;82:15-18.

Diagnosis of Bronchial Asthma 113

42. Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial responsiveness to histamine:
relationship to diurnal variation of peak flow rate, improvement after bronchodilator, airway
caliber. Thorax 1982;37:423-29.
43. Galvez RA, McLaughlin FJ, Levison H. The role of the methacholine challenge in children with
chronic cough. J Allergy Clin Immunol 1987;79:331-35.
44. Hunter CJ, Brightling CE, Voltman G et al. A comparison of the validity of different diagnostic
tests in adults with asthma. Chest 2002;122:1051-57.
45. Jeffery P. Immunopathology: Comparison of COPD and asthma. In: Hansel TT, Barnes PJ (Eds):
New Drugs for Asthma, Allergy, and COPD. Prog Respir Res. Basel, Karger, 2001; 31:24-29.
46. Chan-Yeung M, Malo JL. Occupational asthma. New Engl J Med 1995;333:107-12.
47. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and
management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health,
Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991.

114 Bronchial Asthma

7
Prognosis of Bronchial Asthma
FACTORS FOR ASTHMA MORTALITY
Although the possibility of asthma-related death exists for all patients with asthma, several
studies have revealed factors associated with an increased risk of such deaths.1-6 Several
studies from many countries of the world including Britain, New Zealand, United States,
France, Germany, and Canada have shown increases over the last two decades in the
incidence of deaths from asthma. The cause of such increase in deaths remains a puzzle.
There are many hypotheses to explain this, but little emphasis has been placed on the
possibility that confidence in better drug treatment may modify patients behaviour so as
to place him at greater risk of illness. Excessive confidence in bronchodilator inhalers and
nebulisers can make patients stay away from hospitals too long during acute attacks. It is
also very likely that prevention of symptoms by use of antiasthma drugs could allow patients
to spend more time in environments containing antigens or other agents that provoke
asthma, resulting in more serious and long-lasting bronchial inflammation and reactivity.
Some of these recognised factors that increases the susceptibility to death from asthma are
as follows.
Age and Ethnicity
Asthma-related death rates are higher among older patients than in any other age group.
Although the death rate is relatively low in younger patients, an increased trend in asthma
deaths among these individuals between the age group of 5 to 34 years have been noted
during the last 10 years. People in their late teens and early twenties, particularly members
of minority groups, are over represented in asthma mortality statistics groups. AfricanAmericans have asthma related mortality rates that are higher than those of Caucasians,
especially in relatively young age groups, and the mortality rate in this group has increased
significantly during the past decade. In 1979, African-Americans of both sexes were about
twice as likely to die of asthma as Caucasians.
Previous Life-threatening Acute Asthma Exacerbations
Individuals who have had acute exacerbations of asthma that resulted in respiratory failure
and required intubation are at increased risk for subsequent fatal exacerbations. Those who
have experienced respiratory acidosis without requiring intubation are also high-risk
patients.

Prognosis of Bronchial Asthma 115

Hospital Admission for Asthma within the Last Year
Those patients hospitalised for asthma within the last year have a greatly increased risk of
dying from asthma when compared to severity-matched asthma patients in the community
that have not been hospitalised. Those with more than two hospitalisations for status
asthmaticus in spite of long-term oral steroid therapy are at the highest risk of dying from
asthma.
In some patients, deterioration during an acute exacerbation occurs very rapidly.
Underestimation of the severity of such exacerbations may lead to a life-threatening delay
in starting medical treatment or seeking medical care.
Some patients may fail to appreciate a poor response to treatment during an acute
exacerbation and may rely on frequent repetitive use of inhaled 2-agonist far in excess of
recommended doses for therapy at home. This treatment may temporarily blunt symptoms
but mask increasing inflammation and airway hyperresponsiveness, which may in turn,
lead to abrupt and severe deterioration of lung function. Without the documented objective
measures of pulmonary function or realisation by the patient and/or the physician of the
severity of the disease, risk of death is increased.
Psychological and Psychosocial Problems
Depression leads to increased death particularly in children. Other psychological problems
that have been documented as associated with those at increased risk include alcohol abuse,
documented depression, recent family loss and disruption, recent unemployment, and
schizophrenia. Patients who have experienced a life-threatening asthma exacerbation have
been reported, on the whole, to deny that they are at risk of death. Following a near fatal
exacerbation, they tend to either develop decompensating psychiatric disease and symptoms
of extreme anxiety or develop even higher levels of denial. Some tend to minimise their
symptoms and avoid access to health care. Other associations include life crises, family
conflict, and social isolation.
Regardless of the possible physiologic and psychological interactions that link anxiety,
depression, and asthma fatality, it is evident that patients who have these psychological
disruptions are at increased risk for death.7-15
Lack of Access to Medical Care
Lack of access to medical care is another risk factor associated with asthma-related death.
Patients of lower socioeconomic class are unable to obtain routine preventive asthma care.
As a result, these patients seek help only when their asthma symptoms are severe and
report to the emergency room for initial care.16 In rural areas, lack of access to adequate
emergency care can result in life-threatening delay in medical treatment during
exacerbations. Even in some urban centers, adequate facilities like ventilatory support are
not available.
Medication Use
Medications, particularly steroids, are underused at the time of death. The controversy of
the asthma mortality because of -agonist use is still on.17-19

116 Bronchial Asthma

REFERENCES
1. Wissow LS, Gittelsohn AM, Szklo M, Starfield B, Mussman M. Poverty, race, and hospitalisation
for childhood asthma. Am J Public Health 1988;78:777.
2. Miller BD. Depression and asthma: A potentially lethal mixture. J Allergy Clin Immunol
1987;80:481.
3. Strunk RC. Identification of the fatally-prone subject with asthma. J Allergy Clin Immunol
1989;83:477.
4. Rea HH, Scragg R, Jackson R et al. A case-controlled study of deaths from asthma. Thorax
1986;41:833.
5. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423.
6. Barriot P, Riou B. Prevention of fatal asthma. Chest 1987;92:460.
7. Campbell DA, McLennan G, Coates JR et al. A comparison of asthma deaths and near fatal
asthma attacks in South Australia. Eur Respir J 1994;7:490-97.
8. Strunk RC, Mrazek DA, Fuhrmann GSW, LeBreque JF. Death from asthma in childhood. Can
they be predicted? JAMA 1985;254:1193-98.
9. Wareham NJ, Harrison BDW, Jenkins PF, Nicholls J, Stableforth DE. A district confidential enquiry
into death due to asthma. Thorax 1993;48;1117-20.
10. Campbell DA, Yellowlees PM, McLennan G, et al. Psychiatric and medical features of near fatal
asthma. Thorax 1995;50;254-59.
11. Creer TL. Psychological factors and deaths from asthma; Creation and critique of a myth. J Asthma
1986;23;261-69.
12. Boseley CM, Fosbury JA, Cochrane GM. The psychological factors associated with poor
compliance with treatment in asthma. Eur Respir J 1995;8;899-904.
13. Fitzgerald JM. Psychological barriers to asthma education. Chest 1994;1069(Suppl4):2S-3S.
14. Gibson GJ. Perception, personality, and respiratory control in life-threatening asthma. N Engl J
Med 1994;330:1329-34.
15. Weiss KB, Wagener DK. Geographical variations in US asthma mortality: Small area analysis of
exercise mortality, 1981-85. Am J Epidemiol 1990;132:s107.
16. Barger LW, Vollmer WM, Felt RW, Buist AS. Further investigations into the recent increase in
asthma death rates; a review of 41 asthma deaths in Oregon in 1982. Ann Allergy 1988;60:31-39.
17. Crane J, Flatt A, Jackson R et al. Prescribed fenoterol and death from asthma in New Zealand,
1981-83: Case control study. Lancet 1989;1:917-27.
18. Crane J, Pearce N, Burgess C, Beasley R. Asthma and the beta agonist debate. Thorax
1995;50(Suppl 1):S5-S10.
19. Suissa S, Ernst P, Boivin JF et al. A cohort analysis of excess mortality in asthma and the use of
inhaled beta agonists. Am J Respir Crit Care Med 1994;149:604-10.

Complications of Bronchial Asthma 117

8
Complications of
Bronchial Asthma
Infections, pneumothorax, pneumomediastinum, and atelectasis due to mucus plugging
are the complications of acute bronchial asthma. Allergic broncho-pulmonary mycosis
(ABPM) is an important complication of asthma.1 The most common fungus involved is
Aspergillus fumigatus. Sensitisation to aspergillus antigens may occur in asthmatics without
full-blown picture of ABPA. The prevalence of such sensitisation reportedly occurs in
20-50% of cases of bronchial asthma and the incidence of full-blown pictures of ABPA occurs
in about 65 of cases, although higher figures have been reported.2-11 Other organisms that
can cause such bronchopulmonary reactions include other species of Aspergillus, Candida
albicans, Pseudoallescheria boydii, Stemphylium sp, Helminthosporium sp, Pseudomonas
aeruginosa, Curvularia lunata, Drechslera hawaiiensis, Torulopsis glabrata, Rhizopus, Penicillium,
Bipolaris, and Fusarium vasinifectum.12 Cor pulmonale secondary to bronchial asthma is
extremely uncommon and in fact, the presence of this complication should be an indication
that the underlying problem is not asthma. Respiratory failure is common during acute
severe asthma.
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)
Allergic bronchopulmonary aspergillosis is a complex hypersensitivity reaction to
Aspergillus antigens because of the presence of the fungus in the bronchial tree and the
disorder characterised by bronchospasm, pulmonary infiltrates, eosinophilia, and
immunologic evidence of allergy to the antigens of Aspergillus species. Aspergillus fumigatus
is the one responsible for the condition although other species may also be responsible.
The first three cases were diagnosed in 1952 in England by Hinson et al.13 Subsequently
the entity has been reported more frequently from that country as well as from other regions
of the world like Australia,14 North America15 and parts of Asia.16 It was first reported from
India in 197117 and a few case series have subsequently been documented.18-27 The disease is
typically seen in patients with long-standing asthma or cystic fibrosis. The incidence of the
condition in asthmatics is reported to vary from 3 to 20% of corticosteroid dependent asthma
patients28 and 6% of patients with cystic fibrosis meet the diagnostic criteria of ABPA.29
Pathophysiology
Patients with ABPA are usually atopic and have a history of bronchial asthma. The basic
underlying pathophysiologic process in ABPA is a hypersensitivity reaction to the presence

118 Bronchial Asthma

Flow Chart: Clinical spectrum of inhalation of Aspergillus spores
Inhalation of Aspergillus

Colonisation

Normal host

No sequel

Cavitary lung
disease

Aspergilloma

Chronic lung disease or

mild immunocompromised

Chronic Nercotising
Aspergillosis

Immunocompromised host

Invasive Pulmonary
Aspergillosis

Asthma

ABPA

Colonisation

Tracheobronchitis

Ulcerative
Tracheobronchitis
Pseudomembranous
tracheobronchitis

of fungus in the bronchial tree. Tissue invasion by the fungus usually does not occur. The
factors favouring the initial colonisation of the bronchial tree are unclear. Other host factors,
including cellular immunity, may contribute to the pathologic changes seen in ABPA.30,31
The changes brought about by the ensuing local immunologic reactions and the tenacious
sputum of bronchial asthma favour the trapping of fungal spores and further colonisation.
Antigenic material from the fungus stimulates production of IgE, IgG, and IgA antibodies.
A number of immunologic reactions, notably type I (immediate) and type III (antigenantibody, immune complex) hypersensitivity reactions occur in this condition. The type I
immediate hypersensitivity reaction is IgE mediated and account for the bronchospastic
symptoms of the condition. Type III reactions mediated by IgG result in polymorph
aggregation, inflammation of bronchial and peribronchial tissue and is responsible for the
radiological features of ABPA. Both these reactions play a central role in the pathogenesis
of ABPA.32,33 Recently a possible role of type IV hypersensitivity reaction has been inferred
from the demonstration of in vitro lymphocyte transformation in response to Aspergillus
antigens in patients with ABPA and the presence of parenchymal granuloma and
mononuclear cell infiltration seen on histopathology. Alternate pathway complement

Complications of Bronchial Asthma 119

activation may also take part in the inflammatory response of ABPA. Long-standing
involvement of the bronchial tree leads on to bronchiectasis, fibrosis, lung contraction, and
lobar shrinkage.
Lung biopsy in ABPA (done rarely as diagnosis is mainly clinical and laboratory findings)
demonstrates different stages of chronic inflammatory process involving bronchial walls
and peribronchial tissues. There is no tissue invasion by the fungus and granulomas may
be seen. The most significant findings involve bronchi and bronchioles34 with bronchocentric
granulomas and mucoid impaction. Other findings include granulomatous inflammation.
The cellular infiltration consists of eosinophils, monocytes, plasma cells and multinucleated
giant cells. The bronchi are dilated and are filled with tenacious exudates containing
eosinophilic material and mycelia. In long-standing cases variable degrees of interstitial
and alveolar fibrosis are seen. Presence of immune complexes has been demonstrated in
some cases with immunofluorescent studies. Vasculitis is very rare.
Bronchi contain tenacious mucus, fibrin, Curschmanns spirals, Charcot-Leyden crystals,
eosinophils, and mononuclear cells. Fungal hyphae may be seen in the bronchial lumen
without tissue invasion.34
Clinical Features of ABPA
The patient is usually an atopic individual with established bronchial asthma of many years.
There is no clear relationship between exposure to antigens and the onset of symptoms.
The onset is insidious with nonspecific complaints like anorexia, progressive fatigue,
headache, generalised aches and pains, low grade fever, and loss of weight. The underlying
asthma usually increases in frequency and severity with less degree of control with the
usual anti-asthmatic medications. The increased frequency of wheezing is associated with
intermittent or continuous sputum production. Rubbery golden-brown plugs of sputum
production are characteristic of this condition and have been reported in 5 to 54% of cases.
Expectoration of such plugs is associated with a dramatic improvement in symptoms
particularly wheezing.35 These plugs consist of fungal hyphae with eosinophils and mucus.
Cough is universal and dyspnoea may be present in a substantial number of cases.
Haemoptysis has been reported in 34 to 85% of cases. Pleuritic chest pain may be present in
about half of the patients and is usually localised to the side involved on chest X-ray. Chronic
cases may present with symptoms compatible with bronchiectasis. Patients may exhibit
minimal symptoms, yet demonstrate extensive pulmonary consolidation on chest radiography. Wheezing and diffuse crepitations are the common findings on chest examination.
Five stages have been identified in patients with ABPA,36,37 which help to guide the
management of the disease. It is not necessary for a patient to progress through all these
stages. The stages are:
Stage I
(Acute stage);
Stage II
(Remission stage);
Stage III
(Exacerbation stage);
Stage IV
(Corticosteroid-dependent asthma stage); and
Stage V
(Fibrotic stage).

Stage I The classic signs, symptoms, and laboratory findings present at diagnosis
characterize the acute stage. Bronchial asthma, a markedly elevated IgE levels, peripheral
eosinophilia, pulmonary infiltrates, and the presence of IgE and IgG antibodies to A.fumigatus
characterize this stage. In practice, patients are rarely identified at this stage.

120 Bronchial Asthma

Stage II The remission stage is characterised by radiological clearing, a decline in total

serum IgE levels, but not to the normal levels, eosinophilia is absent, control of respiratory
symptoms, and a discontinuation of corticosteroid therapy over a six month period without
recurrence of ABPA. Serum IgG antibodies to Aspergillus may be slightly elevated.
Prolonged and permanent remissions may occur after treatment of the acute stage with
steroids, and maintenance therapy is not required in these patients. In some, asthma may
become refractory to aminophylline, -agonists and Cromolyn and inhaled steroids may
be necessary.
Stage III The exacerbation stage is the one when the patent is a known case of ABPA and
demonstrates all characteristics of the acute stage or when there is a two-fold rise in the total
serum IgE levels in association with radiological finding in the absence of other causes of
infiltrates like bacterial or viral pneumonias. Remission after an exacerbation is induced in
these patients with corticosteroids and prolonged therapy is not necessary.
Stage IV The corticosteroid-asthma stage is present when patients require oral steroid therapy
to control asthma (steroid-dependent asthma) or to prevent recurrent exacerbations. The dose
of steroids needed to control asthma usually is not sufficient for preventing the exacerbations
of ABPA or the occurrence of both. Attempt to taper steroid therapy will result in worsening
of symptoms and the development of pulmonary infiltrates.
Stage V The fibrotic lung disease stage is present when there are extensive fibrotic changes
on chest X-ray (end-stage lung disease) with irreversible obstructive lung disease on
pulmonary testing. Steroid therapy is not able to reverse these changes completely.
Dyspnoea, cyanosis, crepitations, clubbing, cor pulmonale, respiratory failure and death
may occur in some patients. The serum IgE level and eosinophil count may be low or high.
A minority of patients progress to this stage.
ABPA may precede the clinical recognition of the disease for many years. Usually there
are two sets of ABPA patients based on the onset of asthma before the age of 30 who have
greater skin reactivity to other common allergens, and who show additional features of
allergic disease such as eczema and allergic rhinitis. In the other subset of patients who
have the onset of their asthma after the age of 30, generally have less cutaneous skin reactivity
to common allergens and no other clinical symptom suggests allergic disease.
Radiology
The roentgenography changes in ABPA may be normal in early stages of the disease or
they may be transient or permanent.38 (Figs 8.1 to 8.5 plate 1 and 2) During acute exacerbations,
the typical changes are fleeting pulmonary infiltrates that tend to be in the upper lobe and
central in location. Transient changes, which may clear with or without steroid therapy is
due to parenchymal infiltrates, mucoid impactions or secretions in damaged bronchi. These
transient findings include:
i. Perihilar infiltrates simulating adenopathy;
ii. Air-fluid levels from dilated central bronchi filled with fluid and debris;
iii. Massive homogenous consolidation which may be unilateral or bilateral;
iv. Radiographic infiltrates;
v. Tooth-paste shadows due to impaction of mucus in the damaged bronchi;
vi. Gloved-finger shadows due to distally occluded bronchi filled with secretions;
and,

Complications of Bronchial Asthma 121

vii. Tram-line shadows, which are two parallel hairline shadows extending out from
the hilum. Permanent changes include:
i. Proximal bronchiectasis;
ii. Parallel line shadows which are tram-line shadows resulting from bronchiectasis; and
iii. Ring shadows which are dilated bronchi. Other rare findings may be cavitation,
local emphysema, contracted upper lobes, honeycomb fibrosis, total lung
collapse due to mucus impaction, and spontaneous pneumothorax. Normal
chest X-ray does not exclude the diagnosis of ABPA. The chest CT may be
more sensitive in demonstrating the above changes and has replaced the
necessity of bronchography.
Laboratory Findings
Peripheral eosinophilia is common, and sputum contains eosinophils in most of the patients.
Leucocytosis and raised ESR are found during acute episodes.
The serological abnormalities include a marked increase in total serum IgE and specific
IgE and IgG antibodies against A.fumigatus. The levels of both total and specific serum IgE
levels are high during the development of pulmonary infiltrations; the levels decline after
remission. Serial determination of total serum IgE may thus be helpful in detecting patients
with ABPA or following the course of ABPA and determining the onset of an acute
exacerbation.39 Occasionally, the serum IgE may be low.
Skin testing with potent A.fumigatus extracts demonstrates an immediate wheal and flare
reaction in most cases. This reaction is frequently followed by a late onset of erythema and
edema occurring at the injection site over the next 4 to 6 hours. The reaction reaches its peak
by 8 hours and subsides by 24 hours. These late reactions are due to deposits of IgG, IgM,
IgA, and complement components. Serologic tests using double gel diffusion method reveal
precipitating antibodies in most patients of ABPA. Radio immunoassay or ELISA techniques
detects antibodies specific for Aspergillus belonging to several immunoglobulin classes. It
has been demonstrated that up to 25% of patients of asthma have immediate skin reactivity
to A.fumigatus and 10% demonstrate positive precipitating antibodies against this. Thus,
neither of these parameters is specific for ABPA.
Aspergillus can be cultured from sputum of nearly two-thirds of patients during acute
episodes of ABPA. Repeated cultures are necessary to demonstrate the fungi.
Bronchial challenges with A.fumigatus characteristically show a dual response in patients
with ABPA. -2 agonists can prevent the immediate reaction and the late reaction may be
prevented by corticosteroids. Cromolyn sodium may prevent both types of reactions.
However, bronchial challenge test is not required to confirm ABPA and may be risky.
Abnormalities of pulmonary function tests in ABPA depend upon the stage at which
they are performed. During the earlier stages of pure bronchospasm there will be an
obstructive physiologic profile, whereas during the irreversible stages of the disease with
bronchiectasis and fibrosis, the tests will reflect a restrictive physiologic profile. The degree
of reversibility is much less compared to that in classic extrinsic-asthma. The diffusion
capacity is reduced in most patients with a good correlation with the duration of the
disease.

122 Bronchial Asthma

Diagnosis
There are no universally accepted criteria for the definite diagnosis of ABPA. Rosenberg
et al35 have suggested the following which is accepted by most investigators. Greenberger
and Patterson recently modified the diagnostic criteria for ABPA.39 They are listed in Tables
8.1 and 8.2.
Table 8.1: Rosenberg criteria for diagnosis of ABPA

Primary
1.
2.
3.
4.
5.
6.
7.
Secondary
1.
2.
3.

Episodic bronchial obstruction

Peripheral blood eosinophilia
Immediate skin reactivity to Aspergillus antigens
Precipitating antibodies against Aspergillus antigens
Elevated serum IgE
History of infiltrates in the chest X-ray
Central bronchiectasis

Aspergillus in sputum
History of mucus plug expectoration
Late skin (Arthus) reactivity to Aspergillus antigen

The diagnosis of ABPA is considered likely if the first six primary criteria are present; certain if all
seven are present.
Table 8.2: Modified diagnostic criteria of ABPA
1.
2.
3.
4.
5.
6.
7.
8.

Bronchial asthma
Immediate skin reactivity to Aspergillus
Serum precipitin to A.fumigatus
Increased serum IgE and IgG to A.fumigatus
Total serum IgE > 1000 ng/ml
Current or previous pulmonary infiltrates
Central bronchiectasis
Peripheral eosinophilia (1,000 cells/L)

Not all of these criteria need to be present to diagnose ABPA. Withholding therapy until
the development of all clinical symptoms and evidence of bronchiectasis may lead to a
missed diagnosis in a significant number of patients and to delayed treatment resulting in
irreversible pulmonary damage. Therefore, ABPA may be subdivided into the following
groups of patients with or without central bronchiectasis.40
A. Essential criteria for the diagnosis of ABPA with central bronchiectasis :
Asthma,
Immediate skin reactivity to Aspergillus antigen
Serum IgE > 1000 ng/ml
Central bronchiectasis
B. Minimal criteria for the diagnosis of ABPA without central bronchiectasis: (labelled
ABPA-seropositive)
Asthma,
Immediate skin reactivity to Aspergillus antigen
Serum IgE > 1000 ng/ml
History of pulmonary infiltrates
Elevated levels of serum IgE and IgG antibodies to A.fumigatus

Complications of Bronchial Asthma 123

From a North Indian hospital (PGIMER, Chandigarh) a total of 651 patients with clinical
suspicion of ABPA27 were reported during a period of 8 years (January 1991 to December
1998). Overall, 338 cases (52%) were positive either by sputum microscopy/culture (66 of
203 patients), by skin reactivity (150 of 309 cases), or by precipitating antibodies (122 of 338
cases) against Aspergillus species. However, in 89 patients, diagnosis was confirmed on
the basis of Rosenbergs criteria. Clinical profile and laboratory findings showed that the
disease was more common among males. Poor control of asthma, constitutional symptoms,
mucopurulent expectoration, increased dyspnoea or wheezing and rhonchi were the main
presenting symptoms. Skin reactivity against aspergillin was seen in 73 (82%), precipitating
antibodies against aspergillus species were positive in 64 (72%) and sputum microscopy/
culture was positive in 56 (63%) of these 89 patients. Central bronchiectasis and fleeting
shadows were the most common radiological findings.
Differential Diagnosis
A number of disorders may be confused with ABPA. Tuberculosis, because of its similar upper
lobe involvement on chest X-ray, may be the initial diagnosis. It is not uncommon to find
patients receiving antitubercular therapy. A high degree of suspicion is necessary to avoid
this confusion.19 History of asthma with such chest X-ray should arouse the suspicion.
Repeated sputum examination will be negative for acid-fast bacilli. In that situation a
diagnostic work-up for ABPA is warranted. Cystic fibrosis patients also may be confused
with ABPA. In fact, these patients have a number of features in common with ABPA
including isolation of the fungus from the sputum, bronchospasm, skin test reactivity and
elevated serum IgE levels. However, the age of onset of cystic fibrosis, sweat chloride test,
and other associated nonpulmonary features will help to distinguish the two conditions.
Carcinoma of the lung, particularly, bronchoalveolar cell carcinoma, may some times be
confused with ABPA particularly in elderly individuals. The other etiologies of eosinophilic
pneumonias can usually be differentiated on clinical and immunological grounds. Although
classically ABPA is caused by Aspergillus fumigatus, some cases can also be due to other
species of Aspergillus. In recent years, allergic bronchopulmonary reactions have also been
observed due to moulds or bacteria. Stemphylum species, Helminthosporium species,
Pseudomonas aeruginosa, Curvularia lunata, Candida albicans, Dreschslera hawaiiensis, and
Torulopsis globata are examples which have been shown to cause such reactions similar to
ABPA in the lungs.
Treatment
Therapeutic approach to treat ABPA may be directed to achieve two goals: (i) to remove
the source of antigenic stimulation by eliminating the fungus from the bronchial tree; and
(ii) suppressing the bronchial hypersensitivity reactions and their associated local
parenchymal changes. The first one was thought to be achieved by employing inhalation of
anti-fungal agents such as amphotericin B, nystatin, natamycin, and cotrimazole. However
this approach has now largely been abandoned because of frequent recurrences and because
of the need for repetitive treatments more often.
Oral corticosteroid therapy is the treatment of choice in ABPA. They act by suppressing
the allergic inflammatory reaction by suppressing the immunologic response to aspergillus
antigen and decrease sputum production. Because of the later effect the bronchus becomes

124 Bronchial Asthma

less favourable for further fungal colonisation. Resolution of radiographic infiltrates and
improvements in symptoms have been observed in most patients. Prednisone therapy
maintains clinical improvement in over 80% of patients by relief of bronchospasm, clearing
of pulmonary infiltrates, and decreasing serum IgE level and peripheral eosinophilia.41,42
The current treatment of exacerbation of ABPA consists of daily administration of
prednisone in a dose of 0.5 mg/kg, given as a single morning dose for a period of two
weeks and then gradually decreasing the dose.43 This dose is usually sufficient to improve
pulmonary lesions in two weeks, at which time the same dosage is changed to a single
alternate-day regimen. This dosage is maintained for a minimum of three months. Most
patients, however, require more prolonged therapy to control their symptoms and minimize
relapse.43,44 If the chest X-ray shows improvement and there is a substantial reduction in
total serum IgE levels, slow reduction of prednisone, at a rate of 5 mg/day may be attempted.
Treatment must be individualised depending upon the stage of ABPA, frequency of
exacerbations, and severity of asthma. Monthly serum IgE levels are to be obtained, and
when a twofold increase is present, a chest X-ray should be obtained to rule out exacerbation.
Usually there is an exacerbation of symptoms during particularly seasons due to an increase
in the fungal spores in the atmosphere. This varies with geographic locations and accordingly
the steroid therapy should be reduced with caution during these months. The frequency of
chest X-ray to be taken in following a patient of ABPA is not known. It is perhaps best to
obtain the X-ray every three to six months during the first year of follow-up and on a yearly
basis thereafter to avoid missing intercurrent pulmonary damage. Serum IgE levels should
also be monitored regularly. Pulmonary function tests should be obtained yearly.
Inhaled therapy may be beneficial, but its use is limited by the degree of obstruction and
mucus plugging. Inhaled steroids are not helpful in preventing the progression of lung
damage associated with ABPA.45,46
Since there are side effects associated with long-term use of corticosteroid therapy,
including an increased risk of invasive aspergillosis,47 attempts were made to use alternative
drugs. The role of itraconazole, an anti-fungal agent has been evaluated.48 When the drug is
used in a dose of 200 mg twice daily for 4 months, 46% of the patients showed a significant
response (a 50% reduction in corticosteroid dose, a decrease of at least 25% in the serum IgE
level, and a 25% improvement in exercise tolerance or pulmonary function test results, or
the resolution or absence of pulmonary infiltrates). The study concluded that patients with
ABPA generally benefit from concurrent itraconazole therapy without much side effect
and suggested that a lower dose of 200 mg daily is equally beneficial and may be used as a
maintenance therapy to sustain remission.
The disease has been seen throughout the world and has been a subject of extensive
review from across the globe.49-53
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population is over 1 percent. Eur Respir J 1991;4(Suppl 14):1715.
2. Aggarwal AK, Behera D, Malik SK, Kumar L, Talwar P. Skin hypersensitivity and precipitating
antibodies against A.fumigatus in bronchial asthma. Lung India 1989;7:67-69.
3. Behera D, Guleria R, Jindal SK, Chakrabarti A, Panigrahi D. Allergy Bronchopulmonary
Aspergillosis: A Retrospective study of 35 cases. Indian J Chest Dis All Sci 1994;36:173-79.
4. Malik SK, Talwar P. Allergic bronchopulmonary aspergillosis. Bull PGI 1980;14:95-98.

Complications of Bronchial Asthma 125

5. Subramanium S, Viswanathan R. Allergic bronchopulmonary aspergillosis. Ind J Chest Dis
1972;14:72-77.
6. Shah JR. Allergic bronchopulmonary aspergillosis. J Ass Phys India 1971;19: 835-841.
7. Sandhu RS, Mishra SK, Randhawa HS, Prakash D. Allergic bronchopulmonary aspergillosis. in
India. Scand J Respir Dis 1972;503:289-301.
8. Pamra SP, Khan ZU, Sandhu RS, Ilyas M. Allergic bronchopulmonary aspergillosis. Ind J Tubercl
1972;19:61-67.
9. Khan ZU, Sandhu RS, Randhwa HS et al. Allergic bronchopulmonary aspergillosis. A study of
46 cases with special reference to laboratory aspects. Scand J Respir Dis 1976;57:73-87.
10. Shivpuri DN, Aggarwal MK. Studies on the allergic fungal spores of Delhi., India, metropolitan
area. J allergy 1969;44:204-13.
11. Chetty A, Bhargava S, Jain RK. Allergic bronchopulmonary aspergillosis in Indian children with
bronchial asthma. Ann Allergy 1985;54:46-49.
12. Backman KS, Roberts M, Patterson R. Allergic bronchopulmonary mycosis caused by Fusarium
vasinfectum. Am J Respir Crit Care Med 1995;152:1379-81.
13. Hinson KFW, Moon AJ, Plummer NS. Bronchopulmonary aspergillosis. A review and a report
of eight cases. Thorax 1952;7:317-33.
14. Elder JL, Smith JT. Allergic bronchopulmonary aspergillosis. Med J Australia 1967;1:231-33.
15. Patterson R, Golbert F. Hypersensitivity disease of the Lung. University Michigan Med Centre
J 1968;34:8-11.
16. Subramianiam S, Viswanathan R. Allergic aspergillosis. Ind J Chest Dis 1972;14:72-77.
17. Shah JR. Allergic bronchopulmonary aspergillosis. J Ass Phys Ind 1971;19:835-41.
18. Khan ZU, Sandhu RS, Randhawa HS, Menon MPS, Dusaj IS. Allergic bronchopulmonary
aspergillosis: A study of 46 cases with special reference to laboratory aspects. Scand J Respir Dis
1976;57:73-87.
19. Behera D, Guleria R, Jindal SK, Chakrabarti A, Panigrahi D. Allergic bronchopulmonary
aspergillosis: a retrospective study of 35 cases. Ind J Chest Dis All Sci 1994;36:173-79.
20. Bedi RS. Allergic bronchopulmonary aspergillosis: Review of 20 cases. Ind J Chest Dis All Sci
1994;36:181-86.
21. Shah A, Khan ZU, Chaturvedi S, Bazaz Malik G, Randhawa HS. Concomittant allergic Aspergillus
sinusitis and allergic bronchopulmonary aspergillosis with familial occurrence of allergic
bronchopulmonary aspergillosis. Ann allergy 1990;64:507-12.
22. Shah A, Khan ZU, Sircar M, Chaturvedi S, Bazaz Malik G, Randhawa HS. Allergic aspergillus
sinusitis; an Indian report. Respir Med 1990;84:249-51.
23. Aggarwal AK, Behera D, Malik SK, Kumar L, Talwar P. Skin hypersensitivity and precipitating
antibodies against A.Fumigatus in bronchial asthma. Lung India 1989;7:67-69.
24. Chetty A, Bhargava S, Jain RK. Allergic bronchopulmonary aspergillosis in Indian children with
bronchial asthma. Ann Allergy 1985;54:46-49.
25. Sandhu RS, Mishra SK, Randhawa HS, Prakash D. Allergic bronchopulmonary aspergillosis in
India. Scand J Respir Dis 1972;53:289-301.
26. Chakrabarti A, Sharma SC, Chander J. Epidemiology and pathogenesis of Para nasal sinus
mycoses. Otolaryngol Head Neck Surg 1992;107:745-50.
27. Chakrabarti A, Sethi S, Raman DSV, Behera D. Eight-year study of allergic bronchopulmonary
aspergillosis in an Indian teaching hospital. Mycoses 2002;45:295-99.
28. Basich JE, Graves TS, Baz MN et al. Allergic bronchopulmonary aspergillosis in corticosteroid
dependent asthmatics. J Allergy Clin Immunol 1981;68:98-102.
29. Mrouch S, Spok A. Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.
Chest 1994;105:32-36.
30. Knutsen AP, Slavin RG. Invitro T-cell response in patients with cystic fibrosis and allergic
bronchopulmonary aspergillosis. J Lab Clin Med 1989;113:428-35.

126 Bronchial Asthma

31. Chauhan B, Santiago I, Kirschmann DA et al. The association of HLA-DR alleles and T-cell
activation with allergic bronchopulmonary aspergillosis. J Immunol 1997;159:4072-76.
32. Wang JL, Patterson R, Rosenberg M et al. Serum IgE and IgG antibody activity against Aspergillus
fumigatus as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis
1978;117:917-27.
33. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Ann Rev Med 1999;50:303-16.
34. Bosken CH, Myers JL, Greenberger PA et al. Pathologic features of allergic bronchopulmonary
aspergillosis. Am J Surg Pathol 1988;12:216-22.
35. Rosenberg M, Patterson R, Mintzer R et al. Clinical and immunological criteria for the diagnosis
of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14.
36. Patterson R, Greenberger PA, Radin RC et al. Allergic bronchopulmonary aspergillosis: staging
as an aid to management. Ann Intern Med 1982;96:286-91.
37. Patterson R, Greenberger PA, Hawig JM et al. Allergic bronchopulmonary aspergillosis; natural
history and classification of early disease by serologic and roentgenographic studies. Arch Intern
Med 1986;146:916-18.
38. Mintzer RA, Rogers LF, Kruglik GD et al. The spectrum of radiologic findings in allergic
bronchopulmonary aspergillosis. Radiology 1978;127:301-07.
39. Greenberger PA, Patterson R. Diagnosis and management of allergic bronchopulmonary
aspergillosis. Ann allergy 1986;56:444-48.
40. Greenberger PA. Immunologic aspects of lung diseases and cystic fibrosis. JAMA 1997;278:
1924-30.
41. Rosenberg M, Patterson R, Robert M et al. The assessment of immunologic and clinical changes
occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med
1978;64:599-606.
42. Wang JL, Patterson R, Roberts M et al. The management of allergic bronchopulmonary
aspergillosis. Am Rev Respir Dis 1979;120:87-92.
43. Capewell S, Chapman BJ, Alexander F et al. Corticosteroid treatment and prognosis in pulmonary
eosinophilia. Thorax 1989;44:925-29.
44. Safirstein BH, DSouza MF, Simon g et al. Five-year follow-up of allergic bronchopulmonary
aspergillosis. Am Rev Respir Dis 1973;108:450-59.
45. British Thoracic Association. Inhaled beclamethasone dipropionate in allergic bronchopulmonary
aspergillosis: Report to the Research Committee of the British thoracic Association. Br J Dis
Chest 1979;79:349-56.
46. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest
2002;121:1988-99.
47. Ganassinni A, Cazzadori A. Invasive pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis. Respir Med 1995;89:143-45.
48. Stevens DA, Schwartz HJ, Lee JY et al. A randomised trial of itraconazole in allergic
bronchopulmonary aspergillosis. N Engl J Med 2000;342:756-62.
49. Davis SF, Sarosi GA. Role of serodiagnostic tests and skin tests in the diagnosis of fungal disease.
Clin Chest Med 1987;8:135.
50. Pennington JE. Aspergillus lung disease. Med Clin North Am 1980;64:475.
51. Glimp RA, Bayer AS. Fungal pneumonias. Part 3. Allergic bronchopulmonary aspergillosis.
Chest 1981;80:85
52. Ricketti AJ, Greenberger PA, Mintzer RA, Patterson R. Allergic bronchopulmonary aspergillosis.
Chest 1984;86:773.
53. Fink JN. Allergic bronchopulmonary aspergillosis. Chest 1987;87(Suppl):81S.

Management of Bronchial Asthma 127

9
Management of
Bronchial Asthma
A number of guidelines on the management of bronchial asthma, both in children and
adults are developed in recent years.1-11 They include those of the British Thoracic Society,
NHLB, USA, and the Global Initiative for Asthma, etc. The recommendations are based on
the same principle and basically the same. The goals of management of bronchial asthma
as recommended by these agencies are as follows:
i. To recognise asthma
ii. To maintain a normal activity level including exercise.
iii. To maintain a normal or near normal (best) pulmonary function rates.
iv. To prevent chronic and troublesome symptoms like coughing or breathlessness in the
night, early in the morning, or after exertion.
v. To prevent recurrent exacerbations.
vi. To minimise absence from work or school
vii. To enable normal growth to occur in children, and
viii. To use the least minimum drugs to avoid adverse reactions from medications used
for asthma.
Since bronchial asthma is a chronic condition with acute exacerbations, treatment requires
a continuous care approach to control symptoms, to prevent exacerbations, to treat
adequately such exacerbations, and to reduce chronic airway inflammation. Prevention of
exacerbation is an important principle of therapy. This includes avoidance of triggers and
allergens. Round-the-clock medication may be beneficial to many patients. Children and
adults, who have poor exercise tolerance, recurrent symptoms, and frequent nocturnal
attacks and patients with moderate asthma will often benefit from the regular administration
and more aggressive use of antiasthma medication, particularly anti-inflammatory drugs.
In contrast, patients with mild intermittent asthma with uninterrupted sleep at night, and
good exercise tolerance may need only occasional treatment for the relief of symptoms.
Periodic assessment of these patients is essential to assure that their therapy is appropriate.
The treatment of asthma should also be based on the understanding of the underlying
pathophysiologic mechanisms and the objective assessment of severity of the disease. It is
now appreciated that asthma is an inflammatory disease and therapy should include antiinflammatory agents to reduce inflammation and to relieve or prevent symptomatic airway
narrowing. Anticipatory or early interventions in treating acute exacerbations of asthma
reduce the likelihood of developing severe airway narrowing.

128 Bronchial Asthma

Thus, the integral components of asthma therapy include patient education, environmental control, and medication with the use of objective measures to monitor the severity
of disease and the efficacy of therapy. The interrelationship of all these approaches is shown
in Figure 9.1.
Basically the treatment of asthma consists of both;
i. Nonpharmacologic therapy and
ii. Pharmacologic therapy.
The optimal nonpharmacological treatment consists of
i. Patient and family education;
ii. Avoidance of agents that induce or trigger asthma like allergens, irritants like
smoke, and reasonable attempts at reducing exposure to respiratory viruses; and
iii. Immunotherapy.
The pharmacologic therapy is used to treat reversible airflow obstruction and
airway hyper-responsiveness. Medications include bronchodilators and antiinflammatory agents with some acting as both.
NONPHARMACOLOGIC MANAGEMENT
Patient and Family Education
Patient education by the treating physician is a powerful tool for helping patients to gain
self-confidence to control their asthma.12,13 Since much of the day-to-day responsibility for

Fig. 9.1: General principles of management of asthma

Management of Bronchial Asthma 129

managing asthma falls on the patient and the patients family, encouraging active
participation in a partnership with the clinician can improve patient adherence to the
treatment plan and stimulate family effort to improve control of asthma.14,15 In fact a patient
is his best physician since he alone can recognise well about his illness, its progression,
regression, response to treatment, and imminent acute attack. It should start at the time of
diagnosis and should be continued throughout as an integral component during continued
care. Family participation is an essential component of this programme. Establishment of a
partnership with the patient, encouraging adherence to the treatment plan, teaching about
the triggers (exercise, viral respiratory tract infections, allergens and irritants) and how to
avoid, eliminate, or control them, explaining the patient regarding medications both
preventive and rescue therapy, their adverse effects and educating about the adverse drug
reactions are important components of this plan. Moreover teaching the patient how to
recognise the severity of asthma and the appropriate time to seek medical advice during
acute exacerbations are important. Giving information alone does not alter behaviour.
Written and audiovisual reinforcement of spoken language further helps patient confidence.
Giving these informations along with written self management plans will help the patient
who may adjust treatment to keep themselves symptom free that reduces morbidity and
health costs.16,17 Although now there is definite evidence of benefit from patient education
and issuing of self management plans, certain areas like who need them, and what form
they should take (number of action levels, thresholds for intervention) are poorly defined.
Proper use of inhalers is very essential.18,19 Patient should demonstrate use of the metereddose inhaler to the physician, and the technique should be reviewed at every visit. Since
home-monitoring of PEFR is an essential component of asthma management, the patient
needs to be taught how to use a peak flow meter correctly and how to interpret it.20,21
Psychosocial issues as outlined above which increases asthma morbidity and mortality
need to be taken care of.
Management of Allergy
Since allergy has a very significant role in the pathophysiology of asthma, interventions to
control this are important. There can be two ways to approach this problem: (i) environmental
controls; and (ii) immunotherapy.

Environmental Control
Outdoor allergens like pollens and mould are best avoided by staying indoors particularly
during the midday and afternoons. An air conditioned environment is the best way. Various
nasal filters are available, which may be helpful to prevent penetration of allergens. However,
this has not been proved to be very effective.
Indoor allergen elimination is possible by paying special attention to the following. To
avoid exposure to animal danders, the animal should be removed from the house. Removal
of pets may not afford immediate relief even when followed by vigorous cleaning, since
allergens continue to stay in the home for many months. Application of 3% tannic acid will
denature and render such substances nonallergic. If the pet cannot be kept out of the house,
there should be least contact with the patient and the animal should not be allowed at all to
the bed room. Washing and bathing the pet frequently may reduce the amount of dander
and dried saliva to be deposited on carpets and furnitures.22

130 Bronchial Asthma

Reducing exposure to dust mites can be achieved by the following four plans of
attack:23-25
a. By placing barriers between the patient and reservoirs of dust mite Elimination of mite exposure
is possible by encasing the mattress in an airtight cover and encasing the pillow,
particularly plastic mattress covers. These are not only inexpensive, but they effectively
reduce dust mite exposure and clinical symptoms of asthma. Microporous covers are
also available which allow passage of water vapour for patient comfort while excluding
mites and their allergens.
b. To kill and remove mites Regular washing of bedding and pillows by washing it at least
once weekly. The bedding should be washed in hot water (>58C) frequently. This kills
mites and removes mites from an important exposure source. Ascaricides, tannic acid,
dry heating, and liquid nitrogen have been used to kill mites, but they need further
study particularly in terms of side effects to the patient and they need professional
application.26 It is also important to remove the dead mites once they are killed, by
vacuuming otherwise they continue to be the source antigen. HEPA filtration removes
air-borne mites but leaves undisturbed the major reservoir antigen in carpets, beddings,
and upholstery.
c. Making the environment less hospitable for mites The patient should avoid sleeping or lying
on upholstered furnitures. The carpets and other dust collectors that are laid on concrete
are to be removed. Reduction of indoor humidity to less than 50% by air conditioning or
mechanical ventilation are less favourable to the growth of mites. Although not so effective
in removing live mites, regular vacuuming removes their food and shelter.
d. To remove the patient to dust-free environment Although practically inconvenient and
expensive, this is a very effective measure, and can be adopted whenever feasible while
dust busting is completed at home.
To prevent growth of moulds, special attention should be paid to areas with increased
humidity. Such areas like bathrooms, kitchens, and basements require adequate ventilation
and frequent cleaning using chlorine bleach. Sweat on foam pillows encourage mould
growth. They should be encased or changed frequently. While cleaning, the patient should
wear a dust mask. Climate control by air conditioning is beneficial, because it allows
windows and doors to be closed and by reducing indoor humidity, discourages mould and
mite growth. Humidifiers are potentially hazardous. If not cleaned regularly and properly,
they facilitate the growth and aerosolise mould spores. A number of other devices are
available for cleaning allergens from the indoor air. Two such major devices are mechanical
filters and electrical filters.
Other indoor irritants like tobacco smoke,27 wood smoke, strong odours or sprays
(perfumes, talcum powders), household cleaning substances, and fresh paints irritate the
airway and trigger asthma symptoms. Therefore, these should be avoided. Exposure to
ozone and sulphur dioxide worsen asthma by interacting with allergens or other triggers
and should be avoided as far as possible. Since occupational exposure is an important cause
of bronchial asthma in adults, avoidance to such exposure is important. However, patients
with suspected occupational asthma should not be advised to cease work until the diagnosis
is proven and until all methods for reducing exposure at the work place have been explored.
Specialist respiratory physician, occupational physicians, and employers will all need to be
involved in this process.

Management of Bronchial Asthma 131

Immunotherapy
Allergenic extract immunotherapy is in use since the early 1900s in an attempt to protect
against grass pollen. Allergy immunotherapy has been shown to reduce the symptoms of
asthma in a number of double-blind studies with a wide variety of allergens, including
house-dust , grass pollen , cat dander and cladosporium and alternaria.28-31 Such therapy
reduces the late reaction to allergens in the lung, reduces asthma symptoms following
injections. Long-term use also reduces bronchial hyperresponsiveness. These suggest that
allergen immunotherapy can be employed to prevent the development of allergic
inflammation and perhaps the resulting bronchial hyperresponsiveness.32-37 However, the
British Thoracic Society guidelines recommends that hyposensitisation (immunotherapy)
is not indicated in the management of bronchial asthma.9
This therapy is employed only after performing a careful diagnostic study of history and
skin tests to identify possible offending inhalant allergens. The history of symptoms must
correlate accurately with allergen exposure with confirmed IgE-mediated reactivity to one
or more suspected allergens, usually by wheal and flare skin reactivity or by serology such
as RAST.
The decision regarding immunotherapy depends upon three important considerations.
(i) It must be established that there is a clinically important allergic component to asthma.
(ii) In patients with a significant allergic components who are not obtaining full clinical
improvement with standard environmental control and medication, and (iii) Failure of
maximal environmental control measures.
Currently the methods and frequency of administration of allergenic extract
immunotherapy vary considerably. The dosage and frequency vary considerably. The
allergens used are often poorly standardised and characterised, and the methodology is illdefined. With most forms of allergenic extracts, the initial frequency of injections is usually
once weekly, with doubling of the dosage at regular intervals and progression to a series of
monthly maintenance injections, depending upon the antigen preparation employed and
the individual patient requirements. The therapy is dose-dependent and specific for the
allergen employed, the higher the dose, the greater the clinical improvement. Allergic signs
and symptoms may develop subsequent to injections, manifested either as local or systemic
anaphylactic reactions (rare). There are no well-defined guidelines regarding the duration
of therapy.
Most physicians attempt to discontinue therapy after three or four years of a successful
regimen, The National Blood, Heart, and Lung Institute, USA1 recommends that once patient
achieves maintenance levels of immunotherapy, the interval between injections should be
extended, with a goal of monthly injections. If the patients symptoms improve, treatment
is usually continued for 3-5 years, although under some circumstances more prolonged
therapy at monthly intervals may be warranted. If there is no evidence of response following
two allergy seasons after reaching the maintenance or highest level tolerated by the patient,
immunotherapy should be discontinued. Allergy immunotherapy should be administered
only under the direct supervision of a physician who is adequately trained.
The mechanisms for clinical improvement are unknown, but one or more immunological
changes may be responsible for such improvement. Among these changes are:
a. A rise in serum IgG blocking antibodies;
b. Suppression of the usual seasonal rise in IgE antibodies, which follows environmental
exposure,

132 Bronchial Asthma

c. An increase in blocking IgG and IgA antibodies in respiratory secretions,
d. A reduced basophil reactivity to allergens,
e. Reduced lymphocyte responsiveness to allergen, and
f. An increase in specific T-suppressor cell generation.
However, the problem of immunotherapy is the recognisation of the allergen. Most of
the times, identification is not feasible and as mentioned, immunotherapy is only allergenspecific. The duration of treatment is often prolonged and costly. Moreover relapse occurs
in most patients after discontinuation of therapy. Therefore, immunotherapy is not widely
used as an important component in the management of bronchial asthma.
REFERENCES
1. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and
management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health,
Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991.
2. Guidelines for the management of asthma in adults. 1-Chronic persistent asthma. Statement by
the British Thoracic Society, Research Unit of the Royal College of Physicians of London, Kings
Fund Center, National Asthma Campaign. BMJ 1990;301:651-53.
3. Guidelines for the management of asthma in adults. 2-Acute severe asthma. Statement by the
British Thoracic Society, Research Unit of the Royal College of Physicians of London, Kings
Fund Center, National Asthma Campaign. BMJ 1990;301:797-800.
4. Warner JO, Gotz M, Landau LI et al. Management of asthma: A consensus statement. Arch Dis
Child 1989;64;1065-79.
5. International Paediatric asthma Consensus Group. Asthma, a follow-up statement. Arch Dis
Child 1992;67:240-48.
6. International Consensus report on the diagnosis and management of asthma. Clin Exp Allergy
1992;22(Suppl):1-72.
7. British thoracic Society and others. Guidelines for the management of asthma: A summary. BMJ
1993;9:287-92.
8. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax
1997;52(Suppl 1): S2-S8.
9. British thoracic Society, British Paediatric Association, Royal College of Physicians of London,
The Kings Fund Center, national asthma Campaign et al. Guidelines on the management of
asthma. Thorax 1993;48:S1-S24.
10. British thoracic Society, British Paediatric Association, Royal College of Physicians of London,
The Kings Fund Center, national asthma Campaign et al. Summary charts. BMJ1993;306:77682.
11. Global Initiative for Asthma. A practical guide for public health officials and health care
professionals. US Department of Health and human services. NIH Publication No. 96-3659A,
December 1995.
12. Brewis RAL. Patient education, self-management plans and peak flow measurements. Respir
Med 1991;85:457.
13. Feldman CH, Clark NM, Evans D. The role of health education in medical management in asthma.
Clin Rev Allergy 1987;5:195-205.
14. Mellians RB. Patient education is key to successful management of asthma. J Rev Respir Dis
1989;Suppl:S47-S52.
15. Clark NC. Asthma self-management education: Research and implications for clinical practice.
Chest 1989;95:1110-13.
16. DSouza W, Crane J, Burgess C, et al. Community-based asthma care; trial of a credit card
asthma self-management plan. Eur Respir J 1994;7:1260-65.

Management of Bronchial Asthma 133

17. Iganacio-Gracia JM, Gonzalez-Santos P. Asthma self management education programme by
home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151:353-59.
18. Shim C, Williams MH. The adequacy of inhalation of aerosol from canister nebullisers. Am J
Med 1980;69:891-94.
19. Newman SP, Pavia D, Clarke SW. Simple instructions for using pressurised aerosol bronchodilators. J R Soc Med 1980;73:776-79.
20. Vathenen AS, Cooke NJ. Home peak flow meters. Br Med J 1991;302:738.
21. Mendoza GR. Peak flow monitoring. J Asthma 1991;28:161.
22. Glinert R, Wilson P, Wedner HJ. Fel; D1 is markedly reduced following sequential washing of
cats. J Allergy Clin Immunol 1990;85:225.
23. Wallshaw MJ, Evans CC. allergen avoidance in house dust mite sensitive adult asthma. Q J Med
1986;58:199-215.
24. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Sehou C, Wahn U. Reducing domestic
exposure to dust mite allergen reduces bronchial hyper-reactivity in sensitive children with
asthma. J Allergy Clin Immunol 1993;90:135-38.
25. Murray AB, Fergusson AC. Dust free bedroom in the treatment of asthmatic children with house
dust mite allergy: A controlled trial. Paediatrics 1983;91:418-22.
26. Colloft MJ, Ayres J, Carswell F, et al. The control of dust mites and domestic pets: A position
paper. Clin Exp Allergy 1992;22(Suppl 2):1-28.
27. Andrae S, Axelson O, Bjorksten B, Fredriksson M, Kiellman NM. Symptoms of bronchial hyper
reactivity and asthma in relation to environmental factors. Arch Dis Child 1988;63:474-78.
28. Reid MJ, Moss RB, Hsu YP. Seasonal asthma in Northern California; allergy causes and efficacy
of immunotherapy. J Allergy Clin Immunol 1986;78:590-600.
29. Aas K. Controlled trial of hyposensitisation to house dust. Acta Paediatrc Scand 1971;60:264-68.
30. Ohman JL Jr, Findlay SR, Leiterman KM. Immunotherapy in cat-induced asthma: Double-blind
trial with evaluation of in vivo and invitro responses. J Allergy Clin Immunol 1984;74:230-39.
31. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Double-blind, placebo-controlled rush
immunotherapy with a standardised alternaria extract. J Allergy Clin Immunol 1990;85:460-72.
32. Lilja G, Sundin B, Graff-Lonnevig v, et al. Immunotherapy wit cat and dog dander extracts IV.
Effect of 2 years treatment. J Allergy Clin Immunol 1989;83:37-44.
33. Bousquet J, Maasch HJ, Hejjaoui A et al. Double-blind, Placebo-controlled immunotherapy with
mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecularweight preparations in rhinoconjunctivitis and asthma. J Allergy Clin Immunol 1989;84:546-56.
34. Boulet LP, Cartier A, Thomson NC et al. Asthma and increases in nonallergic bronchial
responsiveness from seasonal exposure. J Allergy Clin Immunol 1983;71:399-406.
35. Van Bever HP, Stevens WJ. Suppression of late asthmatic reaction by hyposensitisation in
asthmatic children allergic to house dust mites (Dermatophagoides pteronyssiunus). Clin Expt
Allergy 1989;19:399.
36. Chapman MD. Use of nonstimulatory peptides: A new strategy for immunotherapy? J Allergy
Clin Immunol 1991;88:300.
37. Hoshino K, Hawasaki A, Mizushima Y, Yano S. Effect of antiallergic agents and bronchial
hypersensitivity in short-term bronchial asthma. Chest 1991;100:57.

134 Bronchial Asthma

10
Pharmacologic
Management of Asthma
The drugs used for the treatment of bronchial asthma are classified as:
1. Bronchodilators
-adrenergic agonists
Anticholinergics
Methylxanthines (now can be classified as anti-inflammatory)
2. Anti-inflammatory agents
Corticosteroids
Cromolyn sodium or cromolyn-like compounds
Methylxanthines
Leukotriene antagonists
Miscellaneous compounds including antihistamines.
METHYLXANTHINES
Theophylline, the principal methylxanthine used in asthma therapy over the past six decades
and the most widely prescribed anti-asthma treatment worldwide, is a dimethylxanthine
similar in structure to the common dietary xanthines, caffeine and theobromine.1-3 Other
substituted xanthines have also bronchodilator property and include: Dyphylline
(dihydroxypropyl theophylline), Etophylline (-hydroxyethyl theophylline), Proxyphylline
(-hydroxypropyl theophylline), and Enprophylline (3-propylxanthine).
Many salts of theophylline preparations are commonly marketed and have been in
use over many years. Aminophylline, the ethylenediamine salt is perhaps the commonest
compound used in many countries. Other commonly salts include formulations with calcium
salicylate, sodium glycinate, and choline (oxtryphylline).
Mechanism of action of theophylline remains unclear despite the long history and
widespread use of the drug.4 Various mechanisms proposed for the molecular mechanism
of action has been proposed and are shown in Table 10.1.
Phosphodiesterase Inhibition
Earlier it was believed that theophylline acts as an anti-asthma drug as it relaxes bronchial
smooth muscle. Although the exact mechanism of such relaxation was not known, in vitro,
theophylline inhibits phosphodiesterase (PDE) which breaks down cyclic nucleotides in
the cell, that results in delayed degradation of cAMP and cGMP. Several families of PDE

Pharmacologic Management of Asthma 135

Table 10.1: Mechanism of action of theophylline
Phosphodiesterase inhibition
Adenosine receptor antagonist
Increase in circulating adrenaline
Mediator antagonism (anti-inflammatory effect)
Inhibition of calcium ion flux
Effect on respiratory muscles

are now recognised,5 of which PDE III is predominant in airway smooth muscle relaxation
and PDE IV is important in inflammatory cells.5-8 Theophylline is a nonselective PDE
inhibitor. Such inhibition occurs at concentrations ten-fold higher than those usually attained
clinically. Total PDE activity in human lung extracts is inhibited by only 5-20% at therapeutic
concentrations of theophylline.9,10 However, this modest inhibition may be sufficient to cause
a substantial increase in intracellular cyclic nucleotide levels in the presence of endogenous
activators of adenylyl cyclase.11 Inhibition of PDE could also lead to synergistic interaction
with -agonists. Since there is some evidence that PDE levels may be higher in asthmatics
than normal individuals, theophylline may have a greater than expected inhibitory effects
on PDE in asthmatic airways than in normal airways. 12 Bronchodilating effects of
theophylline appear to closely parallel the serum concentrations. Although a steady-state
serum concentration between 10-20 g/ml gives optimal effect, a more conservative
approach would be to aim for levels between 5-15 mg/ml. Since there is a linear relationship
between log serum concentration and bronchodilator effect within this range, the dose should
be increased if symptoms persist and the patient is at the lower end of the serum
concentration range.
Adenosine Receptor Antagonism
Adenosine causes bronchoconstriction in bronchial asthma both in vitro and clinically when
given by inhalation.13,14 This involves the release of histamine and leukotrienes from airway
mast cells. This bronchoconstricting effect of adenosine is prevented by theophylline.15 This
shows that theophylline is capable of antagonising the effects of adenosine at therapeutic
concentrations. Theophylline is a potent inhibitor of adenosine receptors (both A1 and A2
receptors) at therapeutic concentrations and this may be the basis of its bronchodilator
effect.16 Since the potent bronchodilators enprophylline doxofylline, do not have action against
adenosine receptors, adenosine antagonism may not be the exact cause of bronchodilatation.
However, inhibition of different adenosine receptor types and subtypes may be important
for this differential action.
Increased Catecholamine Release
Intravenous theophylline increases the secretion of adrenaline from the adrenal medulla.17,18
Although the increase is small, it may be important.
Anti-inflammatory Effect
Recent evidence shows that theophylline may also possess some anti-inflammatory activity.19
Theophylline reduces both bronchial hyper-reactivity20,21 and the inflammatory response.
The anti-inflammatory effect has been shown both in vitro and in vivo studies. The effects

136 Bronchial Asthma

include decreased mediator release from mast cells, decreased release of reactive oxygen
species from macrophages, decreased cytokine release from monocytes, decreased basic
protein release by eosinophils, decreased proliferation of T-lymphocytes, decreased release
of ROS (reactive oxygen species), and inhibition of late response to allergens, increased
+
CD8 cells in peripheral blood and decreased T-lymphocytes in airways in asthmatic patients.
Theophylline inhibits plasma exudation in guinea pigs.20 It also demonstrates immunomodulatory effects in vivo because of the inhibitory effects on T-lymphocytes. The antiinflammatory effect is seen in much lower concentrations than its bronchodilatory
concentrations.
Effect on Respiratory Muscles
In addition to bronchodilatation, it improves respiratory function by increasing the strength
and reducing the fatigue of respiratory muscles particularly diaphragm.21,22 A number of
studies suggest that during various contractile maneuvers theophylline increases Pdi/Edi,
where Pdi denotes intrathoracic pressure swings across the diaphragm which reflects muscle
force and Edi is the electromyographic recordings taken at the skin surface opposite the
diaphragm insertion to measure the nervous input to the muscle. The ratio represents force/
unit of input.
Inhibition of Calcium Ion Flux and Other Extrapulmonary Effects
Some evidence suggest that theophylline may interfere with calcium mobilisation in airway
smooth muscle. Although it has no effect on entry of calcium ions through voltage-dependent
channels, it may influence calcium entry via receptor-operated channels. Other possible
effects may be release of calcium from intracellular stores or may have some effect ion
phosphatidylinositol turnover which is linked to release of calcium ion from intracellular
stores. Theophylline may increase calcium uptake into the intracellular stores also.23,24
The drugs also increase mucociliary clearance. Other pharmacological effects of
theophylline include a transient diuretic effect, stimulation of the central nervous system,
cerebral vascular constriction, gastric acid secretion, and inhibition of uterine contractions.
These effects are of little clinical importance when appropriate doses are used for the
treatment of asthma (or apnea of prematurity). Theophylline also exert activity on cardiac
ventricular contractility.
Theophylline is rapidly and completely absorbed from the gastrointestinal tract when it
is administered in the form of solutions and tablets. Once absorbed, it is distributed rapidly
through extracellular body fluid, and to some extent into intracellular space. Theophylline
is then eliminated through multiple parallel pathways that include demethylation and
oxidation. Approximately 90% of orally administered theophylline is metabolised in liver.
The drugs elimination is reduced by such factors as liver disease, congestive heart failure,
sustained high fever, and with drugs like cimetidine, troleandomycin, and erythromycin.
Therefore, the dose of the drug should be reduced in these circumstances. Cigarette and
marijuana smoking, phenobarbital, phenytoin, and intravenous isoproterenol increases the
elimination of the drug. Major changes in diet also have a potential effect with 25% increases
in clearance associated with a low carbohydrate, high protein diet and about a 25% mean
decrease in clearance associated with a high carbohydrate low protein diet. The drug is also
eliminated rapidly from the body by some individuals, especially children. In obese individuals,

Pharmacologic Management of Asthma 137

with greater than 120% ideal body weight, initial theophylline should be calculated on the
basis of ideal rather than actual body weight to avoid overdosing.
Theophylline has long been marketed in a wide variety of formulations. The traditional
preparation for oral and parenteral use has been theophylline with ethylenediamine known
as aminophylline. Suppository and rectal solutions are also available. Fixed dose combinations of theophylline with ephedrine that were the most frequently used formulations
previously were associated with synergistic toxicity while providing a small additive effect.
They are now not been used. During the past decade, newer formulations have been
developed with slower controlled release preparations because of unacceptable fluctuations
during the use of plain tablets. Both twice-dosing and once-a day dosing are now available.
Although once-a-day dosing may be satisfactory in adults who eliminate the drug slowly,
substantial peak-to-trough differences in serum concentrations are found in individuals
who eliminate the drug rapidly. Furthermore, intestinal transit time in some patients may
be so rapid that sustained-release preparations designed to release drugs especially slowly
with long absorption half-lives, will pass out of the gut before absorption is complete. These
longer acting preparations may also be affected by the presence of food in the gut or by the
fat content. In some cases, the rate of drug release is greatly accelerated, and in other cases
drug absorption is impaired. Other products are relatively unaffected by food administration.
One should be familiar with these properties of the product selected.
Theophylline is used for the treatment of both acute and chronic asthma. In chronic
asthma, the usual starting dose is 10 mg/kg/day up to 800 mg maximum dose. In children
the starting dose is 10 mg/kg/day; with usual maximum is as;
1 year or more
< 1 year

16 mg/kg/day
0.2(age in weeks) + 5 = mg/kg/day

For the management of acute asthma, the drug may have an additive effect on other
medications. Intravenous aminophylline has been used in the management of acute severe
asthma for over 50 years. However, its has been questioned recently in view of the risk of
adverse effects compared with nebulised -agonists. Intravenous aminophylline is less
effective than nebulised -agonists.25 Thus some authors recommend that the drug should
be reserved for those patients who fail to respond to -agonists. On the other hand, there
are evidences to suggest that use of aminophylline in the emergency room reduces
subsequent admissions to hospitals.26 There is no added advantage if aminophylline is used
in addition to -agonists. Use of intravenous aminophylline may increase the death rates.27
However, this is a drug which is cheap and still used as an important drug in many hospitals
in the management of acute severe asthma. Whenever a decision is taken to use
aminophylline intravenously, it should be given as a slow intravenous infusion with careful
monitoring and a plasma theophylline concentration should be monitored, if possible, prior
to infusion. The loading dose is aimed for a target serum concentration no higher than the
mid point of the 10 to 20 g/ml that is determined by multiplying the desired change in
serum concentration by an average volume distribution of about 0.5 L/kg. In other words,
each g/ml increase in serum concentration requires 0.5 mg/kg of a loading dose. A repeat
serum concentration 30 minutes after the loading infusion determines the need for an
additional loading dose and provides a baseline for monitoring change during a subsequent
maintenance infusion. A conservative maintenance infusion based on mean clearance and
targeting a steady state serum concentration of 10 g/ml is maintained with as follows:

138 Bronchial Asthma

Infants under age 1
0.008 age in weeks + 0.22 mg/kg/hr
Children (1-9 years)
0.8 mg/kg/hr
Children (9-16 years)
0.6 mg/kg/hr
Adults
0.4 mg/kg/hr
The adult dose should be decreased by one half for those with heart failure or liver disease.
Subsequent infusion is adjusted according to the serum concentration.
The other important use of theophylline is its use as maintenance therapy for chronic
asthma. To attend an optimal dosage one should proceed with patience. Rapid attainment
of therapeutic concentrations is associated with a high degree of minor complaints which
may discourage the patient from continuing therapy. Therefore, the aim should be to attend
such optimum concentration over a period of 1-2 weeks. Because of the variability in the
rates of elimination, the final doses requirements are highly variable. While average doses
are higher on a weight-adjusted basis for children than adults, considerable variability is
observed at all ages. According to these principles the initiation of therapy should be at
doses of 400 mg/day or 16 mg/kg/day, whichever is less. Since this dosage is low, adequate
control of symptoms is not expected and for that period, another drug should be used for
control of symptoms. The dose is then to be increased every three days to 600 mg/day for
those more than 45 mg/kg or if the patient weighs less than 45 mg/kg, either 600 mg/kg or
16-20 mg/kg, whichever is less. After the next three days, the dose is to be increased to
800 mg/kg for those more than 45 kg in weight and if less than 45 kg in weight, the dose
should be 800 mg/day or 18-24 mg/kg/day, whichever is less. The dose is then adjusted
according to the serum concentration which should be measured about 4 hours after a dose
when none have been missed or added for three days.
Theophylline has little or no effect on bronchomotor tone in normal airways, but it reverses
bronchoconstriction in asthmatics. The routine of theophylline in chronic stable asthma has
recently been questioned.28-30 In various guidelines of management of bronchial asthma
(discussed subsequently), theophylline is used as an additional bronchodilator if asthma
remains difficult to control after moderate to high dose inhaled steroids. The recent use of
salmeterol and formoterol may still threaten the position of theophylline. Nonetheless, the
drug is cheap and is in use for several decades in many developing countries as a main stay
of treatment.
Monitoring serum concentrations is an important part of acute or chronic care of asthma.
The frequency of measurements depend upon the specific clinical situation. Monitoring is
required in those who fail to exhibit the expected clinical effect while receiving an appropriate
therapeutic regimen and in patients who develop an adverse effect to an usual dose. It is
useful to monitor serum theophylline concentrations when a patient begins his therapy
and then at 6-12 months, as long as no adverse effects are observed. The therapeutic range
of theophylline was based on measurements of acute bronchodilatation in response to the
acute administration of theophylline.31 However, it is possible that the nonbronchodilator
effects of theophylline may be exerted at lower plasma concentrations. Since side effects
are also related to plasma concentration, these may be markedly reduced by aiming for
plasma concentrations of 5-15 mg/l (28-55M), rather than the previously recommended
doses of 10-20 mg/l (55-110M). This level should be in the steady state (at least 48 hours in
the same dose). Improvements in slow-release preparations, including that of once-a-day
products, have further improved the problem of fluctuations in plasma concentrations.

Pharmacologic Management of Asthma 139

Side Effects
The signs and symptoms of theophylline intoxication involve many organ systems. The
commonest toxicity are caffeine-like side effects including minor degrees of central nervous
stimulation, headache, restlessness and nausea and vomiting or a queasiness of the stomach
occur frequently after a loading dose and have no direct relationship to the serum
concentration. Most patients rapidly acquire tolerance of these side effects when therapy is
maintained and avoid them when the dose is gradually built up. As serum concentrations
exceed 20 g/ml, there is an associated progressively increasing risk of more serious side
effects including seizures and death, most commonly when the level exceeds 40 g/ml.
The seizures may not be preceded by other central nervous system symptoms.
Cardiopulmonary effects include tachycardia, and arrhythmias even at serum concentrations
considered to be therapeutic. Multifocal atrial tachycardia may herald sudden cardiac
death.32 Other adverse effects include stimulation of respiratory center causing tachypnoea,
diuresis, relaxation of the detrusor muscle causing difficulty in urination in older men with
prostatism, and important metabolic effects such as hyperglycaemia and hypokalaemia.
The effect of theophylline on behaviour and learning of children have received attention
recently. Because the drug stimulates the central nervous system, it may produce behaviour
disturbances in children. Of more serious consequence are the reports that its use is associated
with impairment of learning,33-35 although a carefully designed study could not confirm
this.36
Some of the side effects of theophylline like central stimulation, gastric secretion, diuresis,
and arrhythmias may be due to adenosin receptor antagonism and may, therefore, be
avoided by drugs such as enprofylline, which has no significant adenosine antagonism at
bronchodilator doses.37 However, the commonest side effects of theophylline like nausea,
vomiting and headache are also seen with enprofylline.38
Prevention of toxicity is important by monitoring the serum concentrations and by aiming
for lower plasma concentrations as indicated earlier to some extent, side effects may be
reduced by gradually increasing the dose until therapeutic concentrations are achieved .39-41
Acute accidental or suicidal overdoses of theophylline are better tolerated than sustained
high levels encountered due to uncontrolled therapy. Since theophylline-induced seizures
are more dangerous including brain damage and death, an aggressive approach to the
treatment of an overdose is necessary. Initial therapy with ipecac or other measures to
induce vomiting removes remaining aminophylline in the stomach. Activated charcoal stops
further absorption, and simultaneous administration of a cathartic such as sodium sulphate
increases the transit time of charcoal and any remaining undisclosed drug. Repeated doses
of activated charcoal increases the rate of elimination of theophylline already absorbed by
two folds, possibly due to the result of a gastrointestinal dialysis. Extracorporeal charcoal
haemoperfusion allows more rapid clearance. There are many factors which affect serum
theophylline concentrations. These factors and actions to be taken are shown in Table 10.2.
-ADRENERGIC AGONISTS
Normal -adrenergic Receptor Physiology
The autonomic nervous system is responsible for regulating the airway tone through the
release of neurotransmitters that activate specific autonomic receptors. The autonomic

140 Bronchial Asthma

Table 10.2: Factors affecting serum theophylline levels

Factor

Decreases

Increases

Action to be taken

Food

or delays
absorption

absorption
(fatty foods)

Select appropriate
preparation

Diet

metabolism
(high protein)

metabolism
(high carbohydrate)

Major changes in
diet not advised

Systemic, febrile
viral illness

metabolism

dose by 50%, if serum

level not available

Hypoxia,
cor pulmonale
CCF, cirrhosis
Age

metabolism

Decrease dose

metabolism
(<6m, elderly)

Adjust dose as per

serum levels
increase dose

metabolism

Alternative H blockers
(ranitidine/famotidine)

metabolism

Alternative antibiotic
or adjust theophylline
Alternative antibiotic
or adjust theophylline
dose of theophylline

Phenobarbitone
Phenytoin,
Carbamazepine

metabolism
(1-9 y)
metabolism

Cimetidine
Macrolides:
Erythromycin
TAO, Clarithromycin
Quinolones
Ciprofloxacin, etc.
Rifampicin

metabolism

Ticlopidine
Smoking

metabolism

metabolism

metabolism

dose of theophylline
dose of theophylline
advise to quit smoking

system is divided into the parasympathetic or cholinergic system, the sympathetic or

adrenergic system, and the non-adrenergic non-cholinergic inhibitory system. Broadly
speaking, while the parasympathetic system is responsible for bronchoconstriction mediated
by cyclic 3'-5', guanosine monophosphate (GMP), the sympathetic system causes
bronchodilatation via cyclic adenosine monophosphate (cAMP). The sympathetic system
is further subdivided into alpha and beta components. Alpha receptor stimulation is
associated with vasoconstriction and the inhibition of nonepinephrine release. Further, the
-adrenoreceptors are subdivided into 1- and 2-subgroups. -receptors have both
chronotropic and ionotropic effects on the heart, and 2-adrenoreceptors mediate
bronchodilatation.42 -adrenergic receptors are integral membrane glycoproteins. They are
oriented in the membrane in such a way that the adrenergic ligand binding sites expose
directly to the extracellular space.43 Majority of the 2-receptors are located in glial cells,
and on smooth muscle cells like vascular, bronchial, and uterine smooth muscle cells. The
density of these cells in a particular site is important for physiologic responsiveness. Essential
characteristics of receptors are rapid and reversible kinetics of binding, strict specificity,
stereospecificity, and affinity appropriate to the adenylate cyclase-coupled -adrenergic
receptors, and saturability.44 The general effect of activation of 2-receptors at smooth muscle
sites is inhibitory, although this may not be an absolute rule. The effect in other tissues can
stimulate various secretions like insulin. In humans, relaxation of central and peripheral

Pharmacologic Management of Asthma 141

airways is mediated entirely by 2 receptors. Increased bronchial reactivity could result
from a decreased -adrenergic or nonadrenergic inhibitory activity. Most probably it is
caused by decreased responsiveness of -adrenergic receptors.45
-receptors mainly work through the enzyme adenylate cyclase activation and cyclic
AMP formation. The enzyme adenylate cyclase is stimulated by catecholamines in virtually
all tissues in which -receptors can be found. The principal type of receptor coupling to
adenylate cyclase by 2-adrenergic receptors is referred to as a stoichiometric coupling,
in which the biological response elicited is directly proportional to the percentage of receptor
occupied (occupancy theory). A reduction in receptor number will alter the sensitivity of
the tissue to catecholamines. The tissue will require more drug to provide the same degree
of receptor occupation as the receptor concentration is lowered. There is a general mechanism
of hormone to receptor to adenylate cyclase interaction. Mammalian cells controlled by
-adrenergic hormones contain plasma membrane-bound adenylate cyclase and specific
hormone receptors. These systems have a protein(s) which couples their receptors to the
adenylate cyclase catalytic protein. This coupling protein contains a guanine nucleotide
binding site, and is labelled as Ns. The interaction of the hormone, receptor, and guanine
nucleotide binding protein with the adenylate cyclase catalytic unit and in the presence of
magnesium ions, results in the formation of cAMP from adenosine triphosphate (ATP).46,47
Further, cAMP functions as a second messenger of catecholamine or hormonal action by
modifying enzyme activities and permeability barriers. This is possible by the activation of
protein kinases. These enzymes transfer terminal phosphate groups from ATP to amino
acid residues of certain proteins.44 In bronchial smooth muscle, the kinases cause a reduction
of calcium dependent coupling of actin and myosine and this results in smooth muscle
relaxation. Thus, 2 agonists increase intracellular cAMP concentrations which are essential
in the relaxation response.
Recently, it has been become clear that 2 agonists may cause bronchodilatation, at least in
part, via maxi-K channels in airway smooth muscle cells which are directly linked to
relaxation.48-51 Maxi-K channels are opened by low concentrations of 2 agonists which are
likely to be therapeutically relevant. There is now evidence that receptors may be coupled
directly to maxi-K channels via the alpha-subunit of Gs,48 and may therefore, induce
relaxation without any increase in cAMP.
The sympathomimetic bronchodilators are the keystone of therapy of bronchial
asthma.52-62 -2 agonists are often the first and most commonly used drugs for the treatment
of bronchial asthma. Modern bronchodilator therapy started in 1900 when the use of adrenal
extract to treat asthma was described.42 In 1924, ephedrine was introduced into western
medicine, although its parent plant, ma huang, was known to the Chinese for more than
5000 years. These drugs had both alpha and beta-adrenoceptor activity which were described
by Ahlquist in 1948.42 The older sympathomimetic agents ephedrine, epinephrine, and
isoproterenol have been generally replaced by the newer, longer acting, more -2 specific
bronchodilators. Nonetheless, they are still important antiasthma medications. Recognition
of the pharmacologic differences between 1, 2, and receptors has led to the development
of adrenergic agonists that can preferably act on 2 receptors of bronchial smooth muscle
with little direct stimulation of the 1 receptors of the myocardium. At present, 2 agonists
or sympathomimetics, are the preferred and most effective bronchodilators available for
the treatment of bronchial asthma and are often the first and most important drug to be
used worldover.

142 Bronchial Asthma

Biochemistry
The -adrenoceptor agonists are sympathomimetic amines whose parent compound is
-phenylethylamine. They consist of a benzene ring attached to an amine group by two
carbon atoms. The distinctive features of different -agonists depend on the basic structure,
and on the substitution on the amine group in particular. Increasing the size of the terminal
amino group substituent protects the drug against degradation by monoamine oxidase,
and further increases the duration of bronchodilatation. 43 Modification of the
phenylethylamine nucleus has helped to increase 2-specificity and duration of action.
Catecholamines refer generically to all compounds containing a catechol nucleus (benzene
with two adjacent hydroxyl groups) and an amine group. They have a relatively short halflife, because they are subject to removal by active uptake mechanisms and to rapid
metabolism by catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO). They
are orally inactive because of their inactivation by gastrointestinal sulphatases. By
modification of the 3,4-hydroxyl groups on the benzene ring, which are the sites of action
of COMT, prolonged bronchodilating action and oral administration is possible. The various
2-agonists are shown in Table 10.3.
Mechanisms of Action
Sympathomimetic amines have six general types of action: peripheral excitatory, peripheral
inhibitory, cardiac excitatory, metabolic, endocrine, and central nervous system actions.
2-agonists cause a direct relaxation of the pre-constricted or spontaneously contracting human
bronchial smooth muscle. Their bronchodilator action is evident in normal persons, in patients
with chronic obstructive pulmonary disease, and asthma. They cause a marked reduction in
nonspecific bronchial reactivity to stimuli such as histamine, methacholine, or exercise. The
mode of bronchodilatation seems to be due to a decrease in catecholamine-stimulated adenylate

Classification
Ephedrine
Catecholamines
Epinephrine
Isoproterenol
Isoetharine
Resorcinols
Metaproterenol
Terbutaline
Fenoterol
Saligenin
Salbutamol
Miscellaneous
Bitolterol
Pirbuterol
Procaterol
Long acting drugs
Formoterol
Salmeterol

Table 10.3: Adrenergic bronchodilators

Receptor activity
Availability

Duration of action(hours)

, 1, 2.

Oral

2-3

, 1, 2
1, 2
(1), 2

Injection, inhaler
Oral, inhaler, Injection
Inhaler

1-2
1-2
3

2
2
2

Oral, inhaler
Oral, inhaler, Injection
Inhaler

3-5
4-6
4-6

Oral, inhaler, Injection

4-6

2
2
2

Inhaler
Inhaler
Oral, inhaler

6-8
4-6
6-8

2
2

Inhaler
Inhaler

> 12
> 12

Pharmacologic Management of Asthma 143

cyclase activity. The final effect is an increase in cellular cyclic adenosine monophosphate.
This effect derives from and is mediated through a plasma membrane-associated -adrenergic
receptor: the guanine nucleotide regulatory protein, which in turn activates adenylate cyclase
and leads to generation of cAMP. 2-adrenoceptor agonists vary in their selectivity for 2adrenoreceptors, but none is 2-specific. They all stimulate - receptors to a lesser but dosedependent extent. The duration of action is dose dependent, but to a limited extent.
Since the human airway smooth muscle cells express 2-receptors from the trachea to the
terminal bronchioles,63,64 these drugs as functional antagonists can prevent and reverse the
effects of all substances,65 including leukotrienes, acetylcholine, bradykinin, prostaglandins,
histamine and endothelins. Because of the widespread presence of -receptors, the 2- agonists
may affect many cells like stabilisation of mast cells,66 which may be the cause of effectiveness
of these agents in blocking the bronchoconstricting effects of allergens, exercise, and fog.
Further, 2-agonists inhibit cholinergic neurotransmission in the human airway, which can
result in reduced cholinergic-reflex bronchoconstriction. The other mechanisms of action of
-agonists, although not proved conclusively, include, inhibition of mediator release,
modulation of neural pathways, reduction of microvascular leak, and increased mucociliary
clearance.67
Long acting 2-agonists, salmeterol xinafoate and formoterol fumarate, are currently
available in many countries.68-70 They are available in inhaled forms. While salmeterol acts
longer but is a partial agonist, formoterol is a nearly full agonist.71 Both provide effective
bronchodilatation over a 12-hours period and thus, they are more useful for patients who
have nocturnal asthma.72,73 Because these drugs have no anti-inflammatory effect, they should
always be used with an inhaled glucocorticoid. Both drugs also protect against airways
challenge with methacholine for a period of 12 hours.72,74 International guidelines have
recommended both drugs to be added in the treatment of bronchial asthma. Several studies
have demonstrated the superiority of salmeterol and formoterol to regular treatment with
either salbutamol or placebo.75-77 Both these drugs differ pharmacologically, but there is no
difference in the efficacy between the two drugs in any severity of bronchial
asthma,78-80 although formoterol is more potent than salmeterol in vitro, with a faster onset but
a shorter duration of action,81 but with similar bronchodilator action at 12h. Relative potency
estimates show that 50 mg salmeterol corresponds to 9 mg formoterol.82
Optimal Pharmacological Profile of -adrenoceptor Agonists
They exhibit a range of physico-chemical properties, which arise from differences in molecular
structure, and determine their pharmacological profiles with respect to affinity, efficacy, and
duration of action at subtypes of -adrenoceptors in a number of target cells. All -agonists
are racemic mixtures of optical isomers, there being two isomers, R and S in salmeterol and
four isomers (RR, RS, SR, and SS) in fenoterol and formoterol. -agonist activity resides
predominantly in the R-form, which ranges from 40-fold to 1000-fold more potent than the
S-isomer. At 2-adrenoceptors, salmeterol, formoterol, and fenoterol have a higher affinity
than isoprenaline and salbutamol, the associated rank order of potency being: formoterol >
salmeterol > fenoterol = isoprenaline > salbutamol. Fenoterol and formoterol are full agonists,
and salmeterol and salbutamol are partial agonists, compared with isoprenaline. Salbutamol,
and particularly salmeterol are weak and have low efficacy at 1 and 2-adrenoceptors,
whereas formoterol and fenoterol are potent, full agonists. The functional 2-adrenoceptor

144 Bronchial Asthma

selectivity is lowest for fenoterol and highest for salmeterol. 2-agonists such as salbutamol
and fenoterol are hydrophilic and interact with the -receptor directly, whereas formoterol is
moderately lipophilic, and salmeterol is highly lipophilic, gaining access to the active site of
the 2-adrenoceptor through the cell membrane. The rates of onset of action of salbutamol,
fenoterol, and formoterol are more rapid than those of salmeterol. The duration of action is
concentration-dependent for all -agonists, with the exception of salmeterol, which appears
to be intrinsically long-acting (salmeterol >> formoterol>fenoterol>salbutamol) due to
additional exo-site binding in the 2-receptor protein.
Aerosol or oral inhaled therapy is comparable or better than oral therapy in producing
bronchodilatation and cause fewer systemic side effects such as cardiovascular stimulation,
anxiety, and tremor. Inhaled therapy has a more rapid onset of action when compared with
oral formulations and a similar duration of action, even when administered in substantially
lower dosages. Furthermore, inhaled therapy appears superior to oral therapy because the
latter causes more adverse effects and require higher doses to achieve similar effects. 2agonists are the medications of first choice for treatment of acute exacerbations and for the
prevention of exercise-induced asthma. They can be used either intermittently to control
episodic airway narrowing or chronically to aid in the control of persistent airway narrowing.
Salbutamol inhalation reduces hyperinflation of the lungs. Measurements of lung volumes
before and after bronchodilators add sensitivity when examining for bronchodilator
responsiveness.83
Recently there is a trend to use more of inhaled form of these drugs rather than oral
preparations because of adverse effects and slow onset of action. The advantage of slowrelease oral agents has been taken over by the introduction of long-acting inhaled 2- agonists,
which are more effective in preventing induced bronchoconstriction than equivalent doses
of oral 2-agonists.84 Further, inhaled drugs may reach superficial cells in the airways, such
as mast cells and epithelial cells, that are less easily reached by oral drugs. Thus, nebulised
2-agonists are the first choice for acute severe asthma and may be life saving.85 Since the
onset of action is rapid, and the therapeutic ratio of bronchodilatation to side effects is
greatly improved, inhaled administration is preferred. Since there is a rapid action, this can
be attributable to the direct effect of the drug on the smooth muscle -adrenoceptor. When
given by inhalation, all currently available -agonists achieve a measurable effect within
5 minutes and by 10 minutes, 80-90% of the maximal response has actually been achieved.42
Another advantage of giving bronchodilators by inhalation is that they are not distributed
to the rest of the body in large concentrations and therefore may be given in much smaller
doses.
The doses of some of these drugs are given in Table 10.4.
Side Effects
The predictable side effects of -agonists include tachycardia, palpitation, dysrhythmia,
hypokalemia, tremor, restlessness and rarely hypoxemia. Tremor, due to stimulation of 2adrenoceptors in skeletal muscles is a common side effect of these class of drugs. Tremor is
inseparable from bronchodilator action, but, incidence usually declines with continued
administration.86 Since the frequency of adverse effects are directly proportional to the
plasma concentration, administration via inhalation results in less drug absorption and
therefore fewer adverse effects than either oral or inject able routes. Although, the adrenergic
aerosols are currently among the safest drugs available for asthma therapy, there are some

Pharmacologic Management of Asthma 145

Table 10.4: Dosage of sympathomimetic agents per treatment

Drug
Adrenaline (1:1000)
Isoproterenol
Isoetharine
Metaproterenol
Salbutamol
Terbutaline
Bitolterol
Formoterol
Salmeterol

Subcutaneous
(ml)
0.1-0.5

0.5
0.25-0.5

Metered dose inhaler

or MDI (mg)
0.32-0.9
0.16-0.39
0.68-1.02
1.3-1.95
0.18-0.27
0.4-0.6
0.37-1.11
6-12 g
50 g

Nebulizer
(mg)

Oral
(mg)

2.5-22
0.63-3.8
1.25-5
10-15

5-20
2-4
2.5-5

areas of concern. Adverse drug reactions involving the cardiovascular system may also occur.
Cardiovascular complications may result from decreased serum potassium levels or direct
stimulation of the myocardium. Adverse reactions of the cardiovascular system may occur
with the combination of systemic adrenergic agonists and theophylline. However, cardiac
arrhythmias and myocardial ischaemia resulting from -agonist therapy usually occurs in
patients with preexisting cardiovascular disease, especially among the elderly.
Very rarely, patients with asthma may experience paradoxical bronchoconstriction as a
result of inhaled -agonists administered by metered-dose inhalers (MDI). The paradoxical
response is an abrupt worsening of asthma symptoms and/or a decrease in expiratory flow
rates shortly after inhaling a therapeutic aerosol. It is not clear whether the reaction is due to
the drug itself or due to another component or contaminant of the particular canister or batch
of canisters or due to a hypersensitivity reaction to the hydrocarbon propellant. Very rarely
lactic acidosis may occur.
Several recent studies have suggested that regular use of -agonists increases the
responsiveness of airways to challenges with agents such as methacholine and histamine in
children and adults. Similarly some recent reports associate the regular use of a potent inhaled
2-agonist with diminished control of asthma. Although the mechanisms of diminished control
or increased hyperreactivity are not known, possibilities include the development of rebound
airway hyperresponsiveness, increased bronchial secretions, or both. There are also some
concern regarding damage to the mucosal epithelium due to repeated inhalation. There are
controversies regarding the link between the use of fenoterol and increased asthma deaths in
New Zealand.
Another potential reason for increased asthma symptoms during prolonged therapy with
these drugs may be the development of tolerance or subsensitivity resulting from downregulation of -adrenoreceptors. This phenomenon is a tendency of biological responses to
wane over time in the presence of a stimulus of constant intensity, and may develop to the
antiasthmatic effects of inhaled 2-agonists.65,86 Although some evidences suggest that tolerance
to the bronchoprotective effects of both short- and long-acting 2-agonists does develop,87-91
numerous other studies using a recommended dose of -agonists by metered dose inhalers
have failed to show the development of complete tolerance.92 Most studies suggest that clinically
significant tolerance does not usually develop in patients with asthma. When tolerance
develops, it is characterised by a small reduction in the bronchodilator response and by a
slight shortening in the duration of action after inhaling a -agonist. Thus, tolerance is not

146 Bronchial Asthma

usually of major clinical significance and does not diminish the overall usefulness of inhaled
2-agonists in asthma therapy. It is possible, however, that receptor down-regulation could
account for some of the diminished control of asthma and increased airway hyper-reactivity
reported during chronic regular use of these drugs.
Subsensitisation occurs because of the receptors in the tissue are exposed to persistent
stimulation by agonists. The problem can occur at one or several different points in the
formation of cAMP. It could occur at the level of the receptor, stimulatory or inhibitory,
and/or involve down regulation mechanisms. These will involve an uncoupling of the
hormone-receptor complex from the guanine nucleotide binding protein. Further, repeated
exposure to catecholamines may reduce the number of -receptors in the airways that are
free to interact with catecholamine bronchodilators.43 Thus repeated administration of
-agonists makes the airways even less responsive. Tolerance is seen most commonly with
triggers that operates through mast cell activation, such as adenosine, allergens, and exercise.
Whether steroids protect against development tolerance is not known. The problem may
be avoided by taking long acting 2-agonists only at night. Recent studies of the
polymorphism of human 2-receptors suggest that some forms of the receptors may be
more likely to be down regulated.93 Patients having Arg-16 Gly form of the receptor, which
is more likely to be down regulated have more frequent asthma in the night.94 In contrast, the
GlnGlu form, resist down regulation and is having less airway hyperreactivity.95
There is some concern recently regarding the use of 2-agonists and excess asthma mortality.
The two epidemics of asthma death recorded in the literature, one in several countries in the
1960s and the other in New Zealand in the late 1970s, were associated with a rapid increase
in the use of a -agonist formulation delivering a high dose by metered-dose inhalers,
isoprenaline in the 1960s and fenoterol in the late 1970s. Although, reports are conflicting, it
seems likely that those epidemics were due to high-dose 2-agonist use. There is no
epidemiological evidence to suggest that -agonists have an appreciable effect on mortality
outside these epidemics.96-101
Some Controversial Facts About 2-Agonists
Despite the worldwide use and the significant contributions of inhaled synthetic sympathomimetic agents in the therapeutic management of bronchial asthma, the risk/benefit ratio
of these agents have evoked controversy throughout the last half of the 20th century.
Concerns about possible deleterious effects of the first reported from the United Kingdom,
Australia and New Zealand in the mid-1960s, when a sudden increase in asthma mortality
was attributed to overuse of a short-acting, dose-fortified formulation of isoproterenol.102 A
similar phenomenon occurring a decade later in New Zealand appeared to be associated
specifically with regular use of inhaled fenoterol, a more selective, relatively short-acting
2-agonist (SABA),.97 A Canadian retrospective case-control analysis of pressurised SABA
in patients with asthma suggested that increased asthma mortality was not necessarily due
to fenoterol alone but also occurred after overuse of any pressurised SABA of the same
class.96 A subsequent meta-analysis of six similar surveys not only failed to confirm this
conclusion but found that mortality was increased to a slight extent only in patients who
used SABA on a regular basis.103 Even if this controversy keeps on appearing off and on, most
clinicians believe that the mortality attributable to SABA is most likely based on over dosage and/or
abuse by poorly controlled patients.104

Pharmacologic Management of Asthma 147

The above controversies led to more intensive exploration of the nonbronchodilator
properties of SABAs and also long-acting 2-agonists (LABAs). The interactive effects of
these agents as well as individual agents have been studied extensively. 105,106 Such
investigations have revealed a complex and contradictory array of biological activities that
encompass both proinflammatory and anti-inflammatory effects. As examples of antiinflammatory effects, 2-agonists are known to attenuate release of mediators from mast
cells, suppress airway smooth muscle growth, and inhibit the function of immunocompetent
lymphocytes. By contrast, the proinflammatory effects include suppression of interleukin12 production in antigen-presenting cells, intensification of the T-helper type 2 immune
response, augmentation of eosinophil survival and enhancement of the late allergic response.
SABAs may also favor the synthesis of receptors associated with neurogenic inflammation
that could play a role in the phenomenon of increased airway hyperresponsiveness that has
been noted after long-term use of these agents.
Similar concerns were expressed about the LABAs. The lipophilic nature of these agents
would enable them to partition into the outer phospholipid layer of cell membranes, where
they have better access to receptors and downstream signalling cascades. Fortunately, downregulation of 2-agonist receptors on smooth muscle is not clinically relevant, presumably
because of their overabundant distribution and relative refractoriness to tachyphylaxis in
this tissue site. A number of studies in the mid 1980s and early 1990s demonstrated that
regular use of SABAs increased airway hyperresponsiveness and actually worsen asthma
control, and many asthma management guidelines recommended against their regular use
over prolonged periods. Similar concerns were also expressed when LABAs were available,
and in fact early clinical trials reported that both short-term and long-term use of LABAs
dampened the 2-agonist protective effect against methacholine-induced bronchospasm
without evidence of smooth muscle tachyphylaxis.90,107 However, more recent studies
demonstrated that the LABA-induced protective effect against airway hyperresponsiveness
was unimpaired after relatively long-term, continuous use of LABAs without evidence of a
rebound effect after cessation of therapy.108,109 These contradictory results have been ascribed
to patient-specific differences in sensitivity to the deleterious effects of bronchodilators,
variability of allergic status among patient groups, or a masking activity of 2-agonists .110
The later effect might occur because these agents inhibit only the early allergic response
and might exacerbate the ongoing inflammation associated with the late allergic response.
A recent controlled study111 performed over a 6-week period using placebo or salmeterol
that utilised a well-defined allergic phenotype of mild asthma, (pollen sensitive asthmatics),
and a well-defined exposure period (a grass pollen season), measured both direct and indirect
airway hyperresponsiveness using methacholine and adenosine monophosphate and exhaled
NO was measured as an index of airway inflammation. Airway caliber (FEV1), airway
hyperresponsiveness indices and exhaled NO were measured before the administration of
salmeterol or placebo and at mid season. Patients receiving salmeterol experienced significant
protection against a fall in FEV1 during the height of the allergy season. The increase in
airway hyperresponsiveness showed only a small insignificant increase in the treated group
compared to the placebo group. The result emphasised the difference between natural exposure
and a single experimental allergen challenge studies reported earlier. There was a failure to
detect a significant difference in adenosine monophosphate-induced airway responsiveness
between salmeterol-treated and placebo-treated patients when they were challenged with the
agent during the height of the pollen season. Since the adenosine monophosphate indirect

148 Bronchial Asthma

challenge reflects bronchoconstriction caused by mast cell mediators, long-term salmeterol
did not attenuate the chronic effects of mediators during the season and therefore did not
function as an anti-inflammatory agent. The exhaled NO levels were increased both treatment
arms during the height of the pollen season, but there was neither an augmentative nor
inhibitory effect in the salmeterol group. These results strengthened the safety profile of
salmeterol and indicated that long-term use of a LABA alone will not provide a clinically
effective anti-inflammatory effect.
Ultimately perhaps, the balance between the salutary and adverse effect of both SABAs
and LABAs are tilted towards a more clinical benefit to the patient in the management of
bronchial asthma.
Anticholinergics
Anticholinergics are the oldest forms of bronchodilator therapy for asthma and are
recommended as early as the 17th century.112 The recreational and medicinal properties of
atropine have been well-known to many cultures for many centuries. Atropine, in the form
of the leaves and roots of Datura stramonium, was very well known to Indians for use in
respiratory disorders, and it was introduced to Western medicine by the British military
officers in the early 1800s, who in turn learnt its usefulness from Indians. At that time,
stramonium, belladonna, and their alkaloid extract, atropine, had their place in most
pharmacopoeias. Atropine was used for many years for the management of bronchial
asthma. With the availability of potent -adrenergic agonists in the 1920s, its use declined.
In recent years there has been an increased interest in inhaled atropine sulphate, especially
in patients with chronic bronchitis. Atropine is usually given as a powder nebuliser with a
-adrenergic agent. Its side effects include tachycardia, dryness of the oral mucosa, blurred
vision, urinary retention, and constipation. The drug has a delayed onset of action. Atropine
should not be used in patients with narrow angle glaucoma and prostatic hypertrophy.
With the advent of newer more selective drugs without these unpleasant side effects of
atropine, the later is almost no more used.112,113 The newer anticholinergic agents are watersoluble, quaternary ammonium compounds that are poorly absorbed, and when they are
given by inhalation, they cause fewer systemic side effects.114-118 A better understanding of
the cholinergic mechanisms that control airway caliber in health and disease and the
development of newer synthetic analogs of atropine that are poorly absorbed, but retain
the anticholinergic properties of the atropine, have revitalised the interest in anticholinergic
therapy. Several anticholinergic agents that are in use worldwide include:
Atropine
Ipratropium bromide
Thiazinamum
Oxytropium bromide
Glycopyrrolate
Tiotropium bromide

Rationale for the Use of Anticholinergics

To understand the rationale of use of these agents it is important to understand the
mechanisms of bronchoconstriction and bronchodilatation that are mediated by the
autonomic nervous system. The majority of the autonomic nerves in human airways are

Pharmacologic Management of Asthma 149

branches of the vagus nerve, the efferent paraganglionic fibres of which enter the lungs at the
hilum and travel along the airways into the lungs.119 The efferent innervations is derived from
the postganglionic fibres that end in the epithelium, submucosal glands, and smooth muscle
of the airways as well as in the vascular structures. Thus, the release of acetylcholine at these
sites results in smooth muscle contraction and the release of secretions from submucosal
glands stimulated by their muscuranic receptors. Cholinergic pathways are important to
regulate the acute bronchomotor responses, and many stimuli can provoke bronchoconstriction
via vagal pathways. Anticholinergic medications antagonise transmission at the muscarinic
receptors. They will only block reflex cholinergic bronchoconstriction and will have no effect
on bronchoconstriction resulting from the action of, for example, histamine on the airways.
Cholinergic-induced bronchoconstriction appears to involve primarily the larger airways,
whereas -agonist medications relax both large and small airway contraction equally. In
humans, there are at least three pharmacologically distinct subtypes of muscarinic receptors
within the airways, which are known as M1, M2, and M3 receptors.120 Recently, the types
described are up to 5, M1 to M5. The M1 receptors are present within the parasympathetic
ganglion and mediate increased cholinergic transmission. They may facilitate nicotineic
transmission or be responsible for maintaining cholinergic tone. Inhibition would reduce
cholinergic tone and thus would reduce bronchoconstriction. M1 receptors are also found on
alveolar walls, although their function is unknown. Prejunctional M2 receptors on the
postganglionic nerves act as negative feedback loop in neuronal transmission. They are
activated by the release of acetylcholine and promote its reuptake, thereby limiting the degree
of bronchoconstriction produced. These receptors are thought to be dysfunctional in asthma,
resulting in exaggerated cholinergic reflexes. The loss of M2 receptor function has been
demonstrated after viral infections. Similar changes can be seen after ozone exposure or
antigen challenge.121 When the M2 receptors are dysfunctional, the resulting excessive
concentrations of acetylcholine at the motor endplate can promote significant
bronchoconstriction. Finally, M3 receptors are located on the airway smooth muscle. The
receptor activation leads to a release of calcium ions from intracellular stores and a decrease
in intracellular adenosine 3,5-cyclic monophosphate levels, resulting in the contraction of
airway smooth muscle. M3 receptors also are located on submucosal glands, where they are
likely to be involved in mucus secretion.
Ipratropium bromide and oxytropium bromide are quaternary ammonium derivatives of
atropine and are bronchoselective when delivered by inhalation.122,123 Ipratropium bromide is
a muscarinic cholinergic antagonist that inhibits smooth muscle contraction by competing
with the neurotransmitter acetylcholine at the muscarinic receptor.124 These drugs are thus
less effective than inhaled 2-agonists because they counteract only cholinergic neural
bronchoconstriction, which may be a relatively minor part of the broncho-constrictor
mechanism in asthma. As discussed earlier, recently it is recognised that there are at least five
subtypes of muscarinic receptors expressed in the airways.120, 125 The M3 receptors play the
major role in causing bronchoconstriction, whereas the M2receptors mediate the feedback
inhibition of acetylcholine release from airway sensory nerves.126 Atropine, ipratropium
bromide and oxytropium bromide are nonselective antagonists and produce their beneficial
effect by blocking M3 receptors. However by blocking prejunctional M2 receptors, they increase
the release of acetylcholine and thus may have relatively deleterious effects.126 This may
weaken the effect of the postjunctional M3 muscarinic receptor blockade on airway smooth

150 Bronchial Asthma

muscle and submucosal glands. This suggests that antagonists that bind selectively to M1
and M3 receptors may be more effective in inhibiting cholinergic effects on the airways. The
drugs also inhibit hypersecretion of mucus in the airways.127 The anticholinergic drugs act by
reducing intrinsic vagal tone to the airways. They also block reflex bronchoconstriction caused
by inhaled irritants. The agents also block postganglionic efferent vagal pathways. They are
relatively free of systemic side effects because they are minimally absorbed into the systemic
circulation and do not cross blood-brain barrier.
The natural antichiolinergic, atropine, is rarely used in patients at the present time,
however, this drug was used extensively as a nebulised solution by intensivists and
emergency department specialists for years.128 It is readily absorbed across the oral and
respiratory mucosa and when higher doses are used to maximize bronchodilator effect, the
incidence of dry mouth, blurred vision, urinary retention, nausea and tachycardia may
limit the usefulness of atropine. The principal anticholinergic agent is ipratropium bromide,
a nonselective muscarinic antagonist.129,130 The drug is topically active, and the compound
is poorly lipophilic and not significantly absorbed from the respiratory or GI tract. It has no
or very little systemic effect. The drug has been found to be an effective bronchodilators in
patients with COPD and selective patients with asthma both alone and when used in
combination 2-agonists and theophylline. When used via MDI aerosol, the recommended
dose of ipratropium bromide is 2 puffs (40 g) 4 times daily. The drug has been shown to be
effective during status asthmaticus when used in nebulised form in combination with
-adrenergics.131-133 It does not appear to affect mucus secretion and ciliary movement.
Another significant advantage of ipratropium bromide in the critically ill asthma patients
is the lack of tachycardia, which does occur with 2-agonist use.134 The only remarkable
side effect is the inhibition of salivary secretions at high doses. It has no effect on urinary
flow, or intraocular tension, and possible effects on the eye (glaucoma) can be prevented by
using a mouth piece during nebulisation. The onset of action is 3 to 30 minutes with up to
50% of the response occurring in 3 minutes and 80% in 30 minutes, with a peak
bronchodilator effect observed within 1 to 2 hours, and the duration of action is up to
approximately 6 hours. These properties are ideal for acute asthma treatment. Oxytropium
bromide is a quaternary ammonium anticholinergic compound that is based on scopolamine
instead of atropine. It is also a nonselective muscarinic antagonist. The drug is used in a
dose of 200-400 g per day and is perhaps less effective in chronic asthma.134 It has a longer
duration of action, up to 8 hours than ipratropium bromide, but has a slower onset of effect.135
The peak onset of action is 1-2 hours. In children ipratropium has bronchodilator action in
acute exacerbations of asthma. However, the benefits of its use in day-to-day management
of asthma in children and adults have not been established, although its use appears to be
most effective in patients with COPD with partially reversible airflow obstruction. Tiotropium
bromide is a recently developed, long acting, selective, anti-muscarinic medication. This
agent is selective for both M1 and M3 receptors. In human bronchi, the drug has a similar
inhibitory effect with a slow onset of action with the peak bronchodilator effect observed
after 1.5 to 2 hours and a very prolonged effect compared to ipratropium bromide. The
effect lasts for 10-15 hours.136,137 The drug has a prolonged inhibitory effect acetylcholine
released from postganglionic nerve endings in the airways, probably via an inhibitory effect
on M1 receptors. The drug is available as a lactose based powder formulation containing
18 mg of active substance and is used once daily.

Pharmacologic Management of Asthma 151

In certain clinical situations these drugs may be useful bronchodilators for the treatment
of bronchial asthma.138 They are recommended for patients who cannot tolerate -adrenergic
agonists because of severe tremor or underlying cardiac disease and for patients with
bronchospasm precipitated by -adrenergic antagonists139 or acetylcholinesterase inhibitors.
They can be used in combination with -agonists.
Corticosteroids
Glucocorticosteroids are the most potent anti-inflammatory drugs useful in the treatment
of bronchial asthma. With the realisation of the role of inflammation as an essential and
important component of asthma, their frequent use is justified. Inhaled glucocorticosteroids
have revolutionised the treatment of asthma and are highly effective in controlling asthma
in all patients.140
Glucocorticosteroids are active against bronchial asthma, mainly through their antiinflammatory effects.141,142 The anti-inflammatory action of corticosteroids is as follows. The
hormone penetrates freely into the cell and binds to the receptor forming an inactive complex,
which is further activated or transformed to an active complex having an enhanced affinity
for DNA forming the nuclear-bound complex. Then it is translocated to the nucleus where
it binds to specific sequences (glucocorticoid-responsive element) on the upstream regulatory
part of steroid-responsive gene.143 This complex then by binding to regulatory elements
associated with certain genes, can activate or inhibit transcription of these genes. The
hormone thereby increases or decreases the levels of mRNA and usually of the proteins
that the genes encode. These proteins may be enzymes, secretory products, and regulators
of various functions including transcription of other genes, which are the primary effectors
of hormone actions. The particular genes and proteins regulated by corticosteroids depend
on the type of cells. This may increases the production of a substance called lipocortin-1,
which inhibits the enzyme phospholipase A2, an enzyme essential for activation of
arachidonic acid metabolism. The complex may cause reduced transcription with inhibition
of protein synthesis like cytokines. An important effect of steroids in asthma may be the
inhibition of synthesis of key cytokines like IL-3, Il-5, and GM-CSF, which play significant
role in perpetuating the inflammatory response.144
It is also likely that steroids act on many different cells of the airways. Although they do
not reduce the release of mediators from mast cells themselves,145 they lead to a significant
reduction in mast cell numbers, possibly due to inhibition of IL-3, which is necessary for
mast cell survival in the airways.146 Steroids inhibit release of mediators by macrophages,147
but eosinophils are less responsive.148 But, eosinophil survival is markedly reduced due to
blockage of the effect of cytokines like IL-3, Il-5, and GM-CSF.149 Inhaled steroids also reduce
markedly the proportion of circulating low-density eosinophils in asthmatic patients through
inhibition of IL-5 secretion.150 The other most important effect of steroids is on T lymphocytes
where the synthesis of cytokines is reduced. Additional effects directly related to antiinflammatory action include reduced plasma exudation from postcapillary venules in the
airways,151 and inhibition of mucus glycoprotein secretion.152 Further, inhaled steroid therapy
causes a reduction in bronchial hyperresponsiveness to histamine and the underlying
T-cell-dominated inflammation in the bronchial wall.153
Although the molecular mechanisms of the anti-inflammatory action of steroids are better
understood,154 the key cellular targets in asthma have not yet been conclusively established.
It appears that airway epithelial cells are important target cells and besides the above

152 Bronchial Asthma

mentioned mechanisms including the inhibition of expression of cytokines like IL-1, IL-8,
regulated on activation normal T-expressed and secreted (RANTES) and GM-CSF, they also
inhibit lipid mediators,155 nitric oxide,156 and adhesion molecules.157 They also may inhibit the
expression of inducible genes in airway epithelial cells by blocking key transcription factors
such as nuclear factor-kappa B and activator protein-1.154
Thus, the important mechanisms of anti-inflammatory action of corticosteroids can be
summarised as follows:
i. Interference with arachidonic acid metabolism through alteration of lipocortin
synthesis and that of the synthesis of leukotrienes, cytokines and prostaglandins. They
inhibit the production of IL-1, collagenase, elastase, and plasminogen activator.
ii. Prevention of the direct migration and activation of inflammatory cells. Dampening
of the recruitment and activation of eosinophils results from their direct effect on
these cells as well as upon T-lymphocytes, endothelial cells, and macrophages. Local
activation of a variety of cell types including neutrophils, basophils, macrophages
and possibly eosinophils by -interferon may be blocked by inhibition of this substance
from T-lymphocytes by glucocorticoids.
iii. Inhibition of cytokine gene transcription and translation leading to inhibition of
cytokine secretion and increased intranuclear breakdown of these mediators.
iv. Inhibition of cellular response to cytokines, such as increased release of mast cell
mediators, expression of adhesion molecules, and prolonged survival of inflammatory
cells.
v. An acute anti-inflammatory action mediated via inhibition of microvascular leakage.
Direct evidence for the anti-inflammatory effect of inhaled steroids is provided by biopsy
studies in asthmatic patients. After regularly inhaling steroids over one to three months,
bronchial biopsy shows many fewer eosinophils, mast cells, and lymphocytes,146, 153, 158 and
in patients with mild inflammation of the airways, there is complete resolution. In biopsies
of patients after ten years of inhaled steroids, inflammatory cells disappear completely,
although basement membrane thickening may persist.159
Steroids facilitate the action of adrenergic bronchodilators, apparently by altering the
ratio of to - adrenergic receptors on cell surface.160,161 Oral prednisolone therapy prevents
the development of down regulation and subsensitivity of lymphocyte 2-adrenoceptors in
subjects given long-term treatment with oral 2-agonists.162 Effects of corticosteroids in
asthma patients are considerable.163-168 Treatment with inhaled corticosteroids improves FEV1,
peak expiratory flow, and symptoms within weeks. Improvements in airways hyperresponsiveness are slower in onset, and gradual amelioration usually continues up to at
least 1 year.164 Exacerbation rates are markedly reduced by treatment with inhaled
corticosteroids in asthma.164,167,168 Some studies have even indicated that delayed introduction
of inhaled corticosteroids results in an impaired response.169,170 Recent studies on the longterm effect in patients who are treated with terebutaline and beclomethasone dipropionate
indicate that the initial improvement in lung function are well preserved over 5 years.171
Inhaled steroids prevent the accelerated decline of FEV1.172
The wide-ranging clinical benefits associated with corticosteroids are shown in Table 10.5.
Corticosteroids can be administered parenterally, orally, or as aerosols. Because of the
availability of inhaled steroids, there has been less fear now to treat patients with steroids

Pharmacologic Management of Asthma 153

Table 10.5: Clinical benefits of glucocorticosteroids
* Improved pulmonary function
Diurnal variability in pulmonary function
Protection against antigen-induced bronchoconstriction
Asthma exacerbation rate
Hospital admission rate
Asthma mortality rate
* Prevention of long-term lung damage and therefore irreversible airflow obstruction
The anti-inflammatory effects of glucocorticosteroids are shown in Figure 10.1:
Glucocorticosteroids

Eosinophils
Mast cells
T-Lymphocytes
Mucus secretion
Plasma exudation
Mediator formation

CYTOKINES

-Adrenoceptors

INFLAMMATION
Fig.10.1: Anti-inflammatory effects of glucocorticosteroids

either with a short course therapy or for longer times. It is now clear that the duration and
severity of an acute asthma attack can be substantially reduced by therapy with corticosteroids.
Early treatment of severe acute exacerbations of asthma with oral corticosteroids prevents
progression of the exacerbation, decreases the need for emergency visits and hospitalisation,
and reduces the morbidity of the illness. When oral steroids are used to treat acute severe
asthma, the onset of action is gradual, occurring approximately 3 hours after administration
with peak effectiveness occurring about 6-12 hours after administration.
Acute short-term therapy is begun usually with a relatively high dose of 40-80 mg of
prednisone daily and can be maintained up to 5-10 days or tapered over the same interval.
Therapy with oral steroids should be maintained until peak expiratory flow rates are stable
near the best predictable value. The major adverse effects associated with high-dose shortterm systemic therapy are: reversible abnormalities in glucose metabolism, increased appetite,
fluid retention, weight gain, rounding of face, mood alteration, hypertension, peptic ulcer,
and aseptic necrosis of the femur.
In all patients requiring chronic maintenance therapy with steroids, a trial of inhaled
steroids, which have minimal systemic side effects, should be attempted to see if oral
corticosteroids could be reduced or eliminated. Oral therapy can be continued only if that
shows to reduce chronic symptoms substantially or reduce the frequency of severe episodes.

154 Bronchial Asthma

Oral steroids should not be used alone without maximising other forms of therapy. Long-term
oral steroid therapy is associated with significant side effects such as osteoporosis,
hypertension, Cushings syndrome, cataracts, myopathy, hypothalamo-pituitary-adrenal axis
suppression, and in rare instances, impaired immune mechanisms. Therefore, prolonged use
of oral steroids should be reserved for patients with severe asthma despite use of high-dose
inhaled corticosteroids. The lowest possible drug dose should be employed including attempts
of alternate-day therapy. The drug should be given as a single-morning dose and pulmonary
function tests should be used to objectively assess efficacy.
Inhaled steroids are safe and effective for the treatment of asthma. They are very effective
in controlling the symptoms of asthma and usually achieve rapid control. As a companion
drug to 2-agonists, inhaled steroids reduce symptoms, reduce the need for rescue
bronchodilators, and improved lung function compared to regular treatment with 2-agonist
alone.173 Inhaled steroids inhibit the late response reflecting inflammation to allergen and
prevent the increase in airway hyperresponsiveness that follows allergen exposure.174 They
also reduce AHR when given regularly, although the reduction takes place slowly over
two months or more as the chronically inflamed airway heals slowly.175 When discontinued,
symptoms and AHR revert to pretreatment levels.176 In patients with mild asthma treated
with inhaled steroids for a long time, there may be long symptom free periods before
recurrence.177 In patients with atopic asthma, changes in the bronchial eosinophils and lung
function during steroid therapy occur , but independently.178
Some basic principles regarding inhaled corticosteroids include:179,180
Both efficacy and side effects of aerosol glucocorticoids are dose dependent, and
patients vary in their dose requirement. Patients with chronic asthma severe enough
to need large oral maintenance doses are unlikely to respond adequately to inhaled
treatment alone.
Aerosol treatment is not effective in acute severe asthma.
A part of the inhaled drug is absorbed resembling parenteral injection bypassing liver
with reduced hepatic degradation of the active compound and able to produce systemic
effects.
Aerosol treatment is more effective if divided into several doses throughout the day.
The introduction of beclomethasone dipropionate to asthma therapy in the early 1970s
represented a major advance in asthma management. Various guidelines described
subsequently advocate use of inhaled corticosteroids for longer periods of time than
previously recommended in patients with mild asthma and at higher doses than previously
considered feasible in patients with severe asthma. Inhaled corticosteroids are now gaining
widespread acceptance as safe and effective agents for the management of childhood asthma.
They are unique among anti-asthma medicines that no other anti-asthma drug currently
available share such a wide ranging profile of clinical benefits.
An important unresolved question is whether inhaled steroids exert a therapeutic effect
on the airways through a systemic action. Since they reduce the number of circulating lowdensity eosinophils, it is suggested that inhaled steroids have an effect in the circulation or
in the bone marrow.150 However, this phenomenon can be as a result of local airway effect
through inhibition of synthesis of the eosinophil-stimulating cytokine IL-5 and RANTES.
Studies in dogs have suggested that inhaled steroids affect the production of leucocyte
progenitors in the bone marrow, but it is not clear whether this results from affecting the
synthesis of some stimulatory factor in the airways or from the action of the systemically

Pharmacologic Management of Asthma 155

absorbed fraction of the inhaled steroid on the bone marrow.181 It is also uncertain whether
steroids deposited in the proximal airways can be distributed via the airway circulation to the
more distal airways.
The inflammation of asthma affects the whole of the bronchial tree, from the large central
airways down to the small peripheral airways.182,183 Steroid receptors, the site of action of
inhaled corticosteroid therapy, are likewise located through out the bronchial tree.184 Various
inhaled steroids available for clinical use include Beclomethasone dipropionate,
betamethasone valerate, Budesonide, Flunisolide, Triamcinolone acetonide, Fluticasone
propionate, Mometasone furoate, and Ciclesonide.185-189 Beclomethasone is the first inhaler
steroid available nearly for the past 30 years and is used widely. The dose varies from < 400
g per day to as high as 1600 g depending upon the severity of bronchial asthma.
Budesonide is a glucocorticoid aerosol with high ratio between topical and systemic
corticosteroid effects.190,191 The drug is usually administered in a dose of 200-400 g twice
daily. Fluticasone propionate introduced in the 1990s, is one of the most potent inhaled
steroids currently available, and is developed from the androstane 17 -carboxylic acid
and is a highly potent, selective anti-inflammatory steroid which binds with a high affinity
to the glucocorticoid receptor of the human lung (18 times that of dexamethasone and 3 times
that of budesonide). It has greater airway selectivity, rapid fast-pass metabolism (so less
systemic side effects, and increased uptake and retention in the lungs as a result of its high
lipophilicity. It is approximately 2-fold more potent than beclomethasone dipropionate and
4-fold more potent than budesonide.192 500 g b.d. Fluticasone propionate is at least as
effective as beclomethasone dipropionate 1000 g b.d.193 Estimated clinical comparability
of doses for inhaled corticosteroids are shown in Table 10.6.
It is estimated that beclomethasone and budesonide achieve comparable effects at similar
microgram doses by MDI. Beclomethasone has similar effects to twice the dose of
triamcenoline acetonide on a microgram basis. However, fluticasone has effects similar to
twice the dose of budesonide and beclomethasone when given via MDI in a microgram
basis. Budesonide given by a Turbuhaler has effects similar to twice the dose delivered by
MDI, implying greater bronchial delivery by the delivery device. These observations are
made on the basis of clinical trials comparing effects in reducing symptoms and improving
PEFR.
The potency of a glucocorticosteroid is described by its receptor affinity and intrinsic
activity. For all therapeutically used corticosteroids in asthma, the intrinsic activity directly
corresponds to the receptor affinity, which is a compound-specific property. If the receptor
activity of a corticosteroid is determined under standardised conditions (usually with
dexamethasone as reference), the relative receptor affinity can be calculated and compared
with other corticosteroids. The same is shown in Table 10.7.194
Table 10.6: Comparison of potency of inhaled corticosteroids

Drug
Beclomethasone
Budesonide
Flunisolide
Fluticasone
Triamcinolone

Topical potency
(skin blanching)
600
980
330
1,200
330

Corticosteroid receptor
binding half-life (hrs)
7.5
5.1
3.5
10.5
3.9

Receptor
binding affinity
13.5
9.4
1.8
18.0
3.6

156 Bronchial Asthma

Table 10.7: Pharmacokinetic basis for evaluation of efficacy
and safety of inhaled glucocorticosteroids

Glucocorticoid

Activation
in the lung

Beclomethasone
dipropionate
Flunisolide
Triamcinolone
acetonide
Budesonide
Fluticasone
propionate
Mometasone furoate
Ciclesonide

Relative
receptor
activity

Lung tissue affinity Oral

bioavailability
(%)

Expected theoretical
therapeutic ratio

1345

High

41

Intermediate

180
361

Low
Low

20
23

Less favourable
Less favourable

935
1800

Medium/low
High

11
<1

Intermediate
Favourable

1235*
1200

High
High

<1
<1

Favourable
Favourable

Receptor affinity are calculated with respect to dexamethasone as reference compound except * ,
which is based on that for fluticasone dipropionate 813.

Side Effects
Although inhaled glucocorticoids have revolutionised the treatment of asthma being the
most commonly and widely used anti-inflammatory drug treatment, which is highly
effective in controlling asthma in all patients,140 concern has been expressed about their
local and systemic side effects.195
The important local side effects of inhaled steroids are throat irritation, oropharyngeal
candidiasis and dysphonia (huskiness) and only a minority of patients develop these
complications (<5%). However, dysphonia is commonly seen (in more than 50%) if patients
are given high-dose therapy. All these complications are caused by the active drug and not
by the propellant and are clearly related to the daily dose, although other co-determinants
are important. Dysphonia is common, whereas laryngeal thrush is extremely rare. The two
are not causally related. The primary cause of husky voice is a steroid-induced dyskinesia
of the voluntary musculature that control vocal cord tension. This can be alleviated by any
thing that reduces the deposition of the drug around the larynx. These measures include
reduction of the daily dose, slowing the speed of inhalation and/or by using a spacer, a
longer post-inspiratory breath hold to reduce drug deposition during exhalation, and mouth
rinsing immediately after inhaling the drug.196,197 The problem is more common, severe,
and persistent in patients who use their voice maximum like preachers, teachers, singers,
switch board operators, sports coaches or employees in a noisy work place. Compulsive
throat clearing and hypothyroidism aggravates and perpetuates the huskiness. Voice rest
may improve the condition in these patients. Candidiasis and thrush depend upon the
frequency of dosing and the concomitant use of antibiotics and/or oral steroids. The Candida
overgrowth occurs due to the inhibitory effect of the drug on the normal host defense
functions of neutrophils, macrophages, and T-lymphocytes at the oral mucosal surface. A
12-hour interval between doses appears sufficient to allow temporary recovery of these
functions and to prevent this complication. Spacers also markedly reduce the incidence of
this complication. Other rare local complications include esophageal candidiasis; painful

Pharmacologic Management of Asthma 157

and protracted atrophic glossitis; chronic oesophagitis resulting from combined Candidaherpes simplex infection; reflex cough and bronchospasm; and nonspecific symptoms
including nausea, headache, dry throat, gas, pruritus, rash, impaired taste or smell,
abdominal pain, diarrhoea, constipation, and heartburn.
Systemic bioavailability varies with the preparation selected. The systemic activity of
any particular dose in different patients and patient groups depends largely on the fraction
of the emitted dose that reaches the important absorptive surface in the lung periphery.
This fraction is determined by the interaction of numerous factors, including variations in
normal lung anatomy, the degree of pulmonary function impairment and presence or
absence of associated chronic bronchitis, each of which reduces peripheral delivery of the
inhaled drug, and in particular, by the inspiratory techniques used. There is some fear of
systemic effects because of oral, gastrointestinal, and pulmonary absorption of the drugs.140,198
However, they are infrequent. Approximately 80% of an inhaled corticosteroid dose will
be deposited in the mouth and subsequently swallowed, thus giving the potential for
systemic adverse events during long-term therapy. This can be reduced by using a largevolume spacer and mouth rinsing or other steroid sparing agents like cromolyn sodium.
Side effects can also be reduced by choosing a steroid such as budesonide or fluticasone
propionate that undergoes extensive first-pass hepatic metabolism, allowing little of the
drug to enter the systemic circulation. Then, the only source of systemic absorption will be
from the fraction absorbed from lung deposits. The side effects may include bone and skin
thinning, easy bruising, cataract formation, inhibition of longitudinal bone growth in children
and suppression of adrenocortical function. Clinically significant adrenal suppression and
altered bone metabolism are rare below 800 g/day,199-201 but a minimum daily dose should
be sought once clinical response has been achieved. Very large doses of inhaled drugs may
cross the placental barrier as shown in experimental animals.
Because of the importance of airway inflammation in the pathogenesis of asthma, inhaled
corticosteroids are being used more frequently as primary therapy for moderate and severe
asthma. This approach not only provides symptomatic benefit but also reduces airway
hyperresponsiveness.
CROMONES (CROMOLYN SODIUM AND NEDOCROMIL SODIUM)
Cromolyn Sodium
Cromolyn sodium is the best nonsteroidal anti-inflammatory drug for asthma available
currently.202,203 This drug has been available for 35 years. When administered prophylactically, Cromolyn sodium inhibits early- and late phase allergen-induced airway
narrowing and acute airway narrowing after exercise (less than inhaled adrenergic agents),
exposure to cold dry air, and sulphur dioxide. They are also effective in controlling symptoms
in patients with mild asthma.204 There is no way to predict reliably whether a patient will
respond to Cromolyn sodium. A 4-6 week trial may be required to determine efficacy in
individual patients. The drug is available in a capsule form (5 mg) taken as an inhaler as
well as metered dose inhaler and even as a nebuliser solution. It controls the symptoms of
bronchoial asthma and bronchial hyperresponsiveness and reduces the number of acute
exacerbations with an acceptable safety profile.205-207 Cromolyn sodium produces only minimal
side effects, such as occasional coughing upon inhalation of the powder formulation.

158 Bronchial Asthma

Nedocromil Sodium
This is a pyranoquinoline derivative and is shown to inhibit mediator release prophylactically in a variety of in vitro systems.208 It also inhibits allergen-induced acute and late-phase
asthmatic reactions and modulates allergen-induced increases in bronchial hyperresponsiveness. It also reduces the acute airway narrowing response to exercise,
hyperventilation, mist, and sulphur dioxide. Various clinical trials have proved that longterm therapy reduces nonspecific airway reactivity in atopic and nonatopic asthmatics. In
clinical trials the drug has been used in a dose of 4 mg four times a day with most beneficial
therapeutic effects. Therapy with nedocromil is not associated with any significant adverse
effects. The drug, however, is not yet used extensively in clinical practice. Although the exact
mechanism of action of cromones as anti-inflammatory drugs is not clear, it is believed that
the drugs stabilise and prevent mediator release from mast cells.209-213 The drugs are also likely
to affect several other inflammatory cells including sensory nerves.204,208 However, another
study has found no evidence of a decrease of inflammatory cells after treatment with
cromones.214 Other studies suggest that cromones may block swelling-dependent chloride
channels.215 Additional chloride channels in mast cells, sensory nerves, and epithelial cells
may be important.
Advantages of cromones are that they control symptoms of asthma and effectively block
bronchoconstriction induced by a number of agents and factors. Both drugs are safe and have
no significant side effects.216 One study has found that nedocromil has steroid sparing effects
but other studies have not confirmed this. The disadvantage of cromones are that they are
weak anti-inflammatory drugs compared to inhaled steroids, and more costly. They appear to
work best in patients with mild asthma, but not always. It is difficult to predict which patients
will respond. Recent studies have shown that cromones may be most beneficial for patients
whose predominant symptom is coughing. They may be considered as the first line therapy in
children and as a prophylactic agent against allergen-induced asthma. The other disadvantage
of these drugs is their short action, and therefore they are to be used four times a day which is
an inconvenient regimen for long-term prophylaxis.
Ketotifen
Ketotifen is an orally active, prophylactic drug used in many countries in the management of
asthma.217,218 Originally it was thought that the drug is a mast cell stabiliser that has the
additional property of being a potent H1-receptor antagonist. Large double-blind, placebocontrolled trials have proved the efficacy of the drug in the prophylaxis of asthma particularly
in children. Recent data suggests that the ability of the drug to act as a prophylactic agent is
not related to its mast cell stabilising effect nor the H1-receptor antagonistic properties. The
drug like many other prophylactic antiasthma drugs, inhibits PAF-induced eosinophil
infiltration and bronchial hyperresponsiveness. The drug is most effective in mild asthma
and require at least 4-12 weeks to show any clinically significant effect. It is given in a dose of
2-4 mg twice daily and this dose is roughly equivalent to 4 puffs of Cromolyn sodium. The
major advantage of ketotifen over other prophylactic drugs is that it can be used orally. The
major side effect of the drug is sedation.

Pharmacologic Management of Asthma 159

Antihistamines
With the development of new classes of nonsedating antihistamines, there has been renewed
interest in their use.219,220 The rationale for their use was that subjects with asthma demonstrate
hyperresponsiveness airways to histamine and require only small quantities of this mediator
to demonstrate changes in their pulmonary functions. These agents block the acute
bronchoconstricting effect produced by inhaled histamine, but not that produced by
methacholine. They have also bronchodilating action. The newer antihistamines also inhibit
mediator release from in vitro cell systems. Clinical trials have shown their superiority over
placebo in grass and pollen induced asthma. Most of these drugs (terfenadine, astemizole,
azelastine and cetirizine) moderately inhibit the early asthmatic response. Only terfenadine
inhibits exercise induced asthma. The drug also has some calcium channel blocking properties.
Although some studies with H1 antihistamines in asthma have demonstrated some therapeutic
benefits, their role and usefulness in treatment of asthma require additional studies and they
are not recommended as anti-asthma drugs.
Leukotriene Antagonists and Synthesis Inhibitors
Cysteinyl leukotrienes (LT) play a significant part in the pathogenesis of bronchial asthma
as discussed earlier.221-238 These leukotrienes are produced and released from proinflammatory
cells, including eosinophils and mast cells, and are at least 1000 times more potent bronchoconstrictors than histamine or methacholine in normal subjects and patients with bronchial
asthma. They mediate many of the pathophysiologic processes associated with asthma
including microvascular leakage, bronchoconstriction and eosinophil recruitment into the
airways. Since the structure of leukotrienes was described in 1979 ,239 attempts were made to
modulate their pharmacological actions so that they can be of some clinical use by the way of
blocking the leukotriene receptors or inhibition of their synthesis. The therapeutic strategies
were
i. Dietary provision of alternative fatty acid substrates within membrane phospholipids
which will products with less proinflammatory activity,240 but the attempt was
unsuccessful;241
ii. Pharmacological inhibition of specific enzymes, particularly 5-lipoxyenase; and
iii. Modulation of end organ effects with selective cysteinyl leukotriene receptor
antagonists.221,238
Generally four classes of drugs are currently under development and some of them are
available for clinical use as anti-asthma or anti-inflammatory therapy, which interferes with
LT synthesis or activity. They are depicted in Table 10.8 and Figure 10.2.242
Although a number of the above compounds were tried initially, only a few could be
used clinically in human beings because of safety factors.243 Zafirlukast is active both orally
and when administered by inhalation and is the most potent oral cysteinyl LT antagonist.244
Pranlukast, another orally active drug is marked in Japan in the mid-1995.245, 246 These
drugs are at least 200 times more than the early LT antagonists and they cause a shift up to
100-fold in the bronchoconstrictor dose-response curve. They are very active in preventing
bronchoconstriction induced by agonists both in healthy and asthmatic individuals. They
also reduce bronchoconstriction induced by several natural triggers of asthma including
exercise, cold air, allergen and aspirin. A single 20 mg oral dose of zafirlukast produces
marked protection against exercise-induced bronchoconstriction with the maximum effect

160 Bronchial Asthma

Table 10.8: The anti-leukotriene group of drugs

Name
Leukotriene D4 antagonists
Zafirlukast
Probilukast
Pranlukast
Tomelukast
Verlukast
5-Lipoxygenase inhibitors
Zileuton
FLAP Inhibitors

Compound
ICI-204.219
SK and F 104353-Q
ONO-1078
LY 171883
MK-679,-476,-571
A-64077, ABT-761, Z-D2138
MK-886, MK-0591, BAYx1005

Fig.10.2: The four groups of drugs directed against leukotriene synthesis and activity. Thick
arrows shows sites of action that finally prevents the final pathophysiological activity

being observed 5-30 minutes after stimulation.247 400 g of the drug inhaled also produced a
similar degree of protection.248 In aspirin-induced asthma, where there is an increased
production of cysteinyl LTs, the LT-antagonists improve lung function and inhibit
bronchoconstriction induced by aspirin.249,250 Zafirlukast and pranlukast are well tolerated in
clinical trials. Efficacy of objective and subjective measures in patients with symptoms are
dose related and the greater response are achieved with 40 mg total dose of zafirlukast.
Compared with placebo, significant improvement occurs in evening peak flow, a 30%
reduction in rescue use of inhaled 2-agonists, a 46% reduction in night waking, and a 26%
improvement in morning asthma and daily symptoms are observed.251 Doses up to 80 mg

Pharmacologic Management of Asthma 161

twice daily have been given to patients with beneficial effects increasing still further at the
higher doses.252 Besides being effective in preventing bronchoconstriction due to various
triggers, these drugs also affect eosinophil reflux, microvascular permeability, proliferation of
airway smooth muscle cells in chronic severe asthma, mucus secretion, mucociliary transport,
and interaction with nerves. The reported side effects of these drugs are: headache, dry mouth,
and somnolence.251,253-255
The 5-lipoxygenase inhibitor zileuton is the best studied drug.256 Oral zyleuton in a dose
of 800 mg inhibits the early response to allergen challenge and reduced LT synthesis. It also
prevents the response to cold air challenge and to aspirin in aspirin-induced asthma. It also
increases the FEV1. The drug is as effective as theophylline in moderate asthma. It helps in
reducing the symptoms of asthma, -agonist use, and inhaled steroid doses can also be
reduced. The drug also has a steroid-sparing effect in severe asthma. The only disadvantage
of zileuton is its relatively low potency and short half-life (2.5 hours). Therefore, dosing is
to be made four times a day. Even if the drug appears to be safe in clinical trials, this is an
antioxidant and potentially can interfere with redox reactions in other metalloenzymes.
Of the above mentioned drugs, four oral antileukotriene drugs are now available for the
treatment of asthma: monteleukast, zafirleukast, and pranleukast, and the 5-lipoxygenase
inhibitor, zyluton. Clinical studies have shown improvement in FEV1, improvement in
daytime and nocturnal asthma symptom scores, and reduction in reliever 2-agonist use in
patients with patients treated with leukotriene antagonists.257,258 For this reason, recent
asthma guidelines have recommended that antileukotrienes have a role in the management
of bronchial asthma (see below). However, not all patients will show a significant clinical
improvement. No factor has been identified to predict such a response except that cysteinyl
leukotrienes release from leukocytes is correlated with leukotriene receptor antagonist
response.259
In summary, while cysteinyl leukotrienes are important pro-inflammatory and bronchoconstrictor mediators in the pathogenesis of asthma, leukotriene receptor antagonists
demonstrate hybrid anti-inflammatory and bronchodilatory properties.260 A meta-analysis
found that these agents reduced exacerbations by 50% and reduced the requirement of
additional asthma therapy.261 Another meta-analysis from 13 trials showed weighted
estimated protection of leukotriene receptor antagonists amounted to a 0.85 doubling dose
shift, thus the estimated protection amounted to almost one doubling dose reinforcing the
role of these agents as anti-inflammatory therapy in asthma.262 Current International
Guidelines recommend using an leukotriene receptor antagonist as first-line therapy in
patients with mild, persistent asthma, or as second-line therapy in conjunction with inhaled
corticosteroids, as an alternative to increasing the dose of inhaled corticosteroid. Further,
leukotriene-receptor antagonists confers significant additive pro-inflammatory effects to
therapy with a low-dose inhaled corticosteroid.263
Alternative Treatment for Oral Steroid Dependence
Approximately 10% of patients with asthma have severe disease and require high doses of
inhaled or oral glucocorticoids. Some of these patients may have more severe disease because
of relative resistance to the effect of glucocorticoids.264 Although this group may constitute
a very small proportion of the total cases, they consume more than 50% of the resources. They
require more frequent medical attention, need more expensive drugs, more often hospitalised,

162 Bronchial Asthma

and miss more time for work or school than patients with milder form of the disease. Treatment
of patients with severe, persistent asthma who require high doses of systemic steroids presents
a therapeutic challenge. Such high doses of steroids for longer periods of time have multiple
systemic side effects. Several modalities of therapeutic regimens have been advocated/tried
to help reduce oral steroid dependence in severe asthma. Some of these approaches are still
experimental and should be used only in specialised centers.
Before labelling someone having steroid resistance preventable factors need to be considered.
These include poor compliance, occupational factors, gastro-oesophageal reflux, specific
antigens, and dietary factors. Anxiety about asthma deaths might lead to overuse of steroids.
Superimposed psychosocial factors and hyperventilation syndrome may cause further
problem. Some patients are truly corticosteroid resistant, i.e. shows response to bronchodilators
but none to corticosteroids.265,266 These patients should not be prescribed corticosteroids. Some
patients having severe asthma and who show some response to steroids should not be labelled
as steroid resistant cases, but as severe asthma only. Before attempting any of the
following experimental drugs, a trial of high doses of inhaled corticosteroids
(2 to 4 times the usual doses) is essential. This approach has the lowest incidence of adverse
effects and has a high likelihood of clinical efficacy. In the steroid dependent asthma, a
patient, treatment with high-dose inhaled corticosteroids should be maintained over a period
of several weeks to months, and the dose of oral steroids should be reduced slowly while
monitoring pulmonary function. This approach is often helpful.
Various drugs have been proposed as alternatives to systemic steroids, including
troleandomycin, gold, azathioprine, methotrexate, and cyclosporine, intravenous
immunoglobulins, hydroxychloroquine, dapsone, inhaled frusemide, and intravenous
magnesium sulphate. 267-270 Since asthmatic inflammation may be regulated by Th2
lymphocytes, some of these drugs which are immunosuppressive, act due to their action of
inhibition of T-lymphocytes.
Methotrexate is an antimetabolite which antagonizes folic acid by inhibiting dihydrofolate reductase. This interferes with thymidine synthesis and thus blocks DNA synthesis
and cell division. At higher doses, it is an antineoplastic agent and in low doses (5-25 mg/
week) it acts as an anti-inflammatory and immuno-suppressive agent. The mechanism of
action as an anti-inflammatory drug include inhibition of histamine release from basophils,
inhibition of cytokine release (IL-1) from mononuclear cells, and reduction of neutrophil
chemotaxis.271-273 Although some clinical trials have shown benefit from low dose methotrexate,
(15 mg/wk) others do not support this.273-279 The drug is also found useful in children.280,281
There is significant reduction in steroid doses, when methotrexate is added in addition to
subjective improvement. The common side effects are nausea, vomiting, hepatic dysfunction,
alopecia, oral ulcers, and neutropenia. In spite of the controversy and confusion, the following
provisional conclusion may be made from available literature:
i. Methotrexate may be a steroid agent in some steroid-dependent patients;
ii. No predictive factor could be found about the responders;
iii. No consistent effect on airflow or bronchial responsiveness is expected;
iv. To have an appreciable effect, the treatment may be continued for long periods (> 3
months) and unlikely to occur after 1 year;
v. Steroid-sparing effect disappears on discontinuation of methotrexate;
vi. Doses more than 15 mg/wk may have unacceptable side effects;

Pharmacologic Management of Asthma 163

vii. Steroid weaning should be done before methotrexate trial; and
viii. The drug should be viewed as a risky preposition in comparison to long-term oral
steroid therapy.282
Cyclosporin A is a fungal cyclic polypetide used mostly for transplant patients. It inhibits
the activation of T lymphocytes and the synthesis and release of lymphokines like IL-2,
IL-3, Il-4, IL-5, and TNF (tumor necrosis factor). It also inhibits histamine and LTC4 release
from mast cells and basophils and inhibits neutrophil chemotaxis, monocytes-macrophages.283
Use of cyclosporin has shown some result.284,285 Hypertrichosis, hypertension, parasthesia,
tremour, headache, and flue-like symptoms are some of the side effects of cyclosporin treatment.
Cyclosporin appears to be a promising drug in the treatment of steroid-dependent bronchial
asthma.
Gold salts (auranofin) has anti-inflammatory properties and are commonly used for the
treatment of rheumatoid arthritis. The drug has been shown to inhibit IgE-mediated release of
histamine and LTC4 from basophils and mast cells.286 It also inhibits tracheal smooth muscle
contraction in response to histamine and specific antigens in guinea pigs.287 Oral auranofin 3
mg twice daily has been found useful.288,289 Mucocutaneous reactions are the common side
effects of gold therapy.
Other agents like azathioprine,290 intravenous immunoglobulin,291 troleandomycin,292
colchicine,293,294 and hydroxychloroquine295 have been suggested to be alternatives in steroiddependent asthma. But the experience in clinical practice is not much, and they are not
recommended for the routine use in these patients.
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176 Bronchial Asthma

11
Inhalation Therapy
Current therapeutics emphasises the importance of effective delivery of a drug to its site of
actionthe Targeted Drug Delivery.1-6 The advantage of this approach is avoidance of
unnecessary and undesirable exposure of tissues/organs not involved in the disease process
to the drug. It is sufficient and advantageous to have the drug delivered only to the site
where the drug is needed. Targeted delivery of the drug to the desired site of action means
that smaller doses are enough to produce the desired effect and generalised systemic side
effects can be eliminated or minimised and a rapid action of the drug can be obtained. The
value of inhalation as a route of drug administration has been recognised for thousands of
years by the ancient civilisation in India, China, the Middle East and as well as by Hippocrates
and Galen. The Ayurvedic system of medicine advocated the use of datura smoked in a
pipe for a variety of ailments and atropa belladonna was given by smoking as a standard
remedy for asthma. Asthma cigarettes made from Datura leaves are also being used by
herbalists.
Bronchodilator aerosols have been in use since 1935. In the past adrenergic bronchodilators have been given by hand-held squeeze-bulb nebulisers. This was cumbersome,
and modern pressurised aerosols were introduced in 1956 and constituted a breakthrough
in inhalation treatment. In recent times, inhalation therapy for asthma has been developed
to a high level of sophistication although they are simple to use.
The key to inhalation therapy is the aerosol particle. An aerosol is a suspension of fine
liquid or solid particles in air. The efficacy of an inhaled drug depends largely on how
much of the drug is deposited in the peripheral airways. On the other hand, the deposition
of inhaled particles is determined both by the physical characteristics of the air-borne
particles and physiological parameters like airflow to the lungs. Particle size is an important
determinant of aerosol deposition in the lungs. Most devices (discussed below) generate
particles in the size range of 1-10 micron. Only particles in the size range of 2-5 micron can
be inspired deep into the lungs; particles 5 micron or more in diameter are impacted in the
throat or in larger airways. Particles less than 1 micron behave like a gas and are exhaled in
the expired air. Most aerosols contain a wide range of particle sizes and are known as
heterodisperse aerosols. The mass median aerodynamic diameter (MMAD) is the median
diameter of the aerosol multiplied by the square root of particle density. MMAD is important
as regards aerosol deposition rather than the particle sizes. The propellant surrounding the
drug particles evaporates on emerging from the canister and the particle steadily decreases
as the aerosol moves away from the canister. Other factors that count for aerosol deposition
include velocity, inertial impaction, and gravitational sedimentation. However measurements using radioactive teflon particles labelled with technetium-99m with a gamma camera

Inhalation Therapy 177

have shown that about 10% of the drug released from an MDI is deposited in the lung.
About 80% is deposited in the oropharynx and about 10% is trapped on the walls of the
inhaler device.
For the purpose of inhalation therapy an aerosol of the drug can be generated in three
ways:
i. Pressurised aerosol systems;
ii. Dry powder system;
iii. Nebulisers.
Pressurised Aerosol Systems (Metered Dose InhalersMDIs)
Most medications prescribed for the treatment of bronchial asthma for maintenance or rescue,
are administered via a metered dose inhaler (MDI). In Pressurised aerosol systems or metered
dose inhalers micronised finely powdered drug is dissolved or suspended in a liquid
propellant mixture, and packed in a sealed container (Fig. 11.1). The liquid propellants are
highly volatile chlorofluorocarbons, CFC, (Freons) with a high vapor pressure of about 400 kPa.
These freons are gases at room temperature, have a low boiling point, are inert, noninflammable, and odourless. Some surfactant is added so that they are not clumped together.
On actuation, propellants emerge and break up into aerosol particles each consisting of a
drug particle surrounded by the propellant. The valve is metered so that each actuation
releases a fixed amount of the drug-propellant mixture. Therefore, it is named as the metered
dose inhaler (MDI).
During recent years, CFCs have been criticised for their harmful effects on the environment, especially the depletion of the stratospheric ozone layer. The production and use of
CFCs were banned by international treaty (the Montreal protocol) in 1987, although their
use in medications is not as the amount for this use is very small. Such exemptions to the
National and International bans were made for MDIs to allow time for comparative clinical
trials of alternative propellants, as required by worldwide regulatory agencies. Although
no deadline has been set for the United States, Canada aims to achieve total transition by
2005, and the European Commission predicts that there will be no need for CFC-based
MDIs in the European Community by the year 2003. So far, the most promising alternative
propellants for MDIs are derivatives of hydrofluoroalkane (HFA). The HFA agents lack
chlorine, and thus have zero ozone depletion potential.7-9 Preclinical studies have

Fig. 11.1: Components of meter dose inhalers

178 Bronchial Asthma

demonstrated the acceptability of these propellants in terms of pharmacology, toxicology,
and safety.10 Clinical studies also have shown that these propellant are as equivalent or
even better than those use CFCs as propellants.11-18 Clinical trials have demonstrated that
the level of asthma control achieved with CFC-beclomethasone dipropionate may be
obtained with approximately half the total daily dose of HFA- beclomethasone dipropionate.
This is probably due to improved lung deposition with the extra fine aerosol of HFAbeclomethasone dipropionate compared with the suspension of CFC based aerosol lung
deposition is also greater with HFA- beclomethasone dipropionate compared with CFCbeclomethasone dipropionate and CFC-fluticasone propionate. Deposition values are related
to the particle size distribution of each inhaler, with the smaller particles of HFAbeclomethasone dipropionate providing the greatest lung deposition and least oropharyngeal deposition.19
Evaluation of adherence to treatment is one important step in asthma management.
Patients tend to overestimate the usage of MDIs presumably secondary to recall bias or as
an effort to avoid criticism Prescription refill histories as from the issuing authorities or
verification of the medical bill of the patient and canister weighing are more objective
measures, but they do not reflect pattern of usage. Electronic monitors are recently available
for accuracy of MDI use.20
Dry Powder Inhalers
In an attempt to overcome the coordination problem that is required for the successful use
of the pressurised MDIs, a number of dry powder inhalers have been developed. In the dry
powder system, micronised drug is mixed with a carrier substance (lactose) and the mixture
is filled into a gelatin capsule. The capsule is loaded into the inhaler device and is cut open
in the device before inhalation (Fig. 11.2). After piercing or fracturing the gelatin capsule,
the patient only needs to do is to inhale through the device to draw the powder out of the
capsule. The aerosol is generated by means of the energy contained in the inspired air. The
air stream passes the powder in such a way that a turbulent flow is formed which breaks
up the particles into a dust or aerosol. The higher the inspiratory flow rate (>60L/min),
higher the number of respirable particles. Although it is easier to use than a MDI, it is less
convenient because of the need to load the capsule before use. Because of a high flow rate,
many patients, particularly children, cannot generate a sufficient inspiratory flow required
to break up the aggregates during an acute attack. Thus, too large particles are unable to
penetrate into lung periphery. Further, in the panic and distress of an acute situation, the
patient may have difficulty in inserting the capsule into the device. Inhalation of the dry

Fig. 11.2: Dry powder system

Inhalation Therapy 179

powder may cause some irritation and cough in some patients. The gelatin capsules are
subject to environmental influences of moisture and temperature during storage. This will
make the capsule soggy and could not be broken by the system efficiently. Thus, they may
be reserved for those who cannot master the technique of MDI. Recently, a multi-dose,
ready to use, additive free dry powder inhaler effective at low inspiratory flow rates are
available which can overcome the above difficulties.
Different types of DPI such as Turbohalers, Diskhalers, and Accuhalers are available
now. These devices have the advantage of being breath activated, and delivery of an accurate
dose is less dependent on patient technique. Recently, new generation multi-dose dry
powder inhaler (MDPI) is available, which has a triple inhalation control system, so that
the patient has acoustic (click), visual (dose counter), and sensory (oropharyngeal sensation
confirmation of dosing. Other mandatory features of the DPI are an accurate metering
system, a dose counter, and a robust compact design. A unique feature in terms of cost and
flexibility is that the inhaler utilises replaceable cartridges that contain up to 200 doses,
with the future potential for a wide range of therapies.21
Nebulisers
In nebulisation, small droplets are generated suitable for inhalation from a nebulising
solution containing the drug. Two types of nebulisers are used for this purpose:
a. the Jet nebuliser (Fig. 11.3) which is powered by compressed air or oxygen from a
compressor or a cylinder; and
b. the ultrasonic nebuliser which derives the energy required to make an aerosol from high
frequency sound waves (Fig. 11.4). Nebulisers need a power source and use of nebulisers
is time consuming. However, they are useful in very young children or adult patients
who cannot manage the use of inhalers and for delivery of large doses of bronchodilators
as in acute severe asthma. In addition they are used for delivery of drugs that cannot be
formulated in a MDI because of technical reasons since very high doses cannot be packed
and for bronchial challenge tests and lung ventilation scanning. The main advantage of
nebulisers is the ease of use by patients. It can be inhaled with normal tidal breathing
through a mouthpiece or a face mask. Since they can be driven by oxygen, this becomes
an extra advantage in acute asthma. Moisture obtained from wet aerosol may be helpful
in loosening the mucus. Nebulised bronchodilators can also be administered through
pressure-cycled ventilators. Jet nebulisers driven by oxygen/compressed air needs a
flow rate of at least 6-8 litres/min generate aerosol particles in the respirable range. The
solution used for nebulisation needs to be diluted with isotonic and preservative-free
solutions to reduce drug loss due to impacting of aerosols in the dead space of the
apparatus. A minimum volume fill of 4 ml (drug + normal saline) with a flow of 6 litres/
min. is recommended to ensure a high aerosol output, small particle size, And short
treatment time. In infants, the small minute volume of 3-3.5 litres compared to the
nebuliser output of 6 litres/min limits the amount of the drug to be inhaled. Hence, they
will need a higher dose. Other precaution to be taken is that the interior of the container
be cleaned thoroughly after use to avoid bacterial (Pseudomonas aeruginosa) contamination
and the air intake grill and filters to avoid Aspergillus contamination. The choice of the
particular nebuliser is important as not all of them produce desired aerosols. As with
MDI, only about 10-12% of the drug can reach the lungs, most of it being retained as

180 Bronchial Asthma

Fig. 11.3: Jet nebuliser

Fig. 11.4: Ultrasonic nebuliser

large droplets on the internal walls of the nebuliser itself. Thus, in an acute attack of
bronchial asthma, a properly used MDI with a spacer is as effective/useful as a nebuliser.
The main advantages of inhalation devices are the greater asthmatic effect (10-20 times
of an oral dose is required to produce an equivalent response as by inhalers), rapid onset of
action and response, self administration on demand. Short-term prophylaxis and lack of
side effects are the other advantages. Various problems of inhaler use include Hand-Lung
dyscoordination (failure of timing the inspiration with dose release), cold freon effect,
inspiration and breath holding, and cough on inhalation of aerosol.
All aerosolised medications that are used for the treatment of asthma are available as
metered-dose inhalers (MDI) which are pressurised and propellant-powered; or jet and
ultrasonic nebulisers which are electrically powered. The advantage of delivering drugs
directly into the airways is that high concentrations of drug can be delivered to the airways,
while systemic side effects are usually avoided. The major disadvantage of this mode of
drug delivery is that training and skill are required to coordinate activation of the MDI
with inhalation of the drug. Therefore, teaching of proper MDI techniques is very essential

Inhalation Therapy 181

since only about 10% of the inhaled dose penetrates the lower airways, even with optimal
techniques. It is generally agreed that maximum delivery of aerosol into the airways is
obtained by inhaling an aerosol bolus from functional residual capacity. A flow rate of less
than 1 L/sec, with an inhalation time of over 5 second and a breath holding time of 10 seconds
is believed to be the optimal technique. There are two different general approaches to
inhalant techniques with MDI: the open mouth and closed mouth techniques. In the open
mouth technique the inhaler is held approximately 4 cm in front of an open mouth. Other
delivery devices which have been developed in an attempt to overcome the disadvantages
of pressurised MDI include the Roto-Haler, Gentle-Haler, Autohaler, and Turbohalers. The
most important device is the spacer which may be a cone spacer or a tube spacer.
Spacer Devices
Spacer device is an extension chamber interposed between the mouth piece of the MDI and
the mouth of the patient (Fig. 11.5). This device allows time and distance for the aerosol to
travel in space before it is inhaled. The particle size is reduced because of evaporation of
the liquid propellant. The aerosol velocity is also reduced because of resistance offered by
air in the space. Smaller particle size helps better deposition in the peripheral airways and
reduces deposition in the oropharynx. The slowed down particles held in the chamber can
be inhaled few seconds later after the release and there is no need of synchronisation of
inspiration and actuation. This simplifies inhaler use and quite helpful in those who have
coordination problems. Spacer devices are usually of two types: small volume spacers (tube
spacers) and large volume spacers or valved spacers of the volume of about 750 ml. The
aerosol cloud emerging from the MDI expands into a conical shape as it moves away. The
conical shape of the spacer accommodates the enlarging cloud. The spacer is such that
impaction loss on the walls is minimal. The one way valve opens during inspiration and
closes during expiration. This helps retaining the modified aerosol in the chamber until it is
emptied by inhalation. The expired air leaves the mouth piece through a side port.
It is calculated by laser holography studies that one cubic millimeter of air within a
spacer is about 5500 at the end of 5 seconds and is still 3300 after 30 seconds of actuation.
The mass median diameter of the aerosol from an MDI is reduced from 8.4 to 4.9 microns
making possible most of the particles to be in the respirable range. Lung deposition is
increased by 133% and reduces throat deposition by 90%.

Fig. 11.5: Spacer

182 Bronchial Asthma

REFERENCES
1. Hillman B. Aerosol deposition and delivery of therapeutic aerosols. J Asthma 1991;28:239.
2. Newman SP, Clarke SW. Therapeutic aerosols 1- Physical and practical considerations. Thorax
1983;38:881-86.
3. Newman SP. Aerosol deposition consideration in inhalation therapy. Chest 1985;88(Suppl):S15260S.
4. Sackner MA, Kim CS. Auxillary MDI delivery systems. Chest 1985;88(Suppl):S161-S69.
5. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986;315:870-74.
6. Summer W, Elston R, Tharpe L, Nelson S, Haponik EF. Aerosol bronchodilator delivery methods.
Arch Intern Med 1989;149:618-23.
7. Noakes TJ. CFCs, their replacements and the ozone layer. J Aerosol Med 1995;8(Suppl):S3-S7.
8. Smith IJ. The challenge of reformulation. J Aerosol Med 1995;8(Suppl):S19-S27.
9. Fischer DA, Hales CS, Wang WC et al. Model calculations of the relative effects of CFCs and
their replacements on global warming. Nature 1990;344:513-16.
10. CPMP on possible alternatives to CFCs. Scrip 1994;1943:26.
11. Furukawa C, Atkinson D, Forster TJ et al. Controlled trial of two formulations of cromolyn
sodium in the treatment of asthmatic patients > 12 years of age. Chest 1999;116:65-72.
12. Busse WW, Brazinsky S, Jackobson K et al. Efficacy response of inhaled beclomethasone
dipropionatein asthma is proportional to dose and is improved by formulation with a new
propellant. J Allergy Clin Immunol 1999;104:1215-22.
13. Davies RJ, Stampone P, OConner BJ. Hydrofuoroalkane 134a beclomethasone dipropionate
extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone
dipropionate to approximately half the total daily dose. Respir Med 1998;92(Suppl A):23-31.
14. Gross G, Thompson PJ, Chervinsky P et al. Hydrofuoroalkane 134a beclomethasone dipropionate,
400 g is as effective as chlorofluorocarbon beclomethasone dipropionate 800 g for treatment
of moderate asthma. Chest 1999;115:343-51.
15. Leach CL. Improved delivery of inhaled steroids to the large and small airways. Respir Med
1998;92(Suppl A):3-8.
16. Juniper EF, Price DB, Stampone PA et al. Clinically important improvements in asthma-specific
quality of life, but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extra fine beclomethasone
dipropionate. Chest 2002;121:1824-32.
17. Langley SJ, Holden J, Derham A et al. Fluticasone propionate via the disk haler or hydrofluoroalkane-134a metered-dose inhaler on methacholine-induced airway hyper-responsiveness.
Chest 2002;122:806-11.
18. Nayak A, Lanier R, Weinstein S et al. Efficacy and safety of beclomethasone dipropionate extra
fine aerosol in childhood asthma. A 12-week, randomised, double-blind, placebo-controlled
study. Chest 2002;122:1956-65.
19. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of Hydrofluoroalkane
134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone. Chest 2002;122:510-16.
20. Julus S, Sherman JM, Hendeles L. Accuracy of three electronic monitors for metered dose inhalers.
Chest 2002;121:871-76.
21. Hansel TT, Kunkel G. New horizons in asthma therapy: The Novoliser dry powder inhaler.
Curr Opinion Pulm Med 2001;7(Suppl 1):S1-S2.

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

183

12
Therapeutic Approach in
Patients with Asthma
I. Chronic Bronchial Asthma
Asthma is a chronic condition with acute exacerbations having variable course. The course
of disease is not uniform with periods of exacerbations and remissions which varies from
days to weeks to months to years. Management therefore, requires a continuous care
approach to control symptoms, prevent exacerbations, and reduce chronic airway
inflammation. The course of asthma varies among patients. The degree of an individuals
asthma severity may change from one season or year to the next. Therefore, specific asthma
therapy must be selected to fit the need of individual patients. The therapy must be adaptable
to change as the disease changes in the individual.
Over the years a number of guidelines have been developed. Notable amongst them are
those of the National Heart, Lung and Blood Institute of the NIH, USA, British Thoracic
Society, Research Unit of the Royal College of Physicians of London, the Kings Fund Center,
the National Asthma Campaign, Global Initiative for Asthma and WHO.1-11 The basic
principles are the same in all these guidelines. Management of bronchial asthma can be
divided into that for chronic asthma and acute severe asthma.
CHRONIC BRONCHIAL ASTHMAAIMS OF THERAPY
The basic goals or aims of management of chronic asthma are:
i. To recognise asthma and its severity
ii. To abolish symptoms particularly those of the chronic troublesome ones like nocturnal
cough and dyspnoea, and early morning symptoms
iii. To maintain normal activity levels including exercise
iv. To maintain a normal or near normal or the best possible long-term pulmonary
functions
v. To prevent recurrent exacerbations of asthma and the risk of severe attacks
vi. To minimise absence from school or work
vii. To enable normal growth to occur in children
viii. To minimise the need for as needed (quick-relief) 2-agonist therapy
ix. To avoid adverse effects from asthma medications
x. To meet patients and families expectations of and satisfaction with asthma care.

184 Bronchial Asthma

PRINCIPLES OF MANAGEMENT
Certain basic principles of bronchial asthma needs to be considered before administering
any specific therapeutic modalities.
i. Since there are many conditions which mimic bronchial asthma, the diagnosis should
be established.
ii. It should also be realised that asthma is a chronic condition with acute exacerbations
with varying periods of remissions. There is no cure of bronchial asthma but if the
patient follows certain guidelines including medications, the disease can be controlled
and the patient can lead life like a normal individual. Treatment requires a continuous
care approach to control symptoms, to prevent exacerbations, and to reduce airways
inflammation.
iii. Asthma is an inflammatory disease and inflammation may continue even during
periods of clinical remission and even in patients with mild asthma. Therefore antiinflammatory treatment is an essential component of management of bronchial asthma.
iv. The severity of asthma must be evaluated by assessing the activity limitation, by
evaluation of night time symptoms and by assessing pulmonary function.
v. The therapy selected should not have adverse effects that are perceived by the patient
to be worse than the underlying disease. The therapy is usually dictated by the severity
of disease, medication tolerance, and sensitivity to environmental allergens. All these
factors need to be incorporated in the formulation of therapy.
vi. It is essential to deal with common asthma triggers. Environmental control measures
must be under taken to avoid allergens. All types of smoking should be stopped and
exposure to passive smoke should be eliminated. Inhaled 2agonist or Cromolyn
sodium or both taken prior to an anticipated encounter with a known trigger can
prevent or diminish an asthmatic response. This is particularly true for exerciseinduced asthma. The same principle can also be applied to other situations, including
exposure to antigens like animal danders, cold air, or other irritants. Both adults and
children who has upper respiratory tract viral infections, and start to have acute asthma
symptoms may need to add or increase anti-inflammatory asthma medications in
order to control the asthma symptoms. Bacterial otitis and sinusitis should be treated
with antibiotic therapy. Sometimes aggressive antiasthma therapy fails because an
upper respiratory infection has been overlooked. Allergic and nonallergic rhinitis
should be treated with antihistamines, Cromolyn sodium nasal spray, or topical nasal
steroids. The patient must be taught to avoid:
a. Beta blockers (tablets and eyedrops) are contraindicated.
b. If aspirin or NSAIDs are known to induce asthma, they should be avoided.
c. Allergens as outlined above (e.g.; house-dust mite, domestic pets, and pollens.
should be avoided where relevant.
d. Occupational causes must be considered and appropriate steps be taken.
e. Active smoking should be avoided.
f. Passive smoking should also be avoided.
g. Prophylactic treatment for exercise or before exposure to triggers.
vii. Anticipatory or early interventions in treating acute exacerbations of asthma reduce
the likelihood of developing severe airway narrowing.
viii. Asthma therapy has the following integral components:

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

185

a. Patient education and family participation

b. Avoidance of identified causes where possible
c. Use of the lowest effective dose with a target of controlling asthma but with the
minimum of short and long term side effects.
The above three approaches are interrelated in the management and pathogenesis of
bronchial asthma are shown in Figure 12.1.
PATIENT EDUCATION
Health education by the physician is a powerful tool for helping patients gain the motivation
and skill to control their asthma.12-15 There is definite evidence of benefit from patient
education and the issuing of self management plans. Management of asthma requires a
partnership between the patient and family and the health care provider. It should be made
clear from the very beginning that treatment and supervision are likely to be required over
a prolonged period of time. Education should be the basis of sharing of information and the
acquisition by the patient and family of understanding and skills. This will bring about
appropriate change in behaviour only if patients and family are given adequate opportunity
to express any fears or concerns, and time to discuss their expectations of both the disease
and its treatment. Patients and parents require both verbal and written advice and many
will require guided self management plans, so that the patient can keep well and adjust
treatment according to a plan developed with the physician. Giving information alone does
not alter behaviour, but written and audiovisual reinforcement of spoken message aids
patient confidence. All patients should be given information about features which indicate
when their asthma is worsening, and what to do under those circumstances. Giving those
with asthma written self management plans so that they may adjust treatment to keep
themselves well reduces morbidity and health costs.16,17

Fig. 12.1: Approach to therapy of bronchial asthma

depending upon the aetiopathogenesis

186 Bronchial Asthma

Various components of patient education plan includes:
i. Establishing a partnership which improves the patient adherence to the treatment
plan and stimulate family effort to improve control of patients asthma18,19
ii. Encouraging adherence to the treatment plan is the next step which can be achieved
by clarifying patients expectations for treatment and answering questions,20 involving
the patient and family in the development of a treatment plan, simplifying the treatment
plan, providing the patient with diaries to record antecedents of asthma exacerbations,
symptoms, actions taken, and peak expiratory flow rates. Further, an important
question to be kept in mind whether that patient can afford to buy the medications
prescribed, and if not, alternative therapies must be considered. Ignoring this fact is a
very important cause of non-adherence to treatment prescribed. Evaluation of the
result of treatment from time to time helps positive reinforcement plans. If the patient
is not adhering to the treatment plan, then the cause for the same to be identified by
asking the patient the likely problems and a possible solution for the same should be
provided.
iii. Various essentials of patient education includes the content of teaching both written
and audiovisual, explaining to the patient about asthma like what is it, what are the
key points about the symptoms and signs of asthma, the role of inflammation and the
role of various medications, asthma triggers and how to avoid them, the need for
treatment, how the medicines work, adverse effects of drugs and their prevention,
preventive treatment, and early treatment during exacerbations, alleviating patient
fears concerning medications, providing written guidelines, and steps to manage
asthma episodes at home.
iv. The correct use of inhalers should be demonstrated to the patient.21,22 Similarly, the
patient should demonstrate the use of the MDI to the clinician. The patients MDI
technique should be reviewed during each visit. When several inhalers are prescribed,
labelling them is essential and also explaining when to use which one and which
inhaler to be used first.
v. The patient should be able to recognise the early warning symptoms or signs of airflow
obstruction which will enable him to begin treatment immediately. Early warning
signs include a peak flow level below 20% predicted or personal best level; cough or
wheeze, particularly during daily activity; an individual pattern of early signs such
as chest tightness, shortness of breath, or dark circles under the eyes in children.
Indications of immediate report to emergency include cyanosis, difficulty in breathing,
talking or walking, retraction of the chest, neck or ribs and nasal flaring, failure of
medications to control worsening of symptoms, and a steady decline of PEFR.
vi. Knowledge of the optimal use of home peak expiratory flow meterboth its recording
and interpretation are now one of the essential components of asthma management.
vii. Materials and guidelines for individuals and group education and support network
are very helpful. The education must continue in a long-term basis. discussions,
demonstration, group classes, and dramas help patients learn guided self-management
skills. The most effective is for the health care professional to give information verbally,
demonstrate techniques, and then provide reinforcement by several routes. The specific
methods should be selected on the basis of patient and cultural preferences. Some
patients benefit from joining asthma patient support groups or clubs. These groups
vary from area to area, but most provide informative materials, group education, and

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

187

mutual support. Group members exchange personal tips on managing asthma, making
changes at home, and coping with the stress of a chronic disorder in the family.
Currently asthma education worldwide websites are available. However, asthma
education material contains many accessibility barriers, is highly variable in quality, and
content, and takes little innovative use of technology. These informations currently available
in the web fails to meet the information needs of the patient.23
The patient must be made to understand that there are new ways to manage their disease
so that they can prevent problems, be free of symptoms both day and night, and live
productive, active lives. They can learn to control their asthma, handle mild attacks promptly
at home, and prevent serious attacks. Emergency visits should no longer be needed. Regular
medical visits provide periodic opportunities to address concerns, solve problems, and
reach agreement on long-term treatment. This is achieved by having the patient become
actively involved as a partner in his or her care through guided self-management. Guided
self-management means a patient can take medications correctly; understand the difference
between quick-relief and long-term preventive medications, avoid triggers; monitor personal
status using symptoms and if possible, PEFR indicators; recognise signs that asthma is
worsening and take action; follow personalised action steps and stop attacks; and seek
medical help at the appropriate time to stop serious attacks.
Long-term asthma control requires a written management plan that describes what to
do to prevent symptoms and attacks and what to do in case an attack occurs. An asthma
management zone system is effective for guided self-management and should be included in
the management plan. This system classifies levels of asthma control as different zones
based on the frequency and severity of symptoms and peak expiratory flow measurements.
The system then indicates the appropriate therapy for each zone. The zone system helps
patients understand the chronic and variable nature of asthma, monitor their condition,
identifies the earliest possible signs that day to day control of asthma is deteriorating, and
act quickly to regain control. When PEFR readings are available, the patients current reading
must be compared to his or her personal bestthe highest PEFR value achieved when the
patients asthma is under controlis his benchmark for asthma control. The patient then
follows the prearranged action steps appropriate to each of the following three zones.
Green zone It indicates all clear. Asthma is under control with no symptoms or interruption
of activities or sleep. PEFR are usually 80-100 percent of personal best. The variability is
less than 20%. If the patient has stayed for at least 3 months in this zone, a careful stepdown of the therapy can be considered as outlined below.
Yellow zone This signals caution. Some mild asthma symptoms are present. PEFR readings
are 60-80% of personal best. There is 20-30% variability. Readings in this zone indicates
that an acute attack may be present for which a temporary increase in medication is needed,
essentially 2agonist inhalers for quick relief. The patient should develop a treatment plan
with the physician. Also it is possible that an overall deterioration of asthma might have
occurred that require further treatment. A short burst of corticosteroids will be required till
the PEFR comes back to the green zone. In case the patient is taking inhaled steroids, that
should be doubled for 12 weeks or until PEFR improves. Frequent fluctuations into the
yellow zone may indicate poor control of asthma and the green zone therapy has to be
increased.
Red zone This indicates medical alert. Asthma symptoms are present even when the patient
is at rest or interfere with activity. PEFR readings are below 60% of the personal best. The

188 Bronchial Asthma

patient should follow medication plan. An inhaled short-acting -agonist should be taken
immediately. If the PEFR improves after initial bronchodilator therapy, the yellow zone actions
should be continued. After the attack is controlled, the green zone therapy and patient
adherence to the management plan should be reviewed and adjusted accordingly.
IMMUNOLOGICAL MANAGEMENT
Although the benefits of immunotherapy remains unproven, this form of therapy is still
widely practiced by many physicians. Since allergy has a significant role in the
pathophysiology of bronchial asthma, environmental control measures to avoid allergens is
an important step in the control of bronchial asthma. The main method of identifying allergy
is by clinical history. Skin prick tests and in vitro specific IgE measurements are rarely helpful
in diagnosis and management and should be interpreted by a physician familiar with such
tests. In general both active and passive smoking should be avoided.
Outdoor Allergens
Exposure to outdoor allergens is best reduced by remaining indoors, preferably in an air
conditioned environment,24,25 particularly during the midday and afternoon when pollen
and some mould spore counts are highest. Since there is a geographical and seasonal variation
of pollens and other aeroallergens, knowledge of the same is helpful. Use of nasal filters or
masks have been tried with little success. Pollen particles greater than 10 microns are usually
cleared in the nose and mouth and do not generally penetrate the lower airway.26 However,
some plants produce allergen containing particles that are in the respirable range like ragweed,
and congress grass pollination, which are clearly associated with asthma. Mould spores are
generally smaller than pollen grains and are more likely to penetrate the lower airway. Mould
spores exist primarily out of doors and tend to be seasonal. Some fungi sporulate on worm,
dry summer days; others in the rainy seasons. Keeping windows closed during seasons of
high mould production will reduce exposure.
Indoor Allergens
Environmental control to reduce exposure to indoor allergens is a critical component of asthma
management. House dust is an important source of indoor allergens. Although house dust per
se is not an allergen, there are allergic components in house dust. The most important include
mites, cockroach allergen, and animal danders.

Animal Allergens
The best way to avoid animal allergens are just to remove the animal from the house (dog, cat,
rodents, birds, etc). Removal of the animal may not afford immediate relief even when followed
by vigorous cleaning as allergen has been shown to remain in the home for many months.27
Residual allergen can be denatured and rendered nonallergenic by application of 3% tannic
acid solution. If the pet cannot be removed from the house, it should at least be kept out of the
allergic persons bedroom at all times. If the animal is in the bedroom at all, the dander and
saliva will remain for a long time even after the pet leaves. Weekly washing of the pet may
reduce the amount of dander and dried saliva deposited on carpets and furnishings. The

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

189

most reliable reduction of exposure to allergens derived from furred pets is done by completely
excluding the pet from the home and avoiding exposure to pets elsewhere. It is of course not
possible always. It is important to make patients aware of the choices they are making like
more medications, decrease in health related quality of life and to reexamine these choices on
a regular basis. Patients are often interested in alternatives to excluding the pet from the home.
In such a situation, there is hardly anything other than complete avoidance can benefit
asthmatic patients with a documented pet allergy.28 Since there is a dose-response relationship
between parameters of asthma control, and exposure to allergens, it seems reasonable to keep
the cat out of the bedroom, living room, and play- room. Washing of pets as mentioned above
has given variable results and must be repeated so frequently as to be impractical in most
situations. Settled allergens will be removed by methods of removal of house dust (see on page
191). Cat and dog allergens, as opposed to dust mite allergen, are often found on small
particles that are easily airborne. This renders the use of air filtration devices attractive. Due
to small particle size of airborne allergens, HEPA cleaners are likely required. Significant
health benefits are not documented despite the reduction in the amount of airborne particles,29
although an improvement in bronchial hyperresponsiveness has been found in cat allergic
children.30 In a recent meta-analysis, it is reported that use of air filtration systems in patients
with asthma or allergy showed a reduction in symptoms, but not of medication use, and no
improvement in measures of peak flow.31

House-dust Mite
House-dust mites are important causes of allergic asthma. They occur in environments with
sufficient humidity since they are quite dependent for survival on moisture from atmosphere.
Mite antigen is found throughout the home, wherever human dander, the food for the mite, is
found. High levels are obtained in dust obtained from mattresses, pillows, carpets, upholstered
furnitures, bedcovers, clothes, and soft toys.32 The principal allergen is found in the mite
faeces. A gram of dust may contain 1,000 mites and 250,000 faecal pellets. These faecal pellets
are quite large varying in size from 10-40 microns, and therefore do not easily penetrate the
lower respiratory tract. Mite antigen is easily demonstrated in the air during housecleaning
activities, but it is present in only very small amounts in undisturbed air.33 Some mite allergen
is associated with smaller size particles that may be in the respirable range for the lower
airways.34 House-dust mite control measures include encasing the mattress in an airtight
cover; the pillows are also to be encased and be washed weekly; the bedding should be
washed in water at 130 F or 55 C weekly and dry thoroughly in a hot dryer or in the sun;
curtains and childrens soft toys are to be washed regularly; the patient should avoid sleeping
or lying on upholstered furnitures; and carpets laid on concrete are to be removed, if possible
the indoor humidity is to be reduced to less than 50%; carpets may be removed from the
bedroom; and ascaricides may be useful in killing the mites.35-38 If carpet removal is not possible,
vacuuming should be carried out with a high-efficiency particulate air (HEPA) vacuum cleaner
with a double reservoir bag, preferably when the asthmatic patient is not present. Central
vacuum cleaners exhausted to the outside are also likely to be effective.39 Such a multifaceted
and concerted approach to reducing levels of dust mite allergen among asthmatic subjects
with positive allergy skin test results to mite allergens, if successful, is clearly associated with
improvement in the parameters of asthma control like symptoms, need for medications,
measures of airflow, and measures of bronchial hyperresponsiveness.40

190 Bronchial Asthma

Cockroach Allergen
It is important in warmer climates.41 The infested homes should be cleaned thoroughly and
regularly. Pesticides and pesticide sprays are used to eliminate cockroaches. If sprays are
used the patient should not be present at that time.

Indoor Moulds
These are found in environments with increased humidity. Bathrooms, kitchens and basements require adequate ventilation and frequent cleaning using chlorine bleach if necessary.
Dehumidifiers for damp basement areas should be considered, with humidity levels for
less than 50% but above 25%. The unit should be cleaned regularly. Perspiration on foam
pillows may encourage mould growth. Pillows should be encased or changed regularly.

Other Precautions
Since vacuum cleaners are prone to mobilise fine respirable allergen particles, allergic
patients should not vacuum or if they do so, they should use a dust mask, or use a vacuum
cleaner with a high efficiency particulate air filter. Air conditioning is helpful since the
windows and doors need to be closed and it reduces indoor humidity discouraging mould
and mite growth. Humidifiers are potentially harmful. The patient should avoid tobacco
smoke, both active and passive. Wood smoke and other smoke from domestic cooking
should be avoided as they are known to increase respiratory symptoms. To avoid this, all
furnaces and stoves are to be vented outside and the room is to be kept well-ventilated.
Strong odours or sprays produced by cosmetics like perfumes, talcum powder, room
deodorisers, frying, household cleaning products, and fresh paints irritate some patients
airways and trigger asthma symptoms. Those affected by such odours should avoid them.
Exposure to air pollutants like oxidants and sulphur oxides and ozone has been associated
with worsening pulmonary function and increased airway hyperresponsiveness in persons
with asthma. These environmental exposures may interact with allergens and other triggers
in the causation of bronchial asthma.
Other precipitating factors like gastroesophageal reflux, sulphite sensitivity, and medication sensitivities need to addressed in all patients.
All patients with asthma deserve an allergy evaluation to identify sensitisation to common
inhaled allergens. Avoidance of allergens to which a patient with asthma is sensitised is an
integral and effective part of asthma management. Indoor allergens are of particular
importance because of the most part of the time spent indoors. The indoor allergens most
likely to be relevant are dust mites, cockroaches, and furred pets. Avoidance measures for
dust mites,42 and cockroaches,42 are probably effective at improving asthma control if the
measures are strictly adhered to. Air filtration devices are unlikely to be important or effective
over and above the more usual measures, given the characteristic distribution of these
allergens at home. Air filtration devices are effective at reducing levels of pet allergen in
home and may improve asthma control when combined with exclusion of the pet from the
bedroom. This is likely to be less effective than ridding off the pet from the home completely.43
IMMUNOTHERAPY
The role of specific immunotherapy in asthma management is controversial and is under
continual investigation. In fact, the British Thoracic guidelines clearly mentions that the

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

191

hyposensitisation or immunotherapy is not indicated in the management of chronic bronchial

asthma in adults.9 Currently available medications and avoidance strategies usually provide
good control of asthma. Allergen avoidance is always the first recommendation for managing
asthma symptoms. However, when avoidance is not possible and appropriate medications
fail to control symptoms of allergic asthma, referral for allergy immunotherapy may be
considered.1 Allergy immunotherapy has been shown to reduce symptoms of asthma with a
variety of allergens including house dust,44 cat dander,45 grass pollen,46 and alternaria .47
They also reduce the threshold for skin or lungs to the allergen employed and the late reaction
to allergens in the lungs are also reduced.48 However, their efficacy in the overall clinical
management remains controversial. Response to allergy immunotherapy decreases with age
and with lower baseline levels of pulmonary function.49 If immunotherapy is administered, it
is recommended that once patient achieves maintenance levels of immunotherapy, the interval
between injections should be extended, with a goal of monthly injections. If the patients
symptoms improve, treatment is usually continued for 3-5 years, although under some
situations more prolonged therapy at monthly intervals may be needed. If there is no evidence
of response following two allergy seasons after reaching the maintenance or the highest level
tolerated by the patient, immunotherapy should be discontinued. Allergy immunotherapy
should only be administered in a physicians office who is well versant with the therapy and
where facilities and trained personnel are available to treat any life-threatening reaction that
can occur, which is a very rare situation.
PHARMACOLOGICAL THERAPY
Pharmacological therapy for bronchial asthma is often described as step care, in which the
number of medications and frequency of administration are increased or decreased as
necessary. The possibility of toxicity is also increased with this approach. The patient must
have medication, an inhaled 2agonist, available for acute relief of symptoms. If symptoms
occur frequently (more than two times a week), preventive therapy is necessary in addition to
rescue treatment. Rescue treatment itself has a step-care pattern, adding medications as
necessary to control symptoms. Increasing use of rescue treatment by the patient is an indication
to review the medication plan and possibly to increase preventive therapy. As asthma is a
chronic inflammatory condition, anti-inflammatory treatment should be given to most patients.
Treatment is to be considered in a step-wise manner as shown in Figure 12.2. In addition to
those depicted in the figure it is essential that:
a. The patient should avoid provoking factors whenever possible
b. Patient involvement and education should be an integral part
c. The best inhaler device should be selected
d. Treatment may be stepped up as necessary to achieve good response
e. Treatment may be stepped down if control of asthma is good and
f. A peak expiratory flow meter may be prescribed to monitor response to treatment.
The patient should start treatment at the step most appropriate to the initial severity. A
reuse course of prednisolone tablets will be necessary at any time and at any step
A short rescue course of corticosteroid tablets may be needed at any time and at any step
to gain control of asthma. The indications of rescue courses of steroids are as follows:
Symptoms and PEFR get progressively worse day-by-day
PEFR falls below 60% of the patients best

192 Bronchial Asthma

Step V

Regular steroid
tablets added
Step IV

Step III

Step II

Regular inhaled
anti-inflammatory
agents
Step I

Occasional use
of relief
oronchodilator
Inhaled short
acting beta
agonists SOS.
If needed > 1
daily, move to
Step II.
Before altering a
step ensure that
the patient is
having the
treatment and
having proper
inhalation.

Inhaled short
acting beta
agonists SOS
plus
beclomethasone
or budesonide
100-400 mcg bd
or fluticasone
50-200 mcg bd
or cromoglycate
or nedocromil. If
no control, start
inhaled steroids.

High dose
inhaled steroids
and regular
bronchodilators

Inhaled shortacting beta

agonists SOS
plus
beclomethasone
or budesonide
800-2000 mcg od
Inhaled shortor fluticasone
acting beta
400-1000 mcg od
agonists SOS +
via spacer plus 1
beclomethasone or or > 1 of inhaled
budesonide 400long-acting beta
1000 mcg od or
agonist sustained
fluticasone 400release theophyl1000 mcg od via
line inhaled
spacer plus 1 or > ipratropium or
1 of inhaled longoxytropium longacting beta agonist acting beta
sustained release
agonist tablet
theophylline
high dose inhaled
inhaled ipratropium bronchodilators
or oxytropium
cromoglycate or
long-acting beta
nedocromil
agonist tablet high
dose inhaled
bronchodilators
cromoglycate or
nedocromil

High dose inhaled

steroids or low
dose inhaled
steroids + longacting inhaled beta
agonist

Inhaled shortacting beta

agonists SOS
plus
beclomethasone
or budesonide
800-2000 mcg
od or fluticasone
400-1000 mcg
od via large
volume spacer
and one or more
of the longacting
bronchodilators
plus
regular
prednisolone
tablets in a
single daily dose

Stepping
down

Review
every
3-6
months

Fig. 12.2: Step-care management of bronchial asthma (BTS)

Sleep is disturbed by asthma symptoms

Morning symptoms persist till midday
Diminishing response to inhaled bronchodilators
Emergency use is made of nebulised or injected bronchodilators.
In an adult, 30-60 mg of prednisolone is given immediately. This dose is to be continued in
a single morning dose till two days after control is achieved. The drug is then tapered.

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

193

The appropriate treatment with different drugs in various steps are summarised below:
Step 5 Addition of Regular Steroid Tablets Inhaled short-acting beta agonists as required
with inhaled beclomethasone or budesonide 800-2000 g daily or fluticasone 400-1000 g
daily by a large volume spacer and one or more of the long-acting bronchodilators with
regular prednisolone in a single daily dose.
Step 4 High dose inhaled steroids and regular bronchodilators Inhaled short-acting
-agonists as required with inhaled beclomethasone or budesonide 800-2000 g daily or
fluticasone 400-1000 g daily through a large volume spacer plus a sequential therapeutic
trial of one or more of inhaled long-acting beta agonist or sustained release theophylline
or inhaled ipratropium or oxytropium or long-acting beta agonist tablets high dose
inhaled bronchodilators or cromoglycate or nedocromil.
Step 3 High dose inhaled steroids or low dose inhaled steroids plus long-acting inhaled beta
agonist bronchodilator Inhaled short-acting beta agonists as required plus either
beclomethasone or budesonide increased to 800-2000 g daily or fluticasone 400-1000 g
daily through a large volume spacer or beclomethasone or budesonide 100-400 g twice
daily or fluticasone 50-200 g twice daily. In a very small number of patients who experience
side effects with high doses of inhaled steroids, either the long-acting inhaled beta agonist
or a sustained release theophylline may be added to step 2 medications. Cromoglycate or
nedocromil may also be tried.
Step 2 Regular inhaled anti-inflammatory agents Inhaled short-acting beta agonists as
required plus beclomethasone or budesonide 100-400 g twice daily or fluticasone
50-200 g twice daily. Alternatively, use cromoglycate or nedocromil sodium. If control
is not achieved start inhaled steroids.
Step 1 Occasional use of relief bronchodilators Inhaled short-acting beta-agonists as required
for symptom relief are acceptable. If they are needed more than once daily move to
step 2.
Before altering a treatment step, it must be ensured that the patient is having the treatment
and has a good inhaler technique. Any fear the patient might be having must be addressed.
The possible outcome with various steps of treatment are shown below.
Outcome of steps 1-3: Control of asthma
Outcome of step 4-5: Best possible result
Minimal or no chronic symptoms
Least possible symptoms
No nocturnal symptoms
Least need for relief bronchodilators
Infrequent exacerbations
Least possible activity limitations
Minimal need of relief bronchodilators
Least possible variation in PEFR
No activity or exercise limitations
Best PEFR
PEFR variation < 20%, PEFR 80%/more
Least adverse reactions from drugs
Minimum side effects from drugs
The expected line of therapy and possible outcome in different grades of asthma are
depicted in Figure 12.3.
For patients who have established control of their asthma, regular follow up visits at
approximately 1 to 3 month intervals are necessary to review the treatment plan, the patients
management techniques including use of medicines, peak flow measurements, etc. For many

194 Bronchial Asthma

Fig.12.3: Step-care management of asthma and expected outcome

patients with moderate to severe asthma, control of the disease as reflected in normalisation
of pulmonary function and activity levels without symptoms, can be maintained with only
continuous preventive therapy. The aim of therapy should be to use the minimum medication needed to maintain control with minimum risk for adverse effects. Reduction of therapy
can be carefully considered if PEFR variability is less than 10% and there are no asthma
symptoms for a reasonable period (2-3 days for the exacerbation in mild asthma, several
weeks for moderate or severe asthma). If PEFR variability is greater than 10-20%, evaluation
of the patients technique in using the medication, find out environmental aggravators and
the patients efforts to control them will be necessary. The possibility of concomitant upper
respiratory tract disease, and the possibility of increasing the dosage or change of medications
may also need to be considered.
Recently the Expert Panel Report 2 of the National Institute of Health has published guidelines for the diagnosis and management of bronchial asthma in adults and children .50
Although the basic principles of management are the same, some more facts have been
highlighted. The basic components of management include:
A. Measures of assessment and monitoring. The new guidelines includes additional goal
of therapy to meet the expectations of the patient and its family with satisfaction. Periodic
assessment of six domains of patient health is highlighted. These include signs and
symptoms, pulmonary function, quality of life, history of exacerbations, pharmacotherapy, patient-provider communication and patient satisfaction. The panel also
recommends home monitoring of PEFR from twice daily to once in the morning only. If
the morning reading is less than 80% of the personal best PEFR, more frequent monitoring
may be required. The use of the individual patients personal best PEFR is emphasised.
It is emphasised that patients of all severity levels are to monitor symptoms to recognise
early signs of deterioration. Sample questions to use in periodic assessments are also
added.
B. Control of factors contributing to asthma severity is important. Skin testing or in vitro
testing is now specifically recommended for at least those patients with persistent asthma

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

195

exposed to perennial indoor allergens. Adult patients with severe persistent asthma, nasal
polyps, or a history of sensitivity to aspirin or non-steroidal anti-inflammatory drugs are
to be counselled regarding the risk of severe and even fatal exacerbations from using these
drugs. Routine use of chemicals to kill house-dust mite and denature the antigen is no
longer recommended as a control measure. Patients should be treated for rhinitis, sinusitis,
and gastro-oesophageal reflux. Annual influenza vaccinations are specifically
recommended for patients with persistent asthma. Pneumococcal vaccination is considered
not important.
C. The importance of pharmacological therapy is very much there and is an important
component of asthma management. However, medications are now categorised into two
general classes; (a) long-term control medications; and (b) quick-relief medications. While
the former are used to achieve and maintain control of persistent asthma, the later are used
to treat acute symptoms and exacerbations. The most effective medications for long-term
control are those having anti-inflammatory effects and include drugs like corticosteroids,
long-acting 2-agonists, and leukotriene antagonists. The stepwise approach to asthma
therapy emphasises initiating a higher level of therapy at the onset to establish prompt
control and then stepping down. Corticosteroids are the most important anti-inflammatory
drugs and include various inhaled forms as discussed earlier and systemic drugs like
methylprednisolone, prednisolone, and prednisone.
D. Education for a partnership in asthma care includes providing patients both a written
treatment plan for daily self-management and a written action plan for management of
exacerbations. However they do not replace, though supplement, the education by the
physician. Patient education by the principal clinician as well as other members of the
health care team is important. To enhance the delivery of education, detailed questions to
elicit information and educational messages for each visit are to be provided. Key messages
are to be reinforced during each visit. Further, it is necessary to evaluate the outcome in
terms of patient perceptions of improvement, specially quality of life and the ability to
engage in desired activities. Patient education for CFC-free inhalers is gaining importance
in view of the ban on the use of CFC (chlorofluorocarbons).
The Expert Panel50 has changed the classification of the severity of asthma from mild,
moderate, severe to mild intermittent, mild persistent, moderate persistent, and severe persistent
asthma. The clinical features before treatment are shown in Table 12.1.
Stepwise management of bronchial asthma in adults and children over 5 years of age
depending upon the above severity criteria as recommended by the NIH Expert Panel is
shown in Table 12.2.
GENERAL PRINCIPLES OF APPROACH TO TREATMENT OF
CHRONIC PERSISTENT ASTHMA
i. Treatment of chronic persistent asthma should be considered in a stepwise manner as
described above with the patients starting treatment at the step most appropriate for
the initial severity of their conditions.
ii. The stepwise approach presents general guidelines to assist clinical decision making;
it is not intended to be a specific prescription.
iii. Since asthma is highly variable; clinicians should tailor specific medication plans to
the needs and circumstances of individual patients.

196 Bronchial Asthma

Table 12.1. Classification of severity (NIH, USA, 51)

Severity
Step 4
Severe persistent

Symptoms

Night time symptoms

Continuous symptoms Frequent

Limited physical activity
Frequent exacerbations

Lung function
FEV1 or PEFR 60% or
less than predicted
Variability of PEFR
> 30%

Step 3
Daily symptoms
Moderate persistent Daily use of inhaled
2-agonists
Exacerbations affect
activity
Exacerbation 2 or
more/week
May last days

> 1 week

FEV1 or PEFR >60%

> or = 80% predicted
PEF variation > 30%

Step 2
Mild persistent

Symptoms > 2/week,

but < 1 day
Exacerbations may
affect activity

> 2 times a month

FEV1 or PEFR 80% or

more
PEF variation 20-30%

Step 1
Mild intermittent

Symptoms 2 times or
less per week
Asymptomatic and
normal PEFR
between exacerbations
Exacerbations brief

2 times or less
per month

FEV1 or PEFR 80% or

more
PEF variation < 20%

Note: The presence of one of the features of severity is sufficient to place a patient in that category.
An individual should be assigned to the most severe grade in which any feature occurs. The characteristics described above are general and may overlap in view of the variable nature of asthma.
Patients at any levels of severity can have mild, moderate, or severe exacerbations. Some with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of
normal lung function and no symptoms.
Table 12.2: Stepcare management of bronchial asthma50

Step

Long-term control

Step 4
Severe persistent

Daily medications
Anti-inflammatory
Inhaled steroids (high
dose and long-acting
bronchodilators like
long-acting inhaled or
oral 2-agonist,
sustained release
theophylline
Oral corticosteroid

Step 3
Moderate
Persistent

Daily medications
Anti-inflammatory
Inhaled steroid (medium

Quick relief

Education

Inhaled 2-agonists

Intensity of treatment
will depend upon
severity of exacerbations
Use of short-acting
2-agonists on a daily
basis, or increasing use
indicates the need for
additional long-term
control therapy
Inhaled 2
agonists sos

Intensity of treatment

As in step 2 and 3
Individual education

Step 1 action plus

Individual education
if available

Contd...

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

Contd...
Step

Step 2
Mild persistent

Step 1
Mild intermittent

Long-term control
dose) or low-medium
dose and add a longacting bronchodilator,
especially for nighttime symptoms: either
long-acting inhaled
2-agonist, sustained
release theophylline
or long-acting
2-agonist tablets
If needed:
Anti-inflammatory:
Inhaled corticosteroids
(medium-high dose) and
long-acting bronchodilators, especially for
night-time symptoms;
either long-acting
inhaled 2-agonist,
sustained release
theophylline, or longacting 2-agonist tablets
Daily medications:
Anti-inflammatory
Either inhaled steroid
(low doses) or cromolyn
or nedocromil
Alternatively, sustained
release theophylline.
Leukotriene antagonists
may also be tried for the
patients of 12 yrs or >,
although their role in
therapy is not fully
established.
Daily medication not
needed

Quick relief

197

Education

will depend upon

Review and update
severity of exacerself management plan
bations
Use of short-acting
2-agonists on
daily basis indicate
need for term-control
therapy

Short-acting
bronchodilator:
Inhaled 2agonist as needed.
Intensity of treatment
will depend on exacerbation severity.
Use of short acting
inhaled 2-agonists
daily or increasing
use indicates need
for additional longterm control therapy.
Short-acting bronchodilator: Inhaled 2agonist sos
Intensity of treatment
will depend on
severity of exacerbation
Use of above more
than 2 times a week
may need to start

Step 1 action +
teach self monitoring
Group education.
Review and
update self manage
ment plan.

Teach basic facts of

bronchial asthma
Teach inhaler spacer/
holding chamber
technique
Discuss role of medication management
plan
Develop self management plan

Contd...

198 Bronchial Asthma

Contd...
Step

Long-term control

Quick relief
long-term control
therapy

Step down
Review treatment every 1-6 months
a gradual stepwise reduction in treatment
may be possible

Education
Develop action plan to
when and how to take
rescue actions
Discuss appropriate
environment control
measures

Step up
If control is not maintained, consider
step up. First, review patient medication
technique adherence, and environment
control

iv. The control should be gained as soon as possible and then the treatment is to be
decreased to the least medications necessary to maintain control. Gaining control may
be accomplished by either starting treatment at the step most appropriate to the initial
severity of their condition or by starting a high level of therapy like a short course of
oral corticosteroids may be needed at any time and at any step to control their asthma
as mentioned above. Alternatively, a higher dose of inhaled corticosteroid may be
used.
v. Patients should avoid all known factors precipitating their asthma. They may be
chemicals, certain drugs like aspirin and non-steroidal anti-inflammatory drugs.
blockers are contraindicated in asthma.
vi. A rescue course of systemic corticosteroids may be required at any step at any time.
vii. Some patients with intermittent asthma experience severe and life-threatening
exacerbations separated by long periods of normal lung function and no symptoms.
This may be especially common with exacerbations provoked by respiratory
infections. A short course of systemic corticosteroids is recommended in that situation.
viii. At each step the patient should control his environment to avoid or control factors
that make their asthma worse like allergens, irritants, etc. This requires specific
diagnosis and education.
ix. Referral to an asthma specialist for consultation or co-management is recommended
if there are difficulties in achieving or maintaining control of asthma or if the patient
requires step 4 care. Referral may be considered if the patient requires step 3 care.
Quick-relief Medications
Bronchodilators. Short-acting 2-agonists are the therapy of choice for relief of acute symptoms
and prevention of exercise-induced asthma. They are the most effective medications for
relieving acute bronchospasm. A 2-agonist such as salbutamol 100-200 g or terbutaline
250-500 g should be used as required rather than regularly. Patients should be encouraged
to use the minimum dose to control their symptoms. They can be used 2 puffs three to four
times a day. Salbutamol is also available as rotahalers with 100-200 mcg/capsule which can

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

199

be used 1-2 capsules every 4-6 hours as needed and prior to exercise. Increasing use of these
drugs or roughly use of more than one canister in one month indicates inadequate control of
asthma and the need for initiating or intensifying anti-inflammatory therapy. Regularly
scheduled or daily use of these drugs are generally not recommended. Solutions for use in
nebulisers are also available (salbutamol 5 mg/ml or terbutaline 5 mg/ml) for use during
acute exacerbations.
Anticholinergic drugs like ipratropium bromide may provide additive benefit to inhaled
2-agonists in severe exacerbations. It may be an alternative bronchodilator for patients who
do not tolerate inhaled 2-agonists. They may be used as regular maintenance therapy in step
4 (British Thoracic Society) patients who already require high dose inhaled steroids. The drug
is also available in solution forms for nebulisation. The MDI dose is 20 mcg for each puff and
2-3 puffs are used every 6 hours.
Although systemic corticosteroids are strictly not bronchodilators, they are used for moderate
to severe exacerbations to speed recovery and prevention of exacerbations along with other
medications.
Long-term Control Medications
Inhaled anti-inflammatory agents. Patients who need to inhale a bronchodilator more than once
daily or who have night time symptoms require regular inhaled anti-inflammatory drugs.
Various drugs that can be used include corticosteroids, sodium cromoglycate (5-20 mg four
times a day), and nedocromil sodium (4 mg four times daily). Inhaled steroids are the drugs of
choice since they are the most potent and effective anti-inflammatory drugs available currently
for mild, moderate and severe persistent asthma. The small but potential risk of adverse
reactions from the use of inhaled corticosteroids is well balanced by their efficacy. Inhaled
form is used for the long-term control of asthma. Systemic corticosteroids are used in longterm therapy to gain prompt control of the disease and also to manage severe persistent
asthma. Beclomethasone dipropionate or budesonide should be started in doses of 100-400
g twice daily. As the severity increases, the doses are to be increased. Patients with nocturnal
symptoms and more severe and persistent form of disease may need more frequent and higher
doses. Once symptoms and PEFR are controlled, the dose should be reduced to be maintained
with the minimum.
High doses of inhaled steroids. If control is not achieved, spacers and higher doses are needed
after checking the compliance and proper use of inhalers. When the dose exceeds 800 g, a
large volume spacer is recommended to reduce systemic and local effects. The delivery system
is an important determinant of the systemic effects of inhaled corticosteroids. The Turbohaler
delivers approximately twice as much inhaled steroid to the lung,52 and, therefore the dose
may be halved when this device is used. The patient should also be advised to rinse mouth
(rinse and spit) following inhalation. The lowest possible dose of inhaler should be used to
maintain control. Current guidelines recommend that patients should double the dose of
inhaled steroids temporarily if their asthma deteriorates or at the first sign of an upper
respiratory tract infection. To maintain control asthma, particularly nocturnal symptoms, a
long-acting inhaled 2-agonist is to be added to a low-to medium dose of inhaled corticosteroid
rather than using a high dose. For children growth monitoring is essential.
Inhaled corticosteroids are typically associated with a flat dose-response curve when
traditional efficacy values are examined by measurement of FEV1. Thus, by increasing the

200 Bronchial Asthma

dose of inhaled steroids in the asthma management is not necessary and preferably, add-on
therapy should be used rather than increasing the dose of inhaled steroids.53
Estimated comparative daily doses for inhaled steroids are shown in Table 12.3.
There is no indication at present for the routine investigation of, or prophylactic treatment
for, osteoporosis in patients with low dose inhaled corticosteroids. However, in patients
receiving high dose therapy (1000 mcg or more of beclomethasone or budesonide and 500 mcg
or more of fluticasone per day), general measures to counteract osteoporosis such as regular
exercise, hormone replacement therapy, smoking cessation, and adequate dietary calcium
should be considered. For postmenopausal women, supplemental calcium in the dose of
1000-1500 mg per day may be required. In addition, vitamin D is to be administered in a dose
of 400 units a day. Estrogen therapy will be required in these women when the dose exceeds
1000 mcg of inhaled corticosteroids per day.
There is no published trial to show that nebulised budesonide is effective in adults.
Inhaled fluticasone is as effective as beclomethasone and budesonide at half the dose
when given by equivalent delivery systems.54-57 At equipotent doses the drug may have the
potential for producing similar systemic effects.
Cromolyn Sodium and nedocromil These are mild to moderate anti-inflammatory
medications. They may be used as initial choice for long-term control therapy for children.
They can also be used as preventive treatment prior to exercise or unavoidable exposure to
known allergens. Nedocromil has an unpleasant taste. Cromolyn is available as 5 mg/puff.
The dose is 1-2 puffs thrice or four times daily. They are also available as DPI- 20 mg/
capsule.Nedocromil is not available in India yet.
Additional bronchodilators If adequate control of symptoms is not achieved with inhaled
steroids 2 mg each day and standard doses of 2-agonists, a trial of additional ipratropium
(80 g four times daily), oral bronchodilators, or high doses of inhaled bronchodilators
may be considered. Oral 2-agonists and xanthine derivatives should not be used as first
line drugs. However in view of the cost factor, oral 2-agonists and xanthine derivatives are
used often as the first line bronchodilators in some places.
The main indication of methyl xanthines is the presence of symptoms, often nocturnal,
which are not controlled by anti-inflammatory drugs and standard doses of inhaled 2-agonists.
Table 12:3: Daily doses for inhaled corticosteroids

Drug

Low Dose

Medium Dose

High Dose

Beclomethasone
(100,200 mcg/puff)
(DPI same)

200-400 mcg

400-800 mcg

>800 mcg

Budesonide
(200,400 mcg/puff)

200-400 mcg

400-600 mcg

>600 mcg

Flunisolide
(250 mcg/puff)

500-1000 mcg

1000-2000 mcg

>2000 mcg

Fluticasone
(50,125 mcg/puff)
DPI same doses

50-250 mcg

250-660 mcg

> 660 mcg

Triamcenolone
100 mcg/puff

400-1000 mcg

1000-2000 mcg

>2000 mcg

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

201

The addition of long-acting xanthine derivatives may be good enough to control symptoms.
Sustained release theophylline is a mild to moderate bronchodilator used principally as
adjuvant to inhaled corticosteroids for prevention of nocturnal symptoms. They may have
mild anti-inflammatory effect also. Usual starting dose is 10 mg/kg of body weight up to a
maximum of 800 mgm per day.
Long-acting 2-agonists are to be used concomitantly with anti-inflammatory drugs (lowto-medium dose corticosteroid inhalers) for long-term control of symptoms, particularly
nocturnal symptoms. They also prevent exercise-induced bronchospasm. Long-acting 2agonists are not to be used for the treatment of acute symptoms or exacerbations. High doses of
inhaled bronchodilators should be considered only if the patient does not respond to standard
doses. Daily use of long-acting 2-agonists should generally not exceed 80-100 mcg. Salmeterol
is currently available in India and Formoterol is being tried for clinical use in this country.
Oral sustained release salbutamol 8 mgs tablets are available which can be used twice daily.
Leukotriene Modifiers These drugs may be considered as alternative therapy to low doses of
inhaled corticosteroids or cromolyn or nedocromil in mild persistent asthma in patients 12
years or older. These drugs are not yet marketed in India. Further study and clinical experience
are needed to help establish their role in asthma therapy. The leukotriene receptor antagonist
is available in USA as 20 mg tablets and the adult dose is 40 mg daily (1 tablet twice daily).
The 5-lipoxygenase inhibitor Zileuton is available as 300 and 600 mg tablets and the daily
dose is 2400 mgs in four divided doses.
Oral steroids Systemic corticosteroids are used in long-term therapy to gain prompt control
of the disease (Rescue therapy) and also to manage severe persistent asthma. High doses of
inhaled steroids should always be continued in patients receiving oral steroids. These patients
need to be referred to a specialty clinic where additional measures can be considered. For
long-term treatment of severe persistent asthma, single dose is to be administered in a.m.
either daily or on alternate days which may produce less adrenal suppression. Short courses
or bursts are effective for establishing control when initiating therapy or during a period of
gradual deterioration. The burst should be continued till the patient achieves 80% of personal
best PEFR or the symptoms resolve. This usually requires 3-10 days, but may require longer.
The most commonly available oral corticosteroid is prednisolone, although methylprednisolone
or prednisone can also be used. Prednisolone tablets are available in 5 mg, and 20 mg, tablets.
For control of asthma symptoms, a dose of 10-60 mgms daily single doses may be required. For
short-course burst 40-60 mgm per day as single or 2 divided doses may be given for 3-10
days.
Alternative and Complementary Therapies
Alternative and complementary therapies are sought most frequently for many chronic
disabling conditions as a desperate (sometimes with true belief) measure as there is no
definite cure for these conditions. These include back pain, anxiety, depression, arthritis,
headaches, HIV infection, and chronic allergic disorders like allergic rhinitis, and asthma.58,59
These forms of treatment include acupuncture, homeopathy, fish therapy, other herbal therapy
including ayurvedic drugs, ionisers, and antihistamines including ketotifen, chiropractice,
megavitamins, and spiritual healing, which are tried by many but have not stood the test of
controlled clinical trials, although some patients claim benefit. Results of a 1998 survey
indicates that 42% of adults in the United States consult alternative medical practitioners and

202 Bronchial Asthma

spend an estimated $27 billion annually on alternative medical therapies.58 Many physicians
either practice for complimentary/alternative medicine themselves or refer patients for such
treatment.60
Acupuncture is one of the oldest and most widespread complimentary techniques, although
homeopathy and Aurvedic forms of therapy are other forms of therapy in many countries. The
first documented history of acupuncture is ascribed to the legendary Yelloe Emperor (Huang
Di) in China (circa 2000 BC). The first paragraph of the second part of his classic book Huang
Di Nei Jing describes the desire of the benevolent emperor to relieve the suffering of his subjects
affected with disease, instead of the use of poisons of medicine in favour of fine needles to
harmonise the blood and Qi energy.61 British Medical Association has recently approved
acupuncture for practice,62 and many medical schools in the USA offer elective courses in
complimentary/alternative medicine.63 Traditional Chinese medicine has claimed the ability
to favourably influence the course and symptoms of bronchial asthma. However, the published
data on this subject are controversial. Real acupuncture has been shown to have an immediate
effect,64-66 but not a lasting effect on asthma.67-69 Methacholine challenges and exercise have
been shown to be affected. However, most studies performed to date are not controlled or
cross-over in design.70,71 Immunomodulatory changes in lymphocyte subsets and cytokines
have been shown to be affected by acupuncture. In a recent randomised cross over study, it
was shown that a short course of acupuncture treatment in patients with moderate asthma
resulted in no change in lung function, bronchial hyperreactivity, or patient symptoms.72
Thus, acupuncture may not be recommended for bronchial asthma, although still thousands
of patients continue to seek for this form of therapy. If these modalities of complimentary/
alternative medicine are tried, then the conventional treatment should also be continued.
Hyposensitisation or immunotherapy is not indicated in the management of asthma.
Ascaricides may be effective in controlling number of mites but have not produce clinically
relevant benefit.
Referral to a Specialist
Referral to a specialist should be considered for:
i. Patients in whom there is a doubt about the diagnosis for example in elderly and smokers
with wheeze; those with persistent unexplained persistent cough; and those with
systemic symptoms like fever, rash, weight loss, or proteinuria that might suggest
associated disorders such as systemic eosinophilia or vasculitis.
ii. Patients with possible occupational asthma.
iii. Patients with difficult asthma and management problems. Such patients include
those who are recently discharged from a hospital
those with catastrophic severe (brittle) asthma
those with continuing symptoms despite high doses of inhaled steroids
those being considered for long-term treatment with nebulised bronchodilators
pregnant women with worsening asthma, and
patients in whom asthma is interfering with their lifestyles despite changes in
treatment.
iv. Patients suspected to have developed complication like bronchopulmonary mycosis
(i.e.; ABPA).

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

203

These patients most often misdiagnosed as pulmonary tuberculosis. This complication

may be suspected if the patient has uncontrolled symptoms, systemic symptoms, haemoptysis,
weight loss, profuse expectoration, and infiltrates in chest skiagram.
Assessment of Asthma Control
Once a treatment plan is established for a patient of bronchial asthma, it is essential to assess
the asthma control. Most asthma guidelines recommend assessing asthma control according
to a series of criteria based on symptoms and pulmonary function.11,73 As the aim of asthma
treatment is to minimise symptoms, rescue bronchodilator need, and exacerbations, while
optimizing pulmonary function. Recently, methods for assessment of airway inflammation
noninvasively have been developed, but they are not currently integrated into the assessment
of asthma control.74,75 Studies or surveys on asthma generally use an all or none approach or
a strictly qualitative evaluation of asthma control, without specific quantification of its
magnitude or degree compared with optimal goals. Other means of assessing these parameters
include evaluating or scoring each separate component of asthma control and comparing the
effects of treatment or intervention on these specific parameters. This global assessment
approach may overestimate the adequacy of asthma control by the physician and even more
so, by the patient, and may consequentially contribute to the poor asthma control when
current guideline criteria are used.76-78 Quantification of control with tools such as the validated
questionnaire developed by Juniper et al79 are the common ones, but they are too exhaustive to
be used by the busy clinician. A new, simple method of global assessment and quantification
of asthma control has been developed.80 This easy-to-use asthma control scoring system is
based on a percentage of optimal control. The percentage symptom score but not the global
control score of this new method correlates with patients global assessment of asthma control.
This method provides a percentage control for symptoms, baseline expiratory flows, and an
optional parameter for airway inflammation assessed from induced sputum eosinophil count.
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49. Bousquet J, Maasch HJ, Hejjaoui A et al. Double-blind, placebo-controlled immunotherapy with
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51. Glinert R, Wilson P, Wedner HJ. Fel; D1 is markedly reduced following sequential washing of
cats. J Allergy Clin Immunol 1990;85:225.
52. Thorsson L, Edsbacker S, Conardson TB. Lung deposition of budesonide from turbohaler is
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53. OSullivan S, Cormican L, Murphy M et al. Effects of varying doses of fluticasone propionate on
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54. Lundback B, Alexander M, Day J et al. Evaluation of fluticasone propionate (500 mcg per day)
administered either as dry powder via diskhaler or pressurised inhaler and compared with
beclomethasone dipropionate (1000 mcg/day) administered by pressurised inhaler. Respir
Med 1993;87:609-20.
55. Gustaffson P, Tanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy
and safety of inhaled fluticasone pripionate 200 mcg per day with beclomethasone dipropionate
2000 mcg per day in mild and moderate asthma. Arch Dis Child 1993;19:206-11.
56. Leblane P, Minks S, Keistinen T, Saaelainen PA, Ringdal N, Payne SL. A comparison of fluticasone
propionate 200 mcg/day with beclomethasone dipropionate 400 mcg/day in adult asthma.
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57. Conolly A. A comparison of fluticasone propionate 100 mcg twice daily with budesonide 200 mcg
twice daily via their respective powder devices in the treatment of asthma. Eur J Clin Res
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58. Eisenberg DM, Davis RB, Ettner SL et al. Trends in alternative medicine use in the United States.
1990-1997: Results of a follow-up national survey. JAMA 1998;280:1569-75.
59. Fairfield KM, Eisenberg DM, Davis RB et al. Patterns of use, expenditures, and perceived efficacy
of complimentary and alternative therapies in HIV-infected patients. Arch Intern Med 1998;
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60. Austin JA, Marie A, Pelletier KR et al. A review of the incorporation of complementary and
alternative medicine by mainstream physicians. Arch Intern Med 1998;158:2303-10.
61. Wu JN. A short history of acupuncture. J Altern Complement Med 1996;2:19-21.
62. Silvert M. Acupuncture wins BMA approval. BMJ 2000;321:11.
63. Wetzel MS, Eisenberg DM, Kaptchuk TJ. Courses involving complementary and alternative
medicine in US medical schools. JAMA 1998;280;784-87.
64. Yu DY, Lee SP. Effects of acupuncture on bronchial asthma. Clin Sci Mol Med 1976;51:503-09.
65. Virsik K, Kristufek D, Bangha O, et al. The effect of acupuncture on pulmonary function in
bronchial asthma. Progr Respir Res 1980;14:271-75.
66. Takishima T, Mue S, Tamura G et al. The bronchodilating effect of acupuncture in patients with
acute asthma. Ann Allergy 1982;48:44-49.
67. Christensen PA, Laursen LC, Tauderf E et al. Acupuncture and bronchial asthma. Allergy
1984;39:379-85.
68. Jobst K, Chen JH, McPherson K et al. Controlled trial of acupuncture for disabling breathlessness.
Lancet 1986;2:416-19.
69. Biernacki W, Peake MD. Acupuncture in treatment of stable asthma. Respir Med 1998;92:
1143-45.
70. Lewth GT, Watkins AD. Unconventional therapies in asthma: An overview. Allergy 1996;51:
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71. Varon J, Fromm RE Jr, Marik PE. Acupuncture for asthma. Fact or fiction? Chest 2002;121:
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72. Shapira MY, Berkman N, Ben-David G et al. Short-term acupuncture therapy is of no benefit in
patients with moderate persistent asthma. Chest 2002;121:1396-1400.
73. Boulet LP, Becker A, Berube D et al. Canadian Asthma Consensus Report; 1999. Can Med Assoc
J 1999;61(Suppl 11):S1-S62.
74. Jayaram L, Paramswaran K, sears MR et al. Induced sputum cell counts: Their usefulness in
clinical practice. Eur Respir J 2000;16:150-58.
75. Kips JC, Pauwels RA. Use of induced sputum in the diagnosis and follow up of asthma and
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Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma)

207

77. Rabe KF, Vermiere PA, Soriano JB et al. Clinical management of asthma in 1999: The asthma
Insights and Reality in Europe (AIRE) study. Eur Respir J 2000;16:802-807.
78. Kips JC, Pauwels RA. Asthma control. Where do we fall? Eur Respir J 2000;16:797-98.
79. Juniper EF, OByrne PM, Guyatt GH et al. Development and validation of a questionnaire to
measure asthma control. Eur Respir J 1999;14:902-07.
80. Boulet LP, Boulet V, Milot J. How should we quantify asthma control? A proposal. Chest
2002;122:2217-23.

208 Bronchial Asthma

13
Therapeutic Approach in
Patients with Asthma
II. Acute Severe Asthma (SA)
Definition
The term status asthmaticus was previously used to describe a severe attack of asthma, which
had continued for more than 24 hours. Although most severe attacks of asthma develop
over days or weeks prior to presentation to medical care, all recent studies of asthma deaths
have described patients who have died within hours or even minutes of the onset of
symptoms. It is, therefore, not appropriate to include the duration of the attack in a definition
of acute severe asthma. The most important aspect of such an attack is its severity. Another
suggested definition of an acute asthmatic attack is severe airflow obstruction that had
become unresponsive to the patients normal bronchodilator treatment. All patients with
bronchial asthma are at risk of developing a severe asthma attack that places them at risk of
developing respiratory failurethe disorder referred to as status asthmaticus.1-19 The attack
can occur at any time and at any speed. In most cases of severe life-threatening asthma
develops against a background of poorly controlled disease. However, in 10-20% of cases
of fatal or near fatal asthma the onset appears to be sudden and unexpected, with death
occurring at times within a couple of hours. Such episodes are called Sudden asphyxic
asthma.20 This form is quite different from the more slowly progressive forms of airflow
obstruction. These are accompanied pathologically by only mild inflammatory changes
and little mucus plugging of the airways.21 This sudden and unexpected increased airflow
obstruction results primarily from bronchial smooth muscle-mediated bronchospasm. An
important feature of this near fatal asthma is that attacks are often recurrent and a previous
life-threatening episode represents one of the most important factors predicting asthma
deaths.22 Acute severe asthma said to run to type, meaning thereby, if hypercapnia
develops during one severe attack, it is likely to recur in a subsequent episode.23 Both fatal
and near fatal asthmatic attacks have similar features.24
Patients dying of sudden exacerbations of asthma have diminished eosinophils and
increased neutrophils in the airway submucosa20 and less intraluminal mucus.25 This is in
contrast with the relatively slower onset disease. Patients who develop progressive
symptoms over days before finally presenting to the emergency room do so with respiratory
distress. In these patients, inflammation of the airway wall and edema play a significant

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

209

role. Yet many patients fail to perceive the severity to treat effectively their worsening airway
inflammation.26 They fail to appreciate the severity of the final episode because of poor
perception. Reduced chemosensitivity to hypoxia and blunted perception of dyspnoea
perhaps predispose patients to fatal asthma.27
About 1.1 to 7.0% of patients with bronchial asthma die from an acute attack.28-30 It is
difficult to predict which asthma patients will have a fatal or near-fatal asthma attack. In
both these conditions (fatal and near-fatal asthma), there is a female predominance,31,32
history of frequent hospital admissions and emergency department visits, 33 noncompliance,34 psychosocial abnormalities,35 and socioeconomic factors linked to poverty.36
In addition, a significantly decreased response to inspiration against resistance and to
hypoxic hypercapnia27 and a low perception of dyspnoea are other risk factors.37 In a case
control study, the following eight variables were found to be associated with near-fatal
asthma: history of seizures, conflict with parents and hospital staff, inappropriate self-care,
decrement in prednisolone dose by 50%, use of inhaled beclomethasone, increased asthma
symptoms during the week prior to discharge, depressive symptoms, and disregard of
asthma symptoms.38 The variables associated with subsequent deaths include older age,
female gender, smoking, labile asthma, poor compliance, and psychiatric treatment for
anxiety or depression.39 In a recent unmatched, case-control study, the near fatal asthma
was most often associated with the use of bronchodilators or corticosteroids during the last
12 months and these patients had nocturnal symptoms in the previous two weeks, more
severe form of the asthma, and more likely to have had a previous intubation.40 Further,
patients with near fatal asthma have more food allergies and onset of their episodes follows
a visit to the bar, party or restaurant.41 This may be related to hypersensitivity to foods,
such as nuts, or exposure to smoking exposure or substance abuse in this group.42 Another
important contributory factor may be an inadequate access to health care facilities.43
Pathophysiology
Abnormalities of gas exchange occur due to airways obstruction as a result of inflammation
and bronchial smooth muscle contraction. Mucus plugging of both large and small airways
is found at autopsy. Dead space increases as result of hypoperfusion of hyperinflated lung
regions. Mechanical abnormalities of the lung include marked elevation of airways
resistance, inspiratory transpulmonary pressure during quiet tidal breathing increases to
as high as 50 cm H2O and expiration becomes active. Despite increased work of breathing,
FEV1 is reduced to almost 10-20 percent of normal and PEFR is less than 100 L/min in
severe cases. Expiratory time is prolonged and alveolar emptying is not complete at the
end of expiration. Intrinsic or occult positive-end expiratory pressure (PEEPi) is the
consequence of alveolar pressure not reaching atmospheric pressure under the condition
of prolonged expiratory time.
Abnormal circulatory effects of severe airways obstruction result mostly from pleural
pressure excursions associated with breathing. During expiration, increases in intrathoracic
pressure diminish blood return to the right heart. During inspiration, right ventricular
volume may increase sufficiently to shift the interventricular septum towards the left
ventricle compromising the volume of this chamber and resulting in incomplete filling.
These cyclical events result in pulsus paradoxus. Additionally, large negative pleural pressure
may directly impair left ventricular emptying by increasing left ventricular after load.44,45
Further, lung hyperinflation may represent a further after load on the right ventricle by

210 Bronchial Asthma

increasing pulmonary artery pressure.46 During quiet breathing without airways obstruction,
the pulsus measured as the maximal drop in systolic blood pressure during inspiration, is
less than 10 mmHg. During severe asthma this may be greater than 15 mm Hg and is used
as a measure of severity of asthma,47 although presently this is not included as a guideline
in assessing the severity of asthma. Pulsus paradoxus may be faulty if the patient ceases
making sufficient effort to cause large intrathoracic pressure swing, which is possible in a
fatigued asthmatic unable to generate significant changes in the pleural pressure. Thus, the
absence of a wide pulsus paradoxus does not always mean a mild attack.48,49
Further progression to ventilatory failure in status asthmaticus may result from
respiratory muscle fatigue, increased work of breathing due to increased airways resistance,
diaphragm failure as a force generator because of dynamic hyperinflation, and intrinsic
PEEP associated with dynamic gas trapping. All these events are responsible for respiratory
muscle fatigue. Lactate excess is thought to be due to increased muscle production, the
action of catecholamines used during treatment, or diminished clearance related to hypoperfusion. Regardless of etiology, lactic acidosis is a metabolic marker which may be used
to predict an increase risk of progression to ventilatory failure.
Clinical Features
The clinical presentation of a patient with status asthmaticus includes increased breathlessness, cough, wheezing, and chest tightness. The patient is typically anxious, breathless,
fatigued, sitting upright in bed, and is preoccupied with the task of breathing. He is in
apparent respiratory distress. Clinical signs include tachypnoea, tachycardia, hyperinflated
lungs, wheeze, use of accessory muscles, pulsus paradoxus and diaphoresis. The absence
of wheezing does not exclude a diagnosis of bronchial asthma and the classical sign of
wheezing correlates poorly with the degree of airflow obstruction.50 Rather, a silent chest in
a case of status asthmaticus indicates severe airway obstruction with little movement of air
to produce respiratory sound. In the period immediately preceding respiratory arrest the
chest may be completely silent. Presence of localised wheeze and crepitations may indicate
mucus plugging, atelectasis, pneumonitis or some other cause. Adults with status
asthmaticus who assume the upright position usually has a significantly higher pulse rate,
respiratory rate, and pulsus paradoxus and a significantly low arterial oxygen tension, and
low PEFR than patients who are able to lie supine. If upright patients are also diaphoretic,
the PEFR is even lower.51 Use of sternocleidomastoid muscle indicates severe airways
obstruction. Inability to lie supine, diaphoresis, impaired sensorium, inability to speak and
use of accessory muscles are all signs severe disease. However, even patients with severe
obstruction and exhaustion can lie down supine giving a false impression of less severe
disease.
The possible complications of bronchial asthma are shown in Table 13.1.
While examining a patient of status asthmaticus clue for the possible complications should
be looked for.
Electrocardiogram (ECG) in such a patient will show tachycardia. Successful treatment
of airflow obstruction is usually associated with a decrease in heart rate, although some
improving patients may remain tachycardic because of the use of drugs. Successful therapy
will reduce heart rate.52 The rhythm is usually sinus tachycardia. Rhythm abnormalities
that are possible include supraventricular arrhythmias, and atrial, ventricular or combined
arrhythmias.53 Patients with arrhythmias are usually older compared to patients without

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Table 13.1: Complications of acute bronchial asthma

Pneumothorax
Pneumomediastinum
Subcutaneous emphysema
Pneumopericardium
Myocardial infarction
Mucus plugging
Atelectasis
Drug toxicity (theophylline)
Electrolyte imbalances (hypokalemia, hypophosphatemia, hypomagnesemia)
Dehydration
Myopathy
Lactic acidosis
Hypoxic brain injury

them. Status asthmaticus can cause right ventricular strain, which is usually transient and
which resolves within hours of therapy.52,54 However, presence of right heart failure should
suggest some other disease. The possibility of coronary ischaemia should be considered in
older patients with coronary artery disease. Such patients with status asthmaticus are in
increased risk of myocardial oxygen supply/demand imbalance when large decreases in
intrathoracic pressure increases left ventricular after load and possibly decreased coronary
blood flow.55 High dose beta agonists, theophylline and hypoxia can further tilt this balance.
Although effort-dependent, objective physiologic measurements of airflow obstruction
can be made by bedside determination of FEV1 and PEFR. In most patients PEFR can be
measured more easily even if the maneuver is difficult in severely dyspnoic patients. In
these cases, this may be deferred because deep inhalation may worsen bronchospasm56 and
in rare cases, precipitate respiratory arrest.57 However, the measurements are safe in most
patients.
Measurement of arterial blood gas is essential in patients with status asthmaticus. The
measurement is generally recommended when the FEV1 is less than 1 litre or PEFR is less
than 120 L/min. Patients in the early stages of status asthmaticus will exhibit mild hypoxemia
and respiratory alkalosis with low carbon dioxide tension. If respiratory alkalosis persists
for hours to days, compensatory renal bicarbonate wasting may take place manifesting as
a non-anion-gap metabolic acidosis. As the severity of obstruction increases, PaCO2 increases.
This is because of patient exhaustion, inadequate alveolar ventilation, and/or an increase
in physiologic dead space. Hypercapnia has a good correlation with FEV1 and usually does
not occur unless the FEV1 is less than 25% of the predicted.58 Presence of hypercapnia, even
normal PaCO2, indicates a severe degree of airflow obstruction and the possible need for
mechanical ventilation. However, in certain situations, hypercapnia alone is not an indication
for intubation. Such patients may respond to aggressive drug therapy.54,59 On the other
hand the absence of hypercapnia does not exclude the possibility of severe airflow
obstruction and impending respiratory arrest.3 Metabolic acidosis can occur in as high as
28% of patients with status asthmaticus.60 This may occur more likely in men and in patients
with more severe degrees of airflow obstruction and hypoxemia. The possible cause is
because of the elevated anion gap. Although the pathogenesis of lactic acidosis in this setting
is not clearly understood, the possible mechanisms are:61

212 Bronchial Asthma

Increased work of breathing resulting in anaerobic metabolism, tissue hypoxia,
intracellular alkalosis, decreased lactate clearance by the liver because of passive
congestion in the setting of high intrathoracic pressure, and use of parenteral betaadrenergic agonists.62 Repeated blood gas sampling are not necessary to determine
whether the patient is improving or deteriorating. In most cases important clinical
signs described above will be sufficient to judge whether the patient is to be intubated
or not. Patients who are deteriorating on these grounds to the point of respiratory
arrest should be intubated whether or not the PaCO2 is rising. On the contrary, patients
who are more comfortable on pharmacologic drug therapy are to continue with the
same treatment despite an elevated PaCO2. Patients on mechanical ventilation will
however, need serial measurement of arterial blood gas.
Chest radiography has little role in the management of mild to moderate asthma like
arterial blood gas. The benefits of routine chest skiagram are minimal and they contribute
only 1-5% of studies where the treatment is influenced.63 Such changes include normal,
hyperinflation, a minimal increase in interstitial markings. Other changes include focal/
major atelectasis, pneumonitis or one of the above described complications. However, chest
skiagram is definitely indicated in patients with fever, purulent sputum, signs or symptoms
of barotrauma, (chest pain, mediastinal crunch, subcutaneous emphysema, cardiovascular
instability, or asymmetric breath sounds), suggestion of pneumonia, other localising chest
signs, or when it is not clear that asthma is the cause of respiratory distress.
Differential Diagnosis
The differential diagnosis of severe dyspnoea with wheezing includes status asthmaticus,
upper airways obstruction, foreign body aspiration, left ventricular failure or ischaemia,
acute exacerbations of COPD, asthma complicated by pulmonary embolism, pneumonia or
barotrauma. History and physical findings will differentiate many of these conditions.
Assessment of Severity
Assessment of severity of an acute asthma is very important since one has to decide whether
the patient can be managed at home, or needs to be hospitalised or he is to be admitted to
an intensive care unit with or without ventilatory support. It is necessary to manage a
patient with acutely severe asthma with the same sense of emergency as for a 50-year old
person with crushing substernal chest pain suspected of having myocardial ischaemia. The
initial assessment should consist of a brief history pertinent to the exacerbation which include
the time of onset and cause of present exacerbation; severity of symptoms including exercise
limitation and disturbance of sleep, all current medication with the time of last administered
medication and any recent use of systemic corticosteroids, prior hospitalisation, prior
episodes of respiratory insufficiency, and significant prior cardiopulmonary disease. It
generally requires an analysis of several factors, including the medical history, physical
examination, bedside monitoring of airflow obstruction, response to initial therapy, arterial
blood gas measurements, and radiographic studies. This multifactorial analysis is necessary
because no single clinical measurements have been found to predict outcome reliably.64
A brief cardiopulmonary examination should be performed, with emphasis on findings
relevant to assessing the severity or identifying complications (pneumonia, atelectasis,
pneumothorax, and pneumomediastinum). The overall assessment of the patient should

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

213

include alertness, colour, respiratory distress, and fluid status. Although wheezing is a
prominent finding on chest auscultation, extremely severe obstruction may be accompanied
by silent chest. Routine laboratory studies and sputum culture are not necessary for initial
management of patients. A chest X-ray may be needed afterwards to identify any
complication. Measurement of PEFR and FEV1 are very essential. Arterial blood gas should
be obtained in all cases as far as possible, particularly if the patient is not able to perform
pulmonary function tests or for whom intubation and mechanical ventilation are being
considered.
Various indices of acute severe asthma are shown in Table 13.2.
Various clinical parameters helpful for the overall assessment of the patient are shown
in Table 13.3.
Table 13:2. Sherwood Jones index of severity of asthma
Grade 1a

Able to carry out house work or job with moderate difficulty.

Sleep occasionally disturbed.

Grade 1b

Able to carry out house work or job with great difficulty.

Sleep frequently disturbed.

Grade 2a

Confined to a chair or bed but able to get up with moderate difficulty.

Sleep disturbed. Little or no relief from inhalers.

Grade 2b

Confined to a chair or bed but able to get up with great difficulty. Unable to sleep.
Pulse rate > 120/min.

Grade 3

Totally confined to a chair or bed. No asleep. No relief from inhaler.

Pulse rate > 120/min.

Grade 4

Moribund.
Table 13.3: Indices of acutely severe asthma

Symptoms/history
Severe breathlessness, cough, chest tightness, and wheezing
Difficulty in walking for 100 feet or more
Speech fragmented by rapid breathing
Syncope or near syncope
Physical examination
Pulsus paradoxus of > 12 mmHg
Use of accessory muscles of respiration
Diaphoresis, unable to lie supine
Heart rate > 120/min
Respiratory rate > 30/ min
Silent chest
Pulmonary functions
FEV1 or PEFR , 30-50% baseline
Failure of PEFR to improve at least 10% after initial treatment
Arterial blood gas
PO2 < 60 mmHg or O2 saturation of less than 90%
PCO2 > 40 mmHg

214 Bronchial Asthma

NIH Guidelines (1997) has classified severity of asthma exacerbations into four different
categories according to the symptom and signs (Table 13.4), mild; moderate; severe and
imminent respiratory arrest.
Table 13.4: Classification of severity of asthma exacerbations (NIH, 1997)

Mild

Moderate

Severe

On walking;
Can lie down

While talking;
Prefers sitting

While at rest;
Sits upright

Phrases
May be
agitated

Words
Usually
agitated

Usually
agitated

Increased

Increased

Often > 30/min

Accessory
muscles use;
Suprasternal
retractions

Usually not

Commonly

Usually

Paradoxical
thoraco-abdominal
movement

Wheeze

Moderate
Only endexpiratory

Loud
Throughout
expiration

Usually loud
Throughout
inspiration and
expiration

Absent

Pulse/min

< 100

100-120

> 120

Bradycardia

Pulsus
paradoxus

Absent
< 10 mm Hg

Often present
10-25 mm Hg

Present
> 25 mm Hg

Absence
suggests
respiratory
muscle fatigue

SYMPTOMS
Breathless
Talks in sentences
Alertness

SIGNS:
Respiratory
rate

FUNCTIONAL ASSESSMENT:
PEFR (%
80%
predicted or %
personal best)

Respiratory
arrest imminent

Drowsy or
confused

50-80%

<50% predicted or
personal best or
response lasts < 2 hours

PaO2 (air)

Normal
Test usually
not required

> 60 mmHg
Test usually not
necessary

< 60 mmHg
May be cyanosed

and/or PaCO2

< 42 mmHg
Test usually
not required

< 42 mmHg
Test usually not
necessary

= or > 42 mmHg
Possible respiratory
failure

SaO2
(on air at
sea level)

> 95%
Test usually
not required

91-95%

< 91%

Note: The presence of several parameters, but not all, indicates the general classification of the
exacerbations.

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215

Recent data also showed that peak expiratory flow measurements must be interpreted
in the light of other features of severity and the patients past history, particularly previous
admissions to hospital, attendance at the emergency departments and current treatment,
especially corticosteroids. Life-threatening asthma is one where the PEFR is less than 33%
of the personal best. There is also a difference between a patient with PEFR of 50% who has
been on prednisolone for a week and a patient who has a short history and has not yet
started oral steroids. Similarly, pulsus paradoxus need not be measured as it adds nothing
to the assessment and its interpretation is subject to many factors (BTS, 1995). Facilities for
the monitoring of oxygen saturation should be available in all clinical areas that treat patients
with acute asthma. Interpretation of saturation in patients who are on or who have recently
been on oxygen, is difficult, but if the value is 92% or more and there is no feature of an
imminently life-threatening attack, arterial puncture may be deferred (BTS, 1995).
Therapeutic Management
The best strategy for management of asthma exacerbations is early treatment to prevent
deterioration and abort the exacerbation. Therefore early recognition of worsening lung
function, prompt communication between the patient and the physician, appropriate
intensification of antiasthma medication, and removal of the allergen or irritant are important
components of management. Some patients are at increased risk for exacerbations and the
category of high risk for asthma-related death includes patients who have history of :
Prior intubation for asthma,
Two or more hospitalisation for asthma in the past year,
Three or more emergency care visits for asthma in the past year,
Hospitalisation or emergency care visit within the past month
Current use of systemic steroids or recent withdrawal from systemic steroids,
Past history of syncope/hypoxic seizure due to asthma,
Prior admission to hospital based intensive care unit (ICU), and
Serious psychiatric disease or psychosocial problems.
The basic principle of care of acute asthma exacerbations is the rapid reversal of airflow
obstruction with relief of accompanying respiratory distress. This can be achieved by
repetitive administration of inhaled 2-antagonists, early addition of systemic steroids, and
correction of hypoxaemia.
Some acute exacerbations can be managed at home, as an emergency outpatient basis, or
the patient needs hospitalisation with or without admission into the intensive care unit
(ICU). The primary goal of home management of acute exacerbations of asthma is to avoid
delays in initiating antiasthma therapy by having the patient begin treatment at home. It is
equally important that the patient does not delay seeking professional medical help if the
asthma exacerbation is severe or if the response to therapy is not prompt and sustained.
The initial treatment should consist of subcutaneous adrenaline (1:1000) in a dose of
0.5 ml slowly. This can be repeated every 20 minutes for three times. The drug should be
avoided in patients with hypertension, and elderly individuals particularly with underlying
heart disease. Although these drugs were commonly used as the first line therapy earlier,
because of the availability of more 2-antagonist selective inhaled drugs recently, their use
has declined dramatically. Subcutaneous adrenaline, terbutaline, or salbutamol has no

216 Bronchial Asthma

advantage over inhaled -agonists. However, there are situations when these drugs are very
useful. These situations are:
i. when the patient is unable to cooperate to inhale;
ii. patients with impaired sensorium; and
iii. patients with cardiopulmonary arrest.65-67
These drugs can also be tried in intubated patients not responding adequately to inhaled
therapy. If parenteral -agonists are used, potassium monitoring is essential to avoid
hypokalemia, lactic acidosis, and cardiac arrhythmias. In very emergency cases, epinephrine
may be delivered effectively through the endotracheal tube. Other injectable preparations
that can be used include terbutaline and salbutamol.68 Some patients will not need further
parenteral therapy and can be stabilised with oral or inhaled bronchodilators and steroids.
There is no great advantage of more 2-specific drugs over subcutaneous epinephrine. Rather
they cause more cardiovascular side effects like tachycardia for the same degree of
bronchodilatation.69 Adrenaline is contraindicated during pregnancy because it is associated
with congenital malformations and decreases uterine blood flow.70 Terbutaline is the
preferred drug in this setting. However, terbutaline or salbutamol may inhibit uterine
contractility at term. Routine use of infused -agonists are not necessary and they have no
extra advantage. On an individual basis however, intravenously administered -agonists
may be considered in patients below the age of 40 years who do not respond to inhaled or
subcutaneous therapy, and in whom respiratory arrest is imminent or in whom persistent
severe airflow obstruction is associated with alarming levels of lung hyperinflation during
mechanical ventilation. In a recent meta-analysis, it is shown that the clinical benefit of
intravenous -agonists appears questionable, while the potential clinical risks are obvious.
The only recommendations of intravenous 2-agonist use should be in those patients in whom
inhaled therapy is not feasible.71,72
Inhalation of selective 2-agonist bronchodilators by nebulisation is favoured for both
children and adults as the immediate and first-line therapy of status asthmaticus of all
severity. The onset of action is very rapid and their side effects are usually tolerated.
Salbutamol is the most commonly used drug. This has a slightly longer duration of action
and it is more 2-selective. Long-acting -agonists like salmeterol or formoterol are not indicated
in acute asthma since their onset of action is very slow. Terbutaline (2.5-5 mg), or salbutamol
2.5-5 mg, or metaproterenol 15 mg or isoetharine 5 mg can be given 4-6 hourly diluted with
normal saline. This dose can be used every twenty minutes for 1 hour (three doses) followed
by administration every hourly during the first several hours of therapy. A single dose of 7.5
mg nebulised salbutamol and sequential doses of 2.5 mg nebulised salbutamol are clinically
equivalent in the treatment of patients with moderate-to-severe acute asthma and result in
similar disposition from the emergency room.73 Fewer doses can be given in patients with less
severe airflow obstruction who demonstrate a good response. On the other hand, inhaled
treatment can be given continuously to severely obstructed patients until an adequate clinical
response is achieved or adverse effects limit further use. Prior use of inhaled drugs at home
does not prevent further use in hospital. Lower doses are preferred initially but they can be
repeated or increased if necessary. Larger and more frequent doses are necessary in acute
asthma because the dose-response curve and duration of action of activity of these drugs are
affected adversely by the degree of bronchoconstriction.74 Airway narrowing and the
cooperation and breathing pattern of the patient may further reduce the dose of the drug
delivered by inhalation.

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Recent studies have shown that in nonintubated patients, MDIs combined with a spacer
are as useful/effective as that used by a nebulizer.75-78 Further, MDIs are more quicker action
and cheaper still, many prefer the use of nebulizers as they need fewer instructions, less
coordination is required and less supervision is necessary. Moreover, both the patient and
physician feel satisfied psychologically. Both MDIs and nebulizers can also be used in
patients on ventilators,79 although there are controversies regarding the optimal delivery of
inhaled drugs in the intubated and/or mechanically ventilated patient, optimal ventilatory
settings to be used during ventilation for drug delivery, ideal site on the ventilator circuit
for connection of the nebulizer, and maximal acceptable drug dosage.80 Higher dosages are
required to achieve physiologic effects than in nonintubated patients since pulmonary
aerosol deposition is poor in these patients, in the range of 1.2-2.9%.81, 82 In recently extubated
patients, MDIs can be used successfully.
Inhaled 2-agonists are the drugs of choice with which to treat patients with acute severe
asthma. In comparison to systemic approach, inhalation is associated with a more rapid
onset of action, and fewer systemic side effects. There is a consensus that frequent intermittent
nebulisation, every 20 minutes within the first hour, are appropriate, although continuous
nebulisation also has been proposed. Since the late 1980s, there has been considerable clinical
and academic interest in the use of continuous aerosolised bronchodilators for the treatment
of acute asthma.83 A recent meta-analysis supports the equivalence of continuous and
intermittent salbutamol nebulisation in the treatment of acute adult asthma.84 This method
of therapy has potential advantage in terms of time, cost, and medication delivery. This
feature may allow deeper penetration into the airways and greater reduction of bronchoconstriction. Furthermore, this may result in fewer side effects. In children, continuous
salbutamol nebulisation is considered to be better than intermittent therapy.85-87
Since airway inflammation is an important component of airflow obstruction of bronchial
asthma, treatment with corticosteroids is the most important and an integral part of
managing a case of acute severe asthma. Ideally, an intensifying treatment of worsening of
ones asthma should start with aggressive use of corticosteroids, which both the patient
and many physicians do not appreciate. If not intervened early, airway inflammation
proceeds unchecked. Whether patients are using corticosteroids or not when they arrive in
the emergency with severe attacks of asthma, the dose is inadequate. There is evidence to
suggest that failure to use or under use of steroids contribute to asthma deaths.88 Benefits of
steroids are well established in recently confirmed meta-analysis of large number of studies.89
The facts that emerge are that steroids given in the emergency room significantly reduce
the rates of admission and the number of future relapses in the first 7-10 days. It did not
matter whether steroids are given intravenously or orally even if intravenous therapy is
preferred in patients at risk of intubation, as long as a minimum of 30 mg of prednisolone
or its equivalent is given every 6 hourly. Lower doses are less effective and there will be no
obvious benefit by giving higher doses.90-92 It is recommended that 150-225 mg/day of
prednisolone or its equivalent is required to reach maximal therapeutic benefit. Either 40 mgms
of intravenously administered methyl prednisolone every 6 hours or prednisolone 60 mg
orally every 6-8 hours for 36-48 hours depending upon the condition of the patient will be
most ideal. Corticosteroids both intravenous and oral should be started simultaneously.
However, these drugs have a slow onset of action because of their intracellular mode of action
whatever their route of administration. Intravenous administration speeds up their action
marginally by about an hour. Hydrocortisone should be administered 200 mg intravenously

218 Bronchial Asthma

initially followed by 100 mg every 4 hourly in place of methyl prednisolone because the later
is costly. This can also be administered as an infusion in a dose of 0.5 mg/kg/hr. Prednisone
in a dose of 40-60 mg should be administered from the first day for several days followed by
tapering of the dosage according to the response.
A meta-analysis has suggested that the administration of corticosteroids in addition to
inhaled 2-agonists in patients with acute asthma on their arrival at the emergency
department does not improve airflow obstruction nor reduces the need for hospitalisation.93
The failure of steroids to influence the early course of patients with acute asthma is due to
the fact that it may take up to 24 hours for the effect of corticosteroids to become evident.
However, other randomised, placebo-controlled trials94 have shown that high doses of
inhaled glucocorticosteroids together with salbutamol in patients with acute asthma who
are treated in the emergency department significantly improve pulmonary function when
compared to the use of salbutamol alone. The difference becomes evident by 90 minutes. It
is due to the fact that locally acting inhaled corticosteroids cause local vasoconstriction and
thereby decrease edema formation and plasma exudation.95 However, glucocorticosteroids,
either in inhaled form or oral form or parenteral form are the important mode of therapy
for managing a case of acute bronchial asthma. Some studies have shown that after 48 hours
of intravenous treatment with corticosteroids, the use of high-dose inhaled flunisolide
(250 g per activation, eight puffs twice daily is as effective as systemic corticosteroids, in
adults hospitalised for a severe asthma exacerbation.96 A meta-analysis indicates that there
is some evidence that therapy with high-dose inhaled corticosteroids (beclomethasone
dipropionate, > 2,000 mg or equivalent per day) may replace therapy with oral corticosteroids
following the emergency department discharge of patients who have been treated for an
acute asthma exacerbation.97 However, this meta-analysis has not shown any concrete
evidence to change the practice of administering oral prednisolone for a short while for
7-10 days at a dose of 40 mg per day, which is cheap, effective, and safe.98 Addition of
inhaled corticosteroid (budesonide 1600 g/day to oral corticosteroid reduces the number
of relapses.95
If the patient continues to deteriorate despite treatment, with beta-agonists and steroids,
the alternatives are to add nebulised ipratropium bromide 500 g 6 hourly. The drug
augments the bronchodilating effect of 2-agonists in acute asthma.99-101 The role for anticholinergic medications is not well-defined. Thus, the use of therapy with anticholinergics
and 2-agonists, either simultaneously or in sequence, has produced positive as well as
negative results in different trials. Most recent relevant reviews had proved that the use of
multiple doses of ipratropium bromide are indicated in emergency department treatment
of children and adults with severe acute asthma. The studies reported a substantial reduction
in hospital admission (30-60%, number needed to treat 5-11) and significant difference in
lung function favouring the combined treatment. No apparent increase in the occurrence of
side effects was observed. The use of single-dose protocols of ipratropium bromide with
2-agonist treatment produced, particularly in children with more severe acute asthma, a
moderate improvement in pulmonary function without reduction in hospital admission.;
in adults, the evidence showed a similar increase in pulmonary function with an approximately 35% reduction in hospital admission rate. In patients with mild-to-moderate acute
asthma, there is no apparent benefit adding a single dose of an anticholinergic medication.102
Theophylline: Aminophylline is commonly used as an important drug in many developing
countries both as a maintenance drug in chronic asthma as well for treatment during an

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

219

acute attack of bronchial asthma in the form of a continuous drip in many countries because
of its lower cost and if given in proper doses, the drug is not all that unsafe. Moreover,
other modalities may not be available at all places. However, the ready availability of beta
agonists and their safety and quick onset of action has replaced theophylline therapy in
acute asthma. The usual loading dose and maintenance dose is shown in the table below. In
most situations roughly 250 mg, 400 mg, and 500 mg 8 hourly will be required for a small,
medium or large person respectively for maintenance. Serum theophylline level should be
obtained whenever possible. Use of theophylline confers additional benefit on beta agonists
and parenteral steroid therapy.103 Further, administration of theophylline results in fewer
hospitalisations.104 A recent analysis of the use of theophylline had concluded that there is
inadequate evidence to support or reject the use of theophylline in the emergency setting.105
However, theophylline continues to be an important adjunct in the management of acute
asthma particularly in the setting of poor or incomplete response to treatment with beta
agonists and steroids and where economy is a consideration. Theophylline can be, and has
been used, safely if attention is paid to the possible side effects, serum drug levels, and to
factors that increase serum levels. Serum levels should be checked within 6 hours of
intravenous loading to avoid toxic levels.
High concentrations of oxygen (35%) will increase arterial PO2 and will not lead to carbon
dioxide retention unless there is some other associated problem. Obstruction of peripheral
airways will result in V/Q mismatch and hypoxemia. However, true shunt in acute asthma
is only 1.5% of the pulmonary blood flow.106 Therefore, correction of hypoxemia requires
only modest flow of oxygen, 1-3 L/min through a nasal cannula. Only a small proportion
of patients below the age of 45 years develop hypoxaemia. Although there is a good
correlation of FEV1 or PEFR with that of arterial oxygen tension, there is no cut-off value for
either measurement to accurately predict hypoxaemia. The routine administration of low
flow oxygen is an entirely safe practice that is recommended if routine pulse oxymetry is
not available and if there is co-morbid condition such as coronary artery disease. Oxygen
therapy improves oxygen delivery to the peripheral tissues including respiratory muscles,
reverses hypoxic pulmonary vasoconstriction, airway bronchodilatation, and protection
against the modest fall in PaO2 often seen after 2-agonist administration resulting from
pulmonary vasodilatation and increased blood flow to low V/Q units.
Since the attack is frightening reassurance to the patient is essential.
Routine use of antibiotics is not necessary unless there is evidence of bacterial infection
in form of fever, purulence of sputum or radiological evidence of consolidation. However,
sputum that looks purulent, may be due to abundant eosinophils and not polymorphonuclear leukocytes.
Adequate hydration should be maintained.
Sedatives of all kinds should be avoided. Periodic assessment of progress of disease or
the effect of therapy is very essential.
There are reports supporting the usefulness of magnesium sulphate107-111 or heliox in the
treatment of refractory bronchial asthma. This benefit has been described in patients with
normal magnesium levels, although hypomagnesemia has been reported in 50% of patients
with acute asthma.112 Magnesium was first reported as a treatment for acute bronchial asthma
in 1936.113 It has since been shown to be a bronchodilator.114-116 Many case reports showed clinical benefits in patients with respiratory failure complicating bronchial asthma.117,118 Several
trials in paediatric patients demonstrated a benefit from IV magnesium. 119,120 Many

220 Bronchial Asthma

randomised trials of IV magnesium in acute asthma in adults have shown mixed
results.121-123 A recent multicentric trial has shown that administration of 2g of IV magnesium
sulphate improves pulmonary function when used as an adjunct to standard therapy in
patients with very severe, acute asthma.124 The mechanism of action of magnesium is not
known. One hypothesis is that magnesium inhibits calcium channels of airway smooth muscle
and thus, interferes in calcium-mediated smooth muscle contraction. Magnesium decreases
acetylcholine release at the neuromuscular junction, which may interfere with bronchoconstriction. Magnesium also reduces histamine-induced and methacholine-induced
bronchoconstriction in asthmatics and affects respiratory muscle force generation. Although
1-2 gm of the drug is safe, care should be taken to monitor renal function. Further, hypotension,
and loss of deep tendon reflexes can result from magnesium intoxication. Mild complications
include flushing and mild sedation. The drug is not recommended for routine use.
Heliox is a mixture of helium and oxygen (80:20,70:30, or 60:40) with a gas density less
than that of air. It can be delivered through a tight fitting nonrebreathing face-mask in
nonintubated patients and through the inspiratory limb of the ventilator circuit in
mechanically ventilated patients. Because the mixture is lighter than air, airways resistance
is decreased in bronchi with turbulent flow. This decreases the work of breathing and delays
the inspiratory muscle fatigue until definite bronchodilator and anti-inflammatory therapy
becomes effective.125,126
Drugs used in the treatment of status asthmaticus are shown in Table 13.5.
Indications for Admission in the Intensive Care Unit
Each patient should be assessed for response to treatment instituted initially in the emergency
room. Patients who can be discharged include:127
Significant improvement in shortness of breath
Improved air entry on clinical examination
PEFR or FEV1 greater than or equal to 70% predicted.
Observation for a minimum period of 30 minutes after the last dose of -agonist is
administered is necessary to ensure stability before discharge. An incomplete response to
treatment may be defined as the persistence of wheezing or shortness of breath and a PEFR
or FEV1 between 40-70% of predicted. These groups of patients require ongoing treatment
either in the emergency room or in the medical ward where facilities are available. Before
discharge, these patients should be provided with a detailed follow-up plan which includes
written medical instructions and a written plan of action to be followed if there is worsening
of symptoms. Follow-up schedule should be made before the patient is sent home.
However patients having the following problems should be admitted and observed for
treatment in the intensive care unit. These are:
Patients with severe airflow obstruction;
Use of accessory muscles of respiration,
Pulsus paradoxus of > 12 mmHg
Diaphoresis
Inability to recline
Hypercapnia
PEFR < 40% predicted

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

221

Table 13.5: Drugs used in status asthmaticus

Drug

Dosage/Mode of use

Adrenaline

0.3 ml of 1:1000 solution subcutaneous every 20 minutes 3 times. Terbutaline is

favoured in pregnancy. The drug is to be avoided in patients with hypertension,
older patients, and those with coronary artery disease.

Salbutamol

0.5 ml of 0.5% solution (2.5/5 mg) in 3 ml normal saline by nebulisation or 4 puffs by

MDI with spacer every 20 min. for three doses; intubated patients can also given
this drug.

Corticosteroids

Methyl prednisolone 60-125 mg given intravenously every 6 hours or prednisolone

30-40 mg orally every 6 hours. Hydrocortisone can also be given 200 mg start,
followed by 100 mg every 6-8 hourly. The intravenous drugs are to be continued for
at least for a period of 24-48 hours. Oral prednisolone is to be substituted as soon
as possible. In fact, oral drugs are to be started simultaneously so that when the
injectable steroids are withdrawn, they can take-over.

Anticholinergics Ipratropium bromide 0.5 mg by nebulisation hourly or 4-10 puffs by MDI with Spacer
every 20 minutes for three doses.
Theophylline
- Loading dose:

No previous drug -6mg/kg of aminophylline (lean body weight) infused over

30 minutes or can be given slowly diluted with 25% of glucose over 20 minutes
Already on theophylline: Reduce according to serum level as follows: If serum level
is Cs mg/L, then
Vol. of distribution (Vd) = 0.5L/kg Wt (kg)
Loading dose
= Vd desired change in serum level (mg/L)
= Vd (Cs desired -Cs known)
For a patient of 50 kg Wt; with Cs of 8 mg/L and desired Cs of 18mg/L;
Loading dose = 0.5 50 (18 mg/L -8 mg/L) = 250 mg.
Maintenance dose:
Adults
Smokers
Liver disease
Severe COPD
CCF
Viral illness
Children
drug interactions

Oxygen

Infusion Rate (mg/kg/hr)

0.5
0.8
0.4
0.4
0.2
0.4
0.9-1.2
As discussed in section under theophylline

1-3 l/min by nasal canula. Titration by pulse oxymetry

Unproved alternatives
Magnesium
1 gm intravenously over 20 minutes (Total dose 2 gm). If hypomagnesemic, dose
sulfate
adjusted to normalize serum levels.
Heliox

80:20, 70:30, or 60:40 helium:oxygen mixture by tight-fitting, nonrebreathing face

mask. Higher helium concentrations are needed for maximal effect.

Poor response to initial therapy

Less than 10% improvement in PEFR
Those deteriorate despite therapy
Respiratory arrest

222 Bronchial Asthma

Altered mental status
Cardiac toxicity
Tachyrrhythmias, Angina, Myocardial infarction
Further, patients with imminently life-threatening features such as unconsciousness,
confusion, drowsiness, hypoxia (PaO2 < 60 mmHg despite 60% oxygen) or patients with a
raised PaCO2 should be admitted into the ICU. Similarly, patients whose condition is
deteriorating and PaCO2 is rising need to be monitored in an intensive care unit.
Mechanical Ventilation
Many, but not all, of these patients will need ventilatory support. Patients receiving
pharmacological therapy needs to be watched closely for the need for intubation in patients
showing clinical deterioration. Indications for intubation will depend upon:
a. Changes in posture, alertness, speech, use of accessory muscles, and respiratory rate,
all of which indicates worsening respiratory failure. These signs do not need any
arterial blood gas measurement or peak flow documentation;
b. Fatigued patient despite PaCO2 levels
c. Altered mental status despite PaCO2 levels
d. PaCO2 is not an important predictor for intubation since patients who are more
comfortable, better able to speak, and less respiratory distress can continue medical
therapy despite a rise in PaCO2;
Immediate intubation:
e. Patients presenting with cardiopulmonary arrest
f. Near cardiopulmonary arrest (patients unable to speak and/or gasping for air)
g. Coma
h. Significant obtundation
A.

Non-invasive Ventilation

Non-invasive ventilation through face mask mechanical ventilation is an option used by

some clinicians as a short-term ventilatory support in patients with hypercapnic ventilatory
failure who are not
i. Responding adequately to drug therapy; and
ii. Where immediate intubation and mechanical ventilation is not indicated/required.
Patients with encephalopathy or with a need of airway protection are not suitable for
this form of therapy. Various advantages of noninvasive ventilation are; decreased
need of anaesthesia, sedation, and paralysis, decreased incidence of nosocomial
infections, decreased incidence of sinusitis and otitis, and better patient comfort.128-131
Usually a nasal CPAP of 5-7.5 cm H2O will be necessary. Potential disadvantages of
this mode of ventilation include aspiration of gastric contents due to gastric insufflation,
facial pressure necrosis, and less control of the patients ventilatory status.
B. Intubation
Once it is decided to ventilate the patient intubation should be done quickly by an experienced person as manipulation of the upper airways may precipitate laryngospasm. Oral
intubation allows insertion of larger bore endotracheal tubes (8 mm or more), which has

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

223

advantage of better suction and a decrease in airway resistance beneficial at high airflow.
Nasal intubation is safe in most patients particularly if he is awake, breathless and in obese
patients with short necks. Fibre optic guided intubation may be helpful in difficult cases.
The disadvantage with the nasal route is that a smaller endotracheal tube can only be used
and there is a high incidence of nasal polyps and sinusitis in them.
C. Sedation
Sedation will invariably be required in awake patients to prepare for intubation and to
allow for effective mechanical ventilation (to avoid fighting the ventilator). Further, sedation
improves patient comfort, facilitates various procedures, and decreases oxygen demand
and consumption and decreased carbon dioxide production besides decreasing the risk of
barotrauma. Various sedatives that can be used in status asthmaticus are shown in
Table 13.6.
D. Paralysis
Muscle paralysis is required in patients fighting with the ventilator despite sedation and in
those who continue to have asynchronous breathing which is a grave risk factor for
generation of high airway pressure and loss of airway access. The decision, however, will
be based on the clinicians own judgment whether to use neuroparalytic agents or not to
achieve a therapeutic strategy to maintain stable respiratory parameters. Paralysis further
helps to reduce oxygen consumption, carbon dioxide production, and lactic aciodosis in
addition to decreasing the risk of barotrauma with an overall augmentation of sedatives
already used. Because the expiratory effort is eliminated, there is less airway collapse.
The paralytic drugs of choice are vecuronium and atracurium. These are nondepolarising
agents and are free of cardiovascular side effects, although larger doses may cause
hypotension. The drugs are either given intermittently by bolus injection or by continuous
Table 13.6: Sedatives that can be used in status asthmaticus

Drug

Dose

Comments

1 mg IV push slowly, can be

repeated every 2-3 min. as needed.

Hypotension, respiratory depression

Ketamine

1-2 mg/kg IV at a rate of

0.5 mg/kg/min.

Sympathomimetic effects,
respiratory depression,
mood change, delirium

Propofol

60-80 mg/min IV
up to 2 mg/kg followed by
an infusion of 5-10 mg/kg/hr
as needed

Respiratory depression

Before intubation
Midazolam

After intubation for prolonged ventilation:

Lorazepam
Morphine sulphate
Ketamine
Propofol

1-5 mg/hr IV continuous

infusion or bolus
1-5 mg/h IV continuous infusion
0.1-0.5 mg/kg IV
1-4.5 mg/kg/h IV

Drug accumulation
Ileus
As described above
Seizures, hypertriglyceridemia

224 Bronchial Asthma

intravenous infusions. The disadvantages of neuroparalytic agents in acute asthma are:
difficulties in assessing the mental status, greater danger of developing deep vein thrombosis,
disuse muscle atrophy and myopathy.132 The last complication is more pronounced in the
presence of concomitant use of high dose steroids.
E. Mechanical Ventilation
Hypotension and hypoperfusion often follow intubation and positive pressure ventilation.
Slowly bagging (4-6 breathes/min) with 100% oxygen for about 1 min will allow for
prolonged expiratory time to decrease PEEPi which will result in a rise of blood pressure. If
this occurs a fluid bolus of 0.5-1L of normal saline should be given every 10-20 minutes
until adequate circulation is restored.
The goals of mechanical ventilation in status asthmaticus are:
To achieve adequate alveolar ventilation;
Low levels of PEEPi;
Minimal circulatory compromise;
Low risk of barotrauma.
The patient should initially be fully sedated and adequate muscle-relaxation be achieved
to minimize airway pressures. Dynamic hyperinflation is often seen in these patients if an
attempt is made to make them eucapnic. This can be prevented by using small tidal volumes
and high inspiratory flow. Mechanical ventilation should be initiated with a tidal volume
of 8 ml/kg, rate of 12-15/min, and inspiratory flow rate of 60L/min. Measurement of PEEPi
in the sedated patient who has also received muscle relaxant, the expiratory limb of the
ventilator is occluded at end expiration while omitting the subsequent breath. The proximal
airway pressure rises to a plateau (PEEPi).133 If peak airway pressures exceed 55 cmH2O
and PEEPi is greater than 15 cmH2O despite full sedation and muscle relaxation, tidal volume
can be varied in 100-ml increments with corresponding changes in rate and flow in an
attempt to optimize peak airway pressure (Ppk), PEEPi, and PCO2. In some patients, a high
level of PCO2 in the range of 70-90 mmHg is the only way to bring Ppk below 55 cm H2O
and PEEPi below 15 Cm H2O. This is known as controlled hypoventilation. This is
preferable to the risk of barotrauma during an attempt to bring the PCO2 to normal, attempt
to achieve this should never be tried. If associated acute respiratory acidosis is severe (pH
< 7.2), bicarbonate infusion can be given to achieve a serum pH of approximately 7.25.
External PEEP should not be used during ventilation of a patient of status asthmaticus as it
can result in dangerous increases in lung volumes and pressures.
Weaning from mechanical ventilation of the patient of status asthmaticus requires good
planning. The paralytic agents should be discontinued briefly every 4 hours and readministered only if evidence of muscle activity is seen. While some patients with very
labile asthma may respond to therapy within hours, more typically the patient will require
24-48 hours of aggressive bronchodilator therapy until airway pressures and PEEPi fall.
Once this begins, improvement is usually rapid, with resolution of all dynamic hyperinflation
by 12 hours. As airway pressures fall, sedatives, muscle relaxants, and bicarbonate infusions
can be reduced to prepare the patient for a brief period of spontaneous ventilation and then
extubation. Assessment of respiratory muscle strength should be made by determination
of negative inspiratory pressure. If the patient has adequate muscle strength and no sign of
respiratory failure emerge during the brief period of spontaneous breathing, extubation
should be performed since the endotracheal tube itself can perpetuate bronchospasm. A

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

225

quick return to spontaneous breathing can be achieved through a T-piece or by decreasing

the respiratory rate on SIMV. The use of 5-8 cm H2O of pressure support helps overcome
endotracheal tube resistance. Once the patient tolerates a trial of spontaneous breathing,
quick extubation is done. Vigorous bronchodilator and chest physiotherapy should be
continued in the ICU until the next day. During this period and following discharge from
the ICU, a careful programme for education should be implemented to help the patient
identify signs of worsening asthma and optimize the drug regimen to reduce/obviate future
episodes of life-threatening asthma.
F.

Inhalant Anaesthetics

Rarely, the above strategy fails to allow adequate ventilation at a safe level of lung inflation.
In that situation inhalation of general anaesthetic ishalothane and enfluranecan be
considered. These have bronchodilatation activity that can acutely reduce Ppk, and
PaCO2.134,135 But the effect lasts as long as the drugs are in use. The bronchodilating effect
are lost once the drugs are stopped. Inhalation of these drugs are. Inhalation of these drugs
has significant cardiovascular side effects including myocardial depression, arterial
vasodilatation, and arrhythmias.
Recently, nitric oxide has been used to induce bronchodilatation, however, the experience
is limited and at a dose of 80 ppm it exerts a weak bronchodilator effect in asthmatics.136
G.

Bronchoalveolar Lavage

Since mucus plugging is one of the notable features of status asthmaticus, all attempts
should be made to remove the same from the respiratory tract to improve airflow. Strategies
of mucus removal short of bronchodilators or steroids, like chest physiotherapy or mucolytics
are not efficacious.137,138 Bronchoalveolar lavage using saline or acetylcystine, is being tried
to remove mucus plug.139-143 Although there is improved airflow in intubated patients, the
procedure is not without risk in intubated patients which further compromises the airway
lumen. This will increase the expiratory airway resistance and may lead to high levels of
lung hyperinflation. At present, BAL is not recommended as part of a routine management
of patients with status asthmaticus.
Hospital Discharge and Future Plan of Action
After the patient has come out of the ICU, in the general ward itself the question of prevention
and treatment of subsequent asthma attacks should be addressed. This process starts with
extensive patient education, how to recognise the worsening of asthma and what to do at
home in such an eventuality, and when to contact a physician or to visit the emergency
department. Patients should be provided with written medication instructions as well as a
written plan of action to be followed in the event of worsening of symptoms. The proper
agents like inhaled medications with or without spacer as per the need. Their doses,
frequency, etc. should be clearly explained. Similarly, any oral medication required is to be
told to the patient in writing. It is important to explain also the purpose of such medication
plans and the techniques are to be taught, particularly for inhalers. The importance of airway
inflammation and use of anti-inflammatory drugs needs special explanation to the patient.
When inhaled corticosteroids are prescribed, patients must be told not to expect immediate

226 Bronchial Asthma

Assessment of severity:
PEFR measurement < 50% personal best or predicted suggests severe exacerbation.
Signs and symptoms correlate poorly with severity
Accessory muscle use and suprasternal retractions suggest severe exacerbations.

Initial treatment:
Inhaled short-acting 2-agonist; up to three treatments of 2-4 puffs by MDI at 20-minutes
intervals or single nebuliser treatment.

Good response

Incomplete response

Poor response

Mild episode

Moderate episode

severe episode

PEFR > 80% predicted or 50-80% predicted or

personal best
personal best

< 50% predicted or

personal best

No wheezing or shortness Persistent wheezing and

of breath
shortness of breath

Marked wheezing
and breathlessness

Response to 2-agonist
sustained for 4 hours

Add oral steroid

Add oral corticosteroid

May continue above every Continue 2-agonist

3-4 hours for 24-48 hrs

Repeat 2-agonist
immediately

For patients on inhaled

corticosteroids, double
dose for 7-10 days

If distress is severe
and non-responsive, consult
physician and report to
emergency.

Follow up with physician

Contact physician
urgently the same day

Visit emergency
department

Fig. 13.1: Home treatment of asthma exacerbations

relief of respiratory symptoms as they are not bronchodilators. Possible side effects of various
drugs are to be told. The purpose and importance of peak flow measurements is to be
explained. The technique of the manoeuvre, frequency of measurement maintaining a diary,
timings of measurements are to be told. The patient should be told that it is to be measured
at am and pm and the best of three readings each time is to be noted as the representative
PEFR. Most important is to tell the patient what is the best for him and at what level of
reading (severity) he should report to the physician. Appointments are to be made for followup care with primary clinician or asthma specialist. The patient should be given the date,
time and location of appointment within seven days of hospital discharge. Before or at
discharge the action plan has to be decided. The patient or its caregiver should be instructed
on simple plan of action to be taken for symptoms, signs, and PEFR values suggesting
recurrent airflow obstruction.

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

227

ASSESSMENT IN HOSPITAL
Acute severe asthma
If SaO2 < 92% or if the patient has
PEFR 50% or less of predicted or
any life-threatening features, ABG
personal best
measurement is essential
Cannot complete sentence in one breath
Severe, life-threatening, if
Respiration 25/min or more
Pulse > 110/min
Normal (36-45) or high PaCO2
PaO2 < 60 mmHg irrespective of
treatment with oxygen
A low pH
Life-threatening features
No other investigation is required for
management
PEFR < 33% predicted or best
Silent chest, cyanosis, feeble respiratory effort
Bradycardia or hypotension
Exhaustion, confusion, or coma

IMP: Patients with severe or life-threatening attacks may not be distressed and may not have all
these abnormalities. The presence of any one should alert the physician.

1. Immediate treatment
Oxygen 40-60%(CO2 retention is not a problem)
Salbutamol 5 mg or Terbutaline 10 mg by a nebuliser
Prednisolone tablet 30-60 mg or IV Hydrocortisone 200 mg or both if very ill
No sedatives of any kind
Chest radiograph to exclude pneumothorax
If life-threatening features are present: Add ipratropium 0.5 mg to the nebulised beta-agonist
IV aminophylline 250 mg over 20 min or Salbutamol or Terbutaline 250 mcg over 10 min. No
bolus aminophylline to patients already taking oral theophylline.

2. Subsequent management:
If patient is improving:
Continue
40-60% oxygen
Prednisolone 30-60 mg orally daily or Hydrocortisone 200 mg 6 hrly.
Nebulised beta- agonist 4 hourly
If patient not improving after 15-30 min:
Continue oxygen and corticosteroids
Beta-agonists more frequently, up to every 15-30 min.
Add ipratropium bromide 0.5 mg to nebuliser and repeat every 6 hrly until patient is
improving.
If patient is still not improving:
Aminophylline infusion (750-1500 mg/24 hrs for a small and large framed individual); serum
level monitoring essential if continued for more than 24hr
Salbutamol or Terbutaline infusion as an alternative to aminophylline.

Contd...

228 Bronchial Asthma

Contd...
3.

Monitoring treatment:
Repeat measurement of PEFR 15-30 min after starting treatment
Oxymetry
Maintain SaO2 > 92%
Repeat ABG within 2 hrs after treatment if:
initial PaO2 < 60 mmHg
PaCO2 normal or more than normal
Patient deteriorates
Record PEFR before and after treatment and at least 4 times daily throughout hospital stay.

Transfer to ICU accompanied by physician prepared to intubate if:

Deteriorating PEFR,
Worsening or persisting hypoxia
Hypercapnia
Exhaustion, feeble respiration, confusion, drowsiness
Coma or respiratory arrest

4. When discharged from hospital, patient should have:

Been on discharge medications for 24 hours and have had inhaler technique checked
and recorded.
PEFR > 75% of predicted or personal best and diurnal variability of < 25% unless
discharge is agreed with respiratory physician.
Treatment with oral and inhaled steroids in addition to bronchodilators.
Own peak flow meter and written self management plan
Physician follow-up planned within one week.
Follow-up visit to respiratory clinic within 4 weeks.
Cause of exacerbations is also to be determined.
Patient should be given details of record.
Fig. 13.2: Hospital-based/emergency management of
asthma exacerbations (British Guidelines1995)

Patients should be taught how to recognise early warning signs so that they may initiate
appropriate treatment of their own. In general, warning signs of worsening airflow obstruction
include: a 20% drop in PEFR below predicted or personal best; an increase in cough, shortness
of breath, chest tightness, or wheeze. Although mild episodes may be treated by temporarily
increasing the bronchodilator therapy, these alone are not sufficient to treat more severe forms
of asthma. Inhaled 2-agonists at times give a false sense of security and delay the
administration
of
anti-inflammatory
therapy.
Accelerated
use
of
2-agonists should be a warning sign that airway wall inflammation has worsened and
corticosteroid therapy should be initiated. Patients with a history of sudden asphyxic asthma
should also be given a kit of epinephrine for the immediate subcutaneous epinephrine.
The guidelines of the NHLB Institute Expert Panel for management of acute exacerbations
of bronchial asthma at different levels are summarised in Figures 13.1 and 13.2.139

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

229

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70. Rosenfeld CR, Barton MD, Meschia G. Effects of epinephrine on distribution of blood flow in
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71. Tracers AH, Rowe B, Barker S et al. The effectiveness of IV -agonists in treating patients with
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74. Kelly HW. New -2 agonist aerosols. Clin Pharmacol Ther 1985;4:393-403.
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77. Newhouse MT. Emergency department management of life-threatening asthma: Are nebulizers
obsolete? Chest 1993;103:661-63.

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78. Newman KB, Milne S, Hamilton C, Hall K. A comparison of albuterol administered by metereddose inhaler and spacer with albuterol by nebulizer in adults presenting to an urban emergency
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79. Harvey CJ, ODoherty MJ, Page CJ, Thomas SHL, Nunan TO, Treacher DF. Effect of a spacer on
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80. Hess D. How should bronchodilators be administered to patients on ventilators. Respir Care
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82. Fuller HD, Dolovich MB, Posmituck G, Wong Pack W, Newhouse MT. Pressurised aerosol versus
jet aerosol delivered to mechanically ventilated patients. Comparison of dose to the lung. Am
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83. Olshaker J, Jerrand D, Barish RA et al. The efficacy and safety of a continuous albuterol protocol
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84. Rodrigo GJ, Rodrigo C. Continuous vs intermittent -agonists in the treatment of acute adult
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85. Khine H, Fuchs SM, Saville AL. Continuous vs intermittent nebulised albuterol for emergency
management of asthma. Acad Emerg Med 1996;3:1019-24.
86. Papo M, frank J, Thompson AE. A prospective, randomised study of continuous versus
intermittent nebulised albuterol for severe status asthmaticus in children. Crit Care Med
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87. Portnoy J, Aggarwal J. Continuous terbutaline nebulisation for the treatment of severe
exacerbations of asthma in children. Ann Allergy 1988;60:368-71.
88. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423-29.
89. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma:
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90. McFadden ER Jr. Dosages of corticosteroids in asthma. Am Rev Respir Dis 1993;147:1306-1310.
91. Haskel RJ, Wong EM, Hansen JE. A double-blind, randomised clinical trial of methyl prednisolone
in status asthmaticus. Arch Intern Med 1983;143:1324-27.
92. Littenberg B, Gluck EH. A controlled trial of methyl prednisolone in the emergency treatment of
acute asthma. N Engl J Med 1986;314:150-52.
93. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute adult
asthma: An evidence based evaluation. Chest 1999;116:285-95.
94. Rodrigo C, Rodrigo G. Inhaled flunisolide for acute severe asthma. Am J Respir Crit Care Med
1998;157:698-703.
95. McFadden ER. Inhaled glucocorticosteroids and acute asthma: Therapeutic breakthrough or
nonspecific effect? Am J Respir Crit Care Med 1998;157:677-78.
96. Lee-Wong M, Dayrit FM, Kohli AR et al. Comparison of high-dose inhaled flunisolide to systemic
corticosteroids in severe adult asthma. Chest 2002;122:1208-13.
97. Edmonds ML, Camargo CA Jr, Brenner BE, Rowe BH. Replacement of oral corticosteroids with
inhaled corticosteroids in the treatment of acute asthma following emergency department
discharge. Chest 2002;121:1798-1805.
98. Mark PE, Varon J. Oral vs inhaled corticosteroids following emergency department discharge
of patients with acute asthma. Chest 2002;121:1735-36.
99. Rebuck AS, Chapman KR, Abboud R et al. Nebulised and sympathomimetic treatment of asthma
and chronic obstructive airways disease in the emergency room. Am J Med 1987;82:59-64.
100. Bryant DH, Rogers P. Effects of ipratropium bromide solution nebulisation with and without
preservatives in the treatment of acute and stable asthma. Chest 1992;102:742-47.

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101. Kelly HW, Murphy S. Should anticholinergics be used in acute severe asthma? Ann Pharmacothera 1990;24:409-14.
102. Rodrigo GJ, Rodrigo C. The role of anticholinergics in acute asthma treatment: An evidence
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103. Lalla S, Saleh A, Faroog J et al. Intravenous aminophylline in acute, severe bronchial asthma.
Chest 1991;(Suppl):60S.
104. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic
disease in the emergency room. Ann Intern Med 1991;115:241-47.
105. Littenberg B. Aminophylline in severe, acute asthma: A meta-analysis. JAMA 1988;259:16781684.
106. Rodriguez-Roisin R, Ballester E, Roca J, Torres A, Wagner PD. Mechanisms of hypoxia in patients
with status asthmaticus requiring ventilation. Am Rev Respir Dis 1989;139:732-39.
107. Skobeloff EM, Spivey WH, McNamara RM, Greenspon L. Intravenous magnesium for the
treatment of acute asthma in the emergency department. JAMA 1989;262:1210-13.
108. Noppen M, Vanmaele L, Impens N, Schandevyl W. Bronchodilating effect of intravenous
magnesium sulfate in acute severe asthma. Chest 1990;97:373-76.
109. Rolla G, Bucca C, Caria E et al. Acute effects of intravenous magnesium sulfate on airway
obstruction of asthmatic patients. Ann allergy 1986;61:388-91.
110. Okayama H, Aikawa T, Okayama M, Sasaki H, Mue S, Takishima T. Treatment of status
asthmaticus with intravenous magnesium sulfate, J Asthma 1991;28:11-17.
111. Bloch H, Silverman R, Mancherje N, et al. Magnesium sulfate is a useful adjunct to standard
therapy for acute severe asthma. Chest 1992;102(Suppl):83S.
112. Haury VG. Blood serum magnesium in bronchial asthma and its treatment by the administration
of magnesium sulfate. J Lab Clin Med 1940;25:340-344.
113. Boselo SJ, Pla JC. Sulfato de magnesio en la crisis de asthma. Prensa Med Argent 1936;
23:1677-80.
114. Noppen M, Vanmaele I, Impens N et al. Bronchodilating effect of intravenous magnesium
sulfate in acute severe bronchial asthma. Chest 1990;97:373-76.
115. Rolla G, Bucca C, Caria E et al. Acute effect of intravenous magnesium sulfate on airway
obstruction of asthmatic patients. Ann allergy 1988;61:388-91.
116. Okayama H.Aikawa T, Okayama M et al. Bronchodilating effects of intravenous magnesium
sulfate in bronchial asthma. JAMA 1987;257:1076-78.
117. McNamara RM, Spivey WH, Skobeloff E et al. Intravenous magnesium in the management of
acute respiratory failure complicating asthma. Ann Emerg Med 1989;18:197-99.
118. Kuitert LM, Kletchko SL. Intravenous magnesium sulfate in life-threatening asthma. Ann Emerg
Med 1991;20:1243-45.
119. Devi PR, Kumar L, Singhi S et al. Intravenous magnesium sulfate in acute severe asthma not
responding to conventional therapy. Indian Paediatr 1997;34:389-97.
120. Clarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children
with moderate to severe acute asthma. Arch Pediatr Adolesc Med 2000;154:979-83.
121. Blosch H, Silverman R, Mancherje N et al. Intravenous magnesium sulfate as an adjunct in the
treatment of acute asthma. Chest 1995;107:1576-81.
122. Green SM, Rothrock SG. Intravenous magnesium for acute asthma: Failure decrease emergency
treatment duration or need for hospitalisation. Ann Emerg Med 1992;21:260-65.
123. Tiffany BR, Berk WA, Todd IK et al. Magnesium bolus or infusion fails to improve expiratory
flow in acute asthma exacerbations. Chest 1993;104:831-34.
124. Silverman RA, Osborn H, Runge J et al. IV magnesium sulfate in the treatment of acute severe
asthma; a multicenter randomised controlled trial. Chest 2002;122:489-97.
125. Gluck EH, Onorato DG, Castriotta R. Helium-oxygen mixtures in intubated patients with status
asthmaticus and respiratory acidosis. Chest 1990;98:693-98.

234 Bronchial Asthma

126. Manthouse CA, Hall JB, Melmed A et al. Heliox improves pulsus paradoxus and peak expiratory
flow in nonintubated patients with severe asthma. Am J Respir Crit Care Med 1995;151:310-14.
127. National Asthma Education Programme. Expert panel report. Guidelines for the diagnosis and
management of asthma. Bethesda, US Department of Health and Human Services. Publication
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128. Meduri GU, Abou-Shala N, Fox RC, Jones CB, Leeper KV, Wunderink RG. Non-invasive face
mask mechanical ventilation in patients with acute hypercapnic respiratory failure. Chest
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129. Shivram U, Miro AM, Cash ME, Finch PJP, Heurich AE, Kamolhz SL. Cardiopulmonary responses
to continuous positive airway pressure in acute asthma. J Crit Care 1993;8:87-92.
130. Martin JG, Shore S, Engel LA. Effect of continuous positive airway pressure on respiratory
mechanics and pattern of breathing in induced asthma. Am Rev Respir Dis 1982;126:812-17.
131. Mansel JK, Stogner SW, Norman JR. Face-mask CPAP and sodium bicarbonate infusion in acute
severe asthma and metabolic acidosis. Chest 1989;96:943-44.
132. Pollard BJ. Which drug-steroid or benzylisoquinolium? Intensive Care Med 1993;19:46-60.
133. Pepe PE, Marini JJ, Occult end expiratory pressure ion mechanically ventilated patients with
airflow obstruction. Am Rev Respir Dis 1982;126:166-70.
134. Saunier FF, Durocher AV, Deturck RA, Lefebvre MC, Wattell FE. Respiratory and haemodynamic
effects of halothane in status asthmaticus. Intensive Care Med 1990;16:104-07.
135. Echeverria M, Gelb AW, Wexier HR, Ahmad D, Kenefick P. Enflurane and halothane in status
asthmaticus. Chest 1986;89:153-54.
136. Hogman M, Frostell CG, Hedenstrom G. Inhalation of nitric oxide modulates adult human
bronchial tone. Am Rev Respir Dis 1993;148:1474-78.
137. Falliers CJ, McCann WP, Chai H, Ellis EF, Yazdi N. Controlled therapy of iodotherapy for
childhood asthma. J Allergy 1966;38:183-92.
138. Wanner A, Rao A. Clinical indications of and effects of bland, mucolytic, and antimicrobial
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139. Helm WH, Barran KM, Mukerjeee SC. Bronchial lavage in asthma and bronchitis. Ann Allergy
1972;30:518-23.
140. Lang DM, Simon RA, Mathison DA, Tims RM, Stevensopn DD. Safety and possible efficacy of
Fibre optic bronchoscopy with lavage in the management of refractory asthma with mucus
impaction. Ann Allergy 1991;67:324-30.
141. Rogers RM, Shuman JF, Zubrow AB. Bronchoalveolar lavage in asthma. Chest 1973;63(Suppl):
62S-64S.
142. Smith DL, Desnazo RD. Bronchoalveolar lavage in bronchial asthma. Am Rev Respir Dis
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143. Millman M, Millman FM, Goldstein IM, Mercandetti AJ. Use of acetylcystein in bronchial asthma:
another look. Ann Allergy 1985;54:294-96.

Management of Asthma with Special Problems 235

14
Management of Asthma
with Special Problems
EXERCISE-INDUCED ASTHMA (EIA)
The term exercise-induced asthma (EIA) is often used to describe the asthma of persons
in whom exercise is the predominant or at times the only identified trigger to airflow
limitations. The goal of EIA is to enable patients to participate in any activity they choose
without experiencing asthma symptoms and to enable the patient to achieve a normal
exercise capacity. For some asthmatics, this goal means an ability to walk short distances
and to work regularly without limitation due to breathlessness. While for other, like children
and young adults, it implies the freedom to run about and to compete in sports without
respiratory disability. For highly trained athletes with asthma, it means to compete at
extremely high levels of physical activity and ventilatory performance. Therefore, the goals
of managing asthma in relation to exercise are: (i) to maximise lung function prior to exercise,
(ii) to protect bronchoconstriction during exercise.
The presence or absence of bronchospasm induced by exercise can be established by
spirometry before and after the exercise task in question. Some difficulty is encountered
when the exercise cannot readily be performed in the laboratory. In that situation, the
condition must be mimicked as closely as possible in the laboratory by having the patient
exercise with a stationary bicycle or treadmill to the levels of ventilation and with inspired
air temperature and humidity that simulates the actual exercising condition. Testing worldclass athletes in an otherwise well equipped pulmonary laboratory becomes still difficult
because of difficulty in providing a sufficiently strenuous exercise work load. In this setting,
eucapnic voluntary hyperventilation can be substituted for physical exertion, and the target
level of ventilation to be sustained can be set without limit. Formal pulmonary evaluation
before and after exercise can also be used effectively to evaluate the impact of preventive
therapies. In athletes failing to respond to conventional prophylactic treatment, identical
exercise challenges can be performed following administration of various medications in
varied doses and combinations, thereby objectively assessing their success.
Bronchoconstriction induced by exercise are generally rapidly eliminated by administration of inhaled 2-agonists. However, the bigger problem is preventing the development
of significant airflow obstruction during and following exercise so as to minimise the impact
of asthma on athletic participation and performance. Optimised control of asthma in general
as outlined is the first step towards prevention. The less is the underlying bronchial hyperresponsiveness and higher the pre-exercise level of expiratory airflow, the less likely it is

236 Bronchial Asthma

that a particular exercise task will provoke asymptomatic airflow obstruction. In some
asthmatics, regular use of inhaled corticosteroids will be needed to achieve these goals.
Inhaled corticosteroids are currently approved by the International Sports authorities for
this purpose.
Most patients with EIA are otherwise asymptomatic. In these patients, inhaled 2-agonists,
used prior to exercise, will prevent EIA in more than 80% of subjects. These may be taken
from less than 10 to 20 minutes prior to exercise in standard doses (1-2 inhalations) and are
helpful for up to several hours. They provide excellent protection for 2 hours. Because they
do not enhance exercise performance in any way other than prevention of air-flow
obstruction, they are permitted and approved for use in world-class competitions. Fenoterol
is an exception as its metabolite parahydroxyamphetamine, which is not allowed for athletes.
The newer, longer-acting -agonists, salmeterol and formoterol, offer effective prevention
of exercise-induced symptoms for as long as 8 hours following a single, pre-exercise
dose.1,2
Cromolyn sodium (2 puffs) before exercise is another acceptable pre-treatment,
particularly in those who cannot tolerate beta-agonists. This drug is virtually devoid of any
side effect. The peculiarity of the drug is that when used as an anti-inflammatory agent for
chronic asthma, it takes several weeks for its effect. But as a prophylactic in EIA, a single
dose prior to exercise is effective. Regular use of the drug does not enhance the protective
action.3 The small percentage of patients who still encounter difficulty are helped by an
increase in the dosage of 2-agonist or use of both this and Cromolyn.
Many other drugs have been shown to inhibit the bronchoconstrictive effect of exercise.
They are ipratropium bromide, theophylline, calcium channel blocking agents, nedocromil,
terfenadine, leukotriene D4 antagonists and lipoxygenase inhibitors, inhaled frusemide4,
and inhaled heparin5 are some of the conventional and newer therapies active in modifying
the response to exercise. However, use of many of these are rarely required. Their use can
be considered when conventional therapy with -agonists and cromolyn fails.
Patients who experience a refractory period during continuous exercise may benefit
from a warm-up period before exercise utilising submaximal exercise and may not need
repeated medications during periods of continuous exercise. They should avoid a sudden
change to a warm, moist environment immediately after exercise which will help in
modifying the post-exercise response. Specially designed low-resistance heat and moisture
exchange face mask has been shown to help asthmatics in cold environments.6
Medications that are approved by the US Olympic Committee for use in competition
include 2-agonists (aerosol or inhalant forms of salbutamol, bitolterol, and terbutaline),
Cromolyn sodium, theophylline and inhaled steroids.
PREGNANCY AND ASTHMA
The natural history of asthma during pregnancy is variable. Several physiological changes
occur during pregnancy that could worsen or improve asthma. However, it is not clear
which are the factors that will decide the ultimate course. It is reported that symptoms of
asthma worsens during pregnancy in 43% of patients and improves in 14%.7 In a perspective
cohort study of 366 pregnancies in 330 women with asthma, the disease worsened during
pregnancy in 35%.8 Other studies suggest that 11-18% of pregnant women with asthma
will have at least one emergency department visit for acute asthma and of these, 62% will
require hospitalisation.9,10 Exacerbations of asthma symptoms usually occurs during the

Management of Asthma with Special Problems 237

last trimester. In a large cohort study the most severe symptoms were experienced by patients
between the 24th and 36th week of pregnancy. Thereafter symptoms decreased significantly
in the last four weeks and 90% had no asthma symptoms during labor or delivery. Only two
patients required additional medications beyond bronchodilators.8 Another study has also
confirmed that during the last months of pregnancy asthma is least likely to exacerbate.11
Some other reports suggest that there is no change in the course of asthma during pregnancy.12
Women tend to follow the same pattern during all pregnancies with respect to the course of
their asthma.13, 8 Women with extrinsic (atopic) asthma tend to have fewer symptoms during
pregnancy than patients with intrinsic asthma.14 A cohort study comparing 198 pregnant
women with asthma with 198 women without asthma observed that non-atopic patients
with asthma tend to have more severe asthma. Pre-eclampsia was also more common in this
group. However, with proper surveillance and treatment, pregnancy and delivery related
complications could be avoided. A systematic review has shown that baseline asthma severity
does determine what happens to asthma in pregnancy and asthma may affect the risk of
adverse outcome.15 Severe asthma is likely to worsen during pregnancy than mild asthma.8
However, some patients with severe asthma may experience improvement, whilst symptoms
may deteriorate in some with mild asthma. A meta-analysis of 14 studies concluded and
agreed with the commonly quoted generalisation that during pregnancy about one-third of
asthma patients experience an improvement in their asthma, one-third experience a worsening
of symptoms, and one-third remains the same.16 During pregnancy 40% of the patients managed
with the same asthma medications as before pregnancy; 18% needed less; and in 42% the
need was more.17
Bronchial asthma in the mother has been associated with increased perinatal morbidity
and mortality,18,19 and also with increased morbidity during infancy.18 Obstetric complications
have been observed more often in asthmatics than in control subjects.18 Pre-eclampsia occurred
more often in asthmatics than controls, especially in patients with severe asthma. Hypoglycemia
occurred more often in infants of mothers with severe asthma than in infants of mothers with
less severe disease. Uncontrolled asthma is associated with many maternal and fetal
complications, including hyperemesis, hypertension, pre-eclampsia, vaginal hemorrhage,
complicated labor, intrauterine growth retardation, pre-term birth, increased perinatal
mortality, and neonatal hypoxia.20-23 A large Swedish population based study using record
linkage data demonstrated increased risks for preterm birth, low birth weight, perinatal
mortality, and pre-eclampsia in women with asthma. The risk of prematurity and low birth
weight were higher in women with severe asthma necessitating admission.24 In contrast, if
asthma is well controlled throughout pregnancy there is little or no increased risk of adverse
maternal or fetal complications.9,10 Pregnancy, therefore, should be an indication for
optimisation of therapy and maximising lung function in order to reduce the risk of acute
exacerbations.
Theophylline at term did not influence labor or delivery. Thus, severe asthma or systemic
corticosteroid treatment or both during pregnancy seems to increase the incidence of mild
pre-eclampsia in the mother and hypoglycaemia in the newborn.19 Poorly controlled asthma
has adverse effect on the fetus, resulting in increased perinatal mortality, increased prematurity,
and low birth weight. For this reason, the use of drugs to obtain optimal control of asthma is
justified even when their safety in pregnancy has not been unequivocally proven. For most
antiasthma drugs, clear documentation of teratogenic effects is lacking. On the other hand,
these drugs have not yet been proved to be safe. Thus all drugs can be used without increased

238 Bronchial Asthma

risk to the fetus25,26 except alpha-adrenergic compounds. Reports on the adverse effects of
corticosteroids during pregnancy are contradictory. Apgar reported an increased incidence
of cleft palate in two series of pregnancies in women treated with systemic corticosteroids in
early pregnancy.27 The incidence of stillbirths was eight times higher in women having
continuous steroid treatment than in a corresponding group of untreated women with the
same diseases.28 However, the alarming findings in these studies may be a part of the
underlying severe disease rather than the treatment.29 However, two other studies of pregnant
asthmatic women, some having short-term and some long-term systemic corticosteroids,
showed no complications attributable to steroid treatment.30,31 Thus, although the direct effects
of systemic steroids on the fetus appears to be small, their indirect effects (hypertension, preeclampsia, hypoglycemia) may still form a risk for the infant. However, as an acute exacerbation
of asthma carries even greater risks for the mother and child, systemic steroids should not be
withheld when the need arises. Higher theopylline concentrations in the mother might be
associated with complications of labor and delivery due to uterine atony. On the other hand,
inhaled steroids may be quite safe in recommended doses. Immunotherapy should not be
started during pregnancy, if that is considered. It is important to avoid fetal hypoxia during
acute exacerbations. No special treatment is required for asthma during labor except for those
who have received daily parenteral steroids for a week or three separate courses in the
preceding year, in whom hydrocortisone supple-mentation (100 mg every 8 hours) should be
given for the stress of delivery unless there is documentation of normal adrenal responsiveness.
Terbutaline and salbutamol can cause delayed/poor uterine contraction during labor. During
acute attacks, drug therapy should be the same as for the non-pregnant patient. Oxygen
should be delivered to maintain saturation above 95%. Continuous fetal monitoring is
recommended for severe asthma. In women with poor control of asthma, there should be close
liaison between the respiratory physician and obstetrician.
In general, the medicines used to treat patients of asthma are quite safe in pregnancy.32 The
risk of harm to the fetus from severe or chronically under treated asthma outweighs any small
risk from the medications used to control asthma. 2-agonists, corticosteroid inhalers are to be
used as normal during pregnancy.33,34 No significant association has been demonstrated
between major congenital malformations or adverse outcome and exposure to
methylxanthines.32,35 Although there were some concerns of use of oral steroids during early
pregnancy, they were unfounded and steroid tablets are to be used as normal when indicated
during pregnancy for severe asthma and they should not be withheld because of pregnancy.
Data regarding the safety of leukotriene antagonists are limited. Animal studies and postmarketing surveillance for zafirlukast and monteleukast are reassuring. There are concerns
about animal data on zyleuton.36 Leukotriene antagonists should not be started during
pregnancy. They may be continued in women who have demonstrated significant improvement
in asthma control with these agents prior to pregnancy not achievable with other medications.
Acute attacks of asthma are very rare in labor due to endogenous steroid production. In
women receiving steroid tablets there is a theoretical risk of maternal hypothalamic-pituitaryadrenal axis suppression. Women with asthma may safely use all forms of pain relief in
labor. In some studies there is an association between asthma and an increased caesarean
section rate., which may not be conjectural. Risk of postpartum exacerbation of asthma is
increased in women undergoing caesarean section. This may be related to the severity of
asthma rather than caesarean section per se. The women should continue their usual asthma
medications in labor. In the absence of acute severe asthma, caesarean section should be

Management of Asthma with Special Problems 239

reserved for usual obstetrics indications. If anaesthesia is required, regional blockade is
preferable to general anaesthesia in women with asthma. Women receiving steroid tablets at
a dose exceeding prednisolone 7.5 mg per day for more than two weeks prior to delivery
should receive parenteral hydrocortisone 100 mg 6-8 hourly during labor. Prostaglandin F2
should be used with extreme caution in these women with asthma because of the risk of
induction of bronchoconstriction.
Antiasthma drugs may pass into the breast milk, and earlier, mothers have, therefore, been
advised not to breastfeed. However, no evidence has shown that inhaled drugs or moderate
doses of theophylline or systemic steroids taken by mouth by the lactating mother would be
harmful to the infant.37 Breastfeeding, thus, is to be encouraged.19 All medications used to treat
asthma including steroid tablets have been shown in early studies to be safe to use in nursing
mothers.15 There is less data with newer agents. Less than 1% of the maternal dose of
theophylline is excreted into the breast milk. Prednisolone is secreted in breast milk, but milk
concentrations of prednisolone are only 5-25% of those in serum.16. The proportion of an oral
or intravenous dose of prednisolone recovered in breast milk is less than 0.01%. For maternal
doses of at least 20 mg once or twice daily, the nursing infant is exposed to minimal amounts
of steroid with no clinically significant risk. Thus, asthma drugs should be used as normal
during lactation, in line with manufacturers recommendations.
SURGERY AND ASTHMA
Possible intraoperative and postoperative complications can occur in patients of bronchial
asthma because of bronchial hyper-reactivity, airflow obstruction, and mucus hypersecretion.38-40 Possible complications are many and may include the following. Acute attacks
may be triggered during intubation which stimulates sensory receptors in the upper airway
that can lead to reflex efferent neurotransmission via the vagus nerve, resulting in bronchial
smooth muscle contraction. Increased airway obstruction may result due to suppressed cough
and mucus plugging following surgery. This will result in ventilation-perfusion mismatching
and may contribute to impaired gas exchange resulting in hypoxaemia and possibly
hypercapnia during and following surgery. Severe airflow obstruction along with
postoperative pain, can impair the effective cough. Retained airway secretion can further
impair airflow and gas exchange. Further, mucus impaction can cause atelectasis and
associated diminished respiratory excursion will result in respiratory infection and further
impairment of gas exchange. The likelihood of these complications will depend upon the
severity of the patients airway hyperresponsiveness, the degree of airways obstruction, and
the amount of mucus plugging at the time of surgery. These variables can be assessed by
history, physical examination, and spirometry. Other factors that influence the rate of
postoperative complication include the type of surgery (thoracic and upper abdominal surgery
have the greatest risk) and type of anaesthesia (general anaesthesia with endotracheal
intubation carries the greatest risk).
All patients with active asthma should undergo preoperative respiratory evaluation. Even
asymptomatic patients with bronchial asthma should undergo evaluation as they may have
significant airflow obstruction and bronchial hyper-responsiveness. Patients with moderate
to severe disease, the evaluation should begin several days prior to surgery. When the asthma
is uncontrolled, the patient should be hospitalised for a day or more prior to surgery for
optimisation of lung function. Patients having frequent nocturnal awakening, frequent or

240 Bronchial Asthma

continuous use of steroids, prior perioperative complications related to asthma, large volume
of sputum production, and co-morbid cardiovascular disease are associated with a high risk
for perioperative complications. Spirometry is the best way to assess the degree of airflow
obstruction and all attempts should be made to achieve a normal or near normal lung function
prior to surgery.
Asthma patients experiencing wheezing, productive cough, chest tightness, or dyspnoea
should receive intensified treatment of their asthma prior to elective therapy, even if this
necessitates delay of surgery. An attempt should be made to improve lung function in patients
with an FEV1 or PEFR < 80% of predicted or < 80% of their recent best value. Frequently a brief
course of corticosteroids will be required to achieve this goal. Modification of anaesthetic
approach may be possible in some at increased perioperative risk. Spinal, epidural, or local
anaesthesia may in some cases be substituted for general anaesthesia and postoperative pain
control may be achieved with epidural analgesia rather than parenteral narcotics. Even in the
asymptomatic or minimally symptomatic patient, it is useful to administer an inhaled 2agonist bronchodilator immediately prior to surgery. Patients receiving daily medications for
asthma should generally be maintained on these drugs. Intravenous aminophylline can be
used to maintain therapeutic levels who are taking this drug, but are not permitted to take
anything by mouth. The usual maintenance dose of theophylline is intravenous aminophylline
of 0.6 mg/kg/hour by continuous infusion. Inhaled bronchodilators can be maintained during
surgery even patients receiving general anaesthesia and mechanical ventilation. To prevent
depressed adrenal-pituitary response to stress, intraoperative and postoperative steroid
supplementation should be given to patients who have received systemic steroids for more
than 2 weeks within the last 6 months or more than two courses of systemic steroids within
the last 12 months. Patients who have been taking high-dose inhaled corticosteroids more
than the conventional recommended doses, should also be considered at risk of relative
adrenal-pituitary suppression and should be given perioperative steroid replacement therapy.
The usual dose of replacement corticosteroid therapy during stress is 300 mg of hydrocortisone
per day. Hydrocortisone of 100 mg each should be given intravenously on the day of surgery
in the morning, intraoperatively, and postoperatively. The dose is then tapered over the next
few days. Clearance of airways is an important aspect of postoperative care.
OLDER PATIENTS WITH ASTHMA
Although asthma affects all age groups, morbidity and mortality is particularly high in the
elderly. In New York City, asthma-attributable mortality rates in adults > 65 years of age are
six times higher than those in adults < 40 years of age.4 Whereas many factors contribute to
the urban asthma problem, sensitisation to indoor allergens may play a particularly significant
role. The presence of cockroach-specific serum IgE in a population of elderly urban patients
with asthma, is associated with more severe asthma, as reflected by an increase in airway
obstruction and hyperinflation.42 Asthma is frequently under diagnosed in the elderly because
of a number of differential diagnosis, difficulty in measurement of lung function, and underreporting of symptoms.43 The later may occur because of reduced expectations or because of
an age related reduction in perception of breathlessness.44 A similar age related difference
in the physical signs associated with severe asthma may lead to underestimation of severity
and under treatment.45 Simple tests of mental functioning may be necessary to ensure that
elderly people with asthma are capable of acquiring the necessary skills for treating and
monitoring their condition.46 Increased asthma mortality is more common in elderly patients

Management of Asthma with Special Problems 241

above the age of 55 years. This may be due to difficulty in diagnosis (COPD and congestive
cardiac failure). The precise cause of severe airflow obstruction is difficult to diagnose at
times. Some cases asthma diagnosed in older individuals may actually be a combination of
asthma and COPD or of asthma and congestive heart failure. Further, coexistence of other
diseases (myocardial ischaemia), can cause additional problems. For example, ischaemic
heart disease in a case of bronchial asthma may be more dangerous because of associated
hypoxaemia which could result in decreased myocardial oxygenation followed by myocardial
infarction or rhythm disturbances. Frequent intake of drugs by people of this age are known
to aggravate asthma (beta blockers for hypertension and eye drops, aspirin and other
nonsteroidal anti-inflammatory drugs). Since arthritis is a known disease of this age, if the
patient takes aspirin and other non-steroidal anti-inflammatory drugs may cause sudden
and severe asthma exacerbations. Further, epinephrine and theophylline have the potential
of precipitating the underlying heart disease. Although treatment of chronic and acute asthma
exacerbations should be the same as per the recommended guidelines, certain special
considerations are necessary in elderly individuals. All patients of asthma above the age of
55 years old should be evaluated for coexisting disease conditions. Particular attention should
be given to the monitoring of hypoxemia if he has concomitant heart disease. Theophylline
may increase the risk of urinary retention in older men with prostatism apart from its potential
cardiac side effects. These patients should carefully be monitored for steroid side effects.
Monitoring of hematocrit and blood sugar periodically is essential to rule out hyperglycemia,
hypokalemia, and gastrointestinal bleeding. Eye examination is to be conducted annually to
rule out cataract and glaucoma. Evaluation of possible alterations in calcium homeostasis is
essential particularly in whom there is a greater concern of bone loss as in postmenopausal
women. Anticholinergic bronchodilator therapy may have a greater role in this age group
than in the younger patients.47 Oxygen should also be used with caution if there is associated
COPD to avoid precipitation of carbon dioxide retention. Depression and other associated
serious psychiatric illness needs detail assessment. Older individuals are more prone for
depression, which in turn is identified as a risk factor for fatally-prone asthma. Family loss
and disruption, difficult adjustments to retirement, and other psychosocial problems are
more common in this age group. Certain other impairments more common in older individuals
may interfere worth treatment. These include arthritis, which may require special devices
such as a spacer to assist actuation. Nebulisers might be more useful. Patients with visual
impairment may be unable to read the numbers on the peak flow meter in which colour codes
might help. Further, there may be difficulty in reading instructions either on the drug or
prescriptions given by the physician. Some other family member may be helpful in this situation.
Patients with memory difficulties might forget to adhere to medical regimens that require
several drugs and frequent schedules. Patients with hearing difficulties may not tell the
health provider that they have not heard or understood the instructions. Asking the patients
to state the information and/or instructions in their own words will help ensure understanding.
OCCUPATIONAL ASTHMA
The diagnosis should be suspected in all adults with airflow obstruction and with a positive
history of high-risk occupations or exposures. Patients with pre-existing asthma aggravated
non-specifically by dust and fumes at work (work aggravated asthma) should be distinguished
from those with pre-existing asthma who become additionally sensitized to an occupational
agent. The subject is usually better on days away from work and better on holidays. Although

242 Bronchial Asthma

they are not specific for occupational asthma, but are important clues for investigation for an
occupational agent. These symptoms are also present in asthmatics due to sensitizing agents
at home and in those who do much less physical exertion. An accurate history taking is
important which should include exposures to chemicals, organic dusts and other possible
agents both at the current time as well as in the past.
The diagnosis and management of occupational asthma are difficult and can be divided
into three parts:
Confirming the diagnosis of asthma;
Confirmation of the relationship between asthma and work exposures; and
Finding the specific cause
The first step is to confirm that the patient is having asthma by using standard measures
like peak expiratory flow measurements, lung function tests, and reversibility testing. COPD
and non-respiratory causes of breathlessness should be excluded. The next step is the
establishment of a relationship between asthma and work exposure. These include serial
measurements of PEFR at home, and at work, measurements of non-specific airway hyper
reactivity after days at and away from work, measurements of specific IgE to an occupational
agent, and specific bronchial provocation testing. The decision of making a case of
occupational-induced asthma remains a matter of clinical judgment. Measurements of PEFR
should be made every two hours from working to sleeping for four weeks keeping treatment
constant and documenting times at work.48 Minimum standards for diagnostic sensitivity
of > 70% and specificity of > 85% are (a) at least three days in each consecutive work period;
(b) At least three series of consecutive days at work with three periods away from work
(usually about three weeks); and (c) at least four evenly spaced readings per day. Nonspecific responsiveness measurements with methacholine or histamine can be undertaken
after a period at end away from work exposure. A more than 3.2-fold changes in PC20
indicates a significant change outside the 95% confidence intervals for repeat measurements.
The diagnostic sensitivity, however, is only 40%, which is substantially worse than serial
PEFR measurements.49 The third step is identification of the cause of occupational asthma,
which is often difficult. There should be information about the sources of exposure (risk
assessment). IgE measurements are possible for most biological agents and a few low
molecular weight chemicals. These include latex in health care workers, flour and enzymes
in bakers, rodent urine extracts, and animal epithelia in laboratory animal workers and
veterinary surgeons, and acid anhydrides in exposed workers. Carefully controlled exposure
to workplace agents and suitable controls is the gold standard for diagnosis.50 Tests are
difficult to do and are not widely available, and are not always possible for some types of
workplace exposures.
The ideal treatment for patients with occupational asthma with a latency period is removal
from exposure. Early diagnosis and removal from exposure is associated with a favourable
prognosis. Eliminating exposure should be tried. In some instances, reducing exposure by
improving ventilation or providing a respirator may allow a person to return to the same
job. However, once sensitisation occurs, bronchoconstriction will often be triggered by
subsequent minimal exposure. Once well established, occupational asthma may not be
completely reversible. Recovery, if occurs may take months to years after removal from
exposure. A worker might be transferred to a job without exposure in the same company. Most
people with occupational asthma have to be retained for a job with another employer in a
different field. Before advising the worker to leave the job, attempt should be made to see if

Management of Asthma with Special Problems 243

changing the job process or activities can be changed to reduce exposure or if protective
equipment is useful. When the employees have irritant-induced asthma, or work-aggravated
asthma, employer should make every effort towards reasonable accommodation by
improving the workplace as required. The physician should advise the patient regarding
compensation as per the law of the particular country.
If the patient returns to the same job, should have close medical follow-up. Worsening of
asthma should lead to immediate removal from exposure. Pharmacological treatment of
occupational asthma is similar to the treatment of patients with other forms of asthma.
However, continuing monitoring is important. Although removal from the source of
exposure lead to improvement, patients may continue to require medication and have airflow
limitation or bronchial hyperresponsiveness for many months or years.
Patients should be referred to compensation boards or similar other agencies. Patients
should be evaluated for temporary impairment and disability when their asthma is under
good control. Evaluation for potential permanent impairment and disability should take
place after two years, when improvement in asthma has plateaued.
Irritant-induced asthma (Reactive airway dysfunction syndromeRADS) is another form of
asthma associated with the workplace, in which a wheezing illness starts within 24 hours,
and usually less than that, of a single large exposure to an irritant. The condition is
inflammatory and does not involve immunological recognition of the irritant, so that
continued low levels of exposure to the causative agent can be tolerated without problems.
RADS is diagnosed by the presence of non-specific responsiveness and a compatible history.
The prognosis varies, but there is a good likelihood of improvement.
DRUG-INDUCED ASTHMA
Even an initial reaction to aspirin or other nonsteroidal anti-inflammatory drug (NSAID)
may be severe and an adverse reaction can occur at any time, typically following years of
employing these drugs without difficulty. Therefore, all patients of asthma should avoid
this group of drugs. Usually safe and alternative drugs are acetaminophen, sodium salicylate,
or disalcid. Reaction to aspirin or an NSAID produce a refractory state lasting 2-7 days and
do not occur if patients ingest the drugs on a daily basis.51 If the patient is avoiding these
drugs, the initial dose in the form of a rapid graded challenge should be given in the presence
of a physician. If the patient has severe asthma requiring steroids or has severe asthma
with compromised pulmonary function, or if the patient reports a previous bronchoconstrictive reaction to these drugs, a more conservative treatment approach is indicated
and should be undertaken by a physician familiar with the technique.51 Aspirin use may be
a special problem in patients with nasal polyps, chronic rhino sinusitis, and steroid
dependency. If there is a concern regarding the use of aspirin in these patients, a sensitivity
challenge should be conducted.
GASTRO-OESOPHAGEAL REFLUX AND ASTHMA
The relationship of asthma to gastro-oesophageal reflux is a matter great debate, although
most people now believe that this is an important precipitating factor for asthma.52,53 In some
studies, medical and surgical treatment of gastro-oesophageal reflux has resulted in
improvement in symptoms of oesophagitis and also a decrease in asthma symptoms,

244 Bronchial Asthma

particularly those occurring in the night. On the other hand, other studies have failed to
document similar benefits.
Medical management of the reflux include elevation of the head of the bed 6-8 inches,
eating smaller but frequent meals, avoiding food or drink between dinner and bed time,
inhibition of gastric acid production using H2-antagonists and maintenance of lower
oesophageal sphincter pressure by avoiding fatty meals, spices, ethanol, theophylline, caffeine,
and avoiding drugs like metoclopromide that increase lower oesophageal sphincter pressure.
Surgery is indicated for severely symptomatic oesophagitis that is not responsive to medical
therapy, for complications like stricture, and for established pulmonary complications of
nocturnal reflux. Since surgery is extensive and is not successful for everyone, emphasis
should be on medical management.
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13. Schatz M, Harden K, Forsythe A et al. Course of asthma post-partum (PP) and during successive
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18. Gordon M, Niswander KR, Berendes H, Kantor AG. Fetal morbidity following potentially
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19. Bahna SL, Bjerkedahl T. The course and outcome of pregnancy in women with bronchial asthma.
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20. Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring
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21. Perlow JH, Montogomery D, Morgan MA et al. Severity of asthma and perinatal outcome. Am
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25. Spector SL. The treatment of the asthmatic during pregnancy and lactation. Ann allergy
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26. Greenberger PA, Patterson R. Beclomethasone dipropionate for severe asthma during pregnancy.
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27. Apgar V. The drug problem during pregnancy. Clin Obstet Gynec 1966;9:623-30.
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32. Schatz M, Zieger RS, Harden K et al. The safety of asthma and allergy medications during
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33. Rayburn WF, Atkinson BD, Gilbert K et al. Short term effects of inhaled albuterol on maternal
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34. Dombrowski M, Thom E, McNellis D. Maternal Fetal Medicine Units (MFMU) studies of inhaled
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37. Chung KF, Barnes PJ. Prescribing in pregnancy. Treatment of asthma. Br Med J 1987;294:103-05.
38. Banatar SR. Anaesthesia for the asthmatic. S Afr Med J 1981;59:409.
39. Kingston HG, Hirshman CA. Perioperative management of the patient with asthma. Anaesth
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40. Oh SH, Patterson R. Surgery in corticosteroid-dependent asthmatics. J Allergy Clin Inmmunol
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41. New York City department of Health. Asthma facts. New York, NY: New York City Department
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42. Rogers L, Cassino C, Berger KL et al.Asthma in the elderly. Cockroach sensitization and severity
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44. Connoly MJ, Crowley JJ, Chatran NB, Nielson CP, Vestel RE. Reduced subjective awareness of
bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as
measure in a simple awareness scale. Thorax 1992;47:410-13.
45. Petheram IS, Jones DA, Collins JV. Assessment and management of acute asthma in the elderly:
a comparison with the younger asthmatic. Postgrad Med J 1982;58:149-52.
46. Allien AC, Prior A. What determines whether an elderly patient can use a metered dose inhaler
correctly? Br J Dis Chest 1986;80:45-59.
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salbutamol in asthma. Thorax 1981;36:523-29.
48. Burge PS, Pantin CF, Newton DT et al. Development of an expert system for the interpretation
of serial peak expiratory flow measurements in the diagnosis of occupational asthma. Midlands
Thoracic Society Research Group. Occup Med 1999;56:758-64.
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and bronchial responsiveness with specific inhalation challenges in occupational asthma. Am
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50. Cartier A, Bernstein IL, Burge PS et al. Guidelines for bronchoprovocation on the investigation
of occupational asthma. Report of the Subcommittee on Bronchoprovocation for Occupational
Asthma. J Allergy Clin Immunol 1989;84:823-29.
51. Stevenson DD, Simon RO: Aspirin sensitivity: Respiratory and cutaneous manifestations, In:
Middleton E, Reed C, Ellis EF et al (Eds): Allergy Principles and Practice, (3rd Ed). St. Louise,
CV Mosby, 1988.
52. Larrin A, Carrasco E, Galleguillos F, Sepulveda R, Pope CE. Medical and surgical treatment of
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New Treatment Modalities/Newer Drugs for Bronchial Asthma 247

15
New Treatment Modalities/Newer
Drugs for Bronchial Asthma
A number of advances had taken place in the management of bronchial asthma and a number
of national and international guidelines have been developed on this regard.1-10 The most
recent one is the British Thoracic Society Guidelines-(2003).11 The main therapy consists of
inhaled 2-agonists, and corticosteroids along with other supplementary drugs. All these
guidelines emphasize that add-on or adjunctive therapies to inhaled corticosteroids,
including long acting 2-agonists and leukotriene antagonists, are clearly a better option for
asthmatic persons receiving lower doses of inhaled corticosteroids than merely increasing
the dose. A number of studies have demonstrated that in patients on moderate doses of
inhaled corticosteroids, addition of a long acting 2-agonist to the regimen is a better option
than merely increasing the dose of inhaled corticosteroids.12 The addition of a long acting 2agonist is also effective in reducing the number and severity of exacerbations.13 Combination
therapy of inhaled corticosteroid and long-acting 2-agonist, salmeterol or formoterol delivered
simultaneously by a single device may be beneficial.14
Although, current asthma therapy is effective and well-tolerated, there are certain
limitations. There are still concerns about side effects of corticosteroids, particularly in children
and in patients requiring very high doses of the drug. Many patients are also reluctant to take
steroids because of the fear of side effects. In general there is a corticophobia in the mind of
many. There are also concerns about the osteoporosis and fracture which is in direct correlation
with the overall drug intake. Inhaled 2-agonists, although effective bronchodilators, there
are concerns about side effects particularly tremor, tachycardia, and tachyphylaxis.
Theophylline, similarly has potentially serious side effects. About ~5% of asthma patients are
steroid-resistant. They do not respond to high doses of corticosteroid therapy. This group of
patients will need some other forms of therapy. Thus, there is a need for the development of
newer drugs for the treatment of asthma.
It is now firmly established about the cellular and mediator basis of the inflammatory
processes in bronchial asthma. This knowledge has been harvested through advancement in
biotechnology, by which new treatment options are being provided.15 Currently, a number of
different therapies are under investigation, and in some stages of clinical trial, which include:
Anti-immunoglobulin E (IgE) antibodies
Soluble interleukin-4 receptors (sIL-4Rs), and
Anti-interleukin-5 antibodies.
The basis of these therapeutic strategies are depicted in Figure 15.1.

248 Bronchial Asthma

Anti-immunoglobulin E (IgE) antibodies-(E25)
Anti-IgE is a specific monoclonal antibody that inhibits IgE activity by binding both to
circulating IgE and to IgE on the surface of B cells.16 However, it does not bind to IgE on the
IgE receptors (both low-affinity and high-affinity types, Fc receptors). They block the
binding of IgE to its receptors on effector cells, like mast cells and basophils, but do not
trigger the activation of these cells. The molecule is nonanaphylactogenic. It forms antiIgE-IgE complexes, which are central to the action of the drug. The maximum demonstrable
size of these complexes is as hexamers, which consist of three molecules of soluble IgE and
three molecules of anti-IgE. Soluble IgE has a half-life of only a few days. The half-life of the
hexamer, on the other hand, is considerably longer, and it acts as a sump for the allergen,
and also has a role in antigen presentation. They lower serum free IgE in rodents and block
passive sensitisation of lung fragments by serum from sensitised individuals.
Humanised version of murine monoclonal anti-IgE antibodies - rhuMab-E25 and CGP
51910- are developed by grafting the variable immunoglobulin region of murine origin
onto a backbone of the constant region of human IgG1.17 This reduced the immunogenicity
of the monoclonal antibody and thus, enabled examination of the role of IgE in human
disease. The safety and efficacy profile of the anti-IgE antibody E25, was studied by
repeated injections of the antibody to allergic human subjects which did not provoke
anaphylaxis and lowered the serum IgE levels by > 99%.18 The treatment also reduced
basophil receptor density and histamine release by > 96% and 90% respectively. The effects
were then examined to see the preventive effect on the allergen provoking
bronchoconstriction. The drug had protective effects on both the early and late responses
to allergen challenges.19,20 E25 treatment also reduced the number of circulating eosinophils
and the increases in bronchial reactivity and in sputum eosinophilia provoked by allergen
challenge. The drug also reduced the eosinophilic-inflammation of the airways provoked
by antigen challenge in sensitised mice.21 The treatment also inhibited production of IL-4
and IL-5.
Antigen

B-cell

IgE

IL-4

Mast cell

Th2

IL-5

Acute symptoms
(early asthma
reaction)

Eosinophil (Late asthma reaction)

Fig. 15.1: Therapeutic basis of anti-IgE antibody, IL-4 and IL-5

New Treatment Modalities/Newer Drugs for Bronchial Asthma 249

The first large scale clinical trial of the efficacy of the humanised, monoclonal anti-IgE
antibody, E25, examined the effects of repeated dosing on the severity of allergic rhinitis,22
and showed beneficial results. When given as regular treatment to patients with moderate
to severe asthma requiring regular treatment with corticosteroids, inhaled or oral, E25
showed safety and efficacy.23 The double blind, prospective study of 317 patients compared
the effects of placebo with that of a low dose E25 (2.5 g /kg/ngIgE/ml) or a high dose E25
(5.8 g /kg/ngIgE/ml) as adjuvant therapy every two weeks for 20 weeks. In both active
IgE treatment groups, serum free IgE dropped rapidly, and remained low throughout the
study period, significantly improved the morning PEFR, quality of life scores, the need for
rescue treatments, and the severity of asthma symptoms. There was a significant reduction
in the reduction in dose for corticosteroid treatment. Apart from a slight increase in urticaria,
adverse events were not more than those in the placebo group. Another large study also
has shown E25 to be effective in adults and children with ragweed allergic rhinitis.24 Other
studies of E25 in adults and asthma with moderate severity confirm the safety and efficacy
in terms of a significant reduction in the frequency of exacerbations as an adjunct or during
tapering off of steroids.25 The above clinical studies, thus shows that the monoclonal antiIgE antibody, E25 treatment, significantly improves asthma, but does not cure asthma.
Development of more selective, apparently safe anti-IgE monoclonal antibody holds great
promise not only as a research tool for defining the role of IgE in health and disease, but
also as a novel therapeutic tool in the treatment of bronchial asthma.
Soluble Interleukin-4 Receptors (sIL-4Rs)
Interleukin-4 plays a number of important roles in the allergic process and is critically
important for the development of allergic inflammation. Important functions include
secretion of IgE by B lymphocytes, induction of VCAM-1 expression on vascular endothelium
in promoting cellular inflammation by which it directs the migration of T lymphocytes,
monocytes, basophils, and especially eosinophils to the site of inflammation. Other
mechanisms of eosinophilic inflammation are increasing eotaxin expression, inhibition of
eosinophil apoptosis, and mucus gene expression and hypersecretion. The most important
of all these is the biological activity of its ability to drive the differentiation of Th-0
lymphocytes into Th-2 cells. It shares a number of activities with IL-13 and because of its
ability to prevent apoptosis of T lymphocytes, it is important in allergic immune responses.
The IL-4 levels are increased in the BAL fluid of allergic individuals, and peripheral blood
mononuclear cells produce IL-4 in response to dust mite antigen. Aerosolised IL-4
significantly increases airway hyper-responsiveness in patients with mild asthma. Further,
there is altered regulation of IL-4 in atopic individuals as well atopic individuals have
higher number of T cells. In view of a wide variety of important contribution of IL-4 in
asthma pathogenesis,26-41 anti- IL-antibody is an important target for asthma therapy.
A soluble IL-4 receptor is currently under investigation for the treatment of bronchial
asthma.40,41 Preclinical studies in mice has shown prevention of the development of allergenspecific IgE and reduction of eosinophilic inflammation. The drug is proved to be safe and
effective in patients of bronchial asthma. In 25 patients of mild to moderate persistent
asthma on inhaled corticosteroid therapy, were randomised to placebo or IL-4R at doses of
0.5 or 1.5 mg once by nebuliser42 and their steroid therapy was discontinued. There was no
side effect of the drug, neither there was development of any antibody. Treatment with

250 Bronchial Asthma

1.5 mg IL-4R resulted in significantly better FEV1 at 2 hrs after treatment, and the
improvement persisted till 2 weeks. Asthma symptom score also improved significantly.
Bronchial reactivity to methacholine was reduced in 6 of the 8 patients tested. Its antiinflammatory effect was obvious by a reduction of exhaled NO scores. In further phase
I/II randomised, double blind, placebo-controlled study in 62 patients with moderately
severe persistent asthma, treatment was given with 0.75, 1.5, or 3.0 mg of IL-4R twice weekly
by nebulisation or placebo administration.43 The steroid inhalation was discontinued. Il-4R
was safe and well tolerated. Antibodies to IL-4R developed in <3% without any symptom.
The results were similar to that of the earlier study.
Thus, it is apparent that IL-4 receptor is potentially a safe and effective treatment for
asthma without the use of corticosteroids. Once-weekly dosing targeting the lungs will
improve patient compliance. Long-term disease progression can be prevented by IL-4 as it
inhibits the central inflammatory process.41
Anti-interleukin-5 Antibodies
Eosinophils are important in the inflammatory pathophysiology of bronchial asthma.
Interleukin-5 is thought to be associated with the late stages of maturation and release of
eosinophils that occur within the bone marrow in different allergic diseases. Two different
monoclonal antibodies against IL-5 in clinical trials have shown that single intravenous
infusion with 2.5 or 10 mg/kg reduced the eosinophil levels to low normal values in the
blood and sputum from patients with asthma, which is maintained up to 4 months. No effect,
however was noticed on bronchial hyperresponsiveness.44 Another study using a single
dose of anti-IL-5 provided only a small increase in FEV1 in noneosinophilic bronchial
asthma.45
Other Cytokine-directed Therapy
a. TNF Antagonism. Based on findings from experimental animals and the presence of elevated
TNF levels in patients with bronchial asthma, there is a rationale for TNF antagonism to be
deployed in asthmatics. TNF seems to play an important role in determining the severity of
asthma. TNF antagonism may be useful in treating cases of severe persistent asthma as
well as acute severe asthma.46
b. Interleukin-13 antagonism. IL-13 plays an important role in the induction of airway hyperreactivity, mucus formation, and airway remodelling in animal models of pulmonary
disease. There is an increased production of IL-13 in atopic and non-atopic asthma, atopic
dermatitis, allergic rhinitis, and chronic sinusitis. Recent human genetic data also show
association of genes of the IL-13 signalling pathway to allergic disease and bronchial
asthma. These findings suggest the possible role of IL-13 antagonists in the treatment of
bronchial asthma.47
c. IL-10 therapy. IL-10 deficiency is associated with several inflammatory diseases like
bronchial asthma and cystic fibrosis. Animal studies have shown that endogenous IL-10
suppresses excessive inflammation in the lung. Clinical studies have shown that
constitutive IL-10 protein concentrations are reduced in BAL fluid from asthmatic
compared to normal subjects and the IL-10 production by monocytes is reduced. The
effect of IL-10 may thus, provide a physiological form of anti-inflammatory therapy.48

New Treatment Modalities/Newer Drugs for Bronchial Asthma 251

d. Antihistamine drugs like H1- antihistamines (cetirizine, terfenadine, loratadine, astemizole,
azelastine, fexofenadine, mizolastine etc.) are useful drugs for associated conditions like
allergic rhinitis. They do not have any direct effect on bronchial asthma.49 Similarly,
H3antihistamines, particularly in combination with H1-antihistamines, are useful for
the treatment of allergic rhinitis. This combination provides a better treatment approach
for allergic nasal congestion without the hypertensive liability of current alpha-adrenergic
agonist decongestive therapy.50
e. Other future targeted therapeutic approaches. Because of the role of a large number of
cytokines and other mediators in the pathophysiology of bronchial asthma, theoretically
there is a wide scope of manipulating these products, which can be used as anti-asthma
therapy. These are
i. Mediator inhibitors and agonists like kinin receptor antagonists, endothelin
antagonists, tachykinin antagonists, selective iNOS inhibitors, mucus regulation,
and P2Y receptor antagonists;
ii. Allergen-and IgE-directed therapy;
iii. T-cell immunomodulation like GATa-3, mycobacterial immunisation, macrocyclic
immunosuppressants;
iv. Chemokine receptor inhibition;
v. Adhesion molecule inhibitors;
vi. Inhibition of cell signalling;
vii. Therapies acting on transcription and
viii. Genetic therapy, which includes antisense therapy, ribozyme therapy and gene
therapy.
f. Vaccines for bronchial asthma. Asthma is not curable by the currently available drugs.
However, some investigators believe that the disease is potentially curable through
strategies that prevent or reverse the immunological abnormalities in atopy. There are
several approaches to reduce the preponderance of Th2 cells in atopy by switching the
balance in favour of Th1 cells. This can be achieved in animals by exposure to bacterial
products such as BCG, Mycobacterium vaccae, or unmethylated cytosine-guanosine
dinucleotidecontaining oligonucleotides (CpG ODN).51-53 This suggests that vaccination
with allergens, immunomodulators and adjuvants may be a future strategy for the
prevention or cure of asthma.54
PDE4 Inhibitors
Phosphodiesterase 4 (PDE4) is present in a number of inflammatory cells responsible for
the development of asthma. One of the mechanisms of action of theophylline for
bronchodilatation is inhibition of PDE4. However, the potency of the drug is relatively
poor at therapeutic concentrations. A number of highly selective PDE4 inhibitors have been
developed to overcome this problem. Phosphodiesterase inhibition increases the intracellular
levels of cyclic AMP, which is important for regulation of cell function.55,56 PDE4 inhibitors
reduce eosinophil survival, inhibit eosinophil chemotaxis, degranulation, adhesion molecule
expression, and leukotriene synthesis. Other functions of PDE4 inhibitors include attenuation
of proliferation of mononuclear cells in atopic individuals and Th1 and Th2 cells. They also
inhibit cytokine generation. Thus, PDE4 inhibition suppresses various characteristic features
of inflammation including recruitment of inflammatory cells to the lungs, airway hyperreactivity, and airway edema.

252 Bronchial Asthma

The drugs of this class include:
Rolipram,
Cilomilast , and
Roflumilast
These drugs suppress various aspects of allergic inflammation. The orally active PDE4
selective inhibitor CDP840 when administered orally for 9.5 days, attenuates the development
of the late asthmatic response in mild asthmatics while showing effect on the acute response
and with no significant side effects.57 The inhibition of the late asthma response is due to their
anti-inflammatory property and not due to bronchodilator action per se. Single oral
administration of the drug is without any significant bronchodilator activity. Hence, it is
suggested that a mixed PDE3/4 inhibitor would seem to be a better option provided that they
have minimal side effects. Another PDE4 inhibitor RP73401 has also no acute effect.58
Roflumilast is more potent than CDP840 acts against late asthma response, suppresses the
development of bronchial hyper-responsiveness following antigen challenge in asthma, and
improves various indices of lung function, and effective in allergic rhinitis.59-61 Cilomilast,
another orally active PDE4 inhibitor attenuates bronchoconstriction following exercise, and
also various features of allergic rhinitis62 and improves various pulmonary function parameters.
The drug is well tolerated up to a dose of 15 mg bid.
Apart from the potential anti-inflammatory action, they perhaps act by suppression of
neural reflexes by suppressing neuropeptide release from sensory C-fibres and inhibition of
bronchoconstriction by vagal nerves. The major side effect of this class of drugs is
gastrointestinal disturbances.63
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256 Bronchial Asthma

16
New Guidelines for
Asthma Management
(Non-pharmacological Management)
The British Thoracic Society has recommended the new guidelines for the management of
bronchial asthma in 2003.1 The first British Guidelines on Asthma Management in adults
were first published in 1990 after a joint initiative between the Thoracic Society, the Royal
College of Physicians of London, the Kings Fund Center, and the National Asthma
Campaign. These were updated in 1993 when the addition of childhood asthma and further
updated in 1995. Simultaneously Guidelines were also developed by the American
Physicians, by the Global Initiative for Asthma (GINA), the International Consensus Report
and the WHO. These guidelines are already discussed earlier.2-12 The Scottish Intercollegiate
Guidelines Network (SIGN) published its first asthma guidelines in 199613 and has
subsequently published on primary care management of asthma in 199814 and management
of acute asthma in 1999.15 Further, both the British Thoracic Society and the SIGN have
recognised the need to update their asthma guidelines, using evidence-based methodology
to cover all aspects of asthma care. The two organisations jointly produced the
comprehensive new guideline, which was strengthened by collaboration with the National
Asthma Campaign, the Royal College of Physicians of London, the Royal College of
Paediatrics and Child Health, General Practice Airways Group, and the British Association
of Accident and Emergency Medicine. The outcome is the new British Guideline on the
Management of Asthma.1
One important and new feature in this new guideline is the levels of evidence and grades
of recommendations used in these guideline. The panel of experts have taken into account
the evidence-based medicine, a more scientific way of expressing a particular conclusion .16
However, it is emphasised that the grade of recommendation relates to the strength of the
evidence and not necessarily the clinical importance of the recommendation in patient
management. Where there are only low grade recommendations in important clinical areas,
this should be seen as a stimulus for further research. The recommendations levels are
graded into 8 subtypes (1++, 1+, 1-, 2++, 2+, 2-, 3, and 4) depending on whether the inference
from high-level meta-analyses, systemic review of randomised controlled-trials (RCTs),
RCTs with a very low-risk of bias, well-conducted meta-analysis, systemic reviews, RCTs
with low-risk bias, meta-analyses, systemic reviews, or RCTs with high-risk of bias, High
quality systemic reviews of case-control or cohort studies, High quality case control or

New Guidelines for Asthma Management (Non-pharmacological Management) 257

cohort studies with a very low-risk of confounding or bias or a high probability that the
relationship is causal, well conducted case control or cohort studies with low-risk of
confounding or bias and a moderate probability that the relationship is causal, case control
or cohort studies with a high-risk of confounding or bias and a significant risk that the
relationship is not causal, non-analytical studies like case reports, case series, and expert
opinion. The grades of recommendations are from A-D depending on the levels of evidence.
Good practice points are also given based on clinical experience of the guideline development
group.
NON-PHARMACOLOGICAL MANAGEMENT
There is increasing interest in factors which, if avoided might facilitate the management of
asthma, reducing the requirement for pharmacotherapy, and which may have the potential
to modify fundamental causes of asthma. However, evidence has been difficult to obtain
for many approaches and more studies are required.
Primary Prophylaxis
Primary prophylaxis is employed before there is any evidence of disease in an attempt to
prevent its onset. A number of potential strategies are suggested.

Allergen Avoidance
There is a strong correlation between allergic sensitisation to common aeroallergens and
the subsequent development of asthma. There is also a strong association between allergen
exposure in early life and sensitisation to these allergens, although it has not been possible
to demonstrate an association between allergen exposure and the development of asthma.
Majority of allergen avoidance studies focus on dietary manipulation to prevent atopic
eczema and have paid little attention to aeroallergen avoidance. Two trials in progress are
investigating the consequences of introducing house dust mite reduction in early pregnancy,
and are following up the children born to the participating mothers. Although accurate
asthma phenotyping is not possible in infancy, outcomes at one year of age indicate a modest
but significant reduction in wheezing illnesses.
Allergen avoidance after birth has been studied in a number of controlled (but no double
blind) trials. There appears to be a transient reduction in the prevalence of atopic eczema
in the first two years of life but no evidence of sustained benefit in relation to asthma. A
number of epidemiological studies suggest that close contact with a cat or dog in very early
infancy reduced subsequent prevalence of allergy and asthma. This may be a consequence
of high allergen exposure inducing tolerance.
However, no recommendations on prenatal or postnatal allergen avoidance can be made
in relation to primary prevention of asthma.

Breastfeeding
A systematic review and meta-analysis involving 8183 subjects followed for a mean of four
years revealed a significant protective effect of breastfeeding against the development of
asthma. The effect was greatest in children with a family history of atopy. In contrast, a
more recent study in 1246 patients found that breastfeeding was associated with a reduced

258 Bronchial Asthma

risk of infant wheeze, but also with an increased risk of asthma at six years. Thus, breastfeeding should be encouraged and its benefits include a protective effect in relation to early
life wheezing.

Modified Infant Milk Formulae

Trials of modified milk formulae using partial and extensive hydrolysates of whey or casein
or soy formulae compared with conventional formulae have not shown any consistent
significant long-term benefits in relation to asthma. Variation in study design, intervention
used, co-interventions and outcome definition make meta-analysis problematical.

Other Dietary Modifications

Limited epidemiological evidence suggests that fish oil consumption may protect against
asthma in childhood. Trials of lipid supplementation during pregnancy and postnatally to
prevent atopic disease are in progress.

Microbial Exposure
The hygiene hypothesis suggests that early exposure to microbial products will switch
off allergic responses preventing allergic diseases such as asthma. Epidemiological studies
comparing large populations who have or have not had such exposures support the
hypothesis. A double blind placebo trial of the probiotic, lactobacillus CG, reported a reduced
incidence of atopic eczema but no effect on IgE antibody sensitisation. Small sample size
and early outcome age limit the interpretation of this study. In the absence of good quality
intervention studies, no recommendation can be made at present.

Immunotherapy and Primary Prevention

Three observational studies, in over 8000 patients, have shown that immunotherapy in
individuals with a single allergy reduces the numbers subsequently developing new allergies
over a three to four years follow-up compared with contemporaneous untreated controls.
No double blind placebo controlled trials of immunotherapy as primary prevention have
been conduced, and at present immunotherapy cannot be recommended for primary
prevention. Preliminary results from an ongoing parallel group study using contemporaneous untreated children as the control group for pollen immunotherapy in children
with allergic rhinitis suggest a lower rate of onset of asthma in the treated group.

Avoiding Pollutants
No evidence was found to support a link between exposure to environmental tobacco smoke
and other air pollutants and the induction of atopic asthma. An early meta-analysis suggested
an association between gas cooking and respiratory illness, but this has not been brought
out in larger studies. Increased risk of infant wheeze is associated with smoking during
pregnancy and maternal postnatal smoking. Pregnancy smoking affects an infants airway
function, increasing susceptibility to wheeze. There are many other adverse effects on the
young child of such exposures.

Pharmacotherapy
There are some pharmacological trials of treatments designed to prevent onset of the disease.
Children given ketotifen (206 infants, in two trials) showed significantly less asthma at one

New Guidelines for Asthma Management (Non-pharmacological Management) 259

and three years follow-up compared with those receiving placebo. In the third study, using
cetirizien, 18 months treatment had no effect in the intention to treat population but
significantly reduced asthma in children with atopic dermatitis sensitised to either grass
pollen or house dust mite. Cetirizien had additional benefits for atopic dermatitis alone and
reduced the frequency of urticaria.
Secondary Prophylaxis

Allergen Avoidance
Allergen avoidance measures may be helpful in reducing the severity of existing disease.
Increasing allergen exposure in sensitised individuals is associated with an increase in asthma
symptoms, bronchial reactivity and deterioration in lung function. Treatment requirements,
hospital attendance and respiratory arrest are associated with increased exposure to high
concentrations of indoor allergens.
Threshold concentrations of allergens that can be regarded as risk factors for acute attacks
include:
10 g/g dust of group l mite allergen
8 g/g dust of Fel d l, the major cat allergen
10 g/g dust of Can f l, the major dog allergen
8 g/g dust of cockroach allergen.
Evidence that reducing allergen exposure can reduce morbidity and mortality is tenuous.
In uncontrolled studies, children and adults have both shown benefit from exposure to a very
low allergen environment. However, the benefits in such circumstances cannot be necessarily
attributed to the allergen avoidance.

House dust mite control measures There have been two Cochrane reviews on house dust
mite control measures and the management of asthma. The first concluded that current
chemical and physical methods were ineffective and could not be recommended as
prophylactic treatment for asthma patients with sensitivity to house dust mites. An amendment
concluded that physical reduction methods may reduce asthma symptoms. The reviewed
studies used various chemical, physical or combinations of methods to reduce mite exposure.
The combined meta-analysis showed no difference in improvement in asthma between patients
in experimental groups compared with controls. There was heterogeneity between studies
with regard to intervention, and in some studies intervention allocation was not adequately
concealed. Larger and more carefully controlled studies are required to demonstrate any clear
benefit from house dust mite avoidance. At present, this does not appear to be a cost-effective
method of achieving benefit.
In committed families with evidence of house dust mite allergy and who wish to try mite
avoidance, the following are recommended.
Complete barrier bed covering systems
Removal of carpets
Removal of soft toys from bed
High temperature washing of bed linen
Acaricides to soft furnishings
Dehumidification

260 Bronchial Asthma

Other allergens Animal allergens, particularly cat and dog, are a potent cause of asthma
symptoms. Observational studies have not found that removing a pet from a home improves
asthma control. In a study in adults with cat sensitivity, randomisation to either bedroom air
cleaner and covers for bedding or no active intervention with restriction of cats away from the
bedroom, resulted in no differences between groups with regard to symptoms, peak flow,
lung function of bronchial reactivity. Alternatively, there is a suggestion that maintaining a
high exposure to cat allergen in the domestic environment might actually induce some degree
of tolerance. Many experts still feel that removal of pets from the home of individuals with
asthma who also have an allergy to that pet should be recommended. Cockroach allergy is not
a common problem in some countries like UK, but important in some other areas. There is no
conclusive evidence regarding the impact of cockroach allergen reduction on asthma
symptoms. Although fungal exposure has been strongly associated with hospitalisation and
increased mortality in asthma, to date no controlled trials have addressed fungal exposure
reduction and asthma.
Environmental Factors
Smoking The association between passive smoking and respiratory health has been
extensively reviewed. There is a direct causal relationship between parental smoking and
lower respiratory illness in children up to three years of age. Infants whose mothers smoke
are four times more likely to develop wheezing illnesses in the first year of life. The
independent contributions of prenatal and postnatal maternal smoking to the development
of asthma in children are difficult to distinguish. Maternal pregnancy smoking has been
shown to have an adverse influence on lung development. There is little evidence that
maternal pregnancy smoking has an effect on allergic sensitisation. Exposure to tobacco
smoke in the home contributes to the severity of childhood asthma. A US Institute of
Medicine review identified a causal relationship between environmental tobacco smoke
(ETS) exposure and exacerbations of asthma in pre-school children. Average exposure is
associated with a 30% increased risk of symptoms. One small study suggests that by stopping
smoking, parents decrease the severity of asthma in their children. Parents who smoke
should be advised about the dangers for themselves and their children and offered
appropriate support to stop smoking.
Starting smoking as a teenager increases the risk of persisting asthma. Only one study
was identified that examined the incidence of asthma related to taking up smoking. This
showed a relative risk of 2.1 for the development of asthma over six years in 14 years old
children who have started to smoke. No studies were identified that directly related to the
question of whether smoking affects asthma severity. One controlled cohort study suggested
that exposure to passive smoke at home delayed recovery from an acute asthma attack.
Studies of interventions designed to reduce environment tobacco smoke exposure in the
home have been largely ineffective in reducing the degree of exposure and none were
designed with primarily clinical (as opposed to smoking outcomes. In one observational
study giving up smoking in adults was associated with improved severity of asthma scores.
Smoking cessation should be encouraged as it is good for general health and may decrease
asthma severity.
Air pollution There is evidence that changing from a high particulate sulphur dioxide
(coal burning) environment to a low sulphur dioxide/high diesel particulate environment

New Guidelines for Asthma Management (Non-pharmacological Management) 261

increases the incidence of asthma and atopy. In the UK, asthma is more prevalent in 12-14
years olds in non-metropolitan rather than metropolitan areas. However, many differences
between environments might explain the variation in asthma and allergy risk. There is
some laboratory evidence that various pollutants can enhance the response of patients with
asthma to allergens, but there is no firm epidemiological evidence that this has occurred in
the UK or elsewhere.
Time series studies suggest that air pollution may provoke acute asthma attacks or
aggravate existing chronic asthma, although the effects are minimal in comparison with
factors such as infection. The short-term fluctuations in levels of air pollution currently
encountered in the UK may be responsible for small changes in numbers of hospital
admissions and emergency attendances for asthma.
No evidence was identified regarding asthma and indoor air pollutants, such as volatile
organic compounds, formaldehyde or nitrogen oxides. Further research in this area is
required.
Complementary and Alternative Medicine

Herbal and Traditional Chinese Medicine

Currently available evidence does not allow any firm judgment to be made on herbal
remedies in general or individual preparations in particular. Seventeen trials were identified
but the combined results are inconclusive. Nine of the 17 trials reported some improvement
in lung function, but it is not clear that the results reported would be generalised.

Acupuncture
A Cochrane review of 21 trials raised many methodological concerns. Only seven trials
(174 patients) achieved randomisation to active (i.e. recognised in traditional Chinese
medicine to be of benefit in asthma) or sham acupuncture (i.e. points with no recognised
activity) for the treatment of persistent or chronic asthma. Binding was a common problem,
and only achieved for those making the observations. The difficulty in making sham
acupuncture convincing and part of the holistic approach of traditional Chinese medicine
was emphasised. There was wide inconsistency in methodology. Acute trials show that
acupuncture has a beneficial effect, but this is less in magnitude than that achieved by
inhaled bronchodilators or cromones. Demonstrating that this effect can be transferred to
persistent asthma using regular treatment was achieved in one RCT reported in the Cochrane
review. The Cochrane review found no evidence for a clinically valuable benefit from
acupuncture, with no statistically significant improvement in lung function being demonstrated. More rigorous research methodology and attention to outcomes other than lung
function are required.

Air Ionisers
Ionisers are widely advertised and marketed as being of benefit to patients with asthma,
however, there is no evidence that they are of value in ameliorating the symptoms of asthma
or improving lung function. They do reduced mite allergen levels in the room in which
they are used, and could be incorporated into a coordinated allergen avoidance programme,
but this has not been formally tested. One study has raised concerns that ionisation may

262 Bronchial Asthma

produce an increase in nocturnal cough. The use of ionisers cannot be encouraged, as there
is no evidence of benefit and a suggestion of adverse effect.

Homeopathy
A Cochrane review identified only three methodologically sound randomised controlled
trials. In the first trials (24 patients), homeopathy improved symptom scored and forced vital
capacity (FVC) but had no effect on FEV1 or bronchial reactivity. The second study
demonstrated improvements in both active and placebo groups. The third, poorly reported,
trial demonstrated an increase in lung function in patients receiving the active preparation.
There is insufficient information regarding the value of homeopathy in the treatment of
asthma. Large well designed trials using defined remedies and a spectrum of patients are
warranted.

Hypnosis
Studies of hypnosis in patients with asthma are generally poorly controlled and patient
characteristics and outcome measured vary enormously. The conclusions from a critical
review were that hypnosis may be effective for asthma with the biggest effect in susceptible
subjects, but more randomised and appropriately controlled studies are required.

Manual Therapy including Massive and Spinal Manipulation

A Cochrane review identified four relevant randomised controlled trials. The two trials of
chiropractice suggest that there is no place for this modality of treatment in the management
of asthma. No conclusions can be drawn on massage therapy.

Physical Exercise Training

A Cochrane review has shown no effect of physical training on PEF, FEV1, FVC or VEmax.
However, oxygen consumption, maximum heart rate, and work capacity all increased
significantly. Most studies discussed the potential problems of exercise-induced asthma,
nut none made any observations on this phenomenon. As physical training improves indices
of cardiopulmonary efficiency, it should be seen as part of a general approach to improving
lifestyle and rehabilitation in asthma, with appropriate precautions advised about exerciseinduced asthma.

Breathing Exercise Including Yoga and Buteyko

The underlying principle of Yoga and Buteyko is to reduce hyperventilation by lowering
respiratory frequency. A Cochrane review found no change in routine measures of lung
function. Two studies reported a reduction in use of medication, and two a reduced
frequency of attacks. At present it is not possible to make an evidence-based recommendation
about breathing exercises for asthma.

Family Therapy
A Cochrane review identified two trials, in 55 children showing that family therapy may be
a useful adjunct to medication in children with asthma. Small study size limits the
recommendations.

New Guidelines for Asthma Management (Non-pharmacological Management) 263

Dietary Manipulation

Minerals
Low magnesium intakes have been associated with higher prevalence of asthma. An
intervention study of magnesium supplementation has suggested a reduced rate of bronchial
hyperresponsiveness and wheeze. Studies of sodium and antioxidant supplements such as
selenium and vitamin C have produced little or no evidence of benefit amongst patients with
asthma.

Fish Oils and Fatty Acids

In vitro studies suggest that supplementing diet with the omega n-3 fatty acids found
predominantly in fish oils might reduce the inflammation associated with asthma. Controlled
clinical studies in small numbers have on the whole been negative, with a Cochrane review
concluding that there was little evidence to recommend fish oil supplements in asthma.
Weight Reduction in Obese Patients with Asthma
A small randomised parallel group study has shown improved asthma control following
weight reduction in obese patients with asthma.
REFERENCES
1. New British Guidelines on Management of Asthma. Thorax 1993;58(Suppl 1):1-94.
2. Guidelines for the Management of Asthma in Adults. 1-Chronic persistent asthma. Statement
by the British Thoracic Society, Research Unit of the Royal College of Physicians of London,
Kings Fund Center, National Asthma Campaign. BMJ 1990;301:651-53.
3. Guidelines for the Management of Asthma in Adults. 2-Acute severe asthma. Statement by the
British Thoracic Society, Research Unit of the Royal College of Physicians of London, Kings
Fund Center, National Asthma Campaign. BMJ 1990;301:797-800.
4. Warner JO, Gotz M, Landau LI, et al. Management of Asthma: A consensus statement. Arch Dis
Child 1989;64;1065-79.
5. International Paediatric Asthma Consensus Group. Asthma, a follow-up statement. Arch Dis
Child 1992;67:240-48.
6. International consensus report on the diagnosis and management of asthma. Clin Exp Allergy
1992;22(Suppl):1-72.
7. British Thoracic Society and others. Guidelines for the management of asthma: A summary.
BMJ 1993;9:287-92.
8. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax
1997;52(Suppl 1): S2-S8.
9. British Thoracic Society, British Paediatric Association, Royal College of Physicians of London,
The Kings Fund Center, National Asthma Campaign, et al. Guidelines on the management of
asthma. Thorax 1993;48:S1-S24.
10. British Thoracic Society, British Paediatric Association, Royal College of Physicians of London,
The Kings Fund Center, National Asthma Campaign, et al. Summary charts. BMJ 1993;306:77682.
11. Global Initiative for Asthma. A practical guide for public health officials and health care
professionals. US Department of Health and human services. NIH Publication No.1995;96:3659A,.
12. National Asthma Education and Prevention Program. Expert Panel Report II: Guidelines for the
diagnosis and management of asthma. Bethesda, MD: National Institute of Health. 1997.

264 Bronchial Asthma

13. Scottish Intercollegiate Guidelines Network (SIGN). Hospital inpatient management of acute
asthma attack. SIGN Publication No. 6, Edinburgh, SIGN, 1996.
14. Scottish Intercollegiate Guidelines Network (SIGN). Primary care management of asthma. SIGN
Publication No. 33, Edinburgh, SIGN, 1998.
15. Scottish Intercollegiate Guidelines Network (SIGN). Emergency management of acute asthma.
SIGN Publication No. 38, Edinburgh, SIGN, 1999.
16. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines.
BMJ 2001;323:334-36.

New Guidelines for Asthma Management (Pharmacological Management) 265

17
New Guidelines for
Asthma Management
(Pharmacological Management)
The aims of pharmacological management of asthma are:
The control of symptoms, including nocturnal symptoms and exercise-induced asthma
Prevention of exacerbations
Achievement of best possible pulmonary function
With minimal side effects.
It is not appropriate to define a fixed level of lung function or symptom control which
must be achieved, as individual patients will have different goals and may also wish to
balance these aims against the potential side effects or inconvenience of taking the medication
necessary to achieve perfect control. In general terms, control of asthma is assessed against
these standards:
Minimal symptoms during day and night
Minimal need for reliever medication
No exacerbations
No limitation of physical activity
Normal lung function (in practical terms FEV1 and/or PEF>80% predicted or best)
A stepwise approach aims to abolish symptoms as soon as possible and to optimise peak
flow by starting treatment at the level most likely to achieve this. Patients should start
treatment at the step most appropriate to the initial severity of their asthma. The aim is to
achieve early control and to maintain control by stepping up treatment as necessary and
stepping down when control is good. Before initiating a new drug therapy practitioners
should check compliance with existing therapies, inhaler technique and eliminate trigger
factors.
All doses of inhaled steroids in this section refer to beclomethasone (BDP) given via a
metered dose inhaler (pMDI). Adjustment may be necessary for fluticasone and/or other
devices.
STEP 1: MILD INTERMITTENT ASTHMA
The following medicines act as short acting bronchodilators:
Inhaled short acting 2-agonists
Inhaled ipratropium bromide

266 Bronchial Asthma

2-agonist tablets or syrup
Theophyllines
Short acting inhaled 2-agonists work more quickly and/or with fewer side effects than the
alternative. An inhaled short acting 2-agonist should be prescribed as short-term reliever therapy for
all patients with symptomatic asthma.
Frequency of Dosing of Inhaled Short Acting 2-Agonists
There is no consistent evidence of any benefit or harm from regular (four times daily) use of
short acting 2-agonists compared with as required (sos) use. Unless individual patients
are shown to benefit from regular use of inhaled short acting 2-agonists, then as required
use is recommended.
Using two or more canisters of 2-agonists per month or > 10-12 puffs per day is a marker
of poorly controlled asthma. Patients with high usage of inhaled short acting 2-agonists
should have their asthma management reviewed.
STEP 2: INTRODUCTION OF REGULAR PREVENTER THERAPY
For steps 2, 3 and 4, treatments have been judged on their ability to improve symptoms,
improve lung function, and prevent exacerbations, with an acceptable safety profile
improvement of quality of life while important is the subject of two few studies to be used
to make recommendations at present.
Inhaled Steroids
Inhaled steroids are the most effective preventer drug for adults and children for achieving
overall treatment goals. They are the recommended preventer drug for adults and children
for achieving overall treatment goals. The threshold for introduction of inhaled steroids
has never been firmly established. There is strong evidence that patients requiring short
acting 2-agonists more than two to three times a day should be treated with inhaled steroids,
but patients with lower inhaler requirements may also benefit. Inhaled steroids should be
started for patients with;
Recent exacerbations,
Nocturnal asthma,
Impaired lung function, or
Use of inhaled 2-agonists more than once a day.

Starting Dose of Inhaled Steroids

In mild to moderate asthma, starting at very high doses of inhaled steroids and stepping
down confers no benefit. Start patients at a dose of inhaled steroids appropriate to the
severity of disease. In adults, a reasonable starting dose will usually be 400 g per day and
in children 200 g per day. In children under 5 years of age, higher doses may be required
if there are problems in obtaining consistent drug delivery. The dose is to be titrated to the
lowest dose at which effective control of asthma is maintained.

Frequency of Dosing of Inhaled Steroids

Current inhaled steroids are slightly more effective when taken twice rather than once
daily. There is little evidence of benefit for dosage frequency more than twice daily. Initially,

New Guidelines for Asthma Management (Pharmacological Management) 267

the inhaled steroids are to be given twice daily. Once a day inhaled steroids at the same total
daily dose can be considered if good control is established.
Safety of Inhaled Steroids
The safety of inhaled steroids is of crucial importance and a balance between benefits and
risks for each individual needs to be assessed. Account should be taken of other topical
steroid therapy when assessing systemic risk. There is little evidence that doses below 800 g
day cause any short-term detrimental effects apart from the local side effects of dysphonia
and oral candidiasis. However, the possibility of long-term effects on bone has been raised.
Cross-sectional studies have shown possible dose related reduction in bone density. Other
studies have shown effects on adrenocortical function of uncertain significance.
In children, inhaled stereoids of 400 g day of beclomethasone dipropionate or equivalent
may be associated with systemic side effects like growth retardation, and adrenal suppression.
The later may manifest as hypoglycaemic episodes. The smallest dose of inhaled steroids
required to maintain adequate asthma control must be used. At higher doses, add-on therapy
like long acting 2-agonists should be considered. The height of the children should be
monitored on a regular basis.
Comparison of Inhaled Steroids
Many studies comparing different inhaled steroids are of inadequate design and have been
omitted from further assessment. In view of the clear differences between normal volunteers
and asthma patients in the absorption of inhaled steroids, data from normal volunteers have
not been taken into account. Only studies in which more than one dose of at least one of the
inhaled steroids or both safety and efficacy has been studied together in the same trial were
evaluated. Non-blinded studies also has to be considered because of the problems of obtaining
competitors delivery devices. All comparison used BDP-CFC (chlorofluoro-carbons) as the
reference.
Beclomethasone dipropionate (BDP) and budesonide are approximately equivalent in
clinical practice although there may be variations with different delivery devices. There is
limited evidence from two open studies of less than ideal design that budesonide via the
turbohaler is more clinically effective. However, at present a 1:1 ratio should be assumed
when changing between BDP and budesonide. Fluticasone provides equal clinical activity to
BDP and budesonide at half the dosage. The evidence that it causes fewer side effects at doses
with equal clinical effect is limited.
Other Preventive Therapies
Inhaled steroids are the first choice preventive drugs. Alternative, less effective preventive
therapies in patients taking short acting 2-agonists alone are:
Cromones (have an inconvenient dosing frequency).
Sodium cromoglycate is ineffective in children.
Nedocromil sodium is of benefit in 5-12 years old.
Leukotriene receptor antagonists have some beneficial effect (side effects are common and
monitoring of plasma levels is required).
Long acting inhaled 2-agonists have some beneficial effects but they are not recommended
as first line preventive therapy.
Antihistamines and ketotifen are ineffective.

268 Bronchial Asthma

STEP 3: ADD-ON THERAPY
Before initiating a new drug therapy one should recheck compliance, inhaler technique and
eliminate trigger factors. The duration of a trial of add-on therapy will depend on the desired
outcome. For instance, preventing nocturnal awakening may require a relatively short trial of
treatment (days or weeks), whereas preventing exacerbations of asthma or decreasing steroid
tablet use may require a longer trial of therapy (weeks or months). If there is no response to
treatment the drug should be discontinued.
CRITERIA FOR INTRODUCTION OF ADD-ON THERAPY
No exact dose of inhaled steroid can be determined, the correct dose at which to add another
therapy. The addition of other treatment options to inhaled steroids has been investigated
at doses from 200-1000 g in adults and up to 400 g in children. Many patients will benefit
more from add-on therapy than from increasing inhaled steroids above doses as low as
200 g/day. Furthermore, at doses of inhaled steroid above 800 g/day side effects become
more frequent. An absolute threshold for introduction of add-on therapy in all patients
cannot be defined. Thus, one should carry out a trial of other treatment before increasing
the inhaled steroid dose above 800 g/day in adults and 400 g/day in children.
Add-On Therapy
Option for add-on therapy are summarised in Figure 17.1. In adult patients taking inhaled
steroids at doses of 200-800 g/day and in children taking inhaled steroids at a dose of
400 g/day the following interventions are of value.
First choice would be the addition of an inhaled long acting 2-agonists (LABA), which
improves lung function and symptoms, and decreases exacerbation. The first choice as
add-on therapy to inhaled steroids in adults and children (5-12 years) is an inhaled long
acting 2-agonists. If, as may happen occasionally, there is no response to inhaled long
acting 2-agonist, the LABA should be stopped and the dose of inhaled steroid to be increased
to 800 g/day (adults) or 400 g/day (children) if not already on this dose. If there is a
response to LABA, but control remains poor, one should continue with the LABA and
increase the dose of inhaled steroid to 800 g/day (adults) or 400 g/day (children 5-12
years).
Leukotriene receptor antagonists provide improvement in lung function, a decrease in
exacerbations, and an improvement in symptoms.
Theophylline improves lung function and symptoms, but side effects occur more
commonly.
Slow release 2-agonists tablets also improve lung function and symptoms, but side effects
occur more commonly.
If control is still inadequate after a trial of LABA and after increasing the dose of inhaled
steroid, one may consider a sequential trial of add-on therapy, i.e. leukotriene receptor
antagonists, theophyllines, slow release 2-agonist tablets in adults.
Addition of anticholinergics is generally of no value. Addition of cromones is of marginal
benefit. In patients on inhaled steroids whose asthma is stable, no intervention has been
consistently shown to decrease inhaled steroid requirement in a clinically significant manner
compared to placebo.

New Guidelines for Asthma Management (Pharmacological Management) 269

Inadequate control on lowdose inhaled steroids
Add inhaled long-acting 2agonist (LABA)
Assess control of asthma
Good response to LABA and
good control:
Continue LABA

Benefit from LABA, but control still

inadequate:
Continue LABA and
Increase inhaled steroid dose to
800 g/day (adults) and 400 g/
day (children, 5-12 years)
If control still inadequate, go
to step 4

No response to LABA:
Stop LABA
Increase inhaled steroid
dose to 800 g / day
(adults) and 400 g/day
(children 5-12 years)
Control still inadequate: Trial of
other add-on therapy, e.g. leukotriene receptor antagonist or
theophylline
If control still inadequate
go to step 4

Fig. 17.1: Summary of step 3: add-on therapy

Combination Inhalers
There is no difference in efficacy in giving inhaled steroid and long acting 2-agonist in
combination or in separate inhalers.
STEP 4: POOR CONTROL ON MODERATE DOSE OF INHALED STEROID +
ADD-ON THERAPY: ADDITION OF FOURTH DRUG
In a small proportion of patients asthma is not adequately controlled on a combination of
as required short acting 2-agonist, inhaled steroid (800 g/day), and an additional drug,
usually a long acting 2-agonist. There are very few clinical trials in this specific patient
group to guide management. The following recommendations are based on extrapolation
from trials of add-on therapy to inhaled steroids and on previous guidelines.
If control remains inadequate on 800 g daily in adults and 400 g/day in children, of an
inhaled steroid plus a long acting agonist, 2-agonist, the following interventions are to be
considered:
Increase the inhaled steroids to 2000 g/day in adults or 800 g/day in children of
5-12 years of age.
Leukotriene receptor antagonists
Theophyllines
Slow release 2-agonist tablets, (caution needs to be taken in patients on long acting
2-agonist)

270 Bronchial Asthma

There is no control trial indicating which of these is the best option. If a trial of an add-on
treatment is ineffective, the drug is to be stopped, or in case of increased dose of inhaled
steroid, the dose is to be reduced to the original dose). Before proceeding to step 5, the physician
should consider referring the patient with inadequately controlled asthma, especially children,
to specialist care.
STEP 5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS
Prevention and Treatment of Steroid Tablet-induced Side Effects
Patients on long-term steroid tablets (e.g. longer than three months) or requiring frequent
courses of steroid tablets (e.g. three to four per year) will be at risk of systemic side effects
Blood pressure should be monitored
Diabetes mellitus may occur
Osteoporosis commonly occurs and should be monitored and treated.
Growth should be monitored in children
Cataracts should be screened for in children
Steroid TabletStarting Medication
The aim of treatment is to control the asthma using the lowest possible dose, or if possible, to
stop long-term steroid tablets completely. Inhaled steroids are the most effective drug for
decreasing requirement for long-term steroid tablets. There is limited evidence for the ability
of long acting 2-agonists, theophyllines, or leukotriene receptor antagonists to decrease the
requirements for steroid tablets, but they may improve symptoms and pulmonary function.
In adults, the recommended method of eliminating or reducing the dose of steroid tablets is
inhaled steroids, at doses of up to 2000 g/day if required. In children of aged 5-12 years,
doses above 1000 g/day should be added cautiously. There is a role for a trial of treatment in
adults with long acting 2-agonists, leukotriene receptor antagonists, and theophyllines for
about six weeks. They should be stopped if no improvement in steroid dose, symptoms or
lung function is detected.
Immunosuppressants (methotrexate, cyclosporin and oral gold) decrease long-term steroid
tablet requirements but all have significant side effects. There is no evidence of persisting
beneficial effect after stopping them; and there is marked variability in response.
Immunosuppressants (methotrexate, cyclosporin and oral gold) may be given as a three month
trial, once other drug treatments have proved unsuccessful. Their risks and benefits should be
discussed with the patient and their side effects carefully monitored. Treatment should be in
a center with experience of using these medicine. Colchicine and intravenous immunoglobulin
have not been shown to have any beneficial effect in adults.
Continuous subcutaneous terbutaline infusion has been reported to be beneficial in severe
asthma but efficacy and safety have not been assessed in randomised controlled trials.
Steroid Formulations
Prednisolone is the most widely used steroid for maintenance therapy in chronic asthma.
There is no evidence that other formulations offer any advantage. Although popular in

New Guidelines for Asthma Management (Pharmacological Management) 271

paediatric practice, there are no studies to show whether alternate day steroids produce fewer
side effects than daily steroids.
-Blockers
-blockers, including eye drops, are contraindicated in patients with asthma.
Stepping Down
Stepping down treatment once asthma is controlled is recommended, but often not
implemented leaving some patients over treated. There is little evidence regarding the most
appropriate way to step down treatment. Regular review of patients as treatment is stepped
down is important. When deciding which drug to step down first and at what rate, the
severity of asthma, the side effects of the treatment, the beneficial effect achieved, and the
patients preference should all be taken into account. Patients should be maintained at the
lowest possible dose of inhaled steroid. Reduction in inhaled steroid dose should be slow as
patients deteriorate at different rates. Reductions should be considered every three months,
decreasing the dose by approximately 25-50% each time.
SPECIFIC MANAGEMENT PROBLEMS
Onset of Exacerbation Asthma
Although, recommended for both adults and children in previous guidelines and as part of
asthma action plants, doubling the dose at the time of an exacerbation is of unproven value.
In adult patients on a low dose (220 g) of inhaled steroids, a five-fold increase in dose at the
time of exacerbation leads to a decrease in the severity of exacerbations. This five-fold increase
should not be extrapolated to higher doses of inhaled steroids.
Exercise-induced Asthma
For most patients exercise-induced asthma is an expression of poorly controlled asthma and
regular treatment including inhaled steroids should be reviewed.
The following medicines give protection against exercise-induced asthma:
Inhaled steroids
Short acting 2-agonists
Long acting 2-agonists
Theophyllines
Leukotriene receptor antagonists
Cromones
2-agonist tablets
The following medicines do not give protection against exercise-induced asthma at normal
doses:
Anticholinergics
Ketotifen
Antihistamines
Long acting 2-agonists and leukotriene antagonists provide more prolonged protection

272 Bronchial Asthma

than short acting 2-agonists, but a degree of tolerance develops with LABA particularly with
respect to duration of action. No tolerance has been demonstrated with leukotriene receptor
antagonists.
If exercise is a specific problem in patients taking inhaled steroids who are otherwise well
controlled, the following therapies are to be considered:
Leukotriene receptor antagonists
Long acting 2-agonists
Cromones `
Oral 2-agonists
Theophyllines
Immediately before exercise, inhaled short acting 2-agonists are the drug of choice.
Rhinitis
Patients with asthma often have rhinitis. The most effective therapy is intranasal steroids.
Treatment of allergic rhinitis has not been shown to improve asthma control.
Allergic Bronchopulmonary Aspergillosis
In adult patients with allergic bronchopulmonary aspergillosis (ABPA), itraconazole may
decrease steroid tablet dose and improve asthma control. In adult patients with ABPA, a
four-month trial of itraconazole should be considered. Careful monitoring of side effects,
particularly hepatic dysfunction, is recommended.
Aspirin Intolerant Asthma
There are theoretical reasons to suggest that leukotriene receptor antagonists might be of
particular value in the treatment of aspirin intolerant asthma. However, there is little
evidence to justify managing patients with aspirin intolerant asthma in a different manner
to patients tolerant of aspirin, apart from the rigorous avoidance of non-steroidal antiinflammatory medications.
NOVEL THERAPIES
Anti-IgE Monoclonal Antibody
In highly selected patients an anti-IgE monoclonal antibody has some beneficial effect, but
its role in the stepwise treatment of asthma is unclear. At present this drug does not have a
license in many countries.
Mometasone
Mometasone is a new inhaled steroid and the relatively limited number of studies suggests
it is equivalent to twice the dose of BDP-CFC. The relative safety of mometasone is not fully
established.
Tiotropium Bromide
Tiotropium bromide is a once daily long acting anticholinergic agent. Its value in the treatment
of asthma has not been evaluated.

New Guidelines for Asthma Management (Pharmacological Management) 273

STEP5: CONTINUOUS OR
FREQUENT USE OF ORAL
STEROIDS
Use daily steroid tablet in lowest dose
providing adequate control

Maintain high dose inhaled

steroid of 2000 g /day

Consider other treatments to

minimize the use of steroid tablets
STEP4: PERSISTENT POOR CONTROL
Consider trials of:

Increasing inhaled steroid up to 2000 g/

day

Addition of a fourth drug, e.g.

leukotriene receptor antagonist, SR
theophylline, 2-agonist tablet

STEP3:
1.
2.

ADD-ON THERAPY
Add inhaled long acting 2-agonist (LABA)

Assess control of asthma:

Good response to LABA continue LABA
Benefit from LABA but control still inadequate
continue LABA and increase inhaled steroid
dose to 800 g /day (if not already on this dose)
No response to LABA-stop LABA and increase
inhaled steroid to 800 g /day
if control still inadequate, institute trial of other
therapies, e.g. leukotriene receptor antagonist or
SR theophylline

STEP2: REGULAR PREVENTER THERAPY

Add inhaled steroid 200-800 g /day ;

400 g /day is an appropriate starting dose in many patients

Start at dose of inhaled steroids appropriate to severity

STEP1: MILD INTERMITTENT ASTHMA

Inhaled short acting 2-agonist as required

Inhaled steroids indicate beclomethasone dipropionate or equivalent

Step care management of bronchial asthma in adults.

274 Bronchial Asthma

STEP5: CONTINUOUS OR FREQUENT

USE OF ORAL STEROIDS
Use daily steroid tablet in lowest dose
providing adequate control

Maintain high dose inhaled steroid of

800 g /day

Refer patient for specialist care

STEP4: PERSISTENT POOR CONTROL

Consider trials of:

Increase inhaled steroid up to 800 g/

day

STEP3:
1.
2.

ADD-ON THERAPY
Add inhaled long acting 2-agonist (LABA)
Assess control of asthma:
Good response to LABAContinue LABA
Benefit from LABA but control still inadequate

continue LABA and increase inhaled steroid

dose to 400 g /day (if not already on this dose)
No response to LABA-stop LABA and increase
inhaled steroid to 400 g /day
if control still inadequate, institute trial of other
therapies, e.g. leukotriene receptor antagonist or
SR theophylline

STEP2: REGULAR PREVENTER THERAPY

Add inhaled steroid 200-400 g /day ;

(Other preventer drugs if inhaled steroid cannot be used)
200 g/day is an appropriate starting dose in many patients
Start at dose of inhaled steroids appropriate to severity

STEP1: MILD INTERMITENT ASTHMA

Inhaled short acting 2-agonist as required

Inhaled steroids indicate beclomethasone dipropionate or equivalent

Step care management of bronchial asthma in children, aged 5-12 years.

New Guidelines for Asthma Management (Pharmacological Management) 275

STEP4: PERSISTENT POOR CONTROL

Refer to Paediatrician with

respiratory specialization

STEP 3: ADD-ON THERAPY

In children aged 2-5 years consider trial of leukotriene

receptor antagonist
In children under 2 years consider proceeding to Step 4.

STEP
2: REGULAR PREVENTER THERAPY
Add inhaled steroid 200-400 g/day ; or
Leukotriene receptor antagonist if inhaled steroid cannot be used
Start at dose of inhaled steroids appropriate to severity

STEP
1: MILD INTERMITTENT ASTHMA
Inhaled short acting 2-agonist as required

Inhaled steroids indicate beclomethasone dipropionate or equivalent. Higher nominal doses may
be required if drug delivery is difficult.
Step care management of bronchial asthma in children less than 5 years.

276 Bronchial Asthma

18
New Guidelines for
Asthma Management
(Acute Asthma)
Confidential enquires into over 200 asthma deaths in the UK have concluded that three
important factors associated with the diseasethe medical management and the patients
behaviour or psychosocial status-contributed to the death. Most deaths occurred before
admission to hospital.

Disease Factors
Most patients who died of asthma had chronically severe asthma. In a minority the fatal
attack occurred suddenly in a patient with only mild or moderately severe background
disease.

Medical Management
Many of the deaths occurred in patients who had received inadequate treatment with inhaled
steroid or steroid tablets and/or inadequate objective monitoring of their asthma. Follow
up was inadequate in some and others should have been referred earlier for specialist advice.
There was widespread underuse of written management plans. Heavy or increasing use of
2-agonist therapy was associated with asthma death.
Deaths have continued to be reported following inappropriate prescription of -blocker
therapy or heavy sedation. A small proportion of patients with asthma were sensitive to
nonsteroidal anti-inflammatory agents; all asthma patients should be asked about past
reactions to these agents.

Adverse Psychosocial and Behavioural Factors

Behavioural and adverse psychosocial factors were recorded in the majority of patients
who died of asthma. The most important are:
I. A combination of severe asthma:
Previous near fatal asthma, e.g. previous ventilation or respiratory acidosis
Previous admission for asthma especially if in the last year
Requiring three or more classes of asthma medication

New Guidelines for Asthma Management (Acute Asthma) 277

Heavy use of 2-agonist
Repeated attendances at emergency for asthma care especially in the last year
Brittle asthma.
II Adverse behavioural or psychological features:
Non-compliance with treatment or monitoring
Failure to attend appointments
Self-discharge from hospital
Psychosis, depression, other psychiatric illness or deliberate self-harm
Current or recent major tranquilliser use
Denial
Alcohol or drug abuse
Obesity
Learning difficulties
Employment problems
Income problems
Social isolation
Childhood abuse
Severe domestic, marital or legal stress
Case control studies support most of these observations. Compared with control patients
admitted to hospital with asthma, those who died were significantly more likely to have
learning difficulties; psychosis or prescribed antipsychotic drugs; financial or employment
problems; repeatedly failed to attend appointments or discharged themselves from hospital;
drug or alcohol abuse; obesity; or a previous near fatal attack.
Compared with control patients with asthma in the community, patients who died had
more severe disease; more likelihood or a hospital admission or visit to emergency
department for their asthma in the previous year; more likelihood or a previous near fatal
attack; poor medical management; failure to measure pulmonary function; and noncompliance. Health care professionals must be aware that patients with severe asthma and
one or more adverse psychosocial factors are at risk of death.
Studies comparing near fatal asthma with deaths from asthma have concluded that
patients with near fatal asthma have identical adverse factors to those described above,
and that these contribute to the near fatal asthma attack. Compared with patients who die,
those with near fatal asthma are significantly younger, are significantly more likely to have
had a previous near fatal asthma attack, are less likely to have concurrent medical conditions,
are less likely to experience delay in receiving medical care, and more likely to have ready
access to acute medical care.
Not all patients with near fatal asthma require intermittent positive pressure ventilation.
For those with near fatal asthma, adults as well as children, it is always wise to involve a
close relative when discussing future management. Patients with brittle asthma should
also be identified. Patients who have had near fatal asthma or brittle asthma should be kept
under specialise supervision indefinitely.
In the UK there is a peak of asthma deaths in young people (aged up to 44 years) in July
and August and, in December and January in older people, and similar seasonal deaths
might also be true for other countries.

278 Bronchial Asthma

PREDICTION AND PREVENTION OF A SEVERE ASTHMA ATTACK
Most (88-92%) attacks of asthma severe enough to require hospital admission develop
relatively slowly over a period of six hours or more. In one study, over 80% developed over
more than 48 hours. There should therefore be time for effective action and the potential to
reduce the number of attacks requiring hospitalisation. There are many similarities between
patients who die from asthma, patients with near fatal asthma and asthmatic controls who
are admitted to hospital. A respiratory specialist should follow up patients admitted with
severe asthma for at least one year after the admission.
I. ACUTE ASTHMA IN ADULTS
Recognition of Acute Asthma
Definitions of increasing levels of severity of acute asthma exacerbations are as follows:
Near fatal asthma
Raised PaCO2 and/or requiring mechanical ventilation with raised
inflation pressures
Life threatening asthma Any one of the following in a patients with severe asthma:
PEF<33% best or predicted Bradycardia
SpO2<92%
Dysrhythmia
PaO2<60 mmHg
Hypotension
Normal PaCO2 (4.6-6.0 kPa) Exhaustion
Silent chest
Confusion
Cyanosis
Coma
Feeble respiratory effort
Acute severe asthma
Any one of
PEF 33-50% best or predicted
Respiratory rate > 25/min
Heart rate > 100/min
Inability to complete sentences in one breath
Moderate asthma exacerbation
Increasing symptoms
PEF >50-75% best or predicted
No features of acute severe asthma
Brittle asthma
Type 1: Wide PEF variability (> 40% diurnal variation for 50%
of the time over a period > 150 days) despite intense therapy
Type 2: Sudden severe attacks on a background of apparently
well controlled asthma.
Predicted PEF values should be used only if the recent best PEF (within two years) is
unknown.
Self Treatment by Patients Developing Acute or Uncontrolled Asthma
Many patients with asthma and all patients with severe asthma should have an agreed
written action plan and their own peak flow meter, with regular checks of inhaler technique
and compliance. They should know when and how to increase their medication and when

New Guidelines for Asthma Management (Acute Asthma) 279

to seek medical assistance. Asthma action plans have been shown to decrease hospitalisation
for and deaths from asthma.

Initial Assessment
All possible initial contact personnel, should be aware that asthma patients complaining of
respiratory symptoms may be at risk and should have immediate access to a doctor or
trained asthma nurse. The assessments required to determine whether the patients is
suffering from an acute attack of asthma, the severity of the attack and the nature of treatment
required are detailed above as well as follows: It may also be helpful to use a systematic
recording process. Proformas have proved useful in the emergency settings.
Clinical features

Clinical features, symptoms and respiratory and cardiovascular signs

are helpful in recognising some patients with severe asthma, e.g.
severe breathlessness (including too breathless to complete sentences
in one breath), tachypnea, tachycardia, silent chest, cyanosis or
collapse.
None of these singly or together is specific and their absence does not
exclude a severe attack

PEF or FEV1

Measurements of airway caliber improve recognition of the degree

Or severity, the appropriateness or intensity of therapy, and decisions
about management in hospital or at home.
PEF or FEV1 are both useful and valid measures of airway caliber
PEF is more convenient and cheaper.
PEF expressed as a percentage of the patients previous best value is
more useful clinically. PEF as a percentage of predicted gives a rough
guide in the absence of a known previous best value. Different peak
flow meters give different readings. Where possible the same or
similar type of peak flow meter should be used.

Pulse oximetry

Measurement of oxygen saturation (SpO2) with a pulse oxymeter is

necessary in acute severe asthma to determine the adequacy of oxygen
therapy and the need for arterial blood gas (ABG) measurement. The
aim of oxygen therapy is to maintain SpO2 > 92%.

Blood gases (ABG)

Patients with SpO2<92% or other features of the threatening asthma

require ABG measurement.

Chest X-ray

Chest X-ray is not routinely recommended in patients in the absence

of:
Suspected pneumomediastinum or pneumothorax
Suspected consolidation
Life threatening asthma
Failure to respond to treatment satisfactorily
Requirement for ventilation.
Systolic paradox (pulsus paradoxus) has been abandoned as an
indicator of the severity of an attack for pragmatic reasons.

Systolic paradox

280 Bronchial Asthma

Prevention of Acute Deterioration
A register of patients at risk may help primary care health professionals to identify patients
who are more likely to die from their asthma. A system should be in place to ensure that
these patients are contacted if they fail to attend for follow up.

Criteria for Admission

One should refer to a hospital if one comes across any patients with features of acute severe
or life threatening asthma. Other factors, such as failure to respond to treatment, social
circumstances or concomitant disease, may warrant hospital referral.

Criteria for Admission

Patients with any feature of a life threatening or near fatal attack should be admitted. Also
patients with any feature of a severe attack persisting after initial treatment need to be
admitted. Patients whose peak flow is greater than 75% best or predicted one hour after
initial treatment may be discharged from emergency, unless they meet any of the following
criteria, when admission may be appropriate:
Still have significant symptoms
Concerns about compliance
Living alone/socially isolated
Psychological problems
Physical disability or learning difficulties
Previous near fatal or brittle asthma
Exacerbation despite adequate dose steroid tablets pre-presentation
Presentation at night
Pregnancy
Criteria for admission in adults are summarised subsequently.
Treatment of Acute Asthma in Adults

Oxygen
Patients with acute severe asthma are hypoxaemic. This should be corrected urgently using
high concentrations of inspired oxygen (usually 40-60%) and a high flow mask such as a
Hudson mask. Unlike patients with COPD there is little danger of precipitating hypercapnia
with high flow oxygen. Hypercapnia indicates the development of near fatal asthma and
the need for emergency specialist/anaesthetic intervention. Oxygen saturations of at least
92% must be achieved. In view of the theoretical risk of oxygen desaturaion while using air
driven compressors to nebulise 2-agonist bronchodilators, oxygen-driven nebulisers are
the preferred method of delivery in hospitals, ambulances and primary care. (in order to
generate the flow rate of 61/min required to drive most nebulisers, a high flow regulator
must be fitted to the oxygen cylinder). The absence of supplemental oxygen should not
prevent nebulised therapy from being administered where appropriate. In hospital,
ambulance and primary care, nebulised 2-agonist bronchodilators should be driven by
oxygen. Outside hospital, high dose 2-agonist bronchodilators may be delivered via large

New Guidelines for Asthma Management (Acute Asthma) 281

volume spacers or nebulisers. Whilst supplemental oxygen is recommended, its absence
should not prevent nebulised therapy being given if indicated.

2-Agonist Bronchodilators
In most cases of acute asthma, inhaled 2-agonist given in high doses act quickly to relieve
bronchospasm with few side effects. There is no evidence for any difference in efficacy
between salbutamol and terbutaline, although rarely patients may express a preference.
In acute asthma without life threatening features, 2-agonist can be administered by
repeated activations of a pMDI via an appropriate large volume spacer or by wet nebulisation
driven by oxygen, if available. Inhaled 2-agonist are at least as efficacious and preferable
to intravenous 2-agonist (meta-analysis has excluded subcutaneous trials) in adult acute
asthma in the majority of cases. High-dose inhaled 2-agonist are to be used as first line
agents in acute asthma and should be administered as early as possible. Intravenous
2-agonist should be reserved for those patients in whom inhaled therapy cannot be used
reliably.
In acute asthma with life threatening features the nebulised route (oxygen-driven) is
recommended. Parenteral 2-agonists, in addition to inhaled 2-agonist may have a role in
ventilated patients or those patient in extremes in whom nebulised therapy may fail; however
there is limited evidence to support this.
Continuous nebulisation of 2-agonist is at least as efficacious as bolus nebulisation in relieving
acute asthma. Most cases of acute asthma will respond adequately to bolus nebulisation of
2-agonist. In severe asthma (PEF or FEV1 <50% best or predicted) and asthma that is poorly
responsive to an initial bolus dose of 2-agonist, continuous nebulisation may be considered.
Repeated doses of 2-agonist should be given at 15-30 minute intervals or continuous
nebulisation of salbutamol at 5-10mg/hour (requires appropriate nebuliser) used if there is
an inadequate response to initial treatment. Higher bolus doses, e.g. 10 mg of salbutamol,
are unlikely to be more effective.
Steroid Therapy
Steroid tablets reduce mortality, relapses, subsequent hospital admission and requirement
for 2-agonist therapy. The earlier they are given in the acute attack the better the outcome.
Steroid tablets are to be given in adequate doses in all cases of acute asthma. Steroid tablets
are as effective as injected steroids, provided tablets can be swallowed and retained. Doses
of prednisolone of 40-50 mg daily or parenteral hydrocortisone 400 mg daily (100 mg sixhourly) are as effective as higher doses. For convenience, steroid tablets may be given as
2 25 mg tablets daily rather than 8-12 5 mg tablets. The duration of prednisolone
40-50 mg daily is for at least five days or until recovery.
Following recovery from the acute exacerbation steroid tablets can be stopped abruptly
and doses do not need tapering provided the patient receives inhaled steroids (apart from
patients on maintenance steroid treatment or rare instances where steroids are required for
three or more weeks). There is no evidence to suggest that inhaled steroids should be
substituted for steroid tablets in the treatment of patients with acute severe, or life threatening
asthma. Further randomised controlled trials to determine the role of inhaled steroids in
these patients are required. Inhaled steroids do not provide benefit in addition to the initial

282 Bronchial Asthma

treatment, but should be continued (or started as soon as possible) to form the start of the
chronic asthma management plan.

Ipratropium Bromide
Combining nebulised ipratropium bromide with a nebulised 2-agonist has been shown to
produce significantly greater bronchodilation that a 2-agonist alone, leading to a faster
recovery and shorter duration of admission. Anticholinergic treatment is not necessary
and may not be beneficial in milder exacerbations of asthma or after stabilisation.
Nebulised ipratropium bromide (0.5 mg 4-6 hourly) should be added to 2-agonist
treatment for patients with acute severe or life threatening asthma or those with a poor
initial response to 2-agonist therapy.

Intravenous Magnesium Sulphate

A single dose of IV magnesium sulphate has been shown to be safe and effective in acute
severe asthma. The safety and efficacy of repeated doses have not been assessed in patients
with asthma. Repeated doses could give rise to hypermagnesaemia with muscle weakness
and respiratory failure.
Indications of giving a single dose of IV magnesium sulphate for patients are:
Acute severe asthma who have not had a good initial response to inhaled
bronchodilator therapy
Life threatening or near fatal asthma
IV magnesium sulphate (1.2- 2g IV infusion over 20 minutes) should only be used
following consultation with senior medical staff. More studies are needed to determine the
optimal frequency and dose of IV magnesium sulphate therapy.

Intravenous Aminophylline
In acute asthma, the use of intravenous aminophylline is not likely to result in any additional
bronchodilation compared to standard care with inhaled bronchodilators and steroid tablets.
Side effects such as palpitations, arrhythmias and vomiting are increased if IV aminophyline
is used. Intravenous aminophylline is to be used only after consultation with senior medical
staff.
Some individual patients with near fatal asthma or life threatening asthma with a poor
response to initial therapy may gain additional benefit from IV aminophylline (5mg/kg
loading dose over 20 minutes unless on maintenance oral therapy, then infusion of 0.5-0.7
mg/kg/h). Such patients are probably rare and could not be identified in a meta-analysis
of trials involving 739 subjects. If IV aminophylline is given to patients, on oral aminophylline or theophylline, blood levels should be checked on admission. Levels should be checked
daily for all patients on aminophylline infusions.

Leukotriene Receptor Antagonists

There is no published study of the use of leukotriene receptor antagonists in the management
of acute asthma.

New Guidelines for Asthma Management (Acute Asthma) 283

Antibiotics
When an infection precipitates an exacerbation of asthma, it is likely to be viral in type. The
role of bacterial infection has been overestimated. Routine prescription of antibiotics is not
indicated for acute asthma.

Heliox
The use of heliox (Helium/oxygen mixture in a ratio of 80:20 or 70:30) in acute adult asthma
cannot be recommended on the basis of present evidence.

Intravenous Fluids
There are no controlled trials or even observational or cohort studies of differing fluid regimes
in acute asthma. Some patients with acute asthma require rehydration and correction of
electrolyte imbalance. Hypokalaemia can be caused or exacerbated by 2-agonist and/or
steroid treatment must be corrected.

Referral to Intensive Care

Indications for admission to intensive care facilities or a high dependency unit include
patients requiring ventilatory support and those with severe acute or life threatening asthma
who are failing to respond to therapy, as evidenced by:
Deteriorating PEF
Persisting or worsening hypoxia
Hypercapnea
Arterial blood gas analysis showing fail in pH or rising H+ concentration
Exhaustion, feeble respiration
Drowsiness, confusion
Coma or respiratory arrest
Not all patients admitted to the Intensive Care Unit (ICU) need ventilation, but those
with worsening hypoxia or hypercapnea, drowsiness or unconsciousness and those who
have had a respiratory arrest require intermittent positive pressure ventilation. Intubation
in such patients is very difficult and should ideally be performed by an anaesthetist or ICU
consultant. All patients transferred to intensive care units should be accompanied by a
doctor suitably equipped and skilled to intubate if necessary.
Non-invasive Ventilation
Non-invasive ventilation (NIV) is now well established in the management of ventilatory
failure caused by extrapulmonary restrictive conditions and exacerbations of COPD.
Hypercapneic respiratory failure developing during the evolution of an acute asthmatic
episode is regarded as an indication for urgent admission to the ICU. It is unlikely the NIV
would ever replace intubation in these very unstable patients but it has been suggested that
this treatment can be used safely and effectively. Future studies might usefully examine its
role in the gradually training patient, but at present this treatment cannot be recommended
outside randomised controlled trials.

284 Bronchial Asthma

Further Investigation and Monitoring

Measurement and recording of PEF 15-30 minutes after starting treatment, and thereafter
according to the response is necessary. Measurement and recording of PEF before and after
nebulised or inhaled 2-agonist bronchodilator (at least four times daily) throughout the
hospital stay and until controlled after discharge is quite helpful.
Recording of oxygen saturation by oximetry and maintaining arterial SaO2 >92% is very
helpful. Repeat measurements of blood gas tensions within two hours of starting treatment
is indicated if:
The initial PaO2 is < 8 kPa unless SaO2 is >92%; or
The initial PaCO2 is normal or raised; or
The patients condition deteriorates
One should ensure them again if the patients condition has not improved by 4-6 hours.
Measure and record the heart rate.
Measure serum potassium and blood concentrations.
Measure the serum theophylline concentration if aminophylline is continued for more
than 24 hours (aim at a concentration of 55-110 mol/l.
Asthma Management Protocols and Proformas
The use of structured proformas has been shown to facilitate improvements in the process
of case in emergency departments and hospital wards and to improve patient outcomes. The
use of this type of documentation can assist data collection aimed at determining quality of
care and outcomes.
Hospital Discharge and Follow-Up

Timing of Dsicharge
There is no single physiological parameter that defines absolutely the timing of discharge
form an admission with acute asthma. Patients should have clinical signs compatible with
home management, be on medical therapy they can continue safely at home. Although
diurnal variability of PEF is not always present during an exacerbation, evidence suggests
that patients discharged with PEF<75% best or predicted and with diurnal variability >25%
are at greater risk of early relapse and readmission.

Patient Education
Following discharge from hospital or emergency departments, a proportion of patients reattend emergency departments, with more than 15% re-attending within two weeks. Some
repeat attendees need emergency care, but many delay seeking help, and are under-treated
and/or under-monitored. Prior to discharge, trained staff should give asthma education.
This should include education on inhaler technique and PEF record keeping , with a written
PEF and symptom based action plan being provided allowing the patient to adjust their
therapy within recommendations. These measures have been shown to reduce morbidity
after the exacerbation and reduce relapse rates. There is some experience of a discrete
population of patients who inappropriately use emergency departments rather than the
primary care services for their asthma care. For these groups there is a role for a trained
asthma liaison nurse based in, or associated with the emergency department.

New Guidelines for Asthma Management (Acute Asthma) 285

Follow-Up
A careful history should elicit the reasons for the exacerbation and explore possible actions,
the patient should take to prevent future emergency presentations. Medication should be
altered depending upon the assessment, and the patient provided with an asthma action
plan aimed at preventing relapse, optimising treatment and preventing delay in seeking
assistance in the future. Follow-up should be arranged prior to discharge with the patients
general practitioner or asthma nurse within two working days; and with a hospital specialist
asthma nurse or respiratory physician at about one month after admission. It is essential
that the patients primary care practice is informed within 24 hours of discharge from
emergency or hospital following an asthma exacerbation treated in hospital. Ideally this
communication should be directly with a named individual responsible for asthma care
within the practice, by means or fax or e-mail.
ACUTE ASTHMA IN CHILDREN AGED OVER 2 YEARS
Initial Assessment
The details of criteria for assessment of severity of acute asthma attacks in children are:
Acute severe
Cant complete sentences in one breath
Or too breathless to talk or feed

Life threatening

Silent Chest
Cyanosis
Poor respiratory effort
Hypotension
Respiration >30 breaths/min aged>5 yrs
Exhaustion
>50 breaths/min aged 2-5 yrs
Confusion
Coma
Before children can receive appropriate treatment for acute asthma in any setting, it is
essential to assess accurately the severity of their symptoms. The following clinical signs
should be recorded:
Pulse rate (increasing tachycardia generally denotes worsening asthma; a fall in heart
rate in life threatening asthma is a pre-terminal event).
Respiratory rate and degree of breathlessness (i.e. too breathless to complete sentences
in one breath or to feed).
Use of accessory muscles of respiration (best noted by palpation of neck muscles)
Amount of wheesing (which might become biphasic or less apparent with increasing
airways obstruction).
Degree of agitation and conscious level (always give calm reassurance).
Clinical signs correlate poorly with the severity of airways obstruction. Some children
with acute severe asthma do not appear distressed. Objective measurements of PEF and
SpO2 are essential. Suitable equipment should be available for use by all health professionals
assessing acute asthma in both primary and secondary care settings. Low oxygen saturations
after initial bronchodilator treatment selects a more severe group of patients. Intensive
inpatient treatment for children with SpO2 <92% on air after initial bronchodilator treatment
should be considered.
Pulse

>120 in children aged > 5 years

>130 in children aged 2-5 years

286 Bronchial Asthma

Decisions about admission should be made by trained physicians after repeated
assessment of the response to further bronchodilator treatment. A measurement of <50%
predicted PEF or FEV1 with poor improvement after initial bronchodilator treatment is
predictive of more prolonged asthma attack. An attempt has to be made to measure PEF or
FEV1 in all children aged >5 years, taking the best of three measurements; ideally expressed
as percentage of personal best for PEF (as detailed in a written action plan) or alternatively
as percentage of predicted for PEF or FEV1. Chest X-rays and ABG measurements rarely
provide additional useful information and are not routinely indicated.
TREATMENT OF ACUTE ASTHMA IN CHILDREN AGED OVER 2 YEARS
Emergency units attending to children with acute asthma should have a registered sick
childrens nurse available on duty at all times and staff familiar with the specific needs of
children. The use of proformas can increase the accuracy of severity assessment. An
assessment driven algorithm has been shown to reduce treatment costs and hospital stay.
The use of structured care protocols detailing bronchodilator usage, clinical assessment,
and specific criteria for safe discharge is recommended.
Oxygen
Children with life threatening asthma or SpO2 < 92% should receive high flow oxygen via
a tight fitting face mask or nasal cannula at sufficient flow rates to achieve normal saturations.

2-Agonist Bronchodilators
Inhaled 2-agonist are the first line treatment for acute asthma. pMDI + spacer is an effective
alternative to nebulisers for bronchodilator inhalation to treat mild to moderate asthma.
Children receiving 2-agonist via pMDI+ spacer are less likely to have tachycardia and
hypoxia than when the same drug is given via a nebuliser. pMDI+ spacer are the preferred
option in mild to moderate asthma. Information about implementing evidence-based
guidelines using such devices has been published. Children aged < 3 years are likely to
require a face mask connected to the mouthpiece of a spacer for successful drug delivery.
Inhalers should be actuated into the spacer in individuals puffs and inhaled immediately
by tidal breathing. Frequent doses of 2-agonist are safe for the treatment of acute asthma,
although children with mild symptoms benefit from lower doses. Drug dosing is to be
individualised according to severity and adjust according to the patients response.
Two to four puffs repeated every 20-30 minutes according to clinical response might be
sufficient for mild attacks although up to 10 puffs might be needed for more severe asthma.
Children with acute asthma in primary care show have not improved after receiving up to
10 puffs of 2-agonist should be referred to hospital. Further doses of bronchodilator should
be given as necessary, whilst awaiting transfer. Treatment of children should be given before
they are transported to hospital by ambulance with oxygen and nebulised 2-agonist during
the journey. Children with severe or life threatening asthma should be transferred urgently
to hospital to receive frequent doses of nebulised 2-agonist (2.5-5 mg albuterol or 5-10 mg
terbutaline). Doses can be repeated every 20-30, omits. Continuous nebulised 2-agonist
are of no greater benefit than the use of frequent intermittent doses in the same total hourly
dosage.

New Guidelines for Asthma Management (Acute Asthma) 287

IV Salbutamol
The role of intravenous 2-agonist in addition to nebulised treatment remains unclear. One
study has shown that an IV bolus of salbutamol given in addition to near maximal doses of
nebulised salbutamol results in clinically significant benefits. The early addition of a bolus
dose of intravenous salbutamol (15 g/kg) can be an effective adjunct to treatment in severe
cases. Continuous intravenous infusion should be considered when there is uncertainty
about reliable inhalation or for severe refractory asthma. Doses above 1-2 g/kg/min
(200 g/ml solution) should be given in a Paediatric intensive Care Unit (PICU) setting (up
to 5 g/kg/min) with regular monitoring of electrolytes.
Steroid Therapy

Steroid Tablets
The early use of steroids for acute asthma can reduce the need for hospital admission and
prevent a relapse in symptoms after initial presentation. Benefits can be apparent within
three to four hours. Prednisolone is to be given early in the treatment of acute asthma
attacks. A soluble preparation dissolved in a spoonful of water is preferable in those unable
to swallow tablets. The dose is 20 mg for children 2-5 years old and 30-40 mg for children
> 5 years. Oral and intravenous steroids are of similar efficacy. Intravenous hydrocortisone
(4 mg/kg repeated four hourly) should be reserved for severely affected children who are
unable to retain oral medication. Larger doses do not appear to offer a therapeutic advantage
for the majority of children. There is no need to taper the dose of steroid tablets at the end
of treatment. A dose of 20 mg prednisolone for children aged 2-5 years and a dose of
30-40 mg for children > 5 years is appropriate. Those already receiving maintenance steroid
tablets should receive 2 mg/kg prednisolone up to a maximum dose of 60 mg. The dose of
prednisolone in children who vomit may be repeated and intravenous steroids in those
who are unable to retain orally, ingested medication should be considered. Treatment for
up to three days is usually sufficient but the length of course should be tailored to the
number of days necessary to bring about recovery.

Inhaled Steroids
There is insufficient evidence to support the use of inhaled steroids as alternative or
additional treatment to steroid tablets for acute asthma. One need not initiate inhaled steroids
in preference to steroid tablets to treat acute childhood asthma. Children with chronic asthma
not receiving regular preventive treatment will benefit from initiating inhaled steroids as
part of their long-term management. There is no evidence that increasing the dose of inhaled
steroids is effective in treating acute symptoms, but it is good practice for children already
receiving inhaled steroids to continue with their usual maintenance doses.

Ipratropium Bromide
There is good evidence for the safety and efficacy of frequent doses of ipratropium bromide
used in addition to 2-agonist for the first two hours of a severe asthma attack. Benefits are
more apparent in the most severe patients. If symptoms are refractory to initial 2-agonist
treatment, add ipratropium bromide (250 mg/dose mixed with the nebulised 2-agonist

288 Bronchial Asthma

solution). Frequent doses up to every 20-30 minutes (250 g/dose mixed with the 2-agonist
solution in the same nebuliser) should be used early. The dose frequency should be reduced
as clinical improvement occurs. Repeated doses of ipratropium bromide should be given
early to treat children poorly responsive to 2-agonist. Children with continuing severe
asthma despite frequent nebulised 2-agonist and ipratropium bromide and those with
life-threatening features need urgent review by a specialist with a view to transfer to a
High Dependency Unit or PICU.

IV Amniophylline
There is no evidence that aminophylline is of benefit for mild to moderate asthma and side
effects are common and troublesome. However, one well conducted study has shown
evidence for benefit in severe acute asthma unresponsive to multiple doses of 2-agonist
and steroids. Aminophylline is not recommended in children with mild to moderate acute
asthma. However, one may consider aminophylline in a High Dependency Unit or PICU
setting for children with severe or life-threatening bronchospasm unresponsive to maximal
doses of bronchodilators and steroid tablets. A 5 mg/kg loading dose should be given over
20 minutes with ECG monitoring (omit in those receiving maintenance oral theophyllines)
followed by a continuous infusion at 1 mg/kg/hour. Estimation of serum theophylline
levels in patients already receiving oral treatment and in those receiving prolonged treatment
will be necessary.
Other Therapies
There is no evidence to support the use of heliox or leukotriene receptor antagonists for the
treatment of acute asthma in childhood. There is insufficient evidence to support or refute
the role of antibiotics in acute asthma, but the majority of acute asthma attacks are triggered
by viral infection.
Antibiotics are not to be given routinely in the management of acute childhood asthma.

Intravenous Fluids
Children with prolonged severe asthma not tolerating, oral fluids will require intravenous
hydration. Two-third of the childs maintenance requirement should be given because of
the possibility of inappropriate antidiuretic hormone secretion. Serum electrolytes should
be measured and hypokalamia corrected, if detected. ECG monitoring is mandatory for all
intravenous treatments.

IV Magnesium Sulphate
Intravenous magnesium sulphate is a safe treatment for acute asthma although its place in
management is not yet established. Doses of up to 40 mg/kg/day (maximum 2g) by slow
infusion has been used. Studies of efficacy for severe childhood asthma unresponsive to
more conventional therapies have been inconsistent in providing evidence of benefit.

Further Investigation and Monitoring

Children can be discharged when stable on 3-4 hourly inhaled bronchodilators that can be
continued at home. PEF and/or FEV1 should be >75% of best or predicted and SpO2>94%.

New Guidelines for Asthma Management (Acute Asthma) 289

Adult studies show that optimal care comprising self-monitoring, regular review and
a written asthma action plan can improve outcomes. Acute asthma attacks should be
considered a failure of preventive therapy and thought should be given about how to help
families avoid further severe episodes. Discharge plans should address the following:
Check inhaler technique
Consider the need for regular inhaled steroids
Provide a written asthma action plan for subsequent asthma with clear instructions
about the use of bronchodilators, seeking urgent medical attention in the event of
worsening symptoms and, if appropriate, starting a course of oral steroids
Arrange follow-up by a General Practitioner within one week
Arrange follow-up in a paediatric asthma clinic within one to two months.
ASSESSMENT OF ACUTE ASTHMA IN CHILDREN AGED LESS THAN 2 YEARS
The assessment of acute asthma in early childhood can be difficult. Intermittent wheesing
attacks are usually due to viral infection and the response to asthma medication is
inconsistent. Prematurity and low birth weight are risk factors for recurrent wheesing. The
differential diagnosis of symptoms includes aspiration pneumonitis, pneumonia,
bronchiolitis, tracheomalacia, and complications of underlying conditions such as congenital
anomalies and cystic fibrosis. These guidelines are intended for those who are thought to
have asthma causing acute wheeze. They should not be used as a guide for treating acute
bronchiolitis.
TREATMENT OF ACUTE ASTHMA IN CHILDREN AGED < 2 YEARS
2-Agonist Bronchodilators
A trial of bronchodilator therapy should be considered when symptoms are of concern. If
inhalers have been successfully administered but there is no response, review the diagnosis
and consider the use of other treatment options. Oral 2-agonists have not been shown to
affect symptom score or length of hospital stay for acute asthma in infancy when compared
to placebo. Oral 2-agonists are not recommended for acute asthma in infants. Inhaled
2-agonists are the treatment of choice for the initial treatment of acute asthma. Close fitting
face masks are essential for optimal drug delivery. The dose received is increased if the
child is breathing appropriately and not taking large gasps because of distress and screaming.
There is good evidence that pMD+ spacer is as effective as, if not better than, nebulisers for
treating mild to moderate asthma in children aged <2 years. For mild to moderate acute
asthma, a pMDI+ spacer is the optimal drug delivery device. Whilst 2-agonists offer
marginal benefits to children aged < 2 years with acute wheeze, there is little evidence for
an impact on the need for hospital admission or length of hospital stay.
Steroid Therapy
Steroid tablets in conjunction with 2-agonists have been shown to reduce hospital admission
rates when used in the emergency department. Steroid tablets have also been shown to
reduce the length of hospital stay. Steroid tablets are to be considered in infants early in the
management of moderate to severe episodes of acute asthma in the hospital setting. One

290 Bronchial Asthma

study has shown similar benefits when comparing oral and nebulised steroids for acute
asthma. Steroid tablet therapy (10 mg of soluble prednisolone for up to three days) is the
preferred steroid preparation for use in this age group.
Ipratropium Bromide
The addition of ipratropium bromide to 2-agonists for acute severe asthma may lead to
some improvement in clinical symptoms and reduce the need for more intensive treatment.
It does not reduce the length of hospital stay either in combination with 2-agonists or in
comparison with placebo. Inhaled ipratropium bromide in combination with an inhaled
2-agonist may be considered for more severe symptoms.
Further Investigation and Monitoring
Many children with recurrent episodes of viral-induced wheesing in infancy do not go on
to have chronic atopic asthma. The majority do not require treatment with regular inhaled
steroids. Parents should be advised about the relationship between cigarette smoke exposure
and wheezy illnesses. Referral to suitable agencies should be offered to those who wish to
give up smoking. Parents of wheezy infants should receive appropriate discharge plans
along similar lines to those given for older children. Management of acute severe asthma
in adults and children is shown in the following diagrams.
Management of acute severe asthma in adults in general practice
Many deaths from asthma are preventable, but
delay can be fatal.
Factors leading to poor outcome include:
Doctors failing to assess severity by objective
measurement
Patients or relatives failing to appreciate
severity
Under use of corticosteroids
Regard each emergency asthma consultation
as for acute severe asthma until it is shown to be
otherwise.

Assess and record:

Peak expiratory flow (PEF)
Symptoms and response to
self treatment
Heart and respiratory rates
Oxygen saturation by pulse oxymetry, if
available
Patients with severe or life threatening
attacks may not be distressed and may
not have all the abnormalities listed below.
The presence of any should alert the doctor.

Moderate asthma

Acute Severe Asthma

PEF > 50% best or predicted

PEF 33-50% best or predicted

Life Threatening Asthma

Initial Assessment
PEF < 33% best or predicted

Further Assessment
Speech normal
Respiration , 25/min
Pulse < 110/min

Cant complete sentences

Respiration > 25/min
Pulse > 110/min

SpO2 < 92%

Silent chest, cyanosis, or
feeble respiratory effort
Bradycardia, dysrrhythmia,
or hypotension
Exhaustion, confusion or coma

Contd...

New Guidelines for Asthma Management (Acute Asthma) 291

Contd...
Management
Treat at home
Assess response to treatment

Consider admission

Arrange immediate ADMISSION

Treatment
High-dose 2-bronchodilator:
ideally via oxygen-driven
nebulizer (salbutamol 5 mg
or terbutaline 10mg)
Or via spacer or air-driven
nebulizer (1 puff 10-20 times)
If PEF > 50-70% predicted:
Give prednisolone 40-50 mg
Continue or step up usual
treatment
If good response to first nebulised
treatment (symptoms improved,
respiration and pulse setting, and
PEF > 50%) continue or step up
usual treatment and continue
prednisolone

Oxygen 40-60% if available

High-dose 2-bronchodilator:
ideally via oxygen-driven
nebulizer (salbutamol 5 mg
or terbutaline 10mg)
Or via spacer (1 puff 2-agonist
via a large volume spacer and
repeat 10-20 times) or airdriven nebulizer
Prednisolone 40-50 mg or IV
hydrocortisone 100 mg
If no response in acute
severe asthma, Admit

Admit to hospital if any:

If admitted patient to hospital:
Life threatening features
Stay with patient till ambulance
Features of acute severe
arrives
asthma present after initial
Send written assessment and
treatment
referral details to hospital
Previous near-fatal asthma
Give high dose 2-bronchoLower threshold for admission if:
dilator via oxygen-driven
Afternoon or evening attack,
nebulizer in ambulance
Recent nocturnal symptoms
or hospital admission
Previous severe attacks
Patient unable to assess own
condition
Concern over social circumstances

Oxygen 40-60%
Prednisolone 40-50 mg
or IV hydrocortisone
100 mg immediately
High-dose 2-bronchodilator and ipratropium:
Ideally via oxygendriven nebulizer (salbutamol 5 mg or
terbutaline 10 mg and
ipratropium 0.5 mg)
Or via spacer (1 puff
2-agonist via a large
volume spacer and
repeat 10-20 times)
or air-driven nebulizer

Follow up after treatment

or discharge from hospital:
General Practitioner
review within 48 hr
Monitor symptoms and
PEF
Check inhaler technique
Written asthma action
plan
Modify treatment according to guidelines for
chronic persistent asthma
Address potentially
preventable contributors
to admission

292 Bronchial Asthma

Management of Acute Severe Asthma in Adults in Emergency Room
Time

Measure PEFR and arterial saturation

PEFR 33-75% best or
predicted
Moderate-Severe
Features of severe asthma
PEF<50% best or predicted
RR > 25/min
Pulse > 110/min
Can not complete sentence
in one breath

PEFR > 75%

predicted
Mild

5 min

15-30
min

Give usual
bronchodilator

Clinically
stable, PEF >
75%

Patient
recovering
and PEF >
75%
60
min

Give 5 mg salbutamol
by oxygen-driven nebulizer
if any life threatening feature

Clinically
stable, PEF >
75%

No life threatening
feature PEF 5075%

Obtain senior ICU help now

Life
threatening
features OR
PEF < 50%

No sign of severe
asthma and PEF
50-75%

Sign of severe asthma or

PEF < 50%

120
min

Immediate Management
High concentration O2
(60%)
Salbutamol 5 mg
+ipratropium 0.5 mg by
oxygen-driven
nebulizer
Prednisolone 40-50 mg
orally or IV hydrocortisone, 100 mg
Monitor ABG. Markers
of severity:
Normal or PaCO2
(35 mmHg)
Severe hypoxia
(PaO2 < 60 mHg)
Low pH

Observe
Monitor SpO2,
RR and HR

Patient stable and

PEF > 50%

PEFR < 33% best or

predicted or any lifethreatening feature
SpO2 < 92%
Silent chest, Cyanosis, poor
respiratory effort
Bradycardia, arrhythmia,
hypotension
Exhustion, confusion, coma

Signs of severe
asthma or PEF
< 50%

Potential Discharge: Extended observation if

-agonist before presentation; Prednisolone 40-50 mg for 5 days;
ensure inhaled drugs and technique; arrange GP follow-up with
detailed instructions; referral in appropriate cases

Give/repeat as above
after 15 minutes
Continuous
salbutamol nebulizer
5-10 mg/hr
Consider IV magnesium sulphate 1-2 gm/
20 min.
Fluid/electrolyte
balance monitoring
(specifically K+)
Chest X-ray
ADMIT
Patient should be
accompanied by a nurse
or doctor at all times

Alternate Treatments in Asthma 293

19
Alternate
Treatments in Asthma
Standard asthma therapy, as defined by various management guidelines includes oral and
inhaled corticosteroids, leukotriene antagonists, short-acting and long-acting -agonists,
cromolyn, theophyllines, and nedocromil. Although these agents are generally successful
in controlling asthma symptoms, a small but significant number of patients will continue
with persistent symptoms, frequent exacerbations, and no improvement in objective
pulmonary function parameters despite maximum standard therapy. The long-term use of
oral and high-dose inhaled corticosteroids is often associated with significant side effects.
Thus there is need for alternate agents that are effective in the treatment of asthma.
Alternate agents those have been evaluated in prospective randomized trials or have
novel mechanisms of action are shown in Table 19.1.1-4
Table 19.1: Alternate agents for bronchial asthma
Methotrexate
Azathioprine
Gold
Hydroxychloroquine
Troleandomycin
Cyclosporine
IVIG
Inhaled heparin
Inhaled furosemide
Dapsone
Anti-IgE and soluble interleukin (IL)-4 receptor therapy

Methotrexate

Mechanism of Action
Methotrexate is a folate antagonist. It has anti-inflammatory properties at low doses.
Therefore, it is widely used in a variety of autoimmune and inflammatory diseases, including
severe steroid-dependent asthma. A number of potential reasons for its effectiveness have
been proposed, the mechanism of action of methotrexate in asthma remains unclear. The
drug inhibits leukotriene B4-mediated and leukotriene C5a-mediated neutrophil chemotaxis
in vitro5 although inflammatory cell numbers in vivo appear to be unaltered during
treatment.6 It affects function of many cytokines. The drug inhibits the expression of Ia, a

294 Bronchial Asthma

marker of macrophage activation and monocyte IL-1 production, IL-6, IL-8, and histamine
release, and platelet-activating factor-induced eosinophil chemotaxis.6-8 The inhibition of
purine metabolism by methotrexate diminishes lymphocyte proliferation and antibody
formation6 and increases in CD8+ T-suppressor cells and suppression of B-cell differentiation
have been observed. No significant interference with steroid metabolism has been noted.9
Methotrexate may enhance the sensitivity of peripheral blood monocytes to glucocorticoids
in cases of steroid-refractory asthma.10
A number of randomized trials11-21 have been made using methotrexate in bronchial
asthma and three meta-analyses have been performed since then with mixed results.22-24 Of
the 11 prospective randomized trials, 10 evaluated the use of oral or IM low-dose
methotrexate vs placebo in steroid-dependent asthma patients using either parallel or
crossover design. A three-arm study compared methotrexate, 15 mg weekly orally, with a
single dose of triamcinolone, 360 mg IM, or placebo.20 Most trials required that patients had
received a minimum of 12 months of long-term corticosteroid therapy to be eligible for
enrolment (range, 5 months to 28 years). The majority received oral methotrexate, 15 mg
weekly, and many used a variety of run-in periods to maximize asthma therapy prior to
starting treatment. The duration of methotrexate therapy ranged from 12 to 24 weeks, with
no further reported long-term follow-up. Most studies reported significant reductions in
oral steroid use in their placebo groups, which was attributed to the close-interval followup and the education that patients received during enrolment. Others reported a statistically
significant reduction in corticosteroid dose using methotrexate, some demonstrating
reduction of mean oral corticosteroid use up to 50%.12 Other trials, however, could not
demonstrate a significant difference in corticosteroid reduction between the methotrexate
and placebo groups. Small patient numbers further limits the interpretation. Many trials
had significant dropout rates. No statistically significant changes in peak flow, spirometry,
or mean values for the dose of methacholine provoking a 20% fall in FEV1 were observed
in patients taking methotrexate neither reduction in steroid-related side effects were
reported.12-21
Although responses to methotrexate have been reported after 3 months in patients with
immunologic diseases such as rheumatoid arthritis, treatment for 12 weeks may be
insufficient to demonstrate an adequate therapeutic response in patients with asthma. Some
studies reported statistically significant reductions in the baseline prednisone dose, with
over half were weaned off all steroid therapy.25, 26
Common side effects of methotrexate include liver function test abnormalities, GI
symptoms (including abdominal pain, nausea, and diarrhea), oral ulcers and stomatitis,
constitutional symptoms (including fatigue and decreased concentration), headache, rash,
and less common ones like opportunistic infections (Pneumocystis carinii pneumonia),
increased incidence of bacterial pneumonia, disseminated varicella zoster. However, side
effects were transient and reversible and only minimal from the administration of low-dose
methotrexate. No bone marrow toxicity was observed at the dosages used, and follow-up
was too short to address issues of potential hepatic fibrosis. Methotrexate competes with
the hepatic metabolism of theophylline, with an average decrease in theophylline clearance
of 19% in one case series.
Methotrexate is well-known to cause a variety of pulmonary manifestations, including
drug-induced hypersensitivity reaction, chronic pneumonitis and fibrosis, bronchiolitis

Alternate Treatments in Asthma 295

obliterans with organizing pneumonia, noncardiogenic pulmonary edema, and bronchospasm.27
Troleandomycin
Troleandomycin (TAO) is a macrolide antibiotic and was first described as a treatment for
steroid-dependent asthma in 197428 The drug is believed to have a synergistic effect when
administered with oral corticosteroids. In vitro data using its parent compound,
oleandomycin, at a concentration of 5 g/mL demonstrated a 44% reduction in the
concentration of methylprednisolone that was required to inhibit human lymphocyte blast
transformation by 50% (p < 0.005).29
It is believed that Troleandomycin alters corticosteroid bioavailability by decreasing
hepatic metabolism and excretion.30-32 Subjective patient improvement has not been
correlated with evidence of infection using sputum culture, suggesting that a direct
antimicrobial effect is less likely.28,32
Clinical efficacy data on troleandomycin showed improvement in clinical symptoms
and/or a reduction in corticosteroid dosage in when used as 14 mg/kg/d TAO (maximum
dose, 1 g.33-35 These benefits, however, were less convincingly demonstrated in another trial
of TAO efficacy.36 The results were limited by significant patient The authors concluded
that patients who had been randomized to TAO experienced no advantage and appeared
to develop greater steroid-related side effects than did placebo subjects.
Steroid-related side effects are common with the use of TAO, especially in earlier trials
when patients were given doses of 1 g daily.33,34 Cushingoid features, weight-gain, fluid
retention, and glucose intolerance were the most common findings. GI distress and
hepatotoxicity, ranging from transient liver enzyme abnormalities37 to prolonged cholestasis38
and jaundice39 have been reported, predominantly at higher doses. The doses of theophylline
and other medications with hepatic metabolism must be adjusted to avoid toxicity. Decreased
IgG levels and one case of varicella zoster has been reported with its use.
Gold
Gold is an immunomodulatory agent that has been used commonly for the treatment of a
variety of inflammatory and autoimmune conditions. Although the complete mechanism
of anti-inflammatory activity is unknown, gold has been demonstrated to decrease neutrophil
and macrophage phagocytosis, and lymphocyte reactivity to antigenic stimulation.40 It also
inhibits antibody production and lysosomal enzyme release from phagocytic leukocytes.41
Gold inactivates C1 (complement), decreases prostaglandin and leukotriene production in
vitro, and inhibits IgE-mediated release of histamine from isolated basophils and lung mast
cells.40-44 The enhancement of eosinophil survival with IL-5 is inhibited by the presence of
gold.45
The beneficial effects of gold in the treatment of asthma were reported as early as 1932.
Improvements have been reported in bronchial reactivity and oral corticosteroid
requirements have been decreased46-48 oral or parenteral gold treatment was used for 12 to
22 weeks. There have been three prospective randomized studies examining the efficacy of
gold. Other studies have reported benefit. The Auranofin Multicenter Drug Trial49 has been
the largest clinical trial to examine the efficacy of oral gold. After a 4-week observation
period 275 patients with daily oral prednisone requirements of 10 mg mg were randomized

296 Bronchial Asthma

to auranofin, 3 mg twice daily, or placebo for a period of 6 months. The results were limited
by a significant patient dropout rate (auranofin group, 40%; placebo group, 46%) due to
adverse effects, protocol violations, and voluntary withdrawals, and no intention-to-treat
analysis was performed. No significant differences were found in symptoms or objective
measurements of pulmonary function, although more patients treated with gold were able
to reduce their daily oral corticosteroid dose by 50% compared to those receiving placebo
(60% vs 32%, respectively; p < 0.001). Statistically significant reductions in serum IgE level
(reduction, 44.63 IU/mL; p = 0.003) were also observed in the auranofin group.
Gold has been associated with a variety of side effects, including GI upset and diarrhea,
pruritic rash, cytopenias, oral ulcerations, proteinuria, and frank nephrotic syndrome. Nearly
40% of patients in the prospective randomized trials that were detailed earlier
experienced.49-51 All side effects were self-limited with discontinuation or reduction of therapy.
Some experts have argued that the relative lack of severe side effects with gold therapy,
compared to methotrexate therapy, make it a preferable agent for the treatment of severe,
glucocorticoid-dependent asthma, but no clear consensus exists on the issue.
Cyclosporine
Cyclosporine is an immunomodulatory and anti-inflammatory drug and is a fungal metabolite
that is commonly used in organ transplantation. Cyclosporine binds to cyclophilin, inhibiting
cytokine messenger RNA transcription and CD4+ T-cell activation.52 The drug also reduces
the synthesis and release of inflammatory mediators from mast cells and basophils, and it
decreases B-cell IgE synthesis and release.53 Cyclosporine has been demonstrated to reduce
the macrophage synthesis of IL-1, tumor necrosis factor, superoxide, and hydrogen peroxide,
and has been shown to decrease neutrophil chemotaxis and serum soluble IL-2 receptor
concentrations.40,54 The production of granulocyte macrophage colony-stimulating factor
(GMCSF) and IL-5 from stimulated monocytes is also reduced with drug therapy, inhibiting
eosinophil proliferation and survival activity.55,56
Cyclosporine has been shown to block the late asthmatic reaction and to inhibit the
production of eosinophil-related cytokines after allergen challenge.52,57 Statistically significant
improvement in airway hyperreactivity has been observed in steroid-dependent asthma
patients after 12 weeks of therapy with cyclosporine. Three prospective randomized trials
that have examined the effect of cyclosporine in asthma patients, which have shown a 12%
increase in morning peak expiratory flow rates (PEFRs) (p < 0.004), a 17.6% increase in
FEV1 (p < 0.001), and a 48% reduction in exacerbations requiring increased steroid dosing
(p < 0.02) compared to those receiving placebo. 58 In another study treatment with
cyclosporine (initial dose, 5 mg/kg/d) for 36 weeks in resulted in a statistically significant
reduction in the median daily prednisolone dosage (62% vs 25%, respectively; p = 0.043)
along with improvements in PEFR.59 However, another study with a longer follow-up period
demonstrated no statistically significant effects of cyclosporine using the objective markers
of pulmonary function and steroid-sparing effects.60
The side effects of cyclosporine are dose-dependent nephrotoxicity, tremor, hirsutism,
hypertension, gum hyperplasia, and infectious complications. The majority of these side
effects are not observed in the low doses that were used in the trial listed above. Several
patients experience hypertrichosis and a worsening of pre-existing hypertension that may
result in the discontinuation of therapy. Treatment-limited neuropathy also has been
observed.

Alternate Treatments in Asthma 297

IVIG
IVIG has been shown to reduce immediate skin test reactivity to allergens, to decrease total
serum IgE levels, to inhibit lymphocyte activation and the production of IL-2 and IL-4 in
vivo, and to suppress cytokine-dependent lymphocyte proliferation in vitro.61-63 IVIG also
has been shown to increase lymphocyte sensitivity to the suppressive effects of
dexamethasone, even in patients with prior documented steroid resistance.64
Monthly administration of high-dose IVIG resulted in a three-fold reduction in the oral
glucocorticoid dose, a reduction in symptoms, and in improved PEFRs with decreases in
serum total IgE levels and skin test reactivity to allergens.61 These steroid-sparing effects
are observed both in adult and pediatric asthma patients.65,66 Other investigators have
observed after 3 months of therapy a reduction of oral corticosteroid doses67, others failed
to identify a significant difference in steroid dose reductions, pulmonary function testing
results, or the number of clinical exacerbations among patients in the IVIG groups and the
placebo group.68
The minor adverse effects of therapy include headache and nausea, which generally occur
with the infusion and are self-limiting. Although current commercial preparations should
have no risk of transmission of viral hepatitis, there remains the remote possibility of IVIG
transmission of a yet-undefined viral illness. More serious reactions can be associated with
patients who have IgA deficiency, and IVIG administration should be avoided in this
population. It also has been rarely associated with interstitial nephritis and aseptic meningitis,
as was mentioned above.68
Heparin
Heparin is an endogenous glycosaminoglycan and is extensively used as an anticoagulant.
Its flexible structure and high anionic charge allow heparin to interact with a variety of
molecules in vivo and it is involved in airway inflammation. Elevated levels of heparin-like
anticoagulants have been demonstrated in atopic asthma patient and have been induced in
some patients after antigen inhalational challenge leading to further interest in investigating
the role of heparin in this disease.69-71
Heparin binds and inhibits a variety of cytotoxic and inflammatory mediators, including
eosinophilic cation protein and peroxidase.72 It also increases the association rate of secretory
leukocyte protease inhibitor with human neutrophil elastase and cathepsin G, reducing
their activity.73 Heparin has been associated with the inhibition of lymphocyte activation74,
neutrophil chemotaxis75, smooth muscle growth, and vascular tone.76 It also reduces
complement activation.77 It has been suggested78 that the sulfate groups on the heparin
molecule may attenuate antigen-induced bronchoconstriction via the inhibition of inositol
1,4,5 triphosphate-dependent, IgE-mediated mast cell histamine release. Perhaps heparin
is bound to cell surface proteins in the airway epithelium may modulate smooth muscle
tone either by inhibiting inositol 1,4,5 triphosphate-mediated calcium release or by
preventing C-fiber stimulation, decreasing bronchial responsiveness, and reducing airway
hyperreactivity.69
Subjective improvements in asthma symptoms have been reported with the use of IV
heparin.79-81 Inhaled heparin therapy administered at a maximum dose of 80,000 U preserved
specific airway conductance (sGaw) better than did 20 mg inhaled cromolyn or placebo
following exercise82 but not following histamine challengen.83-85 Conflicting data exist

298 Bronchial Asthma

regarding the effects of heparin pretreatment on the early asthmatic response to inhaled
allergen challenge (dust mite extract), with mild but statistically significant protective effects
in FEV1 seen 7 to 8 h postchallenge (p < 0.05). Trials examining the effects of inhaled heparin
on bronchoprovocation using methacholine also have yielded mixed results, with variable
effects on the provocative concentration of methacholine causing a 20% fall in FEV1, but
with no significant effects on FEV, airway resistance, or sGaw postchallenge. Two cases of
corticosteroid-resistant asthma patients who responded to 100,000 U inhaled heparin during
asthma exacerbations have been reported.
No adverse effects associated with the use of inhaled heparin at the doses described
above have been reported. Heparin inhalation alone has not been demonstrated to affect
baseline FEV1 despite the frequent use of isotonic saline solution as its carrier. No bleeding
complications have been reported, and no significant changes in serum partial prothrombin
time or anti-factor Xa activity have been observed with unfractionated and low-molecularweight heparin, respectively.
Furosemide and Other Diuretics
Changes in water concentration and surface osmolarity of the airway epithelium are
important contributing factors to exercise-induced bronchospasm that prompted the first
use of inhaled frusemide (ie, furosemide) as a potential treatment for asthma.86 Furosemide
is a loop diuretic that acts in the kidney by inhibiting the Na+/K+/2 Cl- cotransporter in the
ascending limb of the loop of Henle. Despite early speculations about the effects of furosemide
on airway water concentration, its mechanism of action does not appear to be related to the
diuretic effects of the drug. Furosemide is not effective against asthma when administered
orally at the usual diuretic doses and must be inhaled at relatively high doses (i.e. 20 to 40 mg)
for significant antiasthma effects.86
Furosemide attenuates bronchoconstriction by reducing apical chloride channel activity
and by decreasing the potential difference and short-circuit current in airway epithelial
cells.87,88 The drugs inhibition of chloride transport also appears to inhibit the release of
eosinophil mediators89 and may be related to the modulatory effects observed on presynaptic
neuropeptide release from noncholinergic, nonadrenergic sensory nerves and cholinergic
neural responses in animal models.90 Furosemide acts by inhibiting the release of histamine
and leukotrienes from passively sensitized human lung.91 Conflicting data exist regarding
the effects of furosemide on airway prostaglandins. Furosemide is well-known to enhance
renal synthesis of prostaglandin E292 and the stimulation of inhibitory prostaglandins from
the airway epithelium may be the cause of its protective role in some challenges.93 Further,
it is suggested that the drug inhibits the production of bronchoconstricting prostaglandins.94
Effects of cyclooxygenase inhibitors on the activity of furosemide have been mixed95,96
reinforcing the lack of clarity in this area. Other postulated mechanisms of action based on
animal data include the reduction of airway temperature variation through local airway
vasodilation following dry air challenge97 and the enhancement of paracellular water
movement in response to an osmotic stimulus.98 However, other data have shown that
furosemide has little99 or no effect100 on mucociliary clearance, an indirect measure of the
rate of recovery of periciliary fluid volume after isocapnic hyperventilation.
Furosemide appears to attenuate the effects of indirect bronchoconstrictor mechanisms,
including early and late responses to allergen101 and the effects of exercise86 distilled water102
adenosine 5'-monophosphate103 sodium metabisulfite104,105, aspirin105 and propranolol.106

Alternate Treatments in Asthma 299

Bronchoconstrictors that work directly on airway smooth muscle like histamine 103
methacholine104,107 and prostaglandin F2108 are not affected by furosemide. The similarities
between the protective spectrum of furosemide and cromolyn have led to speculation about
a common mechanism of action, although cromolyn has been shown to have a statistically
greater protective effect on airway reactivity when equal doses of the two inhaled drugs
were compared.109
Inhaled furosemide has been shown to inhibit the cough response induced by the
inhalation of low-chloride-content solutions110 in healthy volunteers, but not in asthmatic
patients.111 The presumed effect of the drug is due to changing the local concentration of
chloride ions in the vicinity of myelinated afferent nerve fibers that are acting as cough
receptors at the airway surface.112
A significant steroid-sparing effect using a combination of lysine acetylsalicylate (LASA)
and furosemide is observedin severe steroid-dependent asthma for 10 to 28 weeks.113-115
Effect of inhaled furosemide in acute asthma exacerbations showed mixed results.115 Serial
FEV1 measurements showed a mean increase of 14.9 10.5% in FEV1 with furosemide therapy
alone (difference not significant) compared to an increase of 42.9 15.2% with metaproterenol
therapy (p = 0.003) and no additive benefit with combination therapy.116 Others have reported
similar results.117 Others reported statistically significant improvements in PEFRs (p < 0.05)
in acute asthma exacerbations, FEV1 had increased by > 2 SDs compared to those receiving
placebo, although no differences between the good responders and the poor responders
could be identified.118 A follow-up case series119 reported clinical improvement in 9 of 11
patients with severe asthma exacerbations that were refractory to conventional medical
therapy with the addition of inhaled furosemide.
Furosemide can cause allergic reactions due to its incorporated sulfa moiety and has
been reported to cause ototoxicity with high-dose rapid IV infusion. None of the clinical
trials using inhaled furosemide have reported significant side effects, and no diuretic effect
has been reported.
CONCLUSION
Standard anti-asthma therapy is highly successful in most patients. Therefore, the use of
alternate agents for treating asthma should be reserved for the steroid-resistant asthma
patient or for the steroid-dependent asthma patient in whom a thorough evaluation to
exclude other diagnoses and exacerbating factors has been performed.
Of all the agents that have been examined in prospective randomized trials, methotrexate
and gold appear to be the most important in terms of steroid-sparing and side effect.
Methotrexate has been shown to reduce oral corticosteroid requirements modestly in steroiddependent asthma patients in some short-term, randomized, clinical trials, although its
mechanism of action remains unclear and the data examining this issue remain limited and
conflicting. Two case series have suggested that long-term therapy with methotrexate may
be required to demonstrate objective benefit. Gold also has significant steroid-sparing effects
in patients with high daily corticosteroid requirements, but this conclusion must be made
with caution due to the confounding effects of the high dropout rate in the Auranofin
Multicenter Drug Trial. Side effects with gold therapy are common but generally are minor
and self-limited with dose reduction or the cessation of therapy. Until further data from
controlled clinical trials are available, however, it is unclear whether methotrexate or gold

300 Bronchial Asthma

offers a significant risk/benefit ratio compared to close follow-up, intensive standard
therapy, and patient education alone.
Cyclosporine offers an attractive mechanism of action and reasonable efficacy data in
two of three small prospective randomized trials, but it also carries with it a significant side
effect profile. Because of the risk of permanent renal damage and the need for intensive
monitoring, further studies with larger prospective randomized trials should be performed
before cyclosporine is considered as an appropriate alternate agent for asthma therapy.
Although troleandomycin (TAO) appears to be an effective methylprednisolone dosereducing agent, the drug has not been shown to significantly improve asthma control or to
reduce steroid-related side effects, and it was associated with an increased rate of
osteoporosis and hypercholesterolemia in one clinical trial. Data demonstrating the beneficial
effects of IVIG also are limited, while cost, convenience, and a possible risk of aseptic
meningitis are all potential detractors to this therapy. At this time, the use of TAO appears
to offer no advantage over conventional asthma therapy and patient education, and therapy
with IVIG should be limited to clinical trials.
Although its postulated mechanism of action and effects on exercise-induced
bronchospasm are intriguing, the majority of clinical data currently available on inhaled
heparin therapy is limited to single-blind trials involving < 20 patients. The enoxaparin
data suggest that the accepted dosing regimens may be too low to demonstrate a full
therapeutic effect, and larger prospective placebo-controlled trials are needed to determine
the efficacy, dose, and patient population that may benefit from this therapy. Furosemide
and other loop diuretics appear to attenuate a variety of indirect bronchoconstrictor
mechanisms, although their exact mechanism of action remains unknown. The fact that
loop diuretics seem to have little direct effect on bronchial smooth muscle is a likely
explanation for their lack of effect as a single agent or in combination with -agonists alone in
patients with asthma exacerbations. The current data and the lack of significant side effects
make them potential steroid-sparing agents in the long-term treatment of mild persistentto-severe asthma. The current clinical data are limited, however, and larger randomized
trials are necessary to confirm the efficacy of loop diuretics and their role in the treatment of
asthma.
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306 Bronchial Asthma

20
Severe Asthma
(Fatal Asthma, Refractory Asthma)
INTRODUCTION
Severe or fatal asthma or refractory asthma constitutes about <5% of all the asthmatics. The
entity is poorly understood clinically, physiologically, and pathologically. Severe forms of
the disease often remain refractory to the best current medical care. Although some patients
with severe asthma have had severe disease for most of their lives, a second group develops
severe disease in adulthood. It is not clear which genetic and environmental elements may
be the most important in the development of severe disease. Physiologically, these patients
often have air-trapping and may have loss of elastic recoil, as well. The pathology
demonstrates a wide variety of findings, those include continued eosinophilic inflammation,
structural changes, distal disease, and, in at least one third of patients, a different pathology.
Treatment remains problematic. These patients respond poorly to the usual treatment and
are very difficult to manage. Accordingly the cost of treatment is very high with poor
outcomes. The introduction of high-potency inhaled corticosteroids (CS) had a marked
impact on the numbers of patients who were dependent on therapy with oral CS. However,
beyond those medications, little further progress has been made in understanding the disease
and improving its treatment.
Definition
Severe or refractory asthma was defined by the workshop sponsored by the American
Thoracic Society.1 This definition includes the following:

Major Criteria
Continuous high-dose inhaled corticosteroids or
Oral corticosteroids for > 50% of the previous year

Minor Criteria

Aspects of lung function,

Exacerbations,
Disease stability,
Amount of additional medications
For a diagnosis of fatal asthma at least one major and additional two of the seven minor
criteria are to be fulfilled. Patients also must have had compliance and exacerbating factors

Severe Asthma (Fatal Asthma, Refractory Asthma) 307

should be fully addressed. These definitions are a guide, but the list of criteria still may not be
definitive and may have many pitfalls. Some suggest that expanding the minor criteria
requirements to three would likely improve the capture of those who fulfill the spirit of the
definition, rather than the letter of the definition.
Epidemiology
Very little is known about the development of severe asthma. It is not clear whether most
patients with severe asthma have a life-altering event in childhood that irreversibly alters
their lungs, from which they will never recover, or whether they slowly but steadily decline
over the years. It is also not certain whether those patients with a history of adult-onset
disease actually have some level of asthma as children those were ignored, or if at all they
have a more rapid decline in function once the asthma begins. No satisfactory answer to
these questions has been found although some information has come from the large cohort
of asthma patients studied in Melbourne, Australia followed for 35 years.2 Those data
suggest that reduced lung function in childhood leads to reduced lung function in adulthood,
although there is little progressive decline of the mean data. Two studies3,4 from Europe
have suggested that late-onset asthma is associated with a more rapid decline in lung
function. In the database of > 100 patients with severe asthma who were seen at National
Jewish Medical and Research Center (Denver, CO), approximately two-thirds of patients
had onset in childhood, and the remaining one third experienced onset after the age of
20 years.5 Existence of any distinct phenotypic differences in adult-onset and childhood
onset asthma or severe asthma is not known.
Aetiology
Various risk factors for development of severe asthma are shown in Table 20.1.
Table 20.1: Various risk factors for development of severe asthma

Genetic
Mutations in both the interleukin-4 gene or the interleukin-4 receptor
Non-T helper (Th) type 2 factors
Transforming growth factor (TGF)-1
Monocyte chemotactic protein-1
Environmental factors
Allergens (house dust mite; cockroach; alternaria exposure)
Smoking
Pet allergy
Infections
Respiratory syncytial virus infections in childhood
Mycoplasma and Chlamydia infections in adults
Lung-externa factors
Obesity (Increased body mass index)
Gastroesophageal reflux disease
Chronic sinusitis
Compliance/adherence to medications
Inadequate response to therapy

308 Bronchial Asthma

As is the case for many diseases, risk factors can be divided into genetic and environmental. Unfortunately, asthma itself is a disease involving multiple genes. Severe asthma is
not likely to be different and is less well-studied. There are reports6,7 of relevant mutations in
both the interleukin-4 gene or the interleukin-4 receptor, some of which have been linked to
loss of lung function, and others to near-fatal events. Interestingly, two non-T helper (Th) type
2 factors also have been associated with severity of asthma, transforming growth factor (TGF)1 and monocyte chemotactic protein-1, both of which can promote fibrotic reactions.8,9 Whether
mutations of the receptors for the primary treatments for asthma (2 and glucocorticoid receptors
[GRs]) decrease responsiveness to medications and influence outcomes is not yet clear.
Environmental factors include both allergen and tobacco exposure, with the strongest data
for house dust mite, cockroach, and Alternaria exposures.10-12 Additionally, many patients
will continue to smoke or own a cat despite being aware of the negative effects.13 Infection also
may contribute to severe disease, with respiratory syncytial virus infections implicated in
childhood, while pathogens like Mycoplasma and Chlamydia may play a role in adults.4
Although not precisely environmental, additional lung-external factors may include
obesity, gastroesophageal reflux disease, and chronic sinusitis. Epidemiologic study of patients
with severe/difficult-to-treat asthma suggested that body mass index increases with increasing
severity of disease and that 76% of the cohort of patients with severe disease were either
overweight or obese.14 However, similar to gastroesophageal reflux disease and chronic
sinusitis, the relationship of effective treatment of obesity to severity of disease is not clear.
Another external factor related to severity of disease is compliance/adherence to
medications. Studies15 have suggested that in children and adolescents, instability of disease
is related to adherence to therapy with corticosteroids. Adherence to medication may be
influenced by lack of responsiveness to medication. If the patient is receiving therapy with
oral corticosteroids, the early-morning measurement of cortisol level can be helpful in
determining compliance. If this is not helpful, then treatment trials with injectable longacting steroids, such as depomethylprednisolone or triamcinolone, can be informative.16
Physiology
Progressive increase in airflow limitation, which is often irreversible leads to a more
rapid decline in the FEV1, although there is poor correlation between FEV1 and disease
symptoms .17 This may be true in some patients. Others may have severe airflow limitation
at presentation, while others, particularly adults, may develop a more rapid decline in lung
function over a 10-year-period of time.4 These changes are not completely irreversible. There
may be irreversibility to current aggressive medical management. However, it does not
necessarily mean the lungs are in a fixed fibrotic state.
Airway hyperreactivity also plays a role in the severity of asthma. The provocative
concentration causing a 20% fall in FEV1 with disease severity is often present but is poor
indicators.18 This instability may be an important aspect to the symptomatology of a subgroup
of patients with severe asthma, in whom continuous airflow limitation may play a role.19
FEV1 and airway reactivity changes do not adequately explain disease severity. It is
possible that other physiologic factors, such as changes in elastic recoil and/or small airway
physiology, are important. The elastic recoil properties of the lung in asthma patients are
not normal.20,21 Compliance is increased in patients with moderate persistent asthma,
although the precise pathologic mechanism behind the change is not clear. It is suggested
that the airways and the parenchyma are more collapsible than are the airways in healthy

Severe Asthma (Fatal Asthma, Refractory Asthma) 309

individuals.22 The FVC1 slow vital capacity ratio is decreased in a group of patients with
severe asthma who had persistent eosinophilia.23 These patients are at a higher risk of nearfatal events than those with a more normal (1:1) ratio.
There is air-trapping in patients with severe asthma, without associated hyperinflation.
Residual volumes are routinely > 200% of predicted in severe asthma, with only modestly
increased thoracic gas volumes.23 Whether this increase in residual volume may be reflective
of small airway disease. There is no correlation of physiologic measures with inflammatory
or structural changes.
Pathology
Up to two-thirds of patients with severe asthma have persistent tissue eosinophils, despite
continued therapy with high-dose systemic steroids. There are associated increases in T
lymphocytes and markers for activation of a Th-2 pathway.23 This pattern of inflammation
represents steroid resistance, whereas a Th-2 pattern of inflammation persists despite the
presence of high-dose steroid therapy. This lack of effect is due to a number of factors those
include high levels of proinflammatory mediators sequestering the glucocorticoid receptors
(GR), diminished binding of the GR to the genome, or increased levels of an alternatively
spliced GR (i.e. GR-), which has lessened inhibitory capabilities.24-26 Other, non-Th-2,
proeosinophilic factors also play a role in the process. These changes lead to poor/modified
drug response in patients with more unstable asthma.
The apparent progressive loss of lung function in more severe forms of asthma is due to
structural or remodeling changes in the airways and perhaps the parenchyma as well
although tthe precise changes are unclear. Numerous structures have been implicated,
including the sub-basement membrane (SBM), epithelium, smooth muscle, nerves, and blood
vessels. Although the SBM is thickened in asthma patients, the relationship to disease severity
is unclear. Patients with severe asthma with persistent eosinophil levels had the thickest
SBM when compared to those of healthy control subjects, patients with milder cases of
asthma. This thickened SBM was seen in association with high numbers of TGF--positive
cells in the submucosa.23,27 However, the absolute increase in thickness is small and cannot
explain the increase in airflow limitation. It may be used as a marker for abnormalities in
composition, distribution, or quantity of extracellular matrix elements in other regions of
the airway or parenchyma.
The epithelium is abnormal in asthma patients. There is an increase in the ratio of goblet
cells to ciliated epithelial cells. Mucus plugging of the small and medium airways contributes
further to airflow limitation and air trapping in patients with severe asthma. Other studies28,29
suggested alterations in epithelial growth factor receptor and TGF-1 and/or TGF-2 in
asthma patients, which may contribute to inappropriate and inadequate repair process,
augmenting goblet cell metaplasia and mucus production.
The amount (and perhaps phenotypes) of smooth muscle in the airways of patients with
severe asthma is also increased. Patients dying of status asthmaticus have increased smooth
muscle mass in the airways from the largest airways to nearly the smallest.30 Relationship
of increased airway smooth muscle to severity of disease is possible although relationship
of any of these structural changes to functional changes is not very clear. In addition to
airflow limitation, airtrapping, hyperresponsiveness, and loss of elastic recoil/collapsibility
are important. Alterations in the alveolar attachments to the airways and the airways
themselves play a role in collapsibility, but the cause of changes in elastic recoil is not clear.

310 Bronchial Asthma

Elastin levels have been shown to be abnormal (i.e. decreased or disordered) in patients who
have died of asthma. The numbers of proteolytic enzymes that alter elastin composition are
increased in several instances in asthma.31,32 It is possible that changes in elastin composition,
secondary to chronic inflammatory elements, contribute to the unique structural/functional
relationships of patients with severe asthma.
Physiologic and pathologic data suggest that inflammatory changes exist in the lung
periphery. Autopsy studies33,34 have suggested that both increased inflammation and wall
thickness may exist in patients who have died of asthma, as opposed to those with milder
asthma and healthy control subjects. Studies35,36 of living asthma patients also have suggested
that distal lung inflammation may be more important than proximal lung inflammation.
These observations have implications for current drug therapy, as most inhaled medications
are unlikely to reach the lung periphery in high amounts.37 These structural and inflammatory
changes in the small airway and parenchyma may interact to a greater degree in the small
airways than the large airways due to the smaller general mass of the airway structure.
Classically bronchial asthma has continued eosinophilic inflammation but, patients with
severe asthma have neutrophil predominance or very little inflammation23,38, 39 The patients
without eosinophils also do not appear to have the same degree of collapsibility and have
less severe asthma attacks, also supporting a different presentation for this disease subtype.
Recently CT scan findings confuse the issue whether other, less well-defined obstructive
diseases like bronchiolitis obliterans also could masquerade as severe asthma.40
Management
The treatment of severe asthma remains difficult. Corticosteroids remain the drug of choice
because of their broad and nonspecific effects, and there are few alternatives in existence.
Leukotriene modifiers may be helpful in some cases, especially as a large percentage of
patients with severe asthma may be aspirin-sensitive.41 Anti-IgE also appears to be efficacious
in patients with more severe forms of asthma and may be of benefit in some of these patients.42
Other forms of therapy, such as cyclosporine and methotrexate have limited value.43
However, use of alternate agents in treating asthma patients, whose disease remains poorly
controlled while receiving standard therapy, may be considered. It is important to recognize
that the reasons for lack of response to treatment are numerous, and the clinical approach to
the patient with poorly controlled asthma must be systematic and individualised. The
objective confirmation of asthma and the exclusion of other pulmonary conditions with
screening blood tests, chest radiograph, spirometry, bronchoprovocation challenge, and
cardiopulmonary exercise testing is vital in any patient who does not respond to asthma
therapy. It is of importance of maximising standard asthma therapy with close outpatient
follow-up, patient education, and compliance monitoring.
The treatment of concomitant gastroesophageal reflux44 and chronic sinusitis45,46 and the
removal of environmental triggers of asthma have been shown to improve asthma control.
Glucocorticoid absorption and metabolism can be affected by thyroid disease and a variety
of drugs, including antacids, rifampin, cholestyramine, and numerous antiepileptic agents.47
The increased detection of Mycoplasma pneumoniae and Chlamydia pneumoniae by polymerase
chain reaction in the airways of patients with chronic asthma has led to questions regarding
their role in pathogenesis48 and several small case series49,50 have demonstrated statistically
significant improvements in lung function and reductions in bronchial reactivity to histamine
after treatment with macrolides. Due to the significant side effects of many alternate asthma

Severe Asthma (Fatal Asthma, Refractory Asthma) 311

therapies, it is essential to thoroughly address these issues before going for a novel treatment
strategy.
It is also important to distinguish the difficult-to-manage asthma patient from the patient
who is steroid-resistant. This asthma subgroup, which was first described in 196851 is
characterised by patients with larger than usual daily oral corticosteroid requirements and
poor symptom control, a blunted eosinopenic response to cortisol-21-succinate, and increased
clearance of cortisol. Other clinical characteristics that are associated with steroid resistance
include African-American race, symptoms requiring oral glucocorticoid agents at an early
age, and < 15% improvement in FEV1 following 7 to 14 days of treatment with high-dose
(i.e. > 40 mg daily) oral glucocorticoids.52 The recognition and early identification of these
patients may isolate a subgroup of patients who could benefit from early intervention with
alternate asthma therapies with better long-term asthma control and reduction in corticosteroid side effects.
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2. Oswald H, Phelan PD, Lanigan A, et al. Childhood asthma and lung function in mid-adult life.
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4. Ten Brinke A, van Dissel JT, Sterk PJ, et al. Persistent airflow limitation in adult-onset nonatopic
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5. Gibbs R, Miranda C, Wenzel S. Initial demographic information from an extensive data base of
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6. Sandford AJ, Chagani T, Zhu S, et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and
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7. Burchard EG, Silverman EK, Rosenwasser LJ, et al. Association between a sequence variant in
the IL-4 gene promoter and FEV1 in asthma. Am J Respir Crit Care Med 1999;160:919-22.
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Teeter JG, Bleecker ER Relationship between airway obstruction and respiratory symptoms in
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Kam JC, Szefler SJ, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptorbinding affinity and T cell response to glucocorticoids. J Immunol 1993;151:3460-66.
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with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest 1998;102:
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Leung DY, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increased
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Minshall EM, Hogg JC, Hamid QA. Cytokine mRNA expression in asthma is not restricted to the
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Howat WJ, Holgate ST, Lackie PM. TGF- isoform release and activation during in vitro bronchial
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Vignola AM, Riccobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of
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Lemjabbar H, Gosset P, Lamblin C, et al. Contribution of 92 kDa gelatinase/type IV collagenase
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Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in
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Severe Asthma (Fatal Asthma, Refractory Asthma) 313

36. Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in
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severity. Am J Respir Crit Care Med 2000;161:9-16.
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bronchiolitis obliterans. Radiology 2000;217(suppl):595.
41. Virchow JC, Jr. Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving
high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:578-85.
42. Holgate S, Bousquet J, Wenzel S, et al. Efficacy of omalizumab, an anti-immunoglobulin E
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of a systematic management protocol. Chest 1993;103:1662-69.
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48. Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae in the airways of
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49. Ekici A, Ekici M, Erdemoglu AK. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. J Asthma 2002;39:181-85.
50. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma:
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314 Bronchial Asthma

21
Asthma in Children
The previous chapters have dealt with bronchial asthma in general, which is applicable, both
in cases of adult as well as childhood asthma. However, this chapter will highlight certain
important points about childhood asthma.
PREVALENCE
International Scene
A worldwide rise in the prevalence of asthma is being reported with increase in wheeze at an
alarming rate of 5% per year. From 1983 onwards an increase in asthma mortality and
morbidity has been noticed worldwide.1 Data on prevalence of bronchial asthma on children
are few from most countries but many from countries like Australia and UK.2 Table 21.1
shows the prevalence of current asthma, diagnosed asthma, wheeze ever, airway
hyperresponsiveness, and atopy in children.
There are large differences in the prevalence among the rich, partly rich, and poor
populations, with the highest prevalence found in Australia. It is possible that the differences
may be as a consequence of responses to different allergens, to different allergen loads, or to
other factors in the environment in the affluent and not-so-affluent populations. There are
some suggestions that patients with high levels of parasitic infections are less atopic, although
there is no convincing experimental confirmation. This protection of parasitic infections
against asthma may be a cause of less prevalence of the later in many developing countries.
Diet may also be a factor. Exposure to allergens may be important although the most common
allergen, the house dust mite has been found everywhere it has been looked for. However,
these mites are mainly found in bedding and it is possible that steeping on a bed rather than
on a floor, which many poor children do, increases exposure to them.
There was considerable concern that the prevalence of asthma and allergic diseases is
increasing in Western and developing countries. However, the etiology of these conditions
remains poorly understood, despite a large volume of clinical and epidemiological research
within populations that has been directed at explaining why some individuals and not
others develop asthma and allergies. Little is known about such worldwide variations in the
prevalence of asthma and allergic diseases. More authentic data was available from the
International Study of Asthma and Allergies in Childhood (ISAAC) designed in late 90s.3
The study allowed comparisons between populations in different countries. ISAAC Phase
One used standardized simple surveys conducted among representative samples of school
children from centres in most regions of the world. Two age groups (13-14 years and

Asthma in Children 315

Table 21.1: Prevalence of asthma in children in different countries

Country

Number

Age

Current
asthma

Diagnosed Wheeze
asthma
ever

Airway
Hyperresponsiveness

Atopy
(SPT)

Australia

1,487
1,217
1,575

8 to 10
8 to 11
8 to 11

5.4
6.7
9.9

11.10
17.3
30.8

21.7
26.5
40.7

10.1(H)
10.0 (1.1)
16.0 (H)

29.3
31.9
37.9

New Zealand

813
1,084
873

9
6 to 11
12

11.1
9.1
8.1

27.0
14.2
16.8

22.0 (M)
20.0 (H)
12.0 (E)

45.8

27.2
26.6

England
Wales
Germany
Denmark
Spain
Indonesia
China
Papua
New Guinea

1,613

8.0

965

5.3

1.2
7.9

5,768

9 to 11

4.2

14.8*
22.3

?(H)
8.0 (E)
?

527

7 to 16

5.3

2,216

9 to 14

406

7 to 15

1.2

2.3

14.5

2.2 (H)

11 to 17

1.9

2.4

6.3

4.1 (H)

?30

1.7

1.0 (H)

17

3,067

16.0 (H)
?

257

6 to 20

Kenya
Australia
Indigenous

402

9 to 12

3.3

11.4

Aborigines

215

7 to 12

0.1

31

6.9(E)

10.7 (E)

1.4

1.8(H)

20.5

Current asthma: Airway hyperresponsiveness (AHR) + wheeze in the last 12 months;

Diagnosed asthma: asthma ever diagnosed; H:histamine; M:methacholine; E: exercise;
All figures are a percentage of the population tested.

6-7 years) with approximately 3,000 children in each group were studied in each centre. The
13-14 years-old (n = 463,801) were studied in 155 centres (56 countries) and the 6-7 year-old
(n=257,800) were studied in 91 centres (38 countries). There were marked variations in the
prevalence of asthma symptoms with up to 15-fold differences between countries. The
prevalence of wheeze in the last 12 months ranged from 2.1-32.2% in the older age group and
4.1-32.1% in the younger age group and was particularly high in English-speaking countries
and Latin America. A video questionnaire completed in the older age group in 99 centres
(42 countries) showed a similar pattern.
The major differences between populations found in the International Study of Asthma
and Allergies in Childhood Phase One are likely to be due to environmental factors. The
results provide a framework for studies between populations in contrasting environments
that are likely to yield new clues about the aetiology of asthma.3 Self completed wheezing
questionnaire data in 13-14 years and 6-7 years old age group from different regions of the
world are shown in Tables 21.2 and 21.3.
The ISAAC study has demonstrated, by means of simple standardized questionnaires,
that there are large variations in the prevalence of asthma symptoms throughout the world.
The self-reported 12 months prevalence of wheezing among 13-14 years-old between countries

316 Bronchial Asthma

Table 21.2: Twelve months prevalence of bronchial asthma (%) in
school going children 13-14 years old age group

Region

Wheeze

4Attacks

Severe
wheeze

Exercise
wheeze

Night
cough

Ever had
asthma

Number
studied

Africa

11.7

3.4

5.4

23.3

23.3

10.2

20,475

Asia Pacific
Eastern
Mediterranean

8
10.7

2.2
2.9

1.8
3.8

16
16.9

17.8
20.2

9.4
10.7

83,826
28,468

Latin America
North America

16.9
24.2

3.4
7.6

4.5
9.2

19.1
30.9

28.6
33.7

13.4
16.5

52,549
12,460

Northern and
Eastern Europe
Oceania

9.2

1.9

1.8

12.3

12.2

4.4

60,819

29.9

9.9

8.1

39.0

29.3

25.9

31,301

South East Asia

Western Europe

6.0
16.7

1.6
4.6

3.0
4.2

9.5
20.0

14.1
27.1

4.5
13.0

37,171
1,35,559

Grand Total
(All World)

13.8

3.7

3.8

18.8

22.3

11.3

4,63,801

Table 21.3: Twelve months prevalence of bronchial asthma (%) in

school going children 6-7 years old age group

Region

Wheeze

4Attacks

Severe
wheeze

Exercise
wheeze

Night
cough

Ever had
asthma

Number
studied

Asia Pacific

9.6

2.2

1.5

5.0

17.6

10.7

39,476

Eastern
Mediterranean
Latin America
North America

6.8

1.7

1.7

4.0

13.6

6.5

12,853

19.6
17.6

4.0
5.5

4.5
3.0

9.1
9.6

30.6
25.1

12.4
14.7

36,264
5,755

Northern and
Eastern Europe
Oceania

8.8

2.0

1.5

3.6

11.4

3.2

23,827

24.6

8.9

4.6

15.9

29.4

26.8

29,468

South East Asia

Western Europe

5.6
8.1

1.5
1.9

1.9
1.5

3.6
3.7

12.3
16.1

3.7
7.2

31,697
68,460

11.8

3.1

2.4

6.2

19.1

10.2

2,57,800

Grand Total
(All World)

ranged from 2.1% in Indonesia to 32.2% in the UK. Parental reported 12 months prevalence of
wheezing in 6-7 years-old ranged from 4.1% in Indonesia to 32.1% in Costa Rica. The highest
values for 12-moth prevalence of wheeze were found in developed English-speaking countries
(e.g. Peru and Costa Rica). There were considerable variations within regions, e.g. the 12 months
prevalence in the 13-14 years-old age group varied within Europe from <5% in Centres in
Albania, Georgia, Greece, Italy, Romania, and Russia; to >30% in the UK; and within Latin
America from <10% in centres in Argentina, Chile, and Mexico to >25% in centre in Brazil and
Peru.

Asthma in Children 317

The analysis shows that there is consistently more variation between countries than within
countries. Three countries with a very large number of centres were represented across the
range of prevalence, India with 14 centres representing the low prevalence group, Italy with
14 centres representing the middle prevalence group and the UK with 15 centres representing
the high prevalence group. However, it must be remembered that the countries, and centres
within countries were self-selected, and it is possible that countries with larger within-country
variation did not participate.
The only other comparable international survey of asthma is the European Community
Respiratory Health Survey (ECRHS),4,5 which studied males and females aged 20-44 years.,
mainly from European centres. Among the 13 centres 10 countries that were reported in both
studies, the ranking of prevalence of wheeze in the last 12 months was similar, with the
English-speaking countries (Australia, New Zealand, Republic of Ireland, and the UK) having
the highest and Italy and Greece the lowest rates. Subsequent other studies from different
parts of the world also show similar trends.6-14
Indian Scene
The ISAAC data from 12 different parts of the country shows wide variability in the history of
wheeze over a 12 months period in children between 13-14 years-old age group ( Table 21.4).
In Akola the prevalence was 1.6% whereas the highest figures was reported from Kottayam
(17.8%) in the South. The children from this town also had history of Ever had asthma of
12.4%. The prevalence was also the highest 24.6% from Kottayam in the 6-7 years-old age
group (Table 21.5). There is a difference in the prevalence of asthma in children from Northern
and Southern part of the country. From the Northern part of the country the figure varied
between 5.4 to 6.9% in the 6-7 years-old age group. The figures from the Western part were less
compared to those from the Northern and Southern regions.5 Another hospital based study
from South India, Bangalore on 20,000 children under the age of 18 years from 1979, 1984,
1989, 1994 and 1999 in the city of Bangalore showed a prevalence of 9%, 10.5%, 18.5%, 24.5%
and 29.5% respectively. The increased prevalence correlated well with demographic changes
of the city. Further to the hospital study, a school survey in 12 schools on 6,550 children in the
age group of 6 to 15 years was undertaken for prevalence of asthma and children were
categorized into three group-depending upon the geographical situation of the school in
relation to vehicular traffic and the socioeconomic group of children. Group Ichildren from
schools of heavy traffic area showed prevalence of 19.34%, group IIchildren from heavy
traffic region and low socioeconomic population had 31.14%, and group IIIchildren from
low traffic area school had 11.15% respectively. A continuation of study in rural areas showed
5.7% in children of 6-15 areas. The persistent asthma also showed an increase from 20% to
27.5% and persistent severe asthma 4% to 6.5% between 1994-99.15 Another study from Delhi
in 1999 revealed the prevalence of current asthma was 11.9% while past asthma was reported
by 3.4% of children. Exclusive exercise-induced asthma was reported by 2.1% while that
associated with colds by 2.4% of children. Boys had significantly higher prevalence of current
asthma as compared with girls (12.8% and 10.7%, respectively). Multiple logistic regression
analysis showed that male sex, a positive family history of atopic disorders, and the presence
of smokers in the family were significant factors influencing the development of asthma while
economic class, air pollution (total suspended particulates), and type of domestic kitchen fuel
were not. The prevalence of current asthma in children in Delhi is 11.9%. Significant risk
factors for its development are male sex, a positive family history of atopic disorders, and the

318 Bronchial Asthma

Table 21.4: Twelve months prevalence of bronchial asthma (%) in
school going children 13-14 years old age group in different parts of India

Region

Wheeze

4Attacks

Severe
wheeze

Exercise
wheeze

Night
cough

Ever had
asthma

Number
studied

Akola
Bombay (Area 1)

1.6
1.9

0.5
1.2

1.0
1.0

2.7
2.6

3.8
6.5

2.6
3.6

2,138
4,225

Bombay (Area 2)
Bombay (Area 3)

10.6
3.6

1.8
1.0

3.2
1.4

11.1
7.4

22.4
14.9

6.5
5.2

2,226
3,178

3.4
4.2

0.6
1.5

1.6
2.7

5.3
8.0

10.2
8.0

5.9
3.3

3,878
3,139

10.7
17.8

3.5
1.7

4.8
13.5

15.9
17.9

18.4
32.2

6.4
12.4

1,094
2,047

8.4
6.0

1.9
3.3

2.9
3.6

7.7
7.4

14.6
11.5

2.8
1.8

1,903
3,086

13.0
6.0

3.0
1.9

4.8
2.5

18.4
23.2

25.8
16.9

5.3
2.4

3,026
3,281

3.8
1.8

0.8
0.8

2.1
1.3

6.8
4.0

13.5
9.4

2.8
4.9

1,248
2,702

Borivali
Chandigarh
Jodhpur
Kottayam
Madras (Area 1)
Madras (Area 2)
New Delhi
Neyveli
Orissa
Pune

Table 21.5: Twelve months prevalence of bronchial asthma (%) in

school going children 6-7 years old age group in different parts of India

Region

Wheeze

4Attacks

Severe
wheeze

Exercise
wheeze

Night
cough

Ever had
asthma

Number
studied

Akola
Bombay (Area 1)

5.6
0.8

1.5
0.6

1.9
0,6

3.6
1.0

12.3
3.3

3.7
1.3

31,697
2,030

Bombay (Area 2)
Bombay (Area 3)

3.8
1.8

1.3
0.7

1.6
0.7

3.0
1.8

12.6
8.3

3.8
2.3

3,967
3,568

Borivali
Chandigarh

5.2
5.4

2.0
1.9

1.7
2.8

3.1
3.8

12.3
10.7

3.4
2.8

1,672
2,891

3.5
24.6

1.3
4.7

1.4
7.5

2.9
13.3

13.6
27.0

4.1
14.4

1,104
2,156

Madras (Area 1)
Madras (Area 2)

7.2
8.5

2.1
2.4

1.4
2.5

2.5
3.8

16.4
15.4

1.4
2.2

1,406
2,491

New Delhi
Neyveli

6.9
1.5

1.4
0.1

1.6
0.3

4.1
1.4

14.6
8.1

3.7
1.0

2,938
1,498

Orissa
Pune

4.1
2.3

1.4
1.0

2.2
1.3

3.8
2.5

8.7
9.5

3.8
4.2

1,520
3,248

Jodhpur
Kottayam

presence of smokers in the family.16 A more recent study from Chandigarh, North India
examined the prevalence of asthma and its association with environmental tobacco smoke
exposure among adolescent school children. Using a previously standardized questionnaire,
data from 9,090 students in the 9 to 20 years age range were analyzed. There were 4,367 (48%)
boys, in whom the observed prevalence of asthma was 2.6%. Among 4,723 (52%) girls, asthma

Asthma in Children 319

was present in 90 (1.9%) students. 31% students reported presence of one or more respiratory
symptoms. More students with asthma had either parents or other family members smoking
at home as compared to nonasthmatics (41% vs. 28%, p<0.0001). The odds ratio for being
asthmatic for patients exposed to ETS compared to those not exposed to ETS was 1.78 (95%
confidence interval 1.33-2.31). ETS was also positively associated with prevalence of all the
respiratory symptoms, with odds ratios varying between 1.6 and 2.25.17
Risk Factors
A number of risk factors have been identified for the causation of bronchial asthma in children.
They include male sex a positive family history of atopic disorders, and the presence of
smokers in the family,16 urbanization, air-pollution, environmental tobacco smoke,15,17 and
other socio environmental factors.18
Intrauterine Exposure
Some studies have suggested a link to maternal, not paternal, allergy in the development of
allergy and asthma. While it has been suggested that preferential acquisition of the mothers
genes (genomic imprinting) may account for this phenomenon, such an occurrence is
excessively uncommon and the intrauterine environment is a more likely cause. A positive
relationship has been found between greater head circumference at birth and the later
development of allergy and high serum IgE levels. At first, such an association may sound
strange, but placental and nutritional factors that increase brain growth in the last trimester
of pregnancy may well influence the maturation of the thymus gland, the origin of the immune
system. It has been suggested that after 26 weeks gestation, the fetus adopts a Thl immunephenotype, to prevent maternal rejection and that, in the last trimester, with increased IFN-
production, this phenotype converts to a more Thl picture. IL-4 is produced by the human
amnion epithelium throughout pregnancy, and IL-10, a cytokine that inhibitors have been
found in human placenta. If, on account of factors, the Th2 mode is maintained rather than
converting to a Thl mode, an allergic diathesis might be expected to occur. Such a mechanism
might also be invoked as a factor in sudden infant death syndrome in which mast cell tryptase
and eosinophils are encountered in the lung and circulation.
It is also possible that allergens crossing the placenta may be involved in subsequent
development of allergy and asthma since mothers exposed to high concentrations of allergens,
such as birch pollen, during the last trimester of pregnancy are more likely to have children
who develop allergy and asthma. It is not known, however, how minute amounts of allergen
taken in by the mother can cross the placenta to sensitive offspring. However, it has been
shown, that children who subsequently develop allergy or asthma, have impaired cord blood
T-lymphocyte production of IFN- at birth in response to exposure to specific allergens. This
impaired response suggests an impaired inhibitory mechanism for shutting down a Th2
response rather than one that primarily enhances it. Other environmental factors that may
direct the placental-fetal relationship towards a Th2 response include young maternal age
and smoking during pregnancy.
Several studies have reported an increased prevalence of respiratory symptoms like cough,
wheeze and reduction in lung function in children or adolescents who were born as premature
infants or who had a low birth weight.19,20

320 Bronchial Asthma

Viral Infection
It has long been recognized that viral infections, especially the common cold viruses, can lead
to deterioration of asthma lasting several weeks. In infants, respiratory syncytial virus (RSV)
is responsible for most wheezing illnesses. These observations have suggested that viral
infections may be intimately involved in the development of asthma and allergy. It has been
shown that over 80% of acute asthma exacerbations in school children and about 60% in
adults result from viral infections (mostly common cold viruses). One explanation of the
susceptibility of the asthmatic airway to viral inflammation is that persistent allergic mast
cell and eosinophil-driven inflammation stimulates the release of cytokines such as tumour
necrosis factor-alpha, which cause an increase in the expression of receptors for human
respiratory viruses on the airway lining epithelium. In the case of most rhinoviruses, the
receptor is an adhesion molecule, intracellular adhesion molecule-1. Once the virus enters the
epithelial cells, it replicates and is able to generate wide variety of proinflammatory cytokines,
which further enhance eosinophil and mast cell inflammation.
Protective Infections
Curiously, an important additional socioeconomic factor may be a reduction in early childhood
infections (viral, bacterial, or parasitic) associated with improved living conditions. While
viral infections can undoubtedly cause deterioration of established asthma, there is evidence
that viral or bacterial infection during the first 3 years of life may serve a protective function
against the development of allergic diseases.
One of the most consistent risk factors for allergy relates to family size. The prevalence of
mucosal allergy and positive skin tests in children declines markedly in the last-born child
with increasing numbers of siblings. A working hypothesis is that over the past 30 years,
opportunities for acquiring infections from siblings or playmates in early childhood have
declined with reduction in average family size, vaccination programs, and higher standards
of personal hygiene. Most viruses and some bacteria are able to evoke a Thl like protective
response with the generation of IFN- and IL-12. Thus, if multiple infections occur during the
first few years of life, high concentrations of these Th1, cytokines could inhibit the release of
Th2 cytokines, thereby biasing the mucosal immune response away for this hypothesis is
seen in an African study of, from allergen sensitization. Support adolescents infected with
measles during the first year of life compared to those vaccinated later. Those infected early
had a 63% lesser chance of developing positive skin tests to common aeroallergens. Repeated
Bacille Calmette-Guerin (BCG) vaccination in young Japanese children also exerts a protective
effect against the development of allergy. Both measles and BCG are potent stimulatorsof
the Th1 cytokine response.
It has also been suggested that the increase in asthma and allergy with movements to
urban centres may be related to the decrease in early exposure to parasitic infections common
in some rural areas. One study tested the effect of anti-helminthic treatment on the allergic
reactivity of children in a slum area of Caracas, Venezuela. One group was treated for 22 months
while a second group who declined treatment was used as a control. Active treatment
eliminated worms in children (from 68 to 5%) and resulted in a decrease in total serum IgE
levels (from 2,543 to 1,124 IU/ml) but was accompanied by an increase in skin test reactivity
to house dust mite (from 17 to 68%). In contrast, in the untreated group, parasite colonization
continued to increase (43 to 70%), IgE levels increased (1,649 to 3,697 IU/ml), but dust mite

Asthma in Children 321

sensitization fell (26 to 16%). Further testing showed that polyclonal stimulation of IgE
synthesis by the parasites resulted in mast cell receptor saturation and suppression of specific
IgE antibody synthesis. From a public health stand point; high levels of nonspecific IgE may
protect rural dwellers exposed to parasites from allergy and asthma. It follows that eradication
of parasites or reduced opportunities for infection could, in part, explain the rural to urban
differences in the prevalence of allergic diseases.
Some investigators believe that early childhood respiratory symptoms are a risk factor for
asthma.21 This inference however, is weakened by the possibility of recall bias. Perhaps,
respiratory symptoms reported by parents very early in life are not significantly associated
with future asthma, but those symptoms that begin at or persist through age 3 to 4 years are
likely to be associated with asthma.22
Diet
As societies become affluent, the dietary habits change and such changes are linked with
increased prevalence of asthma observed in recent years.23-25 Prospective studies have shown
that breastfeeding has a transient beneficial effect on the incidence of eczema, food allergy,
atopic sensitization, and wheezing illness in the first three years of life.26,27 However, there is
little evidence for a persistent protective effect of breastfeeding on the incidence of childhood
asthma.28-30 In the UK, the amount of salt eaten with food seems to be correlated with bronchial
hyperreactivity and asthma mortality.31 The severity of asthmanot its inceptionhas been
linked to increased salt intake, but only in males.32 Recent studies have shown lower prevalence
of asthma and bronchial hyperresponsiveness in children with a high intake of fresh oily
fish,33 a source of polyunsaturated oils. Other studies also have shown an association of a,
high fish consumption and improved baseline FEV1.34 Children who eat fish regularly
consume more omega-3 fatty acids, which may protect them from bronchial hyperresponsiveness.
Air-Pollution
Air-pollution has been cited asa causal factor in the development of asthma. The US
Environmental Protection Agency concludes that35 passive exposure to tobacco smoke is
causally related to:
i. An increased risk of lower respiratory tract infections, such as bronchitis and pneumonia
in infants and young children,
ii. A small but significant dose-dependent reduction in pulmonary function, and
iii. Additional episodes and increased severity of asthma symptoms in asthmatic children.
Exposure to tobacco smoke is also considered to be a risk factor for the development of new
cases of asthma in children.36 Trucson Childrens Respiratory Study has shown that
maternal smoking is related to both transient early wheezing and persistent wheezing.37 The
role of sulphur dioxide and particulate matters in the causation of asthma is not well
established.38-41 Traffic pollutions42 and effects of ozone may also be of consequence for
childhood asthma.43
Evolution of Asthma
Asthma may develop during the first few months of life, but it is often difficult to make a
definite diagnosis until the child is older. In infants, the most common cause of wheezing is

322 Bronchial Asthma

respiratory viral infections. However, there is a correlation of early wheeze with reduced lung
function before the onset of symptoms, which suggests that small lungs may be responsible
for some infant wheeze that resolves with the childs growth. Those children with asthma
continue to wheeze in later childhood. Recurring exacerbations of asthma may be associated
with exposure to allergens. In the susceptible infant, atopy may predispose the airways to
sensitization by environmental allergens or irritants and the child experiences recurrent
episodes of wheezing. In particular, early exposure to Alternaria, housedust mite, and animal
allergens in high quantities appears to be important as discussed above.
During early childhood, wheezing and cough may occur at infrequent intervals. In some
infants wheezing becomes more frequent and asthma is well established at an early age. It is
reported that the majority of 7-years-old children with airway hyperresponsiveness suffered
from atopy during their infancy.44 Asthma also affects development of the lung. Asthma in
infancy can result in a decrease in lung function by approximately 20% in adulthood,45
although subsequent studies did not confirm the same.46
The predominant feature associated with asthma in children is allergy, and house dust
mite represent major allergens worldwide in, both affluent and partly affluent countries.47
The role of viral infection in the causation of asthma in older children is less clear, although
in atopic children viral infection is clearly important triggers of asthma exacerbations. By the
age of 8 years, a proportion of children develop airway hyperresponsiveness and the associated
symptoms of moderate to severe persistent asthma, while others continue to have mild
intermittent asthma.48 Lung growth is unaffected in most children with asthma, but it can be
reduced throughout childhood and adolescence in those with severe and persistent symptoms.
A longitudinal study in New Zealand concluded that improved spirometric function was
impaired in children with airway hyperresponsiveness and/or allergy to house dust mite or
cat allergen.49
Although childhood asthma has long been considered as a single, easily recognizable
disease characterized by reversible airflow limitations,50 recent findings have challenged this
concept. Martinez et al21 studied the natural history of children (0-6 years) and found that
approximately half of them experienced wheezing at some time during the study period. They
recognized three patterns of wheezing:
1. Transient early wheezing. Wheezing occurred in life but resolves by the age of three years
2. Late onset wheezing. Some experience wheezing between the ages of three and six years
3. Persistent wheezing. Wheezing illness throughout the entire study period.
The outcomes of these patterns are associated with different risk factors. Children with
transient early wheezing had reduced pulmonary function as measured by functional residual
capacity shortly afterbirth and before any lower respiratory tract illness had occurred. The
risk also increases in childrenof mothers who smoked during pregnancy, had lower lung
function values compared to those whose mothers did not smoke. Thus, the authors concluded
that congenitally smaller airways might predispose children to wheeze illness later in life.
Persistent and late onset wheezing is more likely associated with atopy with their mothers
being asthmatics. Lung function in persistent wheezers is also less.
The long-term prognosis of childhood asthma is a matter of controversy and of major
concern. It has often been believed that the child grows out of its asthma when he or she
reaches adulthood (asthma disappears). However, epidemiological studies are less
convincing.46,51,52 Although there are methodological difficulties it is estimated that asthma
disappears in 30 to 50% of children at puberty, but often reappears in adult life. Up to

Asthma in Children 323

two-third of children with asthma continue to suffer from the disorder through puberty and
adulthood. Even when asthma symptoms disappear, the lung function frequently remains
altered or airway hyperresponsiveness or cough persists. The prognosis of asthma becomes
worse when the child has eczema or there is a family history of eczema. Wheezing in the first
year of life is not a prognostic indicator for asthma or for more severe asthma or for more
severe asthma later in childhood. About 5 to10 % of children with asthma that is considered
trivial will have severe-asthma in later life. Therefore, childhood asthma should never be
neglected with the hope that the child will grow out of it. Children with mild asthma are likely
to have a good prognosis, but those with a moderate to severe asthma probably continue to
have some degree of airway hyperresponsiveness and will be at risk of the long-term effects of
asthma throughout life.53 Some, clinical studies have reported that up to 80% of asthmatics
become asymptomatic during puberty.54,55 In a cohort study of Australian school children56
tested initially at the age of 8 to 10 years and then again at 12-14 years of age, the persistence
if bronchial hyperresponsiveness at 12 to 14 years of age was found to be related to the
severity of disease at 8 to 10 years of age, the atopic status of the child, and the presence of
asthma in the parents. Most of the children who had a slight or mild degree of bronchial
hyperresponsiveness at 8 to 10 years of age lost their increased response by the age of 12-14
years. However, only 15.4% of children with severe or moderate bronchial hyperresponsiveness
at initial assessment had normal levels of bronchial responsiveness at the later assessment.
There are several factors why asthma often goes unrecognized and tends to be under treated
in teenagers because usually this is a period of turmoil, awkwardness, rebelliousness, and
intolerability.53-59
Notwithstanding the factors described above as the factors responsible for the induction of
asthma in childhood, occurrence of asthma within families is the strongest risk factor for the
development of asthma in children.60-63
DIAGNOSIS
Various symptoms and signs of bronchial asthma are not different than those in adults as
discussed earlier. However, in children there is more chance of under diagnosis in this age
group. This is a frequent problem and occurs most often when young children who wheeze
only when they have respiratory infections and are dismissed as having wheezy bronchitis,
asthmatic bronchitis, bronchitis, bronchiolitis, or pneumonia, despite evidence that the signs
and symptoms are most compatible with a diagnosis of bronchial asthma.
Although, recurrent episodes of cough and wheezing are almost always due to asthma in
both children and adults, it is to be remembered that all that wheezes is not asthma always.
There are other causes of airways obstruction leading to wheezing. The differential diagnosis
will be as follows.
Infants and Children

Obstruction in the Large Airways

1. Foreign body in trachea, bronchus
2. Vascular rings
3. Laryngotracheomalacia

324 Bronchial Asthma

4.
5.
6.
7.

Enlarged lymph nodes or tumors

Laryngeal webs
Tracheal stenosis
Bronchial stenosis

Obstruction Involving both Large and Small Airways

1.
2.
3.
4.
5.
6.
7.
8.
9.

Bronchial asthma
Viral bronchiolitis
Cystic fibrosis
Chlamydia trachomatis infection
Obliterative bronchiolitis
Bronchopulmonary dysplasia
Aspiration
Vascular engorgements
Pulmonary oedema

Miscellaneous
1.
2.
3.
4.

Primary ciliary dyskinesia syndrome

Primary immune deficiency
Congenital heart disease
Congenital malformations causing narrowing of intrathoracic airways.

Asthma in childhood can present a particularly difficult problem largely because episodic
wheezing and cough are among the most common symptoms encountered in childhood
illnesses, particularly in the under-3-years-old. Although health care professionals are
increasingly encouraged to make a positive diagnosis of asthma whenever recurrent wheezing,
breathlessness, and cough occur (particularly if associated with nocturnal and early morning
symptoms), the underlying nature of the disorders process may differ in infants from that in
older children and adults. The use of the label asthma to describe such children has important
clinical consequences. It implies a syndrome in which there is airway inflammation and for
which there is a specific protocol of management. The younger the child, particularly below
ages 5, the greater the possibility of an alternative diagnosis for recurrent wheeze as described
above. Chest radiography is important as a diagnostic test to exclude alternative causes.
Features such as a neonatal onset of symptoms, associated failure to thrive, vomitingassociated symptoms, and localized lung or cardiovascular signs all suggest an alternative
diagnosis and indicate the need for investigations, such as a sweat test to exclude cystic
fibrosis, measurements of immune function, and reflux studies.
Among those with no alternative diagnosis, there is the possibility that the problem does
not have a uniform underlying pathogenesis. Nonetheless, there are two general patterns of
wheezing in infancy. Some infants who have recurrent episodes of wheeze associated with
acute viral respiratory infections, often with a first episode in association with respiratory
syncytial virus (RSV) bronchiolitis, come from nonatopic families and have no evidence of
atopy themselves. These infants usually outgrow their symptoms in the preschool years and
have no evidence of subsequent asthma, though they may have minor defects of lung function

Asthma in Children 325

and airway hyperresponsiveness. This syndrome may have more to do with airway geometry
than airway inflammation, and thus may differ mechanistically from the more established
chronic inflammatory condition that underlies asthma in older children and adults.
Other infants with asthma have an atopic background often associated with eczema and
develop symptoms later in infancy that persists through childhood and into adult life. In
these children, characteristic features of airway inflammation can be found even in infancy.
However, there are no practical clinical tests that can be done to establish the presence of
airway inflammation. Only associated atopic problems can be used as a guide to prognosis.
Early age (less than 2 years) of onset of wheeze is a poor predictor of continuing problem in
later childhood.
It is likely that the issue of asthma associated with recurrent virus-related episodes and the
later development of persistent asthma requires further study. Apart from the confusion over
aetiological mechanisms of asthma in childhood, there is also considerable reluctance in
establishing a diagnosis and, as a consequence, initiating appropriate therapy. Because lower
respiratory tract symptoms similar to symptoms of asthma are so common in childhood (and
frequently occur in association with upper respiratory tract symptoms), either a correct
diagnosis is not made or an inappropriate diagnosis is given, thereby, depriving the child of
antiasthma medication.
Although in these young children there is the possibility of over treatment, the episodes of
wheezing may be foreshortened and reduced in intensity by the effective use of antiinflammatory drugs and bronchodilators rather than antibiotics, and it is for this reason that
health care professionals are encouraged to use the word asthma rather than other
terminology to describe this syndrome.
Asthma in all age groups may present only as repeated coughing especially at night, with
exercise, and with viral illness, but these are particularly common forms of presentation of
asthma in childhood. The presence of recurrent nocturnal cough in an otherwise healthy
child should raise awareness of asthma as a probable diagnosis. Although repeated infections
of the sinuses, tonsils, and adenoids may explain nocturnal coughing, the occurrence of this
symptom awaking the child in the early hours of the morning is almost always diagnostic of
asthma.
Under the age of 5 years, the diagnosis of asthma has to rely largely on clinical judgment
based on a combination of symptoms and physical findings. Because the measurement of
airflow limitation and airway hyperresponsiveness infants and small children requires
complex equipment and is difficult, it can therefore only be recommended as a research tool.
A trial of treatment is probably the most confident-way in which a diagnosis of asthma can be
secured in children (and in many adults as well). Prognostic features include a family history
of asthma or eczema and presence of eczema in a young child with respiratory symptoms.
Children aged 4 to 5 can be taught to use a peak expiratory flow (PEF) meter and obtain
reliable readings. However, unless there is careful parental supervision over when and how
the measurements are made, PEF recording in childhood can be unreliable.
Some children with asthma only present with exercise-induced symptoms. In this group,
or when there is doubt over the existence of low-grade asthma in childhood, exercise testing
is helpful. A 6-minute running protocol is easily performed in clinical practice, and when
used in-conjunction with measurements of airflow limitation (FEV, or PEF), it can be most

326 Bronchial Asthma

helpful in establishing a firm diagnosis, especially if the cough produced by the exercise is
similar to that occurring spontaneously at night.
MANAGEMENT OF ASTHMA IN CHILDREN
Several guidelines have been published since 1990 with the aim of improving management of
asthma both in children and adults. However, a systematic analysis of guidelines till 1995
had brought out several controversial-issues as well as gaps in knowledge. In May 1997, an
expert committee of the National Heart Lung and Blood Institutes of USA published guidelines
about management of asthma where they have tried to overcome many of the previous lapses.
These guidelines along with the recent British thoracic society guideline have been discussed
in previous chapters.
The need for similar guidelines has always been felt amongst the physicians managing
children in India, but no uniform guidelines are available for the disease as seen in India. It.
was felt that the guidelines originating in India would have much more relevance to the
ground situation and the status of health services. To setup the process of achieving consensus,
towards suitable guidelines, a Consensus Conference was held on April 17 and 18, 1998 at
the Advanced Paediatric Centre of the Post Graduate Institute of Medical Education and
Research, Chandigarh in which, 15 experts who manage asthma patients and have published
papers in this field, participated. Recent evidence was accessed using searches on Medline,
Embase, Index Medicus, and Excerpta Medica. Some of the contentious issues were resolved
with the help of the Cochrane Library.64 Since the consumer of health care in India is not
sufficiently literate, physicians have been assigned a lot of responsibility in decision making
for the patients. The guidelines are required to be updated periodically and provide flexibility
to individualize patients. Since in a large area in our country, all the recommended modalities
may not be available then suitable improvisations must be made.
The objectives of the conference were:
i. To reach at a uniform treatment approach towards children with asthma keeping in
mind the limitations of resources in the Indian context and to develop guidelines based
on available evidence for the pediatricians, and
ii. To prepare a consensus document for management of children with asthma which
would provide guidelines to a general pediatricians managing asthma in India.
Various components discussed included pathogenesis, definition, classification of severity,
measure of assessment and monitoring, referral, control of factors contributing to asthma in
seventy, pharmacological therapy and education of patient, family and health professionals
regarding asthma care.
The Expert Group I recommended that for the diagnosis of asthma in children a detailed
medical history, careful physical examination and peak-expiratory flow rate (PEFR)
measurement to demonstrate obstruction with reversibility of variable airflow obstruction are
needed. To establish the diagnosis of asthma the clinician must determine that:
i. Episodic symptoms of airflow obstruction, more than 3 episodes are present
ii. Airflow-obstruction is at least partially reversible
iii. Alternative diagnoses are excluded.

Asthma in Children 327

Physicians who care for children with asthma should be well versed in PEFR monitoring.
They should perform spirometery wherever possible.
Measures of Assessment and Monitoring
A child with asthma is to be monitored for clinical signs and symptoms of asthma with the
help of asthma diary given to the patients/parents and record of PEFR with a standardized
peak flow meter. PEFR must be monitored at the physicians office, asthma clinics (where
spirometry should be available) and in the emergency room, and patients must be encouraged
and trained to monitor their PEFR at home once a day routinely and twice a day if the morning
reading is abnormal to determine their PEFR variability. Patients personal best should be
assessed and used subsequently. Spirometry has been kept optional, and emphasis must be
given to patients quality of life. Emphasis must be on self-management but physicians
supervision must still be the prima mode. Patients must be given a written crisis management
plan where literate. Otherwise verbal communication at each contact must continue.
Classification of Asthma Severity
Asthma severity classification was accepted as changed to be mild intermittent, mild persistent,
moderate persistent and severe persistent asthma (Table 21.6). Since spirometry is not routinely
available to pediatricians in this country it was felt that more emphasis be placed on PEFR
measurement, especially at the physicians office. Patients personal best be used as the
standard but in its absence expected PEFR according to norms published on children in India
must be used.65 It was also mentioned that a severe form of asthma requiring daily oral
steroids or stronger treatments like immunosuppressants is extremely uncommon in Indian
children, and most of the children get controlled with inhaled medications.
Goals of Asthma Therapy
The goals of asthma therapy are:
Prevent chronic and troublesome symptoms
Maintain near normal (PEFR)
Maintain normal activity levels (including exercise and physical activity)
Prevent recurrent exacerbations of asthma and minimize the need for emergency room
visits and hospitalization
Provide optimal pharmacotherapy with minimal side effects
Meet patients and familys expectations of satisfaction with asthma care.
Pharmacological Therapy
Pharmacological therapy is the cornerstone of management. It must be instituted with proper
environmental control measures. Medications are classified into two broad categories:
i. Long-term control medications or the preventatives, and
ii. Medications or rescue medications. Long-term control medications, are, inflammatory
compounds. Early intervention with inhaled steroids can improve control and normalize
lung function, and preliminary studies show that it might prevent irreversible airway
injury. These are to be administered with the help of a metered dose inhaler (MDI) and

328 Bronchial Asthma

a spacer (in patients who cannot afford the spacers a home-made spacer can be used).
Another cheaper alternative is a dry powder inhaler (transparent rotahaler). A step care
approach management of asthma starting at a higher level and then stepping-down as
control is established (Table 21.7). Table 21.8 gives details of assessment of severity of
asthma in children and Figures 21.1 and 21.2 outline management of asthma
exacerbation.
Table 21.6: Classification of asthma severity

Guide

Symptoms

Night-time symptoms

Lung Function

Severe
persistent
Step 4

Continual symptoms

Frequent

PEFR < 60 %
predicted

> 1 time/week

PEF>60 to <80%
predicted

>2 time/month

PEF 80 % predicted

2 time/month

PEF 80 %

Moderate
persistent
step 3
Mild
persistent
step 2
Mild
intermittent
step 1

Limited physical activity

Frequent exacerbations
Daily symptoms
Daily use of beta-agonist
Exacerbation affecting activity,
2/weeks, lasting days
Symptoms > 2/week
But <1 /day
Exacerbation may affect activity
Symptoms 2/week
Exacerbation brief,
Asymptomatic between
exacerbations

The presence of one of the features is sufficient to place a patient in that category. A child should be
assigned to the most severe category in which any feature occurs. An individual classification may
change over a period of time
Table 21.7: Stepwise approach in long-term management of children with asthma

Grade

Long-term

Severe
Daily therapy high dose inhaled, steroid
pesistent (BDP 1200 g or BUD>600 or FP*
step 4
200-400 g + Long acting beta sympathomimetic or SR Theophylline or oral
steroids. For infants 2 years inhaled
medication with spacer and/or mask
Moderate Daily therapy. Medium-dose inhaled
pesistent steroid (BDP 600-1200 g or BUD
step 3
400-600 or FP 100-200 g) or
Low-medium dose inhaled steroid +
SR Theophylline or long acting beta
sympathomimetic. For infants inhaled
medication with spacer and mask
Mild
Daily medication NSAIDs like Cromolyn
persistent (1-5 mg/dose Oh) or low-dose inhaled
step 2
steroid (BDP 200-600 or BUD 100-400 or

Quick relief

Education

Short-acting broncho- Step 1 + selfdilator. Infants as

monitoring
in step 1
Group education

Short-acting broncho- Step 1 + selfdilator Infants as

monitoring
in step I
education/
counselling

Short-acting broncho- Step 1 + selfdilator. Infants as in

monitoring
step 1
Group education

Contd...

Asthma in Children 329

Contd...
Grade

Mild
asduna,
intermittent
step 1

Long-term

Quick relief

Education

FP50-100 g) and Theophylline 5-15 mg/kg

spacer and mask for infants 2 years
No daily medications needed
Short acting bronchodilator, inhaled 2
agonists sos use of
2-agonist > 2 times/
week indicates need
for preventative drugs.
For infants (< 2 years)
bronchodilator as
needed for symptoms.
Use facemask with
holding chamber or
nebuliser or oral 2agonist

Basic facts about

inhaler
technique,
discuss role of
medication, selfmanagement
and action
plans, environmental control

Abbreviation: BDP-beclomethasone dipropionate, BUD-budesonide, FP-fluticasone propionate,

SR-sustained release, FP is recommended for children older than 4 years
Table 21.8: Classifying severity of asthma exacerbations

Mild

Moderate

Severe

While at rest
(infantstops
feeding)

Can lie down

While talking
(infantsofter,
shorter cry; difficult
feeding)
Prefers sitting

Phrases

Words

Symptoms
Breathlessness While walking

Talks in
sentences
Alertness

May be agitated Usually agitated

Signs
Respiratory rate Increased

Increased

ReiTiratory Arrest
Imminent

Sits upright

Usually agitated

Drowsy/confused

Often >30/ m

(Guide to breathing rates in awake children):

Age
Normal rate
< 2months
< 60/niin
< 2-12 months < 50/n-dn
1-5 years
< 40/n-dn
6-8 years
< 30/min
Use of
accessory
muscles:
Suprasternal
retractions

Usually not

Commonly

Usually

Paradoxical thoracoabdominal movement

Contd...

330 Bronchial Asthma

Contd...
Mild

Moderate

Severe

ReiTiratory Arrest
Imminent

Wheeze

Moderate
often only
end expiratory

Loud; throughout
exhalation

Usually loud;
throughout
inhalation and

Absence of wheeze

Pulse/min

< 100

100-120

> 120

Bradycardia

(Guide to heart rate in normal children):

Age
Normal rate
2-12 months
< 160 min
1-2 years
< 120 min
2-8 years
< 110 min

Ask and record

Examine for

1.
2.
3.
4.

1. Sensorium
2. Respiratory rate, heart rate, colour, use
of accessory muscles, breath sounds
intensity, wheeze
3. Saturation-SaO2 if pulse oxymeter is
available
4. Peak expiratory flow rate

Duration of present episode

Medications already being used
Time of last aminophylline dose (if taking)
Precipitating factorsinfections, exercise,
drugs, stress, seasonal, etc.
5. Severity of previous episodes of treatment
required

Treatment Phase IIst one hour

1. Oxygen by mask to achieve saturation >90% (minimum 5 L/min through simple facemask)
2. Start 2 sympathomimetic nebulisation 0.15 mg/kg/dose (minimum dose 2.5 mg) every 20 min
for 3 doses. For delivery dilute aerosols to minimum of 4 ml of saline at (flow of 6-8 1/minutes)
or 2 sympathomimetic through MDI and spacer with/without facemask 4 to 8 puffs every
20 minutes (10-20 puffs in one hour).
In case of nonavailability of nebuliser or MDI and spacer or where the patient cannot move
the needle of the peak flowmeterparenteral beta-agonists (adrenaline/terbutaline) should
be given in the dose of 0.01mg/kg up to 0.3 to 0.5 mg every 20 minutes for 3 doses in the first
hour subcutaneously.
3. All children presenting with acute exacerbation should receive systemic steroids. Prednisolone 2 mg/kg/dose or methylprednisolone 1-2 mg/kg/dose or hydrocortisone 10 mg/kg/dose.
At the end of hour repeat assessment with more emphasis on symptoms and signs, PEFR
done if possible. In interpreting PEFR value is compared with predicted value of Indian children or personal best of the child if available. From the assessment 2 groups are identified:
A. Good response
Physical examination normal (decrease in heart rate from the previous value, respiratory rate,
pulses paradoxus <10 mm Hg, no usage of accessory muscles, alert sensorium) O2 saturation
>90 per cent, PEFR>70%.
B. Incomplete response/poor response
Mild to moderately severe symptoms and signs (see Table No. 21.8) for mild, moderate and
severe classification of symptoms signs, PEFR< 50 to < 70%.

Contd...

Asthma in Children 331

Contd...
Phase IIManagement
A. Good response group
- Discharge home,continue treatment with 2-agonist and course of oral systemic corticosteroid 1-2 mg/kg/day maximum 60 mg/day in a single or 2 divided doses for 3-10 days.
- Patient education, review medicine use, initiate action plan, recommend close medical
follow-up.
B. Incomplete/Poor responders
- Continue O2, 2-sympathomimetic inhalation every 20 mts Continuous nebulization can
also be used under strict monitoring for heart rate and blood potassium levels.
- Continue systemic steroids.
- Add ipratropium bromide nebulization 250 micrograms every 20 mts for three doses, May
mix in same nebulizer with 2-sympathomimetic.
- If no response, aminophylline infusion, (0.25 mg/kg/hr) can be tried.
- IV Magnesium sulphate 50% 50 mg/kg/dose IV infusion in 30 ml normal saline/30 mt can be
given before transfer to ICU.
Continue to assess every onehour, continue same treatment for 4 hours.
Improvement at end of 6 hours since initiation of treatment decrease the frequency of 2sympathomimetic inhalations every 1 to 4 hr as needed, Stop parenteral aminophylline, Continue systemic steroids 1-2 mg/kg/day in 2 divided doses for 3-10 days.
If no deterioration continue same treatment.
If deterioration, follow intensive care of the child with asthma in pediatric ICU for possible intubation and mechanical ventilation in presence of:
i. Exhaustion, shallow respiration, confusion or drowsiness
ii. Coma/respiratory arrest
iii. Worsening or persisting hypoxia.
Fig. 21.1: Management protocol for acute exacerbation of
childhood asthma emergency room

Assess Severity
Measure PEF: Value <50% personal best or predicted suggest severe exacerbation
Note signs and symptoms: Degrees of cough, breathlessness, wheeze and chest tightness correlate
imperfectly with severity of exacerbation. Accessory muscle use and suprasternal retraction
suggests severe exacerbation.
Initial Treatment
Inhaled short-acting beta-agonist: Up to three treatments of 2-4 puffs by MDI at 20-minute intervals
or single nebuliser treatment.

Good response

Incomplete response

Poor response

Mild episode
PEF>80% predicted or
personal best

Moderate episode
PEF 50-80% predicted or
personal best

Severe episode
PEF<50% predicted or
personal best

Contd...

332 Bronchial Asthma

Contd...
No wheezing or shortness
of breath
Response to 2-agonist
sustained for 4 hours
May continue 2-agonist
every 3-4 hours for
24-48 hours
For patients on inhaled
corticosteroids, double dose
for 7-10 days

Persistent wheezing or
shortness of breath
Add oral corticosteroid
Continue 2-agonist

Marked wheezing or
shortness of breath
Add oral corticosteroid
Repeat 2-agonist
immediately
If distress is severe
and nonresponsive,
call your doctor and
proceed to emergency
department, consider
calling ambulance

Contact clinician for

follow-up instructions

Contact clinician urgently

(this day) for instructions

Proceed to emergency
department

Fig. 21.2: Home treatment of asthma exacerbation in children

Referral
Patients must be referred to a special clinic of asthma if any of the following problems arise:
Failure to meet the goals of therapy
Atypical signs or symptoms or uncertain diagnosis
Presence of complications
Need for additional diagnostic testing like skin tests, pulmonary function tests endoscopy,
incremental growth assessment etc.
Severe symptoms such as step 4 care
Nonadherence to therapy
Need for good asthma education
Significant psychosocial or psychiatric problems
Environmental Control and Prevention of Asthma

Allergen Avoidance
Indoor allergens Cockroach, house dust mite, fungal spores, animals (pets) are the main
sources. Skin testing can be used, for the diagnosis. Following control measures are suggested.
Cockroaches Leave no food uncovered. Traps are better than the anticockroach chemicals.
House dust mite Sun the bedding weekly. No carpets or stuffed, the house. Proper mapping
of the country needs I to be done to see where dust mite is an important allergen-expected in
warm, humid climate.
Pets Pets like dogs, cats or birds should not be kept. Reports on pets are very few in this
country. If pets are already in the house contact with the patients should be minimized or they
should be kept out of the premises.
Moulds or indoor fungal spores Prevent see page of water through rooms or walls during the
rainy season. Keep rooms well ventilated and allow sunlight in.

Asthma in Children 333

Seasonal exposure to pollens and fungi can be reduced by keeping the doors and windows
closed from every morning till evening. Wherever affordable, air-conditioning can be used. In
case an allergen is found to contribute significantly to patient problem, he or she should be
referred to a specialist for skin testing and if required, for immunotherapy. In children less
than 5 to 6 years of age immunotherapy is avoided.

Irritants or Chemicals
Avoid tobacco smoke, strong odours, fumes from various kinds of stoves/chullah, using
kerosene, wood, cowdung.
In high risk families (atopy on both sides or even one side), exclusive breastfeed to continue
for 4 to 6 months and mother to avoid well-known allergenic food in diet while baby is
exclusively breastfeed.
Psychosocial Aspects of Asthma Management in Children
Children with chronic illnesses are at an increased risk for developing psychological
disturbances.
Children with severe asthma have been found to be three times more likely to develop
emotional/behavioural problems as compared to healthy children. It was decided at the
meeting that the primary physician to the patient be able to deliver the necessary preventive
services like explaining the basic facts about the disease and try to improve the quality of life
by optimum care. Mental health workers can provide important services to asthmatic children,
who have obvious psychological or behavioural problems, experience school difficulties and
are noncompliant with treatments.
Family therapy aimed at modifying family interaction problems and parent-child
relationships can help in improved management of asthma and also improve the overall
quality of life. Hence, family therapy is considered an adjunct to the conventional treatment in
asthma in children with severe disease. It is important that psychologists be part of the
multidisciplinary treating team in order to provide comprehensive services to children with
asthma.
Health Education
The experts stressed the need for health education not only in asthma clinic or hospital but
also on TV, radio and other communication media. The attitudes and practices concerning
this disease demonstrate a high degree of ignorance and misinformation. Written material
containing information regarding basic facts of asthma should be made available to the
patient and the parent at the time of transmission of information regarding the diagnosis.
Special measures were recommended to be taken to educate the people about the harms of
passive smoking.
Future Directions for Research
The data presented indicates gross inadequacy of information regarding basic facts of asthma
to patients and their parents. Intervention in the form of written material significantly improves
the knowledge of these individuals. More studies need to be done to assess the knowledge,
attitudes and practices of these patients and specific materials developed to improve the
baseline information and change attitudes towards inhalational therapy. All the participants
felt that there was a local social stigma attached to the disease, and parents of the patients

334 Bronchial Asthma

were specially concerned about the inhalatinal therapy having potential for producing drug
dependence. Why incidence of asthma is relatively less in India and the disese is less severe
as compared to some of the Western countries, information regarding it is not available. More
data need to be generated towards epidemiology of asthma in this country. Research into
usefulness of yogic breathing exercises and role of Ayurveda needs to be evaluated, although
at present they have no proven scientific value.
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Index 337

Index
A

Acupuncture 261
Acute severe asthma 208, 276
anti-immunoglobulin E 248,
272
assessment 212,226
in children 285
clinical features 210
complications 211
definition 208
differential diagnosis 212
indices 213
management 215, 290
pathophysiology 209
therapeutic approach 227
Add-on therapy 268
Adhesion molecules 48
Adrenergic bronchodilators 142
Allergens 16, 20, 188
Allergic bronchopulmonary
aspergillosis 117, 272
Allergy 14, 129
management 129
Alternative and complementary
therapies 201
Alternative treatment
oral steroid dependence 161
Animal allergens 19
Anticholinergics 148
comparison 155
side effects 156
Antihistamines 159
Arachidonic acid 43
Aspirin 22, 67, 272
Assessment of asthma control
202
Asthma
definition 1
sign 99
symptoms 98
Asthma remission 89
Atopy 14

2-agonists 281
Basophils 48
Beta-adrenergic receptors 62,
139, 143
Bradykinin 52
Brittle asthma 96
Bronchial asthma
aetiology 14
complication 117
diagnosis 98
epidemiology 1
management 127
pathology 86
pathophysiology 40
pharmacologic management 134
prognosis 114
Bronchial asthma, management
127, 235
acute severe asthma 208
diet modification 258
nonpharmacologic 128, 256,
257
pharmacologic 134, 191
step-care 192, 194, 196
Bronchial hyperreactivity 40, 61
Bronchoprovocation test 103

Dietary manipulation 263

Diuretics 298
Drug-induced asthma 243
Drugs 22
Dry powder inhalers (DPI) 178

C
Childhood asthma 7
Chronic bronchial asthma 183
Chronic eosinophilic bronchitis
44
Complementary and alternative
medicine 261
Corticosteroids 151
Cough variant asthma 92
Cromones 157
Cyclosporin 163, 296
Cytokines 49, 53, 55, 250

E
Early asthmatic reaction 40
Endocrinal factors 30
Environmental factors 32, 129,
260
Environmental tobacco smoke
30
Eosinophils 44
Epithelial-mesenchymal trophic
unit 89
Exercise-induced asthma 23, 69,
235, 271
Extrinsic asthma 93
F
Fatal asthma 306
Food allergen 20
G
Gastro-oesophageal
(GER) 27, 243
Genes 32
Genetics 31
Gold salts 163, 295
Gut hormones 59

reflux

H
Heparin 297
Histamine 52
Hospital discharge 284
House-dust mite 18, 189, 259
Hygiene hypothesis 258

338 Bronchial Asthma

I

Immunotherapy 131,190
Infection 20,21
Inflammation 55, 64, 65
Inflammatory mediators 49
Inhalation therapy 176
Interleukin 249
Intrinsic asthma 93

Natural history 6
Nebulisers 179
Nedocromil sodium 158
Neural control 59
Neurogenic inflammation 60
Neuropeptides 59
Neutrophils 48
Neutrophins 58
New guidelines for asthma
management 256, 265, 276
Newer drugs 247
Nitric oxide 58, 64
Nocturnal asthma 72, 95

Refractory asthma 306

Remodelling 57, 88
Rhinitis 27, 272

K
Ketotifen 158
L
Laboratory findings 100
Late asthmatic reaction 40
Late onset asthma 93
Leukotriene 43, 49
antagonists 159
Lymphocytes 45

O
Objective tests 102
Occupational asthma 24, 70, 94,
106, 109, 241
Oxygen radicals 57

M
Macrophages 47
Mast cells 42
Mechanical ventilation 224
Mediators 58
Metered dose inhalers 177
Methotrexate 162, 293
Methylxanthines 134
Monocytes 47
Morning dippers 96
Mortality 4,6,114
Mould 16

P
Patient education 128, 185,
284
Phosphodiesterase inhibition
134, 251
Platelet 52
Pollen 16
Pollution 29, 260
Pregnancy 236
Prostaglandins 52
Provocateurs 21

S
Secondary prophylaxis 259
Severe asthma 306
Sherwood-Jones index 213
Sinusitis 27
Smoking 260
Spacer devices 181
Status asthmatics 208
drugs 221
Step-care management 273,
274, 275
Sulphite sensitivity 26
Surgery 239
Sympathomimetic agents 145
T
Tartrazine 26
Theophylline 140
Tiotropium 272
Tokyo-Yokohama asthma 29
Troleandomycin 295
V
Ventilator 222
noninvasive 283
Virus-induced asthma 69
Y
Yin-Yang hypothesis 60