Accepted Manuscript

Severe asthma: Comparison of different classifications of severity and control

Alexssandra Maia Alves, Luane Marques de Mello, Aline Silva Lima Matos, Álvaro
Augusto Cruz

PII: S0954-6111(19)30239-2
DOI: https://doi.org/10.1016/j.rmed.2019.07.015
Reference: YRMED 5756

To appear in: Respiratory Medicine

Received Date: 30 October 2018

Revised Date: 27 June 2019
Accepted Date: 13 July 2019

Please cite this article as: Alves AM, Marques de Mello L, Lima Matos AS, Cruz ÁAugusto, Severe
asthma: Comparison of different classifications of severity and control, Respiratory Medicine (2019), doi:
https://doi.org/10.1016/j.rmed.2019.07.015.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Severe Asthma: comparison of different classifications of severity and control

AUTHORS:

PT
Alexssandra Maia Alvesa, MD; Luane Marques de Mellob, MD, PhD; Aline Silva Lima

RI
Matosa, RPh, PhD; Álvaro Augusto Cruza, MD

SC
a. ProAR Foundation and Federal University of Bahia, Brazil

U
b. Ribeirão Preto Medical School, University of São Paulo, Brazil
AN
Corresponding Author
M

Alexssandra Maia Alves, MD

D

Programa de Pós-Graduação em Ciências da Saúde da Universidade Federal da Bahia,

TE

Brasil. Address: Rua Carlos Gomes, 270, Centro de Saúde Carlos Gomes, 7º andar -

CEP 40060-330, Salvador, BA, Brazil. Phone: +55 71 3013-8462.

EP

E-mail: alexssandra.maia@yahoo.com
C

Funding Source:
AC

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) - Brazil –

Grant # 471057/2014-2, Fundação de Amparo à Pesquisa do Estado da Bahia
(FAPESB). An additional grant was obtained by an investigator initiated proposal of
Alvaro A. Cruz supported by Trust in Science, a GlaxoSmithKline's programme.
Conflicts of interest: the authors declare no further conflicts of interest in relation to this
manuscript.
 ACCEPTED MANUSCRIPT

ABBREVIATIONS:

ACQ - Asthma Control Questionnaire

AQLQ - Asthma Quality of Life Questionnaire

PT
ATS - American Thoracic Society

ERS - European Respiratory Society

RI
FEV1 - Forced expiratory volume in 1 second

SC
GERD - Gastroesophageal reflux disease

GA2LEN/ARIA - Global Allergy and Asthma European Network/Allergic Rhinitis and

Its Impact on Asthma

U
AN
GINA - Global Initiative for Asthma

ICS - Inhaled corticosteroids

M

LABA - Long-acting beta 2-agonist

D

NIH-NHLBI - National Institute of Health - National Heart, Lung, and Blood Institute
TE

OCS - Oral corticosteroids

PEF - Peak expiratory flow

EP

ProAR - Asthma Control Program of Bahia

SBPT - Brazilian Society of Pneumology and Pthisiology

C

WHO - World Health Organization

AC
 ACCEPTED MANUSCRIPT

ABSTRACT

Background: Criteria of asthma severity and control lack standardization. Objective: to

compare classifications of asthma severity and control, applied to patients from a severe

asthma clinic. Methods: Cross-sectional study of 473 patients followed up for ≥ 6

PT
months, reclassified using three criteria: 1) the World Health Organization (WHO)

2010, 2) the American Thoracic Society (ATS) 2000, and 3) the European Respiratory

RI
Society (ERS)/ATS 2014. In order to evaluate disease control, the 2012 and 2014

SC
Global Initiative for Asthma (GINA) classifications were compared. Results:

According to the definition of WHO 2010, 429 had Difficult-to-treat severe asthma and

U
only 12 presented Treatment-resistant severe asthma. 114 patients had Refractory
AN
asthma by ATS 2000 and 88 had Severe asthma by ERS/ATS 2014. Considering the

definitions of WHO 2010, only 9 out of 12 with Treatment-resistant and 64 out of 429
M

with Difficult-to-treat severe asthma met the criteria of ATS 2000 and ERS/ATS 2014.
D

As for GINA classification of control, 208 (44%) of the 473 subjects were classified as
TE

having asthma controlled by the 2014 criteria, whereas only 45 (10%) patients had

controlled asthma by the GINA 2012 criteria. The Kappa statistic indicates the highest
EP

agreement of the severity classification occurred between the criteria of ATS 2000 and

ERS/ATS 2014 (0.64). Conclusion: Good agreement was found between Refractory
C

asthma ATS 2000 and Severe asthma ERS/ATS 2014 classifications. However, poor
AC

agreement was observed between the severity rating proposed by the WHO and other

classifications. The GINA control classifications of 2012 and 2014 also agreed poorly.

KEYWORDS

Asthma, therapy, classifications, disease management

 ACCEPTED MANUSCRIPT

1. INTRODUCTION

Asthma constitutes a clinical syndrome associated to complex etiopathogenic

mechanisms that lead to a variable limitation of expiratory airflow and several clinical

PT
symptoms that vary over time in their occurrence, frequency, and intensity1.

The main treatment option for asthma is inhaled corticosteroids, although

RI
approximately 5% of patients do not respond adequately, even at moderate and high

SC
doses and in combination with other medications2, being considered as patients with

severe asthma. Despite its minority, this group exhibits high morbidity and is

U
responsible for most of the health expenditures, which are higher than those of other
AN
chronic diseases, such as diabetes and nephropathies3.
M

The categorization of severity involves understanding the definitions of severity

and control. Severity is defined by the intensity of medication required by the patient to
D

maintain adequate control of their symptoms, and control is evaluated by clinical

TE

manifestations (symptoms and limitations), which should be minimized with treatment4.

EP

The definitions of severity and control are essential for case definition in clinical

investigation and comparability of results, as well as for the treatment of each individual
C

patient. Several classifications have been proposed over the years, but there is still no
AC

uniformity in their application. In 1997, an NIH-NHLBI Panel of Experts5 defined

severe asthma according to frequency of symptoms, symptom intensity, limitations,

frequency of exacerbations, and abnormalities in lung function, regardless of prior

treatment. The Global Initiative for Asthma (GINA) created by the NIH-NHLBI

adopted the same criteria in 20026. In 2000, the ATS7 proposed the term "Refractory

asthma" for patients with a disruptive disease, reflected by the need for high doses of
 ACCEPTED MANUSCRIPT
ICS to maintain adequate control of symptoms, or those with persistent symptoms,

exacerbations or airway obstruction, despite high doses of the medication. Such

definition utilized major and minor criteria, based on treatment, pulmonary function,

and exacerbations. In 2010, a group of experts gathered at the WHO8 proposed the

following severity classification: (i) Untreated severe asthma, when the condition of

PT
severity was due to lack of access to treatment; (ii) Difficult-to-treat severe asthma,

when factors related to adherence, the inhalation technique, and control of comorbidities

RI
were present and interfered in the condition of severity; (iii) Treatment-resistant severe

SC
asthma, when the severity condition persists to the exclusion of the factors mentioned

above. Finally, in 2014, an ERS and ATS task force proposed a new definition of severe

U
asthma9, based on the need for higher doses of continuous ICS or OCS to maintain
AN
disease control, or when not even high doses of ICS associated with other medications

can control the disease (Table 1).

M

Since 2006, GINA has introduced the classification of control in its strategy10.
D

Up to the 2012 GINA strategy report, asthma control encompassed current symptom
TE

control, lung function, and future risks11. As of the 2014 GINA Report, the term

‘clinical control’ was replaced by ‘symptom control’ and ‘future risks’ were redefined
EP

as ‘risk factors for unfavorable outcomes’, such as exacerbations12. Abnormal

C

pulmonary function, which previously pertained to the current control criteria, began to
AC

be considered a risk criterion for exacerbation since 2014 (Table 2).

International terminology and definitions of severity and control have been

modified over time. Thus, their standardization is crucial to facilitate the comparability

of different studies and applicability of their results.

In this context, the present study aimed to verify the agreement of the

categorizations according to the main current international severity classifications

 ACCEPTED MANUSCRIPT
proposed by experts gathered at the WHO, ATS, and ERS/ATS, as well as the

agreement between the current control criteria (from 2014) and old GINA criteria, in a

sample of patients treated at a reference outpatient clinic for severe asthma, created in

2003, when the definitions of severity were different from current criteria.

PT
2. METHODS

RI
2.1 Study Design

SC
The present cross-sectional study was performed by analysis of secondary data

from a larger project entitled "Risk factors, biomarkers and endophenotypes of severe

U
asthma." Some results of this project have already been published, thus contributing to
AN
the understanding of the severe asthma phenotypes in our sample13,14.
M
D

2.2 Study population

TE

The study population consisted of adult patients, followed up regularly from

2003 at the outpatient clinic of the Asthma Control Program of Bahia (ProAR), a
EP

reference clinic for patients with severe asthma in Salvador, Bahia, Brazil. In order for

enrollement to the outpatient clinic, patients were required to meet at least one of the
C

following criteria of severity, in effect at the time, based on the directives of the NIH-
AC

NHBLI Guidelines for the Diagnosis and Management of Asthma (1997)15 and GINA

(2002)16: daily symptoms; limitation of daily activities (symptoms with minimal

efforts); nocturnal symptoms > 2 times a week; use of bronchodilators > 2 times a day;

PEF or FEV1 < 60% of the predicted value. This group of patients constitutes the ProAR

Severe Asthma Cohort. The sample of the present assessment comprehended all patients
 ACCEPTED MANUSCRIPT
of the ProAR Asthma Cohort patients under regular care who fulfilled the inclusion

criteria and accepted to participate in the study.

2.3 Asthma diagnosis

PT
At the beginning of the original study, each patient was reassessed by two

specialists for validation through a medical record review, when the presence of typical

RI
symptoms of asthma and spirometric abnormalities were verified, and at least one

SC
spirometry presenting an obstructive ventilatory disorder with significant reversibility

(increase ≥ 12% and > 200 mL in FEV1 post-bronchodilator). When divergence in

U
validation occurred, a third expert was consulted.
AN
M

2.4 Inclusion and exclusion criteria

D

The inclusion criteria of the present study comprised the following: age ≥ 18
TE

years, residency in Salvador or Lauro de Freitas – BA, Brazil, validated asthma

diagnosis, and follow-up in the program for at least six months.

EP

Patients were excluded from the study when they presented conditions that could

interfere with result interpretation, such as COPD, extensive tuberculosis sequelae,

C
AC

structural lung abnormalities, and pregnancy.

2.5 Study procedures

After the selection, eligible individuals were invited by phone to participate in

the study, and a visit to the unit was scheduled. The patients who attended the unit were
 ACCEPTED MANUSCRIPT
received by a member of the team and informed about the research details, and those

who agreed to participate were invited to sign a Term of Informed Consent. A well-

trained multidisciplinary team, composed of physicians, nurses, pharmacists,

physiotherapists, nutritionists, and psychologists, performed the clinical evaluations and

research procedures. The study was conducted in the period between January 2013 and

PT
July 2015.

RI
The anthropometric measurements were performed with the patient fasted.

Individuals with BMI ≥ 30 kg/m2 (WHO standard17) were considered obese. The Skin

SC
Prick Test was conducted according to GA2LEN/ARIA guidelines18 and evaluated

U
hypersensitivity to the following aeroallergens: Dermatophagoides pteronyssinus,
AN
Dermatophagoides farinae, Apergillus flavus, Apergillus niger, Aspergillus fumigatus,

Alternaria alternata, Cladosporium herbarum, dog epithelium, cat epithelium, Blatella

M

germanica, Periplaneta americana, Paspalum notatum (Bahia grass), Cynodon dactylon

(Bermuda grass) (GREER®) and Blomia tropicalis (FDA allergenics). Results were
D

considered positive when papules were ≥ 3 mm in comparison with the papule of the
TE

negative control.
EP

Spirometry was carried out by a technician trained and certified by the Brazilian

Society of Pneumology and Pthisiology (SBPT), using a Koko® spirometer (PDS

C

Instrumentation Inc., Louisville, CO, USA), following the 1995 American Thoracic
AC

Society protocol19. The software of the spirometer was updated with Brazilian normality

values20.

2.6 Adherence and inhalation technique

 ACCEPTED MANUSCRIPT
The inhalation technique was checked systematically with each patient using the

following devices: pressurized inhaler with and without a spacer, aerolizer, turbuhaler,

and diskus. The absence of any of the following steps was considered a serious error:

placing the device between the lips, inhaling, holding breath (all devices); actuate

(pressurized inhaler); open the compartment and place the capsule inside, press the

PT
buttons of the inhaler (aerolizer), rotate the device (turbuhaler). Since most patients used

more than one device, the number of evaluations was higher than the sample size.

RI
Adherence was assessed subjectively, through self-report, when the patient

SC
reported the consumption of at least 70% of the doses in the evaluation week.

U
AN
2.7 Asthma control
M

The Asthma Control Questionnaire (ACQ-6) was used to evaluate the control of

the disease21. Based on a study by Leite et al. (2008) of validation of the ACQ
D

questionnaire in Brazil, asthma was considered controlled in the present study when
TE

ACQ-6 < 0.75 and uncontrolled when ACQ-6 > 1.522; intermediate scores indicated

partially controlled asthma. The ACQ-6 does not take into account lung function. The
EP

2012 and 2014 GINA control classifications were also considered for comparison.
C
AC

2.8 Sociodemographic and clinical variables

The patients were also assessed regarding sex, age (in years), self-reported skin

color, age of symptom onset (before age 18), symptoms of chronic rhinitis, symptoms

of gastroesophageal reflux disease, treatment, and history of current or past smoking.

Low schooling was considered when the patient was illiterate or had only elementary

education.
 ACCEPTED MANUSCRIPT

2.9 Definitions

Difficult-to-treat severe asthma WHO 2010

Based on the definition used in the document submitted to WHO8, the individual

was classified as a Difficult-to-treat severe asthma WHO 2010 patient when presenting

PT
partially or poorly controlled symptoms (according to GINA 2012 control

classification)11 and/or > 2 exacerbations per year, associated with any of the following

RI
factors: use of ICS subdoses (<1000mcg/day of fluticasone or equivalent); inappropriate

SC
use of inhaler; low adherence to treatment; significant environmental exposure, and

inadequate control of comorbidities that hindered asthma control. Environmental

U
exposure was considered when the patient reported frequent contact with mold, dust,
AN
smoke, or domestic animals to which he/she had allergies.
M

Treatment-resistant severe asthma WHO 2010

D

Considering the definition used in the document proposed to WHO8, Treatment-

TE

resistant severe asthma WHO 2010 was considered when the patient was using a high

dose of ICS (>1000 mcg/day of fluticasone or equivalent), with partially/poorly

EP

controlled symptoms and/or > 2 exacerbations/year and appropriate inhaler use, good

adhesion, without a relevant environmental exposure, and adequate control of

C

comorbidities. Controlled patients requiring high doses of ICS (>1000 mcg/day of

AC

fluticasone or equivalent) were also considered as Treatment-resistant severe asthma

patients, according to WHO 2010.

Refractory asthma ATS 2000

 ACCEPTED MANUSCRIPT
Based on the ATS 20007 proposals, Refractory asthma was identified when the

patient presented one or two major criteria and two minor criteria, of those cited below:

Major criteria: treatment with high doses of ICS (>1000 mcg/day of fluticasone

or equivalent) or continuous use of OCS or use of OCS for periods > 50% of the year

prior to the evaluation.

PT
Minor criteria: associated daily use of LABA, theophylline or antileukotriene (in

addition to ICS); daily asthma symptoms requiring immediate relief medication;

RI
persistent bronchial obstruction (FEV1 < 80% or PEF variation > 20%); one or more

SC
visits to the emergency room per year; > 3 courses of OCS/year; rapid deterioration

with < 25% reduction in ICS or OCS dosage; near-fatal asthma in the past.

U
AN
Severe asthma ERS/ATS 2014

According to the document presented by the ERS/ATS task force9, Severe

M

asthma ERS/ATS-2014 was considered when the patient used a high doses of ICS (>
D

1000 mcg/day fluticasone or equivalent) associated with another controller (long-acting

TE

bronchodilator, antileukotriene or theophylline) and/or OCS for periods ≥ 50% of the

year prior to evaluation.

EP

Patients who exhibited control of asthma symptoms on medium or low doses of

ICS (< 1000 mcg/day of fluticasone or equivalent) were not included in any
C

classification of severe asthma.

AC

The WHO 2010 and ATS 2000 classifications were performed by a physician at

the time of clinical evaluation during data collection. ERS/ATS 2014 classification was

carried out through a retrospective analysis of the database since it did not exist when

the study began.

 ACCEPTED MANUSCRIPT
Statistical analysis

The Statistical Package for the Social Sciences software for Windows version

20.0 (SPSS Inc., Chicago, IL, USA) was used in the present study, and the variables

were described using the median and interquartile interval. The agreement analysis was

performed by calculating the Kappa Index, and interpretation of the results was based

PT
on the classification proposed by Landis and Koch23 (< 0.00 = poor; 0.00-0.20 =

discrete; 0.21-0.40 = acceptable; 0.41-0.60 = moderate; 0.61-0.80 = substantial; 0.81-

RI
1.00 = almost perfect).

SC
The data are presented in a logical diagram (Venn Diagram), with the purpose of

graphically representing the divergences and overlaps of the distinct categories of the

U
analyzed sample, obtained from the different classifications utilized.
AN
Ethics
M

This study was approved by the National Commission of Ethics in Human

D

Beings (CONEP), protocol No. 450/10.

TE
EP

3. Results

The application of the different definitions to the data obtained from the 473
C

analyzed patients showed that the category represented by the majority of the patients
AC

was Difficult-to-treat severe asthma (WHO 2010) [429 (90%)], followed by Refractory

asthma (ATS-2000) [114 (24%)], Severe asthma (ERS/ATS 2014) [88 (18%)], and

Treatment-resistant severe asthma (WHO 2010) [12 (2,5%)]. Thirty-two patients were

not fit to any classification since their asthma was controlled with medium or low doses

of ICS at the time of the study.

 ACCEPTED MANUSCRIPT
A predominance of the female sex was observed in all groups, although the

Treatment-resistant severe asthma (WHO 2010) group presented a lower proportion of

females (66%) than the other categories [Difficult-to-treat severe asthma WHO 2010

(80%), Refractory asthma ATS 2010 (85%), and Severe asthma ERS/ATS 2014 (87%)].

Table 3 depicts the general characteristics of the study groups. The median age in the

PT
Difficult-to-treat severe asthma WHO 2010 group was slightly lower [52 years (IQ 43-

61)] when compared to the other groups: Treatment-resistant severe asthma WHO 2010

RI
[54 years (IQ 46-68)], Refractory asthma ATS 2000, 53 years (IQ 45-61), and Severe

SC
asthma ERS/ATS 2014, 53 years (IQ 45-62).

U
Most of the patients began observing symptoms before age 18 [Difficult-to-treat
AN
severe asthma WHO-2010 (62%), Refractory asthma (59%), and Severe asthma

ERS/ATS-2014 (55%)], except for the Treatment-resistant severe asthma WHO-2010

M

group (41%). The majority of the patients also presented positive skin tests for

aeroallergens [difficult-to-treat severe asthma WHO-2010, severe asthma ERS/ATS-

D

2014 (59%), and refractory asthma (54%)]. However, in the treatment-resistant severe
TE

asthma group WHO-2010, such proportion was 50%. Only five patients reported current
EP

smoking 5 (1%), with equal proportions in both the difficult-to-treat severe asthma

WHO-2010 and refractory asthma ATS 2000 groups. The self-reported adherence rate
C

was significantly high in all groups: difficult-to-treat severe asthma WHO-2010 (79%),
AC

refractory asthma (88%), and severe asthma ERS/ATS-2014 (77%). Moreover, of the

977 evaluations of inhalation technique performed using different devices, only 6

(0.6%) assessments presented serious errors due to compromised inhalation technique.

The primary comorbidities reported in all categories were symptoms of chronic

rhinitis (85%), GERD (70%), and obesity (42%). The proportion of patients with

chronic rhinitis, GERD, and obesity were 85%, 70%, and 42%, respectively, in patients
 ACCEPTED MANUSCRIPT
with difficult-to-treat severe asthma WHO-2010, 95%, 84%, and 52% in the group with

refractory asthma ATS-2000, and 96%, 82%, and 48% in the group with severe asthma

ERS/ATS-2014.

The median ACQ-6 was lowest in the difficult-to-treat severe asthma WHO

PT
2010 [1.0 (0.5-5.8)] category.

In all groups, the most commonly used drugs were budesonide+formoterol,

RI
beclomethasone, and fluticasone+salmeterol. Among the patients with difficult-to-treat

SC
severe asthma WHO 2010, the frequency distribution of medication was 77%, 40%, and

18%; treatment-resistant severe asthma OMS 2010 83%, 41%, and 8%; Refractory

U
asthma 78%, 39%, and 14%, and severe asthma ERS/ATS-2014 76%, 42%, and 17%,
AN
respectively.
M

When analyzing the agreement between classifications by applying the Logical

Venn Diagram, a partial overlap of categories was observed. Nine (2%) patients were
D

simultaneously categorized as treatment-resistant severe asthma - WHO 2010,

TE

refractory asthma-ATS 2000, and severe asthma-ERS/ATS 2014. Meanwhile, sixty-four

(13%) patients were also concurrently classified as difficult-to-treat severe asthma

EP

WHO 2010, refractory asthma-ATS 2000, and severe asthma-ERS/ATS 2014 (Diagram
C

1).
AC

When the data were analyzed according to the control classification using GINA

2014 criteria, the proportion of controlled, partially controlled, and uncontrolled asthma

patients was 208 (44%), 171 (36%), and 94 (20%) respectively. In turn, when applying

GINA 2012 criteria, the proportion of controlled, partially controlled, and uncontrolled

patients was 46 (10%), 267 (57%), and 157 (33%), respectively. When considering the
 ACCEPTED MANUSCRIPT
ACQ-6 instrument, 191 (40%) patients were classified as controlled asthma and 173

(36%) as uncontrolled asthma (Graph 1).

In order to outline the agreement between the classifications, the Kappa

coefficient was determined. When calculating the coefficient of agreement between

difficult-to-treat severe asthma WHO 2010 and severe asthma-ERS/ATS 2014, a value

PT
of -0.21 was obtained, and between difficult-to-treat severe asthma WHO 2010 and

RI
refractory asthma ATS 2000, -0.02, suggesting disagreement (negative values).

Regarding treatment-resistant severe asthma WHO 2010 and severe asthma ERS/ATS

SC
2014, the value found was 0.16, and between treatment-resistant severe asthma WHO

U
2010 and refractory asthma-ATS 2000, 0.13, indicating poor agreement. According to
AN
the Kappa coefficient, the agreement between refractory asthma ATS 2000 and

ERS/ATS 2004 was of 0.64, considered strong. Among the GINA 2014 and GINA 2012
M

control classifications, the Kappa value was 0.30, suggesting reasonable agreement

(Table 4).
D
TE

4. Discussion
EP

In the present study, the majority of patients were classified as having difficult-
C

to-treat severe asthma, according to WHO 2010 criteria. Such result is explained by the
AC

high frequency of comorbidities and individuals classified as partially

controlled/uncontrolled asthma patients. It is noteworthy that the definition of control

utilized to compose this variable was based on the GINA 2012, in effect at the

beginning of the original study, which included pulmonary function abnormalities as

one of the criteria for poor control.

 ACCEPTED MANUSCRIPT
Andrade et al.24 studied children and adolescents with severe uncontrolled

asthma also based on the WHO classification, in a Brazilian reference center. Contrarily

to the present findings, the authors reported a higher frequency of patients with

treatment-resistant severe asthma (55.6%) when compared to difficult-to-treat severe

asthma (44.4%). Meanwhile, in a study conducted in Denmark, Bullow et al.25 found

PT
56% of patients classified as difficult-to-treat asthma (due to sub-optimal adherence or

poor inhaler technique) and 12% as severe asthma by the ERS/ATS-2014 in a total of

RI
117 patients with difficult-to-control asthma, from a sample of 1034 asthma patients

SC
treated at a specialized outpatient clinic. In another study carried out in Sweden,

Backman et al.26, while evaluating a cohort of patients with asthma, observed a

U
prevalence of severe asthma, according to three definitions: 3.6% (US SARP), 4.8%
AN
(ERS/ATS 2014), and 6.1% (GINA) among subjects with current asthma. The

frequency of severe asthma by the ERS/ATS-2014 in this study was higher than the
M

others cited, probably since the present sample came from an outpatient clinic for
D

patients with severe asthma, according to previous definitions. In order to be admitted in

TE

the ProAR, such patients are required to meet the severity criteria in effect at the time of

program initiation (NIH-NHBLI Guidelines for the Diagnosis and Management of

EP

Asthma (1997)5 and GINA (2002)6.

C

The data obtained herein showed a predominance of women, a fact that has also
AC

been observed in several other studies27,28 and which is based on discussions regarding a

possible influence of sex hormones on asthma, although the pathophysiological

explanation is not yet well defined29,30. The majority of patients presented a history of

early-onset asthma and atopy profile, a phenotype already well described in the

literature31.
 ACCEPTED MANUSCRIPT
The proportion of current self-reported smokers was low. In Brazil, the

prevalence of smokers in the general population is reduced, approximately 10%, much

lower than the global prevalence32, which is around 20%. A Brazilian study33,

previously performed among asthma patients, revealed a lower prevalence, of around

3%, despite the possibility of some omission in the patients’ reports34.

PT
The present study also showed a satisfactory rate of adherence to asthma

RI
treatment and a low proportion of serious errors in the use of inhalation devices, which

can compromise the inhalation technique. In ProAR, patients receive free asthma

SC
medication, provided by the country’s Sistema Único de Saúde (SUS), and are

U
submitted to a process of continuing education in health and multiprofessional care,
AN
factors which explain the atypical results. The observed adhesion rate was higher than

that found in the literature, ranging from 22 to 63%35 in patients with asthma in general
M

and 50%36 in those with severe asthma. Santos et al., in an earlier study with severe

asthma patients followed up at the ProAR outpatient clinic using objective methods37,
D

found a similar adherence rate to that observed in the present study, of around 80%.
TE

The high frequency of comorbidities such as rhinitis, GERD, and obesity has
EP

been reported in other studies involving patients with severe asthma27,28,38,39.

The agreement of the WHO classification and other classifications was low, as
C

observed both in the Logic Venn Diagram (Figure 1) and by the Kappa coefficient
AC

(Table 4). One of the reasons for such observation may have been an excessive rigor in

not classifying any patient with obesity, GERD, rhinosinusitis, environmental exposures

or psycho-social problems, as having Treatment-resistant severe asthma (WHO 2010).

The best agreement was found between the ATS 2000 and ERS/ATS 2014

classifications, as verified by the Venn diagram and the Kappa coefficient. Despite

some similarities, the doses of ICS considered high differ between the two definitions
 ACCEPTED MANUSCRIPT
enough to justify the differences in the number of patients included in the two

categories.

In spite of the acceptable agreement according to Kappa statistics, there was a

significant difference in the proportion of patients with the change in GINA control

classification. The classification used in the 2014 report (which remains to the present

PT
day) resulted in a higher proportion of controlled patients, while the 2012 classification

RI
indicated in a higher proportion of uncontrolled patients. We also observed that the

proportion of patients whose asthma was classified as controlled by the ACQ-6

SC
approached that of patients with controlled asthma according to GINA 2012, and the

U
proportion of patients with uncontrolled asthma by the ACQ-6 was close to that of
AN
patients with uncontrolled asthma according to GINA 2014 (Graph 1). Thus, the

questionnaire can be considered as a suitable tool for assessing control since it agrees
M

with GINA definitions.

The most favorable aspects of the present report are related to the extended
D

follow-up of the cohort of patients with more severe forms of asthma, allowing a
TE

detailed cross-sectional study (nested in the cohort) to obtain previous detailed

information relevant to a large sample of patients with severe asthma. Its main
EP

limitations are associated with the lack of an objective method of measuring adherence
C

to treatment in the real-life environment and the variability of treatment due to the need
AC

to adapt to free or cheaper drugs.

The change in GINA control classification may greatly interfere with patient

management and even clinical trial results since the level of control constitutes a major

indicator for stepwise management of asthma and eligibility criteria for clinical trials.

Many studies have revealed a high proportion of uncontrolled patients in Brazil40 and

other countries41 when using the old classification.

 ACCEPTED MANUSCRIPT
In conclusion, the agreement between the refractory asthma ATS-2000 and

severe asthma ERS/ATS-2014 classifications was good, although poor between the

WHO severity rating and other definitions, as well as between the 2012 and 2014 GINA

control classifications. These results deserve attention, given they highlight the

discrepancy of sub-samples selected based on diverse severity criteria and reinforce the

PT
need to adopt a uniform classification. Moreover, the lack of standardization may

compromise the comparability and external validity of clinical trials.

RI
SC
5. References

1. Global Initiative for Asthma (GINA). A Pocket Guide for Health Professionals

U
Updated; Global Strategy for Asthma Management and Prevention. 2019.
AN
2. Hekking PW. Wener RR. Amelink M. Zwinderman AH. Bouvy ML. Bel EH. The
M

prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015; 135(4):

896-902.
D

3. Oneil S. Sweeney J. Patterson CC. Gow AM. Niven R. Mansur AH et al. The
TE

coast of treating severe refractory asthma in the UK: an economic analysis from

British Thoracic Society Difficult Asthma Registry; Thorax. 2015;70: 376-378.

EP

4. Taylor DR. Bateman ED. Boulet. HA. Boushey W. Busse WLP et al. A new

perspective on concepts of asthma severity and control. Eur Respir J. 2008; 32:
C
AC

545–554.

5. Expert panel report 2: guidelines for the diagnosis and management of asthma

(EPR⎯2 1997). NIH Publication No. 97-4051. Bethesda. MD: U.S. Department of

Health and Human Services; National Institutes of Health; National Heart. Lung.

and Blood Institute; National Asthma Education and Prevention Program. 1997.
 ACCEPTED MANUSCRIPT
6. National Institutes of Health National Heart. Lung. And Blood Institute. Global

Strategy for Asthma Management and Prevention Revised. 2002.

7. Proceedings of the ATS workshop on refractory asthma: current understanding.

recommendations. and unanswered questions. American Thoracic Society. Am J

Respir Crit Care Med. 2000; 162(6):2341-51.

PT
8. Bousquet J. Mantzouranis E. Cruz A. Aït-Khaled N. Baena-Cagnani CE. Bleecker

ER. et al. Uniform definition of asthma severity. control. and exacerbations:

RI
document presented for the World Health Organization Consultation on Severe

SC
Asthma. J Allergy Clin Immunol. 2010; 126(5): 926-38.

9. Chung KF. Wenzel SE. Brozek JL. Bush MC. Sterk PJ. Adcock IM et al.

U
International ERS/ATS guidelines on definition. evaluation and treatment of
AN
severe asthma. Eur Respir J. 2014; 43 (2):343-73.

10. Global Strategy for Asthma Management and Prevention (GINA) 2006.
M

11. Global Strategy for Asthma Management and Prevention (GINA) 2012.
D

12. Global strategy for asthma management and prevention. NHLB/Who Report.
TE

2014; 63(7):932-8.

13. Lima-Matos A. Ponte EV. de Jesus JPV. Almeida PCA. Lima VB. Kwon N. et al.
EP

Eosinophilic asthma. according to a blood eosinophil criterion. is associated with

disease severity and lack of control among underprivileged urban Brazilians.

C

Respir Med. 2018; 145:95-100.

AC

14. A.A. Cruz. Ponte EV. Almeida PCA. Biao-Lima V. Figueiredo CA. Riley JH et al.

Cross-Sectional Analysis of Adults with Previously Untreated Severe Asthma

(SA) Followed Up AfterTreatment: A Brazilian Severe Asthma Cohort (ProAR).

A34 Asthma Clinical Studies I 2018. p. A1382-A.

 ACCEPTED MANUSCRIPT
15. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of

Asthma-Summary Report 2007. J Allergy Clin Immunol 2007; 120(5 Suppl):S94-

138. 17.

16. Global Strategy for Asthma Management and Prevention. Global Initiative for

Asthma (GINA) 2002.

PT
17. Obesity: preventing and managing the global epidemic. Report of WHO

consultation. World Health Organ Tech Rep Ser. 2000.

RI
18. Bousquet J. Heinzerling L. Bachert C. Papadopoulos NG. Bousquet PJ.Burney PG

SC
et al. Practical guide to skin prick tests in allergy to aeroallergens. Allergy. 2012.

67:18–24.

U
19. ATS. Standardization of Spirometry. 1994 Update. Am Journal of Respiratory and
AN
Critical Care Medicine. 152: 1107-36. 1995.

20. Pereira. C. A. Sato. T. and Rodrigues. S. C. New reference values for forced
M

spirometry in white adults in Brazil. J Bras Pneumol. 2007; 33 (4):397-406.

D

21. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and
TE

validation of a questionnaire to measure asthma control. Eur Resp J. 1999;

14(4):902-7.
EP

22. Leite M, Ponte EV, Petroni J, D'Oliveira Júnior A, Pizzichini E,Cruz AA.

Avaliação do questionário de controle da asma validado para uso no Brasil. J Bras

C

Pneumol. 2008; 34 (10):756-763.

AC

23. Landis JR. Kock GG. The measurement of observer agreement for categorical

data. Biometrics 1977; 33:159-75

24. de Andrade WC. Lasmar LM. Ricci Cde A. Camargos PA. Cruz ÁA. Phenotypes

of severe asthma among children and adolescents in Brazil: a prospective study.

BMC Pulm Med. 2015; 15:36.

 ACCEPTED MANUSCRIPT
25. von Bülow A. Backer V. Bodtger U. Søes-Petersen NU. Vest S. SteffensenI.

Porsbjerg C. Differentiation of adult severe asthma from difficult-to-treat asthma–

Outcomes of a systematic assessment protocol. Respir Med. 2018; 145: 41-47.

26. Backman H. Jansson SA. Stridsman C. Eriksson B. Hedman L. Eklund BM et al.

Severe asthma - A population study perspective Clin Exp Allergy. 2019 (ahead of

PT
print).

27. Teague WG. Phillips BR. Fahy JV. Wenzel SE. Fitzpatrick AM. Moore WC et al.

RI
Baseline Features of the Severe Asthma Research Program (SARP III) Cohort:

SC
Differences with Age. J Allergy Clin Immunol Pract.2018; 6(2):545-554.

28. Chipps BE. Haselkorn T. Paknis B. Ortiz B. Bleecker ER. Kianifard F et al.

U
Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens
AN
Study Group.More than a decade follow-up in patients with severe or difficult-to-

treat asthma: The Epidemiology and Natural History of Asthma: Outcomes and
M

Treatment Regimens (TENOR) II; J Allergy Clin Immunol. 2018; 141(5): 1590–
D

97.
TE

29. Zein JG. Erzurum SC . Asthma is Different in Women. Curr Allergy Asthma Rep.

2015; 15(6):2.
EP

30. Fuseini H. Newcomb DC. Mechanisms Driving Gender Differences in Asthma.

Curr Allergy Asthma Rep. 2017; 17(3):19.

C

31. Papi, A., Brightling, C., Pedersen, S. E., & Reddel, H. K. Asthma. The Lancet.
AC

2018; 391(10122), 783–800.

32. WHO global report on trends in prevalence of tobacco smoking 2000–2025.

Second Edition. Geneva: World Health Organization; 2018.

 ACCEPTED MANUSCRIPT
33. Dias-Júnior AS. Pinto RC. Angelini L. Fernandes FL. Cukier A.Stelmach R.

Prevalence of active and passive smoking in a population of patients with asthma.

J Bras Pneumol. 2009; 35(3):261-5.

34. Pinheiro GP. Souza-Machado C. Fernandes AGO. Mota RCL. Lima LL. et al.

Tabagismo entre asmáticos: avaliação por autorrelato e dosagem de cotinina

PT
urinária. J Bras Pneumol. 2018; 44(6). 477-485.

35. Barnes CB. Ulrik CS. Asthma and adherence to inhaled corticosteroids: Current

RI
status and future perspectives. Respir Care. 2015; 60 (3):455-68.

SC
36. Bourdin A. Halimi L. Vachier I. Paganin F. Lamouroux A. Gouitaa et al.

Adherence in severe Asthma Clin Exp Allergy. 2012; 42(11):1566-74.

U
37. Santos PM. D'Oliveira Júnior A. Noblat LA. Machado AS. Noblat AC. Cruz AA.
AN
Preditores da adesão ao tratamento em pacientes com asma grave atendidos em um

centro de referência na Bahia. J. bras. pneumol. 2008; 34(12): 995-1002.

M

38. Shaw DE. Sousa AR. Fowler SJ. Fleming LJ. Roberts G. Corfield J et al. Clinical
D

and inflammatory characteristics of the European U-BIOPRED adult

TE

severe asthma cohort. Eur Respir J. 2015; 46(5):1308-21.

39. Jesus JP. Lima-Matos AS. Almeida PC. Lima VB. Mello LM. Souza-Machado A
EP

et al. Obesidade e asma: caracterização clínica e laboratorial de uma associação

frequente. J Bras Pneumol. 2018; 44(3):207-212.

C

40. Machioro J. Gazzoti MR. Nascimento AO. Montealegre F. Fish J. Jardim JR;
AC

Level of asthma control and its relationship with medication use in asthma patients

in Brazil. J Bras Pneumol. 2014; 40(5):487-494.

41. Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000

European patients: the REcognise Asthma and LInk to Symptoms and Experience

(REALISE) survey NPJ Prim Care Respir Med. 2014; 12 (24):14009.

 ACCEPTED MANUSCRIPT
Table 1. Severe asthma criteria according to different organizations
Classification Criteria
Refractory Major Characteristics
Asthma In order to achieve control to a level of mild–moderate persistent asthma:
a 7
ATS 2000 -Treatment with continuous or near continuous (>50% of year) oral
corticosteroids
-Requirement for treatment with high-dose inhaled corticosteroids#

PT
Minor Characteristics
-Requirement for daily treatment with controller medication in addition to
inhaled corticosteroids, e.g., long-acting agonist, theophylline or leukotriene

RI
antagonist
-Asthma symptoms requiring short-acting β-agonist use on a daily or near daily

SC
basis
Persistent airway obstruction (FEV1 < 80% predicted; diurnal PEF variability >
20%)

U
-One or more urgent care visits for asthma per year
-Three or more oral steroid “bursts” per year
AN
-Prompt deterioration with < 25% reduction in oral or inhaled corticosteroid dose
-Near-fatal asthma event in the past
M

WHOb 20108 Untreated severe asthma: patients without access to medication.

Difficult-to-treat severe asthma: poor control due to factors extrinsic to asthma,
D

such as incorrect inhalation technique and environmental exposure, and

comorbidities, including allergic rhinitis*, obesity*, and gastroesophageal reflux
TE

disease*.
Treatment-resistant severe asthma: classification following exclusion of extrinsic
factors that interfere in control (cited above*). May be controlled or not (cortico-
EP

resistant).
C

Severe Asthma Asthma which requires treatment with guideline suggested medications for
c 9
ERS/ATS 2014 GINAd steps 4–5 asthma (high dose ICSe## and LABAf or leukotriene
AC

modifier/theophylline) for the previous year or systemic CSg > 50% of the
previous year to prevent it from becoming “uncontrolled” or which
remains “uncontrolled” despite such therapy
Uncontrolled asthma defined as at least one of the following:
-Poor symptom control: ACQh consistently > 1.5, ACTi< 20 (or “not well-
controlled” by NAEPP/GINAj guidelines)
-Frequent severe exacerbations: two or more bursts of systemic CS (> 3 days
each) in the previous year
-Serious exacerbations: at least one hospitalization, ICUk stay or mechanical
 ACCEPTED MANUSCRIPT
ventilation in the previous year
-Airflow limitation: after appropriate bronchodilator withhold FEV1 < 80%
predicted (in the face of reduced FEV1/FVC defined as less than
the lower limit of normal)
Controlled asthma that worsens on tapering of these high doses of ICS or
systemic lCS (or additional biologics)
# ##
Dose inhaled corticosteroids (ICS) > 880 mcg de Fluticasone; Dose > 1000 mcg of
Fluticasone (HFA, MDI or DPI) in older than 12 years of age; aAmerican Thoracic Society; cWorld

PT
c d e
Health Organization; European Respiratory Society; Global Initiative for Asthma; Inhaled
f g h i
corticosteroids; Long-acting agonist; Systemic corticosteroids; Asthma Control Questionnaire; Asthma

RI
j k
Control Test; National Asthma Education and Prevention Program; Intensive Care Unit
l
Corticosteroids.

U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT
Table 2. GINA control classifications
REPORT CRITERIA CLASSIFICATION
UTILIZED
Well-controlled Partially Uncontrolled
controlled
11
GINA 2012 Daytime symptoms <2 week >2x/week >2x/week
Reliever need <2 week >2x/week >2x/week

PT
Activity limitation None Any Any
Night waking None Any Any

RI
Lung function (PEF Normal < 80% < 80%
or FEV1*

SC
GINA 201412 Daytime symptoms <2x/week >2x/week >2x/week
Reliever need <2x/week >2x/week >2x/week

U
Activity limitation None Any Any
Night waking None Any Any
AN
GINA-Global Initiative for Asthma *The functional parameters used FEV1 < 80%.
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 3. Sociodemographic and clinical characteristics of the patients (n = 473)

Characteristics Difficult-to- Treatment- Refractory Severe
treat severe resistant asthma Asthma
asthma severe ATS 2000 ERS/ATS2014

PT
WHO 2010* asthma
WHO 2010*

RI
Frequency n (%) 429 (90) 12 (2.5) 114 (24) 88 (18)
Female sex n (%) 344 (80) 8 (66) 97 (85) 77(87)

SC
Age, years M (IQ 25- 52 (43-61) 54 (46-68) 53 (45-61) 53 (45-62)
75)
Mixed ethnicity n (%) 214 (49) 9 (75) 57 (50) 40 (45)
Black n (%) 180 (41)
U
1 (8.3) 41 (36) 33 (37)
AN
Other ethnicities n 35 (8) 2 (16) 16 (14) 4 (4)
(%)
M

Low schooling n (%) 103 (24) 3 (25) 28 (24) 25(28)

Asthma beginning 270 (62) 5 (41) 68 (59) 49 (55)
D

before 18 years
n (%)
TE

Adherence by self- 342 (79) 12 (100) 101(88) 68 (77)

report
EP

n (%)
Positive skin prick 258 (59) 6 (50) 62 (54) 52 (59)
C

test for aeroallergens

n (%)
AC

Smokers n (%) 5 (1) 0 (0) 5 (1) 0

Ex-smokers n (%) 121 (28) 4 (33) 30 (26) 22 (25)
Chronic rhinitis n (%) 406 (85) 0 (0) 110 (95) 85 (96)
Symptoms suggestive
of GERD n (%) 304 (70) 0 (0) 96 (84) 73 (82)
Obesity n (%) 179 (42) 0 (0) 59 (52) 43 (48)
FEV1 post-BD (L) M 67 (57-78) 69 (58-84) 66 (57-79) 67 (55-80)
 ACCEPTED MANUSCRIPT
(IQ)
ACQ-6 M (IQ) 1 (0.5-1.8) 1.2 (0.4-1.7) 1.6 (1-2.5) 1.5 (0.8-2.3)
*32 patients did not fulfill the WHO classification since their asthma was well
controlled with low doses of inhaled corticosteroids; ATS-American Thoracic Society;
ERS-European Respiratory Society; WHO-World Health Organization; GINA-Global
Initiative for Asthma; ACQ-Asthma Control Questionnaire; FEV1-Forced Expiratory

PT
Volume in 1 second; LABA- long-acting beta2-agonist; SABA-Short-acting beta2-
agonist.

RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 4. Agreement of classifications by Kappa analysis

Severe asthma Refractory Treatment- Difficult-to- GINA
ERS/ATS 2014 asthma resistant treat severe 2012**
ATS 2000 severe asthma asthma
WHO 2010 WHO 2010

PT
Difficult-to-treat -0.21* -0.02* NA NA NA
severe asthma

RI
WHO 2010
Treatment- 0.16* 0.13* NA NA NA

SC
resistant severe
asthma
WHO-2010
Refractory 0.64*
UNA 0.16* -0.02* NA
AN
asthma
ATS-2000
M

GINA 2014** NA NA NA NA 0.30*

WHO- World Health Organization; ERS-European Respiratory Society; ATS-American
Thoracic Society; GINA-Global Initiative for Asthma; *p <0.01 **Control classification; NA-
D

No applicable.
TE
C EP
AC
 ACCEPTED MANUSCRIPT
DIAGRAM 1- DISTRIBUTION OF PATIENTS ACCORDING TO SEVERITY RATINGS
n=473

DIFFICULT-TO-TREAT SEVERE ASTHMA

WHO 2010 n=429

314
SEVERE ASTHMA
ERS/ATS 2014 12

PT
n=88
2
64
1

RI
9 39

SC
REFRACTORY ASTHMA ATS 2000
G n=114
TREATMENT-RESISTANT SEVERE ATSHMA
WHO 2010

U
AN
Thirty patients did not meet any classification since their symptoms were controlled using low doses of ICS
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT
Graph 1. Patient distribution according to the control classification

57%

44%
40%
36% 36%
33%

PT
20%

10%

RI
GINA 2012 GINA 2014 ACQ-6

SC
controlled partially controlled uncontrolled

GINA-Global Initiative for Asthma; ACQ-6-Asthma Control Questionnaire

U
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT
Highlights

• The definitions of asthma severity and control have changed over the last 20 years
• The agreement between ERS/ATS 2014 and ATS 2000 classifications is good
• The agreement between WHO classification, ATS and ERS/ATS classifications is
poor
• The agreement between asthma control by GINA 2012 and GINA 2014 is poor
• Classifications of severity and control are arbitrary and subjective, thus variable

PT
RI
U SC
AN
M
D
TE
C EP
AC