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Mini-Symposium: Asthma Phenotypes

Inammatory Phenotypes in Stable and Acute Childhood Asthma


Xiao Yan He
2,3
, Jodie L. Simpson
2,3
, Fang Wang
1,2,3,
*
1
Department of Pathogenobiology, Norman Bethune College of Medicine, Jilin University, Xinmin Street 126, 130021, Chang Chun City, Ji Lin Province, China
2
Centre for Asthma and Respiratory Disease, University of Newcastle, Callaghan, NSW, Australia
3
Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, New Lambton, NSW, Australia
INTRODUCTION
Asthma is a heterogeneous syndrome comprising different
phenotypes that manifest with cough, wheeze, shortness of breath,
and chest tightness. It is the most common chronic disease in
childhood and the prevalence has been increasing in industrialised
countries over decades. Although both childhood and adulthood
asthma share similar features, there are epidemiological andclinical
characteristics suggesting a difference in the nature, disease history
and magnitude of airway inammation
1,2
. In children with asthma,
the patterns of inammation and remodelling vary among
individuals. We cannot yet differentiate with certainty whether
the future course of a child with wheezing will be persistent asthma
or transient wheeze
3,4
. The reasons for the variability in the clinical
course of asthma that leads to persistence and even progression in
some children but is intermittent in others remain unknown. The
temporal course and causes of chronic airway inammation and
remodelling, as well as the interplay between these key histopatho-
logic changes in asthma, are also poorly claried
5
.
Childhood asthma frequently persists to adulthood and the
available evidence suggests that the severity of childhood asthma
predicts the severity of asthma in adulthood
1,2
. Children with
severe asthma experience persistent symptoms despite maximal
conventional treatment. Fraction of exhaled nitric oxide (FEno) and
sputum eosinophils can be used as markers of airway inamma-
tion to guide treatment with corticosteroids, but very few data are
available on their utility in children
6
. Currently there is no standard
denition for what constitutes disease persistence as opposed to
disease progression in asthma or criteria on how and when
progression should be measured or evaluated. Despite the
availability of evidence based guidelines for the management of
paediatric asthma, a signicant gap remains between accepted
best practices for paediatric asthma care and actual care delivered
to asthmatic patients. Current therapies are targeting both airway
inammation and airway hyperreactivity, which often effectively
relieve and prevent symptoms in the majority of patients.
However, some patients experience persistent symptoms and a
progressive decline in lung function, described as irreversible or
Paediatric Respiratory Reviews 12 (2011) 165169
A R T I C L E I N F O
Keywords:
Inammatory phenotype
eosinophilic inammatory phenotype
peripheral or distal airways
paediatric asthma
S U M M A R Y
Asthma is a complex disease with a signicant inammatory component characterized by repeated
episodes of exacerbation and inammatory changes in both large and peripheral airways. The clinical
course of childhood asthma varies substantially among individuals. The reasons why the clinical course
of asthma displays persistence and even progression in some children but is intermittent in others
remains unclear. Children with asthma are different from adults with asthma. Inammatory
involvement in children with asthma appears to be localised more in peripheral than central airways,
and the inammatory phenotype displays differences from adults. Children with acute asthma display a
dominant eosinophilic inammatory phenotype instead of the neutrophilic phenotype that is seen in
adults with acute asthma. Corticosteroids do not alter the natural history of the disease and may not
prevent progressive decline of lung function in the subset of severe asthma. The underlying
inammatory mechanisms involved in the decline of lung function remains to be elucidated. Non-
invasive biomarkers for monitoring lung function and inammation are needed in children to track and
monitor pathological changes in the distal airways, as is the development of therapeutic strategies that
effective to peripheral airway in this vulnerable population. This review summarises our present
understanding of airway inammatory phenotypes in children with asthma and factors determining
disease severity in exacerbations of asthma, and focuses on studies evaluating relationships between
clinical features and the dominant inammatory phenotypes in disease prognosis in a variety of asthma
populations. This presents the crucial steps for describing the strategies associated with improvements
for paediatric asthma care.
2011 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +86 431 85619574; Fax: +86 431 85619803.
E-mail address: wf@jlu.edu.cn (F. Wang).
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
1526-0542/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.prrv.2011.04.007
refractory asthma. There are many unanswered questions about
different inammatory phenotypes in relation with airway
remodelling; the contribution of distinct airway resident cells to
development of irreversible asthma; the role of biomarkers in
predicting persistent asthma; and effectiveness of current
therapies on childhood asthma and disease progression.
FEATURES OF CHILDHOOD ASTHMA
Normally the lower airway is sterile. Nonetheless, defects in the
local immune system can lead to infection in the lower airways
7,8
.
Both clinical and experimental evidence suggest an important role
for respiratory infections as triggers of asthma attacks in adults and
in children. Viral respiratory infections are considered the most
common precipitating factors of acute asthma and have been
shown to be associated with more than 80% of asthma exacer-
bations in children
9,10
. Atypical bacteria, such as Chlamydia
pneumoniae and Mycoplasma pneumoniae infection have also been
associated with chronic stable asthma, and may precede asthma
onset or an acute exacerbation
10
. The physiologic features of
airway disease in childhood asthma display many distinguishing
features from adult asthma and even from childhood-onset adult
asthma
2
. Adults with asthma are more likely to exhibit a persistent
pattern, whereas episodic asthma is typical in children
11
. The
younger the child, the more episodic it is likely to be. How early
does airway inammation and remodelling occur in children?
Bush et al described that there is no evidence of eosinophilic
inammation or remodelling in wheezing infants in rst year of
their life, but that both are detectable by the age of 3 years
5
.
Neutrophilic inammation has been suggested in early wheezing,
and children who become persistent wheezers can have impaired
lung function in the pre-school years. Children are generally more
atopic than adults with higher serum IgE levels. It is known that
children are more capable of hyperinating through an increase in
residual volume leading to increases in total lung capacity and tend
to have less airway resistance to airow
12
. Further studies have
indicated that children with different levels of asthma severity can
have relatively normal FEV
1
values when clinically stable
2,13,14
.
The distal airways are more affected, and increased distal lung
resistance, in the absence of signicant large airway involvement,
likely explains the unimpaired FEV
1
values
15
.
It is clear that increased eosinophils distribute throughout the
large and distal airways of patients with mild and severe asthma
16
.
Although there is no obvious distinguishing clinical manifestations
of lower airway inammation, inammatory cells and mediators
have been found in the lower airways of children with allergic
rhinitis without asthma
17,18
, conrming the inammatory link of
the upper and lower airways
19
. It is likely that poorly controlled
inammation in the peripheral airways might exacerbate asthma,
contribute to the accelerated decline in lung function, and promote
airway remodelling. The total volume and combined surface area
of the distal airways is much greater than the combined volume
and surface area of the large airways. As a consequence,
inammatory changes in the distal airways in paediatric patients
with asthma can have a dramatic effect on the pathogenesis and
treatment of the disease. New therapeutic strategies should target
the distal airway inammation in children with asthma.
INFLAMMATORY PHENOTYPES IN STABLE CHILDHOOD ASTHMA
The airway inammatory patterns in asthma are heterogeneous
and current guidelines describe asthma as a disorder where many
cells and cellular elements play a role in disease pathogenesis
20
.
Asthma can be dened as eosinophilic or non-eosinophilic based
on the presence of eosinophils in sputum. Further studies
demonstrated that inammatory process in asthma is more
heterogeneous in terms of response to treatment
5
. Atopy and
eosinophilic bronchitis are important in asthma, and about 50% of
asthma can be attributed to eosinophilic airway inammation
21
.
However, there is also a meaningful percentage of patients with
non-eosinophilic asthma. Increasing evidence indicates that
neutrophils may play an important role in the pulmonary
inammatory process in asthma. The role of neutrophilic asthma
in children is less described.
Heterogeneity of the inammatory response is important in
adulthood asthma, where non-eosinophilic forms of asthma are
relatively common and unresponsive to corticosteroids. We have
categorized airway inammation into four subtypes based on
sputum eosinophil and neutrophil proportions
22
. The subtypes are
eosinophilic asthma with increased sputum eosinophils >3%,
neutrophilic asthma with increased sputum neutrophils >61%,
mixed granulocytic asthma in which both sputum eosinophils and
neutrophils are increased, and paucigranulocytic asthma where
sputum eosinophils and neutrophils are within the normal range.
This new classication of inammatory phenotypes has offered a
reliable solution in guiding airway inammation treatment.
Understanding the patterns of inammatory phenotypes in
childhood asthma may be important for designing the correct
treatment strategies in this specic population
22
.
In stable asthma, there is heterogeneity of the inammatory
response, but in stable childhood asthma it is less well understood
than in adult asthma. In stable adult asthma, the inammatory cell
prole in asthma is heterogeneous but clinical features are similar
across different inammatory phenotypes. Children with asthma
are different to adults in that they display two main stable
phenotypes of airway inammation: (i)Eosinophilic asthma (37%)
and (ii) Paucigranulocytic asthma (46%). Neutrophilic asthma was
uncommon in stable childhood asthma (3%)
23,24
. Children with an
eosinophilic phenotype had more severe asthma, higher atopic
status, impaired lung function, and increased airway hyper-
responsiveness [AHR] compared to children with paucigranulo-
cytic asthma. Thus, in contrast to adults with asthma, there are two
main phenotypes of airway inammation in Australian children
with asthma and the clinical features of asthma differ between
phenotypes.
INFLAMMATORY PHENOTYPES IN ACUTE CHILDHOOD ASTHMA
Acute asthma is one of the most common problems confronting
the emergency department. The least understood phenotype in
human asthma is the severe form of the disease exemplied by
acute severe exacerbations requiring hospitalisation. One of the
underlying trigger mechanisms is the consistent observation at the
time of hospitalisation that most affected children also have
respiratory viral infections. This suggests that inammationarising
from host antiviral defence may interact with underlying atopic
inammation to drive cumulative airway tissue damage above the
critical threshold necessary to precipitate severe acute asthma
attacks. Subrata at el showed that in atopic children the underlying
effects of atopy on innate immune function is the constitutive
expression of the type I Immunoglobulin E receptor [FceRI] on
circulating monocyte/dendritic cells[DC], which correlates quan-
titatively with their levels of serum immunoglobulin E [IgE]
25
. The
functional consequences of this receptor on monocyte/DC can
enhance pro-inammatory mediator production via mechanisms
dependent on activation of the transcription factor nuclear factor
Kappa B [NF-kB], and interference with development of sterilising
immunity and increased capacity to stimulate allergen-specic
type 2 T-helper lymphocytes Th2.
During anacute exacerbation of asthma inchildren, the common
inammatory pattern is eosinophilic phenotype, and patients in
this subgroup have increased clinical severity
26
. Table 1 shows
X.Y. He et al. / Paediatric Respiratory Reviews 12 (2011) 165169 166
results from our recent cross-sectional study of children with
asthma
26
. The most common inammatory phenotype in children
with stable asthma was the paucigranulocytic phenotype (49%);
with the eosinophilic phenotype being the next most common
subtype in stable asthma at 29% of children. It has been suggested
that patients with the eosinophilic inammatory phenotype may
face a higher risk for adverse clinical conditions
26,27
.
The study also revealed that more eosinophilic inammatory
reactions emerged in children with acute asthma than that in
adults with acute asthma, with more impaired lung function and
lower FEV1% (53%predicted) compared to adults (73%predicted)
with acute asthma
26
. When eosinophils are activated they release
eosinophilic cationic protein (ECP). A signicant inverse correla-
tion has been found between FEV
1
and sputum ECP levels in a
number of studies
2730
. However, the relationship is not upheld
when examining the children with mild to moderate stable
asthma
2729
. These studies suggested that eosinophils may be
important determinants of the severity of airway obstruction in
acute asthma and the hallmark of exacerbation
3133
. Interleukin-5
[IL-5] is a major cytokine that stimulates eosinophil proliferation
and differentiation. Recent clinical trials of a-IL-5 treatment have
shown efcacy in patients with frequent exacerbations associated
with an eosinophilic phenotype
32,33
.
Glucocorticosteroids have a major effect in both chronic and
acute asthma. However, the effect may be modest during an
exacerbation
30
. In infants and children, the inhaled corticosteroids
failed to have any disease-modifying effects. Early institution of
inhaled corticosteroid therapy does not inuence the natural
history of asthma in pre-school children
34
. The underlying reasons
for the therapeutic limitations of corticosteroids may be due to the
heterogeneity of inammation both between patients and in the
same patient at different stages of the disease. In stable asthma,
sputum analysis demonstrated increased eosinophils, but neu-
trophils and total cell counts are not elevated
6,11
. Apart from a
dominant eosinophilic phenotype in acute asthma, neutrophils
were a prominent cell contributing to airway inammation in this
sub-group
26
. It is well known that neutrophilic asthma responds
poorly to corticosteroids
23,24
. These observations indicate a
potential therapeutic benet by targeting neutrophils or neutro-
phil inammatory mediators, such as IL-8, during severe exacer-
bations in childhood asthma, or possibly infectious agents such as
Chlamydia pneumoniae and Mycoplasma pneumoniae
26,35
.
Currently, the inammatory phenotype has been determined
mainly by proximal luminal cellularity. However, this does not
account for any variation of cellularity over time or distal airway
changes to relative mucosal inammatory changes. A better
understanding the multiple phenotypes of asthma presenting
clinically requires a longitudinal thorough understanding of early
life events and their consequences over many decades. Retro-
spective recall of childhood events is of limited value, but
comparison of disease features in children and adults with various
phenotypes of asthma may provide some clues for understanding
disease progression and airway specic age related physiological
changes.
COMPARISON OF INFLAMMATORY PHENOTYPES BETWEEN
ADULTS AND CHILDREN
A cross-sectional study investigated each of the four different
inammatory phenotypes in adults and children with stable and
acute asthma. The different patterns of inammatory phenotypes
are summarised in Figure 1
26
.
The distribution of phenotypes was similar between adult
stable asthma and children with stable asthma. However, there
were differences in the relative frequency of the phenotypes
between acute adult asthma and children with acute asthma
(Figure 1), as well as between acute asthma and stable asthma. In
adults with stable asthma, the most frequent inammatory
phenotype was paucigranulocytic followed by neutrophilic. This
is supported by another study
36
. Similarly, in children with stable
asthma, the most frequent inammatory phenotype was pauci-
granulocytic followed by eosinophilic. The eosinophilic phenotype
was much higher in children than in adults with stable asthma.
However, another study found no difference in eosinophil level
between children (6.5%) and adult (5%) with asthma although the
total cells counts was higher in children compared to adults
27
.
The pattern of inammatory phenotype in acute asthma is
different between children and adults. In adults, the inammatory
phenotype was predominantly neutrophilic, with the remainder
being mixed granulocytic. In children, the predominant phenotype
was eosinophilic followed by the mixed granulocytic phenotype
(Figure 1). Children with acute exacerbation are concurrent with a
signicantly higher eosinophilic subtype and impaired lung
function compare to children with stable asthma
26
. These
differences are associated with clinically signicant alterations
in lung function and suggest the involvement of different
mechanistic pathways in acute exacerbation in children. There
is a so called adult-onset phenotype characterised by female
gender with worse lung function despite an apparently shorter
duration of disease and less atopy compared with early-onset
disease
37
. Patients in this sub-group have persistent wheezing at
age 6 years and airway eosinophilia, a marker of more severe
disease
38
. This is the classic phenotype that indicates the
importance of paediatric-adult collaboration and the understand-
ing of early life events. There is more to be learned about this
Table 1
Inammatory phenotypes in stable and acute asthma in children (derived from 26)
Healthy Control Stable Asthma Acute Asthma P value
Number of subjects 9 49 28
Neutrophilic only 0 10 (20.4%) 2 (7.1%) 0..82
Eosinophilic only 0 14 (28.6%) 14 (50.0%) 0.011
Mixed 0 1 (2.0%) 10 (35.7%) <0.0001
Paucigranulocytic 9 (100%) 24 (49.0%) 2 (7.1%) <0.0001
Neutrophilic Asthma (including neutrophilic and mixed phenotype) 0 11 (22.5%) 12 (42.9%) 0.024
Eosinophilic Asthma (including eosinophilic and mixed phenotype) 0 15 (30.6%) 24 (85.7%) <0.0001
Numbers are n(%), Fishers exact test

Figure 1. Inammatory phenotypes in adults and children with stable and acute
asthma
ASA: Adults with stable asthma (n = 29); CSA: Children with stable asthma (n = 49);
CAA: Children with acute asthma (n = 28); AAA: Adults with acute asthma (n = 22).
X.Y. He et al. / Paediatric Respiratory Reviews 12 (2011) 165169 167
phenotype. Clearly the differences in inammatory phenotypes
between adult and children with acute asthma may constitute the
different disease processes, and may partially contribute to
different disease prognosis.
POTENTIAL BIOMARKERS ON MONITORING DISTAL AIRWAY
INFLAMMATION
Endobrochial biopsy and bronchoalveolar lavage (BAL) have
been traditionally been used for assessment of airway inamma-
tion. A number of research groups have demonstrated an
association between FeNO and airway eosinophils, measured
either using BAL or endobronchial biopsy in children with
asthma
6,39
. However, bronchoscopy is not particularly practical
for most children or most centres. Even in specialised centres,
bronchoscopic assessment of airway inammation cannot be
performed on multiple occasions. To date the best performing
biomarker for clinical asthma appears to be inammatory
phenotype in sputum cell type, but the practical difculties of
sputum induction in patients and technical variation in sputum
processing and analysis limit the application clinically
39
. Current
biomarker studies in urine and circulating blood have insufcient
clinical predictive value.
Developments in modern biology offer the potential for more
effective methods to monitor disease and determine inammatory
phenotypes. Gene expression proling of sputum inammatory
cells
40
and bronchial epithelial brushings
41
has been used to dene
inammatory phenotypes and Th2 gene expression phenotypes.
Both experimental and clinical research using plasma proteomic
biomarkers for airway disease diagnosis, inammatory phenotype
and disease severity have been carried out positively in respiratory
diseases
42
. Using blood-based biomarkers in childhood asthma
assessment may provide useful and easily accessible samples for
analysis, particularly for younger children who have difculties
participating in sputum induction. The biomarker assays will add
new depth in our understanding of mechanisms by which the
distal lung function was impaired in childhood asthma.
CONCLUSIONS AND FUTURE DIRECTIONS
This review has given an outline of airway inammatory
phenotypes in various forms of asthma in children with a
developmental perspective on similarities and differences to
adults with asthma. Asthma still remains a challenge because
the number of emergency visits and hospitalizations for asthmatic
children. There are many factors underlying the exacerbation-
prone phenotypes and these have recently been reviewed
43
. Most
of these factors are probably common to children and adults, but
there are only limited data available in children at present. The
least understood phenotype is the most severe form of the disease
exemplied by acute exacerbations requiring hospitalisation.
These occur often in children who have respiratory viral infections
and are also atopic. Clearly, there is a pressing need for biomarkers
of the exacerbating phenotype, of the impending exacerbation as
well as diagnostic biomarkers indicating the relationship between
distal airway inammation and prognosis of asthma.
Longitudinal data are needed to determine the stability of
phenotypes and their prognosis from childhood to adult life of
patients with severe asthma. Undoubtedly, the distal airway
inammation represents the pathogenesis of childhood asthma,
which also underpins more effective therapeutic strategies. A
number of global initiatives have been undertaken to further our
understanding of severe asthma phenotypes using an international
network approach. The increased collaboration across age ranges
will allow understanding of how childhood disease interacts with
later environmental risk factors to produce adult disease. This will
improve our knowledge of pathologic mechanisms and of the
phenotype-clinical prognosis correlation in severe asthma.
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