Review

The need to differentiate

between adults and children
when treating severe asthma
Expert Rev. Respir. Med. 9(4), 419–428 (2015)
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Valentina Fainardi1,2 Severe asthma at all ages is heterogeneous incorporating several phenotypes that are distinct
and Sejal Saglani*1 in children and adults, however, there are also numerous similar features including the
1 limitation that they may not remain stable longitudinally. Severe asthma in both children and
Leukocyte Biology and Respiratory
Paediatrics, National Heart and Lung adults is characterized by eosinophilic airway inflammation and evidence of airway
Institute, Imperial College London, remodeling. In adults, targeting eosinophilia with anti-IL-5 antibody therapy is very successful,
London, UK resulting in the recommendation that sputum eosinophils should be used to guide treatment.
2
Department of Clinical and
Experimental Medicine, Parma
In contrast, data for the efficacy of blocking IL-5 remain unavailable in children. However, its
University Hospital, Parma, Italy effectiveness is uncertain since many children with severe asthma have normal blood
*Author for correspondence: eosinophils and the dominance of Th2-mediated inflammation is controversial. Approaches
Tel.: +0044 0 2075943167 that have revealed gene signatures and biomarkers such as periostin that are specific to adult
Fax: +0044 0 2075943119
s.saglani@imperial.ac.uk disease now need to be adopted in children to identify effective pediatric specific therapeutics
For personal use only.

and minimize the extrapolation of adult therapeutics to children.

KEYWORDS: asthma phenotype . early-onset asthma . innate cytokines . lung development . severe asthma
. steroid resistance

A diagnosis of severe asthma commonly

depicts a clinical picture characterized by per-
sistent symptoms, significant airflow obstruc-
tion and recurrent exacerbations despite
maximal pharmacological therapy [1].
A common definition and guidelines for man-
agement of severe asthma have recently been
proposed for all patients aged 6 years and
over. Although a significant advantage of com-
mon guidelines is the ability to trial novel
treatments using similar criteria, some key dif-
ferences underlying the evolution and patho-
physiology of severe asthma between children
and adults must be considered, and an auto-
matic extrapolation of findings from adult
clinical trials to children may not always be
appropriate. An important initial step before
severe asthma is diagnosed at any age is to
confirm the diagnosis, exclude alternative diag-
noses and ensure the patient does not have dif-
ficult to treat asthma because of underlying
modifiable factors such as poor adherence to
therapy or persistent allergen exposure [1–3].
This review will focus on factors that charac-
terize severe asthma in adults and children
after difficult asthma has been excluded.
Severe asthma: pathophysiology
Severe asthma in children is characterized by
eosinophilic airway inflammation, male pre-
dominance, severe atopy with multiple aero-
allergen sensitization and evidence of airway
remodeling including increased reticular base-
ment membrane (RBM) thickness and
increased airway smooth muscle mass [4,5].
Eosinophilic airway inflammation is com-
monly assessed directly by induced sputum
and bronchoscopy, indirectly by peripheral
blood eosinophil count and fraction of exhaled
nitric oxide. However, in children eosinophilic
inflammation can be difficult to assess and
monitor. Sputum eosinophilia does not always
reflect lower airway inflammation [4] and is
not stable over long periods [6]. Furthermore,
in children, blood eosinophils rarely reflect air-
way eosinophils [7]. In addition, inflammatory
phenotype switching is common [8] and the
dominance of Th2-mediated inflammation is
controversial as demonstrated by the relative
absence of Th2 cytokines (IL-5 and IL-13) in
bronchoalveolar lavage, biopsies and sputum
of children with severe asthma [4].

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2015 Informa UK Ltd ISSN 1747-6348 419

 Review Fainardi & Saglani
Severe asthma in adults is also predominantly atopic and
eosinophilic. In contrast to children, it is recommended that
when possible sputum eosinophil counts should be used in
addition to clinical criteria to direct therapy [1]. In children,
however, the evidence to date does not support such a strategy.
Another key factor that contributes to the diagnosis of severe
asthma in adults is the presence of obstructive airflow limita-
tion on spirometry, which in most cases can be reversed after
administration of bronchodilator. However, in children spirom-
etry is often normal [9]. Adult severe asthma is characterized by
extensive airway remodeling including increased thickness of
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the RBM, increased airway smooth muscle mass and angiogen-
esis [10]. Of these features, increased airways smooth muscle is
most closely associated with a reduction in lung function, espe-
cially persistent airflow limitation in both adults and chil-
dren [5,11,12]. Although it was thought that Th2 mediators are
the predominant drivers of adult disease, it is now recognized
that only a proportion of adults with asthma have evidence of
Th2 inflammation, and in a similar manner to children, there
are many adult asthmatics without a Th2 phenotype [13]. There
are therefore features that are quite distinct in pediatric and
adult disease, but several factors that are very similar (TABLE 1).
These contrasting features and their impact on current thera-
peutic decisions and future identification of novel targets will
For personal use only.
be discussed in this review.
Phenotypes of severe asthma in adults & children
Severe asthma at all ages is a heterogeneous disease and presents
several phenotypes that may differ in childhood and adult-
hood [1,14–19]. However, a common feature of all phenotypes,
whether based on airway inflammation or identified from unbi-
ased analyses, is that they may not remain stable longitudi-
nally [6,20] and there is little evidence that they can be used to
predict disease progression [21]. This may therefore limit the
utility of phenotypes when deciding optimal therapies.
Age at symptom onset is a feature that frequently distin-
guishes phenotypes in unbiased cluster analyses [22]. A meta-
Table 1. Features of childhood onset and
adult-onset severe asthma.
Childhood onset Adult onset
Atopy (multiple and severe sensitization) Occupational exposure
Predominantly male Female predominant
Eosinophilic Aspirin sensitization
All features of airway remodeling Nasal polyps
Fixed airflow obstruction
Common features and risk factors
Obesity
Genetic susceptibility
Smoke exposure – increased risk of steroid resistance
420
analysis of all such studies has revealed age 12 years commonly
distinguishes childhood (early)-onset from adult (late)-onset
disease. Early-onset asthma is associated with atopy and fre-
quent exacerbations, while late- or adult-onset disease tends to
be characterized by female predominance, smoking and
increased fixed airflow obstruction [22,23]. Importantly, when
only considering severe asthma, the prevalence of severe disease
was similar in both early- and late-onset disease, and the
highlighted clinical phenotypic differences were no longer
apparent [22]. This suggests the pathophysiology of severe
asthma may be similar regardless of age at onset. A very specific
sub-group of adults with near-fatal asthma have been assessed
by cluster analysis and revealed three clusters that characterize
these patients. The first included older patients with clinical
criteria of severe asthma, the second included those who
required mechanical ventilation and the third included younger
patients who were under-treated with anti-inflammatory ther-
apy and had a predominance of sensitization to the fungal
allergen Alternaria alternata [24]. An important point
highlighted here is the risk of severe and near-fatal episodes
that result from poor adherence to therapy and a failure to
comply with a written asthma action plan, especially in youn-
ger patients, in concurrence with the National Review of
Asthma Deaths Report from the UK [25].
A cluster analysis that included children who were enrolled
in the Severe Asthma Research Program showed those with
severe asthma were equally present in all clusters, and no clus-
ter corresponded to definitions of asthma severity that were
proposed in treatment guidelines [26]. The heterogeneity and
longitudinal variation are therefore further highlighted, and
question the use of clusters alone to define treatment strategies.
A possible explanation for the mix of patients of varying disease
severity when cluster analyses have been undertaken is the fail-
ure to ensure the basics of asthma management were addressed
prior to enrolment. Phenotypic distinctions where patients with
difficult asthma have been excluded, and only those with true
severe asthma are assessed, are currently not available for chil-
dren. It therefore seems appropriate to consider pathophysio-
logical features, in addition to clinical features, in order to
guide therapy.
An approach that has been undertaken recently is to per-
form transcriptomic analysis of airway samples to identify gene
signatures that may relate specifically to clinical features includ-
ing disease severity, to identify transcriptomic endotypes. Such
an analysis using both sputum, to reflect airway genes and
comparing with blood has shown two gene clusters were found
that distinguished those with more severe disease [27]. The first
transcriptomic endotype included patients with a history of
intubation, lower lung function and higher exhaled nitric
oxide, the second included those with the most hospitaliza-
tions. These were identified in sputum and blood from adults
and considered endotypes associated with more severe disease.
Interestingly, when assessed in blood samples from children
similar gene signatures were apparent that related to more
severe disease, suggesting similarities between factors that
Expert Rev. Respir. Med. 9(4), (2015)
 The need to differentiate between adults & children when treating severe asthma
determine disease severity regardless of age. The key issue of
longitudinal stability of such transcriptomic profiles remains
uncertain and needs confirmation in serial assessments. An
assessment of temporal changes in bronchial wall dimensions
on CT scans from adults with severe asthma has been under-
taken to determine longitudinal changes in remodeling, and
interestingly has shown that clusters assigned during a first CT
scan track differently over time. Patients with the highest bron-
chial wall and lumen area on a first CT had the greatest
increase in both parameters over time, whereas those with the
lowest measurements had relatively little change in wall dimen-
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sions over time. Importantly, this signal was lost when all asth-
matics were combined, even though all had severe disease [28].
Although there were some inconsistencies in the methods used
to make measurements, overall, these data illustrate the impor-
tance of making distinctions within severe asthma, since the
progression over time may be very different in different
phenotypes.
Specific characteristics of adult-onset disease
Late-onset adult severe asthma mainly affects non-atopic
women, commonly involves neutrophilic inflammation and is
believed to be more steroid resistant as many of these patients
require oral steroids to achieve symptom control [29,30]. Late-
For personal use only.
onset disease is also associated with several co-morbidities
including nasal polyps, sinus inflammation, gastro-oesophageal
reflux and obstructive sleep apnea, the latter often being a con-
sequence of obesity [31]. Obesity is a co-morbidity associated
with both childhood- [32] and adult-onset [33] severe asthma
and has been linked to corticosteroid insensitivity [34]. An adult
subphenotype not present in children is that associated with
persistent eosinophilic inflammation, nasal polyps and sinusitis
and aspirin-exacerbated respiratory disease [35]. Identifying this
phenotype and in particular distinguishing eosinophilic inflam-
mation from non-eosinophilic inflammation is considered
important because of the impact on treatment options, includ-
ing efficacy of steroids and monoclonal antibody therapies
including the anti-IL-5 Ab mepolizumab [36].
Risk factors needing specific consideration for asthma
onset in children
Early sensitization [37,38], in particular to inhalant and perennial
allergens with high levels of specific IgE [39], is an important
risk factor determining progression to asthma in school age and
early, multiple sensitization predicts a severe disease trajec-
tory [40]. In addition, genetic susceptibility is an important fac-
tor that contributes to childhood severe asthma [41]. Several
genes identified from genome-wide association studies have spe-
cifically been associated with childhood asthma including
IL-33, which has also been associated with severe disease in
both children [42] and adults [43]. In addition, when the sub-
group of children with severe exacerbations are considered,
IL-33 was again identified as a susceptibility locus, but a novel
gene CDHR3 that was specific to early, severe disease was also
identified [44].
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Review
The impact of lung growth & development on pediatric
disease manifestation
The pathogenesis, clinical manifestation and evolution of
asthma in children are significantly influenced and determined
by underlying lung growth and development. Lung develop-
ment starts from the third week of gestation and continues
including both alveolar development and airway growth postna-
tally until adolescence [45].
This period of lung growth is an important window of sus-
ceptibility during which the lungs are vulnerable to environ-
mental factors such as pathogens (virus or bacteria), allergens,
smoking, pollution and diet. All of these may induce perma-
nent changes in pulmonary development and may therefore
influence asthma pathogenesis. In fact, compared to adults,
these exposures are likely to have different consequences on
an immature system that grows and differentiates very
quickly. The theory of the possible origin of adult chronic
lung disease starting in early life, called the ‘foetal origins’
hypothesis, was formulated in the early 1990s and has been
supported by experimental animal models where antenatal fac-
tors such as intrauterine growth restriction (IUGR) [46] or
smoking [47] and postnatal environmental factors such as viral
infection [48] and pollution [49] can cause anatomical altera-
tions in the developing lung. Evidence for the long-term
effect of early life exposures has also been confirmed from
longitudinal birth cohorts that have shown an early reduction
in lung function by school age in children with asthma that
subsequently tracks to adulthood, without recovery [50]. The
relationship between childhood severe asthma and adult
COPD appears even stronger [51].
Early life infections & aberrant immune responses
The burden of a viral or bacterial infection on the developing
lung that can occur in the early stages of life can determine
more serious effects compared to the same infection in later
life.
Increasing evidence suggests asthma pathogenesis in children
is influenced by early exposure to specific viral infections which
may skew immune responses to future allergen exposure and
impact the development of particular asthma phenotypes later
in life [52–54].
Most research has focused on the role of respiratory syncytial
virus (RSV) and human rhinovirus (RV) infections in early life
and a recent review estimated that these infections were associ-
ated with up to 12-fold increased risk in asthma develop-
ment [55] with a direct relationship between infection severity
and asthma severity [56].
Animal models suggest that age plays an important role in
the immune response to respiratory viral infection and subse-
quent risk of developing asthma. In mice an early RSV infec-
tion during the neonatal period is associated with development
of IL-13-induced airway hyperreactivity and hypereosinophilia
after re-infection in adult life, however, this Th2-skewed
response is absent if the primary infection occurs at a later
age [57]. Furthermore, if early RSV infection is followed by
421
 Review Fainardi & Saglani
allergen exposure, the IL-13 immune pathway is exacerbated
with asthma-like features [58]. Similarly, RV infection causes
long-term airways hyperresponsiveness, mucus production and
IL-13 expression in neonatal mice but not in adult mice and
predisposes to allergic inflammatory responses if the mouse is
then sensitized to allergens [59]. The persistent asthma-like air-
way changes observed during viral infections in early life may
specifically be dependent on the activation of type 2 innate
lymphoid cells [60].
Differences between an immature and a developed immune
system have also been observed during bacterial infection. In
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neonatal mice, co-infection with Chlamydia increased the sever-
ity of allergic airway disease and induced long-lasting effects on
lung structure, such as emphysema, by a IL-13-mediated path-
way, however, this was not apparent when bacterial infection was
introduced in adult mice [61,62]. An early Chlamydia infection
may also alter the development of the immune system towards a
persistent Th2 activation predisposing the subject to asthma [63].
Further experiments on neonatal mice have confirmed that
when exposed to bacteria inducing Th1 or Treg responses mice
were protected from eosinophilic lung inflammation and airway
hyperreactivity [64,65]. Thus suggesting the nature of early life
infections determines subsequent immune responses and deter-
mines either an increased predisposition or protection from the
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development of allergic airways disease. A critical contributory
factor is underlying genetic susceptibility. Recurrent RV infec-
tions in the first 3 years of life have been shown to increase the
risk of asthma development 30-fold, but only in a high-risk
birth cohort with at least one atopic parent [54]. Further eluci-
dation of the genetic risk has revealed a specific susceptibility
in subjects with variants in the 17q21 locus [66].
In addition to external pathogen infections, the role of com-
mensal organisms and the host microbiota is now recognized as
playing an important role in modifying immune responses and
the development of an early susceptibility to asthma. Inhaled
allergen exposure in neonatal, pre-weanling and adult mice
showed that house dust mite induced a significantly higher
eosinophilic and Th2 cellular inflammatory response in neonatal
mice, with an associated markedly increased airway hyperrespon-
siveness [67]. An explanation for this dramatic response only in
very early life is the impact of progressive airway microbial colo-
nization, which causes the activation of a specific family of Treg
cells. In a mature mouse, the developed airway microbiome had
the ability to induce Helios( ) Tregs via programmed death-
ligand 1. However, in early life, the absence of microbial coloni-
zation and programmed death-ligand 1 resulted in an exagger-
ated allergic airways response [67]. The diversity of bacteria
determining microbial colonization of the airways can have a
protective effect, or may increase susceptibility to asthma devel-
opment. 1-month old babies who had nasal colonization with
the pathogens Streptococcus pneumoniae, Haemophilus influenzae
or Moraxella catarrhalis were found to be at increased risk for
asthma at 5 years of age [68] which increased when bacterial
pathogens co-existed with a virus during an acute respiratory
infection [69]. Conversely, Staphylococcus, Corynebacterium and
422
Alloiococcus seem to be common and stable components of a
normal airway microbiome [70]. A direct impact of the gut
microbial flora and diet on the composition of the airway
microbiome has also been shown in murine allergic airways dis-
ease [71]. These data suggest that manipulation of the infant gut
microbial flora with probiotic supplements may allow an alter-
ation of the airway microbiome to prevent the long-term conse-
quences of early-life viral infections and thus the risk of later
asthma [72]. However, convincing data from clinical trials for
such an effect are still lacking. A recent study on nasopharyngeal
colonization in infants has reported an association between
asymptomatic Streptococcus colonization before any respiratory
infections and incidence of wheezing at 5 years of age in particu-
lar among atopic children [70]. Interactions between the airway
microbiome, early allergen sensitization and virus can therefore
influence the development of the immune system and subse-
quently dictate the development of chronic airway disease.
Increasing data suggest that these alterations in immune
responses occur during a critical developmental window in the
first few years of life. Although the period of susceptibility seems
to be the first 2 weeks in mice, we now need data to determine
the period of development and the composition of the gut and
lung microbiota in humans to determine the optimal time and
therapeutic with which to intervene.
Smoke exposure & childhood asthma development
Maternal smoking is the major cause of preterm birth and
IUGR [73], both associated with decreased lung function and
increased respiratory morbidity in childhood [74] and adult-
hood [75,76]. In utero smoke exposure has been associated with
an increased risk of incident asthma in school age children [77,78]
and, in those with asthma, to decreased lung function [79] and
reduced response to inhaled corticosteroids [80]. Smoke exposure
in the fetal period may cause gene alterations increasing suscep-
tibility to adverse environmental factors [81] or may directly
injure the developing lung. In animal models smoke exposure
during the fetal period and during lactation is associated with
remodeling with fewer and larger alveoli [82], increased collagen
deposition and airway smooth muscle thickness [83]. In addi-
tion, these structural alterations are associated with airway
hyperreactivity and increased neutrophils and mast cells after
allergens exposure [83]. Maternal smoking also has a role in
skewing the innate immune response of the newborn towards a
Th2 response which may predispose to allergic airways disease,
but also to more severe infection.
Furthermore tobacco smoke, outdoor and indoor pollutants
like ozone, carbon monoxide, nitrogen dioxide and particulate
matter (PM) are important contributors to lung impairment in
addition to chronic respiratory and allergic diseases [84]. Experi-
mental studies on mice exposed to PM in the pre- and postna-
tal period demonstrated significant and permanent alteration of
lung structure with incomplete alveolarization and stiffer
lung [49]. A recent study on the effect of the reduction of air
pollution in California showed a progressive improvement in
lung function both in healthy and asthmatic children [85].
Expert Rev. Respir. Med. 9(4), (2015)
 The need to differentiate between adults & children when treating severe asthma
Steroid responsiveness in adult & pediatric severe
asthma
In adults, steroid response is based on an improvement in %
predicted FEV1 to >80% following a trial of systemic steroids,
usually a 2-week course of high-dose prednisolone [86]. How-
ever, in children an agreed definition of steroid responsiveness
is not available, and as a result the term corticosteroid insensi-
tive is more appropriate [1]. A fundamental difference between
adult and pediatric ‘steroid resistant’ severe asthma is the adult
definition is based on reduced lung function, whereas children
may have very severe disease characterized by persistent symp-
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toms, frequent exacerbation and eosinophilic airway inflamma-
tion, whilst having normal spirometry. This means a definition
for steroid responsiveness in children needs to encompass more
than just lung function, and needs to take account of symp-
toms, inflammation and exacerbations. When assessed using
such an approach in a cohort of children with difficult asthma,
only 11% were completely corticosteroid unresponsive follow-
ing a 2-week course of oral prednisolone whereas 89% showed
some degree of corticosteroid responsiveness [87]. However,
adherence could not be guaranteed with oral prednisolone, it is
therefore possible that steroid responsiveness might improve
further using parenterally administered steroids.
Consideration of response to steroids in different clinical
For personal use only.
parameters such as symptoms, lung function and inflammation
may be important because the pattern of response may help
delineate the mechanisms underlying a patient’s asthma sever-
ity, and the most appropriate add-on or steroid sparing agent
that might be beneficial.
Mechanisms underlying response to steroids in severe
asthma
Serum vitamin D & severe asthma
In non-asthmatic patients IL-10, an anti-inflammatory cytokine
produced by CD4+ T cells, may play a role in limiting
Th2 responses and its secretion is thought to be enhanced by
corticosteroid treatments [88]. Adults with severe asthma have
reduced IL-10 levels, which are not induced by steroids [89,90].
However, the active form of vitamin D can restore
IL-10 production from CD4+ cells [91]. In a similar manner,
children with severe asthma have significantly reduced
IL-10 secretion from both peripheral immune cells and reduced
airway IL-10 levels compared to healthy controls, but addition
of vitamin D significantly enhances IL-10 secretion in response
to steroids in T cell cultures in a dose-dependent manner [92].
A direct effect of vitamin D deficiency on Th2 skewing and
promoting eosinophilia has been shown in a neonatal mouse
model of inhaled house dust mite exposure, and importantly
supplementation of vitamin D reduced both of these features
while increasing numbers of CD4+IL-10 positive cells, thus
confirming a link between IL-10 and vitamin D. Low serum
vitamin D levels are associated with increased disease severity
in children and is associated with worse airway remodeling,
reflected by increased airway smooth muscle mass [93]. There-
fore, although it is unlikely that vitamin D deficiency causes
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Review
asthma, it is becoming increasingly certain that vitamin D defi-
ciency is associated with increased disease severity and steroid
insensitivity. Thus, supplementation specifically in patients
with severe asthma is likely to improve response to steroids and
act as a steroid-sparing agent.
Smoke exposure & steroid resistance
A further factor that contributes to steroid resistance in both
children and adults with severe asthma is cigarette smoke expo-
sure. Passive smoking worsens symptoms in both adults and
children with asthma [94,95] and in the latter has been linked to
a greater risk of exacerbations and persistence of asthma in later
ages [95]. Interestingly, in children passive smoke exposure
results in the same molecular abnormalities that are thought to
cause steroid resistance in adults who smoke [96]. Oxidative
stress induced by smoking can reduce the expression of histone
deacetylase (HDAC)-2, an enzyme that regulates DNA expres-
sion and switches off activated inflammatory genes. In children
with severe asthma exposed to passive smoking airway macro-
phages show a reduction in HDAC-2 expression and activity
and in vitro dexamethasone is not as effective as in severe asth-
matics not exposed to passive smoking in suppressing tumor
necrosis factor-a-induced IL-8 production [97].
Fungal sensitization & steroid resistance
Severe asthma with fungal sensitization (SAFS) is a recognized
sub-phenotype of severe asthma in both adults and chil-
dren [98,99], characterized by sensitization to at least one fungal
aero-allergen, very high levels of serum IgE, reduced lung func-
tion and increased eosinophilic inflammation [99,100]. Until
recently, it was thought that the use of anti-fungal agents may
be an appropriate steroid sparing strategy in these patients.
However, mechanisms underlying SAFS were unknown. It is
now apparent that murine allergic airways disease induced by
the fungal allergen Alternaria Alternata is characterized by
higher levels of the innate mediator IL-33 and the airway
hyperresponsiveness generated is resistant to steroid therapy [101].
This was confirmed in children with SAFS who had higher lev-
els of bronchoalveolar lavage IL-33, increased endobronchial
biopsy IL-33 expression and were on more maintenance oral
steroids than those without SAFS. These data have highlighted
a novel mechanism mediated by IL-33 that may explain why
SAFS is associated with very severe disease, and have supported
the hypothesis that innate cytokines in severe asthma are rela-
tively steroid resistant [42].
Viral infections & steroid resistance
The majority of asthma exacerbations in both adults and chil-
dren with severe asthma are precipitated by viral infec-
tions [102,103]. It is recognized that frequently exacerbations,
especially in patients with severe asthma, are prolonged and less
responsive to steroids, which form the mainstay of therapy.
Interestingly, it has recently been shown that exacerbations
caused by RV are associated with an induction of the innate
cytokines IL-33 [104] and IL-25 [105]. As both cytokines have
423
 Review Fainardi & Saglani
also been associated with steroid resistance [42,106], this may
serve to explain the relatively poor response of infection-
induced exacerbations to steroids, and suggests therapies that
block the action of innate cytokines should be investigated as
alternative approaches.
A specific phenotype of wheezing seen in preschool children
is characterized by frequent episodes precipitated by viral infec-
tions. These episodic viral wheezers are also not responsive
to either oral steroid bursts [107] or maintenance inhaled steroid
therapy [108], but the mechanisms underlying this steroid
resistance remain unknown. RSV infection is recognized to
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be steroid resistant as it downregulates the epithelial gluco-
corticoid receptor [109,110], but many episodic viral wheezers
have RV causing their symptoms. Having seen the role of
IL-33 in RV-induced asthma exacerbation and that is steroid
resistant, it is possible that IL-33 also mediates RV-induced
acute viral wheezing episodes in preschool children. The role
of innate cytokines IL-25, IL-33 and thymic stromal lympho-
poietin in inducing preschool wheezing therefore warrants
investigation.
Innate cytokines, severe asthma & steroid resistance
There is increasing interest in the role of the innate epithelial
cytokines IL-25, IL-33 and thymic stromal lymphopoietin in
For personal use only.
mediating asthma pathogenesis [111]. This is of particular rele-
vance to severe asthma because of increasing evidence suggest-
ing these mediators are relatively steroid resistant [42,106].
Moreover, their role in inducing type 2 innate lymphoid cells
which secrete Th2 mediators, without the need for an adap-
tive immune response may explain the mechanism underlying
adult, non-atopic, eosinophilic severe asthma [112]. Although
their role (IL-33 in particular) in asthma inception has been
investigated, translation to human disease is lacking. It seems
IL-33 may be more important in persistence of chronic dis-
ease than in initiation [113]. However, a lack of reliable
reagents to measure levels in human airways and a lack of
blocking antibodies mean their role as therapeutic targets
remains unconfirmed.
Expert commentary & five year view
Mediators of severe asthma: therapeutic implications for
adults & children
In adults with severe asthma, targeting airway or peripheral
blood eosinophilic inflammation with the anti-IL5 antibody
mepolizumab has been very successful both in reducing exac-
erbations and in achieving an oral glucocorticoid sparing
effect [36,114]. Indeed, the success of eosinophil-targeted ther-
apy has resulted in the recommendation that sputum eosino-
phils should be used to guide treatment. However, data for
the efficacy of blocking IL-5 remain unavailable in children.
It is uncertain whether treatment will be as successful as in
adults since many children with severe asthma have a normal
blood eosinophil count, especially when on maintenance oral
steroids [8]. It is also difficult to detect IL-5 in these
patients.
424
Investigation of epithelial gene signatures using transcrip-
tomic profiling has uncovered adults with asthma can be split
into those that are ‘Th2 high’, with a predominance of the
classical Th2 cytokines (IL-4, IL-5 and IL-13) mediating their
disease and a ‘Th2 low’ group who do not have Th2-medi-
ated disease, in whom underlying mechanistic pathways
remain uncertain. The gene signatures corresponded to a
serum biomarker periostin, which in patients with moderate
disease was used to determine response to anti-IL13 antibody
therapy [115]. Response to therapies that block the action of
the Th2 cytokines may therefore be determined in adults
using blood biomarkers such as periostin. However, utility of
this biomarker in children in unknown, but is unlikely to be
successful, since periostin is derived from bone and is there-
fore unlikely to be reliable in growing and developing chil-
dren. A key missing facet in the discovery of novel biologicals
for pediatric severe asthma is a lack of a gene signature that
characterizes the disease, and a limited understanding of the
underlying mechanistic pathways. Approaches that have
revealed biomarkers and gene signatures in adults now need
to be adopted in children to identify pediatric specific
therapeutics.
Longitudinal assessments of severe asthma phenotypes:
stability & prediction of outcome
Although numerous phenotypes and endotypes of severe
asthma are apparent, especially in adult disease, longitudinal
follow-up of patients who have been ‘clustered’ or assigned a
phenotype is lacking. The natural history of the identified phe-
notypes and their role, if any, on prognosis/outcome is
unknown. An important facet of future work is therefore to
patients to determine whether phenotype assignment has any
clinical implications. A step prior to this, however, for children
is to uncover clinical phenotypes that incorporate pathophysio-
logical parameters, and then follow-up. An additional unan-
swered question for children is the optimal definition of
steroid response, and whether a response pattern may be used
to predict/determine the optimal add-on molecular-targeted
therapy.
The goal for both adult and pediatric severe asthma is
to achieve symptom control and reduce exacerbations
using individualized therapies that are determined by the
patient’s pathophysiological profile and gene signature.
This goal seems within reach, at least for adult patients,
while children remain a challenge. However, the ultimate
goal, especially in childhood, is to determine the optimal
target for early intervention that will allow secondary pre-
vention and disease modification by preventing the loss in
lung function that is established by school-age and tracks
to adulthood. Neither the target nor the marker that iden-
tifies the child in whom to intervene is available. Key
issues and goals for the future therefore include a focus
on pediatric clinical trials in which therapeutic targets that
have been identified from children, and not extrapolated
from adults, are tested.
Expert Rev. Respir. Med. 9(4), (2015)
 The need to differentiate between adults & children when treating severe asthma Review

Financial & competing interests disclosure This includes employment, consultancies, honoraria, stock ownership or
The authors have no relevant affiliations or financial involvement with options, expert testimony, grants or patents received or pending, or
any organization or entity with a financial interest in or financial con- royalties.
flict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript.

Key issues
. Although there are some pathophysiological differences of severe asthma in children and adults (TABLE 1), many features including
eosinophilic airway inflammation and significant airway remodeling are similar in both groups.
. In children blood eosinophil counts and sputum eosinophilia do not always reflect eosinophils in the airways and the dominance of
Th2-mediated inflammation is controversial.
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Emory University on 08/09/15

. Antenatal and postnatal lung development can be vulnerable to pathogens, allergens, smoking, pollution and diet with potential
influence on asthma pathogenesis. Abnormal immune responses to allergens and pathogens in early life may have an influence on the
development of allergic airways disease.
. Although evidence of reversible airflow obstruction is present in most children with severe asthma, there may be some patients with
normal spirometry in whom an airway challenge test is needed to confirm the diagnosis.
. In children a definition of steroid responsiveness is lacking. Response to steroids cannot rely on lung function alone, but needs to take
account of symptoms, inflammation and exacerbations.
. Innate epithelial cytokines such as IL-33 and type 2 innate lymphoid cells seem to have a role in steroid insensitivity and severe asthma
pathogenesis.
. Early intervention on asthma development with individualized therapies specific for the pediatric age may prevent permanent respiratory
impairment in later life.
For personal use only.

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