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Title: The need to differentiate between adults and children when treating severe asthma
Summary
Severe asthma at all ages is heterogeneous incorporating several phenotypes that are distinct in
children and adults, but also numerous similar features including the limitation they may not remain
stable longitudinally. Severe asthma in both children and adults is characterised by eosinophilic
airway inflammation and evidence of airway remodelling. In adults, targeting eosinophilia with
anti-IL5 antibody therapy is very successful, resulting in the recommendation that sputum
eosinophils should be used to guide treatment. In contrast, data for the efficacy of blocking IL-5
remain unavailable in children. However, its effectiveness is uncertain since many children with
severe asthma have a normal blood eosinophils and the dominance of Th2 mediated inflammation is
controversial. Approaches that have revealed gene signatures and biomarkers such as periostin that
are specific to adult disease now need to be adopted in children to identify effective paediatric
specific therapeutics and minimise the extrapolation of adult therapeutics to children.
Introduction
A diagnosis of severe asthma commonly depicts a clinical picture characterized by persistent
symptoms, significant airflow obstruction and recurrent exacerbations despite maximal
pharmacological therapy [1]. A common definition and guidelines for management of severe
asthma have recently been proposed for all patients aged 6 years and over. Although a significant
advantage of common guidelines is the ability to trial novel treatments using similar criteria, some
key differences underlying the evolution and pathophysiology of severe asthma between children
and adults must be considered, and an automatic 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 diagnoses and ensure the
patient does not have difficult to treat asthma because of underlying modifiable factors such as poor
adherence to therapy or persistent allergen exposure [1,2,3]. This review will focus on factors that
characterise severe asthma in adults and children after difficult asthma has been excluded.
Severe asthma: pathophysiology
Severe asthma in children is characterised by eosinophilic airway inflammation, male
predominance, severe atopy with multiple aero-allergen sensitisation, and evidence of airway
remodelling including increased reticular basement membrane (RBM) thickness and increased
airway smooth muscle mass [4,5]. Eosinophilic airway inflammation is commonly assessed directly
by induced sputum and bronchoscopy, indirectly by peripheral blood eosinophil count and fraction
of exhaled nitric oxide (FeNO). 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 airway
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 BAL, biopsies and sputum of children with severe asthma [4].
Severe asthma in adults is also predominantly atopic and eosinophilic. In contrast to children, it is
recommended that when possible sputum eosinophil counts 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 limitation on spirometry, which in most cases can be reversed after
administration of bronchodilator. However, in children spirometry is often normal [9]. Adult severe
asthma is characterised by extensive airway remodelling including increased thickness of the RBM,
increased airway smooth muscle mass, and angiogenesis [10]. Although it was thought that Th2
mediators are the predominant drivers of adult disease, it is now recognised 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 [11]. There are therefore features that are quite
distinct in paediatric and adult disease, but several factors that are very similar and these contrasting
features and their impact on current therapeutic decisions and future identification of novel targets
will be discussed in this review.
Phenotypes of severe asthma in adults and children
Severe asthma at all ages is a heterogeneous disease and presents several phenotypes that may differ
in childhood and adulthood [1,12-17]. However, a common feature of all phenotypes, whether
based on airway inflammation or identified from unbiased analyses, is they may not remain stable
longitudinally [6,18] and there is little evidence that they can be used to predict disease progression
[19]. This may therefore limit the utility of phenotypes when deciding optimal therapies.
Age at symptom onset is a feature that frequently distinguishes phenotypes in unbiased cluster
analyses [20]. A meta-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 frequent exacerbations, while late or adult onset disease tends to be
characterised by female predominance, smoking and increased fixed airflow obstruction [20, 21].
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 [20]. 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 3 clusters that characterise these patients. The first included older patients
with clinical criteria of severe asthma, the second included those that required mechanical
ventilation and the third included younger patients that were under treated with anti-inflammatory
therapy and had a predominance of sensitisation to the fungal allergen Alternaria alternata [22]. 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
younger patients, in concurrence with the National Review of Asthma Deaths Report from the UK
[23].
A cluster analysis that included children that were enrolled in the Severe Asthma Research Program
(SARP) showed those with severe asthma were equally present in all clusters, and no cluster
corresponded with definitions of asthma severity that were proposed in treatment guidelines [24].
The heterogeneity and longitudinal variation is therefore further highlighted, and questions 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 failure 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 children. It therefore seems appropriate to consider
pathophysiological features, in addition to clinical features, in order to guide therapy.
An approach that has been undertaken recently is to perform transcriptomic analysis of airway
samples to identify gene signatures that may relate specifically to clinical features including 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 [25]. 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 hospitalisations. 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 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 undertaken to determine longitudinal changes in
remodelling, and interestingly has shown that clusters assigned during a first CT scan track
differently over time. Patients with the highest bronchial 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 dimensions over time. Importantly, this signal was lost when all
asthmatics were combined, even though all had severe disease [26]. Although there were some
inconsistencies in the methods used to make measurements, overall, these data illustrate the
importance 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 [27, 28]. Late-onset disease is also associated with several
comorbidities including nasal polys, sinus inflammation, gastro-oesophageal reflux and obstructive
sleep apnoea, the latter often being a consequence of obesity [29]. Obesity is a comorbidity
associated with both childhood [30] and adult onset [31] severe asthma and has been linked to
corticosteroid insensitivity [32]. An adult subphenotype not present in children is that associated
with persistent eosinophilic inflammation, nasal polyps and sinusitis and aspirin-exacerbated
respiratory disease [33]. Identifying this phenotype and in particular distinguishing eosinophilic
inflammation from non-eosinophilic inflammation is considered important because of the impact on
treatment options, including efficacy of steroids and monoclonal antibody therapies including the
anti-IL5 Ab mepolizumab [34].
Risk factors needing specific consideration for asthma onset in children
Early sensitisation [35,36], in particular to inhalant and perennial allergens with high levels of
specific IgE [37], is an important risk factor determining progression to asthma in school age and
early, multiple sensitisation predicts a severe disease trajectory [38]. In addition, genetic
susceptibility is an important factor that contributes to childhood severe asthma [39]. Several genes
identified from GWAS studies have specifically been associated with childhood asthma including
IL-33, which has also been associated with severe disease in both children [40] and adults [41]. 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 [42].
The impact of lung growth and development on paediatric disease manifestation
The pathogenesis, clinical manifestation and evolution of asthma in children is significantly
influenced and determined by underlying lung growth and development. Lung development starts
from the third week of gestation and continues including both alveolar development and airway
growth postnatally until adolescence [43].
This period of lung growth is an important window of susceptibility during which the lungs are
vulnerable to environmental factors such as pathogens (virus or bacteria), allergens, smoking,
pollution and diet. All of these may induce permanent 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 90s and has been supported by experimental animal
models where antenatal factors such as intrauterine growth restriction (IUGR) [44] or smoking [45]
and postnatal environmental factors such as viral infection [46] and pollution [47] can cause
anatomical alterations 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 [48]. The relationship between childhood severe asthma and adult
COPD appears even stronger [49].
Early life infections and 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 [50-52].
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 associated with
up to 12-fold increased risk in asthma development [53] with a direct relationship between infection
severity and asthma severity [54].
Animal models suggest that age plays an important role in the immune response to respiratory viral
infection and subsequent risk of developing asthma. In mice an early RSV infection 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 [55]. Furthermore, if early RSV infection is followed by
allergen exposure, the IL-13 immune pathway is exacerbated with asthma-like features [56].
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 sensitised to allergens [57]. The persistent asthma-like airway
changes observed during viral infections in early life may specifically be dependent on the
activation of type 2 innate lymphoid cells [58].
Differences between an immature and a developed immune system have also been observed during
bacterial infection. In neonatal mice, co-infection with Chlamydia increased the severity of allergic
airway disease and induced long-lasting effects on lung structure, such as emphysema, by a IL-13-
mediated pathway, however, this was not apparent when bacterial infection was introduced in adult
mice [59,60]. An early Chlamydia infection may also alter the developing of the immune system
towards a persistent Th2 activation predisposing the subject to asthma [61].
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 [62,63]. Thus suggesting the nature of early life infections determines subsequent
immune responses and determines either an increased predisposition or protection from the
development of allergic airways disease. A critical contributory factor is underlying genetic
susceptibility. Recurrent rhinovirus infections 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 [52]. Further elucidation of the genetic risk has revealed a specific susceptibility in subjects
with variants in the 17q21 locus [64].
In addition to external pathogen infections, the role of commensal organisms and the host
microbiota is now recognised 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 hyperesponsiveness [65]. An explanation for this dramatic response only in very early life is
the impact of progressive airway microbial airway colonization, 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 PD-L1. However, in early life, the absence microbial colonisation and
PD-L1 resulted in an exaggerated allergic airways response [65]. The diversity of bacteria
determining microbial colonization of the airways can have a protective effect, or may increase
susceptibility to asthma development. One month old babies that had nasal colonisation with the
pathogens Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis were
found to be at increased risk for asthma at 5 years of age [66] which was increased when bacterial
pathogens co-existed with a virus during an acute respiratory infection [67]. Conversely,
Staphylococcus, Corynebacterium and Alloiococcus seem to be common and stable components of
a normal airway microbiome [68]. 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 disease [69].
These data suggest manipulation of the infant gut microbial flora with probiotic supplements may
allow an alteration of the airway microbiome to prevent the long-term consequences of early-life
viral infections and thus the risk of later asthma [70]. However, convincing data from clinical trials
for such an effect is 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 particular among atopic children [68].
Interactions between the airway microbiome, early allergen sensitisation and virus can therefore
influence the development of the immune system and subsequently dictate the development of
chronic airway disease, increasing data suggest 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 and childhood asthma development
Maternal smoking is the major cause of preterm birth and IUGR [71], both associated with
decreased lung function and increased respiratory morbidity in childhood [72] and adulthood
[73,74]. In utero smoke exposure has been associated with an increased risk of incident asthma in
school age children [75,76] and, in those with asthma, to decreased lung function [77] and reduced
response to inhaled corticosteroids [78]. Smoke exposure in the foetal period may cause gene
alterations increasing susceptibility to adverse environmental factors [79] or may directly injure the
developing lung. In animal models smoke exposure during the foetal period and during lactation is
associated with remodelling with fewer and larger alveoli [80], increased collagen deposition and
airway smooth muscle thickness [81]. In addition, these structural alterations are to be associated
with airway hyperreactivity and increased neutrophils and mast cells after allergens exposure [81].
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.
In addition to tobacco smoke, outdoor and indoor pollutants like ozone, carbon monoxide, nitrogen
dioxide and particulate matter (PM) are important contributors to lung impairment, chronic
respiratory and allergic diseases [82]. Experimental studies on mice exposed to PM in the pre- and
postnatal period demonstrated significant and permanent alteration of lung structure with
incomplete alveolization and stiffer lung [47]. A recent study on the effect of the reduction of air
pollution in California showed a progressive improvement in lung function both in heathy and
asthmatic children [83].
Steroid responsiveness in adult and paediatric 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 [84]. However, in
children an agreed definition of steroid responsiveness is not available, and as a result the term
corticosteroid insensitive is more appropriate [1]. A fundamental difference between adult and
paediatric “steroid resistant” severe asthma is the adult definition is based on reduced lung function,
whereas children may have very severe disease characterised by persistent symptoms, frequent
exacerbation and eosinophilic airway inflammation, 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 symptoms, inflammation and exacerbations. When assessed using such
an approach in a cohort of children with difficult asthma, only 11% were completely corticosteroid
unresponsive following a two-week course of oral prednisolone whereas 89% showed some degree
of corticosteroid responsiveness [85]. 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 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 severity, 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 and 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 [86]. Adults with severe asthma have reduced IL-10 levels, which are not induced by
steroids [87,88]. However, the active form of vitamin D can restore IL-10 production from CD4+
cells [89]. 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 [90].
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
remodelling, reflected by increased airway smooth muscle mass [91]. Therefore, although it is
unlikely that vitamin D deficiency causes asthma, it is becoming increasingly certain that vitamin D
deficiency 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 and steroid resistance
A further factor that contributes to steroid resistance in both children and adults with severe asthma
is cigarette smoke exposure. Passive smoking worsens symptoms in both adults and children with
asthma [92,93] and in the latter has been linked to a greater risk of exacerbations and persistence of
asthma in later ages [93]. Interestingly, in children passive smoking results in the same molecular
abnormalities that are thought to cause steroid resistance in adults who smoke [94]. Oxidative stress
induced by smoking can reduce the expression of histone deacetylase (HDAC)-2, an enzyme that
regulates DNA expression and switches off activated inflammatory genes. In children with severe
asthma exposed to passive smoking airway macrophages show a reduction in HDAC-2 expression
and activity and in vitro dexamethasone is not as effective as in severe asthmatics not exposed to
passive smoking in suppressing TNF- induced IL-8 production [95].
Fungal sensitisation and steroid resistance
Severe asthma with fungal sensitisation (SAFS) is a recognised sub-phenotype of severe asthma in
both adults and children (96,97], characterised by sensitisation to at least one fungal aero-allergen,
vary high levels of serum IgE, reduced lung function and increased eosinophilic inflammation
[97,98]. 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 characterised by higher levels of the innate mediator IL-33 and the airway
hyperresponsiveness generated is resistant to steroid therapy [99]. This was confirmed in children
with SAFS who had higher levels of BAL 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 innate cytokines in severe asthma are relatively steroid
resistant [40].
Viral infections and steroid resistance
The majority of asthma exacerbations in both adults and children with severe asthma are
precipitated by viral infections [100,101]. It is recognised 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
rhinovirus are associated with an induction of the innate cytokines IL-33 [102] and IL-25 [103]. As
both cytokines have also been associated with steroid resistance [40,104], 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 characterised by frequent episodes
precipitated by viral infections. These episodic viral wheezers are also not responsive to either oral
steroid bursts [105] or maintenance inhaled steroid therapy [106], but the mechanisms underlying
this steroid resistance remain unknown. RSV infection is recognised to be steroid resistant as it
down regulates the epithelial glucocorticoid receptor [107,108], but many episodic viral wheezers
have rhinovirus causing their symptoms. Having seen the role of IL-33 in rhinovirus induced
asthma exacerbation and that is steroid resistant, it is possible that IL-33 also mediates rhinovirus
induced acute viral wheezing episodes in preschool children. The role of innate cytokines IL-25, IL-
33 and TSLP in inducing preschool wheezing therefore warrants investigation.
Innate cytokines, severe asthma and steroid resistance
There is increasing interest in the role of the innate epithelial cytokines IL-25, IL-33 and TSLP in
mediating asthma pathogenesis [109]. This is of particular relevance to severe asthma because of
increasing evidence suggesting these mediators are relatively steroid resistant [40,104]. Moreover,
their role in inducing type 2 innate lymphoid cells which secrete Th2 mediators, without the need
for an adaptive immune response may explain the mechanism underlying adult, non-atopic,
eosinophilic severe asthma [110]. 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 disease than in initiation [111]. However, a lack of reliable reagents to
measure levels in human airways and a lack of blocking antibodies means their role as therapeutic
targets remains unconfirmed.
Five year View and Key Issues
Mediators of severe asthma: therapeutic implications for adults and 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 exacerbations and in
achieving an oral glucocorticoid sparing effect [34,112]. Indeed, the success of eosinophil targeted
therapy has resulted in the recommendation that sputum eosinophils 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 [7]. It
is also difficult to detect IL-5 in these patients.
Investigation of epithelial gene signatures using transcriptomic 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 mediated disease, in whom underlying mechanistic pathways remain uncertain. The gene
signatures corresponded with a serum biomarker periostin, which in patients with moderate disease
was used to determine response to anti-IL13 antibody therapy [113]. 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 therefore unlikely to be reliable in growing
and developing children. A key missing facet in the discovery of novel biologicals for paediatric
severe asthma is a lack of a gene signature that characterises 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 paediatric specific
therapeutics.
Longitudinal assessments of severe asthma phenotypes: stability and prediction of outcome
Although numerous phenotypes and endotypes of severe asthma are apparent, especially in adult
disease, longitudinal follow-up of patients that have been “clustered” or assigned a phenotype is
lacking. The natural history of the identified phenotypes 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 pathophysiological
parameters, and then follow-up. An additional unanswered 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 paediatric severe asthma is to achieve symptom control and reduce
exacerbations using individualised 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 prevention 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 identifies the child in whom to intervene is available. Key
issues and goals for the future therefore include a focus on paediatric clinical trials in which
therapeutic targets that have been identified from children, and not extrapolated from adults, are
tested.
Key issues
In children and adults severe asthma present different pathophysiological features (Table 1).
In children blood eosinophil counts and sputum eosinophilia rarely reflect eosinophils in the
airways and the dominance of Th2 mediated inflammation is controversial.
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.
In children a definition of steroid responsiveness is lacking. Response to steroids cannot rely
on lung function only 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
paediatric age may prevent permanent respiratory impairment in later life.
Financial disclosure
No conflict of interest to declare
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Tables
Childhood onset Adult onset
Atopy (multiple and severe sensitisation) Occupational exposure
Predominantly male Female predominant
Eosinophilic Aspirin sensitisation
All features of airway remodelling Nasal polyps
Fixed airflow obstruction
Common features and risk factors
Obesity
Genetic susceptibility
Smoke exposure – increased risk of steroid resistance
Table 1. Features of childhood onset and adult onset severe asthma.