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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.