Severe Asthma in Children: Therapeutic Considerations

Dr Louise Selby1,2, Professor Sejal Saglani1,2

1. Dept of Respiratory Paediatrics, Royal Brompton Hospital, London, UK

2. National Heart and Lung Institute, Imperial College London, UK

Key Words:

Asthma, adherence, difficult asthma, asthma phenotyping, severe therapy resistant asthma (STRA),

long acting muscarinic antagonists (LAMAs), biologics, omalizumab, mepolizumab, eosinophilic

asthma, neutrophilic asthma.

Word count (excluding subheadings and references):

2,964 words

Abstract

Purpose of review: Children with poor asthma control despite maximal maintenance therapy have

problematic severe asthma (PSA). A step-wise approach including objective adherence monitoring

and a detailed multi-disciplinary team assessment to identify modifiable factors contributing to poor

control, is needed prior to considering therapy escalation. Pathophysiological phenotyping in those

with true severe treatment refractory asthma (STRA) and the current array of add-on therapies will

be discussed.

Recent findings: Adherence monitoring using electronic devices has shown only 20-30% of children

with PSA have STRA and need additional therapies. Omalizumab and mepolizumab are licenced for

children with STRA aged 6 years and older. Although robust safety and efficacy data, with reduced

exacerbations, are available for omalizumab, biomarkers predicting response to treatment are

lacking. Paediatric safety data are available for mepolizumab, but efficacy data are unknown for

those aged 6-11 years and minimal for those 12 and older. A sub-group of children with STRA have

neutrophilia, but the clinical significance and contribution to disease severity remains uncertain.

Summary: Most children with PSA have steroid sensitive disease which improves with adherence to

maintenance inhaled corticosteroids. Add-on therapies are only needed for the minority with STRA.

Paediatric efficacy data of novel biologics and biomarkers that identify the optimal add-on for each

child are lacking. If we are to progress towards individualized therapy for STRA, pragmatic clinical

trials of biologics in accurately phenotyped children are needed.

Introduction

Problematic Severe Asthma

Severe childhood asthma which remains uncontrolled has a long-term detrimental effect on adult

lung function and is associated with development of chronic obstructive pulmonary disease (COPD)(1). Problematic Severe Asthma (PSA) is an overarching term describing a child with a confirmed

diagnosis who has persistent symptoms despite maximal conventional treatments (2),(3),(4)**. Before

escalating treatments further, PSA should be stratified into Difficult Asthma (with modifiable factors,

such as allergen avoidance, smoke exposure, adherence to prescribed medications and psychosocial

issues) or true Severe Therapy Resistant Asthma (STRA) - poor control after modifiable factors and

the basics of asthma management have been addressed(5). A step-wise approach to diagnosis and

management(6) of PSA ensures poor control is not because of a wrong diagnosis, or a potentially

easily remediable factor is not wrongly treated with expensive biologics (Figure 1).

Difficult Asthma (DA)

Simple modifiable factors contributing to “difficult” disease include incorrect prescription of inhaled

corticosteroids (ICS), poor inhaler technique, inappropriate device for the age of child, poor

adherence and lack of family asthma education (7). However, multiple complex factors often

contribute to asthma being difficult and can only be identified following multi-disciplinary team

(MDT) input(3). These include persistent exposure to aero-allergens to which the child is sensitised

(house dust mite, pet dander, moulds) and tobacco smoke. Objective confirmation of smoke

exposure by measuring urinary or salivary cotinine levels helps ensure the family seek cessation

advice(8). Minimising aero-allergen exposure in sensitised children is essential as there is a known

relationship between exposure and increased disease severity (9). A nurse-led home visit helps

identify and tackle modifiable risk factors, and in a cohort of difficult asthmatic children prevented

treatment escalation in just over half of all children (7),(10)*. Breathing pattern disorders including vocal

cord dysfunction and hyperventilation may also contribute to DA and are often present with anxiety

and psychosocial exacerbators. Ideally, all children with PSA should have a physiotherapy

assessment to allow detection and management of dysfunctional breathing (11), and clinical

psychology assessment(10)*. The complex interplay of factors contributing to difficult asthma control

means the MDT evaluation may need to be undertaken during an in-patient stay. This approach

showed improvement in asthma control from 18% to 69% in children with DA (12). Moreover,

immediate and sustained improvement in objective measures including spirometry, exhaled nitric

oxide and exacerbations was demonstrated in 24/26 children following a 2-week in-patient

assessment(10). Alarming features prompting in-patient assessment include excess use of short acting

bronchodilator, discrepancy between symptom reporting and objective markers of disease severity,

and safeguarding concerns(10).

Objective assessments of adherence to ICS

The most common modifiable factor underlying DA is poor adherence to maintenance therapy,

encompassing 45-55% of all patients (adults and children) (4),(13). Good adherence is defined as the

administration of >80% of prescribed doses of ICS(14). The British Thoracic Society (BTS) Guidelines

state all patients with asthma must have an annual adherence assessment (15), and the proposed gold

standard method is using an electronic monitoring device (EMD), however other options include

prescription pick up/refill. For children with PSA, we propose objective assessment is an absolute

requirement prior to consideration of therapy escalation.

EMDs provide data on the date and time of inhaler actuation. An observational prospective cohort

study assessed spirometry with bronchodilator reversibility, fractional exhaled nitric oxide (FeNO),

asthma control test (ACT) scores and quality of life scores before and a median of 92 days after an

EMD was given to children (median age 12.4 years). Suboptimal adherence (<80%) was

demonstrated in 58%. Children with good adherence were split into those with improved control

(need encouragement to maintain adherence), or those with persistent poor control (severe therapy

resistant asthma (STRA)). Among children with poor adherence, there was a sub-group whose

control improved (likely over-treated), and a second sub-group with persistent poor control, the

latter requiring an adherence intervention such as directly observed therapy (DOT). The prevalence

of STRA was 18% of the entire cohort with PSA (4). The utility of an EMD as an intervention to improve

adherence is questionable. A multi-centre, open-label, parallel-group trial in which all participants

received EMDs for 3 months, but an intervention group had a review of their adherence data and

personalised intervention strategies (such as alarm reminders) were compared. Average adherence

was higher in the intervention group compared to controls (70% vs 49%) over a 12-month period,

while adherence rates declined over time in the control group. The intervention group had reduced

exacerbations requiring oral steroids or hospitalisation(16)*. EMDs alone may not change adherence

behaviours. The complexity and variation in adherence interventions means no single approach will

work for all children and just as biological treatments need to be personalised, interventions to alter

adherence behaviours also need to be individualised if they are to succeed (17).

Although currently not used routinely in children with PSA, an alternative measure of adherence is

the exhaled nitric oxide suppression test (normalisation of FeNO following a period of DOT with ICS).

This distinguishes patients with DA with steroid sensitive disease from those with true steroid

refractory asthma. To date, this was only undertaken following a period of DOT in hospital, but a

web-based interface with integrated remote monitoring technology has now been used to deliver

FeNO suppression testing at home(18). 80% of adults with DA completed the test remotely, and 64%

of those had a positive FeNO suppression test with good adherence, and thus did not have STRA.

Objective assessments of adherence show only 20-30% of all children with PSA have true STRA

needing therapy escalation. However, there is one group of high-risk children who remain a

significant challenge. Approximately 18% of children with PSA have persistent poor adherence and

persistent poor control, despite all efforts to improve adherence. These children are at high risk of

asthma death(19) and have been called “Refractory Difficult Asthma” (6). This is a group for whom

biologics administered in hospital may be the only safe option, even though, in truth, their disease is

not necessarily treatment refractory.

Pathological phenotype should guide add-on therapy in Severe Therapy Resistant Asthma (STRA)

As a group, children with STRA have multiple aero-allergen sensitisation, eosinophilic airway

inflammation and airway remodelling(20),(21)*, but there is a wide spectrum of disease heterogeneity.

Poor control despite high dose ICS, or regular oral steroids, means additional treatments to improve

control and minimise the adverse effects of steroids need to be considered. However, investigations

allowing an assessment of the airway pathological phenotype should be undertaken first (Figure 1).

A detailed assessment of allergen sensitisation, bronchoscopy to determine upper airway

abnormalities such as tracheomalacia, lower airway inflammation and infection are important prior

to adding new treatments. A trial of high dose systemic steroids allows assessment of the specific

pattern of clinical response. Whether improvement occurs in lung function, airway eosinophilia, or

symptoms may enable a targeted choice of add-on treatment(22). Children with STRA who had an

improvement in FeNO after intramuscular triamcinolone were most likely to respond to

omalizumab(23). Until very recently, choice of licenced add-on therapies for paediatric STRA was

limited to the monoclonal antibody to IgE, omalizumab. However, mepolizumab, an anti-interleukin

(IL)-5 antibody has now been licensed and additional biologics, such as the anti-IL-5 receptor

antibody, benralizumab, have been approved in adults (24),(25),(26) and may follow for children, making

the need for detailed clinical and pathological phenotyping in the individual child prior to deciding

add-on therapy essential(27)*.

Therapeutic considerations for allergic, eosinophilic STRA: omalizumab and mepolizumab

Molecular-based therapies allow control of a predominant airway phenotype and may enable

reduction in ICS dose(28), use must therefore be matched to disease phenotype (Figure 1) (29).

Omalizumab reduces cell-bound IgE, down-regulates IgE receptors and prevents pro-inflammatory

mediator release. Childhood STRA is characterized by allergen sensitization in the majority (2), thus

making omalizumab an attractive therapeutic option. It is indicated as add-on to maintenance

therapy for children aged >6 years with severe persistent asthma with elevated serum IgE (>30 and

<1500IU/ml) and positive specific IgE to at least one aeroallergen(30). Many studies have assessed

and confirmed real-life efficacy and safety of omalizumab in children with severe asthma (reviewed

in detail elsewhere(31)*,(32)). Overall, reduction in exacerbations and oral corticosteroid withdrawal are

apparent(33). However, only approximately two-thirds of children benefit, with no impact on lung

function(34). The STELLAIR study was a retrospective review which related omalizumab effectiveness

to blood eosinophils; assessing exacerbation rates, clinical evaluation and a combination of both.

Mean annual exacerbation rate reduced by 70.4% and hospitalisations by 73.2% in children, but

omalizumab efficacy was unrelated to blood eosinophils, suggesting this is a not a good biomarker of

response(35)**. The presence of multiple and severe allergies in childhood STRA(36) often limits

omalizumab use because of restrictive prescribing guidelines within a relatively narrow serum IgE

range. Approximately 30% of children with STRA have IgE levels higher than the recommended (22)

range. However, the prescribing range has been derived from adult studies and a recent report has

shown omalizumab was safe in children with a serum IgE higher than approved and 10/11 had

reduced need for corticosteroids, emergency department visits, or hospitalizations in the year after

therapy(37). Studies that confirm the optimal serum IgE range for children are lacking. Given the

majority of children have both elevated IgE and eosinophils, if a therapeutic trial of omalizumab has

failed, mepolizumab needs to be considered (Figure 2).

Anti-IL-5 immunomodulators

Mepolizumab is an anti-IL-5 humanised monoclonal antibody that reduces circulating eosinophils (38)*

and is licenced for use as add-on therapy in severe refractory asthma in patients with a peripheral

blood eosinophil count of >300cells/l in the past 12 months with >4 exacerbations requiring oral

corticosteroids, or continuous use of oral corticosteroids for >6 months. Abundant safety and

efficacy data is available in adults with severe eosinophilic asthma showing reduced exacerbation

frequency (especially in those with blood eosinophils >150cells/l(39)), improved quality of life and

asthma control(40). Unfortunately, neither convincing efficacy nor safety data is available for children.

Pooled data obtained from the MENSA and DREAM trials showed reduction in exacerbation rates for

12-17 year olds and no adverse events (41)*. However, only approximately 30 of the total 800

participants in the trials were in this age group. Despite this scant evidence, and no efficacy data at

all in children aged 6-11 years, in August 2018, the European Medicines Agency (EMA) approved

mepolizumab as an add-on therapy for children aged 6-17 years with STRA based on safety data

being similar between children aged 6-12 years and those >12 years (42). The extrapolation of efficacy

and safety data to enable licensing for children is a concern. Especially when it has been reported

that despite 85% of STRA children having airway eosinophilia, levels of Th2-signature cytokines IL-4,

IL-5 and IL-13 were difficult to detect(2). A sub-group had higher levels of Th2 cytokines, but efficacy

of mepolizumab in all children with eosinophilic disease is highly questionable. Now that both the

Federal Drugs Agency (FDA) and the EMA have approved mepolizumab in children, it is essential the

we urgently undertake pragmatic trials of safety and efficacy in children(28). At present, and until we

have paediatric specific biomarkers of response, we suggest mepolizumab should be used in children

who are either ineligible for, or have had a failed trial of, omalizumab (Figure 2).

Numerous biologics are now availablefor severe asthma with recent approval for use of reslizumab

and dupilumab. These predominantly target Th2 high disease; reslizumab is an anti-IL5 antibody

administered intravenously, dupilumab an antibody directed against the alpha subunit of the IL-4

receptor which functions by blocking the early signal transduction of the Th-2 mediated immune

response(43) and downstream signaling of IL-13(44)(45)** and bendralizumab, another antibody against

the IL-5 receptor. However, trials were undertaken in patients >12 years, including a minority of

children, which means true efficacy and safety in children remains unknown, and potential

biomarkers that predict response may not be applicable. Importantly, all are compared to placebo

which means currently we have no way of deciding optimal add-on treatment for individual patients.

Pragmatic trials assessing and comparing efficacy of biologics in children aged 6-17 years with STRA

who have been accurately clinically and pathologically phenotyped are needed. If this does not

happen, there is huge potential for us to cause harm, especially as complete depletion of circulating

inflammatory cells such as eosinophils may disrupt immune homeostasis and have deleterious

consequences(46).

Other therapeutic considerations:

Muscarinic Antagonists

Long acting muscarinic antagonists (LAMAs) such as tiotropium bromide are bronchodilators which

work via non-specific blockade of the muscarinic acetylcholine receptor, inhibiting smooth muscle

contraction and mucus secretion(28). The Global Initiative for Asthma (GINA) guideline includes

tiotropium as add-on therapy at step 4 and 5 of asthma management in patients aged >12 years (47)

following results of a phase-III 48-week double-blind placebo-controlled parallel-group study in

adolescents. This showed significantly improved lung function when tiotropium was used in addition

to ICS maintenance therapy(48). Two phase-III trials with the primary aims of analysing safety and

efficacy of once-daily tiotropium Respimat in children aged 1-5 and 6-11 years have been

undertaken but were not limited to severe asthma (49),(50)**. 402 children aged 6-11 years were

randomised to placebo, low or high dose tiotropium. Primary endpoint was change from baseline

response in FEV1 within 3 hours of dosing. Secondary outcomes included symptom control,

symptom-free days, weekly mean rescue medication use and peak flow response. Tiotropium

showed a significant improvement in spirometry, not symptom scores (50). There are no specific data

of the efficacy of LAMA in STRA, but given this data and impact on lung function,, it is an attractive

option, especially in children with markedly reduced lung function.

Future directions: targeting neutrophils in STRA

Are neutrophils helping or harmful in childhood STRA?

Asthma has been traditionally associated with Th2 cells producing signature cytokines IL-4, IL-5, and

IL-13; however cluster analyses in adults have shown ‘Th2 low’ and ‘Th2 high’ phenotypes (51),(52). In

childhood, there appears to be a close association between pathophysiological phenotype and age.

A paediatric cluster analysis revealed age-related inflammatory clusters with a neutrophilic steroid-

refractory cluster with a mean age of 40 months comprising severe preschool wheezers, while a

steroid-refractory eosinophilic cluster had a mean age of 11 years (21).

Neutrophilic inflammation has been associated with severe disease in adult asthma(53),(54) and

increased levels of IL-17 in bronchoalveolar lavage (BAL), blood and sputum have also been

associated with more severe disease(55). A Brazilian prospective cohort study of 48 children aged 6-

18 years investigated sputum inflammatory profiles in STRA children and compared them to children

with DA who achieved symptom control. Non-asthmatic controls were not included. Subjects

underwent 3 visits, with confirmation of STRA at the last visit (defined as ACT score <20, frequent

severe exacerbations with >2 courses of systemic corticosteroids and at least one hospital admission

requiring high dependency or ventilation and an FEV1 <80% throughout the study period). 13/42

(32.5% children) were classified as STRA and had higher induced sputum neutrophils at the third

study visit and higher levels of IL-10, IFN-, TNF- and granulocyte-macrophage colony-stimulating-

factor (GM-CSF). TNF- and GM-CSF negatively correlated with ACT scores(56). A further study has

defined neutrophil-high and neutrophil-low STRA sub-groups based on inflammation in BAL and

shown children with neutrophil-predominant phenotypes had proinflammatory neutrophils with

increased neutrophil activation, recruitment/migration, granule release and enhanced survival (57)*.

Again, comparisons were made within the severe asthma subgroup, not with non-asthmatic

controls. Comparison of STRA children to non-asthmatic controls has not revealed increased airway

neutrophils in BAL or in the submucosal region of bronchial biopsies. However, location-specific

examination of endobronchial biopsies showed significantly increased intra-epithelial neutrophils in

a sub-group of children with STRA associated with better lung function, symptom control and lower

prescribed doses of ICS(58). Although this data may appear to contradict the other two studies, it

must be remembered that the airway compartments analysed were different and highlights the

importance of relationships and interactions between inflammatory and structural cells in

determining functional outcomes. BAL and biopsy IL-17A were not significantly different between

controls and STRA children, although IL-17 receptor expression was increased in STRA (58)*. Blockade

of this receptor has been associated with reduced airway inflammation and hyper-reactivity in

murine models(59), but a clinical trial has not shown benefit (60). The functional role of neutrophils and

IL-17A in driving disease in paediatric STRA remains uncertain. We do not know whether both may

be induced by steroid therapy, with no functional consequence(61), or whether either or both are

disease-causing contributing to severity. It may be that luminal neutrophils are pro-inflammatory in

STRA because they are required to fight infection or external exposures such as pollution. Subclinical

microbial dysbiosis which may only be detected using molecular diagnostic techniques may explain

the highly activated and increased luminal neutrophils in this subgroup (57). A potential therapeutic

approach for this “Th2 low” asthma phenotype is azithromycin, which has anti-inflammatory

properties, and has been shown to reduce exacerbations with regular use in adults with persistent,

uncontrolled asthma(62). However, there are no data for efficacy in children, and key to

understanding whether neutrophils may be protective or pathogenic in childhood STRA is not to

extrapolate data from adult studies(63),(56), but to undertake interventional studies incorporating

mechanistic and functional outcomes in accurately clinically phenotyped sub-groups.

Summary

A step-wise approach to diagnosis and management of school-aged children with PSA, undertaken in

specialist centres, is essential. Before therapy escalation, detailed MDT assessments that allow

identification and correction of reversible factors contributing to poor asthma control are needed.

Recent studies suggest only 20-30% of all children with PSA have STRA, highlighting the importance

of the MDT in management. The most common reversible factor is poor adherence to maintenance

ICS and objective adherence monitoring must be undertaken. Detailed pathophysiological

assessments of children with STRA will define phenotype, but currently, paediatric efficacy data of

novel biologics (other than omalizumab) and biomarkers that identify the optimal add-on therapy for

each child are lacking. If we are to progress towards effective individualized therapy for children, we

urgently need pragmatic clinical trials of biologics in accurately phenotyped children.

Acknowledgements

None

Financial work and sponsorship

None received

Conflict of interests

None

References

1. Tai A, Tran H, Roberts M, Clarke N, Wilson J, Robertson CF. The association between childhood asthma and adult chronic obstructive pulmonary disease. Thorax. 2014;69(9):805-10.2. Bossley CJ, Fleming L, Gupta A, Regamey N, Frith J, Oates T, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129(4):974-82 e13.3. Cook J, Beresford F, Fainardi V, Hall P, Housley G, Jamalzadeh A, et al. Managing the pediatric patient with refractory asthma: a multidisciplinary approach. J Asthma Allergy. 2017;10:123-30.4. Jochmann A, Artusio L, Jamalzadeh A, Nagakumar P, Delgado-Eckert E, Saglani S, et al. Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children. Eur Respir J. 2017;50(6). **Demonstrates the importance of objective assessments of adherence to identify true severe therapy resistant asthma in a cohort of paediatric patients. 5. Chung KF, Wenzel S, European Respiratory Society/American Thoracic Society Severe Asthma International Guidelines Task F. From the authors: International European Respiratory Society/American Thoracic Society guidelines on severe asthma. Eur Respir J. 2014;44(5):1378-9.6. Bush A, Fleming L, Saglani S. Severe asthma in children. Respirology. 2017;22(5):886-97.7. Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, et al. The importance of nurse-led home visits in the assessment of children with problematic asthma. Arch Dis Child. 2009;94(10):780-4.8. Merianos AL, Jandarov RA, Mahabee-Gittens EM. Secondhand Smoke Exposure and Pediatric Healthcare Visits and Hospitalizations. Am J Prev Med. 2017;53(4):441-8.9. Gent JF, Belanger K, Triche EW, Bracken MB, Beckett WS, Leaderer BP. Association of pediatric asthma severity with exposure to common household dust allergens. Environ Res. 2009;109(6):768-74.10. Nagakumar P, Gambir N, Sanghani N, Hall P, Jamalzadeh A, Beresford F, et al. Role of a prolonged inpatient admission when evaluating children with problematic severe asthma. Eur Respir J. 2018;51(2). *Describes the role of an inpatient stay in problematic severe asthma where there is marked discrepancy between reported symptoms and objective measures of disease. Highlights improvements on spirometry, exhaled nitric oxide and bronchodilator reversibility during the stay that remain sustained at outpatient follow up. 11. Denton E, Bondarenko J, Tay T, Lee J, Radhakrishna N, Hore-Lacy F, et al. Factors Associated

with Dysfunctional Breathing in patients with Difficult to Treat Asthma. J Allergy Clin Immunol Pract. 2018.12. Verkleij M, Beelen A, van Ewijk BE, Geenen R. Multidisciplinary treatment in children with problematic severe asthma: A prospective evaluation. Pediatr Pulmonol. 2017;52(5):588-97.13. Lee J, Tay TR, Radhakrishna N, Hore-Lacy F, Mackay A, Hoy R, et al. Nonadherence in the era of severe asthma biologics and thermoplasty. Eur Respir J. 2018;51(4).14. Santos Pde M, D'Oliveira A, Jr., Noblat Lde A, Machado AS, Noblat AC, Cruz AA. Predictors of adherence to treatment in patients with severe asthma treated at a referral center in Bahia, Brazil. J Bras Pneumol. 2008;34(12):995-1002.15. BTS/SIGN. British guideline on the management of asthma a national clinical guideline https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-2016/: British Thoracic Society and Scottish Intercollegiate Guideline Network; 2016 16. Morton RW, Elphick HE, Rigby AS, Daw WJ, King DA, Smith LJ, et al. STAAR: a randomised controlled trial of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomes for children with asthma. Thorax. 2017;72(4):347-54. * A randomised controlled trial of electronic monitoring devices for maintenance inhaled corticosteroids or electronic monitoring plus reminder alarms and clinician feedback in children with problematic severe asthma. Fewer courses of oral corticosteroids and hospital admissions were observed in the group with reminder alarms and feedback emphasising the importance of objective measures of adherence as an essential component of paediatric asthma management. 17. Boutopoulou B, Koumpagioti D, Matziou V, Priftis KN, Douros K. Interventions on Adherence to Treatment in Children With Severe Asthma: A Systematic Review. Front Pediatr. 2018;6:232.18. Heaney LG, Busby J, Bradding P, Chaudhuri R, Mansur AH, Niven R, et al. Remotely Monitored Therapy and Nitric Oxide Suppression Identifies Non-Adherence in Severe Asthma. Am J Respir Crit Care Med. 2018 EPub.*FeNO suppression testing undertaken remotely using a web-based interface with integrated FeNO monitoring to objectively demonstrate adherence to maintenance inhaled corticosteroids in adults and distinguish those with difficult-to-control asthma from those with true treatment refractory disease.19. Physicians RCo. The National Review of Asthma Deaths (NRAD) https://www.rcplondon.ac.uk/file/868/download?token=JQzyNWUs2014 [20. Saglani S, Lloyd CM. Novel concepts in airway inflammation and remodelling in asthma. Eur Respir J. 2015;46(6):1796-804.21. Guiddir T, Saint-Pierre P, Purenne-Denis E, Lambert N, Laoudi Y, Couderc R, et al. Neutrophilic Steroid-Refractory Recurrent Wheeze and Eosinophilic Steroid-Refractory Asthma in Children. J Allergy Clin Immunol Pract. 2017;5(5):1351-61 e2.*Cluster analysis of BAL from children with severe wheeze or asthma showing a neutrophil predominant preschool group and an eosinophil predominant steroid refractory school-age group.22. Bossley CJ, Fleming L, Ullmann N, Gupta A, Adams A, Nagakumar P, et al. Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach. J Allergy Clin Immunol. 2016;138(2):413-20 e6.23. Fleming L, Koo M, Bossley CJ, Nagakumar P, Bush A, Saglani S. The utility of a multidomain assessment of steroid response for predicting clinical response to omalizumab. J Allergy Clin Immunol. 2016;138(1):292-4.24. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-27.25. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with

severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-41.26. Nair P, Barker P, Goldman M. Glucocorticoid Sparing of Benralizumab in Asthma. N Engl J Med. 2017;377(12):1205.27. Just J, Deschildre A, Lejeune S, Amat F. New perspectives of childhood asthma treatment with biologics. Pediatr Allergy Immunol. 2018. *Comprehensive review of the mechanisms of action of biological drugs for severe therapy resistant asthma; including a summary of clinical trial data, efficacy and safety for both adults and children.28. Martin Alonso A, Saglani S. Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies. Front Pediatr. 2017;5:154.29. Bush A, Pavord ID. 'We can't diagnose asthma until <insert arbitrary age>'. Arch Dis Child. 2018;103(8):729-31.30. NICE. Omalizumab for treating severe persistent allergic asthma https://www.nice.org.uk/guidance/ta278/evidence/review-decision-may-2016-2487605869: National Institute for Health and Clinical Excellence; 2016 May 17 [31. Pelaia C, Calabrese C, Terracciano R, de Blasio F, Vatrella A, Pelaia G. Omalizumab, the first available antibody for biological treatment of severe asthma: more than a decade of real-life effectiveness. Ther Adv Respir Dis. 2018;12:1753466618810192. *A summary of the mechanisms of action of omalizumab as well as a comprehensive review of real-life efficacy and safety data following over a decade of use.32. Tortajada-Girbes M, Bousquet R, Bosque M, Carrera Martinez JJ, Ibanez MD, Moreira A, et al. Efficacy and effectiveness of omalizumab in the treatment of childhood asthma. Expert Rev Respir Med. 2018;12(9):745-54.33. Deschildre A, Marguet C, Salleron J, Pin I, Rittie JL, Derelle J, et al. Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur Respir J. 2013;42(5):1224-33.34. Deschildre A, Marguet C, Langlois C, Pin I, Rittie JL, Derelle J, et al. Real-life long-term omalizumab therapy in children with severe allergic asthma. Eur Respir J. 2015;46(3):856-9.35. Humbert M, Taille C, Mala L, Le Gros V, Just J, Molimard M, et al. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018;51(5).**Retrospective study evaluating effectiveness of omalizumab in adults and children suggesting omalizumab efficacy is not related to peripheral blood eosinophils.36. Sharples J, Gupta A, Fleming L, Bossley CJ, Bracken-King M, Hall P, et al. Long-term effectiveness of a staged assessment for paediatric problematic severe asthma. Eur Respir J. 2012;40(1):264-7.37. Wang KY, Sindher SB, Stinson R, DaVeiga SP. Efficacy and safety of omalizumab in pediatric patients with high immunoglobulin E levels: A case series. Allergy Asthma Proc. 2018;39(4):289-91.38. Kelly EA, Esnault S, Liu LY, Evans MD, Johansson MW, Mathur S, et al. Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma. Am J Respir Crit Care Med. 2017;196(11):1385-95.*Experimental study in adults with allergic asthma with bronchoprovocation before and one month after administration of mepolizumab. Airway eosinophil expression of IL-5 responsive activation markers and receptors for IL-5 family cytokines were not altered by administration of mepolizumab, suggesting eosinophils can be reactivated despite mepolizumab, leading to a potential explanation for why some patients continue to exacerbate despite anti-IL-5 treatment.39. Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4(7):549-56.40. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Reappraisal of the clinical effect of mepolizumab - Authors' reply. Lancet Respir Med. 2017;5(6):e21.

41. Yancey SW, Ortega HG, Keene ON, Mayer B, Gunsoy NB, Brightling CE, et al. Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J Allergy Clin Immunol. 2017;139(4):1167-75 e2.*Meta-analysis of hospitalisation and emergency department visit rates for adult patients with severe eosiniphilic asthma treated with mepolizumab, showing rates of hospitalisation and emergency deparment visits are appoximately halved for patients receiving treatment.42. GSK. European Commission approves Nucala (mepolizumab) for the treatment of children with severe asthma https://www.gsk.com/en-gb/media/press-releases/european-commission-approves-nucala-mepolizumab-for-the-treatment-of-children-with-severe-asthma/: Glaxo Smith Kline; 201843. Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, et al. Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials. J Asthma. 2018:1-10.44. Busse WW, Maspero JF, Rabe KF, Papi A, Wenzel SE, Ford LB, et al. Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma. Adv Ther. 2018.45. Busse WW. Biological treatments for severe asthma: where do we stand? Curr Opin Allergy Clin Immunol. 2018.**Review of the four current biologic drugs approved for clinical use in severe asthma including their mechanisms of action, including efficacy data from clinical trials for each of the four drugs; omalizumab, mepolizumab, reslizumab and benralizumab.

46. Travers J, Rothenberg ME. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015;8(3):464-75.47. GINA. Pocket guide for asthma management and prevention for adults and children older than 5 years https://ginasthma.org/2018-pocket-guide-for-asthma-management-and-prevention/: Global Initiative for Asthma; 2018 48. Hamelmann E, Bateman ED, Vogelberg C, Szefler SJ, Vandewalker M, Moroni-Zentgraf P, et al. Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. J Allergy Clin Immunol. 2016;138(2):441-50 e8.49. Vrijlandt E, El Azzi G, Vandewalker M, Rupp N, Harper T, Graham L, et al. Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2018;6(2):127-37.50. Szefler SJ, Murphy K, Harper T, 3rd, Boner A, Laki I, Engel M, et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol. 2017;140(5):1277-87.**A 12 week randomised, double-blind placebo-controlled parallel group phase III multi centre trial assessing efficacy and safety of tiotropium respimat in 3 escalating doses versus placebo in children aged 1-5 years with persistent asthmatic symptoms. Results concluded the drug was well-tolerated, and though it showed no reduction in daytime symptom scores, may reduce exacerbation rates of asthmatic symptoms in this age group.

51. Bhakta NR, Woodruff PG. Human asthma phenotypes: from the clinic, to cytokines, and back again. Immunol Rev. 2011;242(1):220-32.52. Wills-Karp M. Neutrophil ghosts worsen asthma. Sci Immunol. 2018;3(26).53. Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557-63 e5.54. Hsiao HP, Lin MC, Wu CC, Wang CC, Wang TN. Sex-Specific Asthma Phenotypes, Inflammatory Patterns, and Asthma Control in a Cluster Analysis. J Allergy Clin Immunol Pract. 2018.

55. Newcomb DC, Cephus JY, Boswell MG, Fahrenholz JM, Langley EW, Feldman AS, et al. Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. J Allergy Clin Immunol. 2015;136(4):1025-34 e11.56. Eller MCN, Vergani KP, Saraiva-Romanholo BM, Antonangelo L, Leone C, Rodrigues JC. Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy-resistant asthma? Pediatric Pulmonology. 2018;53(9):1208-17.*Prospective cohort study of children aged 6-18 years with severe asthma who were followed consecutively over 3 visits, with analysis of induced sputum for cytology and inflamamtory cytokines as well as spirometry and exhaled nitric oxide measurements. Those with more severe disease were found to have predominantly neutrophilic sputum with elevated levels of IL-10, GM-CSF, IFN-γ, and TNF-α.57. Grunwell JR, Stephenson ST, Tirouvanziam R, Brown LAS, Brown MR, Fitzpatrick AM. Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance. J Allergy Clin Immunol Pract. 2018.*Analysis of 67 children undergoing bronchoscopy for clinical indications stratified into neutrophil 'high' and neutrophil 'low' groups based on lavage cytology. Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation and degranulation and greater airway proinflammatory cytokine release, suggesting therapies targeting neutrophilic inflammation may be appropriate in this subset of children.58. Andersson CK, Adams A, Nagakumar P, Bossley C, Gupta A, De Vries D, et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J Allergy Clin Immunol. 2017;139(6):1819-29 e11. *Evidence that a subgroup of children with STRA have increased intra-epithelial neutrophils, but they are not associated with worse disease. Thus the location, phenotype and function of airway neutrophils needs to be assessed prior to deciding the use of anti-neutrophilic agents in paediatric STRA.59. Willis CR, Siegel L, Leith A, Mohn D, Escobar S, Wannberg S, et al. IL-17RA Signaling in Airway Inflammation and Bronchial Hyperreactivity in Allergic Asthma. Am J Respir Cell Mol Biol. 2015;53(6):810-21.60. Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188(11):1294-302.61. Gupta A, Dimeloe S, Richards DF, Chambers ES, Black C, Urry Z, et al. Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma. Thorax. 2014;69(6):508-15.62. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10095):659-68.63. Saglani S. Childhood severe asthma: New insights on remodelling and biomarkers. Paediatr Respir Rev. 2017;24:11-3.