E000367 Full

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bmjmed: first published as 10.1136/bmjmed-2022-000367 on 25 June 2023. Downloaded from http://bmjmedicine.bmj.com/ on December 12, 2023 by guest. Protected by copyright.
Advances in the pathogenesis and personalised treatment of
paediatric asthma
Elizabeth Scotney ‍ ‍,1,2 Louise Fleming ‍ ‍,1,2,3 Sejal Saglani ‍ ‍,1,2,3 Samatha Sonnappa ‍ ‍,1,2,3
Andrew Bush ‍ ‍1,2,3
For numbered affiliations see ABSTRACT how to use objective measurements to make the
end of article.
Correspondence to: Andrew The diversity of pathology of severe paediatric diagnosis, and the advances in understanding
Bush, Imperial College London asthma demonstrates that the one-size-f its-a ll of the pathogenesis of paediatric asthma that
NHLI, London SW7 2BX, UK; approach characterising many guidelines is are substantially changing the management
a.bush@imperial.ac.uk
inappropriate. The term “asthma” is best used of asthma. This review will use evidence from
Cite this as: BMJMED
to describe a clinical syndrome of wheeze, clinical studies in children and young people to
2023;2. doi:10.1136/
bmjmed-2022-000367 chest tightness, breathlessness, and sometimes outline a structured objective approach for diag-
cough, making no assumptions about underlying nosing and managing asthma. This approach
Received: 13 September 2022
pathology. Before personalising treatment, it forms the basis of reviewing the efficacy and
Accepted: 5 May 2023
is essential to make the diagnosis correctly usefulness of new treatment options including
and optimise basic management. Clinicians biological medicines targeting type 2 inflam-
must determine exactly what type of asthma mation, the change in the paradigm for reliever
each child has. We are moving from describing treatment, and the heightened awareness of the
symptom patterns in preschool wheeze to importance of asthma attacks and the concept of
describing multiple underlying phenotypes risk.
with implications for targeting treatment. Many
new treatment options are available for school Sources and selection criteria
age asthma, including biological medicines We reviewed articles on paediatric asthma
targeting type 2 inflammation, but a paucity of published from 1 January 1992 to 31 February
options are available for non-t ype 2 disease. 2023. We searched the PubMed database for arti-
The traditional reliever treatment, shortacting cles on paediatric asthma management, patho-
β2 agonists, is being replaced by combination genesis, and diagnosis. We used specific search
inhalers containing inhaled corticosteroids terms (Asthma OR wheez* AND Child OR infant
and fast, longacting β2 agonists to treat the AND management OR treatment OR biologic), and
underlying inflammation in even mild asthma limited the search to clinical trials, randomised
and reduce the risk of asthma attacks. However, controlled trials, meta-analyses, and systematic
much decision making is still based on adult reviews. We also manually searched the reference
data extrapolated to children. Better inclusion of lists of relevant articles for additional references.
children in future research studies is essential, if Manuscripts were reviewed by the authors and
children are to benefit from these new advances selected on the basis of relevance to the review.
in asthma treatment. Only full manuscripts published in English in
peer reviewed journals were included.
Epidemiology of severe asthma

Introduction One in 11 children in UK have asthma,2 which is the
Paediatric asthma is a heterogenous disease, often most common chronic disease during childhood. The
but not invariably characterised by eosinophilic vast majority of cases of asthma can be controlled
lower airway inflammation and reversible airway with low to moderate doses of inhaled corticos-
obstruction. Advances in the understanding of teroids (ICS). About 3-5% of children have severe
the underlying pathogenesis and the identifica- asthma (box 1).3
tion of clinical phenotypes and molecular endo-
types has prompted a shift towards personalised Paediatric asthma across the life course
treatment for children and young people with Personalised treatment is impossible without first
asthma. However, it is increasingly becoming appreciating the developmental changes in the
apparent that personalised medicine is not being different types of asthma as the child matures. The
underpinned by correct diagnosis and high use of a single word (ie, asthma) to describe many
quality basic management. For example, the UK different airway diseases has hindered the percep-
National Review of Asthma Deaths (NRAD) 1 high- tion that schoolchildren are not little adults, and
lighted the urgent need to improve basic asthma toddlers and preschoolers are not small school-
care received by children and young people. children. Mixing pathology and clinical features in
Healthcare professionals caring for children and past definitions of asthma has led to wheeze being
young people with asthma should be aware of considered as an indication for ICS prescription
Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 1

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without considering whether eosinophilic inflam-
BOX 1 | KEY DEFINITIONS mation is actually present.4 However, we now appre-
Type 2 inflammation: ciate that "asthma" is an umbrella term comprising
Inflammation mediated by T helper 2 lymphocytes many different phenotypes and endotypes,5 and so
and type 2 innate lymphoid cells via the typical The Lancet Commission6 defined asthma in purely
signature cytokines interleukin (IL) 4, IL5, and IL13, clinical terms (box 1) with no assumptions about
which drive eosinophilic airway inflammation. the underlying pathology. Just as the diagnosis
Asthma: of arthritis should automatically lead to further
Defined clinically as wheeze, chest tightness, exploration into determining the underlying type
breathlessness, and sometimes cough.6 of arthritis, the same applies to asthma; the asthma
Severe asthma: label is the start and not the end of the diagnostic
Asthma that requires treatment with high dose journey. The next step is to deconstruct and examine
inhaled corticosteroids plus a second controller or in detail the airway, in order to especially delineate
systemic corticosteroids to prevent it from becoming treatable (and untreatable) traits at all ages as far as
uncontrolled, or asthma that remains uncontrolled is possible (box 1 and table 1). The in-depth exam-
despite this treatment.63 ination of the airway and identification of traits
Personalised treatment: enables a better understanding of airway inflamma-
Treatment that is targeted and individualised to a tion in asthma and identification of coexisting and
patient. alternative airway pathologies.7 The methods used
Treatable traits: will depend on the age and developmental maturity
A precision medicine strategy for patients with of the child.
airway disease that is label-free and based on the Deconstructing the airway is particularly important
identification of treatable traits in each patient.7 in preschool asthma. Unlike school age children with
An approach based on treatable traits enables an asthma, many have no evidence of type 2 inflamma-
individualised and personalised approach that tion, and if ICS is prescribed indiscriminately to all
is not disease specific and is not limited by the preschool children with wheeze, no benefit is seen.8
diagnosis. A treatable trait is a treatment target However, use of two biomarkers, peripheral blood
identified through the identification of phenotypes eosinophil count, and aeroallergen sensitisation
or examination of underlying causal pathways. allows delineation of a steroid responsive group.9 10
Building on this finding to delineate other phenotypes
should be a consideration for the future.
Table 1 | Detailed examination of the airway in children with suspected asthma to identify coexisting and alternative
airway pathologies and provide targeted treatment
Treatment
Airway component Investigative method Underlying cause recommendations Treatment outcomes
Fixed airflow obstruc- FEV1 <1.96 SD scores Congenital/environmental Not treatable, aim to prevent Deterioration in airway
tion despite prednisolone (eg, cigarette smoke expo- further deterioration, but do growth halted
and acute administra- sure); acquired remodelling not overtreat
tion of SABA
Variable airflow Variation in spirometry Bronchoconstriction; airway SABA and LABA; airway Bronchodilatation; reduction
obstruction or peak flow by an arbi- malacia118; intraluminal mu- clearance, mucoactive in airflow obstruction
trary threshold (usually cus/inflammatory debris agents
15%) over time or with
treatment
Airway inflammation Induced sputum; FeNO; Eosinophilic; neutrophilic; ICS; neutrophilic asthma is Better asthma control, fewer
peripheral blood eosin- pauci-inflammatory rare in children, no evidence attacks; improved outcomes,
ophil counts base for treatment in chil- especially symptom control;
dren,63 determine underlying reduction in courses of sys-
cause of neutrophilia temic steroids; avoidance of
inappropriate treatments
Airway infection Cough swab; induced Bacterial, viral, or fungal Targeted antibiotics for Improved outcomes, espe-
sputum; bronchoscopy cause related to systemic or bacterial infection; consider- cially symptom control
mucosal immune paresis ation of antifungal treatment
for severe asthma with
fungal sensitisation119
Heightened cough Cough challenge (rarely Mechanisms not understood No licensed treatment in Nothing to change outcomes
reflex performed in children) in children children
FeNO=fractional exhaled nitric oxide; FEV1=forced expiratory volume in 1 second; ICS=inhaled corticosteroids; LABA=longacting β2 agonist; SABA=shortacting
β2 agonist; SD=standard deviation.
2 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

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Personalised treatment: getting the core basics of preschool children can perform spirometry and
diagnosis and management right bronchodilator reversibility in a clinical setting,19
Frequent misdiagnosis of asthma in children and techniques such as offline measurement of frac-
Asthma, although common, is a complex disease; tional exhaled nitric oxide (FeNO), multiple breath
however, diagnoses in children and young people washout, and impulse oscillometry—which require
are often based on reported symptoms that have low no more than passive cooperation—are increasingly
specificity and sensitivity in adult studies,11 and it is used clinically. The peripheral blood eosinophil
unlikely that the findings would be different in children. count is now a validated point-of-care test,20 which
Furthermore, in children with suspected asthma, objec- could make it easier to measure a blood eosino-
tive testing to confirm the asthma diagnosis is done phil count in children. A blood eosinophil count
infrequently.12 13 Overdiagnosis is estimated at between can be used across the developmental spectrum as
30% and 50% of the general population with paedi- a biomarker of airway eosinophilia, and therefore
atric asthma14 15; many of these diagnoses are made for can be predictive of a response to ICS and biological
children who are otherwise healthy but with recurrent medicines such as mepolizumab (see below).
coughs and colds. Underdiagnosis also occurs14 and One caveat is that some children with asthma
the consequences of misdiagnosis are important.16 An could have non-obstructive spirometry when well.
erroneous diagnosis of asthma can lead to healthy chil- There is no one asthma diagnostic test; table 2 lists
dren being given unnecessary drug treatments, or more supportive tests, and the more tests that are negative,
rarely, an important diagnosis might be missed in chil- the less likely the diagnosis. NICE has stressed the
dren whose symptoms are caused by another treatable need for objective testing to support a diagnosis of
condition. asthma.11 The tests that are available will depend on
Both misdiagnosis groups might then be exposed to local resources; in high income settings, spirometry
the risks of side effects of unnecessary asthma treat- should be performed as a minimum, and FeNO is
ments, particularly as ICS doses might be increased increasingly available in primary care. In accordance
when symptoms do not respond. Furthermore, if with NICE guidance, we advise that testing should be
inhalers are given to children with recurrent coughs and done before a diagnosis is made and especially if the
colds who do not need them, the diagnosis of asthma prescription of ICS is being contemplated. Children
might be trivialised and the seriousness of the condi- with suspected asthma or preschool wheeze should
tion underestimated.16 Children with asthma who do be referred to a paediatric respiratory specialist if the
not have a diagnosis are also untreated and are at risk diagnosis is uncertain, the response to treatment is
of asthma attacks and persistent symptoms, leading to poor, and severe attacks are ongoing, or if primary
time off school, reduced exercise tolerance, and affected care or parents request a second opinion. Often the
quality of life. An asthma diagnosis is often made by first step is re-evaluation of the diagnosis and further
primary care and secondary care clinicians who have tests, rather than escalating treatment that might not
little or no paediatric respiratory experience, and who be appropriate.
do not perform objective testing as recommended by the The treatment approaches to asthma vary in
National Institute for Health and Care Excellence (NICE). different childhood age groups: young children (age
This lack of experience commonly results in incorrect ≤5 years), school age (6-11 years), and adolescence
diagnoses and management.15 NRAD highlighted that (age 12-18 years), because what works for one age
the potential for adverse outcomes, including death, in group might not be the best approach for another.
children and young people is poorly recognised among Most school age children with asthma achieve good
healthcare professionals.1 The large number of children
symptom control when treated with low to moderate
with a wrong label of asthma makes it more difficult to
dose ICS with or without a longacting β agonist, but a
identify those with poorly controlled disease or at high
minority (3-5% of children with asthma)3 have severe
risk of an attack, leading to inadequate management.17
disease and poor symptom control despite maximal
Furthermore, a diagnosis based on clinical history
treatment, and these children need further escala-
without objective measurement results in a limited
tion in support and intervention. Not all these chil-
understanding of the type of asthma in the individual
dren with symptoms have severe, treatment resistant
and likely implementation of inappropriate manage-
asthma, which is rare.
ment strategies. Hence, recent NICE guidance stresses
The World Health Organization categorised
the importance of objective tests being performed
severe asthma into three groups21: untreated severe
before making a diagnosis of asthma.11
asthma resulting from a failure of diagnosis or lack
of availability of treatment (which is not confined
Ensuring the correct basic management steps to low and middle income countries); severe
before use of biological medicines asthma that is difficult to treat, whereby social
A crucial initial step is ensuring the accuracy of the and environmental factors or comorbidities hinder
diagnostic label of asthma. A key message11 18 is that the response to treatment; and severe, treatment
objective testing should be used to diagnose asthma resistant asthma that requires high level treatment
in accord with NICE guidelines.15 Even quite young with ICS and other controllers to achieve control or

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Table 2 | Objective tests for asthma diagnosis and management
What to measure When to measure Considerations
Spirometry (FEV1, FVC) Before commencement of asthma treatment Airflow obstruction is variable and spirometry can be normal, even in
if possible, or withhold LABA for 12 hours severe asthma; testing when symptomatic can be very informative.
and SABA for 4 hours.
Peak flow Pre-treatment if possible, for 2 weeks, after Electronic peak flow metres are likely to be much more useful and
which data collection is less accurate and reliable. Clinicians should be aware of the possibility of fabricated
complete; might also be useful to guide measurements with standard peak flow metres.120
management in those individuals with poor
symptom perception.
FeNO Pre-treatment if possible; before other FeNO is a useful measure of adherence to treatment with ICS. If FeNO
forced expiratory manoeuvres.121 levels fall after a period of directly observed treatment with ICS, then
previous adherence to ICS treatment was poor. FeNO will remain ele-
vated despite good adherence to treatment if the child does not have
steroid responsive asthma. FeNO is also raised in individuals who
do not have asthma but have atopic disease (ie, those with allergic
rhinitis, eczema)
Tests of airway hyper- For those individuals aged over 4 years with AHR testing for children not widely available; field tests, such as run-
responsiveness (AHR) consistently normal spirometry and FeNO; ning up and down the stairs in clinic, might be helpful for confirming
LABA must be withheld for 12 hours and exercise induced bronchoconstriction, but has poor sensitivity.
SABA for 6 hours.
Blood eosinophils Consider pre-treatment with ICS for pre- Children of preschool age with a raised blood eosinophil count are
school children; an important test for the more likely to benefit from ICS. In children with severe asthma and
investigation of severe asthma. a low blood eosinophil count, the blood eosinophil count should be
checked at least three times. In children on maintenance OCS, the
blood eosinophil count should be checked on the lowest possible
dose of OCS to maintain asthma control. The highest blood eosinophil
count within a 12 month period should be used to determine non-type
2 airway inflammation.122 If the blood eosinophil count is high in a
person with asthma, it does not need to be repeated. In low to middle
income countries, blood eosinophilia could reflect helminth infection.
Skin prick testing Consider testing in preschool children; Preschool children with aeroallergen sensitisation might be more
useful to identify aeroallergen triggers in likely to respond to ICS; useful to identify aeroallergen triggers and
children with poorly controlled asthma. guide avoidance strategies.
AHR=airway hyper-responsiveness; FeNO=fractional exhaled nitric oxide; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; ICS=inhaled
corticosteroids; LABA=longacting β2 agonist; OCS=oral corticosteroids; ppb=parts per billion; SABA=shortacting β2 agonist; pre-treatment if possible=ideally
before prescribing and starting regular maintenance asthma treatment.
that remains uncontrolled despite high level treat- However, preschool wheezing is heteroge-
ment (figure 1). neous with multiple underlying pathologies, all
A multidisciplinary approach is paramount in presenting with similar symptoms, which bear
children with severe asthma.22 Severe asthma neces- little relation to the underlying phenotype.29 30
sitates a broader approach that recognises extrapul- Most preschool wheeze is managed in primary
monary influences such as adherence, family values, care, and if simple intermittent treatment suffices
comorbidities such as exposure to tobacco smoke, to control attacks of wheeze and any interval symp-
ongoing exposure to aeroallergens to which the child toms, further tests might be unnecessary. The main
is sensitised, obesity, breathing pattern disorders, goals of therapeutic intervention are to control symp-
and poor symptom perception. Ancillary testing to toms and prevent or reduce the severity of attacks.
exclude alternative diagnoses might be indicated.22 Importantly, and unlike in older children, about 60%
This team approach is essential to ensure that the of preschool age children do not develop recurrent
right children are prescribed expensive and invasive wheezing after their first episode, so clinical guide-
biological medicines. lines31 recommend maintenance treatment should
only be considered for those with recurrent wheezing
New concepts in preschool wheeze: from symptom (four or more episodes of wheeze per year). However,
based treatments to personalised treatment if the initial episodes are so severe that, for example,
The prevalence of wheezing in preschool age treatment in a high dependency unit or paediatric
children has tripled in the past 30 years. 23 24 In intensive care unit is necessary, preventive treatment
the UK, the number of children aged 1-5 years can be initiated earlier.
presenting to primary care with acute wheezing
has steadily risen between 2007 and 2017,25 by Management of eosinophilic, allergic, preschool
contrast with acute presentations at school age.26 wheeze
Management of recurrent preschool wheezing Twenty five per cent of children with preschool
is suboptimal because it has been driven by wheeze have eosinophilic allergic preschool wheeze,
symptom based labels (episodic viral wheeze, which is associated with blood eosinophilia and
multiple trigger wheeze,27 persistent wheeze28). aeroallergen sensitisation. Use of maintenance ICS
for preschool age children with recurrent wheezing

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Problematic severe asthma
Confirm asthma diagnosis

(Spirometry with BDR, +/- peak flow variability, +/- FeNO)
Asthma plus Asthma Not asthma:

comorbidities wrong diagnosis
Multidisciplinary team assessment
Difficult asthma Severe treatment

resistant asthma
• Adherence: poor (<80%) or
environmental triggers • Adherence: good (≥80%)
• Management: education,
consider DOT, once daily or
MART ICS regimen, treat
comorbidities, repeat
adherence monitoring
Refractory difficult asthma

• Adherence: persistently poor
(<80%) despite supportive Immunophenotyping and
intervention consider biological medicines
Figure 1 | Stepwise protocol for assessment and management of children with severe asthma. BDR=bronchodilator
reversibility; DOT=directly observed treatment; FeNO=fractional exhaled nitric oxide; ICS=inhaled corticosteroids;
MART=maintenance and reliever treatment
associated with aeroallergen sensitisation and blood blood eosinophil cut-off points for predicting wheeze
eosinophilia is often very effective; but in the absence exacerbation and explore the usefulness of elevated
of blood eosinophilia and aeroallergen sensitisa- FeNO in preschool age children as a non-invasive
tion, a response is unlikely. Studies of lower airway biomarker of response to ICS.
inflammation have shown tissue and airway luminal
eosinophilia in a subgroup of people with severe, Management of non-allergic wheeze associated
recurrent wheeze.32–34 The INFANT trial (n=300) was with infection
among the first to show benefit with ICS in preschool About 75% of preschool age children with wheeze
children with wheeze who had aeroallergen sensitisa- have non-allergic wheeze associated with infection
tion or blood eosinophilia, with the optimal response that does not respond to ICS. Recurrent wheezing
in children positive for both.9 However, eosinophilia in preschool children with non-allergic wheeze is
might be present even in those without aeroallergen most commonly triggered by viral upper respiratory
sensitivity,34 so these children might respond to ICS, infections, with many children being completely well
and elevated blood eosinophils could be a biomarker between episodes. Parents of these children are often
for clinical response to ICS. A recent clinical trial therefore reluctant to use daily preventive treatment,
(n=1074) explored the optimal blood eosinophil which in any case is unlikely to be effective.35
cut-off point for predicting a wheeze exacerbation, Unbiased assessment of lower airway inflamma-
by combining the results of three phase 3 studies tion in preschool children with wheeze has shown
of recurrent wheezing in preschool children.10 The a cluster who have predominant neutrophilia, are
risk of a wheeze exacerbation was highest in those steroid refractory, and are distinct from those with
children with higher cut-off points of blood eosin- aeroallergen sensitisation. They also have lower
ophils. Adding allergen sensitisation to the blood airway viral infection (predominantly rhinovirus)
eosinophil count improved the sensitivity of exac- and bacterial infection associated with neutrophilia,
erbation detection. In children who were prescribed even when they are clinically stable.29 This group
daily ICS, a significant reduction in the number might benefit from a prolonged course (2-6 weeks)
of episodes of wheeze was seen in children with a of targeted antibiotics.36 The antibiotic azithromycin
baseline eosinophil count higher than 200 cells/ also has anti-inflammatory and immunomodulatory
µL and with aeroallergen sensitisation. Exploratory effects.
analysis showed a reduction in FeNO in children on The Early Administration of Azithromycin and
daily ICS with a blood eosinophil count higher than Prevention of Severe Lower Respiratory Tract
150 cells/µL. Further studies are needed to validate Illnesses (APRIL) trial (n=607) showed a significant

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Preschool wheeze
Confirm wheeze
Recurrent wheeze (>3/year) or Infrequent episodes

severe episode (HDU/PICU) of mild wheeze
Assess for treatable traits Treat symptoms

Blood eosinophil count with as needed SABA
≥0.3 x 109/L and/or
aeroallergen sensitisation
STEP 1 - Trial of low dose ICS

for 6-12 weeks
STEP 2 - Stop ICS

and reassess
Consider referral to paediatric
• If symptoms improved on ICS
respiratory specialist
and then reoccur, restart on
low dose ICS • Uncertain about diagnosis
• If symptoms do not improve • Poor treatment response
on ICS, check inhaler • Severe attacks
technique and consider • Parents or doctor request
alternative diagnoses second opinion
Figure 2 | Overview of a proposed approach for the non-acute assessment and management of wheeze in children
of preschool age. HDU=high dependency unit; ICS=inhaled corticosteroids; PICU=paediatric intensive care unit;
SABA=shortacting β2 agonist
reduction in number of upper respiratory infections admission or emergency care attendances, a referral
that progressed to acute wheeze with the early use to a specialist paediatric respiratory centre is essen-
of azithromycin compared with placebo.37 However, tial to enable further investigation of the underlying
time to next episode was unaffected and bacterial disease process and separate children according
macrolide resistance was concerning. A second trial to allergen sensitisation, evidence of eosinophilia,
(n=72) in children aged 1-3 years showed a signifi- evidence of neutrophilia or infection, or evidence
cant shortening of acute episodes, especially with of airway obstruction. This approach might require
early initiation of treatment.38 However, a third trial additional testing (eg, bronchoscopy and induced
(n=300) that assessed the usefulness of azithromycin sputum) to investigate the presence and nature of any
on presentation to the emergency department with underlying airway inflammation (figure 3). Although
an acute wheeze attack showed no benefit of azith- biomarkers for patients with type 2 inflammation are
romycin over placebo.39 All these studies, however, known, there is currently an urgent need for non-
relied only on clinical phenotyping, so whether a invasive biomarkers that can identify preschool age
particular cluster would benefit cannot be deter- children with wheeze who have airway neutrophilia
mined. The evidence suggests that early azithromycin with bacterial dysbiosis, and interventional studies
might prevent progression to a severe attack, but that focus on non-allergic wheeze in preschool age
clinical benefits must be balanced against concerns children.
for antimicrobial resistance.
Before deciding how preschool children with more When to reduce the use of SABA
than trivial recurrent wheezing should be treated, the Asthma attacks are red flags because they point to a
type of airways disease should be defined, particu- high risk of future attacks and asthma deaths.40 41 A
larly in those with severe episodes of recurrent systematic review of factors associated with future
wheeze requiring recurrent admission to hospital asthma attacks in children observed that previous
and intensive treatment. Skin prick testing for aeroal- attacks were associated with a greatly increased risk
lergen sensitisation and measuring blood eosinophil of future attacks.41 Additionally, asthma attacks are
count for evidence of airway eosinophilia are both associated with a less favourable evolution of lung
useful initial measurements that can be done before function and prognosis.40 42 Most patients at risk can
initiating ICS treatment in preschool children with be readily identified in primary care. Alerts should
recurrent wheeze (figure 2). In children with severe include those individuals prescribed more than six
episodes of recurrent wheeze that require hospital SABA canisters/year and those not accessing ICS

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Severe recurrent wheeze in preschool aged children
Pathological
Allergic Infection
phenotype
Blood eosinophils Induced sputum

Aeroallergen Bronchoscopy/
Investigations sensitisation testing: bronchoalveolar lavage
skin prick tests
or specific IgE
Management Inhaled corticosteroids Targeted antibiotics
Figure 3 | Phenotype guided assessment and management of severe recurrent wheeze in children of preschool age.
Overview of proposed pathological phenotype approach using objective measurements to guide directed management
prescriptions43 44; recent discharge from hospital Secondly, no data are available for 4-11 year olds,
after a severe asthma attack; those who have attended and fewer randomised controlled trials have been
emergency departments in the previous year; and conducted in younger children with asthma, owing
those who repeatedly do not attend follow-up consul- to a preference from the pharmaceutical industry to
tations.45 High FeNO and blood eosinophil count fund studies in adults.57 58
predicts risk of asthma attacks at least in adults.46 Research in children of all ages is challenging for
At least two major asthma paradoxes exist. Firstly, multiple reasons.59–61 These include ethical consid-
we prescribe SABA at step 1 of asthma management erations; for example, neither a child nor parent can
guidelines,11 with no anti-inflammatory treatment, give consent to a procedure of more than minimal
but not LABA as solo agents at any stage, despite risk purely for research purposes, limiting the use
the belief that type 2 inflammation underlies even of, for example, CT scanning or bronchoscopy.
mild asthma during school age. The second paradox Physiological testing (eg, spirometry) might not be
is that the morbidity of so-called mild asthma is able to be performed by young children. Research
considerable,47 and indeed about half of all deaths visits might need to be scheduled after school, during
from asthma are not in those individuals with severe antisocial hours. Whatever the reasons, many more
asthma. Overuse of SABA and underuse of ICS are randomised controlled trials are performed in adults
risk factors for serious asthma attacks.1 However, than children. The ethical and logistical challenges
despite asthma being driven by type 2 inflamma- of delivering research studies in children can be over-
tion and strong evidence for harm, SABA alone still come, for example, by opportunistically recruiting
continues to be widely prescribed.48 children having a clinically indicated bronchos-
Salmeterol is a partial β agonist with a slow copy to mechanistic research studies; by arranging
onset of bronchodilatation and thus is unsuitable research study visits around clinic consultations;
as a reliever. Formoterol has as rapid an onset as and by involving children and their parents early in
salbutamol and is a full agonist. Combined budeso- the research study design to ensure that the study is
nide/formoterol as regular and reliever treatment in acceptable to children and their family.
young people aged ≥12 years49 (SMART regimen) is
well established; but with only one study in 6-11 year
olds.50 Budesonide/formoterol (used as needed) Assessment of asthma severity
results in important reductions in severe asthma Currently, many guidelines classify school age asthma
attacks even in patients with mild asthma aged ≥12 severity predominantly on symptoms and lung func-
years.51–55 The dose of ICS with this approach is tion and do not include underlying markers of airway
substantially less than regular low dose ICS in step 2 inflammation in the definition of severity.62 Asthma
asthma management.11 severity is mostly determined in retrospect, based on
The Global Intiative for Asthma (GINA) now recom- doses of prescribed drugs.47 62 63 NRAD reported that
mend formoterol/budesonide as reliever treatment at more than two thirds of asthma deaths occurred in
all levels of asthma severity,56 which we consider to patients classed as having mild to moderate asthma,
be correct for children and young people aged ≥12 based on the drug treatments prescribed.1 Also, the
years; there is no biological reason why SABA alone paediatric U-BIOPRED cohort study (n=282) showed
is a good option in school age asthma. However, there that severe and mild/moderate asthma cohorts
are two problems. Firstly, the European Medicines according to standard classifications were very
Agency has not approved this indication because it similar in terms of morbidity, atopy, lung function,
has slightly less symptom control than SABA alone, and bronchodilator reversibility at baseline.47 Hence,
although by less than the minimally clinically impor- a definition of asthma must incorporate components
tant difference. However, asthma attacks are the of future risk, and assessment of risk should be part
cause of asthma mortality, not day-to-day symptoms. of asthma care at all levels.

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Paediatric severe asthma
Clinical criteria High dose treatment (high dose ICS and another maintenance treatment or oral steroids)
and ≥4 asthma exacerbations in previous 12 months
Perennial aeroallergen sensitisation Blood eosinophils ≥0.3 x 109/L (1) Blood eosinophils ≥0.15 x 109/L,
Prescribing indications (positive skin prick test or serum (or ≥3 asthma exacerbations (2) FeNO ≥25 ppb, and (3) failed
specific IgE) and IgE 30-1500 IU/mL and blood eosinophils ≥0.4 x 109/L) treatment with anti-IL5 or not eligible
Anti-IgE antibody Anti-IL5 antibody Anti-IL4Rα antibody

Biological medicine
• Omalizumab for age ≥6 years old • Mepolizumab for age ≥6 years old • Dupilumab for age ≥12 years old
treatment
• 2-4 weekly subcutaneous injections • 4 weekly subcutaneous injections • 2 weekly subcutaneous injections
Figure 4 | Licensed biological medicine treatments for severe asthma in children. Summary of prescribing indications for biological medicine
treatments licensed in the UK as an additional treatment for children with severe treatment resistant asthma. No evidence or guidance currently
exists on which biological medicine should be prescribed if a child is eligible for treatment with more than one biological medicine treatment.
IgE=immunoglobulin E; FeNO=fractional exhaled nitric oxide; IL4Rα=interleukin 4 receptor; IL5=interleukin 5; ppb=parts per billion; SPT=skin prick
test
Pathology of severe asthma: new insights Th17 proinflammatory cytokines; frequent viruses
Airway inflammation can persist in the absence and bacteria in BAL; and elevated type 2 cytokines
of symptoms, and the extent of pathophysiolog- that correlated with total serum immunoglobulin
ical abnormalities is variable.64–67 Several clinical (Ig) E. They also observed increased levels of IL5,
and inflammatory phenotypes are described based IL33, and IL28A/interferon lambda 2 in children
on analysis of induced sputum, bronchoalveolar sensitised to multiple allergens. In addition, BAL
lavage (BAL), and endobronchial biopsies.68–70 IL5 levels increased with age, and correlated with
Most school age children with mild or moderate peripheral blood eosinophil count. These findings
asthma have steroid-sensitive allergic, eosinophilic could have important implications for studies of anti-
airways disease associated with type 2 immune IL5 strategies in children (see below).
responses, including elevated interleukin (IL) 4, In summary, not all paediatric severe asthma is
IL5, and IL13.71 72 Severe asthma in children is often driven by type 2 inflammation or will respond to
but not invariably associated with persistent eosin- anti-
IL5 strategies. Critically determining what is
ophilic airway inflammation, which might be rela- driving the airway pathology is key to personalising
tively resistant to treatment with ICS73 and persist treatment.
despite reduced levels of type 2 cytokines. The
absence of these cytokines with persistent eosino- Beyond long term oral steroids—novel biological
philia in severe, treatment resistant asthma has led medicines
to the hypothesis that innate mediators such as IL33, Biological medicine agents are monoclonal anti-
which appear to be relatively steroid resistant, could bodies that currently can only target specific mole-
dominate the immune response in severe, treatment cules that drive allergic, eosinophilic asthma
resistant asthma.73 The Severe Asthma Research (figure 4). They are an important step change
Program network reported that severe asthma in chil- because they result in a substantial reduction in
dren was neither type 1 nor type 2 dominated, but asthma attacks and an improved quality of life, while
observed elevated growth related oncogene (GRO, enabling oral steroid sparing.
CXCL1); elevated regulated on activation; normal T
cell expressed and secreted (RANTES, CCL5); and Omalizumab
elevated IL10, IL12, and interferon gamma in these The anti- IgE humanised monoclonal antibody
children.74 omalizumab was the first biological medicine to be
An observational exploratory study of cytokines licensed for children and has been studied exten-
in BAL from (n=91) children with severe asthma sively in the paediatric population.77 78 Omalizumab
has shown a variable picture of type 1, type 2, and antagonises IgE by binding to free circulating IgE,
T helper (Th) 17 sometimes associated with BAL hence preventing allergen specific IgE binding
neutrophilia.75 In a prosective observational study to high affinity IgE receptors (FcεRI).79 In addi-
of 350 children with moderate/severe asthma, tion, the reduction in free circulating IgE results in
researchers observed that children with neutrophilic reduced expression of FcεRI on antigen presenting
inflammation were younger than those with eosino- cells, mast cells, and basophils.79 Omalizumab is
philic or non-neutrophilic inflammation (median age licensed for use in severe allergic asthma from age
6, 11, and 10 years, respectively), suggesting that 6 years and above. Omalizumab can be prescribed
neutrophilic disease is more common in preschool if both perennial aeroallergen sensitisation (posi-
asthma.33 In a further observational study76 of lower tive skin prick test or serum specific IgE) and a total
airway inflammation in 52 children with asthma, serum IgE count of 30-1500 IU/mL are present.80 The
researchers observed a mixture of Th1, Th2, and limited IgE range for prescription of omalizumab

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prevents the use of omalizumab in a third of chil- baseline and at week 52. A considerable downreg-
dren who would have otherwise been eligible.81 A ulation in the type 2 pathway after treatment was
meta-analysis of three randomised controlled trials seen with mepolizumab. However, eosinophil acti-
including 1380 children showed a 49% decrease in vation and hypersecretion were unchanged, as were
exacerbation rate (odds ratio 0.51, 95% confidence neutrophil chemotaxis and type 1 interferon regula-
interval 0.44 to 0.58, P<0.001) and a reduction in tion associated with lower attack rates. Benefit from
hospital admissions, despite a reduction in the dose mepolizumab was seen in children using a lower
of ICS by omalizumab compared with placebo.77 82 blood eosinophil cut-off point than used in adult
Given that there is most paediatric experience with trials, but the effect size was also less than seen in
omalizumab, most doctors would use this agent first adult studies, both factors highlighting the need for
in eligible patients rather than anti-IL5 and anti-IL4/ trials in children.
IL13 biological medicines. Currently, the main biomarker used to decide
eligibility for mepolizumab is a blood eosinophil
count of >300 cells/µL, extrapolated from adults.
Mepolizumab However, healthy children younger than 18 years
Mepolizumab is an anti-IL5 humanised monoclonal have significantly higher blood eosinophils than
antibody. Mepolizumab inhibits the pleiotropic adults.91 The optimal cut-off point for blood eosino-
effects of IL5 on eosinophils, including proliferation, phils as a biomarker for children is unknown (data
differentiation, activation, survival, and migration.83 from the MUPPITS-2 study suggest a lower cut-off
Mepolizumab is licensed for use in children aged ≥6 point might be optimal). Eosinophils also have plei-
years with severe eosinophilic asthma. Mepolizumab otropic functions and are involved in immune home-
is recommended for those children with blood eosin- ostasis as well as disease,92 and are active against
ophil counts ≥0.3×109/L and four asthma attacks many pathogens, including viruses and parasites.93
requiring high dose steroids (or ≥3 asthma exacerba- Thus, complete eosinophilic ablation might result in
tions and blood eosinophil counts of ≥0.4×109 /L).84 unwanted effects, including excessive infections.
Large randomised controlled trials of mepolizumab
in adults and adolescents with severe eosinophilic
asthma have shown a significant reduction in asthma Dupilumab
attacks, hospital admissions, and maintenance Dupilumab is a humanised anti- IL4Rα mono-
oral steroids, and an improved quality of life.85–88 clonal antibody, blocking IL4 and IL13 signalling.
Elevated blood eosinophil count before commencing Dupilumab was recently licensed in the UK for use
mepolizumab treatment is strongly associated with a in children with severe asthma aged ≥12 years.
clinical response to treatment. Secondary analysis of Dupilumab is recommended by NICE for those with
phase 3 studies showed a 52% reduction in asthma four severe asthma attacks in the previous year, and
exacerbations (rate ratio 0.48, 95% confidence failed treatment or ineligibility with anti-IL5 treat-
interval 0.39 to 0.58) if the baseline blood eosinophil ment, and a blood eosinophil count of ≥0.15×109/L,
count was ≥150 cells/µL, and a 70% reduction in and FeNO ≥25 parts per billion. The Liberty Asthma
asthma exacerbations (0.30, 0.23 to 0.40) if the blood QUEST phase 3 multicentre study of dupilumab in
eosinophil count was ≥500 cells/µL. Mepolizumab 1902 adults and adolescents with moderate to severe
did not reduce asthma exacerbations in those with asthma recruited patients without any restriction on
a blood eosinophil count of ≤150 cells/µL.89 A post baseline type 2 inflammatory markers. Dupilumab
hoc meta-analysis of 34 adolescents with eosino- significantly reduced asthma attacks and improved
philic severe asthma who were included in phase lung function. A greater clinical response was seen
3 studies of mepolizumab suggested similar effects in those with high baseline eosinophil count and
in this group and in the overall population studied, FeNO.94 Recently, the VOYAGER trial demonstrated
but the small sample precluded conclusions. The efficacy of dupilumab in children. In a randomised
safety profile among adolescents appeared similar to controlled trial of 408 children (aged 6-11 years)
adults, although the number of patients who could with uncontrolled moderate to severe asthma, dupi-
be evaluated was small. lumab significantly reduced severe attacks and
The MUPPITS-2 study90 is the first randomised improved lung function and asthma related quality
controlled trial of mepolizumab in children aged of life. Dupilumab had the greatest clinical effect in
children with biomarkers of type 2 (inflammation)
6-17 years. The study recruited children from soci-
high asthma (ie, elevated baseline blood eosinophil
oeconomically disadvantaged areas in the US with
counts >150 cells/µL or FeNO >20 parts per billion).95
≥2 asthma attacks in the previous year and blood
eosinophil counts of ≥150 cells/µL. Researchers
randomised 146 children to mepolizumab and 144 to Limitations of paediatric data
placebo, and observed a 27% reduction in attacks in Despite the promise of these new approaches, several
the mepolizumab group (rate ratio 0.73, 95% confi- limitations remain in their application to childhood
dence interval 0.56 to 0.96; P=0.027). All children severe asthma. As mentioned above, childhood
underwent nasal lavage and RNA sequencing at severe asthma is heterogeneous, and evidence of

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type 2 inflammation is less likely in school age chil- bacterial infections are an important driver of symp-
dren than in adults. Therefore, although much but toms. Likewise, the European Respiratory Society/
not all childhood severe asthma is characterised American Thoracic Society task force on severe
by multiple and severe aeroallergen sensitisation, asthma management found insufficient evidence
with airway eosinophilia96 and the recently licensed supporting the use of macrolides in type 2 low
biological medicines for children target eosinophils, asthma in children.63
we need more evidence of efficacy in young children Tezepelumab has some promise for those individ-
and this is an important evidence gap. In addition, uals with type 2 low asthma, although evidence of
the absence of head-to-head clinical trials of biolog- benefit in children and young people is awaited. It
ical medicines in children is a considerable research inhibits thymic stromal lymphopoietin, a bronchial
gap to inform the optimal choice for each child with epithelial cell derived alarmin implicated in multiple
type 2 high severe asthma. downstream processes including the regulation of
A Cochrane review of anti- IL13, anti-IL4, anti- type 2 immunity. However, tezepelumab has also
IL5, and anti- IgE treatments in severe asthma been shown to mediate interactions between airway
has confirmed that of 41 randomised controlled structural cells and immune cells, which are not
trials, only five included children and adolescents,
exclusively driven by type 2 inflammation.104 In
accounting for less than 5% of all data available on
the recently published phase 3 study (NAVIGATOR)
efficacy.97 The VOYAGER trial of dupilumab95 and
of 1061 patients (age ≥12 years), researchers saw
MUPPITS-2 trial of mepolizumab90 are the two largest
a significant reduction in attacks compared with
trials of biological medicines in children with severe
placebo even in those without evidence of type 2
asthma. Before the MUPPITS-2 study, only 34 chil-
inflammation (blood eosinophil count <150 cells/µL
dren (aged ≥12 years) were included in randomised
or FeNO <25 parts per billion).105
controlled trials of mepolizumab. More clinical trials
of biological medicines in children are essential to
accurately determine efficacy in children, as well Guidelines
as enable investigation of mechanisms of action in Table 3 lists key recommendations from three inter-
airway samples in children and identify biomarkers national guidelines for the diagnosis and manage-
of treatment success. This need is underscored by ment of asthma in children.11 31 106 Overall, they
the very different results between the MUPPITS-2 are similar in their recommendations for the use of
randomised controlled trial of mepolizumab in chil- objectives measurements to confirm the diagnosis
dren aged 6-17 years and the DREAM study, a multi- of asthma. The guidelines, however, differ in the age
centre, double blind, placebo controlled, randomised brackets used to classify management recommenda-
trial of mepolizumab in 621 adults and adolescents tions, which slightly limits comparisons. A key funda-
aged ≥12 years and over.98
mental difference is that the recent GINA guideline
does not recommend the use of SABA alone for the
Type 2 low asthma management of asthma in children and adolescents
For children with poorly controlled asthma who do aged 6 years and above.31 For mild asthma (step 1
not have evidence of type 2 inflammation (ie, type treatment), GINA advise using a combination of low
2 low asthma), the options for add-on treatments dose ICS and formoterol inhaler as needed. In chil-
are limited. For any add-on treatment, considera- dren aged 6-11 years, owing to device limitations,
tion should be given to increased complexity of the SABA as needed via a metered dose inhaler plus a
regimen, and objective evidence of benefit should dose of ICS at the same time is recommended as step
be measured and treatment stopped if there is none. 1 treatment. GINA further recommend that a combi-
Some evidence suggests that use of a combined ICS/ nation of low dose ICS and formoterol inhaler is used
formoterol reliever inhaler is effective irrespective as a reliever for children aged 12 years and over. The
of the presence of type 2 biomarkers.52 Tiotropium, GINA recommendations are a major change to the
a longacting muscarinic antagonist (LAMA), can management of mild asthma and reliever treatment
be considered particularly for those children with in asthma.
persistently obstructed spirometry.99 The evidence
in children is limited. Two phase 2 studies reported
mixed results; in the adolescent study (n=392), the Future strategies
primary and important secondary endpoints were We suggest that future strategies will include moving
not met; in the trial of younger children (n=401), away from symptom management to primary or
5 µg but not 2.5 µg of tiotropium improved lung secondary prevention of eosinophilic asthma; better
function.100 101 Evidence from clinical trials to inclusion of children in research projects; improving
support the long term use of azithromycin in chil- subtyping of severe asthma and developing treat-
dren is very limited,38 102 103 and its use should prob- ments for type 2 low asthma in children; and the
ably only be considered for those children with a development of biomarkers, especially for risk
pattern of severe, life threatening attacks or in whom prediction.

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Table 3 | Clinical guidelines and recommendations on key issues relating to diagnosis and management of asthma in
childhood
British Thoracic Society/Scottish
Global Initiative for Asthma National Institute for Health and Intercollegiate Guidelines
Key issue guidelines31 Care Excellence guidelines11 Network106
Is objective evidence needed Yes. Strong certainty recommen- Yes. Strong certainty recommen- Yes. Low certainty recommen-
to confirm the diagnosis of dation. dation. dation.
asthma in children aged over 6
years old?
Should SABA be used alone to No. Use as-needed low dose Yes, if infrequent short episodes of Yes, as initial treatment. Moderate
treat asthma in children aged ICS-formoterol (preferred option) wheeze and normal lung function. certainty recommendation.
over 6 years old with mild or low dose ICS whenever SABA
asthma (step 1)? taken.
Should low dose ICS-formoterol Yes, this is the preferred option. Yes, if using ICS-formoterol as Yes, if using ICS-formoterol
be used as a reliever in The alternative, less desirable ap- maintenance and reliever treat- as maintenance and reliever
children? proach is SABA reliever for those ment. Low certainty recommen- treatment.
children on daily maintenance dation.
ICS treatment. Strong certainty
recommendation.
What are the treatment options The additional treatment options Not specified. Not specified.
for children with severe that might be considered by a res-
asthma? piratory specialist, after optimising
existing treatment, include add-on
LAMA, biological medicines.
How is asthma diagnosed in Clinical diagnosis, using a Difficult to diagnose in children Clinical diagnosis. Assess proba-
children younger than 5 years? probability based approach that younger than 5 years. Advise to bility of asthma. If individual has
is based on recurrent symptom treat symptoms based on clinical intermediate probability of asthma
pattern trend, family history, and judgment and confirm diagnosis and symptom pattern suggests
physical examination. when individual is able to undergo asthma, offer a trial of treatment.
A therapeutic trial with daily low objective tests.
dose ICS is a useful test to consid-
er. Low certainty recommendation.
Is maintenance ICS recom- Yes, consider a three month trial Yes, consider an eight week trial of Yes, consider a monitored
mended in children younger of daily low dose ICS if symptom daily moderate dose ICS if symp- 6-8 week trial if individuals is
than 5 years with wheeze? pattern suggests asthma and per- toms are frequent or if symptoms showing symptoms.
sistent symptoms, and recurrent not controlled with SABA alone.
episodes or severe episodes of
wheeze.
ICS=inhaled corticosteroids; LAMA=longacting muscarinic antagonists; SABA=shortacting β2 agonist.
Can asthma be prevented? was followed by definitive clinical trials in people

ICS can treat symptoms, but three large randomised aged ≥12 years. When these were successful, trials
controlled trials show that ICS is not disease modi- were performed successively in younger age groups,
fying107–109—that is, early or prolonged use does not down to 0-1 years. Since the younger children did
permanently switch off the pathways driving type 2 not show visible respiratory symptoms, a surrogate
inflammation (but this has been shown by studying of efficacy had to be found, namely, sweat chloride
two genetically almost identical populations, the that falls substantially at all ages.113 Furthermore,
Amish and Hutterites). Differences in environment in vitro models were developed to demonstrate effi-
driven by different farming methods (traditional and cacy, which correlated with in vivo response.114 115
modern) are associated with substantial differences Of course, a polygenic, environmentally modulated
in atopic disease. These beneficial results have been disease such as asthma is far more complex, but
attributed to increased environmental bacterial and the example of cystic fibrosis should encourage
fungal diversity and lipopolysaccharide content,110 researchers to discover more about basic biology and
and have led to an interest in the use of oral bacterial spread the benefits across the developmental course
lysates as disease modifying treatment.111 The lack of the disease.
of knowledge of the disease pathways could mean
that a potentially muddled approach will flounder
until we understand the basic biology. Treatments for type 2 low asthma
Several biological medicines are licensed, and in
Participation of young children in research development, for the treatment of severe type 2 high
The evidence gaps in young children has been high- asthma. In patients with severe asthma aged ≥12
lighted above, and should not continue, for example, years old with type 2 low biomarkers, tezepelumab
as demonstrated by those affected by cystic fibrosis. (an inhibitor of thymic stromal lymphopoietin)
Knowledge of genetic subtypes of cystic fibrosis led showed a significant reduction in asthma exacer-
to the development of molecular treatments that bations, but this observation was not significant
are specific to different gene subclasses.112 This in the adolescent group.105 Currently, no licensed

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immunomodulating treatments are available for Conclusions
children with type 2 low asthma. Future research For a long time, asthma treatment comprised "a blue
and clinical practice needs to resolve this knowledge and a brown inhaler (… usually left to gather dust
gap by improving the understanding of underlying in the bathroom cabinet), measuring urinary coti-
pathogenesis and the subtyping of severe asthma in nine and looking menacingly at the pet cat."117 We
children. are beginning to better understand the diversities of
pathology underlying the stereotypic symptoms of
Biomarker development airway disease. If children are to benefit, the diag-
We highlighted above the need to move from total nosis must be correctly made, based on objective
reliance on history and examination to a measure- measurements, and standard protocolised manage-
ment culture. FeNO and peripheral blood eosinophil ment correctly implemented. For those individuals
count might be useful risk predictors in adults,46 but who do not respond or are unable to implement the
they are unvalidated in children. Biomarkers must treatment, the next step is to understand the under-
be used in a non-invasive and practical test at the lying pathology.
point of care. The use of exhaled breath with sensing Cluster analysis of preschool wheeze has shown at
devices such as the e-nose116 are obvious areas to least four phenotypes of the disease, and we should
explore. Evidence gaps such as these and other explore the treatment options revealed by this
areas are highlighted in the box of future research approach. New options for severe allergic asthma at
questions. school age include omalizumab, mepolizumab, and
dupilumab, but paediatric data to predict successful
treatment are still needed. Options are currently
scarce for non-type 2 asthma. Asthma attacks are a
QUESTIONS FOR FUTURE RESEARCH serious red flag event, and overuse of shortacting β2
⇒ What are the pathways driving the agonists and underuse of ICS is an important factor.
development of asthma, and can they be The use of ICS longacting β2 agonists in combina-
blocked? tion as rescue treatment offers superior outcomes
⇒ How effective is mepolizumab at treating severe and is more biologically rational, but data in chil-
asthma in young people younger than 12 years? dren aged ≤11 years are lacking. Current asthma
⇒ How effective is combined rescue formoterol research has not focused enough on children, and
and budesonide compared with salbutamol in obtaining evidence to inform treatment across the
children aged 4-11 years? developmental spectrum, rather than relying on
⇒ What are the molecular pathways and data extrapolated from adults, should be a priority.
therapeutic options driving non-eosinophilic Children deserve evidence based and personalised
asthma? treatment, which must be delivered.
⇒ What are the optimal biomarkers that predict
response to inhaled corticosteroids and
biological medicines in children? AUTHOR AFFILIATIONS
1
⇒ What is the role of bacteria in pathogenesis National Heart and Lung Institute, Imperial College London,
London, UK
of preschool wheeze, and is treatment with 2
Royal Brompton Hospital, London, UK
targeted antibiotics useful? 3
Centre for Paediatrics and Child Health, Imperial College London,
London, UK
Acknowledgements We thank the Asthma UK Centre for Applied

PATIENT INVOLVEMENT Research, for their funding contribution to AB and LF.
We spoke with a group of children with severe Contributors ES, AB, LF, SSa, and SSo wrote the initial draft of the
manuscript. AB is guarantor. The manuscript was reviewed and edited
asthma and their parents to gain their perspective by ES and AB; all authors agreed the final version.
on asthma management advances, in particular
Funding The authors have not declared a specific grant for this
personalised treatment. This discussion helped research from any funding agency in the public, commercial or not-
to inform the areas covered in this review, and for-profit sectors.
highlighted the importance of talking to both the Competing interests We have read and understood the BMJ
child and their family about available treatment policy on declaration of interests and declare the following
interests: none.
options in detail, because this makes an important
Provenance and peer review Commissioned; externally peer
positive difference to patient experience, reviewed.
engagement with treatment, and feeling of
Open access This is an open access article distributed in accordance
empowerment. with the Creative Commons Attribution Non Commercial (CC BY-NC
Children and their parents were very supportive of 4.0) license, which permits others to distribute, remix, adapt, build
upon this work non-commercially, and license their derivative works
research in children with asthma, and emphasised on different terms, provided the original work is properly cited,
the need to personalise care, consider each child as appropriate credit is given, any changes made indicated, and the use
individual, and not provide blanket treatment. is non-commercial. See: http://creativecommons.org/licenses/by-nc/
4.0/.

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ORCID iDs 25 Bloom CI, Franklin C, Bush A, et al. Burden of preschool wheeze
Elizabeth Scotney http://orcid.org/0000-0002-9264-4174 and progression to asthma in the UK: population-based cohort
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Samatha Sonnappa http://orcid.org/0000-0002-9189-223X 26 Bloom CI, Saglani S, Feary J, et al. Changing prevalence of
current asthma and Inhaled corticosteroid treatment in the UK:
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OPEN ACCESS SPECIALIST REVIEW

Epidemiology of severe asthma

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 1

2 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 3

4 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Conﬁrm asthma diagnosis

Asthma plus Asthma Not asthma:

Multidisciplinary team assessment

Difficult asthma Severe treatment

Refractory difficult asthma

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 5

Recurrent wheeze (>3/year) or Infrequent episodes

Assess for treatable traits Treat symptoms

STEP 1 - Trial of low dose ICS

STEP 2 - Stop ICS

6 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Blood eosinophils Induced sputum

Management Inhaled corticosteroids Targeted antibiotics

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 7

Anti-IgE antibody Anti-IL5 antibody Anti-IL4Rα antibody

8 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 9

10 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Can asthma be prevented? was followed by definitive clinical trials in people

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 11

Acknowledgements We thank the Asthma UK Centre for Applied

12 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 13

14 Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367

Scotney E, et al. BMJMED 2023;2. doi:10.1136/bmjmed-2022-000367 15

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