Clinical Management Review
Which Wheezing Preschoolers Should be Treated
for Asthma?
Leonard B. Bacharier, MDa, Theresa W. Guilbert, MDb, Tuomas Jartti, MDc, and Sejal Saglani, MDd
Cincinnati, Ohio; Oulu, Finland; and London, United Kingdom
Wheezing disorders in children younger than 5 years are
common, but lack of clarity remains about which children
should be treated to prevent symptoms and acute episodes. The
aim of this review was to discuss a practical approach to deciding
which children younger than 5 years with asthma should be
treated, and if so, with which strategy. The importance of having
a clear definition of “asthma” for this age group, determined by
a collection of presenting respiratory symptoms, without
assumptions about underlying mechanisms is addressed.
Subsequent consideration should be given to timing, severity,
and frequency of symptoms, together with assessment of
objective biomarkers, including aeroallergen sensitization and
blood eosinophils, to inform whether or not a preschooler with
recurrent wheezing requires treatment. Numerous unanswered
questions remain about the optimal management of nonallergic
preschool wheezing and asthma, and areas of specific unmet need
and future directions for research are highlighted. Ó 2021
American Academy of Allergy, Asthma & Immunology (J Allergy
Clin Immunol Pract 2021;-:---)
Key words: Preschool; Infant; Wheeze; Asthma; Phenotype;
Endotype
Asthma often begins in early life,1 and the prevalence of
wheezing in preschool-age children has tripled in the past 30
years.2,3 Up to 50% of all preschool children experience 1
episode of wheezing before age 6 years although only 40% of
these children will develop recurrent wheezing in later child-
hood.4 Preschool-age children with recurrent wheezing experi-
ence twice the rate of outpatient physician visit and emergency
department visits and 5 times the rate of hospitalization.5 The
economic burden of wheezing in preschool children was
a
Division of Pediatric Allergy, Immunology and Pulmonary Medicine, Monroe
Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn
b
Pulmonary Division, Cincinnati Children’s Hospital Medical Center, Cincinnati,
Ohio
c
Department of Pediatrics, Oulu University Hospital and University of Oulu, Oulu,
Finland
d
National Heart & Lung Institute, Imperial College London, London, United
Kingdom
Conflicts of interest: L. B. Bacharier has received consultancy fees and lecture hono-
raria from GlaxoSmithKline (GSK), Genentech/Novartis, Teva, Boehringer Ingel-
heim, and AstraZeneca; personal fees from GSK, Genentech/Novartis, Merck, DBV
Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape,
Sanofi/Regeneron, Vectura, and Circassia outside the submitted work; is on the
scientific advisory board for Merck; is on the data safety monitoring board for DBV
Technologies; has received honoraria for CME program development from
WebMD/Medscape; is on the advisory board for Circassia; and is a consultant and
advisory board member for Vectura. T. W. Guilbert has received personal fees from
Nashville, Tenn;
estimated to be around $3 billion in 2013.6 This emphasizes the
importance of implementing effective strategies aimed at
reducing the substantial morbidity associated with recurrent
preschool wheezing.
THE DEFINITION OF “ASTHMA” IS CENTRAL TO
DECIDING TREATMENT
To provide an answer to the question posed for this review,
having a clear definition for “asthma” in preschool children is
critical. We have numerous labels that are used for the mani-
festation of wheezing in this age group, and this is frequently the
source of confusion for clinicians, scientists, and the families of
the patients we treat. The lack of clarity of a definition for
“asthma” in preschool children is because we understand very
little about the underlying inflammatory and pathological pro-
cesses in this age group, and also because there is no one single
test that makes the diagnosis.7,8

In this review, we will discuss reasons why and why not to
treat preschool children for “asthma,” when asthma is defined
as an allergic, eosinophilic disease. But, if the definition of
“asthma” is broader, and simply a collection of symptoms,
regardless of underlying pathophysiology, then it becomes
apparent that most preschool children should be treated, but
with carefully selected treatments, not a “one-size-fits-all”
inhaled corticosteroids (ICSs). The definition we have used for
preschool “asthma” here is as follows: “a descriptive label for a
collection of symptoms, including wheezing, breathlessness,
difficulty in breathing, presenting as acute attacks with or
without interval symptoms.” This aligns with the definition
agreed in a recent Lancet Commissioned document,9 and
importantly, means no assumptions are made about the
the American Board of Pediatrics, Pediatric Pulmonary Subboard, GSK, Teva, and
Novartis; research support from the National Institutes of Health; royalties fro-
mUpToDate; grants and personal fees from AstraZeneca and Sanofi/Regeneron; fees
from UpToDate outside the submitted work; and research support and personal fees
from Sanofi/Regeneron and AstraZeneca. The rest of the authors declare that they
have no relevant conflicts of interest.
Received for publication December 8, 2020; revised February 5, 2021; accepted for
publication February 20, 2021.
Available online --
Corresponding author: Leonard B. Bacharier, MD, Division of Allergy, Immunology
and Pulmonary Medicine, Department of Pediatrics, Monroe Carell Jr. Children’s
Hospital at Vanderbilt, 2200 Children’s Way, 11205 Doctor’s Office Tower,
Nashville, TN 37232. E-mail: leonard.bacharier@vumc.org.
2213-2198
Ó 2021 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaip.2021.02.045
1
2 BACHARIER ET AL
Abbreviations used
API- Asthma Predictive Index
ICS- inhaled corticosteroid
mAPI- modified API
RSV- respiratory syncytial virus
RV- rhinovirus
pathophysiology leading to this final manifestation of symptoms.
We have not included a minimum number of acute episodes, or
duration of symptoms in the definition, because there is little
consensus. However, 2 acute episodes, severe enough to warrant
health care attendance, and for which no other differential
diagnosis is found, may be sufficient to suggest a label of
asthma.10
When defined in this way, the medications and management
approach used will vary depending on the identification of
“treatable traits.”9 If a preschool child has symptoms sufficient
for parents to seek health care, then of course they must be
treated, but the important consideration is whether the treatment
is simply to manage acute symptoms, or the first attack, or
whether it is being used to prevent future symptoms.
FACTORS TO BE CONSIDERED BEFORE DECIDING
ON THE NEED FOR TREATMENT: SEVERITY/
BURDEN OF DISEASE
Epidemiological studies include reports of wheeze prevalence,
but most children’s symptoms are unlikely to be severe enough
to cause the family to seek health care. The “threshold” and need
for treatment may be very different depending on the impact of
the asthma on the child’s activity and quality of life. Another
point that must be considered is the frequency of the symptoms,
or episodes. Although acute treatment may be needed for an
episode, an isolated, single episode of wheezing is very different
from recurrent episodes of wheeze. Treatment to control symp-
toms and prevent future episodes is needed only if the asthma is
such that parents/carers seek health care, but also if episodes are
recurrent. We have learned from birth cohorts that preschool
children with frequent symptoms are those who also develop
asthma in school-age, with a reduction in lung function per-
sisting into adulthood.11-13
USING ASTHMA MEDICATION IN THE FIRST
WHEEZING EPISODE
Despite the established role of medication in the treatment of
asthma, none of the current major guidelines (eg, The Scottish
Intercollegiate Guidelines Network 2006, Spanish National
Health System 2010, American Academy of Pediatrics 2014,
Finnish Current Care 2014, National Institute for Health and
Care Excellence of UK 2015, Australasian Paediatric Research in
Emergency Departments International Collaborative committee
2018, and Canadian Paediatric Society 2018) recommend their
routine use in the treatment of bronchiolitis.14-19 The non-
recommended medication includes beta2-agonists, leukotriene
receptor antagonists, and corticosteroids.
The heterogenic condition of the broad diagnosis of bron-
chiolitis or first wheezing episode under the age of 2 years has
gained attention recently.20-23 Clinically, pathophysiologically
and even genetically 2 major groups can be identified: the “classic
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2021
bronchiolitis,” that is, respiratory syncytial virus (RSV)-induced
bronchiolitis and rhinovirus (RV) and/or atopy-associated first
wheezing episode.
First, RSV-induced bronchiolitis is characterized by young age of
the patient and mechanical obstruction of the airways due to mucus
and airway epithelial cell debris. RSV is not a very “asthmagenic”
virus: the prevalence of asthma is at approximately 10% to 30% at
school-age after RSV bronchiolitis.21 Also, the association with
atopy is low. Probably, because of the cytopathic virus effects
(epithelial cell destruction, mechanical obstruction of the airways
due to mucus and cell debris) and low likelihood of type 2
inflammation, trials with asthma medications have not shown
efficacy.14,15,17-19,24 Thus, there is no role for asthma medications
for RSV bronchiolitis. For this illness, an effective prophylactic
RSV-specific mAb, palivizumab, is available, and currently recom-
mended for very premature and high-risk infants.25
Second, in contrast to RSV, RV-induced severe first wheezing
episode in the same age group is associated with atopic predisposi-
tion and high risk for subsequent asthma in approximately 30% to
80% at school-age.21 RV is less directly cytopathic than RSV,
instead causing a more robust host cytokine response, and is more
closely associated with asthma-like cytokine milieu in slightly older
wheezing children. Although RV infection elicits proinflammatory
cytokines (principally neutrophil chemoattractants), it can induce
small amounts of type 2 cytokines. RV infections can inhibit some
interferon responses but stimulate interferon lambda secretion. In
general, type 2 polarized immune responses more likely predispose
to more severe RV infections rather than are caused by them.
Interestingly, 2 separate randomized trials using prednisolone have
shown efficacy in both short- (hospitalization time, duration of
symptoms) and long-term outcomes. Most interestingly, time to the
physician-confirmed relapse within the following year decreased by
20% to 30% and to the initiation of asthma controller medication
within the following 5 years by 30% to 40% in first-time wheezing
children with RV etiology. Of note, the design in the earlier study
was post hoc, and in the second trial, efficacy was shown only in
secondary outcomes.26-30 Moreover, these were single-center trials
with small sample sizes (n ¼ 78 and n ¼ 79). Interestingly, all
wheezing children with high RV genome load treated with placebo
developed a new physician-confirmed wheezing episode within 100
days and initiation of asthma control medication within 14
months.29,31 These results generate an interesting hypothesis, that
early systemic anti-inflammatory control targeting the preexisting
and/or virus-induced airway inflammatory response could signifi-
cantly affect the natural course of asthma.
In summary, there is no evidence for, and guidelines do not
support, using asthma medication for RSV-induced bronchiolitis.
Although preliminary data point to the direction that treatment of
bronchiolitis should be administered on a more personalized base
than currently in practice, the level of evidence is still low for using
asthma medication in the RV cluster of first wheeze and not
endorsed by guidelines. Larger trials are warranted to determine
whether first severe wheezing episodes in children with pro-
nounced atopy or those caused by RV require specific treatments.
HETEROGENEOUS PHENOTYPES
Preschool-age children with recurrent wheezing have multiple
paths of disease expression and several phenotypes, which may
reflect different endotypes. Frequently, these phenotypes have
discrete characteristics, but some characteristics can also be
J ALLERGY CLIN IMMUNOL PRACT
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shared. Children may shift between phenotypes or progress into
another.4,32 However, a better understanding of these pheno-
types is needed because each may have an explicit response to
specific therapies. It should be acknowledged that not all of these
phenotypes are precursors of, or manifestations of, childhood
asthma and by extension, differentially responsive to asthma-
directed therapies.
DISEASE RISK MODELS
Asthma predictive indices have been developed from several
risk factors described in cohort studies that include early sensi-
tization to food or aeroallergens, parental asthma, atopic
dermatitis, male sex, peripheral blood eosinophilia at 9 months,
lower early-life lung function, increased airway responsiveness,
and a history of wheezing with lower respiratory tract in-
fections.4,33-38 Significant risk factors that are common across
multiple cohort studies are atopic disease,4,36-39 viral infections,
especially with RV,40-43 frequent wheeze,4,44,45 and decreased
lung function.4,36,38,39,46 Furthermore, a cluster analysis of Eu-
ropean preschool-age children described a severe, persistent
asthma phenotype by the type and severity of allergic sensitiza-
tion, severity of wheezing episodes and triggers for wheezing in
the preschool years, and response to medication.47 Many chil-
dren with recurrent wheeze develop atopic disease in early life (or
vice versa), and atopic disease remains one of the most consistent
risk factors for the development of asthma in later life. A cluster
analysis of 921 infants hospitalized with bronchiolitis identified 1
cluster at significantly elevated risk for subsequent recurrent
wheezing: those who had a history of breathing problems and/or
eczema during infancy, non-RSV (mostly RV) etiology of
bronchiolitis, higher eosinophil counts, higher cathelicidin levels,
and increased proportions of Haemophilus-dominant or Morax-
ella-dominant microbiota profiles.48
However, the overall predictive performance of these asthma
predictive indices is low.34,49 One of the most studied, the
Asthma Predictive Index (API), originated from the Tucson
Children’s Respiratory Study data, a longitudinal birth cohort
that includes risk factors such as recurrent parental asthma,
wheezing, and atopic disease in the child. Children with a pos-
itive index were 7 times more likely to have active asthma at
school-age (sensitivity, 16%; specificity, 97%).50,51 The modi-
fied API (mAPI) substitutes the clinical diagnosis of allergic
rhinitis with objective testing for allergic sensitization. The mAPI
is recognized by the National Asthma Education Prevention
Program Expert Panel Report 3 guidelines51,52 as identifying
children who are more likely to respond to ICSs.53 Moreover, a
positive mAPI magnified the probability of an asthma diagnosis
in later childhood to 90% in a select population of high-risk
preschool children with a parent with atopic disease.54
Recently, the Pediatric Asthma Risk Score was developed from
demographic and clinical data from the Cincinnati Childhood
Allergy and Air Pollution Study birth cohort and replicated in the
Isle of Wight birth cohort.55 Pediatric Asthma Risk Score pre-
dicted asthma development in the Cincinnati Childhood Allergy
and Air Pollution Study (sensitivity, 0.68; specificity, 0.77).
Predictive variables in Pediatric Asthma Risk Score included
parental asthma, eczema, and wheezing apart from colds, early
wheezing, sensitization to 2 or more food allergens and/or aer-
oallergens, and Black race. A recent latent class analysis of pre-
school children with recurrent wheeze enrolled in therapeutic
BACHARIER ET AL 3
trials found that children with evidence of multiple aeroallergen
sensitization or those with sensitization and pet exposure have
the highest risk of asthma56 and experienced the highest rates of
exacerbation (and respond to ICSs),57 potentially identifying
children most likely to benefit from treatment.
DIFFERENTIAL DIAGNOSIS
Several other diseases can lead to wheezing in preschool
children and should be considered before initiating treatment for
preschool asthma. These include, in order of frequency, recurrent
viral respiratory tract infections, gastroesophageal reflux, foreign
body aspiration, airway malacia, congenital anomalies (vascular
ring), cystic fibrosis, bronchopulmonary dysplasia, persistent
bacterial bronchitis, immune deficiency, primary ciliary dyski-
nesia, congenital heart disease, and tuberculosis.58 Symptoms
that should prompt additional investigations include failure to
thrive, failure to respond to asthma medications, hypoxemia
outside of exacerbations, and focal lung, cardiovascular signs, or
finger clubbing.58
GOALS OF THERAPY
The main goals of therapeutic intervention are to control
symptoms and prevent or reduce the severity of exacerbations in
children with severe, recurrent wheezing, with a future goal of
disease modification (ie, prevention of asthma) through treatment
in early life of high-risk children. Because many children may not
develop recurrent wheezing after their first wheezing episode,4
both the Global INitiative for Asthma59 and the National
Asthma Education Prevention Program Expert Panel Report 3
guidelines52 endorse treatment of only at-risk preschool-age chil-
dren with recurrent wheezing. Investigations are ongoing
regarding the identification of at-risk preschool-age children who
present with an RV infection as their first episode of wheeze.60
The National Asthma Education Prevention Program Expert
Panel Report 3 guidelines52 propose that phenotypic differences
may influence treatment choices based on emerging data and
suggest that children who are mAPI positive may be a high-risk
group that may benefit from treatment. Adoption of a pheno-
typic classification according to trigger (allergen-induced, exercise-
induced, virus-induced, and unresolved) has been endorsed by the
Practical allergy (PRACTALL) consensus report,61 proposing that
these phenotypes should be considered when starting medication.
The Global INitiative for Asthma guidelines59 do not yet endorse
specific phenotypes in treatment choices, stating that this is an area
of active investigation but do discuss evaluating the risk factors and
pattern of symptoms suggestive of asthma when considering
treatment of a preschool-age child with recurrent wheezing.
IDENTIFYING “TREATABLE TRAITS” TO DECIDE
TREATMENT
Eosinophilic, allergic—type 2 high
The one type of infant and preschool asthma for which we
have evidence of benefit from treatment with maintenance
inhaled steroids is asthma associated with aeroallergen sensitiza-
tion, peripheral eosinophilia, and “type 2 high” immunity.62,63
Evidence for this endotype is supported by previous lower
airway analyses, which have shown tissue and airway luminal
eosinophilia in a subgroup of severe, recurrently wheezing chil-
dren.64-66 It is important to note that tissue eosinophilia may be
present independently of atopic status.66 This suggests that there
4 BACHARIER ET AL J ALLERGY CLIN IMMUNOL PRACT
MONTH 2021

-dose

FIGURE 1. Phenotype-directed therapy for preschool children with recurrent wheezing. Initial determination should focus on baseline
disease activity—are symptoms intermittent/episodic or do they occur in a persistent manner? Among APIþ children, if a trial of
intermittent high-dose ICS therapy is not effective, consider early azithromycin therapy. ED, Emergency department; Hosp,
hospitalization; LTRA, leukotriene receptor antagonist.

TABLE I. mAPI* vs original API (Castro-Rodriguez et al51) understand how best to treat nonallergic infants and preschool
1. The child must have a history of 4 or more wheezing episodes with at
children with asthma, who make up the majority. The nonal-
least 1 physician diagnosis. lergic group constitutes a very different endotype to the allergic,
2. In addition, the child must have a history of 4 or more wheezing
eosinophilic, steroid-responsive group. Unbiased assessment of
episodes with at least 1 confirmed by a physician. lower airway inflammation in infants and preschool children
mAPI: Major criteria Original API: Major criteria with wheeze has shown a cluster who have a predominant neu-

Parental history of
Parental history of asthma
trophilia, are steroid-refractory, and are distinct to those with
asthma aeroallergen sensitization and steroid-responsive.65 In addition,

Physician-diagnosed
Physician-diagnosed atopic dermatitis studies of lower airway inflammation and infection have shown
atopic dermatitis that approximately 50% of nonallergic infants and preschool

Allergic sensitization to children with wheeze have lower airway bacterial infection
1 aeroallergen associated with neutrophilia, during stable disease.67,69 Three
mAPI: Minor criteria Original API: Minor criteria lower airway bacteria predominated, Moraxella catarrhalis, Hae-

Allergic sensitization to
Physician-diagnosed allergic rhinitis mophilus influenzae, and Streptococcus pneumoniae, and treatment
milk, egg, or peanuts in an observational study with a prolonged course of targeted

Wheezing unrelated to
Wheezing unrelated to colds antibiotics (between 2 and 16 weeks) showed a reduction in
colds exacerbations over the subsequent 12 months.69 An association

Blood eosinophils 4%
Blood eosinophils 4% between acute wheeze episodes and bacterial infection in airway
aspirates in children aged 4 weeks to 3 years has also been
From Guilbert.80
*Differences in indices are in bold.
demonstrated, with evidence of bacterial infections being as
frequent as, but independent of, virus infections.70 The same 3
bacterial species were identified as predominant; however, asso-
may be some children who respond to ICSs even without
ciations with allergic sensitization were not reported. With evi-
aeroallergen sensitization, and elevated blood eosinophils alone
dence for an association between bacterial infection and acute
may be a biomarker for these. The utility of blood eosinophils
wheeze episodes, 3 clinical trials have investigated the role of the
(>300/mL) with and without aeroallergen sensitization as a
macrolide antibiotic azithromycin to treat acute wheezy episodes
biomarker of ICS response in this age group has been demon-
in infants and preschool children (see below). These data suggest
strated,62 but it is uncertain whether these are the optimal bio-
a potential role for targeting bacterial infection and/or neutro-
markers to guide treatment in this group.
philia in nonallergic wheezing children, to prevent acute attacks
(early treatment was most beneficial), in a similar manner to
Nonallergic, bacterial infection, neutrophilic chronic obstructive pulmonary disease.71 However, although no
predominant—type 2 low trials have required demonstration of objective evidence of lower
Although biomarkers and treatment for allergic, eosinophilic airway neutrophilia and bacterial infection during stable disease,
infant and preschool asthma have been identified, only approx- future studies might examine this as a potential predictor of
imately one-quarter of infant and preschool children with asthma response to antimicrobial interventions. Noninvasive biomarkers
have aeroallergen sensitization.13,67,68 We therefore need to that allow identification of such a group, and interventional
J ALLERGY CLIN IMMUNOL PRACT BACHARIER ET AL 5
VOLUME -, NUMBER -

FIGURE 2. (A) Probability of each asthma treatment being the best of the 3. Gray shading depicts participants who did not have a
differential response. (B) Percentage of asthma control days. (C) Probability of an exacerbation. (D) Cumulative probability of an
exacerbation requiring systemic corticosteroids stratified by combinations of aeroallergen sensitization and blood eosinophil counts. (E)
Cumulative probability of an exacerbation requiring systemic corticosteroids stratified by combinations of aeroallergen sensitization and
blood eosinophil counts. LTRA, Leukotriene receptor antagonist. Adapted from Fitzpatrick et al.62

studies that focus on nonallergic infant and preschool asthma, are wheeze and evidence of type 2 inflammation (summarized in
an important avenue for future research. Figure 1).

Recurrent episodic wheezing in the setting of

PHENOTYPE-DIRECTED TREATMENT STRATEGIES
On the basis of literature, not all preschoolers with recurrent
wheezing benefit from treatment. However, in addition to the
treatable trait strategy outlined above, there are several clini-
cally defined recurrent wheezing phenotypes for which high-
quality evidence exists that support that such patients derive
significant benefit from various phenotype-directed treatment
strategies. Given the clinically meaningful effects demonstrated
in a multitude of clinical trials, and the overarching desire to
minimize both illness-associated morbidity and systemic
corticosteroid use in young children, strategies that allow for
such should be implemented in those patients at greatest risk
for those outcomes. These include children with (1) recurrent
episodic wheezing in setting of respiratory tract illnesses, (2)
positive modified asthma predictive indices, and (3) recurrent
respiratory tract illnesses
This highly prevalent phenotype of recurrent wheezing is
characterized by recurrent episodes of wheezing, generally trig-
gered by the frequent viral illnesses experienced by preschool
children. Although substantially symptomatic during acute epi-
sodes, many children have no evidence of between-illness
symptomatology. Parents of such children are often reluctant
to consider daily preventative therapy in this setting. However,
they acknowledge the morbidity associated with acute episodes,
are generally capable of identifying premonitory signs and
symptoms of impending significant episodes,72 and are willing to
use therapies in the short-term to reduce symptom burden and
avoid oral corticosteroid use. As noted above, many children with
this clinical phenotype may express the nonallergic, neutrophil-
predominant (type 2 low) treatable trait, but many children
6 BACHARIER ET AL
with this phenotype express atopic features. In children with
recurrent episodic wheezing in the setting of respiratory tract
illnesses, evidence supports the early use of either high-dose
short-term ICSs73-75 or empiric azithromycin76 as effective
strategies in reducing the risk of episodes requiring oral corti-
costeroids. The Early Administration of Azithromycin and Pre-
vention of Severe Lower Respiratory Tract Illnesses trial showed a
significant reduction in the number of upper respiratory tract
infections that progressed to lower respiratory wheezy illness with
the early use of azithromycin (at illness onset, and not waiting for
lower respiratory tract symptoms) compared with placebo.76
However, time to next event was unaffected and impact on
macrolide resistance was a potential concern. A second trial
included children aged between 1 and 3 years showed a signifi-
cant shortening of acute episodes, especially with early initiation
of treatment.77 Development of macrolide resistance was not
investigated. A third very pragmatic trial assessed utility of azi-
thromycin on presentation of the patient to the emergency
department with an acute wheeze attack. However, there was no
benefit of azithromycin over placebo.33 Although short-term
high-dose ICSs have been demonstrated to be comparable to
daily low-dose ICSs in preschool children with episodic wheezing
and positive mAPIs73 in terms of exacerbation prevention and
symptom control, empiric early azithromycin demonstrated
similar efficacy in children irrespective of mAPI status.76 These
clinical benefits must be balanced against concerns for both
antimicrobial resistance and data relating antibiotic-related
microbiome alterations and subsequent risk of asthma
development.78
Children with recurrent wheeze and positive mAPIs
As discussed previously, preschool children with risk factors
for persistent asthma, such as the mAPI (Table I), have been
identified in asthma guidelines as appropriate recipients of
treatment with ICSs for asthma in an effort to reduce symptom
burden and exacerbation risk.52 This is supported by results from
the Prevention Early Asthma in Kids (PEAK) trial, which
demonstrated significantly more episode-free days and fewer se-
vere exacerbations among children with positive mAPIs who
received daily ICS therapy for 2 years compared with those who
received placebo.53 A post hoc analysis of these data showed that
not all subgroups of children with positive mAPIs similarly
benefited from daily ICS, with greater responses in terms of
symptom control and exacerbations being noted in males,
Caucasians, those who received emergency department care or
hospitalization in the previous year, and those with evidence of
sensitization to an aeroallergen.79 Adding such features to the
decision-making process in a young child with a positive mAPI
allows for further personalization of the approach beyond simply
determination of mAPI status, and helps identify children most
likely to benefit from daily ICS.
Children with recurrent wheeze and evidence of
type 2 inflammation
Children with recurrent wheezing along with underlying type
2 inflammation are at risk of ongoing symptoms and exacerba-
tions. The Individualized Therapy for Asthma in Toddlers
(INFANT) trial was conducted in 300 children aged 12 to 59
months who were candidates for Step 2 therapy based on
symptom or exacerbation frequency.62 In a cross-over design, all
participants received each of 3 therapies in random order—daily
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2021
low-dose ICS, daily leukotriene receptor antagonist, and ICS
used whenever short-acting b-agonist rescue was needed. The
primary outcome was the rate of differential response within
individuals to the 3 therapies based on a hierarchical assessment
of time to first severe exacerbation and annualized asthma control
days. Although 26% of children did not demonstrate a preferred
therapy, the remaining 74% demonstrated a preference. Those
without a preferred therapy experienced very few symptom days
or exacerbations during the trial, and thus had little room to
improve with any therapy and did equally well with all 3 ther-
apies (Figure 2). In contrast, among those who demonstrated a
differential response, daily ICS was the most commonly preferred
therapy, but many children demonstrated a preference for either
leukotriene receptor antagonist or as-needed ICS rather than
daily ICS. These effects were magnified when participants were
categorized by baseline allergic sensitization status and/or blood
eosinophil counts. In children with aeroallergen sensitization
and/or blood eosinophil counts greater than or equal to 300/mL,
the likelihood that daily ICS therapy was preferred was further
increased (Figure 2). These findings, along with findings from a
cluster analysis of preschool children in a series of treatment
trials, strongly support improved clinical course with asthma
controller therapy, especially with daily ICS, among children
with evidence of type 2 inflammation reflected by allergic
sensitization and/or peripheral blood eosinophilia (Figure 1).
SUMMARY
Before deciding whether infants and preschool children with
asthma should be treated, it is essential that the type of asthma is
defined. We need to adopt an approach of separating children
according to allergen sensitization, evidence of eosinophilia, and
evidence of neutrophilia and/or infection. Although biomarkers
for allergic, type 2ehigh patients are known, there is currently an
urgent need for biomarkers and appropriate interventions for
nonallergic, type 2elow children. This should now form the
focus of our research, if we are to improve the substantial health
care burden resulting from asthma in infants and preschool
children.
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