Clinical Commentary Review
Asthma Management in Children
Cassie L. Shipp, MDa,b, Peter J. Gergen, MDc, James E. Gern, MDd, Elizabeth C. Matsui, MD, MHSe, and
Theresa W. Guilbert, MD, MSa,b Cincinnati, Ohio; Bethesda, Md; Madison, Wis; Austin, Texas
INFORMATION FOR CATEGORY 1 CME CREDIT
Credit can now be obtained, free for a limited time, by reading the
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Date of Original Release: January 1, 2023. Credit may be obtained for
these courses until December 31, 2023.
Copyright Statement: Copyright Ó 2023-2025. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects of
allergic disease to those who research, treat, or manage allergic disease.
Target Audience: Physicians and researchers within the field of
allergic disease.
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is
accredited by the Accreditation Council for Continuing Medical Ed-
ucation (ACCME) to provide continuing medical education for phy-
sicians. The AAAAI designates this journal-based CME activity for
1.00 AMA PRA Category 1 CreditÔ. Physicians should claim only the
Asthma is a common, complex heterogeneous disease often
beginning in early life and is characterized by reversible airflow
obstruction. The phenotypic differences that exist in children
with asthma may impact underlying comorbid conditions and
pharmacologic treatment choices. Prenatal factors for increased
risk of asthma could include maternal diet and the maternal
microbiome. Evidence also suggests that postnatal microbial
a
Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center,
Cincinnati, Ohio
b
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati,
Ohio
c
Division of Allergy, Immunology, and Transplantation, National Institute of Al-
lergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
d
Departments of Pediatrics and Medicine, School of Medicine and Public Health,
University of Wisconsin, Madison, Wis
e
Departments of Population Health and Pediatrics, Dell Medical School at University
of Texas at Austin, Austin, Texas
No funding was received for this work.
Conflicts of interest: J. E. Gern reports personal fees from AstraZeneca and Meissa
Vaccines Inc and stock options in Meissa Vaccines Inc. E. C. Matsui reports
grants from National Institutes of Health (NIH) and the Health Effects Institute. T.
W. Guilbert reports grants from GSK, NIH, Sanofi/Regeneron/Amgen, and
credit commensurate with the extent of their participation in the
activity.
List of Design Committee Members: Cassie L. Shipp, MD, Peter J.
Gergen, MD, James E. Gern, MD, Elizabeth C. Matsui, MD, MHS, and
Theresa W. Guilbert, MD, MS (authors); Robert S. Zeiger, MD, PhD
(editor)
Learning objectives:
1. To understand asthma prevalence and the potential mechanisms
leading to childhood asthma inception.
2. To identify key asthma phenotypes and endotypes in children with
preschool and school aged asthma.
3. To understand the latest treatment strategies in preschool and school
age asthma and how social determinants of health impact treatment
efficacy.
4. To recognize children with severe asthma and discuss the latest
management strategies for this group.
Recognition of Commercial Support: This CME has not received
external commercial support.
Disclosure of Relevant Financial Relationships with Commercial
Interests: All authors and reviewers reported no relevant financial
relationships.
exposures and colonization contribute to the risk of allergic
diseases and asthma. After confirming the diagnosis, asthma
management in children centers on 3 broad areas:
pharmacologic treatment, treatment of underlying
comorbidities, and education of the patient and caregivers on
the importance of adherence and device technique. Moreover,
social determinants of health significantly impact on symptom
AstraZeneca; personal fees from Sanofi/Regeneron/Amgen, AstraZeneca,
Novartis, Genentech, Polarean, AiCME and OM Pharma; and royalties from
UpToDate. The rest of the authors declare that they have no relevant conflicts of
interest.
Received for publication August 1, 2022; revised October 5, 2022; accepted for
publication October 18, 2022.
Available online November 9, 2022.
Corresponding author: Theresa W. Guilbert, MD, MS, Division of Pulmonary
Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC
7041, Cincinnati, OH 45229. E-mail: Theresa.Guilbert@cchmc.org.
2213-2198
Ó 2022 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaip.2022.10.031
9
10 SHIPP ET AL
Abbreviations used
APIC- Asthma Phenotypes in the Inner City
ECHO- Environment and Child Health Outcomes
FeNO- Fractional exhaled nitric oxide
GI- Gastrointestinal
GINA- Global Initiative for Asthma
ICS- Inhaled corticosteroids
INFANT- Individualized Therapy for Asthma in Toddlers
LABA- Long-acting b-agonists
LAMA- Long-acting muscarinic antagonist
LRTI- Lower respiratory tract illnesses
LTRA- Leukotriene receptor antagonists
mAPI- Modified predictive index
MART- Maintenance and reliever therapy
NAEPP 2020- National Asthma Education and Prevention
Program 2020 Focused Updates to the Asthma
Management Guidelines
OCS- Oral corticosteroids
PM- Particulate matter
SABA- short-acting b2-agonist
T2- Type 2
burden and treatment response. Ó 2022 American Acad-
emy of Allergy, Asthma & Immunology (J Allergy Clin
Immunol Pract 2023;11:9-18)
Key words: Asthma inception; Asthma management; Asthma
phenotypes; Asthma risk factors; Childhood asthma; Preschool
asthma; School age asthma; Severe asthma; Social determinants
of health
Asthma is a common, complex heterogeneous disease often
beginning in early life and is characterized by reversible airflow
obstruction. This review discusses the gene-by-environment
risk factors of inception. The phenotypic differences that exist
in children with asthma may impact underlying comorbid
conditions and pharmacologic treatment choices. Asthma
management strategies are discussed by age and by the
phenotypic response. Finally, social determinants of health that
impact symptom burden and treatment response will be
examined.
ASTHMA INCIDENCE AND PREVALENCE AND THE
POTENTIAL MECHANISMS LEADING TO
CHILDHOOD ASTHMA INCEPTION
Evaluating incidence rates can provide critical clues about
factors that are temporally associated with the development of
asthma. Two recent publications assessed incidence data for US
children stratified by age, family history, sex, race, and ethnicity.
In the Environment and Child Health Outcomes (ECHO)
study, data from 31 cohorts were evaluated in a meta-analysis.1
As expected, asthma incidence was increased in children with a
positive family history, and boys had a greater incidence than
girls until puberty. Race was associated with marked differences
in age-related asthma incidence. Non-Hispanic Black children
had 2 to 3 times the rate of incident asthma of non-Hispanic
White children during the preschool years. After that, inci-
dence rates steadily declined in Black children but remained
relatively stable in White children. These trends were accentu-
ated in children with a positive family history of asthma.
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2023
The Children’s Respiratory and Environmental Workgroup
consortium, funded by ECHO, published a study of the pooled
data from 10 asthma birth cohorts.2 This pooled data analysis
calculated incidence rates in Hispanic children whose families self-
reported Caribbean or Mexican ethnicity. Incidence rates for these
2 Hispanic populations differed; self-reported Caribbean and Af-
rican children had similarly high incidence rates in early life,
whereas asthma incidence rates for children of self-reported
Mexican and European heritage were similar. These findings
suggest that self-report of African racial and/or ethnic identity,3
which is common in Caribbean Hispanics, is associated with a
higher risk of asthma incidence. The increased rates in Black
children are multifactorial, and many are related to socioeco-
nomics. The evaluation of neighborhood and personal factors
confirmed previously described relationships between low-income,
self-reported Black racial identity and increased incidence of
childhood asthma.4 However, self-reported Black children had
increased asthma incidence even in higher-income neighborhoods,
suggesting that other factors such as stress and depression, struc-
tural inequities, or genetic factors could contribute to racial dis-
parities in asthma incidence rates.
Previous studies in urban neighborhoods with high poverty
rates showed that the combination of allergic sensitization and
exposure to those allergens in the home is associated with
increased risk of asthma morbidity in school-aged children with
asthma.5 However, in the Urban Environment and Childhood
Asthma study, exposure of disadvantaged urban preschoolers to
common indoor allergens (cockroach, mouse, and cat) was linked
to a reduced risk of wheezing and asthma in early life.6-9 Perhaps,
as has been reported for pets and traditional farm exposures,
early-life exposure to a broad array of immunostimulatory sub-
stances, including allergenic proteins, is a stimulus for immune
development.10,11 When considered collectively, the results of
these observational studies suggest multiple strategies to reduce
the risk of childhood asthma. Potential interventions include
optimizing nutrition, promoting biodiverse exposures in early
childhood, treating with probiotics or immune stimulants,
antiviral vaccines or treatments, and reducing exposure to to-
bacco smoke (especially in utero) and air pollutants. A multi-
faceted approach combining several strategies may produce
optimal results. Notably, several interventions (eg, improved
nutrition, biodiversity, reduced exposure to pollutants) depend
on improving economic opportunities or neighborhood condi-
tions that may be the root causes of disparities in childhood
asthma.12
Prenatal factors for increased risk of asthma could include
maternal diet such as intake of fish oil associated with reduced
rates of allergy and wheeze13 and vitamin C linked to reducing
the effects of maternal smoking on reduced lung function and
wheeze in children.14,15 Another key factor may be the maternal
microbiome, as data from animal studies indicate that microbial
metabolites can cross the placenta and help direct fetal immune
system development.16 There is evidence that the fetal gastro-
intestinal (GI) tract may be colonized in utero, and colonizing
microbes can influence immune development.17
Evidence is mounting to link postnatal microbial exposures
and colonization to the risk of allergic diseases and asthma. For
most children, postnatal exposures begin with the maternal
vaginal and skin microbiome, which may be an essential source
to seed the GI and skin microbiome of the child.18 Lack of
contact with the vaginal microbiome could help to explain why
J ALLERGY CLIN IMMUNOL PRACT SHIPP ET AL 11
VOLUME 11, NUMBER 1

TABLE I. Examples of childhood asthma phenotypes

Data elements considered in the analysis
Study Phenotypes Symptoms† Exacerbations Atopy Airway obstruction Other
CAMP33 LLL* Low Low Low
HLL Low-intermediate High Low Atopic dermatitis
HHM Intermediate High High
MHH Intermediate-high Intermediate High
HHH Highest High Atopic dermatitis
NHLBI clinical trials34 Class 1 Highest Highest Multiple sensitization High, partially reversible Highest blood EOS
Class 2 Intermediate Intermediate Multiple sensitization Intermediate, reversible
Class 3 Intermediate Low Some sensitization Intermediate, reversible Increased BMI
Class 4 Intermediate High Multiple sensitization Low Increased BMI
Class 5 Lowest Low Low Low Increased BMI
APIC36 A Low Low Low Low
B High Intermediate Low Intermediate
C Low Low Some sensitization Low
D Low Intermediate Multiple sensitization Intermediate
E Highest High Multiple sensitization High Highest blood EOS

Boldface indicates phenotypes that are similar across different studies.

APIC, Asthma Phenotypes in the Inner City; BMI; body mass index; CAMP, Childhood Asthma Management Program; EOS, eosinophils; NHLBI, National Heart, Lung, and
Blood Institute.
*AOE classification for atopy, obstruction, and exacerbation (symptoms not used in the analysis).
†Asthma Control Test (ACT) or Asthma Control Questionnaire (ACQ) scores.

children who are delivered via C-section lack a full range of gut
commensals9 and have increased rates of allergy and asthma.19
Breastfeeding contains oligosaccharides metabolized by gut mi-
crobes, and the resulting metabolites include factors such as
short-chain fatty acids that promote healthy epithelial and im-
mune development.20 Exposures from barns, pets, and farm
animals increase the diversity of microbes with beneficial prop-
erties.21-23 Farm milk has immunomodulating effects and is
associated with reduced wheeze through microbiome-
independent mechanisms.24,25 Antibiotic treatment courses in
early life reduce the abundance of beneficial commensals and are
associated with an increased risk of developing asthma.26
Notably, there is a temporal association between the campaign
for responsible and informed use of antibiotics to reduce anti-
microbial resistance and the decrease of asthma incidence rates,
supporting a causal link. Although viral respiratory infections are
ubiquitous in preschool children, infections with wheezing in
early life, especially human rhinovirus and respiratory syncytial
virus, are associated with increased risk of asthma in childhood.27
This risk is even greater for preschool children with pathogen-
dominated airway microbiomes28-30 and for children who
develop allergic sensitization at an early age.30,31
ASTHMA PHENOTYPES AND ENDOTYPES IN
CHILDREN
Childhood asthma is a syndrome, and there are different
phenotypes based on characteristics such as wheezing patterns,
allergic sensitization, lung function, and exacerbations. Identi-
fying different asthma phenotypes promises to provide more
homogeneous outcomes than asthma per se, thereby increasing
the ability to link asthma phenotypes to causal factors. Although
consensus on the number of asthma phenotypes has not been
achieved, common phenotypes include transient viral wheeze,
type 2 (T2)-high asthma, and T2-low asthma. Although obesity
can adversely influence lung function and may be linked to
asthma onset and severity,32 it is unlikely that there is a distinct
childhood obesity phenotype. The following sections review
childhood respiratory and asthma phenotypes identified in recent
multicenter or birth cohort studies.
Multicenter studies of childhood asthma
Investigators in multicenter studies have identified asthma
phenotypes in the Childhood Asthma Management Program,33
combined National Heart, Lung, and Blood Instituteefunded
treatment studies of childhood asthma,34 and the Asthma Phe-
notypes in the Inner City (APIC) study.35 These studies had
large data sets that included patterns of symptoms or exacerba-
tions, biomarkers for T2 inflammation (evidence of allergic
sensitization, elevated serum or airway eosinophilia, or elevated
fractional exhaled nitric oxide [FeNO]), and lung function
testing. Some phenotypes were found in each study, such as
children with baseline airway obstruction and multiple allergic
sensitizations (high-T2 asthma, Table I).34-36 This phenotype is
associated with prominent symptoms and the highest exacerba-
tion risk. Another typical phenotype consists of children with
low allergic sensitization, normal lung function, and low symp-
toms and exacerbation risk. How phenotypes with intermediate
features and outcomes were classified in the different studies was
more variable. The APIC analysis identified a “group B” that was
low T2 yet had considerable morbidity.35 Similar phenotypes of
early-onset low-T2 asthma have been identified in studies of
severe asthma in adults.37 Given the variability in the data ele-
ments used in these phenotype analyses and the different pop-
ulations, it is not surprising that agreement between the studies is
modest. Moreover, it is possible that individual or environmental
factors cause childhood asthma phenotypes to evolve over time.
For example, air pollution, exacerbations, and obesity can all
influence the trajectory of lung function, a key feature of asthma,
during childhood.38,39 Further progress in identifying underlying
12 SHIPP ET AL
mechanisms of asthma phenotypes may bring greater clarity to
their definitions and approaches to prevention.
Birth cohort studies
The approach to identifying phenotypes in birth cohorts has
the advantage that patterns of longitudinal data can be assessed.
Many cohorts have evaluated patterns of symptoms such as
wheeze and found 4 or more phenotypes, including transient
viral wheeze that fades in the preschool years, persistent wheeze,
and “late-onset” wheeze that begins after the first few years of
life.40-44 In the past decade, birth cohort studies have linked
early-life exposures and biomarkers to phenotype development.
For example, transient wheeze has been linked to smoke expo-
sure in utero, low allergic sensitization, exposure to other children
at home or in daycare, and increased exposure to particulate
matter (PM) 2.5 in the first year of life.43,44 Persistent wheeze is
more closely related to early sensitization to multiple aero-
allergens and airway obstruction.40 In urban children growing up
in neighborhoods with high poverty rates, maternal stress and
depression during the perinatal period were associated with a
moderate wheeze low-atopy phenotype.45,46
Gene polymorphisms and regulation have also been related to
wheeze and respiratory phenotypes. Polymorphisms in the
17q12-21 locus, which is closely linked to the risk of childhood
asthma, were associated with multiple wheezing phenotypes in
one study47 and specifically with persistent wheezing and a novel
intermittent wheezing phenotype in another.40 A CDHR3
polymorphism, which modifies susceptibility to rhinovirus-C
wheezing illnesses,48,49 was associated with persistent wheeze
and intermittent wheeze.40 In children growing up in disad-
vantaged urban neighborhoods, 6 respiratory phenotypes were
identified by combining wheeze patterns, allergic sensitization,
and lung function.45 The group with the highest rate of asthma
and related health care utilization was a high-atopy, high-wheeze,
low lung function phenotype. In these children, nasal epithelial
cell gene expression revealed a unique upregulation of a cor-
egulated genes network, including MUC5AC, which is overex-
pressed in the lower airways in asthma and contributes to airway
obstruction and plugging.50 In contrast, a moderate wheeze low-
atopy phenotype was related to gene expression patterns indic-
ative of injury and reduced integrity and antioxidant activity.45
LATEST TREATMENT STRATEGIES IN PRESCHOOL
ASTHMA
The management of asthma in the preschool population is
challenging because disease phenotypes are heterogeneous and
developing. Health care utilization for asthma during childhood
is greatest among the 0- to 4-year-old group.51 Parents are often
frustrated as children may experience treatment with multiple
corticosteroid courses, emergency department visits, or hospi-
talizations for wheezing episodes before a controller trial is
considered.
Therapies aimed at control of persistent symptoms and
recurrent exacerbations include inhaled corticosteroids (ICS) and
daily leukotriene receptor antagonists (LTRA), while episodic use
of ICS and azithromycin may result in a decrease of exacerba-
tions among preschoolers with intermittent disease. Other dis-
eases that mimic asthma-like symptoms52 and barriers to
treatment adherence should be considered when managing a
preschool child with uncontrolled asthma symptoms. Two major
asthma management guidelines for preschool and school-aged
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2023
children exist. These are the Global Initiative for Asthma
(GINA)53 and the National Asthma Education and Prevention
Program 2020 Focused Updates to the Asthma Management
Guidelines (NAEPP 2020).54 Daily ICS treatment is currently
preferred therapy for persistent asthma in this age group (step 2
GINA and NAEPP 2020).53,54 The guidelines support treatment
for severe intermittent wheezers, particularly those with a positive
modified predictive index (mAPI), with a 7- to 10-day course of
daily higher dose ICS and short acting b2-agonists (SABAs) at the
first sign of illness (step 1 NAEPP 2020).53,54 Specific preschool
phenotypes may affect management decisions or response to
specific therapies and are outlined below.
Children with evidence of atopy or allergic
sensitization
The Prevention of Early Asthma in Kids trial55 enrolled 285
children 2 to 3 years of age with a positive mAPI and history of
intermittent wheezing, and they were randomized to active
treatment with either inhaled low-dose ICS or placebo for 2
years. Daily ICS use was associated with a greater number of
symptom-free days and fewer exacerbations during the 2 years of
active therapy.56
The components of the mAPI, aeroallergen sensitization or
blood eosinophilia, have also been found to be associated with a
greater response to daily ICS therapy. In the Individualized
Therapy for Asthma in Toddlers (INFANT) study, children aged
12-59 months who were candidates for step 2 (ie, daily
controller) therapy were enrolled to evaluate differential response
to daily ICS, intermittent ICS whenever a SABA was used, and
daily LTRA.57 A differential response in asthma control was
greatest during the daily ICS treatment periods, particularly in
the patients with aeroallergen sensitization or blood eosinophils
(
300/mL).
Children without evidence of atopy or allergic
sensitization
Twenty-six percent of the children in the INFANT study
described above did not demonstrate a clear response to any of
the 3 therapies. Children who were not sensitized to aeroallergens
and had blood eosinophil levels less than 300/mL experienced
similar low exacerbation rates during treatment with all 3 ther-
apies. These findings suggest that children without atopic disease
biomarkers with persistent symptoms and/or recurrent exacer-
bations who are candidates for step 2 therapy can be started on
either a daily ICS or daily LTRA (GINA and NAEPP 2020),
intermittent ICS with illness (GINA), and daily cromolyn
(NAEPP 2020).53,54 Treatment decisions should include
consideration of the above findings and parent preferences.
Intermittent therapy for children with intermittent
disease
In the Maintenance and Intermittent Inhaled Corticosteroids
in Wheezing Toddlers study, episodic high-dose ICS were
initiated at the earliest recognized onset of respiratory tract
symptoms, before progression of wheezing, for a total of 7 days
and were compared with daily low-dose ICS.58 Both ICS treat-
ment strategies were similar with no significant differences in
asthma exacerbations or other indicators of asthma control or
linear growth. A 2016 meta-analysis of 5 studies and over 400
participants found that episodic high-dose ICS decreased exac-
erbations by 35%.59 This episodic ICS strategy has also been
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 11, NUMBER 1
TABLE II. Comparison of differences between GINA and NAEPP 2020 guideline stepwise approach of preferred therapy for management
of asthma
Age group GINA 2021
6-11 y (GINA 2021) Step 1—concomitant low-dose ICS taken whenever
5-11 y (NAEPP 2020) SABAs used
Step 2—daily low-dose ICS and as-needed SABA
Step 3—low-dose ICS-LABA and SABA or medium-
dose ICS or daily and as-needed very low-dose ICS-
formoterol
Step 4—medium-dose ICS-LABA and SABA or daily
and as-needed low-dose ICS-formoterol
Step 5—daily higher dose ICS-LABA and SABA or
add-on therapy (eg, anti-IgE)

12þ y Step 1—as-needed low-dose ICS-fomoterol
Step 2—as-needed low-dose ICS-fomoterol
Step 3—daily and as-needed low-dose ICS-fomoterol
Step 4—daily and as-needed medium-dose ICS-
fomoterol
Step 5—add-on LAMA. Consider daily and as-needed
high-dose ICS-fomoterol. Consider adding asthma
biologics (eg, anti-IgE, anti-IL5, and anti-IL5R)
GINA, Global Initiative for Asthma; ICS, inhaled corticosteroids; LABA, long-acting b-agonists; LAMA, long-acting muscarinic antagonist; NAEPP, National Asthma Education
and Prevention Program; SABA, short-acting b2-agonist.
shown to decrease the use of rescue oral corticosteroids
(OCS).60,61
For children with significant viral-triggered lower respiratory
tract illnesses (LRTI) regardless of if they were mAPI positive or
not, episodic azithromycin started early in the episode is also a
treatment option. Two large clinical trials of the use of azi-
thromycin early in an LRTI have shown efficacy in decreasing the
severity or duration of the episode.62,63 The effect of macrolide
antibiotics may be due to their additional anti-inflammatory and
antineutrophilic properties.64,65 The risk of development of
antibiotic-resistant organisms associated with repeated azi-
thromycin treatment remains a concern. In one trial, these were
infrequently acquired,62 whereas in the other, cohort resistance
was not assessed.63 Additional research is needed. Based on these
studies, and considering concerns regarding potential antimicro-
bial resistance, high-dose intermittent ICS is suggested as the
preferred therapy in children with severe intermittent wheezing
and evidence of atopy or sensitization. In nonatopic children, early
use of azithromycin could be considered. As timing early in the
course of illness is crucial to its effectiveness, this therapeutic op-
tion should be reserved for those patients whose parents have a
clear understanding of the treatment plan.
Preschool asthma is a heterogeneous condition that can
change over time. Recent studies have supported preliminary
evidence-based and phenotype-directed approaches for the young
child with recurrent wheezing and asthma and can help predict
treatment response, particularly in those with T2-high pheno-
types. Monitoring for efficacy of response is critical in developing
an optimal individualized treatment plan. Few trials exist to
SHIPP ET AL 13
NAEPP 2020
Step 1—as-needed SABA
Step 2—daily low-dose ICS and as-needed SABA
Step 3—daily and as-needed low-dose ICS-formoterol
Step 4—daily and as-needed medium-dose ICS-
formoterol
Step 5—daily high-dose ICS-LABA and SABA.
Consider anti-IgE therapy
Step 6—daily high-dose ICS-LABA and oral
corticosteroids and SABA. Consider anti-IgE therapy
Step 1—as-needed SABA
Step 2—daily low-dose ICS and as-needed SABA or as-
needed concomitant ICS and SABAs
Step 3—daily and as-needed low-dose ICS-formoterol
Step 4—daily and as-needed medium-dose ICS-
formoterol
Step 5—daily medium- to high-dose ICS-LABA and
LAMA and SABA. Consider adding asthma biologics
(eg, anti-IgE, anti-IL5, anti-IL5R, and anti-IL4/IL13)
Step 6—daily high-dose ICS-LABA, oral
corticosteroids, and SABA. Consider adding asthma
biologics (eg, anti-IgE, anti-IL5, anti-IL5R, and anti-
IL4/IL13)
support the use of therapeutic options beyond step 2 guideline
recommendations in this population; thus, further research is
needed.53,54
ASTHMA MANAGEMENT IN SCHOOL-AGED
CHILDREN
In school-aged children, both GINA and NAEPP 2020
guidelines use similar approaches. These consensus guidelines are
informed by evidence from various clinical trials that are dis-
cussed in this review. Multiple steps with increasing level of
treatment define the approach to asthma management. There are
4 differences between the guidelines for school-aged children
(Table II). GINA recommends concomitant ICS use with SABA
for children with intermittent disease (step 1), whereas NAEPP
2020 does not. The second difference is that their approach to
comparative dosing in ICS varies between the 2 sets of guide-
lines.66,67 The GINA guidelines are more conservative in their
classification of ICS, using lower cutoffs for low, medium, and
high ICS for children less than 12 years of age than NAEPP. For
example, fluticasone propionate (dry powder inhaler) high is
>200 mcg in GINA and >400 mcg in NAEPP 2020. Also, for
maintenance and reliever therapy (MART), the starting dose is
lower in GINA. GINA offers as an alternative the addition of
long-acting muscarinic antagonist (LAMA) for children with
moderate persistent disease (step 4), whereas NAEPP 2020 does
not offer this alternative.
For
12 years old, the NAEPP 2020 and GINA are more
similar in their approach (Table II). NAEPP 2020
14 SHIPP ET AL
TABLE III. Alternative diagnoses to consider in patients with severe persistent asthma and poor response to therapy
Alternative diagnoses Examples
Structural abnormality Vascular ring/sling, airway malacia
Intrabronchial obstruction Tuberculosis, foreign body
Mucociliary clearance disorder Cystic fibrosis, primary ciliary dyskinesia
Aspiration Dysphagia, neuromuscular disorders
Bronchiectasis Immunodeficiency
Bronchiolitis obliterans Postinfectious
Hypersensitivity pneumonitis ABPA
Pulmonary edema Cardiac disease
ABPA, Allergic bronchopulmonary aspergillosis; CT, computed tomography.
Modified from the paper by Ramratnam et al.78
recommends intermittent SABA as the first treatment for mild
asthma and beginning low-dose ICS at step 2 with either daily
use or intermittent use with SABA. GINA recommends
intermittent treatment but with as-needed low-dose ICS/
fomoterol for the first 2 steps. The next 2 steps are similar
between the guidelines with low- and medium-strength
MART therapy, respectively.
When initiating therapy, there are well-established bio-
markers that are useful for choosing the selection of ICS over
other alternatives. These include markers of atopy such as
increased levels of FeNO, total IgE, eosinophils or low pul-
monary functions, or positive methacholine challenge.68,69
However, when additional therapy is needed, the biomarkers
for the initiation of therapy add little to aid in the selection of
additional therapy. In general, long-acting b-agonists (LABA)
achieve a greater level of control than either increasing the dose
of ICS or adding LTRA.70,71 Genetic variations have been re-
ported to influence the response to all classes of asthma medi-
cations b-agonists, ICS, and LTRA.72,73 The infrequent
occurrence of these genetic variations and the lack of easily
available tests for detection limit their usefulness in selecting
asthma medications. Probably the most important predictor of
response to asthma medications is adherence. Mean estimates of
adherence range from 25% to 50% in many studies.74 Without
ensuring adherence to medication no level of treatment will be
effective. Furthermore, children with asthma should be
encouraged to participate in physical activity.75
SEVERE ASTHMA MANAGEMENT
Pediatric severe asthma has been broadly defined as asthma
that requires GINA steps 4 and 5 and NAEPP 2020 steps 5 and
6 guideline-based therapy for the previous year or systemic cor-
ticosteroids for
50% of the previous year in order to prevent
asthma from becoming uncontrolled or asthma that remains
uncontrolled despite this therapy.53,76 Severe asthma can further
be divided into severe therapy-resistant asthma and severe
difficult-to-treat asthma. Asthma that is difficult to treat may be
related to factors that are easily modified (such as comorbidities,
poor inhaler technique, or poor adherence).77,78 For some chil-
dren, asthma severity may improve once these factors are
addressed and those that remain uncontrolled despite addressing
these factors are labeled severe therapy-resistant asthma. Both the
guidelines have made several changes to their recommendations
for severe asthma management (step 5 GINA and NAEPP 2020
and step 6 NAEPP 2020) (Table II).53,54 For school-aged
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2023
Testing/evaluation
Bronchoscopy, chest CT
Bronchoscopy
Sweat chloride, genetic testing, nasal nitric oxide
Swallow evaluation
Chest CT
Chest CT, lung biopsy
Specific IgE, precipitins, allergy skin tests, sputum culture
Chest X-ray, echocardiogram
children, GINA recommends a daily higher dose of ICS/LABA
or biologic therapy at step 5. NAEPP 2020 recommends daily
high-dose ICS/LABA and considers anti-IgE therapy at step 5
with the addition of OCS at step 6. At step 5, both guidelines
stop MART. For children 12 and older, LAMA has been added
to GINA and NAEPP 2020 step 5 therapy.53,54 At step 5,
NAEPP 2020 recommends stopping MART, but GINA rec-
ommends continuing high-dose MART and considering adding
a biologic. NAEPP 2020 recommends high-dose daily ICS/
LABA at step 5 and the addition of OCS at step 6. At both steps
biologics are to be considered.
An important part of the management of severe and/or difficult-
to-treat asthma is to ensure that alternative diagnoses have been
evaluated and ruled out.77,78 Several conditions can mimic asthma
symptoms, leading to escalation of asthma therapy with poor
response (Table III). Confirming reversible airway obstruction
(pre-post spirometry or bronchial challenge in patients with
normal lung function), assessing atopy, and phenotypic evaluation
are all mainstays of confirming the diagnosis of asthma. Con-
firming the diagnosis of asthma can often be done while simulta-
neously evaluating underlying common comorbidities that may be
impacting asthma control (Table IV).79 After confirmation of
diagnosis and results of phenotypic evaluation, biologic therapy is
often the next step in management in patients with severe asthma
(Table V).80-85 Choice of biologic requires consideration of mul-
tiple patient factors, including age, asthma severity, comorbid
conditions, and asthma phenotype. Omalizumab is approved for
patients 6 and older with severe persistent allergic asthma (dosing
based on weight and total IgE). Mepolizumab, benralizumab, and
dupilumab are all approved for eosinophilic asthma. Mepolizumab
and benralizumab are approved for severe asthma in patients 6
years and older and 12 years and older, respectively. Dupilumab is
approved for patients aged 6 and older for moderate-to-severe
asthma, aged 6 months and older for moderate-to-severe atopic
dermatitis, and aged 12 and older for eosinophilic esophagitis.
Tezepelumab is approved for patients 12 and older with severe
asthma, regardless of phenotype.
SOCIAL DETERMINANTS OF HEALTH AND THEIR
IMPACT ON SYMPTOM BURDEN AND
TREATMENT EFFICACY
A variety of contextual factors, such as social determinants of
health, the physical environment, health care access, and quality,
can contribute to the severity of asthma and affect responsiveness
to medications. These contextual factors are also important
J ALLERGY CLIN IMMUNOL PRACT SHIPP ET AL 15
VOLUME 11, NUMBER 1

TABLE IV. Common comorbidities associated with asthma.

Suspected comorbidity Testing/evaluation
Gastroesophageal reflux pH/impedance probe, EGD, consider 3-month trial PPI
Dysfunction breathing (inducible laryngospasm/vocal cord dysfunction) Bronchoscopy, speech evaluation
Sinus disease Sinus CT scan, nasal endoscopy
Psychological factors (depression, anxiety) Psychological screening/evaluation
Obesity BMI percentile
Obstructive sleep apnea Polysomnography
BMI, Body mass index; CT, computed tomography; EGD, esophagogastroduodenoscopy; PPI, Proton pump inhibitor.
Modified from the paper by Dyer.79

TABLE V. Biologic options for step 5-6 therapy

Omalizumab80,81 Mepolizumab81,82 Benralizumab81,83 Dupilumab81,84 Tezepelumab85
Indication Severe persistent Severe Severe Moderate-severe Severe asthma (no
allergic eosinophilic eosinophilic eosinophilic phenotype)
phenotype phenotype; phenotype phenotype or
chronic EGPA, HES high FeNO;
urticaria, nasal OCS dep, AD,
polyps CRS with NP
Mechanism of Anti-IgE mAb Anti-IL5 mAb Anti-IL5Ra mAb Anti-IL4Ra mAb Antithymic
action stromal
lymphopoietin
cytokine mAb
Dosing and q2w/q4w SQ dose 40 mg 6-11 y if 30 mg SQ q4w 400 then 200 mg 210 mg SQ every
administration by weight and <40 kg and 100 (first 3 doses) <60 kg 4 wk
total IgE mg 12þ SQ then q8w 600 mg then 300
q4w mg
60 kg SQ
q2w
Age FDA and EMA FDA and EMA FDA:
12 y; FDA and EMA: FDA
12 y

6 y
6 y EMA
18 y
6 y
Warnings and Black box Hypersensitivity Hypersensitivity Hypersensitivity Hypersensitivity
common side warning: reactions have reactions have reactions have reactions may
effects anaphylaxis occurred after occurred after occurred, occur after
reported after administration, administration, injection-site administration,
administration headache, injection-site reactions, pharyngitis,
and injection- injection-site reactions, conjunctivitis arthralgia, and
site reactions reactions, back headache, and with AD, back pain
pain, and pharyngitis blepharitis, oral
fatigue herpes, keratitis,
eye pruritus,
other herpes
simplex virus
infection, and
dry eye

AD, Atopic dermatitis; CRS with NP, chronic rhinosinusitis with nasal polyposis; EGPA, eosinophilic granulomatosis polyangiitis; EMA, European Medicines Agency; FDA,
Food and Drug Administration; FeNO, fractional exhaled nitric oxide; HES, hypereosinophilic syndrome; mAb, monoclonal antibody; OCS, oral corticosteroid; SQ,
subcutaneously.

contributors to racial and ethnic disparities in both asthma
burden and treatment,86 particularly socioeconomic status,
which can be conceptualized as the resources that one has or to
which one has access.87,88 Children living in poverty are less
likely to have any or high-quality insurance coverage leading to
less engagement in care and ability to fill prescriptions. Limited
access to transportation similarly impedes access to care. Barriers
to accessing care and filling prescriptions in turn contribute to
uncontrolled asthma and acute health care use. Health literacy is
another socioeconomic resource as it is tied to educational
attainment and quality of education. Low health literacy con-
tributes to lower medication adherence, which limits
responsiveness to the treatment plan, leading to asthma
morbidity.89 Another resource is time; when a parent is working
multiple jobs or odd shifts, he or she may have less access to
insurance, ability to take time off to go to doctors’ appointments,
and consistent supervision of controller medication dosing,
which may lead to increased emergency department visits.
Children may be responsible for medication adherence before
they are developmentally able to do so.90 Thus, an integral part
of asthma management should include the assessment of these
social needs and linkage to resources, such as social worker
support, to address these needs. Treatment plans should be
developed through shared decision-making with parents and
16 SHIPP ET AL
their children to minimize barriers to asthma self-management or
family management. Examples include prescribing controller
medications with the lowest co-pays, considering telemedicine
visits, or partnering with the child’s school to implement at least
some of the treatment plan.91
Environmental exposures are an important cause of asthma
burden and influence treatment responsiveness. Outdoor air
pollution, including PM, ozone, and nitrogen dioxide (NO2),
causes asthma symptoms and exacerbations92 and impedes lung
function growth.38,93 In a recent landmark case, air pollution
exposure was determined to be a significant contributor to the
death of a child in the United Kingdom who lived within 25 m
of one of the busiest roadways in London and was exposed to
PM and NO2 concentrations above the WHO guidelines.79
There is also evidence that air pollutionerelated asthma
symptoms are less responsive to ICS93 or that ICS may increase
vulnerability to air pollution exposure.94 There are steps that
clinicians can take to address potential outdoor air pollution
exposure including understanding the air pollution landscape of
the community and taking a history that ascertains proximity to
air pollution sources, such as major roadways or industrial
sources of air pollution and asthma triggers. Plans such as
moving activities indoors may be a helpful component of
asthma management strategy when air pollution levels are high
for children with significant asthma or history suggestive of
sensitivity to air pollution exposure.95 Outdoor air pollution,
particularly PM, also penetrates indoors and portable high ef-
ficiency particulate air purifiers significantly reduce indoor PM
concentrations in homes located in areas in the United States
with higher outdoor PM concentrations.96
Indoor air pollution, including PM and NO2, are also the
causes of asthma symptoms, may influence treatment respon-
siveness, and inform treatment strategies. The major contributor
to indoor PM is secondhand smoke exposure and counseling to
institute a home smoking ban can reduce PM exposure and
improve asthma.97 Portable high efficiency particulate air puri-
fiers also reduce indoor PM concentrations by 25% to 50% and
reduce asthma symptoms and exacerbations among children with
asthma who live with a smoker.98 Allergens are also major con-
tributors to asthma burden, including lung function growth,99
and can affect treatment responsiveness.100 The major allergens
to consider include dust mite, cat, dog, cockroach, and mouse.
Children who are sensitized and exposed to an indoor allergen
may benefit from strategies to reduce exposure to the relevant
allergen(s). Damp or water-damaged housing is a major risk
factor for fungal exposure, which is also a contributor to asthma
symptoms and exacerbations. The child’s neighborhood, broadly
construed, is also a contributing contextual factor. Parents who
live in neighborhoods with a high level of socioeconomic
disadvantage, including those that were historically redlined, may
experience more neighborhood violence and report feeling less
safe, and these factors are also linked to asthma symptoms and
exacerbations. In order to consider these factors in the manage-
ment plan, a careful environmental history should be taken and
allergic sensitization evaluated. Written educational materials for
environmental interventions can be a helpful resource for chil-
dren with relevant home exposures. Families experiencing pest
infestation or water damage or fungal exposure may be renters,
and local housing advocacy resources can support them in
appealing to the landlord to take adequate steps to ameliorate the
unhealthy housing conditions.
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2023
Racial and ethnic identity and immigrant status are also
important contextual factors. Language and cultural barriers may
influence treatment responsiveness, and minoritized populations
are also more likely to live in segregated, disadvantaged neigh-
borhoods where outdoor air pollution concentrations are high
and housing quality is poor. Families from these communities
also experience marginalization or negative experiences with
health systems, which is associated with reduced likelihood for
subspecialty care for asthma.101 Among publicly insured patients,
non-White patients are less likely to be on biologic therapy than
White patients,102 suggesting differential treatment by racial and
ethnic identity. In addition to screening for social needs and
environmental factors, sensitivity to the role that discrimination
may play in treatment responsiveness can help to shape a man-
agement plan that is most likely to be effective.
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