Paediatric Respiratory Reviews 36 (2020) 118–127

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

Understanding the immunology of asthma: Pathophysiology,

biomarkers, and treatments for asthma endotypes
Melissa D. Gans ⇑, Tatyana Gavrilova 1
Division of Allergy and Immunology, Montefiore Medical Center, 1525 Blondell Ave, Bronx, NY 10461, USA

Educational aims

The reader will come to appreciate that:

 Patients diagnosed with asthma will soon be classified by asthma endotype using identified risk factors and biomarkers.
 An understanding the pathophysiology of the various asthma endotypes can direct targeted therapy.
 There are many emerging biologic treatments for asthma that can greatly reduce morbidity and mortality in severe asthmatics.

a r t i c l e i n f o a b s t r a c t

Keywords: Asthma is a common disease in paediatrics and adults with a significant morbidity, mortality, and finan-
Asthma cial burden worldwide. Asthma is now recognized as a heterogeneous disease and emerging clinical and
Immunology laboratory research has elucidated understanding of asthma’s underlying immunology. The future of
Pathophysiology asthma is classifying asthma by endotype through connecting discernible characteristics with immuno-
Phenotypes
logical mechanisms. This comprehensive review of the immunology of asthma details the currently
Review
known pathophysiology and clinical practice biomarkers in addition to forefront biologic and targeted
Biomarkers
therapies for all of the asthma endotypes. By understanding the immunology of asthma, practitioners will
be able to diagnose patients by asthma endotype and provide personalized, biomarker-driven treatments
to effectively control patients’ asthma.
Ó 2019 Elsevier Ltd. All rights reserved.

INTRODUCTION There is a critical need to treat asthma more effectively. Asthma

There are 24 million people in the United States suffering from
asthma [1]. Asthma prevalence is increasing, affecting 3.1% of the
United States population in 1980 and 8.3% of the population in
2016 [1]. Asthma is one of the leading chronic illnesses of child-
hood and disproportionally affects African Americans and those
living below the poverty level [1]. Asthma exacerbations cause
missed days from school and work, hospitalizations, emergency
department visits, and more than 3000 deaths annually [1].
Asthma also entails a great financial burden, with a cost burden
greatest for those with poorly controlled asthma and in low-
income countries.
⇑ Corresponding author. Fax: +1 718 405 8532.
E-mail addresses: mstone@montefiore.org (M.D. Gans), tgavrilo@montefiore.org
(T. Gavrilova).
1
Fax: +1 718 405 8532.
was previously understood to be a single diagnosis with standard-
ized treatments for all patients; however, asthma is now accepted
to be a heterogeneous, multifactorial disorder with a variety of
genetic and environmental factors where targeted therapies result
in improved asthma control.
The Global Initiative for Asthma (GINA) has recognized demo-
graphic, clinical, and pathophysiological characteristics that are
clustered into distinct asthma phenotypes: allergic asthma, non-
allergic asthma, late-onset asthma, asthma with fixed airflow lim-
itation, and asthma with obesity [2]. However, utility of pheno-
types is limited as these phenotypes are grouped by observable
characteristics with no connection to the underlying disease
process.
The PRACTALL consensus report by experts from the European
Academy of Allergy and Clinical Immunology and the American
Academy of Allergy, Asthma & Immunology in 2011 proposed that
in addition to phenotypes, asthma should be grouped by endotypes

https://doi.org/10.1016/j.prrv.2019.08.002
1526-0542/Ó 2019 Elsevier Ltd. All rights reserved.

Table 1
Risk factors, pathophysiology, and biomarkers used to diagnose the following asthma endotypes: allergic asthma, asthma-predictive indices (API)-positive preschool wheezer,
infection-induced asthma, viral-exacerbated asthma, allergic bronchopulmonary mycosis (ABPM), aspirin-sensitive asthma, airflow obstruction caused by obesity, premenstrual
asthma, neutrophilic asthma, elite-athlete asthma, cross-country skiers’ asthma, steroid-insensitive eosinophilic asthma, late-onset hypereosinophilic asthma, and severe steroid-
dependent asthma. Early-onset eosinophilic asthma and preschooler with episodic viral wheeze are pediatric subendotypes of allergic asthma and infection-induced asthma,
respectively, while exercise-induced asthma is a subendotype of elite-athlete asthma.
Asthma endotype
Allergic asthma
Early-onset eosinophilic asthma
API-positive preschool wheezer
Infection-induced asthma
Preschooler with episodic viral wheeze
Viral-exacerbated asthma
ABPM
Aspirin-sensitive asthma
Airflow obstruction caused by obesity
Premenstrual asthma
Neutrophilic asthma
Elite-athlete asthma
Exercise-induced asthma
Cross-country skiers’ asthma
Steroid-insensitive eosinophilic asthma
Late-onset hypereosinophilic asthma
Severe steroid-dependent asthma
M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127 119
Risk factors Pathophysiology Biomarkers
Environmental allergen sensitivity Th2 response Eosinophils, IgE, periostin, FeNO,
Environmental allergen sensitivity; onset LTE4
in childhood; no systemic eosinophilic
manifestations
Environmental allergen sensitivity; Eosinophils, IgE, LTE4
positive API score based on history of
eczema, allergic rhinitis, wheezing
episodes per year, eosinophilia, wheezing
apart from colds, and family history of
asthma; many different
bronchoconstriction triggers; onset in
childhood
Tobacco smoke exposure, prematurity, Th1 and Th2 response; viruses Neutrophils, LTE4
prior intubation, and recurrent viral also cause direct damage to
infections; non-allergic; typically only airway epithelium which allow
have bronchoconstriction during viral allergen penetration into
illness subepithelial tissues
Viral infection; can have Eosinophils, neutrophils, IgE,
bronchoconstriction apart from viral periostin, FeNO, LTE4
illnesses
Fungal airway colonization typically by Th2 response; fungi release toxic Eosinophils, IgE, FeNO
Aspergillus fumigatus or Candida albicans; proteases to pulmonary
fungi hypersensitivity demonstrated by epithelium that can progress to
elevated specific IgE or positive skin test; bronchiectasis and fixed airflow
patients usually also have pulmonary obstruction if not treated
opacities and peripheral eosinophilia
Aspirin and nonsteroidal anti- Th2 response; overproduction of Eosinophils, periostin, FeNO,
inflammatory drug hypersensitivity leukotrienes LTE4
demonstrated by challenge; patients with
aspirin-exacerbated respiratory disease
also have chronic rhinosinusitis with
recurrent nasal polyps
Obesity, gastroesophageal reflux disease, Th2 response; systemic Unknown
and sleep disordered breathing inflammation from
proinflammatory circulating
cytokines, increased oxidative
stress, and increased leptin
Menstruation triggers Th2 response; sex hormone Eosinophils, FeNO
bronchoconstriction in females surge during premenstrual
phase stimulates exaggerated
Th2 response
Tobacco smoke and diesel exhaust particle Th17 response Neutrophils
exposure
Elite-level exercise and environmental Th2 response; airway Neutrophils
exposures such as chlorine in swimming dehydration from increased
and ultrafine particles in ice skating; fixed ventilation causes increased
bronchoconstriction airway fluid osmolarity and
Amateur-level exercise; reversible airway epithelial damage
bronchoconstriction
Elite-level exercise and cold air exposure; Th2 response; airway Neutrophils
fixed bronchoconstriction dehydration from cold air causes
increased airway fluid
osmolarity
Non-allergic; glucocorticoid receptor Mutations cause increased p38 Eosinophils, FeNO
mutations causing steroid resistance mitogen-activated protein
kinase activity which
phosphorylates the
glucocorticoid receptor and
causes decreased binding of
steroid
Non-allergic; onset in adulthood; Eosinophils directly release Eosinophils, FeNO
systemic eosinophilic manifestations mediators to damage airway
endothelium
Multi-factorial; possibly related to asthma Likely a combination of Th1, Th2, Unknown
genetic mutations in ADAM33, PHF11, and Th17 responses
DPP10, GPRA, or SPINK5
120 M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127
(Table 1) [3]. Asthma endotypes overlap with many asthma pheno-
types but are divergent in the underlying biological mechanism.
These asthma endotypes describe the underlying immunology.
Characterizing asthmatics by endotype can optimize management
and drive personalized therapy targeting specific immunological
mechanisms of underlying disease [4].
This review details the role of pathophysiology in diagnosis, the
utility of biomarkers in clinical practice, and emerging biologic and
traditional treatments for the various asthma endotypes. Under-
standing the immunology of asthma will allow physicians to diag-
nose asthma by endotype and have more targeted and effective
treatment strategies to better control their patients’ asthma.
PATHOPHYSIOLOGY
Allergens, infections, obesity, hormones, tobacco smoke, exer-
cise, cold air, genetic mutations, and systemic eosinophilia are
among known factors that induce chronic airway inflammation
leading to airway obstruction and hyperresponsiveness. The
immunopathophysiology of asthma involves the activation of both
the innate and adaptive immune systems to stimulate chronic air-
way inflammation. Chronic airway inflammation subsequently
causes airway oedema, mucus hypersecretion, mucus plugging,
and airway remodeling. The process of airway remodeling is driven
by subepithelial fibrosis, thickening of sub-basement membrane,
increased airway smooth muscle mass, angiogenesis, and mucous
gland hyperplasia – which result in permanent structural changes.
The pathophysiology of how these known factors induce perma-
nent structural changes in the various asthma endotypes is
through a combination of T helper (Th) 1, 2, and 17 responses in
addition to underlying genetic predisposition (Fig. 1).
Th1 response
The Th1 response is typically activated in infections, particu-
larly viruses. Viruses upregulate interferon-c and interleukin (IL)
27, which aid in eliminating the pathogen but also are involved
in airway inflammation.
Th2 response
Dendritic cells in the airway present inhaled allergens to naïve
T-cells, activating the production of Th2 cells. Th2 cells release Th2
cytokines including: IL-4, IL-5, IL-9, and IL-13. IL-4, IL-9, and IL-13
stimulate B cells to release IgE. IgE then instigates mast cell
degranulation and mediator release (histamine and leukotrienes)
causing bronchoconstriction. These mechanisms are perpetuated
by cytokines such as IL-25, IL-33, and thymic stromal lymphopoi-
etin (TSLP). IL-25 induces expression of IL-4, IL-5, IL-9, and IL-13,
while IL-33 activates dendritic cells to produce IL-5 and IL-13. IL-
5 is important for maintaining eosinophils, while IL-9 and IL-13
contribute to mucous production.
Th17 response
Th17 cells produce both IL-17 and IL-22, which induce asthma
airway remodeling. IL-17 promotes neutrophilic airway infiltration
and induces the airway epithelial to mesenchymal morphological
transition, while IL-22 increases smooth muscle mass.
Genetic predisposition
Asthma is well known to run in families; however, the exact
genetic predisposition for asthma is complex. There are some
genes know to be associated with asthma: ADAM33, PHF11,
DPP10, GPRA, and SPINK5 [5]. ADAM33 is involved with airway
remodeling, independent of inflammation [6]. PHF11 has been
implicated in maintaining epithelial structural integrity [7], while
GPRA has an unknown role in the airway epithelium [8]. There is
also a genetic predisposition for allergic clusters. For instance,
DPP10 is a genetic biomarker for AERD [9], while SPINK5 polymor-
phisms are associated with both asthma and atopic dermatitis [10].
BIOMARKERS
Traditional asthma biomarkers include eosinophils, neutrophils,
IgE, periostin, fraction of exhaled nitric oxide (FeNO), and leuko-
trienes. While there are many other biomarkers being studied in
asthma – such as cytokines, dipeptidyl peptidase-4, and volatile
organic compounds – there is limited data for the utility of using
these biomarkers in clinical practice. Evaluating biomarkers in
patients with asthma can aid in endotype diagnosis (Table 1); how-
ever, biomarker-directed management is still limited and currently
only useful in select asthma endotypes.
Eosinophils
Serum and sputum eosinophils can be used to diagnose eosino-
philic asthma and can be elevated in both allergic and non-allergic
asthma. Though sputum eosinophilia is more accurate, serum
eosinophilia can service as a surrogate marker of sputum eosino-
philia [11].
A meta-analysis in 2010 concluded that sputum eosinophil
count can be used to guide therapy in asthmatics [12]. In particular,
serum eosinophilia can be used to monitor biochemical response to
anti-IL-5 therapy. However, serum eosinophilia cannot be used to
monitor response to dupilumab (anti IL4R) therapy as the eosino-
phil count artificially increases with dupilumab since IL-4 and IL-
13 promote vascular cell adhesion proteins on eosinophils.
For children with asthma, peripheral eosinophilia is associated
with more frequent asthma exacerbations [13]. Of all the biomark-
ers for asthma, serum eosinophil count has the most meaningful
data for asthma endotyping.
Neutrophils
Whereas eosinophils are typically elevated in the Th2 asthma
endotypes, the Th17 endotype predominates in neutrophilic
asthma where there are increased serum and sputum neutrophils.
However, some patients with neutrophilic asthma do not have ele-
vated peripheral neutrophilia, though are still suspected to have
neutrophilic asthma in the absence of peripheral eosinophilia.
IgE
Serum IgE levels and allergic sensitization are well known to be
elevated in all forms of allergic asthma [14]. The Th2 cytokines IL-4
and IL-13 activate class-switch recombination of IgM to produce
elevated levels of IgE. Anti-IgE immunotherapy is effective treat-
ment in patients with allergic asthma, though monitoring serum
IgE levels in evaluating response to therapy is not routinely recom-
mended [15]. IgE also cannot be used to predict asthma disease
severity [16].
Periostin
Periostin is an extracellular matrix protein that is produced by
eosinophils, epithelial cells, and fibroblasts and has a role in Th2-
type allergic disease. IL-4 and IL-13 activate eosinophils to produce
periostin which then provides positive feedback to promote further
 M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127
Fig. 1. Th1 (green), Th2 (orange), and Th17 (blue) underlying pathophysiology for asthma with potential biomarkers (grey).
eosinophil production. IL-4, IL-13, and TGF-b act on fibroblasts and
epithelial cells to produce periostin. Periostin also activates fibrob-
lasts and epithelial cells to produce NF-jB and promote fibrosis,
leading to airway remodeling.
Periostin has been shown to be a biomarker for asthma with
frequent exacerbations [17]. However, periostin’s clinical utility
in children is skewed by normally elevated periostin levels early
in life from bone turnover [18].
FeNO
Measuring exhaled nitric oxide is advantageous over other
biomarkers in that it is easily and noninvasively measured in the
office. In bronchial epithelial cells, nitric oxide is produced by indu-
cible nitric oxide synthase, which is upregulated by IL-4 and IL-13.
Nitric oxide can be beneficial in asthma by stimulating bronchodi-
lation and relaxation of smooth muscle in the airway through cyc-
lic GMP, but it can also be detrimental by increasing mucus
secretion, plasma extravasation, and cellular injury.
FeNO is most commonly used as a marker for allergic asthma
[19]. However, FeNO has also been shown to decrease with omal-
izumab treatment [20] and with adherence to inhaled corticos-
teroids [21]. FeNO might be useful to follow in patients on
dupilumab, as IL-4 and IL-13 promote nitric oxide formation. A
Cochrane review in 2016 concluded that utilizing FeNO levels to
tailor asthma therapy did significantly reduce asthma exacerba-
tions, though there was no significant decrease in hospitalizations
or oral corticosteroid courses [22]. Therefore, the Cochrane review
concluded that FeNO levels should not be universally used to guide
asthma therapy [22]. Another Cochrane review promoted the same
conclusions in the paediatric population [23]. The American Tho-
racic Society has advocated that FeNO is best utilized to identify
Th2-type asthma with eosinophilic airway inflammation [24],
and there is evidence that FeNO can identify controlled asthmatics
who are at risk of progressive loss of lung function [25]. While
FeNO is useful in many different asthma endotypes, FeNO requires
121
cooperation from the patient in order to measure and is therefore
difficult to perform in young or uncooperative patients.
Leukotrienes
Cys-LT is one of the leukotrienes released by intracellular 5-
lipoxygenase within inflammatory cells, such as mast cells. The
production of leukotrienes triggers a Th2 response by the immune
system. Urinary leukotriene E4 (LTE4) has many limitations as col-
lection of a 24-h specimen is logistically difficult, testing is not
widely available, and concurrent administration of leukotriene
receptor antagonists could influence results.
TREATMENTS
Treatment of asthma focuses on rescue and control therapies.
This review will focus on control therapies for asthma (Table 2).
While the GINA has published guidelines for asthma therapy, these
guidelines are generalized for all patients [26]. With a greater
understanding of underlying pathophysiology and biomarkers,
target-directed agents have become available for patients with
severe-persistent asthma. In the upcoming years, step-up therapy
for patients with moderate-persistent asthma will be tailored
according to their asthma endotype.
Corticosteroids
Inhaled corticosteroids are typically the first-line asthma con-
troller medication for all diagnoses of asthma [26]. Systemic corti-
costeroids can be used for acute asthma exacerbations but long-
term treatment with systemic corticosteroids should be avoided
due to potential side effects, especially suppression of the hypotha-
lamic–pituitary–adrenal axis in children [26]. Though the dosage
of inhaled corticosteroids is lower and less likely to be absorbed
systemically, there is some evidence of that there is suppression
of the hypothalamic–pituitary–adrenal axis in children receiving
122 M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127

Table 2
Treatments by asthma endotype.

Asthma endotype Steroid- Leukotriene modifier Other pharmacologic treatments

sensitive responsive
Allergic asthma Yes Yes Allergen immunotherapy, Anti-IgE, Anti-IL-4R,
Early-onset eosinophilic asthma Anti-IL-5
API-positive preschool wheezer Yes Yes Unknown
Infection-induced asthma No No Anti-IgE
Preschooler with episodic viral
wheeze
Viral-exacerbated asthma Partial Partial Anti-IgE
ABPM Yes Partial Anti-IgE
Aspirin-sensitive asthma Yes Yes Aspirin desensitization, Anti-IgE, Anti-IL-5
Airflow obstruction caused by No Yes Unknown
obesity
Premenstrual asthma Partial Yes Oral contraception pills
Neutrophilic asthma No Yes Unknown
Elite-athlete asthma Yes Yes Unknown
Exercise-induced asthma
Cross-country skiers’ asthma No Yes Unknown
Steroid-insensitive eosinophilic No Partial Anti-IL-5
asthma
Late-onset hypereosinophilic Yes Partial Anti-IL-5
asthma
Severe steroid-dependent asthma Yes Partial Anti-IL-5

inhaled corticosteroids [27], and that there is a small reduction in
linear growth velocity [28]. The Canadian Society of Allergy and
Clinical Immunology actually recommends that all paediatric
patients receiving high dose inhaled corticosteroids for at least
6 months are screened for adrenal suppression [29].
Maintenance inhaled corticosteroids decrease baseline airway
inflammation by dampening inflammatory cell infiltration of the
airway tissue, swelling, and mucus production. Corticosteroids
are able to repair epithelial damage by increasing ciliated cells in
the airway, blunting inflammatory mechanisms that damage the
epithelium, and prompting cell–cell adhesion. Therefore, corticos-
teroids are helpful in asthmatic endotypes where the mechanism
is endothelial damage. However, there is conflicting data regarding
whether using higher doses of inhaled corticosteroids for acute
exacerbations is beneficial [30,31].
Corticosteroids help treat the allergic and Th2 components of
asthma exacerbations, though Th1 and Th17 responses are
steroid-resistant. Th17 cells have high levels of BCL-2 proteins,
which are important for regulating cell apoptosis, and protect cells
from glucocorticoid-induced apoptosis.
There are also likely genetic, race, and ethnicity factors that
influence steroid responsiveness. For instance, a cross-sectional
study showed that African Americans on inhaled corticosteroids
have no significant change in the forced expiratory volume in
one second (FEV1) after bronchodilator administration [32]. Addi-
tionally, predicting systemic corticosteroid responsiveness in chil-
dren using clinical phenotypic features has not been successful,
suggesting that molecular endotyping might be more useful in
making these predictions [33]. In fact, there have been identified
single nucleotide polymorphisms (SNPs) that influences inhaled
corticosteroid response in children, likely through a mechanism
of eosinophilic inflammation [34]. These differences in responsive-
ness to inhaled corticosteroids – whether by genetics, race, ethnic-
ity, or asthma endotype – are important for practitioners to take
into account when evaluating a patient’s therapeutic response
and step-up strategy.
Long-acting beta agonists
Long-acting beta agonists (LABA) directly activate beta-
adrenergic receptors to decrease bronchoconstriction through
smooth muscle relaxation of the airways. LABAs can be used for
patients with frequent exacerbations on inhaled corticosteroids
[26]. LABAs should only be used in combination with inhaled cor-
ticosteroids, as there is an increased risk of asthma-related death,
particularly in children, when using LABAs alone [35]. There is no
increased risk of asthma-related event in children or adults using
inhaled corticosteroid with LABA as opposed to inhaled corticos-
teroid alone [36]. While the use of a combined inhaled corticos-
teroid and LABA is known to be effective in asthma, there is a
dearth of evidence regarding individual efficacy in various asthma
endotypes.
Leukotriene modifier
Leukotriene modifiers are competitive antagonists of Cys-LT,
and blocking Cys-LT can decrease inflammation and the Th2
response. Leukotriene modifiers are less effective alone than with
inhaled corticosteroids for patients with mild to moderate asthma
[26]. Leukotriene modifiers are most effective in preventing Th2
and Th17 pathways for asthma and are ineffective in Th1 path-
ways. Additionally, leukotriene modifiers are effective in those
who smoke or have smoke exposure [37], and in those asthmatics
with small airway disease [38].
Theophyllines
Theophylline is another option recommended by the GINA for
add-on asthma therapy in adults [26]. Theophylline is a methy-
lated xanthine derivative that is a competitive nonselective phos-
phodiesterase inhibitor and nonselective adenosine receptor
antagonist. Molecularly, this causes bronchodilation of the airway
smooth muscle. Theophylline also decreases IL-8 secretion, thus
decreasing neutrophil and other inflammatory marker recruit-
ment, to have anti-inflammatory effects. Theophylline is typically
reserved for patients who do not respond to other add-on thera-
pies, often due to concern regarding its low therapeutic index,
though it is safe at low doses. However, its low cost makes theo-
phylline a potential option for asthma particularly in low-income
and middle-income countries.
 M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127
Long-acting muscarinic agents
Long-acting muscarinic agents (LAMAs) are recommended by
GINA as potential add-on therapy after inhaled corticosteroids,
LABA, and leukotriene modifiers have been trialed [26]. LAMAs
alleviate bronchoconstriction by blocking acetylcholine. Acetyl-
choline is released by cholinergic nerves and stimulates bron-
choconstriction. LAMAs are well known to be effective treatment
in chronic obstruction pulmonary disease (COPD), and could be
helpful in COPD/asthma overlap syndrome. There could be a role
for LAMAs in neutrophilic asthma, as this is also triggered by
tobacco smoke, though there has not been any confirmatory
research on effectiveness of LAMAs in different asthma endotypes.
Macrolide antibiotics
The macrolide antibiotic azithromycin is typically used to inhi-
bit bacterial protein synthesis. However, azithromycin assists in
decreasing inflammation in asthma through bronchial reepithe-
lization. The AMAZES trial showed that azithromycin could
decrease asthma exacerbations in adults with uncontrolled asthma
on inhaled corticosteroid and LABA therapy [39]. There is also data
based on subgroup analyses in a Cochrane Review that macrolides
might be potentially beneficial in patients with non-eosinophilic
asthma [40]. However, data is still limited and there are significant
concerns regarding chronic antibiotic use in asthmatics.
Vitamin D
Vitamin D likely influences asthma, though its utility as a treat-
ment agent is not well established. Vitamin D levels have a nega-
tive correlation with Th2 type cytokines, and IL-5, IL-9, and IL-13
have been shown to decrease after vitamin D supplementation in
patients with asthma [41]. This suggests that vitamin D supple-
mentation might decrease the allergic component of asthma and
could alleviate symptoms for those with allergic asthma. A
Cochrane Review showed that in children and adults with asthma,
vitamin D can reduce the risk of asthma exacerbation [42]. While
more trials are needed to elucidate how baseline vitamin D values
and supplementation can be used to help asthmatics, there are
many other well-known positive effects of vitamin D supplementa-
tion and insuring an asthmatic patient has adequate vitamin D
stores is a low-cost and low-risk adjuvant treatment.
Allergen immunotherapy
Immunotherapy can be administered either by subcutaneous
immunotherapy (SCIT) or sublingual immunotherapy (SLIT) for
those with known sensitization to allergens. Allergen immunother-
apy can decrease long-term asthma controller medication use and
improve FEV1 [43].
The overall mechanism of allergen immunotherapy is that the
treatment shifts the immune response from a Th2 to a Th1 process.
When an allergen is initially exposed to the body, epithelial cells
activate dendritic cells, which present the allergen antigen to naïve
T cells to cause an IgE-mediated Th2 response. However, when
allergens are repeatedly exposed to the mucosa, the dendritic cells
instead produce IL-10, IL-12, and IL-27, which stimulate a Th1
response. T-regulatory cells and B-regulatory cells are also acti-
vated by these cytokines, subsequently blocking the Th2 response
directly and producing antibodies to further block the Th2
response. IgG4 also greatly increases during allergen immunother-
apy, possibly due to it down regulating activation of mast cells and
basophils, though its exact function in immune tolerance is
unknown.
123
Allergen immunotherapy should only be given to patients with
confirmed allergic disease, and there are risks of adverse events to
therapy. Systemic allergic reactions occur in approximately 0.1% of
all injection visits [44]. And in fact, a past or present history of
uncontrolled or severe asthma is a significant risk factor for a fatal
reaction to allergen immunotherapy [44]. However, allergen
immunotherapy is the only treatment for asthma that actually
changes the course of asthma, as it is well known to cause
decreased symptoms for years after cessation of therapy [45].
Aspirin desensitization
For patients with aspirin-sensitive asthma, aspirin desensitiza-
tion and continued daily aspirin administration can improve
long-term symptoms of aspirin-exacerbated respiratory disease
and improve quality of life [46]. Sinus surgery to remove nasal
polyps and topical corticosteroids are typically used in addition
to aspirin desensitization for aspirin-sensitive asthma.
Dihydrofolate reductase inhibitor
For severe steroid-dependent asthma, there have been few ther-
apies showing any benefit besides steroids. However, there has
been some promising research showing that methotrexate,
through its anti-inflammatory effects, can reduce the steroid use
in these patients, but this is rarely used as there are significant side
effects to this agent [47].
Hormones
There is evidence to suggest that oral contraception pills pre-
vent premenstrual hormone surges and improve premenstrual
asthma symptoms [48]. This is a viable option for those patients
with premenstrual asthma symptoms who have other medical
indications for hormonal therapy.
Anti-IgE
Omalizumab is a monoclonal antibody administered by subcu-
taneous injection that targets IgE. Omalizumab binds to circulating
IgE and blocks it from binding to IgE receptors on mast cells, result-
ing in a decreased release of inflammatory mediators. Omalizumab
is effective as an add-on treatment in patients with allergic asthma,
elevated IgE levels, and severe-persistent severity [26]. There is
limited data on omalizumab’s effectiveness in non-allergic
patients.
Other targets of IgE, such as quilizumab (NCT01582503) and
ligelizumab (NCTCQGE031B2201) have not been shown as effec-
tive in patients with severe refractory asthma, while lumiliximab
only has preliminary results [49]. However, of all of the emerging
biologic agents for asthma (Table 3), omalizumab has been used
the longest and most widely, so it consequently has the longest
follow-up for its safety and efficacy (Fig. 2).
Anti-IL-4R
Dupilumab is a subcutaneous injection that blocks both IL-4
and IL-13 from binding to IL-4Ra. Dupilumab has been shown to
be effective as add-on therapy in patients with poorly controlled
severe asthma, irrespective of eosinophil counts [50].
Anti-IL-5
Mepolizumab, reslizumab, and benralizumab are all anti-IL-5
therapy. Mepolizumab and reslizumab directly bind to IL-5 and
prevent IL-5 from binding to IL-5Ra on eosinophils, while benral-
124 M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127

Table 3 and are most effective in patients with elevated absolute eosino-
FDA approved biologic treatments for asthma. phil counts [26,51–53].
Drug Dosage Minimum Other approved With multiple options for eosinophilic asthma, practitioners are
approved indications often faced with the challenge of choosing a biologic agent. A net-
age for work meta-analysis comparing benralizumab and reslizumab sug-
asthma
gests that reslizumab may be more efficacious than benralizumab
Omalizumab 75–375 mg SC every 2 or 6 years Chronic in select patients [54]. While logistical factors, such as administra-
4 weeks idiopathic
urticaria
tion route and frequency often influence a provider’s choice, there
Dupilumab 400 mg SC followed by 12 years Atopic are no head-to-head studies to date examining efficacy of the dif-
200 mg SC every other Dermatitis ferent anti-IL-5 therapies or comparing anti-IL-5 therapy to the
week or 600 mg SC other FDA approved biologic treatments for asthma: anti-IgE and
followed by 300 mg SC
anti-IL-4R.
every other week
Mepolizumab 100 mg SC every 4 weeks 12 years Eosinophilic
granulomatosis Anti-IL-1R
with
polyangiitis
Reslizumab 3 mg/kg IV every 4 weeks 18 years N/A
Anakinra binds to the IL-1 type 1 receptor to prevent IL-1a and
Benralizumab 30 mg SC every 4 weeks 12 years N/A IL-1b from binding to their receptor. In neutrophilic asthma, IL-1b
for first 3 doses followed supports Th17 differentiation. Initial studies have shown anakinra
by 30 mg SC every 8 weeks to be effective in reducing neutrophilic airway inflammation [55].

izumab binds directly to IL-5Ra to block IL-5 from binding to its
receptor. While IL-5 typically stimulates terminal differentiation
of eosinophils in the bone marrow, anti-IL-5 targets eosinophil
and basophils for apoptosis by antibody-dependent cell-mediated
cytotoxicity. Mepolizumab, benralizumab, and reslizumab are rec-
ommended as add-on treatment for severe eosinophilic asthma,
Anti-IL-13
Lebrikizumab and tralokinumab block IL-13, a Th2 cytokine.
However, both lebrikizumab (NCT01867125, NCT01868061) and
tralokinumab (NCT02281357, NCT02194699, NCT02161757) have
not been shown to significantly decrease exacerbation rates in
asthmatics.

Fig. 2. All biologic treatments for asthma that are currently FDA approved or in development. Solid line is research completed and dotted line is research underway. Arrows
indicate studies showed favorable results, while circles indicate that the studies either showed unfavorable results or were terminated.
 M.D. Gans, T. Gavrilova / Paediatric Respiratory Reviews 36 (2020) 118–127
Anti-IL-17
There is currently no approved biologic agent targeting neu-
trophilic asthma, which is driven by a predominant Th17 response.
Secukinumab, an antibody against IL-17A, (NCT01478360) has not
been shown to significantly decrease asthma symptoms, while bro-
dalumab, an antibody against IL-17R, (NCT01199289) has only had
moderate success.
Anti-IL-25
ABM125 has been hypothesized as a treatment for asthma by
targeting IL-25, though there have only been mouse studies to date
[56].
Anti-IL-33
ANB020, which targets IL-33, has also been proposed as a
potential asthma treatment, though only mouse studies have been
performed thus far [57].
Anti-TSLP
Tezepelumab is an anti-TSLP antibody that binds to TSLP and
prevents it from binding to its receptor. Initial studies have been
promising (NCT02054130), showing decreased asthma
exacerbations.
CRTh2 antagonist
CRTh2 is a prostaglandin receptor that perpetuates chemotaxis
of Th2 cells and anti-CRTh2 is available as a daily oral medication.
While clinical trials have not yet shown effectiveness for AZD1981
in treating asthma (NCT01197794), there has been some efficacy
for fevipiprant (NCT01437735).
Bronchial thermoplasty
The FDA approved bronchial thermoplasty in 2010 for patients
with severe asthma. Bronchial thermoplasty is a minimally inva-
sive outpatient procedure where thermal energy is applied to the
airway wall to reduce smooth muscle mass. Research has shown
that bronchial thermoplasty can greatly improve asthma control
up to 5 years post-procedure in severe asthmatics, and results
are similar between allergic and non-allergic patients [58]. Histo-
logically, there is no evidence of scarring post-procedure [59].
There is, however, a lack of data on the efficacy of bronchial ther-
moplasty in different asthma endotypes. There are also potential
short and long-term adverse effects from bronchial thermoplasty.
Immediately after the procedure, patients can have shortness of
breath and lobe collapse. The long-term adverse effects beyond
5 years post-bronchial thermoplasty are largely unknown.
CONCLUSIONS
Asthma is a common heterogeneous disease with complex
underlying pathophysiology. Understanding the immunology of
this disease can greatly aid in personalized, specific, directed ther-
apy for all patients suffering from asthma. Additionally, the knowl-
edge of a patient’s endotype can help to determine the patient’s
asthma prognosis and in counseling regarding prevention strate-
gies. However, there are limitations to asthma endotyping. Not
all patients perfectly fit into a described endotype and many
patients likely have underlying immunology overlapping several
125
described endotypes. This review demonstrates the importance
of the shift in the practice of asthma from a catchall diagnosis with
standardized treatments to the classification of asthma endotypes
with targeted therapy. While all of the tools needed for asthma
endotyping are not yet widely available to the common practi-
tioner, practitioners can attempt to endotype patients with the
information currently known. Endotyping is the future of asthma.
DIRECTIONS FOR FUTURE RESEARCH
 This article summarizes the research to date on asthma endo-
types but there is much to discover.
 Genome-wide association studies will help identify genetic
variants associated with underlying asthma pathophysiology.
 There are also many clinical trials underway to evaluate optimal
therapies for various asthma endotypes.
 In the upcoming years, we can expect an increase in safety and
clinical efficacy data for emerging biologic therapies for asthma.
ACKNOWLEDGEMENTS
None.
FUNDING SOURCES
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Practice points
 Asthma is caused by an interplay of Th1, Th2, and Th17
immunologic mechanisms in addition to a genetic
predisposition.
 Eosinophils, neutrophils, IgE, periostin, FeNO, and leuko-
trienes are biomarkers that can be used in clinical practice
to guide selection of treatment and track response to
treatment.
 For severe persistent asthmatics, there is a range of differ-
ent treatments available to step-up therapy.
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