Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Moving toward consensus on diagnosis and

management of severe asthma in children

Désirée Larenas-Linnemann, Antonio Nieto, Oscar Palomares, Paulo Márcio

Pitrez & Gherson Cukier

To cite this article: Désirée Larenas-Linnemann, Antonio Nieto, Oscar Palomares, Paulo
Márcio Pitrez & Gherson Cukier (2017): Moving toward consensus on diagnosis and
management of severe asthma in children, Current Medical Research and Opinion, DOI:
10.1080/03007995.2017.1400961

To link to this article: http://dx.doi.org/10.1080/03007995.2017.1400961

Accepted author version posted online: 03

Nov 2017.

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 Moving toward consensus on diagnosis and management of severe asthma in children

Désirée Larenas-Linnemann1, Antonio Nieto2, Oscar Palomares3, Paulo Márcio Pitrez4, Gherson Cukier5
1
Investigational Unit, Hospital Medica Sur, Mexico City, Mexico
2
Pediatric Pulmonology and Allergy Unit, Children's Hospital La Fe, Instituto de Investigacion La Fe,
Valencia, Spain.
3
Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of
Madrid, Avda. Complutense s/n. Madrid 28040 Spain
4
School of Medicine, Institute of Biomedical Research, Pontifícia Universidade Católica do Rio Grande do
Sul (PUCRS)] Rua Cel. Corte Real, 386/801, CEP: 90.630-080, Porto Alegre/RS, Brazil

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5
Pediatric Pulmonology, Hospital Materno Infantil José Domingo de Obaldía, Hospital Chiriquí, David –

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Panamá

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Corresponding author
Désirée Larenas-Linnemann
Postal address: Investigational Unit, Hospital Medica Sur, Mexico City, Mexico

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Email: marlar1@prodigy.net.mx

Transparency statement an
Declaration of funding
This work was funded by Novartis Pharma AG, Basel, Switzerland.
M
Declaration of financial/other relationships
DLL has received honoraria as a speaker or as coordinator of the safety board of clinical trials, support
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for investigation and/or travel grants from: AstraZeneca, Boehringer Ingelheim, MSD, Novartis,
Grunenthal, Meda, Sanofi, UCB, Pfizer, TEVA, GSK, Chiesi, Amstrong, Siegfried and DBV Technologies.
e

AN has served on advisory boards, speaker panels, or received travel reimbursement from AstraZeneca,
Boehringer-Ingelheim, Merck (Schering-Plough), Novartis. He has conducted multicenter clinical
pt

research trials for approximately ten pharmaceutical companies. He has received research, consulting,
and lecturing fees from AstraZeneca, Merck, Forest Laboratories, Novartis, Schering Plough, Menarini.
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OP has received research grants from Inmunotek SL; payment for lectures from Inmunotek SL,
Stallergenes, Allergy Therapeutics, AstraZeneca and Novartis, and has participated in advisory boards
from Novartis and Sanofi Genzyme. PP has received research, consulting, and lecturing fees from
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Novartis, Vifor Pharma and Boehringer Ingelheim. GC has served on advisory boards, and speaker
panels, for AstraZeneca (Pearl Pharma), Novartis, and has conducted multicenter clinical research trials
for approximately two pharmaceutical companies. CMRO peer reviewers on this manuscript have no
relevant financial or other relationships to disclose.

Author contributions
All authors were involved in the conception and design, or analysis and interpretation of the data; the
drafting of the manuscript, and revising it critically for intellectual content. All authors approved the
final approval of the version to be published. All authors agree to be accountable for all aspects of this
work.
 Acknowledgments
The authors thank Praveen Kaul, PhD and Rahul Lad, PhD of Novartis for providing medical writing
support, which was funded by Novartis Pharma AG in accordance with Good Publication Practice (GPP3)
guidelines.

Abstract

Children with severe asthma continue to experience symptoms despite long-term treatment with high
doses of corticosteroids. Moreover, the heterogeneous nature of asthma and the presence of several
phenotypes has limited our ability to develop an optimized management strategy for these patients.
Adequate management of severe asthma in children necessitates a detailed understanding of what

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makes asthma difficult to control, knowledge of the causal factors, review of diagnosis for accurate

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identification of pediatric patients with severe asthma, and a precise definition of the phenotypes to be
able to better target the therapy. Advancement in all these aspects is likely to improve childhood

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asthma treatment in the future. Although our understanding of severe pediatric asthma has grown in
recent years, there remains a lack of consensus and clarity around critical aspects of this condition. This
review attempts to present a harmonized view on the definition of severe asthma in the pediatric age

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group, identification of phenotypes and diagnosis, the inflammatory cascade, pharmacological and non-
pharmacological treatment strategies, considerations for follow-up and referral to specialists, and
disease prevention strategies. an
Keywords: severe childhood asthma, diagnosis, disease management, consensus
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 Definition: Severe asthma in pediatric age group
Summary

Severe childhood asthma is associated with distinct phenotypes and characterized by sustained
symptoms despite treatment with high-dose corticosteroids that can impact child growth.
Additionally, asthma severity has been shown to be correlated with burden on healthcare system.
The first step towards effectively treating any condition is defining it clearly. However, there has
been a lack of consensus on definition of severe pediatric asthma. Through this section we attempt
to reach a consensus on which patients e.g. based on their level of symptom control, treatment,
exacerbation history or adherence to treatment, etc. should be categorized as severe pediatric
asthma, to accordingly install an effective management strategy.

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Asthma should be suspected in any child presenting with at least two of the four classical symptoms of

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asthma (cough, shortness of breath, wheezing, and chest tightness), fluctuating over time in
presentation and severity. Demonstrating a reversible airflow obstruction with pre-post bronchodilator

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lung function testing, or a trial of corticosteroids, bronchial hyper-responsiveness on exercise or
methacholine challenge tests could confirm the diagnosis of asthma. Asthma in childhood has been
known to be strongly associated with allergies 1, and in the majority of pediatric patients, it can be

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controlled with low- to medium-dose inhaled corticosteroids (ICSs). However, few children require
administration of high-dose ICSs or systemic corticosteroids (SCSs) to control their symptoms. This small
group of pediatric patients represents approximately 5% of asthma cases 2 and is believed to have
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severe asthma.

Although there is a consensus that asthma, in both adults and children, is a complex and heterogeneous
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disorder, there are some additional treatment challenges in children, as high-dose ICSs can interfere
with growth, and several add-on medications have not yet been approved in this age group. In spite of
this, the definitions available for severe asthma do not differentiate the condition between the adult
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and the pediatric populations or include crucial aspects related to asthma in children, such as its impact
on socialization, school performance, family life, etc. 1. Moreover, there is a general lack of agreement
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on the definition of “severe asthma” in children 3, which presents a unmet need to appropriately
identify the right patients in order to personalize treatment to obtain maximum benefits 4. Table 1
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summarizes the differences between adult and pediatric asthma.

Severe asthma, in addition to being heterogeneous, is also known to be associated with several distinct
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phenotypes. Hence, not all forms of the disease respond similarly to the available therapies 5. Genome-
wide association studies have been used to understand the pathogenesis of asthma by searching for
asthma susceptibility genes, such as the encoding cadherin-related family member 3 (CDHR3), which
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was identified as a susceptibility locus for early childhood asthma with severe exacerbations 6. However,
the ability to target a therapy to patients who will benefit most from it is largely dependent on how
accurately the condition can be defined first. Most of the current guidelines are very descriptive and
include details on symptoms, disease triggers and reversibility, and the underlying mechanism, with
information on specific cell types that may be involved. However, the link between inflammation,
bronchial hyper-responsiveness, and symptoms is not clearly defined. The International Collaboration in
Asthma, Allergy and Immunology (iCAALL) proposed an International Consensus (ICON) statement on
pediatric asthma that defines asthma as a chronic inflammatory disorder associated with variable
airflow obstruction and bronchial hyper-responsiveness with recurrent episodes of wheezing, cough,
shortness of breath, and chest tightness 1.Some of the characteristic abnormalities seen in asthma are
known to be due to bronchial hyper-responsiveness, which is known to play an important role in the
pathophysiology of asthma 7. Bronchial hyper-responsiveness is a common feature of childhood asthma
 and is associated with chronic inflammation of the airways involving narrowing of airways in response to
stimuli 8 that may begin as early as infancy 9. Compared to infants with higher lung function, children
born with reduced lung function at birth have been shown to be at a greater risk of current asthma and
severe airway hyper-responsiveness at 10 years of age 10 and increased airway obstruction on lung
function testing at 22 years 11.
Exercise-induced asthma is also common amongst children, but it often goes unrecognized since
children do not always report their symptoms. Approximately 8%–10% of healthy school-aged children
and 35% of the children with asthma are reported to have exercise-induced asthma 12. It is very
important in the diagnostic work-up to clearly distinguish exercise-induced asthma from other causes of
dyspnea. Exercise testing provides a good measure of indirect bronchial responsiveness and a post-
exercise reduction of ≥12% FEV1 predicted in children, and >10% decrease in FEV1 in adults is generally
taken as a sign of exercise-induced bronchoconstriction 8, 13.

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Most of the available guidelines give special consideration to severe asthma. As per the international

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European Respiratory Society (ERS)/American Thoracic Society (ATS) clinical recommendations, patients
aged 6 years are classified as having severe asthma if they required treatment with a combination of a

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high-dose ICS and another controller medication during the previous year, or may need SCS for at least
half of the previous year to prevent their asthma from becoming uncontrolled, or asthma which remains
uncontrolled despite therapy 14. The ERS/ATS clinical recommendations further define uncontrolled

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asthma as having at least one of the following 14:
(i) poor symptom control: ACQ consistently >1.5, ACT <20
(ii) frequent severe exacerbations: 2 bursts of SCSs (>3 days each) in the previous year
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(iii) serious exacerbations: 1 hospitalization, intensive care unit (ICU) stay, or mechanical ventilation
in the previous year
(iv) airflow limitation: Forced expiratory volume in 1 second (FEV1) <80% predicted after appropriate
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bronchodilator withhold
Further, the cut-off points for high dose have been described for various ICSs in relation to patient age
(6-12 years and >12 years) 14. Children diagnosed with severe asthma may either be difficult to treat
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(i.e., with poor control due to incorrect diagnosis or comorbidities or poor treatment adherence) or may
be resistant to therapy (i.e., difficult to control despite management of aforementioned factors) 15. Both
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conditions are considered as severe asthma.

The definition proposed by the ERS/ATS task force has also been adopted by the Severe Asthma
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Research Program (SARP) and highlights that the concepts of asthma severity (intrinsic intensity of the
symptoms) and control (extent to which the symptoms are suppressed by therapy) are related but
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should not be used interchangeably. It also distinguishes asthma that is difficult to treat from asthma
that is resistant to high-dose therapy 16. Difficult-to-treat asthma has partial or poor response to
treatment and includes factors other than asthma e.g. comorbid conditions, poor medication delivery,
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etc. 16. Treatment-resistant severe asthma may either show partial or poor control despite high-dose
corticosteroid based treatments, or only remains well-controlled with the highest level of recommended
treatment 17. Effective management of severe asthma therefore necessitates clearly establishing the
difference between asthma that is resistant to treatment and difficult to treat, while also assessing
comorbidities, such as atopic dermatitis, food allergy, etc. 17.
Despite the availability of diagnostic tools and effective treatment options, some pediatric patients may
remain uncontrolled due to poor adherence to their treatment. In full recognition of the influence of
adherence on asthma control, non-adherent patients should also be considered as having severe
asthma, since it affects their quality of life and places them at higher risk of exacerbations 18.
As a leading chronic illness in children, severe asthma, places significant burden on affected children,
their caregivers and healthcare resource utilization 19. Moreover, asthma morbidity and mortality
remain high among children 20, which add to further complications. Recurrent asthma exacerbations
 during childhood or adolescence may lead to lower maximally attained lung function in early adult life
and also place them at risk of developing COPD 21. A longitudinal follow-up study showed that children
with severe asthma are at an increased risk of developing adult COPD by the age of 50 years 22. Patients
with severe asthma from a large European cohort have been shown to experience more symptoms,
more exacerbations, and higher levels of anxiety and depression compared to those with mild asthma 23.
Additionally, the overall cost of asthma, including individual direct costs, indirect costs, and intangible
quality-of-life costs, are clearly related to severity 24. It is therefore important that the definition of
severe asthma also includes patients who use health resources on a regular basis, or have psychosocial
or environmental factors that impede control 25.

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Patient identification, proper diagnosis, and asthma phenotypes

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Summary
Severe asthma in children is highly heterogeneous and is associated with various phenotypes that

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are distinct from adult phenotypes. A precise definition of each of the distinct phenotypes would
enable identification of patients who are more likely to benefit from a particular treatment. The

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current chapter explores the benefits and challenges associated with clearly defining pediatric
severe asthma phenotypes, how they differ from adult phenotypes, approaches for defining asthma
phenotypes, and the importance of using variables specific to pediatric population to define the
phenotypes. an
Severe asthma in children is recognized to be highly heterogeneous and to be associated with a range of
clinical and inflammatory pheno-endotypes. A phenotype is defined as “the observable and structural
and functional characteristics of an organism determined by its genotype and modulated by its
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environment” 26. The observable nature of phenotypes allows for better targeting of a therapy based on
individual patient phenotypes to improve the treatment outcomes. Asthma phenotypes have been
described based on various factors e.g. triggers (allergic, infectious, etc.), clinical characteristics (fixed
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obstruction, exacerbation prone, late/early onset, etc.), type of inflammation (eosinophilic, eosinophilic,
paucicellular, etc.), and even based on wheeze (early wheeze, transient wheeze persistent wheeze, etc.),
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airway inflammatory mediators (In order to identify factors that make asthma severe and difficult to
control, it is also important to understand how the various phenotypes of severe asthma change over a
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period of time 27 or how these phenotypes could be used to predict the risk of severe asthma 28, 29.
Moreover, the capacity to correctly define asthma phenotypes can be expected to lead to the following:
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(i) increased statistical power for detection of environmental and genetic risk factors 30;
(ii) identification of clinical relevance of phenotypic clusters 31 for improved phenotype-specific
treatment 1, 5 and predicting response to treatment 32, e.g., use of incorporating symptoms, lung
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function, and inflammation into a multi-domain approach to determine responsiveness to

treatment in pediatric patients with severe asthma 33;
(iii) identification of symptoms and risk factors for severe asthma in children that can change over
time 29
(iv) development of effective management strategies, e.g., by using eosinophilic inflammation as a
means for titrating corticosteroid therapy 34, and
(v) increased understanding of the underlying pathophysiology that leads to a particular
phenotype, e.g., children with persistently high tumor necrosis factor (TNF)- expression have
poor asthma control despite aggressive corticosteroid treatment 35, children with severe
therapy-resistant asthma are characterized by increased type 2 innate lymphoid cells (ILC2) 34
and interleukin (IL)-33 36 expression or variable eosinophil counts without detectable T helper 2
 (Th2) cytokines 37, and children with insensitivity to corticosteroids because of passive exposure
to tobacco smoke 38.
The last point illustrates the crucial importance of identifying the pathophysiological mechanisms
leading to a particular phenotype, i.e., identification of the “endotype”. Endotype refers to a “subtype of
a condition which is defined by a distinct functional and pathophysiological mechanism” 39. An endotype
is distinct from a phenotype, which is an outward manifestation of an individual’s interaction between
the environment and the underlying genetics without any implication of the underlying mechanism.
Understanding of these underlying mechanisms observed in subtypes has facilitated further refinement
with regard to defining phenotypes, or more specifically, pheno-endotypes.
Various approaches have been used for identifying asthma phenotypes 40, e.g., the candidate approach,
which attempts to classify asthma based on a pre-determined feature (clinical, functional, pathological,
prognostic, etc.) 41, and the hypothesis-free approach or the exploratory approach 42-46, which uses

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unsupervised, data-driven approaches without applying pre-specified conditions to the number or

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constitution of phenotypes 40. Some of the phenotypes identified using the candidate approach include
allergic and non-allergic asthma (clinical feature), viral, exercise induced, occupational, etc. (triggers),

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eosinophilic or neutrophilic (pathobiology). Cluster analysis is the hypothesis-free technique of
segregating phenotypes on the basis of similar characteristics 47. SARP, a multi-centre study involving
children and adults from the US, used hierarchical clustering to identify four clusters: ‘late-onset

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symptomatic asthma’, ‘early-onset atopic asthma and normal lung function’, ‘early-onset atopic asthma
with mild airflow limitation and comorbidities’, and ‘early-onset atopic asthma with advanced airflow
limitation’ 42. an
There are, however, difficulties associated with phenotyping of pediatric asthma. The phenotypes of
severe asthma are known to show age-related variation. This suggests that phenotypes in children not
only differ from those of adults but are also known to change more rapidly 48, 49. While an adult with
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severe asthma is more likely to present a persistent pattern, a child on the other hand may exhibit a
pattern that evolves rapidly and frequently, with the severity of asthma being more unstable and the
probability of remission being higher. Moreover, severe exacerbations in children are often triggered by
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viral infections and/or allergen exposure; however, such patients remain asymptomatic between these
episodes 50. Hence, a pediatric patient should not be treated as a “small adult”, and adult phenotypic
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classification should not be extrapolated to children without applying a critical view of the clinical
implications. Additionally, the common features of phenotypes (e.g., based on airway inflammation)
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may not remain stable longitudinally 51 and thus offer limited utility. On the other hand, taking into
account the influence of environment on phenotypic expression, extrapolation of phenotypes obtained
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from different populations should be performed with caution. The identification of regional or even local
phenotypes is advisable.
Future research should therefore attempt to identify asthma phenotypes in children by using variables
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that are specific to pediatric populations and, ideally, considering the population where the physician
develops his/her work. This would help to distinctly separate the adult phenotypes from the pediatric
phenotypes toward reducing asthma burden 28, 52, 53, as well as to unify our understanding of the natural
history and pathophysiology of severe pediatric asthma and eventually to link clinical phenotypes with
the endotypes 29, 54, 55. The criteria for linking a phenotype to an endotype could also be applied to
designs of clinical studies and to target therapies to patients who would be most likely to benefit 56.
 The role of IgE in asthma and the allergic inflammatory cascade
Summary
Immunoglobulin E (IgE) is known to play a key role in the inflammatory response to allergens that
characterizes allergic respiratory conditions like asthma. Various studies have shown a correlation
between severity of asthma and IgE levels, and that reduction in IgE levels is associated with
significant reduction in inflammatory response associated with allergic asthma. The goal of this
chapter is to discuss the underlying cellular and molecular events in the downstream inflammatory
cascade and how these leads to airway remodeling.
Allergic respiratory disorders, including allergic asthma, involve an inflammatory response that is
triggered by degranulation of allergen-specific immunoglobulin E (IgE)-bound mast cells upon binding of

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the causative allergen 57. The production of mediators from the airway epithelium upon environmental

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or inflammatory stimulus leads to further activation and recruitment of inflammatory cells that infiltrate
the lungs (Figure 1). The amplification of this inflammatory response causes bronchoconstriction and

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epithelial damage, which can eventually initiate different pathophysiological processes leading to airway
remodeling 58, 59. Elevated levels of IgE have been shown to be associated more with asthmatic patients
vs. non asthmatic patients 60.

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The sensitization phase of the allergic immune response is characterized by the production of allergen-
specific IgE upon exposure to an allergen for the first time. This involves a Th2 response 58 that starts
with the uptake and processing of the allergen by dendritic cells in the airway epithelium, resulting in
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the presentation of parts of the degraded allergen, allergen peptides, on the surface of the dendritic
cells bound to molecules of the major histocompatibility complex II (MHC-II) 61. Additionally, the allergen
uptake is enhanced by specific IgE bound to dendritic cells to facilitate allergen internalization and
presentation 62. The antigen peptide MHC-II complex is presented to the T-cell receptor, thus initiating
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the sensitization and the ensuing immune response to the allergen 63. Allergen-specific Th2 cells produce
IL-4 and IL-13 that promote IgE class switching at the B-cell level. B-cells in turn produce allergen-specific
IgE, which binds to the high-affinity IgE receptor (FcεRI) on the surface of effector cells such as mast cells
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and basophils. At this stage, the patient does not yet show any clinical symptoms. However, upon re-
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exposure to the sensitized allergen, the immediate early-phase response is mediated by the mast cells
and occurs within the first few minutes of re-exposure to the allergen 64. Cross-linking of allergen to
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FcƐRI-bound IgE on the mast cell surface initiates the degranulation and subsequent release of a variety
of preformed mediators such as histamines, prostaglandin D2, and leukotrienes 64 that lead to a variety
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of changes such as contraction of airway smooth muscle, increased vascular permeability, activation of
neuronal reflexes, or stimulation of mucus secretion, which are responsible for the clinical symptoms
associated with this phase. Mediators released from the mast cell during the early-phase begin to recruit
inflammatory cells to set up the late-phase. In the late-phase, inflammatory mediators promote outflow
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of fluid from the blood vessels into the tissues, causing localized swelling, adhesion, and infiltration of
circulating cells of the immune system (primarily eosinophils, basophils, and Th2 cells) into the tissue.
Over several hours, these cells become activated and release additional inflammatory mediators that
reinforce and propagate the inflammation. Mast cells and Th2 cells release cytokines (IL-4, IL-13, and IL-
5) that stimulate further IgE production and attract additional eosinophils to the site of inflammation
which release more pro-inflammatory mediators, resulting in chronic inflammation,
bronchoconstriction, and tissue damage that initiates the remodeling response.
Repeated airway inflammation may eventually lead to airway remodeling, particularly in severe asthma,
which can lead to obstruction of the airways and poor response to treatment 65. Important factors
responsible for remodeling include long-term exposure to allergens and persistence of inflammation 66,
and recent findings seem to indicate that IgE might also play a central role 67. Cytokines produced during
 the late-phase response and during the chronic inflammatory stage have been associated with airway
remodeling. IL-4 induces synthesis and release of IgE from B cells and is suggested to be a mediator of
airway remodeling by increasing synthesis of α-smooth muscle actin and collagen III 68. IL-13 stimulates
eosinophilic airway inflammation and promotes mucus metaplasia, subepithelial fibrosis, and airway
remodeling 68. Eosinophils also produce and express many fibrogenic factors, particularly transforming
growth factor (TGF)-β1 69. IgE might also directly lead to airway remodeling by penetrating and directly
reaching the basal tissue-forming cells because of the inability of the damaged bronchial epithelium to
act as a barrier in severe asthmatics. Antigen-specific IgE can be produced locally in the bronchial
mucosa. In asthmatics, the bronchial epithelial cells express the low-affinity as well as the high-affinity
receptor for IgE 70. Human airway smooth muscle cells also express both low- and high-affinity IgE
receptors 21. Recent in vitro data suggest that IgE might well play a direct role in airway remodeling by
increasing extracellular matrix and collagen deposition, proliferation, and contraction in human airway

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smooth muscle through mechanisms depending on both high- and low-affinity IgE receptors 71, 72.

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Viral infections have long been recognized as a trigger for exacerbations 73. Viruses have been associated
with 80% of wheezing episodes in school-age children and in 50 – 75% of acute wheezing episodes in

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adults. Viruses most commonly associated with asthma exacerbations are human rhinoviruses (HRV),
influenza, and respiratory syncytial virus 74, 75 (RSV; most common in infants).
However, other viruses may also be triggers. Clinical evidence suggests that allergic sensitization and

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viral infections increase the risk of asthma exacerbations 76. In patients with allergic asthma,
plasmacytoid dendritic cells (pDCs) show diminished production of interferon- (IFN-α) and increased
surface expression of FcεRIα. This suggests that in patients with IgE mediated allergic asthma, there is an
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impaired pDC IFN-α antiviral response 77.
Toll-like receptors (TLRs) are known to play a key role in innate immunity because of their ability to
recognize specific microbial products associated with allergic diseases 78. Cross-linking of FcεRIα in
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response to IgE is associated with decreased expression of TLR7 and TLR9 on pDCs as well as with the
impairment of TLR7- and TLR9-mediated INF-α production by pDCs 79. Inhibition of TLR-mediated
signaling pathways as part of a reduction in the anti-viral response caused by IgE may represent the key
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link that explains how viral infections can lead to exacerbations in patients with asthma.
The initiation of the allergic cascade by IgE under continuous allergen exposure leads to sustained,
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chronic allergic inflammation in the airways of asthmatic patients, with IgE being the central element
that maintains this response. Thus, allergic inflammation is always a consequence of the interaction
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between IgE and its specific allergen. Sometimes it is not possible to identify the cause; however, this
does not mean that it does not exist. This concept is essential to develop effective strategies for the
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management of allergic asthma.

There is increasing evidence to suggest that neutralization of IgE represents an effective treatment
strategy not only for allergic asthma52 but also for other allergic conditions.
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Treatment
Summary
Effective treatment of severe asthma involves avoiding triggers, monitoring and controlling
symptoms, and accordingly designing a treatment strategy. One of the important goals of long-term
treatment of severe asthma is to prevent exacerbations. This chapter discusses the pharmacological
as well as non-pharmacological treatment approaches to achieve the treatment goals.

The long-term goals of asthma management are to achieve symptom control and to minimize the future
risk of exacerbations, fixed airflow limitation, and medication side-effects 8. Typically, three types of
medications are used for the pharmacological treatment of asthma: controller medications, rescue
medications, and add-on therapies.
 Controller medications are used for regular maintenance treatment for reducing airway inflammation,
controlling symptoms, and decreasing both the risk of future exacerbations as well as the decline in lung
function. The initial controller medication for patients, including pediatric patients with asthma, includes
a low-dose inhaled corticosteroid (ICS) 80, 81. The controller medication is stepped up or down for
achieving optimal symptom control while also ensuring that the side-effects are minimized 8. Children
who require high-dose ICSs (Global Initiative for Asthma [GINA] Step 4 treatment) 8 to control their
symptoms are classified as having severe asthma. A combination of a long-acting beta2-agonist (LABA)
with a high-dose ICS is indicated in severe asthma for school children and adolescents, but further
increases in ICS dose have been shown to provide limited benefit 82, 83.
Rescue medications are mainly used as needed for relieving symptoms that could lead to worsening of
asthma symptoms or exacerbations. An important treatment goal is therefore to eliminate the use of
the reliever medication and assess the success of the prescribed controller therapy 8. Short-acting beta-

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agonists are the most frequently used rescue medication, and should be avoided as a regular treatment

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84
.
Add-on therapies should be considered for patients with severe asthma if they have persistent

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symptoms and/or exacerbations despite optimized treatment with high-dose controller medications
(usually a high-dose ICS and a LABA) and treatment of modifiable risk factors. In this group of patients
(12 years of age only) on GINA Step 4 and Step 5 treatment, tiotropium, a long-acting muscarinic

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antagonist, may be used as add-on therapy 8, 85. Other options for children and adolescents that can be
added to a medium- or high-dose ICS, although less efficacious than adding a LABA, include leukotriene
receptor antagonists 86, 87 or low-dose sustained-release theophylline 88. Some patients may remain
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uncontrolled on GINA Step 4 treatment and may subsequently receive other additional add-on
treatments. Omalizumab, an anti-IgE antibody, was the first biologic developed for allergic conditions
and represents an important treatment option for patients with moderate-to-severe or severe allergic
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asthma who remain uncontrolled despite current standard therapies 8. Its clinical efficacy has been well
documented in clinical trials and observational studies, involving children, adolescents and adults 89.
Treatment of children with persistent allergic asthma has shown to result in sustained reduction in free
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IgE levels, steroid sparing effect, improvement in asthma control and quality of life, reduction in
exacerbation frequency and healthcare resource utilization 90. The steroid-sparing effect of omalizumab
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in children with severe asthma represents an important outcome considering the risk factors associated
with the use of corticosteroids 91. Omalizumab is recommended for patients from 6 years onward with
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severe allergic asthma 92, while mepolizumab, an anti-IL-5 antibody, has been recently recommended for
patients aged ≥12 years with severe eosinophilic asthma 26, 93.
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Some non-pharmacological strategies are important since they help improve symptom control, e.g.,
smoking cessation, physical activity, avoidance of allergens and medications that make asthma worse
(e.g., non-steroidal anti-inflammatory drugs [NSAIDs] 94 in patients with asthma associated with aspirin
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intolerance), performing breathing exercises, and maintaining a healthy diet.

The idea of personalized care in patients with severe asthma has been driven by the potential
opportunity to identify asthma phenotypes by searching for biomarkers in order to help identify patients
that would benefit from specific therapies.45 FeNO, peripheral blood eosinophil count, total serum IgE
and specific IgE to food and aeroallergens are some biomarkers that are currently considered as
important factors in the management of asthma patients 27.
 Follow-up and prognostics
Summary
Severity of asthma strongly correlates with morbidity and health care resource utilization.
Additionally, asthma originating in childhood does not always lead to resolution of symptoms by the
time the patient is an adult. This chapter provides an overview of the natural course of asthma,
factors influencing its prognosis, biomarkers and clinical features that characterize severe asthma,
and describes considerations for referral to a specialist.

The degree to which a medication is able to suppress the manifestation and symptoms of the disease is
referred to as the level of control of the condition. Some patients with severe asthma may remain
symptomatic despite treatment with high-dose inhaled corticosteroids (ICSs) and another controller
medication, or systemic corticosteroids (SCSs) for at least half of the previous year to prevent it from

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becoming uncontrolled 14. This has led to growing interest in understanding the natural course of

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asthma, its key markers, and their association with clinical endpoints.
The development and prognosis of severe asthma has been studied in at-risk populations, but

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knowledge of the natural history of asthma in the general population is limited.
Sputum eosinophil counts have been used to guide treatment of severe asthma with Th2-directed
therapies 95, 96. Increased levels of blood eosinophils, probably due to IL-5 levels, have also been shown

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to be associated with a higher risk of exacerbations 95, 96. Increased levels of YKL-40, a chitinase-like
protein, has been observed in children with severe, therapy-resistant asthma compared to healthy
children, and those with controlled asthma following adjustment for genotype (CHI3L1 promoter single
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nucleotide polymorphism, rs4950928) 97. Furthermore, determination of the exhaled fraction of nitric
oxide (FENO) provides a quantitative, non-invasive, simple, and safe method to assess airway
inflammation, to monitor responsiveness to ICS therapy in adults 98, and to predict asthma control status
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in children 99. Although lung function does not correlate strongly with asthma symptoms in adults 100 or
children 101, spirometry has been used to identify patients with low FEV1% predicted, since it is indicative
of the risk of exacerbations, particularly in the pediatric population 102. However, spirometry cannot be
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performed reliably in children until the age of ≥5 years, and it is less useful than in adults 26. Additionally,
many children with uncontrolled asthma have normal lung function between exacerbations 8, 50.
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The Asthma Control Test (ACT) provides an effective way to determine if the symptoms are controlled
103
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, especially in adults. However, in the pediatric population, particularly among those aged <5 years, it
is difficult to define the level of symptom control, and health care providers rely on reports from
caregivers. On the other hand, current available tools for evaluating childhood asthma control are
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almost mere translations of those developed for adults, and do not include essential specific items that
must be considered when assessing pediatric asthma (e.g., school performance, impact of medicines on
daily life, school mobbing because of the disease, and impact of asthma on socialization). Presently,
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there are very few objective and validated measures to assess symptom control in children aged <4
years, although the Childhood ACT, and the caregiver-completed questionnaire Test for Respiratory and
Asthma Control in Kids (TRACK) scores have been used for children aged 4-11 years 104 and children up
to 5 years 105, respectively.
Risk factors for developing asthma in adulthood include presence of difficult-to-treat and concomitant
atopic manifestations in childhood, and should be recognized as markers of prognostic significance,
while the absence of these manifestations is predictive of a very low risk of future asthma 106.
Additionally, asthmatic subjects have a higher risk of mortality, and the prognosis for non-allergic
asthma is worse than that for allergic asthma with regard to the rate of decline in lung function.
During the second decade of life, asthma symptoms often abate, and it may seem that the patient has
mild asthma. Although the severity of asthma symptoms fluctuates with time, the inherited tendency
 toward respiratory symptoms never disappears, and many teenagers who seem to be free of symptoms
do, in fact, have persistent asthma. The more severe the asthma in childhood, the more likely it is that
the disease will persist in adulthood 107, suggesting that a complete list of the characteristics of the
disease in childhood and an evaluation of the potential risk factors associated with an unfavorable
prognosis, such as pulmonary function and bronchial responsiveness as well as markers of airway
inflammation are important.
There is a fundamental need to select appropriate uncontrolled asthma patients for referral to a
specialist. However, this requires that we first properly identify children with severe asthma and then
prioritize them over children with less severe forms of asthma, for referrals to a specialist.
Referral for expert advice should be considered for patients who have been hospitalized for asthma, or
who repeatedly present to an acute care setting despite having a primary care provider 8. As per the
international ERS/ATS clinical recommendations, patients with persistent symptoms or exacerbations

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despite correct inhaler technique and good adherence with Step 4

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treatment and in whom other controller options have been considered should be referred to a specialist
with expertise in management of severe asthma 15. The following types of patients should be considered

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for referral for expert advice: difficult to diagnose patients (those with overlap syndrome), patients with
frequent exacerbations, patients at risk of asthma-related death, and patients with significant
treatment-related side-effects. Children aged 6-11 years should be referred to a specialist when there

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are doubts about asthma diagnosis or when respiratory symptoms do not respond to treatment in
children born prematurely or when there are suspected side-effects of treatment related to growth
delay. Additionally, factors such as regular use of SCSs or controller medication, lack of response to
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optimized conventional treatment, or if the disease threatens the life of the patient or seriously impairs
their quality of life should also be considered for referral to a specialist 108. The definition of severe
asthma may also include patients who justifiably use health resources on a regular basis, or have
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psychosocial or environmental factors that impede control 108.
Evidence suggests that follow-up by a specialist is associated with fewer subsequent emergency
department visits or hospitalizations and better asthma control 109. Comorbidities associated with
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asthma should also be considered while referring the patient to a specialist, e.g., children with food
allergy are at a 4-fold higher risk of having asthma compared with children without food allergy 110 and
e

should be referred to a specialist. While implementing clinical services for the treatment of severe
asthma or difficult-to-treat asthma, various specialties should be included (e.g., pulmonology, allergy,
pt

skilled nurses, and respiratory therapy) to ensure effective patient follow-up.

Factors such as severity of the disease at onset, breast feeding, presence of associated atopic disease,
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and a positive family history of atopic disease in first-degree relatives have been shown to influence
prognosis of asthma. It remains uninfluenced by the age of onset of asthma and by the gender of the
patient. Short-term follow-up of such patients often fails to include patients whose asthma remits and
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subsequently relapses 111.

In some cases, asthma symptoms have been shown to recur after much longer periods of time 112. It is
therefore likely that a considerable number of patients thought to be in complete remission remain
latent asthmatics until the symptoms are triggered again. A higher asthma symptom burden in
childhood, which represents more severe asthma, is a well-known risk factor for the persistence of
asthma in adulthood 113.
Long-term studies are needed to evaluate the effects of any single class of a new anti-asthma agent on
asthma prognosis, e.g. the Prevention of Early Asthma in Kids (PEAK) study showed that natural course
of asthma in children at high risk for subsequent asthma was not modified by two years of treatment
with inhaled corticosteroids 114. Such studies would help elucidate whether it is possible to alter the
natural history of the disease
 Preventing and reducing exacerbations
Summary
Although treatment guidelines for asthma focus on achieving control through therapeutic
intervention and accurate assessment, it is also important to understand strategies that lead to
asthma prevention. This chapter reviews the prevention strategies for childhood asthma and its
exacerbations, e.g. identification of population at risk of developing asthma, avoidance of triggers,
therapeutic options, ensuring adherence to treatment, etc.

Children with severe asthma are known to have a significantly higher treatment burden compared to
those with mild or moderate asthma. Poor control and frequent exacerbations are typical characteristics
of severe pediatric asthma 115. An effective strategy to prevent patients from developing asthma and

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allergy is to identify populations at risk of developing allergic sensitization 116 and adopt protective

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strategies, such as breastfeeding 117 or appropriate microbial stimulus, at early ages 118. Once a patient is
sensitized, he/she should continue to avoid tobacco smoke and adopt appropriate environmental

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control 117, 119, 120. Additionally, allergens to which the patient is sensitized should not only be identified
but a plan should also be formulated to eliminate or reduce further allergen exposure 121. Evidence-
based therapeutic interventions may also be used for preventing worsening of childhood severe asthma.

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As stated previously, IgE might enhance proliferation of airway smooth muscle via interaction with its
high and low affinity receptor 72. Omalizumab is a humanized anti-IgE monoclonal antibody approved for
treatment of adults and adolescents (6 years) with inadequately controlled moderate-to-severe allergic
an
asthma 122. Studies in children aged 6 to <12 years have shown that omalizumab reduces clinically
significant exacerbations and is well tolerated 123, 124. Moreover, two clinical trials have shown
omalizumab might reduce airway remodeling in severe asthmatic patients 125, 126.
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Asthma control shows a strong association with severity of symptoms and extent of airway obstruction,
indicating that respiratory symptoms are worse in those with uncontrolled asthma at baseline 74.
Treating asthma, reducing the exacerbation frequency, and thus preventing development of severe
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asthma is important in children, because presence of severe asthma places them at a higher risk of
developing a progressively reduced lung function, which could evolve into chronic obstructive
e

pulmonary disease (COPD) 127. A multicenter study of US children hospitalized with an asthma
exacerbation identified suboptimal patient management due to non-compliance with recommended
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treatment guidelines as a major cause of lack of control 128, thus highlighting the importance of
prevention-oriented asthma care.
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Consequently, an important aspect of asthma management is enhancing patient adherence to

treatment in order to improve asthma control and prevent exacerbations. A systematic review of the
literature was conducted to study the association between adherence to asthma controller treatment
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and risk of severe asthma exacerbations in children and adults; the findings showed that good
adherence to treatment correlated with a lower risk of severe asthma exacerbations 18. However, a high
degree of heterogeneity across studies with regard to adherence and exacerbation measurements,
designs, and analyses precluded a formal meta-analysis 18. Use of electronic monitoring devices with an
audiovisual reminder function on adherence to treatment has also been explored as a means of
improving the poor adherence linked to poor asthma control. A randomized controlled trial showed that
use of such a device linked to inhalers of school-aged children with asthma significantly enhanced the
median adherence in the intervention group (84%) vs the control group (30%, p<0.0001) 129.
Non-compliance to treatment amongst children should also be considered poorly controlled asthma.
Non-compliance or sub-optimal compliance has been shown to be associated with poor disease control
130
, an increased risk of hospital admission 131, and asthma-related mortality 132. It is also important to
ensure that we are able to detect non-adherence amongst patients, since the physician may otherwise
 escalate the medication which can increase both, the cost and the complexity of the treatment regimen
133
.
Acute exacerbations of asthma, especially in children, represent a major cause for frequent visits to
emergency departments of hospitals 134, 135. Inhaled corticosteroids (ICSs) have been shown to result in a
decrease in the frequency of exacerbations; however, poor understanding about asthma, medication
use, and non-compliance to treatment represent major causes of relapse 136. A cross-sectional study in
asthmatic children identified poor knowledge of caregivers about asthma and improper medication use
to be associated with unnecessary and frequent visits to emergency departments 137. This highlights the
importance of patient and caregiver education programs. It is also important to minimize the exposure
to environmental triggers such as allergens and environmental tobacco smoke. Studies have identified
association between exposure to environmental tobacco smoke and increase in the risk of childhood
asthma 138. A study conducted in Scotland found that adoption of a comprehensive smoke-free

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legislation resulted in an 18.2% reduction in the annual rate of hospital admissions for childhood asthma

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139
. This reduction was apparent among both pre-school and school-age children with asthma 139.
Finally, a meta-analysis of children with allergic rhinitis showed that specific immunotherapy can reduce

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the risk of developing asthma 140, and in those already presenting with allergic asthma, co-treatment
with specific immunotherapy can reduce symptoms and medication use and thus enhance control 141.
Prevention of asthma worsening and exacerbations in children can therefore be managed effectively by

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(i) ensuring that the key treatment goals are adhered to and met, (ii) patients are well informed and stay
treatment compliant, (iii) identifying and avoiding precipitating environmental factors, and (iv) adding
specific immunotherapy to those with allergic asthma. an
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 Table 1. Differences between adult and childhood asthma

Characteristic Pediatric asthma vs. Adult asthma Reference

142
Incidence Highest incidence in pre-school aged children than adults
14, 49
Pattern of Evolves rapidly and frequently, with the severity of asthma being more
asthma unstable and the probability of remission being higher
Generally shows a consistent pattern
143, 144
Gender Children with severe asthma are more likely to be males, whereas adults
are ore likely to be females
143
Glucocorticoid In-vitro tests suggest that children responsiveness to suppressive effects of
sensitivity glucocorticoids than adults
143, 145
Lung function Children with severe asthma are more likely to have less impaired lung

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function than adults. However, despite higher lung function, children with

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severe asthma tend to show greater decline in lung function than adults

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 Figure 1. The allergic immune response
Allergens
Pathogens

IL-25 FcεRI receptor

Epithelial cells
IL-33
TSLP
Dendritic cell
IgE

T cell

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IL-4

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IL-4

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Th17 cell Th2 cell IL-13
B cell Plasma cell
IL-5

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IL-17
IL-22
IL-5
IL-9

IL-4
IL-5
IL-9
an
IL-13
M
Eosinophil Mast cell Basophil
Neutrophil

IL-5 and other Histamine, Leukotrienes IL-13

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inflammatory mediators Prostaglandin D2, IL-4, IL-5,

IL-6, IL-1β, IL-13
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Late Phase Response and Early Phase Response

pt

Airway smooth muscle cells

INFLAMMATION
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Fibrosis and Airway Edema, Mucus hypersecretion,

remodeling Chronic bronchoconstriction, Bronchospasm

Modified with permission from Colodenco et al.146

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