Asthma Management for children .pdf

Nom original: Asthma Management for children.pdfTitre: Asthma Management for ChildrenAuteur: Monica J. Federico MD

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Advances in Pediatrics 63 (2016) 103–126

Asthma Management for
Risk Identification and Prevention
Monica J. Federico, MDa, Heather E. Hoch, MDa,
William C. Anderson III, MDb, Joseph D. Spahn, MDb,
Stanley J. Szefler, MDa,*

Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital
Colorado, 13123 East 16th Avenue, Aurora, CO 80045, USA; bPediatric Allergy & Immunology,
University of Colorado School of Medicine, Children’s Hospital Colorado, 13123 East 16th
Avenue, Aurora, CO 80045, USA


Asthma Early asthma Inhaled corticosteroids Lebrikizumab Mepolizumab
Omalizumab Severe asthma Tiotropium

Key points

Children with frequent wheeze, allergies, parental history of asthma, early
illness, and environmental exposures to tobacco smoke and violence or stress
may be at higher risk to progress to persistent wheeze or asthma.

Although strides have been made in terms of developing predictors of asthma
exacerbations in children, continued research is needed to further refine these

Children with severe asthma are less likely to require chronically administered
oral glucocorticoids, have improved lung function, and require less rescue shortacting beta-agonist therapy compared with children in the recent past.

Disclosure Information: S.J. Szefler has consulted for Aerocrine, Astra Zeneca, Boehringer-Ingelheim, Daiischi
Sankyo, Glaxo Smith Kline, Genentech, Merck, Novartis, and Roche and has received research support from
the National Institutes of Health, the National Heart, Lung, and Blood Institute (HL098075), the National
Institute for Allergy and Infectious Diseases (AI90052), the National Institute for Environmental and Health
Sciences (ES018181) and the Environmental Protection Agency, the Colorado Cancer, Cardiovascular, and
Pulmonary Disease Program (13-FLA76546), and Glaxo Smith Kline.
No conflict of interest (W.C. Anderson; M.J. Federico; H.E. Hoch; J.D. Spahn).

*Corresponding author. E-mail address:
0065-3101/16/$ – see front matter

Ó 2016 Elsevier Inc. All rights reserved.




New electronic monitoring devices have the potential to significantly improve adherence and significantly reduce the disproportionate morbidity and mortality in children
with severe persistent asthma.

Emerging therapies are adding to the options of therapeutics for preventing and
managing acute asthma exacerbations.

Almost every 10 years there is a paradigm shift in the way that we look at and
manage asthma. For the last 10 years, we have been focused on asthma control.
The asthma guidelines and strategies, nationally and worldwide, have focused
on achieving control through careful assessment, education, environmental
control, and therapeutic intervention. It is now time to look at the disease in
terms of risk factors for breakthrough symptoms, including exacerbations, as
well as progression of disease that may result in chronic obstructive lung disease persisting into adulthood. This article reviews recent publications
regarding early asthma, asthma exacerbations, severe asthma, and new medications. These 4 sections summarize new information on early asthma, asthma
exacerbations, severe asthma, and new medications.
The diagnosis of asthma at less than 5 years of age is a subject of debate in scientific literature and among providers who care for children who have symptoms of airway obstruction (eg, cough, wheeze) and albuterol response before
5 years of age. The urgency for diagnosing and treating those children is due
not only to the increasing prevalence of asthma and cost of asthma care in
young children but also to recent data indicating that children who are diagnosed with asthma may have lower lung functions as adults and be at higher
risk for chronic obstructive lung disease [1].
Epidemiology of preschool and early wheeze
The prevalence of asthma in children younger than 5 years is increasing. The
Centers for Disease Control and Prevention (CDC) in the United States reported in 2013 that children aged 0 to 4 years are more likely to have an
asthma attack with a prevalence ratio of 1.9 (95% confidence interval 1.5–
2.4). The demographics of early asthma are not as clear because children
aged 0 to 4 years are often included as part of the demographic of children
aged 0 to 17 years. The CDC data published in 2011 show that 14.6% of black
children aged 0 to 17 years, 8.2% of white children, and 18.4% of children of
Puerto Rican descent report asthma. The prevalence of asthma for children
who live at or at less than the Federal Poverty Level (FPL) is 11.7% versus
8.2% of children living at 2 or more times the FPL [2].



Risk factors for preschool and early wheeze
The risk of wheeze in early childhood correlates with patient- and family specific factors and environmental exposures. The risk factors for asthma and for
early wheeze are different. Early wheeze is discussed in this section. The Tucson Birth Cohort Study and the Prevention and Incidence of Asthma and
Mite Allergy along with other birth cohort studies show that early wheeze
in infants that resolves in the first 3 to 5 years (transient early wheeze) is associated with viral, lower respiratory tract infections. Later-onset wheeze and
persistent wheeze is associated with parental history of allergy and aeroallergen sensitization [3,4]. Preterm birth is also associated with early wheeze and,
in the setting of rapid weight gain in infancy, asthma [5,6]. Several studies,
including the Tucson Birth Cohort Study, have evaluated the effect of a
child’s genetic risk factors. No one has reported definitive data showing that
variation of specific genetic loci or mutation are predictable risk factors for
wheeze or asthma. However, there is strong evidence that methylation of
the DNA (epigenetic change) at specific loci may increase the risk of wheeze
and asthma [7]. Epigenetic changes may be due to maternal- or childspecific factors, such as early infection or exposure to tobacco smoke or prenatal stress.
Environmental factors, including pollution and tobacco smoke, psychological stress, aeroallergens, and viral illness, affect risk for wheeze in early childhood. Tobacco smoke both prenatally and after birth is associated with
increased risk for wheeze and more severe illness [8]. Brunst and colleagues
[9] demonstrated that high traffic-related air pollution is associated with transient and persistent wheeze. Psychological stress and prenatal community
violence during pregnancy and after birth is also associated with increased
risk for wheezing illness [10]. Chiu and colleagues [11] found that prenatal
stress may even modify the effect of traffic-related pollution such that there
may be increased impact even at lower levels of pollution.
Human rhinovirus and respiratory syncytial virus have been associated with
recurrent wheeze in early childhood. Children with a first-degree relative with
allergy or asthma followed in the Melbourne Atopy Cohort study were more
likely to have early onset recurrent wheeze if they had a documented lower respiratory tract infection [4]. In children who are atopic, early infection may be
associated with persistent wheeze in school-aged children [12].
The impact of aeroallergens is unclear. Children who are positive for aeroallergen sensitivity are more likely to have persistent wheeze and recurrent
wheeze starting later in early childhood (3 years) [3,13]. However, the impact
of exposure to aeroallergens is variable depending on the timing of the exposure and the sensitivity of the child.
Phenotypes of preschool wheeze
Over the past 30 years, birth cohort studies have been conducted to evaluate
and describe the clinical and physiologic phenotypes of wheeze seen in children
younger than 5 years. One of the challenges to creating those categories is that



there is not a gold standard for the diagnosis of asthma in young wheezing
Several birth cohort studies created similar phenotypes based on the age
symptoms start in the child’s life, the presence or absence of atopy, and the
frequency of symptoms. The clinical application of those early wheeze phenotypes is complicated by the variability of symptoms and wheezing patterns in
individual patients over time [14]. The addition of other biomarkers of disease
may lead to an improved ability to predict long-term outcomes using early
wheezing phenotypes [15].
Pathophysiology of preschool wheeze
The pathophysiology of inflammation and wheeze in children who wheeze
before 5 years of age is unclear [16]. Two recent studies suggest that early
inflammation does not correlate with long-term clinical outcomes [17,18].
Another study of children with episodic wheeze and control shows no difference in airway inflammation between the groups [19].
Airway obstruction as measured by infant lung function studies of children
with preschool wheeze may explain wheeze in children less than 3 years of age
[20]. Children with low infant lung function are more likely to have wheeze
with viral illness [21]. Conversely, infant lung function has not been shown
to correlate with a diagnosis of persistent wheeze in school-aged children
Treatment of preschool wheeze
Limited understanding of the pathophysiology of preschool wheeze leads to
difficulties in predicting the response to treatment. The natural history of
preschool wheeze is waxing and waning symptoms, suggesting that treatment
needs may also vary. Inhaled corticosteroids (ICS) are the cornerstone of
asthma treatment in school-aged children through adulthood. Studies and
meta-analyses evaluating the response to chronic therapy options including
intermittent ICS versus daily ICS are variable. The inconsistent results could
be due to study populations, design, the timing of the initiation of inhaled
therapy, the dose, and the length of therapy [22].
The final recommendation of the most recent review by Ducharme and
colleagues [21] is that daily ICS are more effective than intermittent ICS in
controlling exacerbations. Daily inhaled therapy has not been shown to prevent future wheeze or the progression to persistent asthma [22]. There are
also no data indicating that daily therapy affects lung function in preschool
children [21].
The benefits of daily and intermittent ICS therapy in children must be
weighed against the risks of side effects. Guilbert and colleagues [23] demonstrated the significant impact on linear growth, especially in 2-year-old children
less than 15 kg who were on daily inhaled fluticasone compared with placebo.
The Childhood Asthma Management Program (CAMP) Study demonstrated a
decrease in final height in children, aged 5 to 13 years, who were started on
budesonide for asthma. The impact was greatest in prepubertal children [24].



The impact on height of high-dose intermittent inhaled therapy is less than
daily, although further studies are needed to confirm [25,26].
Several national and international guidelines for the diagnosis and management of children less than 5 years old with wheeze and asthma make treatment
recommendations based on the evidence available and expert opinion. These
guidelines not only summarize the evidence but also discuss the implementation of the evidence into practice. Australia and Canada published updated
guidelines in 2015 [27,28]. The Global Initiative for Asthma (GINA) update
was released in 2014 [28,29]. All of these guidelines and proposed strategies
recommend daily controller therapy for children who meet specific criteria,
such as frequent and poorly controlled symptoms suggesting asthma and the
frequency and severity of wheezing episodes (Table 1). They do not recommend intermittent controller medications for these children. The type of daily
medication recommendation varies by age in the Australian guidelines. All of
these guidelines also recommend frequent reassessment of symptoms and evaluation of side effects of therapy for any child less than 5 years of age on
controller therapy. None of the guidelines recommend oral corticosteroids
for initiation at home for an exacerbation of wheeze.
Progression to persistent wheeze and asthma
It is difficult to predict whether children who wheeze as toddlers will develop
asthma. Many of the children who wheeze before 5 years of age will stop
wheezing by 6 years of age [21]. Predictors of persistent wheeze in cohort
studies include patient characteristics, such as history of wheeze, atopy, and
parental history of asthma, male sex, and tobacco smoke exposure [4,30–32].
Several cohorts developed prediction scores based on the phenotypes identified
early in childhood. The Asthma Predictive Index (API) developed as part of
the Tucson birth cohort study and modified for the Prevention of Early
Asthma in Kids study is the most widely tested and used [33,34]. This index,
like others, has a low sensitivity and positive predictive value for asthma.
Table 1
Long-term controller therapy for young children
Publication medication Oral
Guideline date
if needed corticosteroids













However, the specificity of the index, which has been tested in several large cohorts, is more than 92%. Unfortunately, because of the low sensitivity, a negative API or modified API is not an absolute test of the likelihood of developing
asthma; these children should be followed closely [35].
Bacharier and colleagues [36] recommend that the API can be used in
conjunction with other factors, such as aeroallergen sensitivity, recent severe
exacerbation, and sex, to predict response to ICS. A recent study by Klaassen
and colleagues [37] reports that the ability of the API to predict asthma at
8 years old is significantly improved when combined with exhaled biomarkers
of asthma. Further work will be needed to develop an objective, widely available, predictive score with a high positive predictive value [23,38].
Long-term sequelae preschool wheeze
The long-term clinical outcome of children with early childhood wheeze varies
by the severity and persistence of disease. Infant lung function before
12 months of age is decreased in children with early onset transient wheeze
(wheeze that resolves by 3 years old). However, neither low infant lung function nor transient wheeze seem to predict asthma [15,39]. Cohort studies suggest that children who have persistent wheeze early in life seem to have lower
lung function, increased airway hyperresponsiveness (AHR), and diminished
growth in forced expiratory volume in the first second of expiration (FEV1) until at least 18 years of age [21,40]. Children with an early rhinovirus and persistent wheeze may be specifically more likely to have low lung function until age
8 years of age [23]. The evidence of early changes in lung function suggests that
the decrease in lung function seen in children begins early in life and there may
be an opportunity to alter that trajectory if treatment is initiated early. Further
studies are needed to evaluate whether preventative treatment should be
focused on prevention of early epigenetic change by decreasing exposures,
such as smoke and stress; altering the early microbiome; or preventing early
allergy and inflammation. A combination of strategies may be needed, and
treatment will most likely need to be tailored to each family and child to
improve the short- and long-term clinical outcomes in these children.
Asthma exacerbations remain a target of both asthma therapy and research for
many reasons, perhaps the most important being that exacerbations account
for a significant proportion of the cost of asthma-related care [41] as well as
contribute to significant asthma morbidity. Therefore, predicting and treating
asthma exacerbations is highly important and a focus of recent research.
Predicting asthma exacerbations
Forno and Celedon [42] summarized several risk factors identified in the
asthma literature for asthma exacerbations, including poor control, recent history of severe exacerbations, viral infections, allergen exposure, winter season,
younger age, nonwhite race, tobacco smoke exposure, and outdoor air pollution. Among these, the investigators concluded that a history of recent



exacerbation was the single best predictor of future exacerbation. An analysis
of The Epidemiology and Natural History of Asthma (TENOR) cohort of
more than 4000 children with severe or difficult-to-treat asthma found that
prior asthma exacerbations, short-acting beta-agonist use, and lung function
as well as the Asthma Therapy Assessment Questionnaire were independent
predictors of asthma exacerbations [43]. The National Institute of Allergy
and Infectious Diseases (NIAID) Inner City Asthma Consortium evaluated
400 inner-city children with asthma to determine season-specific risk factors,
due to the seasonal nature of asthma exacerbations [44]. They found that significant risk factors for exacerbations exist (including age, total immunoglobulin E [IgE], allergen skin test positivity, blood eosinophils, exacerbation in
the prior season, treatment step, FEV1/forced vital capacity [FVC] ratio, and
exhaled nitric oxide); for each season, different risk factors were proportionally
responsible for most of the risk. Furthermore, they were able to develop a
predictive index to score individual patients’ risk of exacerbations. To predict
imminent asthma exacerbations, a combination of change in symptoms
and decrease to less than 70% of personal best in peak flow has good predictive value in the 1-week window before an asthma exacerbation in one
evaluation [45].
Environmental factors
Increasing numbers of recent studies have focused on the impact of environmental factors on asthma exacerbations. Ecological studies have compared climatic factors and air pollution with school health records and found that upper
atmosphere temperature, dew point, mixing ratio, and air pollutants predicted
the probability of asthma exacerbations in elementary school-aged children
[46,47]. Another ecological study found that high levels of particulate matter
and other air pollutants predicted asthma exacerbations in elementary
school-aged children in the United States. [48]. These investigators postulate
that monitoring of air pollutants over time could allow for mathematical
modeling to predict asthma exacerbations over large groups of children. Ultrafine pollution particles and carbon monoxide were found to be particularly
associated with increased odds of a pediatric asthma visit in another study
[49]. As national and international focus continues to be directed toward environmental changes and triggers of human disease, the effect of the environment
on asthma health will continue to be evaluated.
Forno and Celedon [42] also summarized biomarkers that had been studied for
exacerbation prediction, including exhaled nitric oxide, sputum eosinophilia,
urine bromotyrosine, urine metabolome studies, and serum vitamin D. Interestingly, urinary bromotyrosine has been shown to track with asthma control
as well as predict the risk of future exacerbations [50]. Exhaled nitric oxide has
even been tested in infants and toddlers and was shown to be predictive of
future acute exacerbations and prediction of wheezing at 3 years of age [51],
though its utility in predicting exacerbations in other ages has not been



consistent [52]. Children with asthma exposed to secondhand smoke are at a
particularly high risk for exacerbations, and urinary leukotriene E4 has been
identified as a predictor of asthma exacerbations in those exposed to secondhand smoke [53]. Although these biomarkers have shown promise, no one
definable biomarker has shown itself to be an adequate predictive marker on
its own. Additionally, the biomarkers discussed earlier are only a small portion
of those currently being assessed for clinical use.
Preventing and managing asthma exacerbations
As the science of predicting asthma exacerbations advances, clinicians are left
with the question of how to treat those who do exacerbate. Acute asthma exacerbations result in more than 2 million emergency department (ED) visits
per year [54]; in 2013, 57.9% of children with a current diagnosis of asthma
experienced an exacerbation [55]. Currently available therapies include
oxygen; fluids; steroids; beta-agonists, including albuterol and terbutaline;
and anticholinergics, including ipratropium, magnesium sulfate, methylxanthines, heliox, and ketamine [56]. Although therapies, such as beta-agonist
and systemic corticosteroid therapy, have been a mainstay for many years,
treatment of acute asthma exacerbations continues to evolve.
Corticosteroids are effective against both acute and chronic inflammation and
have been a mainstay of acute asthma therapy for some time [56]. One current
area of active investigation is the effectiveness of dexamethasone versus prednisone in the treatment of acute asthma exacerbations. Dexamethasone has
been considered as an alternative to prednisone/prednisolone because of its
increased tolerability. Studies have evaluated the use of dexamethasone in
the ED setting and found that dexamethasone is a viable alternative to prednisone, with equivalent effectiveness and improved compliance, palatability
(decreased vomiting), and cost profile [57–59].
Although ICSs have been largely used chronically rather than in acute
exacerbations, recent studies have sought to evaluate their use in the acute
setting. Chen and colleagues [60] found that the addition of inhaled highdose budesonide to nebulized beta-agonists and ipratropium led to clinical
improvement and reduced need for oral corticosteroids. In fact, one systematic
review of 8 pediatric studies found that there was no difference between ICS
and systemic corticosteroids in terms of hospital admission rates, unscheduled
visits for asthma symptoms, and the need for an additional course of systemic
corticosteroids [61].
Inhaled anticholinergics are another option to consider. Inhaled anticholinergics are frequently combined with short-acting beta-agonists in the ED setting
and have been shown to decrease the risk of hospital admission when used in
this way [62], though they have not been shown to be efficacious when used on
their own [63]. However, studies have not supported the use of inhaled



anticholinergics in hospitalized patients because of the lack of significant
benefits in terms of hospital length of stay and other markers of response to
therapy [64].
Other emerging therapies
Other medications are emerging as potential therapies for acute asthma exacerbations. Magnesium sulfate is under study because of its properties as a smooth
muscle relaxant [64]. One retrospective study evaluated the use of intravenous
magnesium sulfate in pediatric patients in the ED and found that it was largely
well tolerated, with only one patient experiencing hypotension, but also found
that dosage as well as time of administration varied widely across the centers
studied [65]. A randomized controlled trial of intravenous magnesium sulfate
found that infusion within the first hour of hospitalization significantly reduced
the percentage of children who required mechanical ventilation [66]. Magnesium sulfate is also available in an inhaled formulation. One systematic Cochrane review found no good evidence that inhaled magnesium sulfate
should be used as a substitute for beta-agonist therapy as well as no clear evidence of improved pulmonary function or reduced hospital admissions, though
individual studies suggested possible improvement in severe asthmatic patients
with low lung function (FEV1 <50% predicted) [67]. Additionally, it may be
efficacious in asthmatic patients with more severe exacerbations [68]. Another
therapeutic target includes inhaled furosemide, which shows promise as an
adjunct to currently available asthma therapies [69].
Preventing asthma exacerbations
Another recent study from the NIAID Inner City Asthma Consortium indicated that a preseasonal approach using omalizumab therapy (anti-IgE) was
effective in preventing a fall exacerbation in those participants with a history
of an asthma exacerbation in the prior year. This strategy was particularly
effective in those children who had an asthma exacerbation in the 6-month
observation period before starting omalizumab therapy and those who
required high levels of treatment of asthma control, namely, high-dose ICS
with supplemental controller therapy [70].
With the development of very effective asthma control medications, most children with asthma can attain and maintain good asthma control. Unfortunately,
a small group of severe asthmatic children will continue to have difficult-tocontrol asthma despite maximal medical therapy. These children are often
described as having difficult-to-control, refractory, treatment refractory,
steroid-resistant, or steroid-insensitive asthma. Most definitions of severe
asthma have included frequent day and nighttime symptoms, need for rescue
bronchodilator therapy several times a day, and an FEV1 less than 60% of predicted. The European Respiratory Society/American Thoracic Society Task
Force Report on severe asthma recently simplified the definition of severe
asthma by stating that severe asthma requires treatment with high-dose ICS



plus a second controller and/or systemic corticosteroids to prevent it from
becoming uncontrolled or that remains uncontrolled despite this therapy
[71]. In addition, severe asthma must be distinguished from uncontrolled
Although severe asthma has been estimated to affect 5% to 10% of all asthmatic patients, the exact prevalence has been difficult to determine because of
the lack of a consistent definition. In a recently published study, Hekking and
colleagues [72] sought to determine the prevalence of difficult-to-treat versus severe refractory asthma. Patients with difficult-to-treat asthma were those with
uncontrolled symptoms despite high-intensity treatment, whereas patients
with severe refractory asthma were the fraction of difficult-to-treat asthmatic patients who had both good adherence and inhalation technique. Approximately
17% of asthmatic patients had difficult-to-treat asthma. Because 50% were nonadherent and 58% had poor inhaler technique, only 20% of the difficult-tocontrol asthmatic patients had severe refractory asthma. Thus, severe asthma
comprised only 3.6% of the adult asthmatic population, a value less than the
estimated prevalence of 5% to 10%. Although difficult-to-control asthma is relatively common, only a fraction of these patients will have severe refractory
asthma. To determine the true prevalence of severe refractory childhood
asthma, future studies must take into account both inhaler technique and
Natural history of severe asthma
Reddy and colleagues [73] sought to determine whether the recent introduction
of highly effective asthma therapies have altered the natural history of severe
childhood asthma. The investigators compared 2 cohorts of children with severe asthma referred to a national asthma referral center before (Historic
Cohort 1993–1997) and following the widespread use of second-generation
ICS alone or in combination with long-acting beta-agonists (LABAs) and leukotriene receptor antagonists (Current Cohort 2003–2007). Children from the
Current Cohort were much less likely to require chronically administered
oral corticosteroid therapy; in those that did, their oral corticosteroid dose
was much lower and they required it for a much shorter period of time
compared with children from the Historic Cohort. Children in the Current
Cohort also had better lung function, required significantly less rescue albuterol, and were less likely to have required intubation/mechanical ventilation in
the past but had more asthma exacerbations per year. They were also less
growth suppressed and had fewer Cushingoid stigmata, but they were as likely
to have osteopenia as the Historic Cohort.
The data presented suggest that, with the development of highly effective
medications, children with severe asthma are less likely to be steroid dependent, have better baseline lung function, require far less rescue albuterol, and
are less growth suppressed. Despite these gains, children with severe asthma
continue to have frequent exacerbations and osteopenia continues to be a common steroid-induced adverse effect.



Whether frequent asthma exacerbations result in a more rapid decline in
lung function over time was addressed by the TENOR study, whereby the effect of asthma exacerbations on annual lung function decline was studied in
more than 2000 subjects with severe asthma over a 3-year period [74]. This
large prospective study found that asthma exacerbations contribute to progressive loss of lung function, especially in children. In addition, ICS therapy did
not seem to ameliorate this effect, as nearly all subjects were on this therapy.
Matsunaga and colleagues [75] made similar observations; they prospectively evaluated the effect of asthma exacerbations on lung function in adults
with stable asthma on ICS therapy over a 3-year period. At least 25% of the
patients had 1 or more asthma exacerbations requiring prednisone or hospitalization during the study. Not only were exacerbations related to loss of lung
function but also those with the most exacerbations had the greatest decline
in lung function.
Of the 25% of participants enrolled in the NHLBI CAMP study who displayed an annual decline in lung function, ICS therapy failed to protect against
this loss, as there was no difference in the percentage of or rate of decline between those who received budesonide versus those who received a matching
placebo over a 5-year period [76].
The annual declines in lung function in the studies mentioned earlier were
small, but the cumulative effect over time is likely to result in a significant
reduction in lung function and may explain why adults with severe asthma
have FEV1 values that are much lower than children with severe asthma
[77]. In addition, these studies suggest that ICS therapy does not seem to
ameliorate loss of lung function and that asthma exacerbations contribute to
asthma progression.
Severe asthma phenotypes
Cluster analysis is an analytical technique that has recently been used to identify asthma phenotypes. Its advantage comes from its ability to distinguish complex phenotypes without a priori (ie, biased) definitions of disease severity. The
NHLBI Severe Asthma Research Program (SARP) study team, using a cluster
approach, found children with severe asthma to be distributed across 4 distinct
clusters [78]. Children in cluster 4 (early onset atopic asthma with advanced
airflow limitation) had the lowest lung function, required several asthma control medications, and had the most asthma symptoms. The mean prebronchodilator FEV1 of these children was 75% of predicted with a postbronchodilator
FEV1 of 90% of predicted. That children with severe asthma were likely to
have FEV1 values of greater than 60% of predicted was first described a decade
ago [79,80].
Of interest, all 4 childhood clusters had varying degrees of atopy. The childhood clusters differed substantially from those identified among the adults with
severe asthma, which were based on age of onset, allergen sensitization, baseline lung function, beta-agonist reversibility, and medication use/health care utilization [81]. When comparing the two cohorts, children had less airway



limitation but required rescue albuterol more frequently. The children were
also found to have frequent exacerbations, yet had little impairment and
normal lung function between exacerbations. This observation has been replicated in several NHLBI-sponsored studies in children with mild and moderate
persistent asthma [82,83].
A second cluster analysis from France identified 2 distinct severe asthma
clusters [84]. Children in cluster 1 were the most atopic, had the highest circulating IgE levels and circulating eosinophils, had long-standing and uncontrolled asthma despite high-dose ICS, and were most likely to have been
hospitalized. Children in cluster 2 were older, had a higher body mass index,
had increased circulating neutrophils, had elevated IgG, IgA, and IgM levels,
and had the lowest lung function. There was no predominance of severe
asthma in any one cluster, and atopic features were present in both groups. Unlike the SARP study, the nature of inflammation varied among the clusters,
with cluster 1 patients having a TH2-mediated and cluster 2 patients having
more of a TH1-mediated inflammatory process.
Mechanisms of severe asthma
In adults with severe asthma, YKL-40 expression is upregulated in CD8þ cells
and serum YKL-40 levels are elevated, correlate positively with airway remodeling, and inversely correlate with lung function [85,86]. Whether YKL-40
levels are also elevated in children with severe asthma was studied by Santos
and colleagues [87], who compared lung function, YKL-40, IgE, and exhaled
nitric oxide (eNO) levels in children with mild, moderate, and severe persistent
asthma to adults with severe asthma. Children with severe asthma did not have
elevated YKL-40 (26 ng/mL) levels compared with the adults with severe
asthma (62 ng/mL). Children with severe asthma also had better lung function
and higher IgE and eNO levels compared with the adults with severe asthma
who had significant airflow limitation and low serum IgE and eNO levels.
Lastly, no relationship between YKL-40 levels and asthma severity was found
among the children studied. These data support the contention that there are
distinct pathophysiologic differences in severe asthma that depend on one’s
Airway remodeling, which involves thickening of the reticular basement
membrane (RBM), goblet cell, and submucous gland hyperplasia, airway
smooth muscle (ASM) hyperplasia, and hypertrophy and angiogenesis, is a
characteristic histologic finding in grade school–aged children and adults
with asthma [15,88]. At present, it remains to be determined when airway remodeling begins, although remodeling was not seen in infants with frequent
wheeze [88].
Lezmi and colleagues [15] evaluated airway remodeling and inflammation in
preschool-aged children with severe recurrent wheeze. Children 36 months of
age or younger comprised group 1, whereas children aged 37 to 59 months
comprised group 2. Group 3 consisted of school-aged asthmatic children.
RBM thickness increased with age, with ASM area being greatest in the



school-aged children. ASM was found to be greater among the atopic versus
nonatopic preschool-aged children. Airway inflammatory cells were similar in
both groups 1 and 2 with an absence of eosinophils and a predominance of neutrophils noted, whereas eosinophils were the predominant airway inflammatory cell in the grade school–aged children. No relationships were noted
between airway inflammation and airway wall structural changes, and there
was no correlation between inhaled steroid dosage and degree of airway wall
Thus, in preschool-aged children with severe wheezing, airway remodeling is
present by 3 years of life and progresses over time. Remodeling and inflammation seem to occur in conjunction, yet the two processes seem to be unrelated.
Neutrophilic inflammation is present in both wheezing infants and preschoolaged children with severe recurrent wheeze. As eosinophilic inflammation is
a characteristic finding in older children and adults, a switch from a neutrophilto an eosinophil-driven inflammatory process must occur in genetically predisposed children with recurrent wheeze who go on to have persistent asthma.
The mechanisms involved in this switch have yet to be determined.
Tumor necrosis factor a (TNFa) plays an important role in TH1-driven diseases, such as rheumatoid arthritis and inflammatory bowel disease. TNFa has
also been noted in the bronchoalveolar lavage fluid of adults with severe asthma.
At one time, TNFa was thought to be an important mediator in severe asthma as
small studies using TNFa antagonists improved lung function, reduced bronchial hyperresponsiveness, and improved quality of life in adults with severe
asthma [89]. When a large placebo-controlled trial evaluating golimumab, a
TNFa antagonist, was discontinued prematurely because of its adverse effects
and lack of efficacy, interest in TNFa and its antagonists waned [90].
Whether TNFa may play a role in children with severe asthma was the aim
of Brown and colleagues [91] who measured plasma TNFa concentrations and
TNFa mRNA expression in children with asthma. This study suggested that,
as in adults with severe asthma, a phenotype of severe childhood asthma exists
that is characterized by TNFa overexpression and poor asthma control despite
high-dose ICS therapy. It is possible that targeted therapy with TNFa antagonists in this asthma phenotype may be an effective therapy.
Suboptimal adherence to prescribed medication is an important contributor to
severe asthma, as many patients who are thought to have severe asthma end up
having poorly controlled asthma due to suboptimal adherence with prescribed
asthma medications. The monitoring of refill rates of prescribed medications
provides a simple and robust measure of adherence, as one cannot be adherent
if one does not fill one’s prescriptions. With that said, adherence may be overestimated, as filling a prescription does not provide proof that the patient actually took the medication. Murphy and colleagues [92] analyzed prescription
refill rates in patients with difficult-to-control asthma residing in Leicester,
United Kingdom. Prescription data were compared with the patients’



prescribed medication regimen to determine each patient’s level of adherence,
with good adherence defined as 80% or greater. Patients with suboptimal
adherence had lower FEV1 values, higher sputum eosinophil counts, and
were more likely to have required mechanical ventilation. For every 10%
decrease in ICS adherence, the odds of having required mechanical ventilation
increased 1.4 times. This finding is in line with that of an epidemiologic study
that found the risk of death from asthma decreased 21% for every additional
ICS canister filled [93].
Another study using prescription refill rates to measure adherence came
from Ireland [94]. In this study, 35% of patients filled their prescribed combination inhaler 50% or less of the time. These poorly adherent patients were
more likely to have been hospitalized 3 or more times in past year, had lower
asthma-specific quality-of-life scores, were on a higher prescribed ICS dose, and
required more frequent use of short-acting beta-2 agonists than patients with
good adherence. Three variables were associated with nonadherence: female
sex, quality of life, and hospital admissions in the preceding 12 months.
Thus, poor adherence is common among patients with severe asthma.
Poorly adherent patients are more likely to have required frequent hospitalizations, have been mechanically ventilated, have greater airflow obstruction,
higher sputum eosinophils counts, and a lower quality of life. Thus, poor
adherence is a significant contributor to poor asthma control. As patient selfreporting is a poor identifier of adherence, objective assessment of adherence
must be part of any systematic evaluation protocol for severe asthma.
Children who are more adherent to controller medications are 21% to 68% less
likely to have asthma exacerbations than those who are not [95]. Unfortunately, adherence to asthma controller therapies only ranges from 30% to
70% [96]. Patients are poor self-reporters of their own adherence, with a large
discrepancy existing between their reported medication use, including on diary
cards, and their actual use [97–100].
Electronic monitoring devices (EMDs) are a new approach to achieving
asthma control, increasing adherence, and preventing exacerbations. EMDs
provide accurate, objective, and detailed information on patient adherence
without significantly disrupting their natural medication taking behavior
[100]. EMDs may record the date, time, and even location of each actuation
through Global Positioning System monitoring as well as provide reminder
prompts to take the medication [100]. EMDs with audiovisual reminders
have been proven to increase adherence rates in both adults and adolescents
as well as children [101–103]. A consistent benefit in asthma outcomes with
EMDs has not been demonstrated, including improvement in exacerbations
over time, school absenteeism, caregiver work absenteeism, FEV1, or ED visits
[103]. Possible reasons for this lack of benefit include the sample sizes involved,
limited duration of intervention, patient awareness of adherence monitoring, or
multiple asthma phenotypes requiring different treatment modalities [104].



Current treatment modalities, including second-generation ICSs and combination ICS/LABAs, are likely responsible for the change in the course of
asthma over the last 20 years, including less use of chronic oral corticosteroids
and improved asthma control [73]. ICSs and ICS/LABAs may not be sufficient
alone for the management of patients with severe asthma, whose persistent
symptoms place them at an increased risk of exacerbations, hospitalizations,
ED visits, and oral corticosteroid use [105]. In patients whose symptoms
remain poorly controlled despite close adherence with optimal current therapy,
new therapeutics, including tiotropium and TH2-directed biologics, may be key
to improving control and preventing exacerbations [106].
When considering the use of new pharmaceutical agents in children with
asthma, attention must be paid to the specific pediatric evidence for their
use. Most recently approved therapies, including omalizumab, mepolizumab,
and tiotropium, are only approved by the Food and Drug Administration
(FDA) for use in patients as young as 12 years old [107–109]. Age-limited
studies often lead to the off-label use of asthma drugs in the pediatric population [110]. Such extrapolation of pharmacologic results from adults to children
cannot be readily made secondary to differences in pediatric respiratory function, immunology, and disease pathogenesis [111].
Tiotropium is a long-acting once-daily anticholinergic initially approved for the
treatment of persistent asthma in 2015 [109]. Tiotropium studies were first conducted with the HandiHaler and then the Respimat device (Boehinger Ingelheim, Ingelheim am Rhein, Germany), which is the currently approved
device for the treatment of persistent asthma [109]. Tiotropium has been studied as an add-on therapy to ICSs in adolescents and children [112–114]. An
improvement in lung function has been demonstrated in symptomatic pediatric
and adolescent patients with asthma with the addition of tiotropium to ICS,
improving peak and trough FEV1 and morning and evening peak expiratory
flow (PEF) [112–114]. However, these pediatric and adolescent studies did
not show a statistically significant improvement in asthma control or quality
of life [112,114], and an effect on asthma exacerbations was not investigated.
Clinical characteristics predicting a response to tiotropium have only been
derived from adult studies. An improvement in FEV1 and PEF with the addition of tiotropium to low-dose ICS was predicated by a response to albuterol, a
decreased FEV1/FVC ratio, and a higher cholinergic tone, reflected by a lower
resting heart rate [115]. Tiotropium has not demonstrated a response association with allergic markers, including atopy, IgE level, sputum eosinophil count,
or exhaled nitric oxide (FENO) [115,116].
Omalizumab is indicated as an add-on therapy in steps 5 and 6 of the NHLBI
Expert Panel Report-3 guidelines for patients 12 years of age and older with
moderate to severe persistent asthma [117]. In this adolescent and adult population, omalizumab decreases rates of asthma exacerbations, annualized rate of



hospital admissions, total emergency visits, unscheduled doctor visits, rescue
therapy use, and ICS dose [118–121]. It also improves asthma symptom scores,
quality of life, and time to first asthma exacerbations [119].
Omalizumab has shown a similar benefit in pediatric patients, aged 6 years
and older, with moderate to severe persistent or uncontrolled asthma with reductions in asthma exacerbation rates, symptom days, hospitalizations, urgent
physician office visits, missed school days, and daily rescue medication use
[122–124]. The impact of omalizumab on pediatric exacerbations was highlighted in the NIAID Inner-City Anti-IgE Therapy for Asthma (ICATA) trial,
which demonstrated near-complete elimination of the seasonal variability of
asthma exacerbations in the fall and spring with its use [122]. Especially important in the pediatric population is the ability of omalizumab to improve exacerbation rates while reducing ICS [70,122–124].
Although omalizumab dosing is based on IgE, weight, and aeroallergen sensitization, its use may be most beneficial in those patients with elevated eosinophilic
biomarkers [107]. In adolescents and adults, a greater reduction in asthma exacerbations was observed in patients with high compared with low baseline FENO,
peripheral eosinophil count, and periostin, based on median split [119,125,126].
Similarly, in the ICATA trial, pediatric patients with a FENO 20 ppb or greater, a
peripheral eosinophil count of 2% or greater, and a body mass index of 25 or
greater had significantly fewer exacerbations with omalizumab treatment
compared with those with lower values of these parameters [127].
Mepolizumab is a humanized monoclonal antibody directed against interleukin
5 (IL-5) that was FDA approved in 2015 as an add-on therapy for the treatment of
severe eosinophilic asthma in patients 12 years of age and older [108]. Mepolizumab studies defined eosinophilic asthma as sputum eosinophil count of 3% or
greater, FENO of 50 ppb or greater, or a peripheral eosinophil count of 0.3 or
greater 109/L [128,129]. Several studies demonstrate a decrease in eosinophil
counts in asthmatic patients with its use [128–132]. In adolescents and adults, mepolizumab has been proven to reduce the rates of asthma exacerbations, to
decrease exacerbations requiring admission or ED visits, and to delay the time
to first exacerbation [128,129,133]. Later studies demonstrated an improvement
in FEV1 and asthma control questionnaire (ACQ) scores [129,133]. Mepolizumab has also been proven to reduce the daily maintenance oral corticosteroid
dose while still improving rates of asthma exacerbations [133]. The rate of clinically significant exacerbations with mepolizumab correlated with blood eosinophil count and number of exacerbations in the year before baseline but not atopic
status, IgE concentrations, FEV1, or bronchodilator response [128].
Reslizumab is an IgG4j humanized monoclonal antibody that also binds IL-5
and reduces serum eosinophilia in patients with asthma similar to mepolizumab
[134,135]. Also like mepolizumab, reslizumab has only been studied in patients
greater than 12 years old [134,135]. However, the definition of eosinophilic



asthma differs between these two therapies with reslizumab using a peripheral
eosinophil count of 400/lL or greater [135]. When used as an add-on therapy
to adult and adolescent patients on ICS or ICS/LABA, reslizumab reduced
asthma exacerbation rates comparable with that seen with mepolizumab,
increased time to first exacerbation, increased FEV1, and improved ACQ
and quality of life scores [134,135].
Lebrikizumab is an IgG4 humanized monoclonal against IL-13, with published
studies to date only in adults. The addition of lebrikizumab to ICS in patients
with high periostin and FENO levels, based on median splits, each correlated
with an improvement in prebronchodilator FEV1 [136]. Furthermore, those patients with a high periostin level had a greater decline in FENO with lebrikizumab [136]. Those patients with an IgE level greater than 100 IU/mL and a
peripheral eosinophil count greater than 0.14 109 cells per liter had a
decrease in their asthma exacerbation rates with lebrikizumab [136].
Questions exist about the utility of periostin as a biomarker in the pediatric
population as it is a product of bone turnover, leading to higher levels in
growing children compared with adults [137]. However, within the pediatric
population, higher levels of periostin have been identified in children who
developed asthma by 6 years of age compared with those who did not and
in healthy children 6 to 15 years of age compared with asthmatic patients
[137,138]. Additional studies examining periostin in relation to IL-13 and lebrikizumab in the pediatric population are needed.
Based on the summary provided here on the current literature, it seems that the
management of children will be continually changing in the coming years. With
new insights into the development of asthma, we can begin to identify those children at risk for asthma onset, exacerbations, and progression. We can also begin
to develop interventions for those who are at risk using risk profiles. That will
lead to new intervention strategies. Because the new immunomodulators have
been effective in reducing exacerbations, it is possible that they may also be helpful in preventing the progression of disease and reversing the natural history of
asthma, including progression to chronic obstructive airway disease in adults.
The future is bright for developing new strategies for managing asthma in children and reducing the burden of disease not only in children but also in adults.
This development will take a concerted collaborative effort among patients, families, clinicians, and the pharmaceutical industry to keep moving forward and the
health care system in reviewing available data and continuing to help those children who are not receiving adequate management.
The authors would like to thank Dr Michael Kappy for the invitation to
contribute to Advances in Pediatrics and to Gretchen Hugen for assistance with
preparation of this review.



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