Obesity and Childhood Asthma
Jason E. Lang, MD1, 2
Division of Pulmonology, Allergy & Immunology, Nemours Children’s Clinic, Jacksonville, Florida
1
2
Center for Pharmacogenomics and Translational Research, Nemours Children’s Clinic, Jacksonville,
Florida
The authors have no financial relationships or conflicts of interest relevant to this article to disclose.
Short title: Obesity and Childhood Asthma.
Keywords. Asthma, Obesity, Children, Adolescents, body mass index, Pulmonary Function
Abbreviations. Body mass index (BMI); Forced Vital Capacity (FVC); Forced Expiratory Volume (1 sec)
(FEV1); Forced Expiratory Flow (FEF25-75); Peak Expiratory Flow Rate (PEFR); PC20
Corresponding Address:
Jason E. Lang
Division of Pulmonology, Allergy & Immunology
Center for Pharmacogenomics and Translational Research
Nemours Children’s Clinic
807 Children’s Way
Jacksonville, FL 32207
904-697-3676
Fax: 904-697-3683
jelang@nemours.org
Introduction
Obesity and asthma are serious public health problems in many parts of the world. The
World Health Organization expects by the year 2015 that the number of overweight
adults will exceed 2.3 Billion[1]. Obesity is also a problem in children. There are more
than 20 million children globally considered overweight below the age of 5. Obesity
rates have increased dramatically among adult in past decades, however the
acceleration of obesity has been greatest among children [2, 3]. These statistics
suggest that obesity in coming decades will evolve into a true public health crisis.
Asthma has also increased in prevalence in recent decades, raising the question of a
possible causal link between obesity and asthma. Over 15 cohort studies have been
conducted in adults and children. Obesity clearly increases the risk for new asthma
diagnosis in adults [4-11] and children [12-18], though the precise nature of the
association remains controversial [19-24]. Obesity also appears to be associated with
distinct asthma characteristics, and therefore optimal management of the obese
asthmatic child requires a thoughtful, tailored approach.
In this brief review, we will discuss what is known about asthma risk among obese
children and the possible causes for this link. We will also discuss how obesity impacts
pulmonary function, symptom severity, symptom control, exacerbation risk, and the best
asthma management in children.
Asthma Risk: Cohort Studies
Assessing incident risk requires prospectively following an affected cohort (obese) and
an unaffected cohort (non-obese) for the development of the condition in question
(asthma), and cannot rely solely on cross-sectional or case-control studies. Several
high-quality cohort studies have been conducted among diverse populations assessing
the risk of incident asthma among lean and obese children [12-18]. These studies
involve children of varying ages, socioeconomic status and race/ethnicity. These studies
followed children without asthma and compared the risk of developing new asthma in
overweight versus normal weight children. Overweight status appears to increase
asthma risk across the complete pediatric age spectrum. Overweight non-asthmatic
infants, toddlers, pre-pubescent school-age children, and adolescents have all been
shown to display increased risk for incident asthma. Though risk ratios vary by study,
obesity appears to roughly double the incident risk for asthma in children [13, 15, 16].
Though obesity-related asthma risk has been reported to be stronger among adult
females, there is not a clear and consistent link with either gender among pediatric
studies. Obesity-related asthma risk also does not appear to be related to greater atopy
[12-14, 17]. Rapid change in adiposity or body habitus, distinct from obesity status itself,
may also influence asthma risk in children. Gold found that extremes in body mass
index (BMI) change and low baseline BMI were also associated with asthma risk [15].
Asthma lacks a precise set of diagnostic criteria, and evidence exists for over-diagnosis
of asthma [25, 26] in some groups. A rationale hypothesis is that obesity alters the
perception of perturbations in airway function, leading to a lower threshold to symptom
reporting. Greater rates of false diagnosis of asthma could contribute to reported
asthma risk among cohort studies using ‘physician-diagnosis’ as the sole outcome
measure. Obesity-related false asthma diagnosis is unlikely to explain the increased
asthma risk. Castro-Rodriguez et al reported increased objective markers of true
asthma (peak flow variability and responsiveness to bronchodilator) in overweight girls
compared with lean girls.
We evaluated lean and obese children referred to a pediatric asthma clinic in
order to determine whether high BMI-percentile is associated with misdiagnosis of
asthma or significantly different objective measures of asthma compared to lean
referrals [25]. We found that the prevalence of high BMI-percentile was the same
among the referral population and the cases confirmed by a specialist with
accompanying objective data. Referring physician-diagnosed asthmatics did not have
higher rates of obesity, and referring physician-diagnosed asthmatics had objective
indicators of asthma that were the same as asthmatics diagnosed by a specialist. There
was good diagnostic correlation between referring physicians and asthma specialists
that was not affected by BMI. Among specialist-diagnosed asthmatics, increased BMIpercentile was associated with significantly reduced forced expiratory volume in 1
second (FEV1), forced expiratory flow during the middle half of the forced vital capacity
(FEF25−75), and FEV1/forced vital capacity (FVC). We concluded that referring
physicians do not appear to overly or erroneously diagnose children with asthma due to
overweight status. Our data confirm that overweight status is extremely high in children
with true asthma and likely increases the risk for true asthma.
Asthma Risk: Possible Etiologies
The etiology underlying the increased asthma risk among overweight children is
unknown. Several theories exist that have been detailed previously [20, 27, 28]. These
include abnormal circulating inflammation and oxidant stress, obesity-related
comorbidities, chest restriction with airway closure, and shared genetics. One or more
of these mechanisms may play a role in animal models of obesity and lung responses.
In murine models, obesity appears to: 1) increase innate airway responsiveness, 2)
increase airway responses to common asthma triggers, and 3) increase airway
inflammatory responses. These same obesity-related responses have not been
conclusively demonstrated in children. Assessing lung inflammation and responses
among obese children remains challenging and limited by current technologies.
Therefore, discussion about the link between obesity and asthma risk among children
remains speculative.
One hypothesis for the obesity-asthma link is that obesity-related circulating
inflammation primes the lung for exaggerated responses to environmental triggers,
leading to asthma-like symptoms. This notion is plausible since chronic inflammation
and oxidative stress are hallmarks of both obesity and asthma. Asthmatic and obesityrelated inflammation involves similar mediators, including TNFα [29, 30] and
leukotrienes [31-33]. Adipose releases pro-inflammatory ‘adipokines’ that impact
multiple organ systems, including the lung [29, 34]. These molecules (e.g. adiponectin,
IL-6, TNFα, leptin) impact inflammation and can alter lung responses [34-37]. Therefore,
obesity-related inflammation may play a role in the development and severity of asthma
[38] that may be a distinct phenotype from the common atopic childhood phenotype.
Despite the excess in circulating markers of inflammation, obesity does not appear to be
independently related to increased airway inflammation in children.
Another hypothesis proposes that obesity-related co-morbidities may increase the risk
for asthma diagnosis. Gastro-esophageal reflux is increased among obese children and
adults, and has been proposed as a trigger for cough and wheezing. However, evidence
in children remains lacking that gastric reflux alone triggers greater asthma diagnosis.
Obesity increases the risk for sleep-disordered breathing including obstructive sleep
apnea. It is rationale to hypothesize that altered sleep leading to episodic hypoxemia or
other mechanisms may predispose to asthma. When controlling for both obesity-related
esophageal reflux and obesity-related sleep apnea, the relationship between obesity and
asthma among adults remains unchanged [39, 40]. These co-morbidities require further
research in the pediatric age group.
In various models, obesity-related chest restriction has been shown to alter healthy
airway physiology in two ways. Compression of the lungs and chest wall reduces
tethering of the airways by the surrounding lung parenchyma, leading to reduced airway
caliber. Obesity-related chest wall restriction also has been associated with reduced
total lung capacity and a breathing pattern characterized by reduced functional residual
capacity and tidal volumes. Normal tidal breathing with periodic deep “sigh” breaths
serves to stretch airway smooth muscle, detach actin-myosin cross-bridges and maintain
normal cyclic bronchodilation and airway caliber. Restricted respiration seen in the
obese involves reduced airway dilation [41], likely due to unloading of airway smooth
muscle and greater smooth muscle tone. Over time these changes could lead to fixed
reductions in airway caliber and enhanced airway responsiveness[42]. These
physiologic characteristics seen in obese adults may be more subtle and variable in
children [43-48] and may play a reduced role in obesity-related pediatric asthma
symptoms.
Lifestyle factors related to obesity may also play a role in asthma risk. The typical
“Western” high-fat diet contains up to 25-fold more omega-6 (n-6) polyunsaturated fatty
acids (PUFA) than n-3 PUFAs. This 25:1 ratio is much higher than the 1-2:1 ratio typical
for humans during the majority of evolution [49-51]. A “Mediterranean” diet higher in
antioxidants from fruits and omega-3 fatty acids appears to protect from recurrent
wheezing in young children[52]. A diet with elevated n-6 PUFA appears to increase
production of inflammatory mediators from the 5-lipoxygenase pathway, and increases
free radical generation and oxidative stress [53-56]. Also, increases in dietary and
inflammatory cell n-3/n-6 fatty acid ratio have been associated with improvements in
asthma outcomes [57-61]. Importantly, obese individuals have been shown to consume
more n-6 dietary PUFAs, and have a reduced n-3/n-6 ratio in their diet compared to
leans [62]. Obese adolescents do appear to have lower n-3 PUFA (especially DHA) and
lower n-3/n-6 PUFA serum levels compared to lean adolesents [63]. The pattern of
essential fatty acids among obese adolescents appears to differ significantly from leans,
suggesting there may exist abnormal essential n-3 PUFA metabolism in the obese. A
typical high-fat ‘Western’ diet maintains a low leukocyte phosholipid membrane n-3/n-6
PUFA ratio, leading to greater cellular expression of 5-lipoxygenase pathway products,
(such as leukotrienes), TNFα, and other molecules important in asthma pathogenesis
[64-67].
A second lifestyle factor that is an important consideration in the obesity-asthma link is
physical activity. Children who are overweight or obese sustain less routine physical
exertion than lean counterparts. Some reports suggest that physical activity may be
important in reducing asthma-risk [68] and reducing asthma symptoms [69-71], though
other reports have not corroborated these findings [14, 52]. Lucas et al has raised the
concern that past cohort studies have not adequately controlled for reduced physical
activity, raising the question of whether reduced activity in combination with other
obesity-related factors may be the cause of increased asthma incidence [21]. Within
repeated exercise comes hyperventilation, cyclic ASM stretch, and bronchodilation. Invitro studies suggest that exercise-related cyclic respiratory epithelial compression may
improve airway clearance and caliber[72].
It would also be rationale to hypothesize that the obesity-asthma link stems from
common genetic origins [28, 73]. It is likely that genes contributing to one multi-factorial
complex disease contribute directly or indirectly to other multi-factorial complex
diseases. To date, our limited understanding has stemmed from discovering
associations between obesity and asthma phenotypes and candidate gene variants. For
example, several promising genomic areas that contain genes connected with both
obesity and asthma (5q23-32, 6p21-23, 11q13, and 12q13-24) have been identified [19,
27, 28, 73, 74] [75, 76]. Only 5 genes have polymorphisms that have been associated
with both obesity and asthma [77, 78]. These are: β2-adrenergic receptor gene
(ADRB2), the TNFα gene, the lymphotoxin-α (LTA) gene, vitamin D receptor (VDR) gene
and PRKCA. Further interrogation of these and other genetic loci is needed among
cohorts with and without obesity and with and without asthma in order to better
understand the nature of the obesity-asthma link.
It is possible that more than one of the above mechanisms (or mechanisms not yet
considered) may act together in increasing asthma risk. We must consider that asthma
is a heterogeneous condition with patients varying widely in terms of severity, airflow
obstruction, exacerbation triggers, symptom frequency, risk for exacerbation, lung
function decline, airflow obstruction, and treatment response. It is possible that the
impact of obesity on asthma-risk varies among individuals, depending on an individual’s
genetic factors (gene-environment or gene-gene interactions) or concomitant
environmental triggers, such as exposure to environmental tobacco smoke or other
pollutants.
The Obese Asthma Phenotype in Children
Obese children with asthma pose a hefty pediatric management challenge. Several
studies have evaluated asthma characteristics among lean and obese children. Several
reports suggest that asthma symptoms are more severe among obese children [38, 7983] while others have found no difference in lung function or asthma severity [84-87].
Data suggest that obese asthmatics are at least as hard to control as their lean
counterparts, and in some reports are less responsive to conventional therapies [88-90]
[81, 82] [89, 91-93]. Much of the data describing obese asthma comes from adults.
Overall, obese adult asthmatics generally have similar lung function (or modest
reductions in lung volumes) and airway responsiveness compared to lean asthmatics.
Obese adult asthmatics generally achieve reduced asthma symptom control and are
less apt to have severe atopy and eosinophil-driven inflammation. There is evidence
that leukotrienes may play a more prominent role in the obese asthma phenotype [94].
Leukotriene production is up-regulated in patients with obesity [95] and is important in
asthma pathogenesis [31, 32]. We previously determined the allele frequencies of the
addition/deletion promoter polymorphism in the ALOX5 gene among a population of
asthmatics undergoing a clinical trial [96, 97]. The ALOX5 gene encodes for 5lipoxygenase which catalyzed the oxidation of membrane arachidonic acids to create
LTA4. Recently we have analyzed the allele frequencies of this ALOX5 polymorphism
among lean and obese participants of this study and a second population of obese and
non-obese, otherwise healthy (non-asthmatic) volunteers (Table).
Among the non-asthmatics, 57% of obese individuals carried the variant allele compared
to 40% for non-obese individuals. The relative risk of obesity in individuals carrying the
variant allele is 2.04 compared to carriers of the wild type (p = 0.0165). It is not clear if or
how this promoter polymorphism contributes
to obesity. Nevertheless, it is rationale
therefore to hypothesize that obese, nonasthmatic persons may be at greater risk for
developing asthma due in part to the mutant
ALOX5 variant and to greater upregulation
of the leukotriene pathway compared to the
those with the wildtype genotype[96, 98].
Furthermore, due to the higher prevalence
of the ALOX5 variant in obese asthmatics,
leukotriene levels may be elevated in a
larger fraction of obese patients, thus
making them prime candidates to benefit
from therapies acting on the leukotriene
pathway.
The obese asthmatic child: Management considerations
Studies in adults have evaluated asthma outcomes following weight-loss interventions
[99-102]. The most consistent findings involve the improvement in breathlessness,
exercise tolerance, asthma symptoms and lung volumes. It has been difficult to
decipher improvements in general cardiorespiratory health and wellness following weight
loss, from asthma-specific improvements. Though the impact of weight-loss in obese
children with asthma has not been adequately studied, it is rationale to expect similar
improvements in symptom control and lung volumes, and striving for a healthy weight
should continue to be a primary goal. Exercise and other life-style intervention remains
an important area of future research for obese children with asthma.
Current research does not support major deviations from current GINA and NHLBI EPR3
guidelines for the care of all asthmatics. However, volume of distribution and the
metabolic/hormonal alterations associated with obesity may impact the
pharmacokinetics and pharmacodynamics of therapeutic agents. Recent research may
provide important guidance to the clinician for individual obese patients. Evidence
suggests that obesity may blunt the response to inhaled corticosteroids [88, 91, 94] and
low-dose theophylline [90]. Limited empirical data suggests that obese asthmatics may
respond more favorably to montelukast with increasing BMI [94].
Since much of the impairment domain of asthma control involves subjective assessment
and quality of life issues, attention to obesity-related sequelae that may interact with
asthma symptoms remains critically important. Though empiric treatment for “silent”
gastro-esophageal reflux so far does not seem warranted [103], some obese patients
with gastro-esophageal reflux and cough may improve with anti-reflux medications.
Clinicians should maintain a high-index of suspicion for certain common obesity-related
comorbidities such as sleep-disordered breathing (especially those with snoring, sleep
disturbance, or daytime behavior changes) and metabolic syndrome (especially among
children with central obesity, acanthosis nigricans, cutaneous striae or recurrent need for
oral corticosteroids).
The most universally effective management plan for obese children with persistent
asthma continues to involve inhaled corticosteroids, weight-loss, daily exercise and
repeated asthma education regarding inhaler technique and trigger avoidance.
Response heterogeneity likely exists among obese asthmatics as it does among lean
asthmatics. This means that a significant portion will respond best to ICS-LABA, a
portion will respond best to ICS plus montelukast, and the remaining will respond best to
a higher dose of ICS [104]. Because of the flat dose-response curve seen among obese
asthmatics, initial step-up therapy for obese asthmatics with poor control with ICS +
montelukast may be warranted. Regardless of the step-up therapy chosen, close followup is critically important to re-iterate proper inhaler techniques, weight-control, low-fat
diet, daily exercise and monitoring of asthma symptoms and medication side-effects.
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