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J Allergy Clin Immunol. Author manuscript; available in PMC 2019 April 01.
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Published in final edited form as:

J Allergy Clin Immunol. 2018 April ; 141(4): 1169–1179. doi:10.1016/j.jaci.2018.02.004.

Obesity and Asthma

Ubong Peters, PhD1, Anne Dixon, MA, BM, BCh1, and Erick Forno, MD, MPH2
1Pulmonary and Critical Care Medicine, University of Vermont, Burlington, VT
2Pediatric Pulmonary Medicine, Allergy, and Immunology, University of Pittsburgh, Pittsburgh, PA

Abstract
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Obesity is a vast public health problem, and both a major risk factor and a disease modifier for
asthma in children and adults. Obese subjects have increased risk of asthma, and obese asthmatics
have more symptoms, more frequent and severe exacerbations, reduced response to several asthma
medications, and decreased quality of life. Obese asthma is a complex syndrome, including
different phenotypes of disease, phenotypes which are just beginning to be understood. We
examine the epidemiology and characteristics of this syndrome in children and adults, as well as
the changes in lung function seen in each age group. We then discuss the better-recognized factors
and mechanisms involved in disease pathogenesis, focusing particularly on diet and nutrients, the
microbiome, inflammatory and metabolic dysregulation, and the genetics/genomics of obese
asthma. Finally, we describe current evidence on the impact of weight loss, and mention some
important future directions for research in the field.
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Keywords
asthma; obesity; obese asthma; metabolic syndrome; microbiome

Introduction
Obesity is both a major risk factor and a disease modifier of asthma in children and adults.
While obesity is defined according to a threshold BMI, recent studies suggest that BMI z-
scores may be unreliable, particularly among children and adolescents with severe obesity.
1–3 In adults, obesity is defined as a body mass index (BMI) of 30 kg/m2 or more, yet a

given BMI may reflect vastly differing physiology and metabolic health. This distinction is
likely important for asthma: while serum interleukin (IL-)6 (produced by macrophages in
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adipose tissue, and a marker of metabolic health) is a marker of asthma severity, some
individuals with BMI’s in the non-obese range have elevated IL-6;4 Sideleva et al found that
adipose tissue inflammation is increased in obese individuals with asthma, compared with
obese controls.5 Metabolic dysfunction is more important than fat mass for asthma in

Corresponding Author: Erick Forno, MD, MPH, Division of Pulmonary Medicine, Allergy, and Immunology, Children’s Hospital of
Pittsburgh, 4401 Penn Ave – Rangos 9130, Pittsburgh, PA 15224, Office: 412.692.8429. Fax: 412.692.7736, [email protected].
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 Peters et al. Page 2

obesity. However, most asthma studies have used BMI and metabolic dysfunction related to
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obesity synonymously; in this article, we will report data on metabolic dysfunction where
available, but will otherwise use obesity as a marker of both fat mass and metabolic
dysfunction.

Epidemiology of Obesity and Childhood Asthma

Asthma affects approximately 6.5 million children (~9% prevalence) in the U.S.6 Likewise,
17% of children in this country are obese, and another 15% are overweight.7 Obesity is now
recognized as a major risk factor for asthma: several longitudinal epidemiological studies
show that obesity or increased adiposity often precedes incident asthma.8–16 Many studies
have reported differing obesity-asthma associations by sex,10,17–20 although results on which
gender is more affected have been conflicting. Obesity is also associated with increased
asthma severity.
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Obesity-induced increases in asthma risk may start in utero. In a meta-analysis of over

108,000 participants, we found that maternal obesity and weight gain during pregnancy are
independently associated with ~15–30% increased risk of asthma in the offspring, and others
have reported very similar findings.21,22 This risk is not merely mediated by the child’s own
obesity.23 Mechanisms involved may include inflammatory or other changes during
pregnancy or early post-natal life,24–26 and these mechanisms may explain why excessive
weight gain in infancy has also been linked to recurrent wheezing and asthma.27,28

Epidemiology of Obesity and Asthma in Adults

A meta-analysis of several prospective studies involving over 300,000 adults found a dose-
response relationship between obesity and asthma: the odds ratio of incident asthma was 1.5
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in the overweight, and 1.9 in the obese compared with the lean group – in effect 250,000
new asthma cases per year in the US are related to obesity.29 This relationship has radically
changed the demographics of asthma in the US: the prevalence of asthma in lean adults is
7.1%, and in obese adults 11.1%. The relationship is more striking in women – the
prevalence of asthma in lean versus obese women is 7.9 and 14.6%, respectively.30

Clinical Characteristics of Obese Asthma in Children

Asthma may on occasion predispose to obesity,31 obesity may confound its diagnosis,32,33
or both may simply co-occur. However, the majority of observational and experimental
evidence points towards an “obese asthma” phenotype, in which obesity modifies asthma.
34,35
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Obese children tend to have increased asthma severity,36–38 poorer disease control,39 and
lower quality of life.40 Many obese children with asthma tend to have Th1-skewed
responses, particularly in response to inflammatory stimuli, with at least part of these
responses mediated by systemic inflammation, insulin resistance, and/or alterations in lipid
metabolism.41–43 These children and adolescents also tend to have a decreased response to
asthma medications. Using data from the Childhood Asthma Management Program
(CAMP), we described that overweight and obese children with asthma had a reduced

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response to inhaled corticosteroids (ICS), leading to increased prednisone courses and

moderate-to-severe exacerbations.44 More recently, McGarry et al reported that obese black
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and Latino adolescents were 24% more likely to be bronchodilator unresponsive than their
non-obese peers.45 Moreover, among children hospitalized for asthma, obesity is associated
with longer length of stay and with higher risk of mechanical ventilation.37 Obese children
with asthma may also be more susceptible to having increased symptoms with exposure to
indoor pollutants.46

Clinical Characteristics of Obese Asthma in Adults

Much like children, obese adults tend to have more severe asthma than lean adults, with a 4-
to 6-fold higher risk of being hospitalized compared with lean adults with asthma.47 Nearly
60% of adults with severe asthma in the US are obese.48 Obese patients also have worse
asthma control and lower quality of life.49 Obese asthmatics do not respond as well to
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standard controller medications such as ICS and combination ICS-long acting beta agonists
(LABA).50 The mechanisms behind the impaired ICS response are likely related to
increased production of inflammatory cytokines in obesity, which reduce induction of
mitogen-activated kinase phosphatase-1 by glucocorticoid, a signalling protein that plays an
important role in steroid responses.51 Impaired response to asthma therapy in obesity is also
due to the altered pathogenesis of disease, which does not respond well to medications
developed to treat conventional allergic asthma.

There are likely several phenotypes within the obese asthma syndrome (Figure 1). Holguin
et al reported that obese asthmatics with earlier-onset disease (who tended to have higher
markers of Th2 inflammation) had the most severe disease among obese asthmatics.47 There
is also a group with later-onset disease, most often female, with little in the way of airway
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inflammation, but significant inflammation in adipose tissue and increased airway oxidative
stress.5 Some have described a phenotype with neutrophilic airway inflammation,52 which
improves with weight loss in women.53 Obese individuals appear to have increased
susceptibility to air-pollutants,54,55 which has been elegantly modeled in animals.56 Whether
this contributes to a distinct phenotype or complicates other phenotypes is not yet clear.

Obesity and Lung Function in Pediatrics

Childhood obesity has a significant effect on lung function. While our initial understanding
of this phenomenon derived from studies in adults (described in the following section), as
early as 1997 Lazarus et al reported that height-adjusted forced expiratory volume in 1
second (FEV1) and forced vital capacity (FVC) were greater in children with higher weight.
57 Tantisira et al described that BMI was associated with higher FEV and FVC but lower
1
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FEV1/FVC among participants in the Childhood Asthma Management Program (CAMP).58

In a recent meta-analysis including dozens of studies we reported that childhood obesity is
associated with normal or higher FEV1 and FVC, but a lower FEV1/FVC.59 We recently
described that childhood obesity is associated with airway dysanapsis, an incongruence
between the growth of the lung parenchyma and that of the caliber of the airways that is
reflected in normal or supra-normal FEV1 and FVC, but with larger effects on FVC that lead

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to a low FEV1/FVC ratio.60 Obese children with asthma and dysanapsis had increased
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symptoms, medication use, and asthma exacerbations.

Many studies of spirometric lung function have found differential associations based on sex.
In the study by Tantisira, the decrease in FEV1/FVC with BMI was more pronounced in
boys than in girls.58 Accordingly, we found that the risk of dysanapsis from obesity was
higher in boys. However, others have found stronger obesity-lung function associations in
girls. Similarly, age is a critical factor. In a large meta-analysis of 24 birth cohorts, Den
Dekker et al showed that greater birthweight and faster infant weight gain was associated
with higher FEV1 and FVC, but lower FEV1/FVC, in school-age children.61 Conversely,
Strunk et al reported that CAMP participants who were not obese during the trial but became
obese later on had significant decreases in FEV1 and FEV1/FVC (compared to participants
who were never obese) at ~26–30 years of age, with no significant associations with FVC.62
This is consistent with data in adults: obese patients with early-onset asthma have more
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severe airflow limitation than obese adults with late-onset asthma.47

The effect of childhood obesity on lung volumes has been less studied, with only a handful
of reports that have described conflicting findings. Davidson et al reported that obese non-
asthmatic children had lower functional residual capacity (FRC), residual volume (RV), and
expiratory reserve volume (ERV) than their non-obese counterparts.63 Rastogi et al recently
reported similar findings, further describing associations with insulin resistance and reduced
high-density lipoprotein (HDL).64 However, others have reported higher total lung capacity
(TLC) in obese adolescents, and yet others have reported no significant associations.65,66
Similarly, it is not clear whether obesity leads to changes in airway hyperresponsiveness
(AHR) in children, with some studies reporting higher67 and others lower AHR.68
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Lung Function and Airway Hyperresponsiveness in Obese Adults

Obesity causes significant changes to normal lung physiology in adults (Figure 2). Excessive
accumulation of fat in the thoracic and abdominal cavities lead to lung compression and an
attendant reduction in lung volume.69 The most notable changes include a reduction in FRC
and ERV.70–72 Radial traction of lung parenchymal attachments around the airways is
attenuated at low lung volumes,73 which may contribute to airway collapse. Indeed, we have
shown that obesity increases the collapsibility of the peripheral airways and parenchyma,
especially among asthmatics with late-onset disease.74

AHR is a distinguishing feature of asthma. The only prospective longitudinal cohort study
that investigated the relationship between obesity and AHR –in more than 7,000 adults–
reported that the risk for AHR increases with BMI, and weight gain was a risk factor for
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developing AHR.75 Some smaller studies failed to find a consistent relationship between
AHR and obesity;76,77 this might be related to small sample sizes or differences between
patient populations.

Misdiagnosis of asthma is common, but no more common in obese than non-obese patients.
Aaron et al conducted a prospective study of 540 individuals with physician-diagnosed
asthma and after rigorous assessment with bronchial reversibility and methacholine

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challenge, and withdrawal of asthma medication, they concluded that 31.8% of obese and
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28.7% of non-obese patients diagnosed with asthma were actually misclassified as having
asthma.78 Diagnosis of asthma should be confirmed by physiological testing in both lean
and obese patients with respiratory symptoms.

The Role of Diet

Specific micronutrients may be involved in the association between obesity and asthma.
Obesity is associated with low circulating vitamin D.79 Vitamin D deficiency may be a risk
factor for the development of both obesity and asthma: prenatal vitamin D insufficiency has
been associated with obesity in the offspring,80 and prenatal vitamin D supplementation led
to a small decrease in the risk of wheezing illness at age 3 (though this did not reach formal
statistical significance).81,82 This could be highly significant for asthma in obesity; there is a
growing literature on the association between vitamin D deficiency and the risk of
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respiratory infections, asthma exacerbations83 and corticosteroid resistance,84 and so

vitamin D deficiency may predispose to the development of obesity, and then to a phenotype
of increased asthma severity and corticosteroid resistance. The efficacy of supplementation
of vitamin D specifically on asthma in obesity is not known.

Diets that promote obesity, such as the Western diet pattern, tend to be high in saturated fatty
acids, low in fiber and anti-oxidants, and high in sugars like fructose. There is a growing
literature on the harmful effects of these specific dietary components on asthma. Ingestion of
a single meal high in saturated fatty acids increases neutrophilic airway inflammation and
decreases bronchodilator responsiveness.85 Animal studies suggest that a high fat diet
increases the number of innate lymphoid cells in the lung, and can induce both innate AHR
and allergic airway inflammation through an IL1β pathway.86,87 Supplementation with a
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high versus low anti-oxidant diet for 14 days (but not an anti-oxidant supplement) improved
spirometric lung function and increased subsequent time to asthma exacerbation, though this
has not been studied specifically in obese asthma.88 Studies in a mouse model of asthma
suggest that a diet high in fructose promotes systemic metabolic dysfunction, and increases
AHR and airway oxidative stress.89 There are few studies of dietary interventions promoting
healthy dietary patterns in obese asthmatics, though a recent pilot study suggests that this
approach may constitute an alternative to simply promoting weight loss.90

Specific dietary and nutritional risk factors may affect children. Breastfeeding has been
associated with lower risks of both obesity and asthma.91,92 High-sugar containing
beverages are a risk factor for asthma,93 as is a diet poor in vegetables and grains but rich in
sweets and dairy products.94 Omega-3 has been associated with lower incidence of asthma,
whereas omega-6 fatty acids are associated with higher risk of asthma in the pediatric age.
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95,96

The studies described above implicate dietary factors as potentially having direct effects on
the airways, but it is also possible that diet could have indirect effects on the airway through
effects on the gut microbiome.

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The Microbiome and the Pathophysiology of Obese Asthma

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Dietary changes lead to alterations in gut microbiome, and the changes characteristic of a
Western dietary pattern which promote obesity might also affect the development of allergic
airway disease. Bacterial colonization of the gut plays a key role in the fermentation of
dietary fiber and the generation of short chain fatty acids (SCFA). Obesogenic diets are
typically high in fat and low in soluble fiber; low fiber is associated with changes in gut
microbiome and circulating levels of SCFA.97 Bacteroidetes bacteria –a major producer of
SCFA– is reduced in the gut in obesity,98 and in the lungs in asthma.99 A low fiber diet
decreases levels of the SCFA propionate; Trompette et al showed that a low fiber diet with
low circulating propionate was associated with exaggerated allergic airway inflammation in
a mouse model, and that increasing propionate decreased the ability of dendritic cells to
promote Th2 responses and so attenuated allergic airway inflammation.100 Conversely,
Thorburn et al showed that a high fiber diet increases levels of acetate, which inhibits the
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development of allergic airway inflammation in a mouse model through effects on histone

deacetylase 9 and Treg function; this effect could also be seen in offspring of mice fed a high
fiber diet, likely through epigenetic modification of the FoxP3 promoter.101 The authors also
reported that high serum acetate in women was associated with lower risk of allergic airway
disease in children. These studies suggest that diets low in fiber lead to changes in the gut
microbiome, which can promote both obesity and allergic asthma.

Another factor that could alter microbiome is antibiotic exposure. Antibiotic exposure early
in life has been associated with asthma102 and with obesity.103 The leading theory is that
early changes in the microbiome may alter the maturation of the immune system, as
anomalous responses to these changes have been reported to precede asthma and atopy.104
Probiotic supplementation in early life (in utero and/or infancy to either the mother, the
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infant, or both) has been shown to reduce the risk of atopy but not asthma.105

The airway microbiome may be altered in obese asthma. A recent study in bronchial
brushings from severe asthmatics showed that BMI was associated with changes in airway
microbial composition and with fewer lung tissue eosinophils.106 It is unclear whether these
microbiome changes cause the reduced eosinophils, or are simply an unrelated consequence
of other changes seen in obesity (such as other immune derangements or increased
gastroesophageal reflux).

Inflammatory and Metabolic Changes in Obese Asthma

Many studies have reported that obesity-related asthma is more often non-atopic; yet, some
studies have reported that obesity in itself is associated with atopy.107,108 In adolescents
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participating in the National Health and Nutrition Examination Survey (NHANES), we

found that obesity was associated with asthma only among participants with normal or low
exhaled nitric oxide (FeNO); however, among those who already had asthma and high
FeNO, obesity was associated with increased asthma severity.109

Classic Th2 inflammation is complicated by the obese state. For example, eosinophilic
airway inflammation is altered in obesity, with altered trafficking of eosinophils into the

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airway lumen – sputum eosinophils and exhaled nitric oxide might underestimate the degree
of Type 2 inflammation in obesity.110 Obesity skews CD4 cells towards Th1 polarization,
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which is associated with worse asthma severity and control, and abnormal lung function.42 It
is worth noting that eosinophils, alternatively activated macrophages and Type 2 cytokines
are thought to play an important homeostatic role in healthy adipose tissue, with infiltration
of pro-inflammatory M1 macrophages and decreased eosinophils associated with the
development of obesity and insulin resistance – how this relates to airway disease is not
clear.111,112

Innate immune responses involving Th17 pathways and innate lymphoid cells (ILCs) have
also been implicated.86,87 ILCs play an important role in adipose tissue homeostasis, and
thus changes in ILC function in obese adipose tissue could contribute to both obesity and
asthma.111,113 Macrophage activation by ILCs and other pathways may constitute an
important link between adiposity and worse asthma outcomes.114 In patients, Zheng et al.
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reported increased sputum neutrophils in “non-atopic obese asthmatics”, while subjects with
“atopy-obesity overlap” exhibited higher sputum macrophage counts, suggesting the
importance of these innate pathawys in obesity-related asthma.115

Changes in pulmonary innate immune function likely contribute to asthma in obesity. For
example, bronchoalveolar fluid levels of surfactant protein A (SPA) –which helps modulate
response to infectious and other insults– are lower in obese asthmatic subjects compared to
their lean counterparts, and mouse models have shown that administration of SPA reduces
lung tissue eosinophilia following allergen challenge,116 suggesting that changes in
surfactant protein function could alter airway eosinophilia in obese asthma.

Adipokines and other cytokines produced or induced by adipose tissue may also affect the
lungs and the airways (Figure 2).117,118 Higher leptin levels in obese adolescents correlate
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inversely with FEV1, FVC, and FEV1/FVC,41,119 and visceral fat leptin expression
correlates with airway reactivity in adults.5 Leptin and adiponectin have also been associated
with exercise-induced changes in lung function.120 Most existing literature is based on
cross-sectional studies, and it is not clear whether adipokine levels may serve as biomarkers
to identify at risk patients, to follow response to management, or are pathogenic mediators of
disease.

Metabolic dysregulation plays an important role in many complications of obesity, including

asthma.121,122 Hyperglycemia and hyperinsulinemia may contribute to AHR and remodeling
via epithelial damage and airway smooth muscle proliferation.123–125 The metabolic
syndrome has been associated with asthma and with lower lung function in adults.126–128
Similarly, we previously reported that insulin resistance and the metabolic syndrome are
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associated with lower lung function in adolescents with and without asthma (Figure 3).129
Obesity-related pro-inflammatory cytokines like IL-6 may play a crucial role in the
relationship between the metabolic syndrome, lung function, and asthma severity.4
Innovative approaches such as breath condensate analytics using nuclear magnetic resonance
have recently identified distinct metabolic signatures in obese asthma, suggesting unique
pathogenic pathways compared to obesity or asthma alone.130 Research is needed to
determine whether pharmacological management of the metabolic syndrome may lead to

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improvements in asthma outcomes. A recent retrospective study reported that metformin use
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was associated with improved asthma outcomes among subjects with both diabetes and
asthma,131 although a prospective study of pioglitazone did not show efficacy in obese
asthma.132

Increased oxidative stress occurs in obesity, and increased airway oxidative stress has been
found particularly in obese adults with late onset asthma.133 This is thought to be related to
reduction in the biovailability of arginine, a substrate for the production of nitric oxide (NO):
NO is an endogenous bronchodilator, and so reduced NO bioavailability may contribute to
airway disease in obesity.53 Altered adaptive and innate immune responses, adipose related
inflammation and increased oxidative stress all likely contribute to asthma in obesity.

Genetics, Epigenetics, and Genomics

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Both asthma and obesity have a considerable hereditary component, and thus investigators
have studied whether there are genetic variants that may represent a link. Yet to date these
studies have been somewhat inauspicious. Candidate gene studies have reported a few genes
associated with asthma and BMI, such as PRKCA, LEP, and ADRB3.134–136 The largest
pediatric genome-wide association study (GWAS) to date, which included over 23,000
children and adults, reported gene DENND1B, although the main single nucleotide
polymorphism (SNP) did not replicate in the independent cohorts.137

Other approaches have yielded more encouraging results. In a gene-by-environment

analysis, Wang et al found seven SNPs in 17q21 (a well-known asthma-associated locus)
were associated with BMI only among subjects with asthma in two independent cohorts.138
In a small pilot study in 32 children, Rastogi et al described differential epigenome-wide
DNA methylation patterns in children according to their obesity and asthma status.139 In a
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CD4+ T-cell transcriptome analysis, they also reported Th1-related pathways that are
differentially expressed in obese vs non-obese asthmatic children.140 And a study in mice
and humans by Ahangari and colleagues found that expression of gene CHI3L1 can be
induced by a high-fat diet, and that its product (chitinase 3-like 1) may contribute to both
truncal obesity and asthma symptoms.141 Thus, while obese asthma may not be directly
determined by genetic polymorphisms, it may be influenced by epigenetic or transcriptomic
regulation.

Genetics have also allowed investigators to dissect the many potential factors that may
confound the association between obesity and asthma, including socioeconomic status,
lifestyle factors, and environmental exposures. Using a Mendelian randomization approach,
Granell et al recently constructed a weighted allele score using 32 SNPs known to be
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associated with BMI, and demonstrated that the score was also strongly associated with
asthma in school-aged children.142 Similarly, in adults, Skaaby and colleagues used a score
of 26 BMI-associated SNPs, and found that BMI is related to higher risk of asthma and
lower lung function.143

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Lifestyle Weight Loss Interventions

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Studies published on the effects of various life-style weight loss on asthma control find
significant improvements in asthma control and spirometric lung function with sufficient
weight loss (Table 1).53,144–152 Interventions vary from liquid diet replacement, to a more
graduated dietary education approach. In adults, it appears that weight loss of at least 5% is
required to produce a significant improvement in asthma control.150 This is typically
associated with improvements in peak flow, spirometric lung function, and ERV. Studies
which have produced the most weight loss appear to be associated with the most significant
improvements in asthma control. Effects on AHR have been variable, with some studies151 –
but not all145– reporting significant improvements in airway reactivity; we speculate the
reasons for these contrasting findings may be related to the different phenotypes of obese
asthmatics. Few studies have reported the effects on markers of airway inflammation. One
recent study compared dietary intervention versus exercise plus dietary intervention and
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found improvements in exhaled nitric oxide with exercise plus dietary intervention;152 but it
is not clear if it this was related to exercise (exercise may reduce allergic airway
inflammation through effects on Treg cell function153) or the weight loss. Scott et al
reported a decrease in airway neutrophilic inflammation in proportion to gynoid fat loss in
women (and reduction in saturated fatty acid intake in men).53

Pediatric studies of weight loss interventions for obesity and asthma are scarce. Non-
controlled studies have reported improvements in FEV1, ERV and TLC that correlate with
BMI,149,154 and changes in adipokine levels that correlate with improvements in FEV1 and
FVC as well as exercise-induced bronchoconstriction.155 However, without control groups
all of these studies are limited to small-group before/after comparisons. In a recent
randomized control trial (RCT), a dietary intervention resulted in significant improvements
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in ERV, although the difference with the control group was not significant.156 Conversely,
another RCT in children with asthma reported a greater improvement in FVC in the
intervention group compared to the control group, but BMI changes were similar in both
groups; there were no differences in FEV1/FVC, ERV, or TLC.157 Finally, in another RCT
Luna-Pech et al showed reduced exacerbations and improved quality of life.148

Bariatric Surgery
The effects of bariatric (weight loss) surgery have been reported by a number of
investigators.158–160 It is the most effective intervention for producing sustained and
significant weight loss, and all studies have reported highly significant improvements in
asthma control, airway reactivity and lung function (Figure 2). Bariatric surgery also has
significant effects on asthma exacerbations. Hasegawa et al studied 2261 patients with
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asthma using a population Emergency Department and in-patient sample database; bariatric
surgery led to a nearly 60% reduction in the risk of having an asthma exacerbation, with a
baseline risk of asthma exacerbation in the population of approximately 22%.161 Reduced
exacerbations may partly be related to effects on lung mechanics and airway reactivity, but
as obesity is associated with worse outcomes related to viral and bacterial infections such as
influenza and bacterial pneumonia,162,163 and impaired response to influenza vaccination,164

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it is also possible that significant weight loss might reduce the risk of certain infections that
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precipitate asthma exacerbations.

Conclusions
Obesity is an important risk factor for asthma and for asthma morbidity, both in children and
adults. While there are many common pathophysiological and clinical commonalities,
certain characteristics differ between both age groups. This is a reflection of an obese
asthma syndrome that is complex and multifactorial. Potential underlying mechanisms
include a shared genetic component, dietary and nutritional factors, alterations in the gut
microbiome, systemic inflammation, metabolic abnormalities, and changes in lung anatomy
and function (Figure 4). There is growing evidence that weight loss interventions also help
improve asthma outcomes. Future studies should characterize obesity beyond BMI,
considering other anthropometric indices and biomarkers, much like asthma is not
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phenotyped merely by the presence or absence of wheezing.

Acknowledgments
Funding: Dr. Forno’s contribution was supported in part by grants HL125666 and HL119952 from the U.S.
National Institutes of Health (NIH), a grant from Children’s Hospital of Pittsburgh of UPMC, and an award from
the Klosterfrau Foundation. Drs. Peters and Dixon were supported by NIH grants HL133920 and HL130847.

Abbreviations/Acronyms
AHR Airway hyper-reactivity or hyper-responsiveness

BMI Body mass index

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CAMP Childhood Asthma Management Program

ERV Expiratory reserve volume

FeNO Fractional exhaled nitric oxide

FEV1 Forced expiratory volume in the first second

FRC Functional residual capacity

FVC Forced vital capacity

GWAS Genome-wide association study

HDL High-density lipoprotein

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ICS Inhaled corticosteroids

IL Interleukin

ILC Innate lymphoid cells

LABA Long-acting beta-agonists

NO Nitric oxide

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RCT Randomized controlled trial

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SCD Stearoyl-coenzyme A reductase

SCFA Short-chain fatty acids

SNP Single nucleotide polymorphism

SPA Surfactant protein A

TLC Total lung capacity

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Future research should aim to

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- Improve our understanding of the different mechanisms and pathways that

underlie obese asthma.

- Identify sub-phenotypes that may have different pathophysiology and thus

respond to different management strategies, as well as find biomarkers that
may help identify these subgroups.

- Develop new therapies and treatment approaches for these patients.

- Phenotype metabolic dysfunction rather than just BMI in asthmatics.

- Investigate how to effectively implement lifestyle interventions targeting

obese asthmatics.
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- Investigate how changes in the diet and microbiome might affect outcomes in
asthma.
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What do we know on the subject?

• Obesity is associated with increased asthma risk and morbidity.

• “Obese asthma” is a complex syndrome with many phenotypes, which may

differ between children and adults.

• Factors and pathways implicated in obese asthma include changes in lung

function, alterations in diet and nutrients, metabolic dysregulation,
microbiome changes, and differences in epigenetic/genomic regulation.

What is still unknown?

• How to accurately classify obese asthma phenotypes, both in children and

adults.
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• Whether new therapies or approaches may be more successful for patients

with obesity and asthma.

• Whether early-life microbiome or immune alterations predispose individuals

to both obesity and asthma.
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 Peters et al. Page 22
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Figure 1. Obese asthma syndrome

The syndrome of obese asthma likely includes many phenotypes: those typically seen in lean
individuals, now complicated by obesity; disease newly arising in obese individuals; and
perhaps a separate phenotype characterized by increased response to environmental
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pollutants. Much work remains to be done to understand whether these are unique
phenotypes that require individualized therapeutic approaches.

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Figure 2. Effect of obesity on biomarkers and clinical outcomes of asthma in adults

Proposed pathways that have been found altered in obesity and asthma in adults. Solid
arrows indicate the effect of obesity. Dashed arrows inside brackets indicate changes that
have been seen after weight loss. *Pathway has not been studied or no significant
associations have been reported.
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Figure 3. FEV1/FVC in adolescents with metabolic syndrome

Metabolic syndrome (MS) and asthma synergistically reduce FEV1/FVC in adolescents.
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Data from NHANES. Models adjusted for age, sex, race/ethnicity, health insurance, family
history of asthma, tobacco smoke exposure, C-reactive protein, and BMI z-score.
Reproduced with permission from JACI 2015 (PMID 25748066).

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Figure 4. Factors contributing to the syndrome of obesity-related asthma

AHR: Airway hyperreactivity. ASM: Airway smoth muscle. ERV: Expiratory reserve
volume. FRC: Functional residual capacity. GWAS: Genome-wide association study. NO:
Nitric oxide. SCFAs: Short-chain fatty acids
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Table 1

Studies of lifestyle weight loss interventions and asthma

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Author Year Number of Subjects Groups/Intervention Main Findings

Hakala144 2000 14 adults (all with asthma) Single arm, very low calorie diet, Significant improvements in peak flow,
8-week intervention spirometry and lung volumes. Mean
weight loss 13.7 Kg.

Aaron145 2004 58 women (24 with asthma) Single arm, meal replacement, 6- Significant improvement in spirometry but
month intervention not in AHR. Mean weight loss 20 Kg.

Johnson146 2007 10 adults (all with asthma) Single arm, alternate day caloric Significant improvements in spirometry
restriction, 2-month intervention and asthma control, but not in spirometry.
Mean weight loss 8% of baseline.

Van de Griendt154 2012 112 children (8–18 years, all Single arm, multidisciplinary FEV1, TLC and ERV improved. Only ERV
without asthma) weight loss intervention for correlated with the reduction in BMI and
severely obese children, 26 weeks’ in waist circumference. Mean weight loss
duration 13.9 Kg.

Da Silva155 2012 76 adolescents (26 with Single arm, multidisciplinary Improvements in adipokines and lung
asthma) weight loss intervention, 1 year function; improved asthma severity in the
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duration group with asthma.

Scott53 2013 46 adults (all with asthma) Randomized to diet, exercise, or Asthma control improved in diet and diet
diet and exercise groups, 10-week +exercise groups; 5–10% weight loss was
intervention associated with improved asthma control.

Jensen156 2013 28 children (8–17 years, all Randomized to intensive dietary Improvements in ERV and asthma control
with asthma) intervention versus wait list in the intervention group. Mean weight
control, 10-week intervention loss 3.4 Kg.

Luna-Pech148 2014 51 children (12–18 years, all Randomized to supervised Weight loss correlated with improved
with asthma) normocaloric versus no asthma control and quality of life. Mean
intervention for 28 weeks weight loss 2.5 Kg.

van Leeuwen149 2014 20 children (8–18 years, all Single arm, dietary intervention, 6 Improvement in quality of life and
with asthma) weeks’ duration exercise-induced bronchoconstriction, but
not in asthma control. Mean weight loss
2.6% of baseline.

Ma150 2015 330 adults (all with asthma) Randomized to intensive dietary Increased odds of improvement in asthma
intervention versus educational control in those who lost ≥ 10% weight.
intervention, 1-year study
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Pakhale151 2015 22 adults (all with asthma) Single arm, liquid meal Improvement in FEV1, FVC, asthma
replacement versus observation control and AHR. Mean weight loss 16.5
control, 3 months’ duration Kg (14.2% of baseline)

Willeboordse157 2016 87 children (6–16 years, all Randomized to multifactorial Weight, lung function, and asthma
with asthma) intervention vs usual care, 18- outcomes improved in both groups;
month duration intervention had greater improvement in
FVC and asthma control.

Freitas152 2017 55 adults (all with asthma) Randomized to dietary and Diet and exercise lost more weight than
exercise intervention versus diet diet alone (6.8 vs 3.1%), greater
only, 3 months’ duration improvements in asthma control, and
FeNO
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