Obesity and Asthma

Abstract

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.

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 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 obesity. However, most asthma studies have used BMI and metabolic dysfunction related to 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.

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 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

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 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 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 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 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.

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 pollutants. Much work remains to be done to understand whether these are unique phenotypes that require individualized therapeutic approaches.

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 FEV₁ and FVC but lower 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 to a low FEV₁/FVC ratio.⁶⁰ Obese children with asthma and dysanapsis had increased 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 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

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

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.

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 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 challenge, and withdrawal of asthma medication, they concluded that 31.8% of obese and 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 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 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.^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.

The Microbiome and the Pathophysiology of Obese Asthma

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 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 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 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 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, 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. 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 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 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 improvements in asthma outcomes. A recent retrospective study reported that metformin use 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

Figure 3. FEV1/FVC in adolescents with metabolic syndrome.

Metabolic syndrome (MS) and asthma synergistically reduce FEV1/FVC in adolescents. 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).

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

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 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 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

Lifestyle Weight Loss Interventions

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 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

Table 1.

Studies of lifestyle weight loss interventions and asthma

Author	Year	Number of Subjects	Groups/Intervention	Main Findings
Hakala144	2000	14 adults (all with asthma)	Single arm, very low calorie diet, 8-week intervention	Significant improvements in peak flow, spirometry and lung volumes. Mean weight loss 13.7 Kg.
Aaron145	2004	58 women (24 with asthma)	Single arm, meal replacement, 6-month intervention	Significant improvement in spirometry but not in AHR. Mean weight loss 20 Kg.
Johnson146	2007	10 adults (all with asthma)	Single arm, alternate day caloric restriction, 2-month intervention	Significant improvements in spirometry and asthma control, but not in spirometry. Mean weight loss 8% of baseline.
Van de Griendt154	2012	112 children (8–18 years, all without asthma)	Single arm, multidisciplinary weight loss intervention for severely obese children, 26 weeks’ duration	FEV1, TLC and ERV improved. Only ERV correlated with the reduction in BMI and in waist circumference. Mean weight loss 13.9 Kg.
Da Silva155	2012	76 adolescents (26 with asthma)	Single arm, multidisciplinary weight loss intervention, 1 year duration	Improvements in adipokines and lung function; improved asthma severity in the group with asthma.
Scott53	2013	46 adults (all with asthma)	Randomized to diet, exercise, or diet and exercise groups, 10-week intervention	Asthma control improved in diet and diet+exercise groups; 5–10% weight loss was associated with improved asthma control.
Jensen156	2013	28 children (8–17 years, all with asthma)	Randomized to intensive dietary intervention versus wait list control, 10-week intervention	Improvements in ERV and asthma control in the intervention group. Mean weight loss 3.4 Kg.
Luna-Pech148	2014	51 children (12–18 years, all with asthma)	Randomized to supervised normocaloric versus no intervention for 28 weeks	Weight loss correlated with improved asthma control and quality of life. Mean weight loss 2.5 Kg.
van Leeuwen149	2014	20 children (8–18 years, all with asthma)	Single arm, dietary intervention, 6 weeks’ duration	Improvement in quality of life and 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 intervention versus educational intervention, 1-year study	Increased odds of improvement in asthma control in those who lost ≥ 10% weight.
Pakhale151	2015	22 adults (all with asthma)	Single arm, liquid meal replacement versus observation control, 3 months’ duration	Improvement in FEV1, FVC, asthma control and AHR. Mean weight loss 16.5 Kg (14.2% of baseline)
Willeboordse157	2016	87 children (6–16 years, all with asthma)	Randomized to multifactorial intervention vs usual care, 18-month duration	Weight, lung function, and asthma outcomes improved in both groups; intervention had greater improvement in FVC and asthma control.
Freitas152	2017	55 adults (all with asthma)	Randomized to dietary and exercise intervention versus diet only, 3 months’ duration	Diet and exercise lost more weight than diet alone (6.8 vs 3.1%), greater improvements in asthma control, and FeNO

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 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 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 it is also possible that significant weight loss might reduce the risk of certain infections that 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 phenotyped merely by the presence or absence of wheezing.

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

Future research should aim to.

• -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.
• -Investigate how changes in the diet and microbiome might affect outcomes in asthma.

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.

• 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.

Abbreviations/Acronyms

AHR

Airway hyper-reactivity or hyper-responsiveness

BMI

Body mass index

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

ICS

Inhaled corticosteroids

IL

Interleukin

ILC

Innate lymphoid cells

LABA

Long-acting beta-agonists

NO

Nitric oxide

RCT

Randomized controlled trial

SCD

Stearoyl-coenzyme A reductase

SCFA

Short-chain fatty acids

SNP

Single nucleotide polymorphism

SPA

Surfactant protein A

TLC

Total lung capacity