Asthma and Three Colinear Comorbidities: Obesity, OSA, and GERD

Abstract

Asthma is a complex disease with heterogenous phenotypes and endotypes that are incompletely understood. Obesity, obstructive sleep apnea, and gastroesophageal reflux disease co-occur in asthmatics at higher rates than non-asthmatics. While these diseases share risk factors, there are some data suggesting these comorbidities have shared inflammatory pathways, drive the development of asthma or worsen asthma control. This review discusses the epidemiology, pathophysiology, management recommendations and key knowledge gaps of these common comorbidities.

Asthma is a heterogeneous disease that is complicated by multiple comorbidities and known risk factors. Comorbidities like obesity, gastroesophageal reflux disorder (GERD), and obstructive sleep apnea (OSA), contribute to disease severity in subjects with asthma. There are a number of shared risk factors among these comorbidities however, emerging evidence demonstrates that there is shared pathophysiology that drive the development and impact control of these conditions. A better understanding of the mechanisms by which these comorbidities contribute to asthma severity may provide insight towards targeted therapeutic approaches for asthmatics with these conditions.

This review discusses the current epidemiologic and pathophysiologic evidence tying each of these comorbidities to asthma and reviews key areas for future research.

OBESITY AND ASTHMA:

Analysis of literature

Asthma and obesity are associated with asthma risk increased by 50% in overweight and obese individuals(1). Obesity appears to have a causal role in asthma, as prospective studies indicate that obesity precedes asthma onset(2–7), and weight gain is associated with the development of asthma in susceptible individuals(3, 4). Obesity rates worldwide continue to rise(8), so a corresponding increase in obese asthma prevalence can be predicted.

Obese asthma has been described as two predominant phenotypes, with markedly different inflammatory profiles(9). Obese individuals with early onset allergic asthma (EOAA) have asthma which developed in childhood independent of obesity and is driven by type 2 inflammation. In EOAA, obesity worsens asthma symptoms, but asthma does not completely resolve with weight loss(9). Late onset nonatopic asthma (LONA) is a different clinical phenotype, in which asthma develops after childhood as a consequence of obesity and is more likely to resolve with weight loss(9). Cluster analyses have consistently identified LONA in older obese women, who have non-T2 inflammation, that is refractory to management with corticosteroids(10–12). The complexity of clinical expression makes obese asthma difficult to manage(13, 14).

Treatments:

Weight loss is the obvious solution to treat obese asthma, and there are multiple strategies that can be used. In uncontrolled studies, bariatric surgery improves asthma outcomes including symptoms, medication use and exacerbation rates(15–17). A systematic review found 6 trials and concluded that weight loss was generally associated with improvements in asthma-related quality of life, asthma control and lung function, regardless of the approach used to achieve weight loss(18). Of particular interest is one three-arm trial which randomized overweight/obese adults with asthma to either dietary intervention, exercise intervention, or a combination and found that 5–10% weight loss resulted in improvement asthma control in 58% and asthma quality of life in 83% of subjects, irrespective of the type of intervention(19). The majority of evidence demonstrates that weight loss improves asthma outcomes, though notably Forno and colleagues demonstrated improvement in asthma control after bariatric surgery only in those who had metabolic syndrome(20).

Improving diet quality is beneficial for obese asthma, independent of weight loss. Obesogenic diets are typically of poor quality, characterized by the consumption of energy-dense foods, high in fat and low in fiber(21), promoting inflammation(22). Clinical intervention studies show that fatty acids induce airway inflammation(23), soluble fiber reduces airway inflammation and improves asthma control (24, 25) and increased intake of fruits and vegetables reduces exacerbation risk(26, 27).

Increasing physical activity is a key element of weight loss interventions for asthma. In addition to weight control, physical activity induces a wide range of benefits, including reduction in all-cause mortality, cardiovascular disease, type 2 diabetes, cancer and depression(28). Physical activity consistently decreases asthma exacerbation rates and healthcare utilization and improves asthma quality of life among all asthma subjects(29, 30). Freitas and colleagues demonstrate that independent of weight loss, asthma control can be improved in obese asthmatics via an exercise intervention, where a corresponding improvement in aerobic capacity is achieved(31).

Pharmacological treatments targeted at specific mechanistic pathways are needed. For example, nitric oxide (NO) bioavailability in the airways of obese asthmatics is reduced, and this contributes to airway dysfunction and substandard response to inhaled corticosteroids(32). In a proof-of-concept, open-label pilot study, 41 obese asthmatics were treated with 15 g/d L-citrulline for 2 weeks. Short-term L-citrulline treatment improved asthma control and exhaled NO(32). A 2010 study found treatment with glucagon-like peptide-1 receptor antagonists in diabetics with asthma reduced asthma exacerbations compared to other diabetes medications(33), and now is a potential treatment for asthmatics with metabolic syndrome.

Knowledge gaps

Effective weight loss strategies are urgently needed and remain a public health priority, relevant to the current global epidemic of chronic lifestyle diseases. Considering the scale of the problem, it is critical that alternative treatment strategies also are developed to improve the management of individuals for whom weight loss is not achieved.

Metabolic abnormalities induced by obesity may contribute directly to asthma pathology, which is an important area for future research. The relationship between asthma and features of metabolic syndrome, including insulin resistance and dyslipidemia, persists after accounting for BMI in many studies(34). While these metabolic abnormalities often co-exist with obesity, there are non-obese asthmatics with other features of metabolic syndrome who may benefit from targeted interventions. High serum triglycerides and low HDL-cholesterol are associated with asthma risk(35). Rastogi and colleagues reported an inverse association between HDL-cholesterol levels and monocyte activation and an inverse association between monocyte activation and pulmonary function that was mediated by HDL-cholesterol in a study of obese children with asthma(36). This suggests the potential for lifestyle or pharmacological interventions aimed at increasing HDL-cholesterol levels as a therapeutic approach for obese asthma.

Gut microbiome manipulation also may have the potential to improve the management of obese asthma. Dietary changes recommended for obese asthma are associated with improvements in the gut microbiome profile which may have immunomodulatory effects in the airways(37, 38). The role of gut microbiota in modulating asthmatic immune responses warrants further investigation.

The role of adipokines, cytokines produced by adipose tissue, as a therapy for obese asthma is another area that requires further research. Evidence is strong for an immunomodulatory role of adiponectin, leptin and resistin in murine models(39). However, human data are less convincing, with majority of evidence coming from epidemiologic observational studies. The therapeutic potential of adipokines in asthma remains unknown.

OBSTRUCTIVE SLEEP APNEA AND ASTHMA

Analysis of literature

Though OSA and asthma are both common medical conditions, subjects with asthma versus those without have a higher prevalence of OSA(40, 41). The prevalence of OSA in asthmatics was found to be 49.5% (95% confidence interval 36.4%, 62.6%), and the pooled odds ratio (OR) for prevalent OSA was 2.64 (1.76, 3.52) among asthmatics compared to non-asthmatics in a meta-analysis(41). Similarly, a large cross-section study found an OR of 2.7 (1.6, 4.6) after adjusting for obesity and other confounders(42). A number of longitudinal studies demonstrate an increased risk of developing incident OSA among subjects with asthma after adjustment for BMI or obesity(43–45). The relationship between OSA and asthma severity is less well understood. Studies show an increased risk of OSA among subjects with severe asthma compared to moderate asthma(46–49), though others find no difference(50, 51).

OSA is linked to worse asthma outcomes including increased emergency department visits, increased number of asthma exacerbations, decreased quality of life and asthma control(45, 52–59). Wang and colleagues were able to demonstrate increased odds of severe exacerbations with an increased apnea hypopnea index (AHI), adjusted OR 1.33 (1.15, 1.52)(59). Despite these findings, others have not found a significant relationship between OSA and asthma outcomes(47, 60).

Pathophysiology

While there are strong epidemiologic ties between OSA and asthma, the mechanism of this association is complex and not well understood, and there is likely a bidirectional association.

Impact of asthma on OSA

Animal studies and a small study in asthmatics show a depressed ventilatory response to hypoxia that appears to be mediated by the carotid sinus and increased Th1 inflammation(61–63). Inhaled corticosteroids (ICS) inhalers are a mainstay of asthma management, though ICS use led to increases in upper airway collapsibility measured by changes in passive critical closing pressure, particularly among older, male subjects with worse baseline asthma control, in a small study of ICS-naïve subjects with mild asthma(64). ICS use is associated with habitual snoring and OSA with frequency of snoring showing a dose-dependent relationship(48).

Impact of OSA on asthma

Features of OSA, particularly chronic intermittent hypoxia (CIH), may lead to inflammation and/or remodeling of the lower airways that may increase asthma morbidity. CIH increases airflow obstruction(65), markers of airway remodeling and fibrosis(66, 67), and Th1 inflammation and peri-bronchial neutrophils in mouse models of asthma(65, 67). Studies indicate that asthmatics with high risk for OSA versus those without were more likely to have sputum neutrophilia (50, 68) and higher matrix metalloprotease 9 and IL-8(68). IL-8 levels were found to correlate with increasing AHI (rho=0.72, p=0.006)(68). There is a well-described neutrophil predominant endotype of asthma(12), suggesting a possible role of shared pathophysiology.

Shared inflammatory pathways

L-arginine and NO metabolism are dysregulated in asthma(69–71). In obesity associated asthma, there is an imbalance in L-arginine and asymmetric dimethyl arginine, leading to inhibition and uncoupling of NO synthase, which is the enzyme that converts L-arginine into L-citrulline and NO(70, 72, 73). There is also evidence that L-arginine metabolism is dysregulated in OSA. OSA subjects have decreased L-arginine bioavailability, decreased NO and increased arginase in cross sectional studies(74–76). This dysregulation seen in OSA subjects share some features with obese asthmatics(70, 72, 73). The role of L-arginine metabolism in subjects with both asthma and OSA has not been investigated to date.

The impact of treating OSA on asthma outcomes

There are limited data on the impact of treating OSA on asthma outcomes. Continuous positive airway pressure (CPAP) use is associated in observational studies with decreased daytime symptoms after adjustment for obesity(57), improved quality of life(77) and improved asthma control(78) and decreased decline in FEV₁(46). Quasi-experimental studies show improvement in asthma control and quality of life, though changes in bronchial responsiveness were variable between studies(79, 80). The only randomized control trial to date, found no difference in asthma control, however those randomized to CPAP had improved quality of life(81). In one observational study, the use of an oral appliance for OSA treatment demonstrated improvement in asthma control(82). Overall, studies to date have consistently demonstrated an improvement in asthma quality of life associated with CPAP, though the effects on asthma control and objective measures of lung function remain less clearly understood.

Knowledge gaps

There is much to be learned about the relationship between asthma and OSA. Asthma is a complex and heterogenous disease with poorly defined clinical phenotypes. Some studies suggest that subjects with OSA and asthma have increased Th1 inflammation and neutrophil predominance(50, 68), though which phenotypes of asthma are at highest risk of developing OSA is not well defined. This is particularly important to understand as Th1 inflammation does not respond to ICS treatment as well as Th2-driven asthma, and data suggest that ICS may increase risk of OSA. Given that OSA risk increases with the duration of asthma, it is possible that age of asthma onset and asthma morbidity may impact the development of OSA. There are not yet life-course or birth cohort studies to examine the natural history and risk factors that may lead to incident OSA. These studies, and others also are needed to better understand mechanisms of incident OSA among asthmatics, especially since there is a lack of understanding of how inflammation, upper airway changes and treatment lead to OSA in some asthmatics. A better understanding of asthma phenotypes also would aid in identifying asthmatics who would benefit from screening in the clinical setting.

GASTROESOPHAGEAL REFLUX AND ASTHMA

Analysis of literature

Asthma and GERD are both common clinical conditions, but their frequent presence as comorbid conditions raises the possibility of shared biological mechanisms underlying these two diseases. Epidemiologic data suggest that GERD occurs in 30–80% of asthmatics subjects(83). Esophageal manometry and 24-hour esophageal pH testing demonstrates frequent GERD in the absence of overt symptoms in stable asthmatics(84), though notably, the majority of subjects reported cough due to laryngopharyngeal reflux independent of other reflux symptoms(85).

Previous studies demonstrate variable associations of GERD with asthma severity and exacerbations. GERD was identified as a significant risk factor, OR 4.9 (1.4, 17.8), for recurrent exacerbations after covariate adjustment in a cross-sectional study of 152 subjects(52). Furthermore, GERD has been associated with exacerbation frequency in large asthma cohort studies(86, 87). Using data from the Severe Asthma Research Project-3, Denlinger and colleagues found an increased rate of asthma exacerbations among those with GERD, rate ratio 1.6 (1.3, 2.0)(86).

Pathophysiology:

There are two proposed mechanisms by which GERD impacts asthma severity and exacerbations: 1) micro-aspiration of gastric contents causing airway inflammation, respiratory symptoms, and lung injury(88, 89), and 2) vagal nerve stimulation that occurs from reflux of acidic gastric contents into the lower esophagus leading to bronchoconstriction and respiratory symptoms(90, 91). Furthermore, bronchoconstriction and hyperinflation in asthma may induce acid reflux due to changes in the pressure gradient between the abdomen and the chest changing lower esophageal sphincter (LES) tone(92).

Impact of GERD treatment on asthma outcomes:

Results of clinical trials of acid suppression on asthma outcomes are inconsistent. Littner and colleagues found that twice daily lansoprazole improved overall quality of life and reduced asthma exacerbations in subjects with symptomatic reflux, with the most pronounced effect occurring in more severe asthmatics(93). These findings have not been replicated in other trials among those with mild to moderate asthma(94, 95), including asthmatics without symptoms of GERD(95). Others have found improvement in asthma symptoms without improvement in lung function(96, 97).

A meta-analysis in 2002 of existing trials by the Cochrane Systematic Review group did not recommend the treatment of GERD in subjects with uncontrolled asthma due to lack of evidence to support their routine use(98). Since that time, trials investigating the impact of GERD treatment on asthma outcomes is limited. However, the common occurrence of these two comorbid conditions and the conflicting data regarding GERD treatment would suggest that additional larger scale randomized clinical trials in this area are warranted.

Knowledge gaps

The routine treatment of GERD in poorly controlled asthmatics without GERD symptoms remains controversial due to the inconsistency of the existing data. Given the common occurrence of these two comorbid conditions, additional investigation of the impact of GERD and GERD treatment on asthma outcomes is essential to address some ongoing knowledge gaps. Additionally, future research should aim to address several unanswered questions with respect to the relationship between GERD and asthma outcomes: 1) efficacy of GERD treatment in manometry or pH probe confirmed subjects with and without GERD symptoms, 2) the impact of proximal versus distal esophageal reflux, and 3) a better understanding of the impact of medication and surgical options for GERD. Well-designed randomized controlled trials are needed to address each of these key issues.

THREE COLINEAR DISEASES: OBESITY, OSA & GERD

There are strong associations and suspected causal pathways between obesity, OSA, GERD and asthma. The estimated prevalence and co-occurrence of each of these diseases is described in Table 1. Among those with asthma, the prevalence of GERD and OSA is higher than that of the general population. The same is true for the prevalence of asthma among those with obesity and OSA. There are certainly shared risk factors that partially explain the high rates of comorbidity, however there are proposed pathophysiological mechanisms that each disease drives the development of or worsens control of another comorbid condition. Table 2 summarizes evidence for treatment of these conditions among asthmatics and key knowledge gaps.

Table 1:

Estimated prevalence of asthma, obesity, OSA and GERD

	Among those with:
Prevalence of:	Asthma	Obesity	OSA	GERD
Asthma	8.0%(108)	16.6%(109)	35.1%(110)	4.6%(111)
Obesity	38.8%(112)	42.4%(113)	13.5–67.9% women 44.6–82.8% men(114)	27.9%(115)
OSA	49.5%(41)	21.8–34.4% women 22.2–62.6% men(116)	4.5%(117)	65%(118)
GERD	50.9%(111)	39.0%(119)	73%(120)	30.9%(121)

The prevalence of each condition (row) among those with asthma, obesity, OSA and GERD (columns)

Table 2:

Evidence for treatment and knowledge gaps in treating obesity, GERD, and OSA in asthma

	Evidence for treatment	Knowledge gaps
Obesity	Weight loss • Increased asthma quality of life, asthma control, improved lung function Physical activity • Increased asthma control Improved diet quality • Increased fruits and vegetables associated with decreased exacerbations • Increased soluble fiber associated with increased asthma control	• Effective weight loss strategies • Targeted pharmacologic therapies for metabolic abnormalities including increased HDL, L-citrulline supplementation, decreased triglycerides • Gut microbiome manipulation • Better understanding of immunomodulatory effects and possible treatment targeting adipokines
OSA	CPAP for sleep apnea • Improves asthma quality of life • Improved asthma control and decreased daytime symptoms in observational studies	• Impact of CPAP treatment in preventing incident asthma • Utility of routine screening for OSA among asthmatics
GERD	Treating symptomatic GERD may improve • Asthma quality of life • Asthma symptoms	• Benefit of screening for and treating asymptomatic GERD • Treatment duration • Impact of medical vs surgical treatment for GERD

Obesity and OSA:

There are many hypothesized mechanisms between OSA and obesity. Increased neck circumference and upper airway tissue in obesity may directly lead to intermittent obstruction that causes sleep apnea(99). Additionally, obese subjects have lower lung volumes, more pronounced when supine. Intermittent hypoxia from OSA leads to increased insulin resistance and leptin levels, both of which are associated with obesity and the metabolic syndrome(100). Weight loss decreases AHI and OSA(100). Treating OSA with CPAP, along with calorie restrictions, leads to more weight loss than calorie restriction alone among obese subjects with OSA(101).

Obesity and GERD:

Obese subjects have increased prevalence of esophageal dysmotility, transient relaxation of LES tone and hiatal hernia, all of which increase the incidence of GERD(102). Obesity also leads to increased intraabdominal pressure, increasing the likelihood of gastric contents being pushed through the LES. Increased leptin, which occurs in obesity, is associated with the development of dysplasia and Barrett’s esophagus(102).

GERD and OSA:

There are a number of theories to causally link GERD and OSA. OSA is thought to lead to increased intrathoracic pressure during apneic episodes, causing the LES to open, with concomitant increase in abdominal pressure. This leads to an increase in gastric reflux. Conversely, nocturnal GERD symptoms may lead to increased sleep arousals, decreased sleep and laryngeal edema leading to increased upper airway collapse. Conflicting data exist for these two theories(103). CPAP decreases GERD symptoms, implying that this treatment may be efficacious for both diseases(104).

Asthma, obesity, OSA and GERD:

While these four conditions are separately linked, to date, no investigation has examined the prevalence of these disorders together. Figure 1 shows a framework for how these disorders relate to each other with proposed mechanisms. Obesity, OSA, GERD and some endotypes of asthma share similar features of Th1-driven inflammation. This may represent a common underlying pathway, though no investigator has identified any common markers of inflammation in subjects with asthma and all three comorbidities.

Figure 1:

Relationships and proposed mechanisms between asthma, obesity, obstructive sleep apnea and gastroesophageal reflux disease

Treatment of OSA can improve asthma symptoms and decrease GERD, inconsistently associated with weight loss(40, 99, 102, 105, 106). Weight loss improves and/or resolves OSA, GERD and asthma in individual studies(40, 99, 102). Finally, treatment of GERD improves asthma control(96, 97) and sleep disturbances(107), though does not lead to weight loss. In summary, though not studied collectively, the identification and treatment of these comorbidities has a positive impact on asthma control.

CONCLUSIONS:

Asthma is associated with comorbid obesity, OSA and GERD and the interplay among these diseases is not fully understood. In studies on the effects of obesity, OSA and GERD individually, there appears to be shared and bidirectional mechanisms that drive the development of asthma and/or worsen asthma control. Data from studies of individual comorbidities and asthma demonstrate improvement in many domains of asthma control and/or lung function with treatment. Although there are many gaps in the understanding of these relationships, it is important to identify and treat these comorbidities in subjects with poorly controlled asthma, even if they may not impact asthma outcomes.

Abbreviations:

GERD

gastroesophageal reflux disease

OSA

obstructive sleep apnea

EOAA

early onset allergic asthma

LONA

late onset atopic asthma

NO

nitric oxide

OR

odds ratio

AHI

apnea hypopnea index

ICS

inhaled corticosteroids

CIH

chronic intermittent hypoxia

CPAP

continuous positive airway pressure

LES

lower esophageal sphincter