Obesity, Inflammation, and Severe Asthma: an Update

Purpose of Review Obesity-associated difficult asthma continues to be a substantial problem and, despite a move to address treatable traits affecting asthma morbidity and mortality, it remains poorly understood with limited phenotype-specific treatments. The complex association between asthma, obesity, and inflammation is highlighted and recent advances in treatment options explored. Recent Findings Obesity negatively impacts asthma outcomes and has a causal link in the pathogenesis of adult-onset asthma. Imbalance in the adipose organ found in obesity favours a pro-inflammatory state both systemically and in airways. Obesity may impact currently available asthma biomarkers, and obesity-associated asthma specific biomarkers are needed. Whilst surgical weight loss interventions are associated with improvements in asthma control and quality of life, evidence for pragmatic conservative options are sparse. Innovative approaches tackling obesity-mediated airway inflammation may provide novel therapies. Summary The immunopathological mechanisms underlying obesity-associated asthma require further research that may lead to novel therapeutic options for this disease. However, weight loss appears to be effective in improving asthma in this cohort and focus is also needed on non-surgical treatments applicable in the real-world setting.


Introduction
Asthma remains common, is characterised by variable symptoms and airflow obstruction, and is associated with a significant global health burden [1]. The UK continues to rank highly in obesity prevalence internationally (8.1% of year-olds with obesity in 2015 [2]), has one of the highest asthma mortality rates in Europe, and has disproportionately increased asthma mortality in young people compared to other European countries [2,3]; for example, the UK asthma mortality rate for ages 20-24 per 100,000 in 2016 was 0.30 (95% CI 0.28-0.33), compared to the same age-specific population in Italy with mortality rate 0.03 (95% CI 0.02-0.05) [2]. Asthma associated with obesity is a particular challenge, being less steroidresponsive and linked to poorer control, increased medication use, longer hospital stays, poorer quality of life, and greater severity of disease [4][5][6][7][8][9]. Moreover, other obesityassociated comorbidities such as obstructive sleep apnoea syndrome (OSAS) appear to worsen outcomes [10]. In this review, we provide an update on associations between obesity and asthma, current understanding of potential immunological mechanisms, recent interventional trials, and possible future therapies.

Obesity
Over 650 million adults are obese worldwide [11]. The rising obesity epidemic over the past few decades has led to increased pressure on healthcare resources and rising morbidity and mortality from obesity-associated disease. Obesity impacts on outcomes in many of the most common lung diseases including chronic obstructive pulmonary disease (COPD), asthma, OSAS, and obesity hypoventilation syndrome (OHS) [12]. The effect of obesity in pulmonary disorders is multifaceted. Obesity alters chest wall dynamics with mass effect directly affecting thoracic mechanics, an integral component of the process of ventilation. Raised body mass index (BMI) is associated with increased airflow limitation; for example, a recent Danish cross-sectional study showed OR 3.1 (95% CI 1.97-4.78, p < 0.001) and OR 1.7 (95% CI 1.08-2.68, p = 0.023) for airway obstruction in overweight and obese subjects respectively [13].
Airway closure is associated with gas trapping and hyperinflation and is one of two elements in FEV 1 reduction (alongside airway narrowing). In asthma, raised BMI has recently been shown to affect airway closure independently of asthma control [14]. A further study has shown that raised BMI, but not waist circumference (WC, a marker of central obesity), worsens airway closure in people with asthma (p = 0.01), suggesting the effect is not entirely related to altered chest mechanics [15].
Dietary changes associated with obesity, such as highsugar, high-fat, and low-fibre intake, are also associated with increased airway inflammation, at least in murine models [16,17].
Obesity has been shown to increase inflammation in people with and without asthma [42•, 43••]. A large Japanese genome-wide association study (n = 9789, 4% with asthma) [43••] found increasing BMI correlates with increased blood neutrophil and eosinophil count (until BMI approximately 40 kg/m 2 when eosinophil counts levels off). However, another interesting find from this study was that those with an elevated eosinophil level at baseline had a negative association with increasing BMI, suggesting deeper complexity in the relationship between adipose excess and inflammation. A recent European prospective study (n = 202) reported an additive effect of asthma and obesity on increased release of pro-inflammatory mediators and airway inflammation as well as modification of the gut, nasal, oral, and lung microbiome, intimately linked with inflammation [42•]. Use of SPECT/CT scanning in obese-asthma has recently shown increased lung eosinophil uptake compared to healthy BMI counterparts further emphasising the impact of obesity on airway inflammation [44]. The presence of dietary polyunsaturated and saturated fatty acids increase release of inflammatory cytokines during respiratory tract infection which may enhance airway inflammation and therefore impact severity of asthma exacerbation [45].
Raised BMI also impacts airways directly through increased airway hyper-responsiveness in populations with asthma [46], and effects on human airway smooth muscle are exaggerated in the obese female adult population [47].
The relationship between increased adiposity and asthma becomes more complicated as visceral adiposity, independent of BMI or waist circumference, affects asthma-related quality of life [48]. Reasons for this include reduced lung function, and increased effects of related comorbidities such as acid reflux and depression; however, the intricate science of adipose tissue and its relationship to inflammation will undoubtedly be important. Further evidence exists to support the argument that obesity-related comorbidities, particularly presence of the metabolic syndrome, also contribute to poorer asthma outcomes [49]. Central obesity, evidenced by raised waist-to-height ratio, and insulin resistance negatively impact lung function in patients with asthma [50].

Adipose Tissue and Inflammation
Adipose tissue is categorised as "brown" (adipocytes with high mitochondria count and numerous small lipid droplets), "white" (few mitochondria and a large single lipid droplet), or "brown-like" or "beige" (intermediate mitochondria and lipid droplet count compared to white or brown adipocytes) [51] and accumulates to form brown adipose tissue (BAT), white adipose tissue (WAT), and beige adipose tissue respectively. A more recently recognised but less well understood peri-vascular adipose tissue (PVAT) has been documented ( Table 2) [52,53]. Adipose "tissue" forms a complex endocrine organ intimately involved in inflammation homeostasis and is not merely an inert energy reservoir as previously thought. Excessive WAT, seen in obesity, plays a pro-inflammatory role, though healthy BAT acts to regulate these negative effects. However, a process of "browning" WAT (i.e., production of beige adipose tissue) can negate the pro-inflammatory effects of WAT also [53]. As such, BAT and beige adipose tissue can be thought of as "protective" against pro-inflammatory states, whilst excess WAT enhances inflammation. Furthermore, BAT activity is reduced in obesity (so called "whitening" of BAT), with increased dysfunctional mitochondria suggested as a factor [54,55]. Further understanding is needed in this area; however, there is a relationship between the immune system and adipose tissue with activated macrophages and CD8 + T cells identified as important players [56]. Upregulation of BAT or browning of WAT may have a role to counteract the low-level systemic inflammation caused in obesity. Following bariatric surgery, adipose tissue composition can significantly change with increased BAT and increased browning of WAT associated with an improved inflammatory state post-operatively [57]. Key cytokines produced from adipose tissue have been identified that may be useful as novel biomarkers in management of obesity and obesity-associated inflammatory disease [58]. A summary of effects is provided in Table 3 [59 -62].
Increased leptin and IL-6 levels in asthma patients have recently been identified in several studies, strengthening  Immunomodulatory effects. Reduces pro-inflammatory cytokine synthesis and decreases macrophage activity.
Reduces release of reactive oxygen species and cytotoxic T-cell response Conflicting reports of both high and low levels in obesity compared to healthy BMI. One suggested explanation for high levels in obesity is of a homeostatic attempt to inhibit other pro-inflammatory adipokines. The presence of metabolic syndrome associated with reduced IL-10, irrespective of the presence of obesity CCL2 [59,60] Immunomodulatory effects in adipose tissue Increased pro-inflammatory effects Chemerin [59] Immunomodulatory effects, pro-inflammatory but has potential anti-inflammatory effects. Role in adipocyte metabolism Increased pro-inflammatory effects the link of these pro-inflammatory cytokines with airway inflammation in asthma [63][64][65].

Obese-Asthma and a Need for Biomarkers
Routinely used markers of allergy and eosinophilic inflammation in asthma include serum total IgE, fractional exhaled nitric oxide (FeNO), and serum and (where available) sputum eosinophils. Evidence suggests that obesity may have direct effects on these biomarkers, and this has implications for accuracy of phenotyping and determination of suitability for currently available biologic treatments [66,67]. Previous studies have shown that increased BMI is negatively correlated with FeNO and this may be related to the increased airway oxidative stress associated with obesity [68,69]. More recently, Winnica et al. [70••] found that respiration at a mitochondrial level varies in obese-asthma, when compared to obese controls, healthy BMI-asthma, and healthy BMI controls, with diminished cellular nitric oxide (NO) bioavailability in this cohort resulting in reduced FeNO.
One US multi-centre study [71••] of 652 adults with mild to moderate asthma revealed poor correlations between increased BMI and the four measured type 2 (T2) inflammatory markers (FeNO, IgE, sputum, and serum eosinophils). FeNO levels were reduced in obese-asthma and, despite > 85% of participants having positive skin prick testing, IgE levels were also reduced in this group compared to their healthy BMI counterparts. Serum eosinophils, total IgE, and FeNO did not correlate with sputum eosinophilia levels in obesity-associated asthma. The differences seen compared to leaner individuals is perhaps related not only to the increased oxidative stress caused by obesity but also to direct disruption of eosinophil recruitment and survival caused by adipocytokines [71••].
Whilst much research has focussed on biomarkers and treatment options for asthma with T2-high inflammation, it remains widely appreciated that further research is needed to elucidate potential biomarkers and treatment options for the non-T2 and/or T2-low endotypes and this may be particularly relevant to obesity-associated asthma [72][73][74][75][76].

Management of Obesity-Associated Asthma: Scope of the Problem
In an era of precision medicine, there remains a dearth of specific treatments for obesity-associated severe asthma. Standard current treatment options comprise escalation of historically available asthma therapies, i.e., inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), longacting muscarinic antagonist (LAMA), leukotriene receptor antagonists, oral theophylline, macrolides and OCS, and more recently available biologic treatments (if eligible). Identification and treatment of treatable traits have more recently been encouraged in the management of asthma; however, there remains a paucity of interventions for T2-low or non-T2 severe obese-asthma. Beyond advising healthy living and referring to local weight management services, there are limited choices for dealing with this "treatable" trait.
Despite the wealth of evidence showing positive impacts of bariatric surgery, access to this remains poor for a variety of reasons [77], and surgical risk is not insignificant. Conservative interventions are needed for those in whom surgical options are not appropriate or desired.
Advanced obese-asthma therapies are limited, and there is a need for precision biomarkers that can be used to target specific interventions.

Weight Reduction Strategies in Asthma: Lifestyle and Surgical Interventions
Further recent studies have evaluated the impact of weight loss strategies on obesity-associated asthma, and in particular the effects of bariatric surgery (Table 4 [78][79][80][81][82][83][84][85][86]). Surgical techniques, such as Roux-en-Y gastric bypass and sleeve gastrectomy, are associated with reduction in both systemic and airway pro-inflammatory markers, improvement in lung function, asthma control and quality of life scores (including ACT, ACS, AQLQ), and a reduction in treatment burden [78][79][80][81]. Some evidence suggests that asthma remission may also result, but this needs to be confirmed [82,83]. Whilst these studies have limitations including small sample size and open-label design, the available evidence is that bariatric surgery may lead to improvements in outcomes in obese asthma, many of which may be sustained in the mid-to-long term. In contrast, another study by Forno et al. [81] showed a lack of improvement, following bariatric surgery in obesity-associated asthma with concomitant metabolic disease (defined as three out of five of the following: abdominal obesity, raised triglycerides, low HDL, hypertension, and hyperglycaemia). This implies that this phenotype of obese asthma is particularly difficult to treat, and that weight loss alone may not be effective in these patients; a multifaceted, individualised, and targeted approach may be necessary.
An open-label, prospective study [84] utilising diet and a structured exercise program for three months in 51 obese women with physician-diagnosed moderate to severe asthma showed that, alongside improvements in lung volumes and airflow on exertion, loss of > 5% of body weight had a favourable impact on asthma biomarkers (FeNO), systemic biomarkers (reduced IL-2, IL-4, increased IL-10), and patient-centred outcomes (ACQ, AQLQ). The impact of dietary factors on asthma is another area that is receiving interest. For example, high-fat and lowfibre intake have been linked to increasing airway inflammation [87]. Whilst robust evidence for treatments in this area is lacking, there is potential for future research. A pilot study of 41 obese adults with poorly controlled asthma demonstrated a decrease in ACQ, despite an increase in FeNO, with oral administration of 15 g/day L-citrulline supplements after 2 weeks [86••]. The authors suggest that obesity and asthma cause uncoupling of airway epitheliumbound nitric oxide synthase (NOS) causing reduced FeNO in this cohort, and that the increased FeNO seen postsupplementation is due to L-citrulline-mediated recoupling of NOS. This increase in FeNO might have suggested a deleterious effect on asthma outcomes; however, the improved ACQ implies otherwise, further highlighting the complexity of the obesity-inflammation relationship and a need for accurate obese-asthma specific biomarkers. The mean ACQ reduction of − 0.46, whilst statistically significant, failed to meet the minimal clinically important difference of 0.5 [88], but nevertheless, this proof-of-concept trial paves the way for a further suitably powered study. Conversely a doubleblind, multicentre, randomised, placebo-controlled trial [85] in adolescent obese asthma did not show any difference in asthma outcomes including biomarkers or lung function with omega-3 fatty acid supplementation although it is possible that higher doses and/or longer course of treatment may have led to more favourable effects.
Further research is needed to clarify the complex mechanisms that underlying the links between obesity and dietaryintake and inflammation in asthma. More evidence from randomised, controlled trials for weight loss in obese-asthma is needed, with pragmatic conservative strategies applicable to the real-world setting.

Potential Treatments
Whilst targeted therapies may be lacking, pursuing obesityinduced inflammation and repurposing current widely used anti-diabetic drugs for weight loss in obese asthma may pose a viable treatment option.
Recent randomised control trials in obese and healthy-BMI adults with asthma (n = 127, n = 23 for two trials [89]) have contributed to the understanding of the interplay between airway inflammation and excessive dietary fatty acid and carbohydrate intake. Nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3)-mediated airway inflammation was observed in healthy BMI individuals with asthma after over-nutrition, and enhanced NLRP3 inflammatory effects were identified in obese asthma participants, including higher levels of IL-5, IL-1β, and sputum neutrophils. Findings suggest that targeting the NLRP3 inflammasome may yield a potential treatment in obese asthma [90]. Anti-diabetic medications that cause weight loss include metformin and glucagon-like peptide 1 agonists/receptor agonists. Neither of these are specific to diabetes, and both are beneficial for non-diabetic weight loss [91][92][93]. Whilst redirecting these medications to tackle the treatable trait of obesity in asthma might be of benefit, this remains to be proven. Nevertheless, preliminary studies do suggest that both metformin and GLP-1 agonists may improve asthma outcomes, independently of weight loss, perhaps due to underlying anti-inflammatory or immunomodulatory effects, or effects on insulin resistance [94,95].

Conclusion
In summary, a better understanding of adipose tissue-associated inflammation and its relationship to asthma is needed. Obesityassociated asthma encompasses several endotypes and phenotypes in addition to the recently recognised adult-onset, femalepredominant, non-allergic obese-asthma phenomenon. The presence of metabolic syndrome is associated with increased morbidity and more difficult to treat disease. Currently available biomarkers may be of limited value in obesity-associated asthma, and identification of novel biomarkers is a priority for this difficult-to-treat subset of patients. Though real-world obesity-specific treatments are lacking, trials aiming at weight loss continue to show improvements and novel therapies for obese-asthma may be on the horizon.

Compliance with Ethical Standards
Conflict of Interest There are no conflicts of interest.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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