Effects of pediatric obesity and asthma on pulmonary physiology, metabolic dysregulation, and atopy, and the role of weight management

Abstract

INTRODUCTION:

Obesity affects about 40% of US adults and 18% of children. Its impact on the pulmonary system is increasingly recognized, and is best described for asthma, another chronic morbidity.

AREAS COVERED:

We reviewed the literature on PubMed and Google Scholar databases, until March 1^st 2019, on the effect of obesity and weight management on lung physiology and pathology, with a focus on asthma. Giving preference to studies published in the last decade, we summarize the pulmonary effects of obesity, including the intrinsic effect on pulmonary mechanics, and influence of metabolic dysregulation and altered systemic immune responses. We discuss the role of weight gain and weight loss on asthma inception and disease burden in context of the pulmonary effects of obesity, and include a distinct approach for diagnosing and managing the disease, including pulmonary function deficits inherent to obesity-related asthma, in light of its poor response to current asthma medications.

EXPERT OPINION:

Given the projected increase in obesity, obesity-related asthma needs to be addressed now. Research on the contribution of metabolic abnormalities and systemic immune responses, intricately linked with truncal adiposity, and of lack of atopy, to asthma disease burden and pulmonary function deficits among obese children is fairly consistent. Since current asthma medications are more effective for atopic asthma, investigation for atopy will guide management by distinguishing asthma responsive to current medications from non-responsive disease. Future research is needed to elucidate mechanisms by which obesity-mediated metabolic abnormalities and immune responses cause medication non-responsive asthma, which will inform repurposing of medications and drug discovery.

1. INTRODUCTION

Obesity, a leading public health concern, has an estimated prevalence of about 40% in US adults and 18% in children, affecting 93.3 million adults and 19.7 million children.[1,2] Its prevalence varies by race and ethnicity, affecting Hispanics and non-Hispanic Blacks more than non-Hispanic Whites.[2] Obesity has been associated with heart disease, type 2 diabetes, dyslipidemia, osteoarthritis, and cancer.[3] Recent studies have highlighted its impact on the pulmonary system, where it is associated with development and/or worsening of asthma, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, aspiration pneumonias, pulmonary embolism and obesity hypoventilation syndrome, occurring in conjunction with pulmonary function deficits.[4,5]

Obesity intrinsically affects pulmonary mechanics and function. In addition, metabolic dysregulation, frequently co-existing with obesity, influences lung function in asthma and COPD.[6] Socio-economic status and environmental factors such as tobacco smoke exposure, environmental pollutants, and allergens can differentially contribute to and modify obesity’s effect on asthma and COPD.[7,8] Furthermore, obesity-mediated systemic immune responses are associated with impaired pulmonary function and disease burden. We reviewed the literature until March 1^st 2019, using PubMed and Google Scholar databases, on the effect of obesity on the lung physiology and pathology, with a focus on asthma, since, among respiratory diseases, the impact of obesity is most extensively investigated for asthma. We summarize mechanistic studies on the contribution of body fat, and obesity-mediated metabolic abnormalities, and immune responses to altered pulmonary physiology and asthma and longitudinal studies of weight management, including those of weight gain and weight loss. For the mechanisms that had studies spanning two decades, preference was given to studies published in the past decade. In addition to summarizing the varied effects of obesity on pulmonary physiology, this review discusses the pertinent diagnostic tests for better disease phenotyping, and the role of weight management in disease burden.

1.1. OBESITY AND ASTHMA

Asthma, like obesity, is the most common chronic pediatric disease, affecting 10% of the pediatric population, with a similar higher prevalence in Hispanics, particularly Puerto Ricans, and non-Hispanic African Americans and among those of lower socioeconomic strata.[9] While asthma increases the relative risk of obesity by 1.5 to 1.7 fold [Contreras PMID 30209194, Chen 28103443], several cross-sectional and prospective studies, as well as meta-analyses, have found obesity to be an independent predictor of asthma[10] with a relative risk of 1.2–1.8 for incident asthma in overweight and obese patients,[11–15] an association that varies by sex.[16,17] Although sedentary lifestyle and decreased physical activity may contribute to incident asthma,[18] airflow obstruction due to physiologic effects of obesity, and dyspnea due to deconditioning may simulate asthma-like symptoms, thus confounding a diagnosis of asthma in obese patients.[19] For instance, BMI, but not lung function, has been associated with decreased functional exercise capacity in obese asthmatic children.[20] Here, we discuss the mechanisms by which obesity contributes to asthma including altered pulmonary physiology, metabolism, and systemic immune responses, which are distinct from classic allergic asthma, and are associated with higher disease severity with poor medication responsiveness and disease control.[21–23]

2. MECHANISMS LINKING OBESITY AND ASTHMA

2.1. Effect of obesity on pulmonary physiology

Several effects of obesity on pulmonary mechanics can be quantified by detailed pulmonary function testing. We summarize the current knowledge on pulmonary function deficits in obese asthmatic children, which have been previously included in a meta-analysis.[24] Spirometry is the most commonly conducted pulmonary function test. Analysis of spirometric indices including both adults and children revealed that overweight/ obese subjects had 2.2% lower forced expiratory volume in 1 second (FEV₁) (95%CI −2.6 to −1.8%) (44 studies; 23,460 subjects). The effect was more prominent in adults as compared to children, in those without asthma as compared to with asthma, and in the obese. Forced vital capacity (FVC) was also 2.2% lower (95%CI −3.7 to −0.6%) among overweight/obese subjects (30 studies; 16,913 subjects), with a similar higher effect in adults compared to children and among the obese. Due to early somatic growth occurring in children related to obesity, overweight/obese children demonstrated an increase in absolute FVC with larger FEV₁, [25–27] but had lower FEV₁/FVC, likely due to dysanapsis, which is an incongruence between growth of lung parenchyma and airway caliber.[28] Analysis stratified by asthma and age revealed decline in FVC only among adults without asthma. FEV₁/FVC ratio (34 studies; 28,494 subjects) was 1.5% lower (95% CI −1.9 to −1.2%) among overweight/obese, with greater decline noted in children compared to adults, but not different by asthma status. Conversely, maximum mid-expiratory flow rates (FEF_25–75%) were 5.4% lower (95%CI −7.3 to −3.5%) in overweight/obese subjects (16 studies; 13,627 subjects), with a greater decrease in children and among asthmatics. Together, these altered pulmonary mechanics differ from those observed in classic childhood allergic asthma and likely contribute to more symptoms and poor asthma control, associated with lower asthma-related quality of life and increased health care utilization among obese children with asthma.[19]

Obesity also impacts lung volumes due to thoracic and abdominal fat deposition, but few studies have quantified lung volumes in children.[29] Functional residual capacity (FRC) (−17.1% (95%CI −25.2 to −9%); 9 studies; 1,235 subjects) and expiratory reserve volume (ERV) are lower in obese patients, including in children, suggesting early inception of obesity-mediated pulmonary function deficits.[30–32] In addition, reductions in TLC ((−4.2% (95%CI −5.4 to −3%); 16 studies; 2678 subjects)), and RV ((−6.6% (95%CI −9.3 to −3.8%); 12 studies; 2,085 subjects), have been reported. Similar to spirometry indices, the meta-analysis reported lung volume decrements to be more pronounced among subjects without asthma and among those who were obese compared to the overweight.[24] Together, these findings suggest intrinsic alteration of lung mechanics by obesity, some of which differ by asthma status. Although Forno et.al.[24] have meticulously analyzed results from a large pool and wide range of studies, we highlight the heterogeneity in the findings of individual studies.

Low tidal volume breaths due to thoracic and abdominal fat deposition lead to low lung volumes,[33] and likely cause alveolar hypoventilation along with increase in airway resistance which in turn causes airway hyper-responsiveness (AHR),[34,35] together resulting in higher respiratory rates and increased work of breathing. Total respiratory system compliance is also reduced, mainly due to a decreased compliance and increased elastic resistance of the chest wall.[36] Together, these changes in pulmonary mechanics cause stiffening of airway smooth muscle (ASM) in obese patients leading to narrowed airways and reduced bronchodilatory effect.[37] Other consequent phenomenon that may simultaneously occur include atelectasis of peripheral lung regions, hypoxia-induced pulmonary vasoconstriction and increased pulmonary pressures, interstitial edema and pulmonary hypertension.[36]

2.2. Association of obesity-mediated metabolic dysregulation with asthma

It is evident that not all obese children develop asthma and the association of incident asthma with obesity is not linear. Hence, other aspects of obesity, such as metabolic dysregulation, may explain the variation observed in pulmonary function in the obese. Obese asthmatic children have higher prevalence of metabolic syndrome and its associated abnormalities, including insulin resistance and dyslipidemia.[Del-Rio-Navarro 2010, Cottrell 2011]. Insulin resistance has been linked with incident asthma, higher asthma severity, and pulmonary function deficits.[31,38–41] Although dyslipidemia has been less well studied, lipid abnormalities including higher levels of total cholesterol and low-density lipoprotein (LDL) [PMID 23517791] and lower levels of high-density lipoprotein (HDL)[Cottrell 2011, Rastogi 2015] are more common in obese asthmatic children and are associated with lower lung function.[31] While the mechanisms that underlie these associations are poorly understood, recent investigations suggest that insulin is associated with non-atopic systemic immune responses and mediates the association of immune responses with pulmonary function.[38] Moreover, insulin is associated with increased ASM contractility.[42] However, an in-vitro investigation of effect of obesity on ASM response revealed greater contractility of obese asthmatic ASM samples compared to non-obese asthmatic samples that was not influenced by insulin pretreatment.[43] These findings suggest that insulin resistance may influence obesity-related asthma by altering systemic immune responses rather than direct influencing ASM contractility.[38] Similar mechanistic details are not known for dyslipidemia.

2.3. Association of obesity with atopy, and systemic and airway inflammation

There is evidence to suggest that obesity-mediated immune responses are associated with asthma.[30,38,44] Traditionally, asthma is associated with Th-2 cellular inflammation with elevated IgE, eosinophils and co-existent atopic diseases, allergic rhinitis, eczema and food allergies. Asthma endotyping has identified obesity-related asthma to be among the phenotypes characterized by neutrophilic predominance and corticosteroid resistance.[45] Aspects unique to obesity-related asthma include the role of non-atopic systemic inflammation in its severity,[46] which is likely driven by adipokines, leptin and adiponectin, that are secreted by adipose tissue. As understood thus far, obesity-mediated inflammation is triggered by adipocyte hypoxia, which releases leptin, the pro-inflammatory adipokine, which shifts the macrophage pool from M2 to M1 macrophages, leading to Th1 cell proliferation with increased IL-6, IL-10, IFN-γ and TNF.[47,48] Serum leptin has been associated with higher Th1/Th2 cell ratio and serum IFN-γ levels, and with asthma, lower airway obstruction and exercise-induced broncho-constriction in obese asthmatics.[38,49–52] Adiponectin, on the other hand, is inversely related with obesity and BMI. In keeping with non-atopic systemic immune responses in obese asthmatics, several studies have reported a lack of association between obesity-related asthma and atopy.[11] However, there are contradicting reports of increased atopy in obese children, particularly among girls,[53] with links between atopy and worse asthma in obese asthmatics.[54] From the mechanistic perspective, leptin may be protective against allergies,[55] although it has been associated with IgE,[52,56] allergic rhinoconjunctivitis and eczema in boys, but not in girls.[52,56,57]

Part of this controversy may be driven by the cross-sectional nature of these studies which fail to distinguish between children with asthma who develop obesity and those that develop asthma as a consequence of obesity. As we understand the complexity of chronology better, it is evident that asthmatic children who become obese are frequently atopic and have worsening of atopic asthma due to obesity, while children who develop asthma as a consequence of obesity are non-atopic and their inherent disease presentation differs from that observed in obese children with atopic asthma.[10,58] Furthermore, since atopic sensitization is not always associated with atopic diseases,[59,60] evidence of atopic airway inflammation, quantified by fractional exhaled nitric oxide (FeNO) may help to distinguish Th2 asthma with co-existent obesity from non-Th2 asthma, likely secondary to obesity. Obese children with asthma lack luminal airway inflammation,[61] and have low FeNO levels.[62,63] However, a few studies have identified rapid weight gain to associated with worse asthma among those with elevated FeNO, while long-standing adiposity is associated with asthma with low FeNO, again supporting the need to distinguish time of onset of asthma relative to obesity.[64] These associations may also be impacted by the participants’ ethnicity since allergic sensitization is more common among Hispanics and African Americans, the same groups that have higher prevalence of obesity, [65] but few studies have directly investigated the links between asthma, obesity and allergic sensitization among minority children.

3. EFFECT OF WEIGHT CHANGE ON ASTHMA

3.1. Weight gain and development of asthma

Having highlighted the importance of distinguishing chronology of development of obesity and of asthma to determine the association of obesity with pulmonary mechanics and atopy, in this review, we focus on longitudinal studies that have investigated the contribution of weight gain to incident asthma. Links between weight gain and incident asthma were first reported in longitudinal studies such as the Tuscon study.[66] Since then, several studies have reported on the contribution of obesity to asthma and can be pooled into two groups [Table 1], those in which in-utero events including maternal pre-pregnancy BMI and maternal weight gain contribute to incident wheeze and those in which early life weight gain contribute to incident asthma later in life. Studies including large cohorts reported a modest but consistent association (HR 1.09 – 1.47) between high maternal pre-pregnancy BMI and early wheeze/ transient wheeze in the first 2 years of life.[67–70] Although some studies found no association [67,69], a meta-analysis[71] reported an association between gestational weight gain and incident wheeze in the offspring. The link between maternal Tumor Necrosis Factor levels with incident wheeze in offspring support a role of maternal obesity-mediated immune responses in the occurrence of wheeze in the offspring associated with maternal weight gain.[72] Maternal diabetes is also associated with childhood asthma, supporting a role of maternal metabolic abnormalities.[73]

Table 1.

Effect of Weight Gain on Development of Asthma

	Study Design	Subjects	Findings
Maternal Weight and Weight Gain During Pregnancy
Pike et al. 2012[70]	6-year longitudinal study	UK Southampton Women’s Study cohort- 940 children	Higher maternal BMI or fat mass associated with childhood transient wheeze, not persistent wheeze. Infant adiposity gain was associated with persistent wheeze
Leemakers et al. 2013[68]	4-year longitudinal study	Generation R study (Netherlands)- 4656 children	Mothers with pre-pregnancy obesity and asthma, and mothers with higher gestational weight gain showed higher risks of wheezing in their offspring.
Halonen et al. 2013[72]	9-year longitudinal study	Tuscon Infant Immune Study	Eczema and wheeze at 1st year and asthma at 9 years were associated with maternal levels of TNF. Infants with persistently elevated LPS-induced TNFα at birth and 3 months had increased risk for childhood asthma and lower FEV1/FVC ratio at age 9.
Forno et al. 2014[71]	Meta-analysis 14 studies	108321 children (14 m-16 years)	Maternal obesity (12 studies) was associated with higher odds of asthma or wheeze ever or current; each 1-kg/m2 increase in maternal BMI was associated with a 2–3% increase in the odds of childhood asthma. High gestational weight gain (5 studies) was associated with higher odds of asthma or wheeze ever (OR 1.16). Meta-regression showed a negative association of borderline significance for maternal asthma history.
Dumas et al. 2016[67]	12-year longitudinal study	Growing Up today Study and Nurses Health Study II- 12963 children and mothers	Maternal pre-pregnancy overweight and obesity were associated with offspring asthma (onset before age 12 years), with non-allergic asthma in boys, but allergic asthma in girls. Gestational weight gain trended to be associated with offspring asthma.
Rajappan et al. 2016[69]		Southampton Women’s study cohort 2799 maternal child pairs	Higher maternal pre-pregnancy BMI was associated with increased risks of offspring wheeze, prolonged cough and lower respiratory tract infection in first year of life. No association with maternal gestational weight gain.
Weight Gain During Childhood
Flexeder et al. 2012[75]	10-year longitudinal study	9086 German children	Weight and height gain in first 2 years of life was associated with asthma development in first 10 years of life.
Sonnenschein-van der Voort et al. 2012[80]	4-year longitudinal study	Generation R study (Netherlands)	IUGR and excessive intrauterine weight gain associated with asthma at age 4 years. Infant weight gain in first 3 months, not intra-uterine weight, associated with wheeze, phlegm and shortness of breath in first 4 years.
Van der Gugten et al. 2012[79]		WHeezing Illnesses STudy LEidsche Rijn cohort (Netherlands)	Rapid as well as slow weight gain in first 3 months of life was associated with occurrence of wheeze between 4th to 12th month, with more days of wheeze in those with rapid gain. Increase in BMI was associated with lower FEV1 and FEF25–75%.
Anderson et al. 2013[74]	6.5-year longitudinal study	PROBIT study (UK) 12171 infants	All weight gain variables except birthweight were positively associated with ever having wheezed. One SD increase in weight gain rate between 0–3 months was associated with a 12% increase in allergic rhinitis ever and ever having wheeze. Weight gain rate between 12 and 60 months was associated with skin prick test results.
Matos et al. 2013[76]	11-year longitudinal study	Brazil 669 children	Children in the slow weight gain group (first 2years of life) had 36% fewer symptoms of asthma.
Rzehak et al. 2013[13]	6-year longitudinal study	8 European birth cohorts	Children with a rapid BMI-SDS gain in the first 2 years of life had a higher risk for incident asthma up to age 6 years than children with a less pronounced weight gain slope in early childhood. A rapid BMI gain at 2 to 6 years of age in addition to rapid gain in the first 2 years of life did not significantly enhance the risk of asthma.
Sonnenschein-van der Voort et al. 2014[77]	Meta-analysis: 31 studies	147,252 children	Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma. Compared with term-born children with normal infant weight gain, preterm birth with high infant weight associated with highest risks of school-age asthma.
Belfort et al. 2015[152]	18-year longitudinal study	Infant Health and Development Program (IHDP) 1080 infants (preterm<37 weeks and low birth weight<=2500 grams)	Each additional z-score gain in BMI from term to 4 months and 4–12 months, increased odds of asthma at age 8 years.
Renosto et al. 2015[153]	Retrospective cohort study	85 children Children less than 9 years age	Excess weight (risk for overweight, obesity) was not associated with the severity of asthma. Low growth rate was found among children with moderate/severe persistent asthma compared to persistent mild and intermittent forms.
Sonnenschein-van der Voort et al. 2015[82]	17-year longitudinal study	Avon Longitudinal Study of Parents and Children (ALSPAC)- UK	Rapid weight gain between 3 and 7 years of age was associated with higher FVC and FEV1 values at age 15 years. Weight growth between 0 and 3 months of age was associated with lower FEV1/FVC ratios at age 8 and 15 years. Rapid length growth was associated with lower FVC and FEV1 values at age 15 years.
Ziyab et al. 2015[154]	18-year longitudinal study	Isle of Wight study	Early persistent obesity conferred an increased risk of asthma, deficit in FEV1/FVC ratio at age 18 years.
Claudia et al. 2016[78]	15-year longitudinal study	GINIplus German birth cohort 1842 children	Peak weight velocity in first 2 years of life was negatively associated with pre-bronchodilation flow rates, after adjustment for potential confounders, including asthma diagnosis.
Popovic et al. 2016[155]	18-month longitudinal study	NINFEA 4492 children	Infant size and weight gain velocity for first 18 months were independently positively associated with wheezing.
Chen et al. 2017[156]		Taiwan Children Health Study. 2450 children Followed from 4th–6th grade	Long-term adiposity status predicted childhood asthma with low FeNO; short-term adiposity increases risks of childhood asthma with high FeNO. Long-term adiposity status associated with reduced pulmonary function, whereas short-term adiposity was associated with atopic diseases and airway inflammation.
Jackson et al. 2018[157]	10-year longitudinal study	882 children (preterm <28 weeks gestation)	Risk factors for asthma at 10 years of age included higher weight gain velocity during the first year and between the 2nd and 10th year.
Tsai et al. 2018[81]	16-year longitudinal study	Boston Birth Cohort 1928 children	Extremely rapid early life weight gain during the first 4 and 24 months of life, as well as overweight at 4, 12 and 24 months were each associated with increased risks of asthma.

BMI, body mass index; TNF, tumor necrosis factor; feNO, fractional exhaled nitric oxide, FEV1, forced expiratory volume at 1 second; FVC, forced vital capacity; FEV1/FVC, ratio of FEV1 and FVC; SDS, standardized BMI according to age and sex specific WHO growth standards

Similar cohort studies have also identified a role of early life weight gain in onset of wheeze. Weight gain in the first two years of life is most consistently linked to incident asthma in the first 10 years of life[13,74–77] and with reduced lung function.[78] Specifically, rapid early life weight gain in the first 3 months has been associated with wheeze at 4^th to 12^th month of life,[79] ever having wheeze,[74] wheeze and shortness of breath at age 4 years,[80] asthma at age 8 years,[81] lower lung function at age 5 years[79] and lower FEV₁/FVC and bronchial responsiveness at age 8 and 15 years.[82] Further highlighting the importance of early life rapid weight gain, rapid weight gain between 2–6 years of life did not confer additional risk in one study,[13] and weight gain between 3 to 7 years was associated with higher FEV₁ and FVC values at age 15 years.[82] Together, these studies provide consistent evidence of early life events, including maternal obesity status, and gestational weight gain, and rapid early life weight gain among infants contributing to onset of wheeze/ asthma and lung function deficits later in life. While rapid adiposity early in life may intrinsically influence pulmonary mechanics, it is unlikely that metabolic abnormalities develop de-novo in the first few months of life. Moreover, the timing of alteration of immune responses and influence of maternal metabolic abnormalities on metabolism in the offspring that may underlie incident asthma are not known.

3.2. Weight loss and impact on asthma

Few studies have been conducted on the effect of weight loss in children. As summarized in Table 2, weight loss can be achieved through dietary modification and lifestyle changes (such as exercise) or through more invasive interventions such as gastric bypass or bariatric surgery. While both adult and pediatric studies have investigated the effects of diet, nutrition and lifestyle modification on weight loss and asthma symptoms,[83–99] studies on the effects of bariatric surgery on asthma symptoms are mostly from the adult literature.[100–111] Irrespective of the approach, weight loss is consistently associated with improvement in asthma control, quality of life and lung function indices, in both asthma and non-asthma patients. However, mixed results have been noted on improvement in airway hyper-responsiveness following weight loss wherein some studies found improvement with dietary interventions,[83] or bariatric surgery,[100,109] while others did not. [84,85,101] In keeping with higher disease burden in obese non-atopic asthmatics, bariatric surgery led to greater improvements in AHR among the non-atopic patients.[100] As summarized in Section 2.1, we speculate that these disparate results are due to inherent alterations in pulmonary physiology, including decreased lung volumes that lead to asthma-like symptoms, in the absence of classic airway hyper-responsiveness.

Table 2.

Effect of Weight Loss on Asthma and Lung Function

	Study Design	Sample size (n)	Intervention	Findings
Effect of Diet, Nutrition and Lifestyle changes in Adults
Hakala et al. 2000[89]		14 obese with asthma	Very low-calorie diet for 8 weeks	Mean weight loss was 13.7 kg. Significant improvements in peak flow, spirometry, lung volumes and decreased airway resistance.
Stenius-Arniela et al. 2000[90]		19 obese patients with asthma and 19 obese controls with asthma	Low energy diet for 8 weeks	Mean weight loss in treatment group was 14.5%. Improved lung function (FEV1, FVC), symptoms, need for rescue medications and improved health status in the treatment group.
Aaron et al. 2004[84]		58 obese women (24 with asthma)	Intensive 6-month weight loss program	Mean weight loss was 20 kg. Significant improvement in lung function (spirometry and lung volumes) but not in AHR.
Johnson et al. 2007[91]		10 obese adults	Alternate calorie restriction for 8 weeks	8% weight loss from baseline. Significant improvement in peak flow and asthma control but not in spirometry.
Scott et al. 2013[88]		46 obese adults with asthma	Randomized to 10 week dietary, exercise or combine dietary + exercise	Mean weight loss was higher for dietary and combined groups. Asthma control better in dietary and combined groups. Sputum eosinophils decreased with exercise Neutrophilic inflammation decreased with decreased gynoid adipose tissue in women and decreased fat intake in men. Quality of life improved in all 3 groups A 5–10 % weight loss was associated with improved asthma control and quality of life.
Dias-Junior et al. 2014[85]		22 patients with asthma and obesity 11 control with asthma and obesity	Randomized (2:1) to weight loss program (low calorie intake, sibutramine and olistat) and control groups	12 patients achieved weight loss goal >10% Improved asthma control and FVC in those who achieved target weight loss in the weight loss group. No change in AHR and markers of airway inflammation (induced sputum cellularity).
Ma et al. 2015[92]		330 obese adults with asthma	Randomized to lifestyle intervention or educational intervention over 12 months	Intervention group achieved greater weight loss. Increased odds of achieving better asthma control for weight loss > 10%.
Pakhale et al. 2015[83]		22 obese adults with asthma	16 patients with behavioral weight reduction and liquid meal replacement and 6 patients were control	Mean weight loss was 16.5 kg. Improvement in lung function (FEV1, FVC, and AHR), asthma control and quality of life.
Freitas et al. 2017[86]		55 obese with asthma	Randomized to weight loss program (calorie restriction and psychological therapy) + exercise (28); and weight loss only (27)	Weight loss + exercise group had greater weight loss (6.8% vs. 3.1%), improved asthma control, lung function, aerobic capacity, FeNO and anti-inflammatory biomarkers, and decreased inflammatory markers.
Effect of Diet, Nutrition and Lifestyle Changes in Children
da Silva et al. 2012[93]		26 obese with asthma and 50 obese non asthmatics	Multi-disciplinary weight loss interventions for 1 year	Significant improvement in adipokine levels, and lung function, reduction of leptin and CRP in both groups with greater improvement in asthma group.
van de Griendt et al. 2012[94]		112 obese children without asthma	Multidisciplinary weight loss intervention for 26 weeks	Mean weight loss was 13.9 kg. Improvement in FVC, FEV1, TLC and ERV.
Jensen et al. 2013[95]		28 obese children (8–17 years)	RCT with dietary intervention group and wait list control group for 10 weeks	Mean weight loss was 3.4 kg. Improved lung function (ERV) and asthma control in the dietary intervention group.
Abd El-Kader et al. 2013[87]		80 obese with asthma	Randomized to treatment group (diet, exercise and medical treatment) and control group (medical treatment)	Mean BMI reduction of 15.9%. Decreased TNF-alpha, IL-6, IL-8, Leptin and increased adiponectin in the treatment group.
Luna-Pech et al. 2014[96]		51 obese children with asthma	RCT with 28 week intervention group with supervised normo-caloric diet vs. no intervention for control group	Mean weight loss was 2.5 kg. Significant improvement in asthma control and quality of life.
van Leeuwen et al. 2014[96]		20 overweight and obese children with asthma	Dietary intervention for 6 weeks	Mean weight loss was 2.6 % of baseline. Improvement in EIB and quality of life, but not in asthma control.
Willeboordse et al. 2016[97]		87 overweight/obese children with asthma	RCT over 18 months with multifactorial intervention vs. usual care	Asthma features and lung function improved in both groups with greater improvement in the intervention group for FVC, asthma control, and quality of life.
Lucas et al. 2018[98]		232 overweight/obese children, 86 with asthma	Nutrition and physical activity intervention program for a median of 9 weeks (range 1–12 weeks)	Significant weight reduction and was associated with improved cardio-respiratory fitness in both groups.
Effect of Bariatric Surgery
Macgregor et al.[102] 1993		40 obese with asthma	Bariatric surgery	Average follow up 4 years (2–11 years). 90% patients with improved asthma symptoms and 48% with complete remission.
Dhabuwala et al. 2000[103]		157 obese (34 with asthma)	Bariatric surgery	Asthma resolved in 50%, improved in 26% at 2 years
O’Brien et al. 2002[104]		709 obese (33 with asthma)	Bariatric surgery (laparoscopic band)	At 1 year follow up, all patients with improvements in symptoms and reduction of medications
Simard et al. 2004[105]		398 obese patients (30% with asthma)	Bariatric surgery	Improved asthma in 79% patients at 2 years follow up.
Ahroni et al. 2005[108]		172 obese	Bariatric surgery	74% patients with improvement in asthma at 1 year follow up.
Zerah-Lancner et al. 2011[101]		120 obese adults without asthma 16 patients with AHR	Bariatric surgery	AHR was not related with BMI. No significant change in AHR following surgery at 18 months to 2 years.
Dixon et al. 2011[100]		23 obese with asthma 21 obese without asthma	Bariatric surgery	Significant change in BMI at 12 months after surgery. Asthmatic patients with significant improvement in asthma control, quality of life. Improved AHR by methacholine challenge in asthma patients, particularly those with normal IgE. Altered immune response with increased CD4+ T-lymphocytic function.
Boulet et al. 2012[109]		23 obese with asthma	12 underwent bariatric surgery and 11 were controls	Mean PC20 methacholine, FEV1, FVC, FRC, FRC/TLC and ERV, and asthma severity/control significantly improved 12 months after surgery.
Chapman et al. 2014[110]		13 obese with asthma (8 Th-2 low phenotype and 5 Th-2 high phenotype)	Bariatric surgery	12 months after surgery, greater reduction in BMI in Th-2 high group. Improved FEV1 and FVC following bariatric surgery in both groups. Sensitivity to airway closure improved in Th-2 low group following surgery, but not in Th-2 high group. Respiratory resistance improved in the Th-2 high group after surgery.
van Huisstede et al. 2015[111]		27 obese with asthma, 39 obese without asthma, 12 control obese patients with asthma	66 patients with surgery and 12 control patients with no surgery	At 12 months after surgery, FEV1, FRC, TLC improved in both groups while FEV1/FVC ratio improved in the asthma group only. Improvement in Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD20 in the asthma + bariatric surgery Small airway function improved in both surgery groups, more in the asthma group Systemic inflammation improved in both surgery groups, while mast cells decreased in the asthma + bariatric surgery group.
Hasegawa et al. 2015[106]		2261 obese with asthma	Bariatric surgery (Retrospective)	60% reduction in odds ratio for asthma exacerbation 12 months after surgery.
Maniscalco et al. 2016[158]		26 obese with asthma	15 patients underwent laparoscopic gastric banding 11 were controls	Significant improvement in ACT and HRQoL at 1 year and 5 years.

ACT, asthma control test; HRQoL, Hea th related Quality of Life; RCT, randomized controlled trial; ERV, Expiratory reserve volume; AHR, airway hyper-responsiveness; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; CRP, C-reactive protein

In addition to improvement in symptoms, reduction in leptin and increase in adiponectin with weight loss,[87,93] and decrease in systemic and/or airway inflammatory markers associated with obesity have been reported.[86–88,111] Together, these studies suggest that although bariatric surgery is an invasive but effective and sustainable approach for weight loss and reversal of asthma symptoms, simple lifestyle interventions such as calorie restriction and exercise can achieve similar results and should be encouraged in the younger obese patients.

The importance of lifestyle modification is further supported by the growing understanding that changes in body fat composition and fat distribution are more pertinent than absolute changes in body weight or BMI z-score in children, since preserving and increasing lean body mass in lieu of body fat mass, is more important that weight loss in isolation, particularly in adolescents.[112–114] Along these lines, one study has shown that a weight loss intervention in the adolescent age group was associated with a more significant change in body fat mass as compared to BMI thus suggesting that body fat may be a better indicator for effective weight loss,[115] but a contemporaneous study also showed that BMI changes correlated with total fat mass changes.[114] However, pediatric studies on the impact of weight loss have not specifically investigated the link between change in asthma outcomes with change in lean vs. fat mass.

4. DIAGNOSIS AND MANAGEMENT OF OBESITY-RELATED ASTHMA

Having summarized the role of weight gain and weight loss in asthma prevention and management, we recognize that high disease burden among obese asthmatics is due to the difficult nature of weight control as well as weight loss. We therefore conclude our review by including a diagnostic and management approach using routinely available and newer diagnostic modalities which will better characterize disease pathophysiology and thereby inform management [Figure 1].

Figure 1.

Diagnostic and management algorithm for obesity-related asthma

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FEV1/FVC, ratio forced expiratory volume in 1 second and forced vital capacity; TLC, total lung capacity; ERV, expiratory reserve volume; FRC, functional residual capacity; RV, residual volume; FeNO, fractional exhaled nitric oxide; NHLBI, National Heart, Lung and Blood Institute

Following a thorough history and physical examination, PFTs including spirometry and lung volumes should be obtained in obese asthmatics [Section 2.1]. Normal spirometry and lung volumes in the context of symptoms should prompt further testing to evaluate for comorbidities and for deconditioning, including for airway hyper-responsiveness by 6-minute walk test (6MWT) or cardiopulmonary exercise testing (CPET), by direct methacholine challenge for bronchial hyper-reactivity, or for airway resistance by impulse oscillometry. Testing for atopy, including atopic airway inflammation, using FeNO, as well as markers of systemic inflammation and metabolic dysregulation would further contribute to understanding the etiology of pulmonary dysfunction in obese children.

4.1. Diagnostic testing for obesity-related asthma

We have developed a suggested algorithm for diagnostic testing in obese children with respiratory symptoms (Figure 1) that could be a useful clinical guide to sub-phenotype respiratory presentations related to obesity. The various diagnosed tests have been explored in details below.

4.1.i. Broncho-provocation Testing, Functional Exercise Capacity, and Cardiopulmonary Exercise Testing

While obesity alone can impact pulmonary function, concomitant asthma is associated with further decline when tested by broncho-provocative challenge. AHR measured by methacholine challenge was independently associated with BMI, asthma symptoms, and atopy in some,[116] and not in other studies[117],[118] possibly because subjects in the latter studies were overweight but not obese. Similar disparate results were observed in non-asthmatic obese adults, where obesity either did not alter sensitivity or maximal response to methacholine,[119,120] was positively correlated,[121] or was negatively associated with AHR.[122]

Using the 6MWT, Consilvo et al[123] reported lower baseline spirometric indices in all obese children compared to normal weight, but the 6-minute walk distance (6MWD) was lower only in the obese asthmatics. Spirometry done post 6MWT showed decline in FEV₁ in both obese and normal-weight asthmatics. Similarly, Rastogi et.al. reported lower 6MWD in obese asthmatics as compared to obese non-asthmatics, which negatively correlated with BMI.[20] Thus, asthma co-existing with obesity exaggerates AHR.[123]

Functional capacity assessed by CPET revealed higher exercise induced bronchospasm (EIB) in obese asthmatics as compared to normal weight asthmatics in some[124] but not all studies.[125] Lung and chest wall expansion against the body fat, with reduced lung and chest wall compliance, may contribute to increased oxygen cost of breathing during exercise, leading to the characteristic shallow and rapid breathing pattern observed in obesity. While absolute peak oxygen consumption (VO2) may be normal or higher, when corrected for body weight, it is typically lower in obese compared to normal-weight individuals,[126] with no difference in metabolic parameters and EIB.[127] Further, reduced respiratory exchange ratio (RER), but not peak VO2 or work rate, was reported in obese adolescents compared to lean participants, which was independently associated with BMI.[128] Identifying a role of obesity-mediated inflammation, EIB in obese asthmatic children quantified by CPET directly correlated with leptin and inversely with adiponectin.[49]

Thus, while these bronchial challenge tests still need further investigation to understand their utility in diagnosing asthma in obesity, a positive result for EIB could be useful to identify airway hyper-reactivity as the cause of asthma symptoms in the obese patient with dyspnea and PFT abnormalities.

4.1.ii. Impulse Oscillometry

Impulse Oscillometry (IOS) test is a non-invasive and effort independent technique of measuring respiratory mechanics, including resistance and reactance, that works by impinging external pressure signals through the airway during tidal breathing at different frequencies ranging from 5Hz to 35 Hz. The lower frequencies are reflected from the upper airways while the higher frequencies penetrate to the lower airways. The resistance between 5 and 20 Hz (R_5–20) is a reflection of lower airway resistance, while the area under the reactance curve (Ax) differentiates between obstructive and restrictive disease. Several studies have used this test for pulmonary assessment in asthma. [129,130] A recent review suggests that IOS may be superior to spirometry in asthma management as it may detect airway obstruction earlier than spirometry in children.[131] In a prospective study, persistent overweight/obesity was associated with higher R_5–20 and Ax^0.5 suggesting peripheral airway resistance.[132] Similarly, in a post-bronchiolitic cohort study of obese children, IOS identified presence of structural airway damage not reversible with bronchodilators.[133] However, another study did not find any increase in airway resistance, despite higher FEV₁ and FVC, and lower FEV₁/FVC in participants, suggesting a greater effect of airway dysanapsis.[134] Although IOS studies in the pediatric obese population are few, they support a role of peripheral resistance quantification as an adjunctive tool to conventional PFTs in the evaluation of obesity-related asthma.

4.1.iii. Fractional Exhaled Nitric Oxide determination (FeNO)

FeNO measured in exhaled breath from asthma patients correlates with eosinophilic airway inflammation, and serves as a measure of responsiveness to inhaled steroids.[135] While FeNO>35ppb indicates eosinophilic inflammation, FeNO<20 ppb indicates absence of eosinophilic inflammation and thereby potential lack of steroid responsiveness, with levels between 20–35ppb are interpreted in the clinical context.[135] While several studies have demonstrated a relationship between FeNO with atopic sensitization, [136,137] its role in obesity and obesity-related asthma needs further exploration. As summarized in Table 3, utility of FeNO studied in the context of obesity with and without asthma has revealed several conflicting results. Low FeNO or lack of association between FeNO and disease burden has been reported in some studies of obesity-related asthma,[62,63,138–141] while others reported higher FeNO in asthmatics, not influenced by their obese status[123,142–144] but linked to their atopic status.[145,146] Longitudinal studies have reported worse asthma outcomes with rapid weight gain among those with high FeNO and no association with FeNO among those chronically obese with asthma.[64] In light of the importance of the chronology of obesity and asthma, we speculate that FeNO plays a role in atopy and therefore atopic asthma in obesity, while it may be low in obesity without asthma. Thus, FeNO may indeed be an important adjunct tool in distinguishing atopy-related asthma with obesity from incident asthma in the obese.

Table 3.

Studies assessing association of FeNO with obesity and asthma in children

Study	Study design	Obesity definition	Sample size (n)	Age range	Population	Finding
Leung et al. 2004[142]	CS	Body weight>120% of the median weight for height	115	7–18 years	Chinese (Hong Kong)	FeNO and LTB4 were increased in asthma but did not differ between obese and non-obese asthmatics
Santamaria et al. 2005[138]	CS	BMI>95th percentile for age and gender	40	6–18 years	Italy	BMI was not related to FeNO when controlled for age
Santamaria et al. 2007[61]	CS	BMI >95th percentile for age and gender	50 obese and 50 controls	8–16 years	Caucasian (Italian)	No association of FeNO with atopy, asthma and BMI
Szefler SJ et al. 2008[145]	RCT NCT00114413	Subgroup analysis; BMI ≥ 30 kg/m2, BMI percentile ≥ 97%	546	12–20 years	Black (64%); Hispanic (23%); Other (13%)	Subgroup analysis revealed that in participants with obesity with higher blood eosinophil counts and greater atopy, using FeNO to guide therapy resulted in a larger decrease in symptom days.
Chow et al. 2009[143]	CS	Body weight>120% of the median weight for height	55	6–18 years	Chinese (Hong Kong)	FeNO was higher in obese asthmatics and non-asthmatics, as well as non-obese asthmatics, with no difference between groups.
Linn et al. 2009[144]	CS		2568	7–10 years	Non-Hispanic White (34.4% F; 35.1% M) Hispanic (55.6% F 55.0% M) African-American (27% F 22% M) Asian-American (40% F 40% M) Other/Unknown (66% F; 62% M)	Positive association between adiposity and FeNO.
Consilvio et al. 2010[123]	CS	2 SD for the mean of age and sex	708	Pre-pubertal (range 6–8 years)	Caucasian (Italy)	Higher FeNO in obese group. Higher FeNO in obese asthmatics compared to obese non-asthmatics FeNO associated with asthma in obesity
Kattan et al. 2010[63]	Prospective	Overweight-BMI >85th percentile Obese- BMI >95th percentile	368	12–20 years	US; African American (62.5%), Hispanic (22.6%)	No association between adiposity and FeNO.
Cibella et al. 2011[146]	CS	Overweight – obese defined as BMI > 85th percentile	708	1–16 years	Italy	Allergic sensitization, asthma and rhino-conjunctivitis predicted increased FeNO
Erkoçoğlu M et al. 2013[139]	CS	BMI >95th percentile for age and gender	194	6–17 years	Turkish	BMI correlated positively with FeNO in non-asthmatic children but not in asthmatic.
Jensen et al. 2013[159]	CS	BMI z-score > 1.64 SD	361	8–17 years	Australia	FeNO significantly lower in the obese non-asthmatic control group, but higher in the obese and non-obese asthmatics with no difference between groups.
Han et al. 2014[62]	CS	BMI >95th percentile for age and gender	2681	6–17 years	NHANES 2007–2010 Caucasians (33.3%), African Americans (20.2%), Hispanics (40.2%) and others (5.7%)	Adiposity markers including BMI associated with asthma among children with low FeNO. In children with asthma and high FeNO, adiposity markers were associated with worse asthma control.
Casas et al. 2016[140]	Prospective	Peak height and weight velocities and BMI at peak adiposity	5364	0–3 years	Netherlands	Peak height and weight velocities and BMI at peak adiposity were associated with increased wheezing at age 6 but not associated with FeNO.
Yao et al. 2017[141]	Prospective	Overweight (BMI≧25 and <30 kg/m2), and obesity (BMI≧30 kg/m2)	1717	5–18	Asia	BMI was inversely proportional to FeNO particularly in the presence of atopy

BMI, body mass index; SD, standard deviation; F, female; M, male; FeNO, fractional exhaled nitric oxide; LTB4, leukotriene B4; CS, cross-sectional; RCT, randomized control trial

4.1.iv. Testing for Atopy

As discussed earlier, atopy may be contributing to an asthma phenotype co-existing with obesity or may be modifying existing inflammatory pathways in obesity resulting in pulmonary function decline. Assessment of systemic atopic sensitization including blood eosinophil counts, serum IgE, skin prick testing or serum allergen testing in conjunction with atopic airway inflammation should be routinely employed to identify an atopic phenotype in obesity-related asthma. This will support use of therapies effective against Th2 inflammation. Identification of absence of atopy is also helpful since it will suggest a larger role of obesity-mediated physiologic effect or non-atopic inflammation or metabolic abnormalities in the pulmonary disease burden and prevent excessive/ erroneous use of medications effective for atopic asthma.

4.1.v. Testing for Metabolic Dysregulation and Inflammatory Markers

Having identified several studies linking metabolic abnormalities to obesity-related asthma [Section 2.2], we suggest that primary health care providers have a low threshold to evaluate obese patients for metabolic dysfunction, including serum lipids and markers of insulin resistance, particularly in patients with respiratory symptoms. Furthermore, a subspecialty visit to an endocrinologist for body weight issues or to a pulmonologist for respiratory issues may be the first opportunity to identify metabolic dysregulation in obese patients and thereby institute early intervention such as nutritional counselling, dietary changes, behavior and lifestyle modification and therapeutic interventions to prevent and/or treat metabolic syndrome.

While most cytokines and T-helper cell specific inflammatory markers are still research tools, we speculate that they may become valuable adjunctive tools in the future to understand the pathophysiologic mechanisms underlying obesity-related asthma, much like IgE quantification in the context of atopy. Similarly, in addition to FeNO, quantification of sputum eosinophils and broncho-alvelolar lavage fluid cell counts may define underlying patterns of airway inflammation.[147,148]

4.2. Management of obesity-related asthma

In light of the mechanisms that underlie obesity-related asthma, it is evident that current asthma medications including inhaled corticosteroids, leukotriene inhibitors, and long-acting beta agonists, are less effective for obese asthmatics, since they target eosinophilic inflammation.[23] Albuterol, the short-acting bronchodilator used as a rescue medication, is also less effective in obese children.[22] Newer biologic agents such as omalizumab, reslizumab, mepolizumab and benralizumab have also been developed to target Th-2 mediated inflammatory pathways.[149] While identification of atopy will support the use of these medications, lack of atopy will suggest that these medications would be less effective in obese asthmatics. Thus, at this time, management options for obese asthmatics include primary prevention, focused on monitoring of early-life weight gain, starting from the time of pregnancy. Recognizing the uphill nature of implementing this, it is reassuring that weight loss at any time in the individual’s lifespan has been associated with improved symptoms and disease burden. Since both metabolic abnormalities and systemic immune responses are intricately linked with adiposity, we speculate that improvement in disease burden with weight loss is multifactorial. Moreover, recognizing the role of weight distribution, we propose that individuals with truncal adiposity, even if their BMI is in the normal-weight range, should be screened for respiratory morbidity. As we further define the pathophysiology of metabolic dysregulation-related pulmonary disease, medications such as metformin,[150,151] that are associated with decreased eosinophilic airway inflammation and reduced airway smooth muscle hypertrophy, may be repurposed for respiratory symptoms.

CONCLUSION

In summary, it is evident that obesity-related asthma is distinct from classic allergic asthma and needs to be assessed and managed differently. Pulmonary evaluation in obese asthmatic children requires more than spirometry, including lung volumes, which interpreted with spirometry, would inform additional testing. Atopy investigated at both systemic and airway-specific levels will guide medical management. Recognizing the role of early weight gain, effort should be made to address maternal pre-pregnancy weight, gestational weight gain, and weight gain in first few months of life. Among those who present with obesity later in childhood, assessment for metabolic abnormalities may help to identify those at-risk. Life style changes including dietary modification and increased exercise will decrease disease burden. Although less studied in children, with increasing use of bariatric surgery, we speculate that surgical weight loss will also be associated with improvement in asthma symptoms.

EXPERT OPINION

Based on the summary of the literature above, in light of the trajectory of obesity prevalence in the past decades, we suggest that the time to address diagnosis and management of obesity-related asthma is now. Current knowledge is consistent on the role of metabolic abnormalities, that are intricately linked with truncal adiposity, in asthma disease burden and pulmonary function deficits. The role of systemic immune responses is also fairly consistent, with a larger number of studies reporting lack of a role of atopy in obesity-related asthma. These associations, while identifying a distinct asthma endotype, also provide data on distinguishing features. These features need to be incorporated for proper phenotyping of the patient. Put in conjunction with the clinical presentation, they will assist in “endotyping” disease. For instance, an obese child with asthma who is atopic and does not have evidence of metabolic abnormalities could be successfully managed with existing asthma medications. On the other hand, identification of the non-atopic obese asthmatic with insulin resistance would suggest that asthma medications, if ineffective, be discontinued and management be focused on weight management. Awareness of these distinguishing features will allow execution of personalized medicine in routine clinical practice leading to cost savings with discontinuation of ineffective medications. These asthma medications may be replaced by life-style modification, which is not currently a part of the mainstream approach for asthma management. Future research in the field hinges on identification of chronology of obesity and asthma. It is also important to identify the key features and chronology of obesity-mediated effects that lead to asthma. Inroads made in the field of cardiology and endocrinology suggest that immune responses precede metabolic abnormalities which then lead to overt disease presentation. We can utilize these details to investigate the timing of respiratory system involvement. Since obesity-mediated immune responses are systemic, the mechanisms by which these responses cause pulmonary disease need to be investigated. In the upcoming decade, we speculate that biomedical research will elucidate the mechanisms by which intrinsic body fat load, metabolic abnormalities and obesity-mediated immune responses influence the pulmonary system. Improved understanding of these mechanisms underlying obesity-related asthma will allow repurposing of existing medications, such as those currently available for metabolic abnormalities. We also propose that specific medications addressing non-atopic obesity-mediated inflammation, such as anti-IL-6 and anti-TNF medications may be used for asthma management. Some of these medications exist but need an improvement in their safety profile. These details together will define obesity-related asthma as a separate disease entity that will inform targeted drug discovery. Lastly, recognizing the role of early life weight gain on asthma, we propose that obesity-related asthma may be amenable to primary prevention with close monitoring of maternal and early-life weight gain in the infant. Among those that develop symptoms due to poor control on weight gain, life style modifications at any time in life can lead to improvement in symptoms and in pulmonary mechanics. Together, the field of the pulmonary consequences of obesity is nascent but the risk factors identified suggest several areas for further investigation, each of which will facilitate better disease management.

ARTICLE HIGHLIGHTS:

• Obesity is an independent predictor of childhood asthma.

• Early life weight gain is associated with wheeze and incident asthma.

• Weight loss at any age is associated with improvement in asthma symptoms.

• Obesity impacts pulmonary physiology in multiple ways including inherent effect of adiposity, and via metabolic dysregulation and altered immune responses.

• Pulmonary function testing can help to distinguish effects of obesity on pulmonary physiology.

• Assessment for atopy may potentially help to distinguish asthma with co-existent obesity from incident asthma due to obesity

• Assessment for metabolic dysregulation in obese children may help to identify obese children at risk for asthma