Immunological characteristics and management considerations in obese patients with asthma

Obesity is associated with severe, poorly controlled asthma that does not respond as well to therapy as asthma in leaner asthmatics. Important insights gained from animal models of obesity and asthma suggests that different forms of obesity may lead to different manifestations of airway disease: obesity is associated with both innate increased airway reactivity and altered responses to aeroallergen and pollutant challenges. In humans, at least two broad groups of obese asthmatics have been recognized: one that is likely unique to obesity and another that is likely lean allergic asthma much complicated by obesity. This article will discuss what we have learned about the immunological and pathophysiological basis of asthma in obesity from animal and human studies, and how this might guide therapy.     

Effects of Diet-Induced Mild Obesity on Airway Hyperreactivity and Lung Inflammation in Mice

Purpose

Obesity has been suggested to be linked to asthma. However, it is not yet known whether obesity directly leads to airway hyperreactivity (AHR) or obesity-induced airway inflammation associated with asthma. We investigated obesity-related changes in adipokines, AHR, and lung inflammation in a murine model of asthma and obesity.

Materials and Methods

We developed mouse models of chronic asthma via ovalbumin (OVA)-challenge and of obesity by feeding a high-fat diet, and then performed the methacholine bronchial provocation test, and real-time PCR for leptin, leptin receptor, adiponectin, adiponectin receptor (adipor1 and 2), vascular endothelial growth factor (VEGF), transforming growth factor (TGF) β, and tumor necrosis factor (TNF) α in lung tissue. We also measured cell counts in bronchoalveolar lavage fluid.

Results

Both obese and lean mice chronically exposed to OVA developed eosinophilic lung inflammation and AHR to methacholine. However, obese mice without OVA challenge did not develop AHR or eosinophilic inflammation in lung tissue. In obese mice, lung mRNA expressions of leptin, leptin receptor, VEGF, TGF, and TNF were enhanced, and adipor1 and 2 expressions were decreased compared to mice in the control group. On the other hand, there were no differences between obese mice with or without OVA challenge.

Conclusion

Diet-induced mild obesity may not augment AHR or eosinophilic lung inflammation in asthma.     

Ovalbumin-sensitized mice are good models for airway hyperresponsiveness but not acute physiological responses to allergen inhalation

Background Asthma is a chronic inflammatory disease that is characterized clinically by airway hyperresponsiveness (AHR) to bronchoconstricting agents. The physiological response of the asthmatic lung to inhaled allergen is often characterized by two distinct phases: an early‐phase response (EPR) within the first hour following exposure that subsides and a late‐phase response (LPR) that is more prolonged and may occur several hours later. Mouse models of asthma have become increasingly popular and should be designed to exhibit an EPR, LPR and AHR. Objective To determine whether a common model of asthma is capable of demonstrating an EPR, LPR and AHR. Methods BALB/c mice were sensitized to ovalbumin (OVA) and challenged with one or three OVA aerosols. Changes in lung mechanics in response to allergen inhalation were assessed using a modification of the low‐frequency forced oscillation technique (LFOT). In order to assess AHR, changes in lung mechanics in response to aerosolized methacholine were assessed using LFOT. Inflammatory cell infiltration into the lung was measured via bronchoalveolar lavage (BAL). ELISAs were used to measure inflammatory cytokines in the BAL and levels of IgE in the serum. Results An EPR was only detectable after three OVA aerosols in approximately half of the mice studied. There was no evidence of an LPR despite a clear increase in cellular infiltration 6 h post‐allergen challenge. AHR was present after a single OVA aerosol but not after three OVA aerosols. Conclusions The lack of an LPR, limited EPR and the absence of a link between the LPR and AHR highlight the limitations of this mouse model as a complete model of the lung dysfunction associated with asthma.     

Obesity and asthma: possible mechanisms

Epidemiologic data indicate that obesity increases the prevalence and incidence of asthma and reduces asthma control. Obese mice exhibit innate airway hyperresponsiveness and augmented responses to certain asthma triggers, further supporting a relationship between obesity and asthma. Here I discuss several mechanisms that may explain this relationship. In obesity, lung volume and tidal volume are reduced, events that promote airway narrowing. Obesity also leads to a state of low-grade systemic inflammation that may act on the lung to exacerbate asthma. Obesity-related changes in adipose-derived hormones, including leptin and adiponectin, may participate in these events. Comorbidities of obesity, such as dyslipidemia, gastroesophageal reflux, sleep-disordered breathing, type 2 diabetes, or hypertension may provoke or worsen asthma. Finally, obesity and asthma may share a common etiology, such as common genetics, common in utero conditions, or common predisposing dietary factors. Novel therapeutic strategies for treatment of the obese patient with asthma may result from an increased understanding of the mechanisms underlying this relationship.     

Asthma and obesity in children: current evidence and potential systems biology approaches

Both obesity and asthma are highly prevalent, complex diseases modified by multiple factors. Genetic, developmental, lung mechanical, immunological and behavioural factors have all been suggested as playing a causal role between the two entities; however, their complex mechanistic interactions are still poorly understood and evidence of causality in children remains scant. Equally lacking is evidence of effective treatment strategies, despite the fact that imbalances at vulnerable phases in childhood can impact long‐term health. This review is targeted at both clinicians frequently faced with the dilemma of how to investigate and treat the obese asthmatic child and researchers interested in the topic. Highlighting the breadth of the spectrum of factors involved, this review collates evidence regarding the investigation and treatment of asthma in obese children, particularly in comparison with current approaches in ‘difficult‐to‐treat’ childhood asthma. Finally, the authors propose hypotheses for future research from a systems‐based perspective.     

Effect of obesity on airway inflammation: a cross-sectional analysis of body mass index and sputum cell counts

BACKGROUND: Several observational studies have demonstrated an association between obesity and asthma. Studies evaluating exhaled nitric oxide levels and obesity have revealed that a higher body mass index (BMI) is associated with elevated exhaled nitric oxide levels. Airway inflammation using sputum cell counts has not been assessed in obese patients with airway diseases. OBJECTIVE: The primary aim of this study was to determine whether obesity (based on BMI) is associated with eosinophilic or neutrophilic bronchitis. METHODS: The results from a database of induced sputum cell counts were compared with BMI and analysed using correlation statistics, regression and parametric and non-parametric analysis. RESULTS: Seven-hundred and twenty-seven adult participants with an equal number of sputum samples were included in the analysis. BMI varied from 14.5 to 55 kg/m(2). Sputum total cell count (mean+/-SD: 12.9 x 10(6) cell/g+/-21.5), eosinophil percent (median; min to max: 0.3%; 0-89.0), and neutrophil percent (mean+/-SD: 63.5+/-26.6%) were within normal limits. Participants with asthma had a higher percentage of sputum eosinophils than those without asthma (P=0.01). However, there was no difference in the total or differential cell counts among the obese and non-obese participants, when the data were analysed according to BMI category, gender, dose of inhaled corticosteroid, and presence or absence of asthma. CONCLUSION: In this large sample of adult asthmatic and non-asthmatic participants, there was no association between BMI and airway inflammation measured by sputum cell counts. Other mechanisms to explain the relationship between obesity and asthma will need to be explored if this association is to be better understood.     

The influence of obesity on inflammation and clinical symptoms in asthma

Obesity and asthma are both important public health issues. Increasing number of studies suggest the association between obesity and asthma which may be causal or accidental. The studies on animal models show innate enhancement of airway hyper-responsiveness which suggest that chronic airway hyper-responsiveness may be related to chronic low-grade systemic inflammation occurring in obesity. These results are confirmed by studies on asthmatic patients which show that levels of inflammation markers were higher in obese asthma patients and are related to the parameters of obesity. However, adipokines secreted by adipose tissue have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma, especially in obese female patients. The studies on the association between adiposity and atopy have conflicting results and the issue needs to be investigated in the future. Obesity also decreases lung volume and increases airway resistance inducing symptoms that could mimic asthma. Clinical studies suggest that asthma in obese subjects may differ from the classical phenotype of the disease. Obese patients referred for asthma exacerbation present a reduced response to standard asthma medications.The review indicates that mechanical and inflammatory effects of obesity may explain the influence on asthma. Further studies on the association between adiposity and atopy on airway inflammation may confirm the active role of fat tissue, not only simple mechanical impairment of the thorax movement. Longitudinal studies are needed to understand the association between asthma, and obesity, which may open new therapeutic options for asthma treatment in obese patients.     

Do mast cells link obesity and asthma?

Asthma is a chronic inflammatory disease of the lungs. Both the number of cases and severity of asthma have been increasing without a clear explanation. Recent evidence suggests that obesity, which has also been increasing alarmingly, may worsen or precipitate asthma, but there is little evidence of how obesity may contribute to lung inflammation. We propose that mast cells are involved in both asthma and obesity by being the target and source of adipocytokines, ‘alarmins’ such as interleukin‐9 (IL‐9) and interleukin‐33 (IL‐33), and stress molecules including corticotropin‐releasing hormone (CRH) and neurotensin (NT), secreted in response to the metabolic burden. In particular, CRH and NT have synergistic effects on mast cell secretion of vascular endothelial growth factor (VEGF). IL‐33 augments VEGF release induced by substance P (SP) and tumor necrosis factor (TNF) release induced by NT. Both IL‐9 and IL‐33 also promote lung mast cell infiltration and augment allergic inflammation. These molecules are also expressed in human mast cells leading to autocrine effects. Obese patients are also less sensitive to glucocorticoids and bronchodilators. Development of effective mast cell inhibitors may be a novel approach for the management of both asthma and obesity. Certain flavonoid combinations may be a promising new treatment approach.     

An economic evaluation of NIOX MINO airway inflammation monitor in the United Kingdom

Background: Fractional exhaled nitric oxide (FE_NO), a marker of eosinophilic airway inflammation, is easily measured by noninvasive means. The objective of this study was to determine the cost‐effectiveness of FE_NO measurement using a hand‐held monitor (NIOX MINO), at a reimbursement price of £23, for asthma diagnosis and management in the UK. Methods: We constructed two decision trees to compare FE_NO measurement with standard diagnostic testing and guideline recommendations for management. For asthma diagnosis, we compared FE_NO measurement with lung function and reversibility testing, bronchial provocation and sputum eosinophil count. For asthma management, we evaluated the impact on asthma control, including inhaled corticosteroid use, exacerbations and hospitalizations, of monitoring with FE_NO measurement vs symptoms and lung function as in standard care. Resource use and health outcomes were evaluated over a 1‐year time frame. Direct costs were calculated from a UK health‐care payer perspective (2005 £). Results: An asthma diagnosis using FE_NO measurement cost £43 less per patient as compared with standard diagnostic tests. Asthma management using FE_NO measurement instead of lung function testing resulted in annual cost‐savings of £341 and 0.06 quality‐adjusted life‐years gained for patients with mild to severe asthma and cost‐savings of £554 and 0.004 quality‐adjusted life‐years gained for those with moderate to severe asthma. Conclusions: Asthma diagnosis based on FE_NO measurement with NIOX MINO alone is less costly and more accurate than standard diagnostic methods. Asthma management based on FE_NO measurement is less costly than asthma management based on standard guidelines and provides similar health benefits.     

Obesity and asthma, what are the links?

PURPOSE OF REVIEW: Obesity is a major cause of morbidity accounting for approximately 300 000 deaths each year and about 7% of the health care budget with an economic impact greater than US dollar 100 billion annually in the United States. Obesity and its sequelae such as cardiovascular disease, diabetes, arthritis or cancer have been on the rise over the last decades. The parallel time trend with an increasing prevalence of asthma has induced a lively debate about a potential link between both conditions. RECENT FINDINGS: A number of prospective studies have shown that weight gain can antedate the development of asthma. Effect modification by sex may occur as some studies have shown effects of body mass index on asthma only among females. However, sex differences are not consistent. Several hypotheses have been proposed to explain the epidemiological associations including alterations in airway mechanics and immune responses, hormonal influences and genetic factors. SUMMARY: There is evidence that obesity and overweight are associated with the development of asthma. Yet, the mechanisms underlying this relation are unclear. Weight reduction among asthmatic patients can result in improvements of lung function demonstrating the potential clinical impact of the findings.     

Obesity promotes prolonged ovalbumin‐induced airway inflammation modulating T helper type 1 (Th1), Th2 and Th17 immune responses in BALB/c mice

Clinical and epidemiological studies indicate that obesity affects the development and phenotype of asthma by inducing inflammatory mechanisms in addition to eosinophilic inflammation. The aim of this study was to assess the effect of obesity on allergic airway inflammation and T helper type 2 (Th2) immune responses using an experimental model of asthma in BALB/c mice. Mice fed a high‐fat diet (HFD) for 10 weeks were sensitized and challenged with ovalbumin (OVA), and analyses were performed at 24 and 48 h after the last OVA challenge. Obesity induced an increase of inducible nitric oxide synthase (iNOS)‐expressing macrophages and neutrophils which peaked at 48 h after the last OVA challenge, and was associated with higher levels of interleukin (IL)‐4, IL‐9, IL‐17A, leptin and interferon (IFN)‐γ in the lungs. Higher goblet cell hyperplasia was associated with elevated mast cell influx into the lungs and trachea in the obese allergic mice. In contrast, early eosinophil influx and lower levels of IL‐25, thymic stromal lymphopoietin (TSLP), CCL11 and OVA‐specific immunoglobulin (IgE) were observed in the obese allergic mice in comparison to non‐obese allergic mice. Moreover, obese mice showed higher numbers of mast cells regardless of OVA challenge. These results indicate that obesity affects allergic airway inflammation through mechanisms involving mast cell influx and the release of TSLP and IL‐25, which favoured a delayed immune response with an exacerbated Th1, Th2 and Th17 profile. In this scenario, an intense mixed inflammatory granulocyte influx, classically activated macrophage accumulation and intense mucus production may contribute to a refractory therapeutic response and exacerbate asthma severity.     

Association between obesity and asthma in a twin cohort

BACKGROUND: Obesity is linked to asthma in a yet poorly understood manner. We examined the relationship between obesity and asthma in a population-based sample of twins. METHODS: From the cohorts born between 1953 and 1982, who were enrolled in The Danish Twin Registry, a total of 29 183 twin individuals participated in a nationwide questionnaire study, where data on height, weight and asthma were collected. Latent factor models of genetic and environmental effects were fitted using maximum likelihood methods. RESULTS: The age-adjusted risk of asthma was increased both in obese females, OR = 1.96 (1.45-2.64), P < or = 0.001 and in obese males, OR = 1.59 (1.08-2.33), P = 0.02. According to best-fitting models, the heritability for obesity was 81% in males and 92% in females, whereas the heritability for asthma was 78% and 68% in males and females respectively. The age-adjusted genetic liabilities to obesity and asthma were significantly correlated only in females, r = 0.28 (0.16-0.38). CONCLUSIONs: Obese subjects have an increased risk for asthma, which in females seems partly because of common genes.     

Asthma symptom perception and obesity in children

This study examined the relationship between obesity and asthma symptom perception in 200 youth with asthma. Repeated subjective and objective peak flow measurements were summarized using the Asthma Risk Grid (Klein et al., 2004), resulting in Accurate, Symptom Magnification and Danger Zone scores. Analyses were stratified by age and included ethnicity.For younger children, obesity was not significantly related to perception scores. For older children, a significant obesity-by-ethnicity interaction for Accurate Symptom Perception scores indicated that obese white children had lower accuracy than white nonobese children, while there was no difference for obese versus nonobese minority children. Obesity was also related to higher Symptom Magnification scores regardless of ethnicity for older children.These findings suggest that obesity may complicate asthma management by interfering with the ability to accurately perceive symptoms for some patients. More remains to be learned about the role of sociodemographic factors underlying this relationship.     

Airway inflammation in obese and nonobese patients with difficult-to-treat asthma

Background: Asthma and obesity are associated disorders, but the contribution of obesity to difficult‐to‐treat asthma as well as the mechanisms responsible for this relationship are unclear. The aim of this study was to investigate the relationship between obesity (body mass index ≥ 30) and factors related with asthma severity in patients with difficult‐to‐treat asthma. Methods: One hundred and thirty‐six nonsmoking asthmatic adults with persistent symptoms despite high doses of inhaled or oral corticosteroids and long‐acting bronchodilators were studied [70% female, median (range) age 44.6 (18–75) years, 32% on daily oral corticosteroids]. The association between obesity, lung function parameters [forced expiratory volume in 1 s (FEV₁), functional residual capacity/total lung capacity (FRC/TLC)], inflammatory markers [blood eosinophils, sputum eosinophils and neutrophils, exhaled nitric oxide (FE_NO), airway hyperresponsiveness, C‐reactive protein (CRP)] and aggravating co‐morbid factors (severe chronic sinus disease, gastro‐esophageal reflux, recurrent respiratory infections, psychopathology and obstructive sleep apnea) was investigated. Results: Obese patients (n = 29) had a higher FEV₁%pred (P = 0.05) and a lower FRC/TLC%pred (P < 0.01) compared with nonobese patients (n = 107). Body mass index was inversely related with sputum eosinophils (r = ?0.36, P < 0.01) and FE_NO (r = ?0.30, P < 0.01). Obese patients had an increased risk for gastro‐esophageal reflux (OR = 2.3) and sleep apnea (OR = 3.1). Conclusion: Obesity in patients with difficult‐to‐treat asthma is inversely related with sputum eosinophils and FE_NO, and positively associated with the presence of co‐morbid factors and reduced lung volumes. This suggests that other factors than airway inflammation alone explain the relationship between obesity and asthma severity.     

Comorbid “treatable traits” in difficult asthma: Current evidence and clinical evaluation

The care of patients with difficult‐to‐control asthma (“difficult asthma”) is challenging and costly. Despite high‐intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype‐driven therapies. However, it is increasingly apparent that extra‐pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as “treatable traits” in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma‐related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.     

Airway hyperresponsiveness is negatively associated with obesity or overweight status in patients with asthma

Background: Obesity is a risk factor for asthma in the general population, but the effect of obesity on airway hyperresponsiveness (AFHR) or airway inflammation in asthma is not clear. This study evaluated the relationship between obesity and asthma, assessing aspects of symptoms, AHR, and severity. Methods: In total, 852 patients with asthma diagnosed by asthma specialists based on AHR as confirmed by a methacholine bronchial provocation test, were enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) adult asthma cohort. The intensity of AHR was assessed by the concentration of methacholine needed to cause a 20% decrease in FEV(1) (PC(20)). Patients were classified into four categories based on body mass index (BMI): underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30). Results: BMI was negatively correlated with FEV(1) (l), FVC (l), and FEV(1)/FVC (%) in lung function tests. The prevalence of wheezing increased with higher BMI after adjustment for age, sex, smoking, medication history, and PC(20) (p < 0.0001). logPC(20) was lower in the normal weight group compared with the overweight group (p = 0.003). The risk of moderate or severe AHR (PC(20) ≤ 4 mg/ml) decreased with increased BMI after adjustment for age, sex, smoking, and medication history (p = 0.035). Conclusions: Obesity is a risk factor for asthma in the general population, but obesity in asthmatic patients is negatively correlated with the intensity of AHR and is not related to asthma severity. Obesity is positively related with the prevalence of wheezing but negatively related to AHR in asthmatic patients.     

Obesity prevention in pediatrics: A pilot pediatric resident curriculum intervention on nutrition and obesity education and counseling

INTRODUCTION: Obesity is a highly burdensome public health issue associated with premature death, multiple comorbid disabilities and staggering healthcare costs. Between 1980-2000, the prevalence of obesity among children and adolescents nearly tripled. Obesity subjects youth to social stigmatization and discrimination. These economic and personal burdens mandate targeted prevention and detection educational programs for all individuals at risk. The most cost-effective method of approaching this obesity epidemic is through education of health professionals. METHODS: As part of an "Obesity Prevention in Pediatrics" curriculum, postgraduate-year (PGY)-2 residents first observed and then participated in the dietary evaluation and counseling of pediatric patients and their families. Attitudinal questionnaires, multiple-choice knowledge examinations and a pre-established checklist of desired skills and behaviors provided evaluation of the curriculum's effect on the participants' ability and willingness to manage actually obese or at-risk pediatric patients and their families. RESULTS: Attitudinal survey and knowledge test scores from control PGY-3 residents generally confirmed that their knowledge and counseling skills on obesity prevention and management were well below expectation. Following participation in the curriculum, study residents' knowledge tended to improve, as did their level of comfort in counseling obese and at-risk children, adolescents and their parents. CONCLUSION: Implementation of an "Obesity Prevention in Pediatrics" curriculum appears to improve participants' knowledge base as well as their skills and level of personal comfort in the recognition, evaluation and management, including counseling, of both obese and at-risk pediatric patients and their families.     

Obesity,adipokines and asthma

Background: The prevalence of asthma and obesity is increasing concomitantly, but many aspects of this link are unclear. Our objective was to examine whether obesity is associated with asthma in three time points of life, and whether immunomodulatory adipokines, leptin and adiponectin are linked to overweight‐associated asthma. Methods: We studied the association between obesity and asthma at ages 3–18 years [mean (SD), 10 years (5), n = 3582, year 1980], 9–24 years [16 years (5), n = 2764, 1986] and 24–39 years [32 years (5), n = 2620, 2001] in a prospective cohort study and further tested for associations with serum leptin and adiponectin concentrations. Data on allergy status, smoking and other laboratory values (serum insulin, plasma C‐reactive protein and serum lipid values) were also analyzed. Results: Allergy and parental asthma were significantly associated with asthma at all ages. At ages 24–39 years, but not earlier, body mass index (BMI) (odds ratio, OR 1.05; P = 0.019) and female gender (OR 1.56; P = 0.031) were independently associated with asthma. Increase in BMI was also associated with incident asthma during adulthood (OR 1.08; P = 0.030). Levels of leptin, adiponectin or any other obesity‐related biomarker were not independently associated with asthma. Conclusions: Asthma is linked with obesity in adults, but our results do not support a significant role for leptin, adiponectin or any other obesity‐related biomarker studied in this association. Other factors should be sought for better understanding the connection between obesity and asthma.     

Improving reproductive performance in overweight/obese women with effective weight management

Obesity and overweight are common conditions in the developed countries and they carry many health consequences, including some reproductive disorders. There is a very high prevalence of obese women in the infertile population and many studies have highlighted the link between obesity and infertility. A large proportion of infertile women have polycystic ovary syndrome (PCOS) which is also linked with increased risk of obesity and other metabolic anomalies. The association between obesity and/or PCOS and hyperinsulinaemia, hyper androgenism and abnormal secretion of other hormones, such as leptin, underlies many reproductive disorders observed in this population. It has been demonstrated that weight loss can improve the fertility of obese women through the recovery of spontaneous ovulation, whereas others will have improved response to ovarian stimulation in infertility treatment. Therefore, it is proposed that following the initial assessment of infertility and body mass index or other measurement of obesity, various weight management interventions, including diet, exercise or pharmacotherapeutic approaches, should be considered for overweight and obese infertile women.