Anne E. Dixon

An official American thoracic society workshop report: obesity and asthma.

RATIONALE The developed world is currently facing an epidemic of obesity. With the increased prevalence of obesity has come the recognition that obesity is a risk factor for asthma. OBJECTIVES The purpose of this workshop was to bring together experts in the field of asthma, with experts in the field of obesity to review the current state-of-the-art knowledge regarding obesity and asthma, with the goal of furthering our understanding of the link between these two disease entities to help define important future directions for research. METHODS Speakers were invited to give presentations highlighting recent developments in their area of expertise that were related to obesity and lung disease. These presentations were followed by interactive discussion. A writing committee from among the participants produced a document summarizing the proceedings. MEASUREMENTS AND MAIN RESULTS The participants found that obesity was a risk factor for asthma in all demographic groups studied. Asthma in the obese may represent a unique phenotype of asthma, with more severe disease that does not respond as well to conventional therapy. Factors that could contribute to the pathogenesis of asthma in the obese include both mechanical factors and altered inflammation and immune responses related to the obese state. CONCLUSIONS There is an urgent need for research to better understand the mechanisms of asthma in the obese, and to develop new therapies specifically targeted to this unique patient population.

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

BACKGROUND Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. OBJECTIVES We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. METHODS We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. RESULTS We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV(1) and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC(20), 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4(+) T cells increased significantly. CONCLUSIONS Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.

Obesity and Asthma An Inflammatory Disease of Adipose Tissue Not the Airway

RATIONALE Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese. OBJECTIVES To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity. METHODS We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time. MEASUREMENTS AND MAIN RESULTS Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = -0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery. CONCLUSIONS Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.

Effect of obesity on clinical presentation and response to treatment in asthma.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.

Allergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

BACKGROUND Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

Extreme Obesity and Outcomes in Critically Ill Patients

BACKGROUND Recent literature suggests that obese critically ill patients do not have worse outcomes than patients who are normal weight. However, outcomes in extreme obesity (BMI ≥ 40 kg/m(2)) are unclear. We sought to determine the association between extreme obesity and ICU outcomes. METHODS We analyzed data from a multicenter international observational study of ICU nutrition practices that occurred in 355 ICUs in 33 countries from 2007 to 2009. Included patients were mechanically ventilated adults ≥ 18 years old who remained in the ICU for > 72 h. Using generalized estimating equations and Cox proportional hazard modeling with clustering by ICU and adjusting for potential confounders, we compared extremely obese to normal-weight patients in terms of duration of mechanical ventilation (DMV), ICU length of stay (LOS), hospital LOS, and 60-day mortality. RESULTS Of the 8,813 patients included in this analysis, 3,490 were normal weight (BMI 18.5-24.9 kg/m(2)), 348 had BMI 40 to 49.9 kg/m(2), 118 had BMI 50 to 59.9 kg/m(2), and 58 had BMI ≥ 60 kg/m(2). Unadjusted analyses suggested that extremely obese critically ill patients have improved mortality (OR for death, 0.77; 95% CI, 0.62-0.94), but this association was not significant after adjustment for confounders. However, an adjusted analysis of survivors found that extremely obese patients have a longer DMV and ICU LOS, with the most obese patients (BMI ≥ 60 kg/m(2)) also having longer hospital LOS. CONCLUSIONS During critical illness, extreme obesity is not associated with a worse survival advantage compared with normal weight. However, among survivors, BMI ≥ 40 kg/m(2) is associated with longer time on mechanical ventilation and in the ICU. These results may have prognostic implications for extremely obese critically ill patients.

The Association Between BMI and Plasma Cytokine Levels in Patients With Acute Lung Injury

BACKGROUND Obesity is associated with poor outcomes in many diseases, although recent data suggest that acute lung injury (ALI) is an exception. This is particularly interesting because obesity is marked by increased levels of proinflammatory mediators associated with increased morbidity and mortality in ALI. We hypothesized that cytokine response might be attenuated in patients who are obese and critically ill or that obesity might modify the relationship between plasma cytokines and clinical outcomes in ALI. METHODS We analyzed plasma biomarker levels (interleukin [IL]-6, IL-8, tumor necrosis factor-alpha receptor 1, surfactant protein D [SP-D], soluble intracellular adhesion molecule, von Willebrand factor (vWF), protein C, and plasminogen activator inhibitor-1) collected at baseline and day 3 in 1,409 participants in prior National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network (ARDSNet) trials. BMI was calculated for each patient, and associations with cytokine levels and ventilator-free days (VFDs), organ failure-free days (OFDs), and mortality were investigated in regression models adjusting for confounders. RESULTS In adjusted analyses, plasma IL-6 (P = .052), IL-8 (P = .001), and SP-D (P < .001) were inversely related to BMI, whereas vWF (P = .001) and WBC count (P = .042) increased proportionally with BMI. BMI was not associated with increased morbidity or mortality and did not modify the association between baseline biomarker levels and mortality, VFDs, or OFDs. CONCLUSIONS Patients who are obese and have ALI have lower levels of several proinflammatory cytokines, suggesting that the inflammatory response may be altered in patients with ALI and a high BMI. Lower SP-D but higher vWF suggests decreased epithelial and increased endothelial injury in the lung of patients who are obese. Mechanisms by which obesity may modulate innate immunity in critical illness are unclear, and future studies should elucidate such mechanisms.

Original Research: ASTHMAAllergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

BACKGROUND Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

The Nonallergic Asthma of Obesity. A Matter of Distal Lung Compliance

RATIONALE The pathogenesis of asthma in obesity is poorly understood, but may be related to breathing at low lung volumes. OBJECTIVES To determine if lung function in obese patients with asthma and control subjects would respond differently to weight loss. METHODS Lung function was evaluated by conventional clinical tests and by impulse oscillometry in female late-onset, nonallergic patients with asthma and control subjects before, and 12 months after, bariatric surgery. MEASUREMENTS AND MAIN RESULTS Patients with asthma (n = 10) had significantly lower FEV1 (79.8 ± 10.6 vs. 95.5 ± 7.0%) and FVC (82.4 ± 13.2 vs. 93.7 ± 8.9%) compared with control subjects (n = 13). There were no significant differences in FRC or TLC at baseline. Twelve months after surgery, control subjects had significant increases in FEV1 (95.5 ± 7.0 to 100.7 ± 5.9), FVC (93.6 ± 8.9 to 98.6 ± 8.3%), FRC (45.4 ± 18.5 to 62.1 ± 15.3%), and TLC (84.8 ± 15.0 to 103.1 ± 15.3%), whereas patients with asthma had improvement only in FEV1 (79.8 ± 10.6 to 87.2 ± 11.5). Control subjects and patients with asthma had a significantly different change in respiratory system resistance with weight loss: control subjects exhibited a uniform decrease in respiratory system resistance at all frequencies, whereas patients with asthma exhibited a decrease in frequency dependence of resistance. Fits of a mathematical model of lung mechanics to these impedance spectra suggest that the lung periphery was more collapsed by obesity in patients with asthma compared with control subjects. CONCLUSIONS Weight loss decompresses the lung in both obese control subjects and patients with asthma, but the more pronounced effects of weight loss on lung elastance suggest that the distal lung is inherently more collapsible in people with asthma.

Obesity Is Associated with Neutrophil Dysfunction and Attenuation of Murine Acute Lung Injury

Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI. Obesity-associated effects on neutrophil chemoattractant response were examined in bone marrow neutrophils using chemotaxis and adoptive transfer; neutrophil surface levels of chemokine receptor CXCR2 were determined by flow cytometry. Airspace neutrophilia, capillary leak, and plasma IL-6 were all decreased in obese relative to lean mice in established lung injury (24 h). No difference in airspace inflammatory cytokine levels was found between obese and lean mice in both obesity models during the early phase of neutrophil recruitment (2-6 h), but early airspace neutrophilia was reduced in db/db obese mice. Neutrophils from uninjured obese mice demonstrated diminished chemotaxis to the chemokine keratinocyte cytokine compared with lean control mice, and adoptive transfer of obese mouse neutrophils into injured lean mice revealed a defect in airspace migration of these cells. Possibly contributing to this defect, neutrophil CXCR2 expression was significantly lower in obese db/db mice, and a similar but nonsignificant decrease was seen in diet-induced obese mice. ALI is attenuated in obese mice, and this blunted response is in part attributable to an obesity-associated abnormal neutrophil chemoattractant response.