Fernando Holguin

Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD

Chronic obstructive pulmonary disease (COPD) is associated with important chronic comorbid diseases, including cardiovascular disease, diabetes and hypertension. The present study analysed data from 20,296 subjects aged ≥45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). The sample was stratified based on baseline lung function data, according to modified Global Initiative for Obstructive Lung Disease (GOLD) criteria. Comorbid disease at baseline and death and hospitalisations over a 5-yr follow-up were then searched for. Lung function impairment was found to be associated with more comorbid disease. In logistic regression models adjusting for age, sex, race, smoking, body mass index and education, subjects with GOLD stage 3 or 4 COPD had a higher prevalence of diabetes (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.1–1.9), hypertension (OR 1.6, 95% CI 1.3–1.9) and cardiovascular disease (OR 2.4, 95% CI 1.9–3.0). Comorbid disease was associated with a higher risk of hospitalisation and mortality that was worse in people with impaired lung function. Lung function impairment is associated with a higher risk of comorbid disease, which contributes to a higher risk of adverse outcomes of mortality and hospitalisations.

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.

Body mass index and asthma severity in the National Asthma Survey

Background: The association between obesity and asthma severity remains controversial and limited to small studies. Methods: We determined the association of body mass index (BMI) and asthma severity in the National Asthma Survey. We included adults (age ⩾18 years) who self-reported symptoms of asthma in the past 5 years. A total of 3095 patients were divided into the following BMI categories: 1080 (35%) non-overweight (BMI <25), 993 (32%) overweight (BMI ⩾25 and <30) and 1022 (33%) obese (BMI ⩾30). Asthma severity measures included respiratory symptoms, healthcare utilisation, medication use, missed work days and the Global Initiative for Asthma (GINA) severity classification. Models were adjusted for: gender, race, age, education, income, employment status, smoking status, family history of asthma, state of residence and residence in a metropolitan statistical area. Results: Compared with non-overweight subjects, obese subjects with asthma were more likely to report continuous symptoms (OR 1.66, 95% CI 1.09 to 2.54), miss more work days (OR 1.35, 95% CI 1.01 to 1.81), use short acting beta agonists (OR 1.36, 95% CI 1.06 to 1.75), use inhaled corticosteroids (OR 1.34, 95% CI 1.01 to 1.79) and use any controller medication according to GINA guidelines (OR 1.37, 95% CI 1.01 to 1.85). Also, obese respondents were less likely to be in asthma remission (OR 0.56, 95% CI 0.38 to 0.82) and were more likely to have severe persistent asthma (GINA IV) (OR 1.42, 95% CI 1.05 to 1.90). Conclusions: In a large, diverse sample of adults with asthma, obesity was associated with measures of asthma severity after adjusting for potential confounders.

Outcomes of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the United States, 1998-2008.

RATIONALE The patterns and outcomes of noninvasive, positive-pressure ventilation (NIPPV) use in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) nationwide are unknown. OBJECTIVES To determine the prevalence and trends of noninvasive ventilation for acute COPD. METHODS We used data from the Healthcare Cost and Utilization Projects Nationwide Inpatient Sample to assess the pattern and outcomes of NIPPV use for acute exacerbations of COPD from 1998 to 2008. MEASUREMENTS AND MAIN RESULTS An estimated 7,511,267 admissions for acute exacerbations occurred from 1998 to 2008. There was a 462% increase in NIPPV use (from 1.0 to 4.5% of all admissions) and a 42% decline in invasive mechanical ventilation (IMV) use (from 6.0 to 3.5% of all admissions) during these years. This was accompanied by an increase in the size of a small cohort of patients requiring transition from NIPPV to IMV. In-hospital mortality in this group appeared to be worsening over time. By 2008, these patients had a high mortality rate (29.3%), which represented 61% higher odds of death compared with patients directly placed on IMV (95% confidence interval, 24-109%) and 677% greater odds of death compared with patients treated with NIPPV alone (95% confidence interval, 475-948%). With the exception of patients transitioned from NIPPV to IMV, in-hospital outcomes were favorable and improved steadily year by year. CONCLUSIONS The use of NIPPV has increased significantly over time among patients hospitalized for acute exacerbations of COPD, whereas the need for intubation and in-hospital mortality has declined. However, the rising mortality rate in a small but expanding group of patients requiring invasive mechanical ventilation after treatment with noninvasive ventilation needs further investigation.

Air pollution and heart rate variability among the elderly in Mexico City.

Background: Suspended particles and ozone have been associated with varying degrees of cardiac autonomic dysfunction Methods: In Mexico City, residents from a nursing home underwent heart rate variability analysis every other day for 3 months. Indoor and outdoor PM2.5 (particulate matter less than 2.5 mm in diameter) were measured daily at the nursing home. Levels of ozone and other atmospheric pollutants were obtained from a nearby automated monitoring station. Results: Of the initial 42 screened participants, 34 (81%) were followed during the study period. The 24-hour average levels of indoor PM2.5 ranged from 15 to 67 &mgr;g/m3, and outdoor PM2.5 ranged from 9 to 87 &mgr;g/m3. Daily 1-hour maximum ozone levels ranged from 47 to 228 ppb. After adjusting for age and heart rate, we observed a strong decrease in the high frequency component of heart rate variability and the average 24-hour concentrations of PM2.5. Participants with hypertension had considerably larger reductions in their HF-HRV (high frequency–heart rate variability) component in relation to both ozone and PM2.5 exposure. Conclusions: Our results suggest that ambient levels of PM2.5 and ozone can reduce the high-frequency component of heart rate variability in elderly subjects living in Mexico City and that subjects with underlying hypertension are particularly susceptible to this effect.

Chronic ethanol ingestion impairs alveolar type II cell glutathione homeostasis and function and predisposes to endotoxin-mediated acute edematous lung injury in rats.

Chronic alcohol abuse increases the incidence and mortality of the acute respiratory distress syndrome (ARDS) in septic patients. To examine a potential mechanism, we hypothesized that ethanol ingestion predisposes to sepsis-mediated acute lung injury by decreasing alveolar type II cell glutathione homeostasis and function. Lungs isolated from rats fed ethanol (20% in water for >/= 3 wk), compared with lungs from control-fed rats, had greater (P < 0. 05) edematous injury (reflected by nonhydrostatic weight gain) after endotoxin (2 mg/kg intraperitoneally) and subsequent perfusion ex vivo with n-formylmethionylleucylphenylalanine (fMLP, 10(-7) M). Ethanol ingestion decreased (P < 0.05) glutathione levels in the plasma, lung tissue, and lung lavage fluid, and increased (P < 0.05) oxidized glutathione levels in the lung lavage fluid. Furthermore, ethanol ingestion decreased type II cell glutathione content by 95% (P < 0.05), decreased (P < 0.05) type II cell surfactant synthesis and secretion, and decreased (P < 0.05) type II cell viability, in vitro. Finally, treatment with the glutathione precursors S-adenosyl-L-methionine and N-acetylcysteine in the final week of ethanol ingestion significantly reduced lung edema during perfusion ex vivo. We conclude that ethanol ingestion in rats alters alveolar type II cell glutathione levels and function, thereby predisposing the lung to acute edematous injury after endotoxemia. We speculate that chronic alcohol abuse in humans predisposes to ARDS through similar mechanisms.

Vitamin D and Asthma

Vitamin D deficiency and asthma are common conditions that share risk factors such as African American ethnicity, inner-city residence, and obesity. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between vitamin D status and asthma or asthma morbidity, including potential protective mechanisms such as antiviral effects and enhanced steroid responsiveness. Because most published epidemiologic studies of vitamin D and asthma or asthma morbidity are observational, a recommendation for or against vitamin D supplementation as preventive or secondary treatment for asthma is not advisable and must await results of ongoing clinical trials. Should these trials confirm a beneficial effect of vitamin D, others will be needed to assess the role of vitamin D supplementation to prevent or treat asthma in different groups such as infants, children of school age, and ethnic minorities.

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

Air pollution, airway inflammation, and lung function in a cohort study of Mexico City schoolchildren.

Background The biological mechanisms involved in inflammatory response to air pollution are not clearly understood. Objective In this study we assessed the association of short-term air pollutant exposure with inflammatory markers and lung function. Methods We studied a cohort of 158 asthmatic and 50 nonasthmatic school-age children, followed an average of 22 weeks. We conducted spirometric tests, measurements of fractional exhaled nitric oxide (FeNO), interleukin-8 (IL-8) in nasal lavage, and pH of exhaled breath condensate every 15 days during follow-up. Data were analyzed using linear mixed-effects models. Results An increase of 17.5 μg/m3 in the 8-hr moving average of PM2.5 levels (interquartile range) was associated with a 1.08-ppb increase in FeNO [95% confidence interval (CI), 1.01–1.16] and a 1.07-pg/mL increase in IL-8 (95% CI 0.98–1.19) in asthmatic children and a 1.16 pg/ml increase in IL-8 (95% CI, 1.00–1.36) in nonasthmatic children. The 5-day accumulated average of exposure to particulate matter < 2.5 μm in aerodynamic diamter (PM2.5) was significantly inversely associated with forced expiratory volume in 1 sec (FEV1) (p = 0.048) and forced vital capacity (FVC) (p = 0.012) in asthmatic children and with FVC (p = 0.021) in nonasthmatic children. FeNO and FEV1 were inversely associated (p = 0.005) in asthmatic children. Conclusions Exposure to PM2.5 resulted in acute airway inflammation and decrease in lung function in both asthmatic and nonasthmatic children.

Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.

The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.