Ferran Morell

Mortality in severe sleep apnoea/hypopnoea syndrome patients: impact of treatment

The aim of this study was to determine mortality in patients with sleep apnoea/hypopnoea syndrome (SAHS) according to the treatments employed and comorbidity. An historical cohort of patients with SAHS diagnosed at a university hospital between 1982 and 1992 and followed until 1996 was studied. From a total of 475 SAHS patients, 444 (94%), with a mean±sd apnoea/hypopnoea index at diagnosis of 55±27, were located and included in the study. SAHS treatments employed were: surgery (88), weight loss (134), continuous positive airway pressure (124) and 98 patients were not treated. By the end of follow-up, 49 patients had died. According to Cox regression analysis, mortality in treated patients was lower than in those not treated, but higher in those with a history of severe chronic obstructive pulmonary disease. Mortality in nontreated patients compared with that of the general population, adjusted for age and sex, showed excessive mortality, which decreased in treated patients. Stratification by age showed a greater mortality rate ratio in patients <50 yrs. These findings were maintained when mortality from cardiovascular causes was compared. In conclusion, a rise in mortality was found in nontreated sleep apnoea/hypopnoea syndrome patients compared with the general population, whereas mortality in those treated for sleep apnoea/hypopnoea syndrome did not differ significantly from that of the general population.

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study

BACKGROUND The clinical features of idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis can be indistinguishable; the need to eliminate occult environmental factors known to cause pulmonary fibrosis in patients suspected to have IPF during diagnostic evaluation is evident. We aimed to investigate occult, putative causes in the environments of patients diagnosed with IPF using tests beyond those conventionally used. METHODS In this case-cohort study, 60 consecutive patients diagnosed with IPF on the basis of the 2000 American Thoracic Society (ATS) and the European Respiratory Society (ERS) criteria were prospectively followed up every 4 months for 6 years between Jan 1, 2004, and Dec 31, 2009. At each visit a uniformly applied questionnaire was administered to these 60 patients to identify occult antigen exposure known to cause hypersensitivity pneumonitis. Patients underwent specific IgG determination, bronchoalveolar lavage, bronchial challenge testing with suspected antigens, and re-review of histopathological features in existing and subsequently obtained surgical lung biopsy samples and from lung explants. Specimens obtained from suspected sources from the patients environment were subjected to cultures in microbiology laboratory. These clinical data and discussions among pulmonologists and radiologists familiar with IPF were used to confirm the diagnosis in accordance with 2011 ATS, ERS, Japanese Respiratory Society, and Latin American Thoracic Association guidelines; 46 of the 60 patients had IPF according to the 2011 guidelines, and our analyses in this study were focused on these 46 patients. FINDINGS 20 of the 46 (43%, 95% CI 29-58) patients with IPF according to 2011 guidelines had a subsequent diagnosis of chronic hypersensitivity pneumonitis: nine patients had positive bronchial challenge testing (eight of whom were also IgG positive and six of these patients also had surgical lung biopsy showing a pattern consistent with chronic hypersensitivity pneumonitis); seven were IgG positive plus had histopathology on surgical lung biopsy that was consistent with hypersensitivity pneumonitis; one was IgG positive plus had greater than 20% lymphocytes in bronchoalveolar lavage fluid; and three had findings on surgical lung biopsy that were consistent with subacute hypersensitivity pneumonitis (and IgG positive). Altogether, 29 of 46 patients diagnosed with IPF who had met the 2011 criteria had lung tissue available for histopathology (surgical lung biopsy in 28 patients and explanted lung in two patients, one of whom also had surgical biopsy) during the study period, and 16 of the 20 patients with chronic hypersensitivity pneumonitis had histopathological features on surgical lung biopsy that were consistent with this diagnosis. 26 of the 46 patients remained with a diagnosis of IPF. INTERPRETATION Almost half of patients diagnosed with IPF on the basis of 2011 criteria were subsequently diagnosed with chronic hypersensitivity pneumonitis, and most of these cases were attributed to exposure of occult avian antigens from commonly used feather bedding. Our results reflect findings in one centre with recognised expertise in chronic hypersensitivity pneumonitis, and further research and studies at other centres are warranted. FUNDING Fondo de Investigaciones Sanitarias; Fundació Privada Cellex; SEPAR 2010.

Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis

Bronchial biopsy specimens from chronic obstructive pulmonary disease (COPD) patients demonstrate increased numbers of CD8+ T-lymphocytes, macrophages and, in some studies, neutrophils and eosinophils. Smoking cessation affects the rate of forced expiratory volume in one second (FEV1) decline in COPD, but the effect on inflammation is uncertain. Bronchial biopsy inflammatory cell counts were compared in current and ex-smokers with COPD. A pooled analysis of subepithelial inflammatory cell count data from three bronchial biopsy studies that included COPD patients who were either current or ex-smokers was performed. Cell count data from 101 subjects, 65 current smokers and 36 ex-smokers, were analysed for the following cell types: CD4+ and CD8+ T-lymphocytes, CD68+ (monocytes/macrophages), neutrophil elastase+ (neutrophils), EG2+ (eosinophils), mast cell tryptase+ and cells mRNA-positive for tumour necrosis factor-α. Current smokers and ex-smokers were similar in terms of lung function, as measured by FEV1 (% predicted), forced vital capacity (FVC) and FEV1/FVC. The results demonstrate that there were no significant differences between smokers and ex-smokers in the numbers of any of the inflammatory cell types or markers analysed. It is concluded that, in established chronic obstructive pulmonary disease, the bronchial mucosal inflammatory cell infiltrate is similar in ex-smokers and those that continue to smoke.

Body weight and comorbidity predict mortality in COPD patients treated with oxygen therapy

The aim of this study was to investigate the association between clinical variables and all-cause and respiratory mortality in patients with chronic obstructive pulmonary disease (COPD) undergoing long-term oxygen therapy (LTOT). The authors retrospectively studied a historic cohort of 128 patients with COPD (126 males, mean age±sd 68.9±9.7 yrs, body mass index (BMI) 25.1±4.5 kg·m−2, and forced expiratory volume in one second 25.4±8.8% predicted), who were being treated with long-term oxygen therapy in a tertiary teaching hospital between 1992 and 1999. Comorbidity, assessed with the Charlson Index, was present in 38% of the patients. Vital status and cause of death were assessed through the population death registry. A total of 78 patients (61%) had died by the end of follow-up. Three-year survival was 55%. Death was due to respiratory causes in 77% of cases. On Cox analysis, BMI <25 kg·m−2, comorbid conditions, age ≥70 yrs and cor pulmonale were associated with all-cause mortality. The BMI and comorbidity were the only significant predictive factors when the analysis was restricted to respiratory mortality. In conclusion, body mass index <25 kg·m−2 and comorbidity were predictors of all-cause and respiratory mortality in a cohort of chronic obstructive pulmonary disease patients treated with long-term oxygen therapy. These factors should be taken into account when considering the management and prognosis of these patients.

Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors

BACKGROUND Aspergillus infection remains a major cause of morbidity and mortality after lung transplantation. Therefore, some strategies have been attempted, one of which is nebulized amphotericin B (nAB); however, the efficacy of this prophylaxis has not been shown clearly. The aim is to study whether nAB can protect against Aspergillus infection in lung transplant recipients. PATIENTS AND METHODS A study of risk factors was conducted in 55 consecutive lung allograft recipients. Twenty-three potential risk factors were analyzed. In 44 (80%) patients, nAB was indicated as prophylaxis. Multivariate analysis using logistic regression was performed. RESULTS Eighteen of the 55 patients (33%) developed infection due to Aspergillus spp. Multivariate analysis showed nAB to be a preventive factor (odds ratio: 0.13; 95% confidence interval [CI] 0.02-0.69; p < 0.05) and cytomegalovirus (CMV) disease was an independent risk factor for developing Aspergillus infection (odds ratio: 5.1; 95% CI 1.35-19.17; p < 0.05). Only 1 patient required withdrawal of the prophylaxis owing to bronchospasm. nAB was well-tolerated in the remaining patients with only a few, mild, easily controlled side effects. CONCLUSIONS The present results show that nAB prophylaxis may be efficient and safe in preventing Aspergillus infection in lung-transplanted patients, and CMV disease increases the probability of Aspergillus infection.

Long-term efficacy of dietary weight loss in sleep apnoea/hypopnoea syndrome

Weight loss is associated with clinical improvement in sleep apnoea/ hypopnoea syndrome (SAHS). The aim of this study was to ascertain whether the therapeutic efficacy of dietary weight loss is maintained in the long-term. From a total of 216 overweight SAHS patients treated by only a weight reduction programme, 24 cured by this method (apnoea/hypopnoea index (AHI) at diagnosis 443+/-27.8, after weight loss 3+/-3.1) were re-evaluated after a mean (+/-SD) period of 94.3+/-27.4 months post-cure. No correlation was found between changes in AHI and body mass index experienced by each patient in the two phases of the study (diagnosis to cure and cure to long-term follow-up), r=0.29, p=0.156, demonstrating a marked intra-individual variability. Six of the 13 patients who maintained their weight presented recurrence of SAHS (AHI 40.5+/-24.1) as did eight of the 11 who had regained weight (AHI 44.3+/-23.). Weight maintenance was more frequent among patients who had continued to attend periodic appointments, 10/11 versus 3/13 (p<0.001). In conclusion, weight-loss efficacy is maintained in the long-term in some sleep apnoea/hypopnoea syndrome patients. This study indicates the need for periodic follow-up of these patients as a reinforcement for weight maintenance and for early detection of the reappearance of sleep apnoea/hypopnoea syndrome.

Preventing Asthma Epidemics Due to Soybeans by Dust-Control Measures

BACKGROUND The inhalation of soybean dust released during the unloading of soybeans into a silo caused outbreaks of asthma in Barcelona, Spain. This study was designed to determine morbidity due to asthma and serum IgE reactivity before and after the installation of filters in the silo. METHODS We measured soybean-allergen concentrations in 136 samples of air collected for 9 months before and 24 months after the installation of filters. We compared the number of days on which there was an unexpected increase in emergency room visits for asthma, the number of days on which the number of emergency room visits for asthma in one four-hour period was so high that it was unlikely to be due to chance, and the mean daily number of emergency room and intensive care unit admissions for asthma for a total of 60 months before and after filter installation. Serum IgE antibodies against soybean allergens were measured in 38 patients before and after filter installation. RESULTS The concentration of airborne soybean allergens on days when soybeans were unloaded decreased from 324 to 25 U per cubic meter after the installation of filters (P < 0.001). The number of days on which there was an unusually large number of visits to the hospital for asthma and the number of days on which asthma was epidemic both decreased significantly (both P < 0.001), from 29 to 6 and from 18 to 0, respectively. The mean daily number of emergency room and intensive care unit admissions for asthma on days when soybeans were unloaded decreased from 8.3 to 5.4 and from 0.26 to 0.01, respectively (both P < 0.001). The mean serum IgE antibody concentrations in the 38 patients studied decreased from 2 Pharmacia reference units per milliliter to 1 (P < 0.001). CONCLUSIONS Installing filters on silos to prevent airborne dissemination of allergenic soybean dust eliminates outbreaks of asthma caused by inhalation of the dust, thus supporting the idea that the avoidance of allergens helps prevent asthma.

Relationship between serum IgE and airway responsiveness in adults with asthma

BACKGROUND General population studies have shown a relationship between total serum IgE levels and airway responsiveness, but this association has not been documented in patients with asthma. OBJECTIVE The study assesses the cross-sectional relationship between IgE levels and airway responsiveness in 208 subjects who had had emergency department treatment for asthma at least 2 years earlier. METHODS All participants completed a standardized respiratory questionnaire and underwent spirometry, allergy skin testing, and a dose-response methacholine challenge test. RESULTS After adjusting for age and gender, the percentage of patients with asthma and airway responsiveness (provocative concentration causing a 20% fall in forced expiratory volume in 1 second [PC20] < or = 8 mg/ml) increased from 52% in the lower quintile of IgE to 72% in the upper quintile (p < 0.01). After adjusting for age, gender, baseline percent predicted forced expiratory volume in 1 second, and smoking, the association between IgE (both in quintiles and continuous) and PC20 appeared consistent and statistically significant (p < 0.01). This association was stronger in patients who were not given inhaled steroid (odds ratio for twice the concentration of IgE, 1.42; 95% confidence interval, 1.09 and 1.84), than in patients treated with inhaled steroid (odds ratio, 1.10; 95% confidence interval, 0.82 and 1.50). Eosinophilia and skin reactivity were associated with PC20 although to a lesser extent. CONCLUSION These findings strengthen the role played by IgE in facilitating the development of bronchial responsiveness in patients with asthma.

Classification of hypersensitivity pneumonitis: a hypothesis.

Background: Regardless of the causative antigen, hypersensitivity pneumonitis (HP) is usually classified as ‘acute’, ‘subacute’ or ‘chronic’. Considerable confusion still surrounds this classification because there are no widely accepted criteria to distinguish the various stages. The objective of this study wasto determine whether the current classification of HP truly reflects categories of patients with distinct clinical features. Methods: Data obtained from a large prospective multicenter cohort study (the HP Study) were used to divide a cohort of patients with HP into a limited number of categories (clusters) with maximally differing clinical patterns, without prejudgment. The results of this cluster analysis were compared with the current classification of HP (acute, subacute or chronic). Results: 168 patients were included in the analysis. A 2-cluster solution best fitted the data. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills and body aches) and normal chest radiographs than those in cluster 2 (127 patients) who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests and fibrosis on high-resolution computed tomography (HRCT). All p values were <0.0001, using Fisher’s exact test. Nodular opacities were seen on HRCT as often in cluster 1 as in cluster 2. There was considerable disagreement between the current classification of HP and the results of our analysis. Conclusion: The current classification of acute, subacute and chronic HP is not supported by our analysis. Subacute HP is particularly difficult to define.