José Luis Álvarez-Sala

Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study

Background: A study was undertaken to evaluate exacerbations and their impact on the health related quality of life (HRQL) of patients with chronic obstructive pulmonary disease (COPD). Methods: A 2 year follow up study was performed in 336 patients with COPD of mean (SD) age 66 (8.2) years and mean (SD) forced expiratory volume in 1 second (FEV1) 33 (8)% predicted. Spirometric tests, questions regarding exacerbations of COPD, and HRQL measurements (St George’s Respiratory Questionnaire (SGRQ) and SF-12 Health Survey) were conducted at 6 month intervals. Results: A total of 1015 exacerbations were recorded, and 103 (30.7%) patients required at least one hospital admission during the study. After adjustment for baseline characteristics and season of assessment, frequent exacerbations had a negative effect on HRQL in patients with moderate COPD (FEV1 35–50% predicted); the change in SGRQ total score of moderate patients with ⩾3 exacerbations was almost two points per year greater (worse) than those with <3 exacerbations during the follow up (p = 0.042). For patients with severe COPD (FEV1 <35% predicted) exacerbations had no effect on HRQL. The change in SGRQ total score of patients admitted to hospital was almost 2 points per year greater (worse) than patients not admitted, but this effect failed to show statistical significance in any severity group. There was a significant and independent seasonal effect on HRQL since SGRQ total scores were, on average, 3 points better in measurements performed in spring/summer than in those measured in the winter (p<0.001). Conclusions: Frequent exacerbations significantly impair HRQL of patients with moderate COPD. A significant and independent effect of seasonality was also observed.

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

A bibliometric evaluation of European Union research of the respiratory system from 1987–1998

This study analyses the evolution of the bibliometric indicators of productivity and repercussion of European Union (EU) research into the respiratory system during the period from 1987-1998, describing the geographical distribution. Using MedLine, a selection was made of those articles by EU authors published between 1987-1998 in 38 respiratory system journals (classification from the Institute for Scientific Information). The journals, country of origin, number of articles and the relation to socioeconomic data, productivity index, visibility index, expected impact factor (EIF) and relative impact factor (RIF) were all analysed. The number of EU publications in respiratory system journals experienced an exponential increase, going from 606 articles (14.3% of world production) in 1987, to 2,325 (33.2%) in 1998. During this same period, the EIF increased from 1,258 to 2,111. The greatest gross productivities were those of the UK, France, Italy and Germany, although when corrected for number of inhabitants, Sweden, the Netherlands, Belgium and Denmark headed the list. The countries with the greatest mean EIF were the Netherlands, the UK, Spain and Belgium. In conclusion, productivity and repercussions of European Union research of the respiratory system experienced an important increase during this period.

Treatment and quality of life in patients with chronic obstructive pulmonary disease

Treatments administered to patients with chronic obstructive pulmonary disease (COPD), especially when used in multiple combinations, are not free of interactions and side effects that can potentially impair health-related quality of life (HRQL). We studied HRQL and its relationship with treatment in a group of 441 patients with stage II or III COPD (age: 66.6 (SD: 8.3) years; FEV1: 32.4% (SD: 8.1%)) using the St Georges Respiratory Questionnaire (SGRQ) and the 12-item short form (SF-12) Health Survey. The most prescribed drugs were ipratropium bromide (87.5%), inhaled corticosteroids (69.4%) and short-acting β-2 agonists (64.9%). Patients with stage III of the disease were receiving more drugs, particularly short-acting β-2 agonists (p = 0.002) and inhaled corticosteroids (p = 0.031). The use of theophyllines was associated with a worse total SGRQ score (β = 4.49; p < 0.001), although this negative association decreased with advanced age. A trend towards worse SGRQ scores was observed with the use of high doses of long-acting β-2 agonists (β = 3.22; p = 0.072). Patients receiving three drugs or more presented worse total SGRQ scores than patients receiving fewer drugs (β = 6.1, p < 0.001; and β = 7.64, p < 0.001, respectively). These findings suggest that the use of multiple drugs in the treatment of patients with COPD is associated with worse total SGRQ scores. The effect of drugs, their dosages and associations with other drugs on HRQL merit further research.

Long-Term Effects of Treatment with Nasal Continuous Positive Airway Pressure on Lung Function in Patients with Overlap Syndrome

We assessed the effects of chronic nasal continuous positive airway pressure (CPAP) therapy on lung function in a series of unselected patients with overlap syndrome, and we determined whether there were differences in the response induced by CPAP between hypercapnic (PaCO2 ≥ 45 mm Hg) and eucapnic patients with overlap syndrome. The study population included 55 unselected patients (48 men, mean age of 58.5 ± 10.5 years) with a concurrent diagnosis of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea-hypopnea syndrome (OSAHS) who had been referred to the Department of Pulmonology of our hospital over 2 consecutive years and in whom work-up studies resulted in the prescription of nasal CPAP therapy. An apnea-hypopnea index (AHI) greater than or equal to 10 in the cardiorespiratory polygraphy was required for the diagnosis of OSAHS. A forced expiratory volume in one second (FEV1) less than 80% and FEV1-forced vital capacity (FVC) ratio less than 70% of the reference values were required for the diagnosis of COPD. Control lung function studies and arterial blood gas measurements were performed at 6 and 18 months of CPAP therapy. These patients with overlap syndrome accounted for 28.5% of all patients with OSAHS treated with CPAP during the study period. The mean AHI was 37.3 ± 26.1 and the mean CPAP level 7.3 ± 1.3 cm H2O. Thirty-three patients were hypercapnic (PaCO2 ≥ 45 mm Hg) and 22 eucapnic. The hypercapnic group had higher AHI value (44.3 ± 26.9) than the eucapnic group (28.6 ± 21.9) (P < 0.05). After 6 months of CPAP therapy, there were statistically significant increases in PaO2, FEV1, and FVC, accompanied by significant decreases in PaCO2, serum bicarbonate levels, and alveolar-arterial oxygen difference. Response of overlap syndrome patients to CPAP therapy was superior in the hypercapnic group, particularly in relation to improvement of arterial blood gases. However, statistically significant differences in all parameters for the comparison between 6 and 18 months were not recorded.

Cigarette smoking behavior and respiratory alterations during sleep in a healthy population.

Background and study objective: The importance of tobacco smoking in the origin of sleep ventilatory abnormalities is disputed. The purpose of our study was to evaluate the influence of cigarette smoking behavior on the sleep respiratory alterations in a healthy population. Design and methods: We studied 38 healthy volunteers (21 M, 17 F; age 42 ± 12 years; BMI 23.7 ± 3.6 kg/m who were divided into two matched groups: current tobacco smokers (n = 18; over 10 pack-years) and nonsmokers (n = 20). All individuals underwent a single nocturnal domiciliary polygraphic study (Polygraphics CNS, Minneapolis, Minnesota). Apnea (AI), apnea-hypopnea (AHI), and desaturation (DI) indexes were defined according to conventional criteria. A nocturnal hypoxia index (NHI) was calculated as an index of the magnitude and duration of oxyhemoglobin desaturation during sleep. The mean transcutaneous oxygen saturation (SpO2) of the first 60 seconds of oxymetric registration (subject supine and awake) was considered basal SpO2. Venous carboxyhemoglobin (COHb) levels were measured (CO-Oximeter AVL-912, Basel, Switzerland) in all individuals before (22:00 h) and after (10:00 h) sleep. A correction factor of 0.9 x COHb was applied to the basal SpO2 values to calculate the corrected basal SpO2 (SpO2 corr). Results: AI, AHI, and DI were not significantly different between smokers and nonsmokers. The smokers have significantly higher NHI than nonsmokers [median (25th percentile–75th percentile): 5.3 (0–39.7) vs. 0.5 (0–1.7); p = 0.017]. There were significant correlations (P < 0.05) in smokers between NHI and pack-years index, between NHI and COHb levels, and between current smoking intensity and COHb levels. As expected, smokers had higher COHb levels at 10:00 as well as at 22:00 hours. The Sp02 corr was significantly lower (p < 0.001) among smokers than nonsmokers (88.9 ± 3.3% vs. 94.7 ± 1.3%). In multiple regression analyses, AHI and DI showed a significant correlation (p = 0.02 and p = 0.05, respectively) with habitual snoring, and NHI with pack-years and BMI (p = 0.02 and p = 0.04, respectively). Conclusions: Cigarette smoking does not seem to be associated with increased apneic activity during sleep. However, it is associated with a decrease in nocturnal oxygen saturation.

Monitoring Breathing Rate at Home Allows Early Identification of COPD Exacerbations

BACKGROUND Respiratory frequency increases during exacerbations of COPD (ECOPD). We hypothesized that this increase can be detected at home before ECOPD hospitalization. METHODS To test this hypothesis, respiratory frequency was monitored at home daily for 3 months in 89 patients with COPD (FEV₁, 42.3% ± 14.0%; reference) who were receiving domiciliary oxygen therapy (9.6 ± 4.0 h/d). RESULTS During follow-up, 30 patients (33.7%) required hospitalization because of ECOPD. In 21 of them (70%), mean respiratory frequency increased (vs baseline) during the 5 days that preceded it (from 15.2 ± 4.3/min to 19.1 ± 5.9/min, P < .05). This was not the case in patients without ECOPD (16.1 ± 4.8/min vs 15.9 ± 4.9/min). Receiver operating characteristic analysis showed that 24 h before hospitalization, a mean increase of 4.4/min (30% from baseline) provided the best combination of sensitivity (66%) and specificity (93%) (area under the curve [AUC] = 0.79, P < .05). Two days before hospitalization, a mean increase of 2.3/min (15% change from baseline) was associated with a sensitivity of 72% and a specificity of 77% (AUC = 0.76, P < .05). CONCLUSIONS Respiratory frequency can be monitored daily at home in patients with COPD receiving domiciliary oxygen therapy. In these patients, breathing rate increases significantly days before they require hospitalization because of ECOPD. This may offer a window of opportunity for early intervention.

Neutral Sphingomyelinase, NADPH Oxidase and Reactive Oxygen Species. Role in Acute Hypoxic Pulmonary Vasoconstriction

The molecular mechanisms underlying hypoxic pulmonary vasoconstriction (HPV) are not yet properly understood. Mitochondrial electron transport chain (ETC) and NADPH oxidase have been proposed as possible oxygen sensors, with derived reactive oxygen species (ROS) playing key roles in coupling the sensor(s) to the contractile machinery. We have recently reported that activation of neutral sphingomyelinase (nSMase) and protein kinase C ζ (PKCζ) participate in the signalling cascade of HPV. Herein, we studied the significance of nSMase in controlling ROS production rate in rat pulmonary artery (PA) smooth muscle cells and thereby HPV in rat PA. ROS production (analyzed by dichlorofluorescein and dihydroethidium fluorescence) was increased by hypoxia in endothelium‐denuded PA segments and their inhibition prevented hypoxia‐induced voltage‐gated potassium channel (KV) inhibition and pulmonary vasoconstriction. Consistently, H2O2, or its analogue t‐BHP, decreased KV currents and induced a contractile response, mimicking the effects of hypoxia. Inhibitors of mitochondrial ETC (rotenone) and NADPH oxidase (apocynin) prevented hypoxia‐induced ROS production, KV channel inhibition and vasoconstriction. Hypoxia induced p47phox phosphorylation and its interaction with caveolin‐1. Inhibition of nSMase (GW4869) or PKCζ prevented p47phox phosphorylation and ROS production. The increase in ceramide induced by hypoxia (analyzed by immunocytochemistry) was inhibited by rotenone. Exogenous ceramide increased ROS production in a PKCζ sensitive manner. We propose an integrated signalling pathway for HPV which includes nSMase‐PKCζ‐NADPH oxidase as a necessary step required for ROS production and vasoconstriction. J. Cell. Physiol. 226: 2633–2640, 2011.

Treatment With the Immunomodulator AM3 Improves the Health-Related Quality of Life of Patients With COPD

BACKGROUND COPD has a severe impact on patient quality of life. AM3 is an orally effective immunomodulator that can normalize the defective antimicrobial functions of the immune system effector cells of COPD patients. OBJECTIVES We analyzed the effect of AM3 on exacerbation frequency and health-related quality of life (HRQL) of COPD patients with moderate disease. DESIGN A randomized, double-blind, placebo-controlled trial. SETTING Outpatient departments of 21 hospitals. METHODS A total of 253 COPD patients with a mean age of 67.7 years (SD, 8.1 years) and mean FEV(1) percentage of predicted of 49.6% (SD, 10.2%) were evaluated. Patients received (orally) either 3 g/d AM3 or a matched placebo for 180 consecutive days. Patient quality of life was measured using the St. Georges Respiratory Questionnaire (SGRQ). RESULTS There were no differences in the exacerbation frequency of the two groups (0.82 episodes per patient in the AM3 arm vs 0.84 in the placebo arm), and 55.3% of patients were exacerbation free in the AM3 arm compared to 48.8% in the placebo arm (p = 0.11). At the end of treatment, quality of life was significantly better in the AM3 arm than in the placebo arm (SGRQ total score, 32.9; SD, 16.4, compared to 37.5; SD, 17.5 [p < 0.05]: activity score, 47.5; SD, 22.4, compared to 54.6; SD, 20.5 [p < 0.05]). The improvements in total SGRQ scores were 8.9 U (SD, 13.4 U) in the AM3 arm and 5.6 U (SD, 15.9 U) in the placebo arm (p = 0.076). Improvements on the symptoms subscale were 15.9 U (SD, 20.7 U) for the AM3 arm and 10.2 U (SD, 21.3 U) for the placebo arm (p < 0.05). Both AM3 and the placebo were clinically, biochemically, and hematologically well tolerated. CONCLUSIONS AM3 is a safe, easily tolerated, effective treatment that improves the quality of life of COPD patients as measured by SGRQ scores. This effect was observed with no significant reduction in the frequency of exacerbations.

Speed of recovery from acute exacerbations of chronic obstructive pulmonary disease after treatment with antimicrobials : results of a two-year study.

AbstractObjective: We performed a multicentre study under a 2-year observational protocol that included data on time to recovery from acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) in patients receiving moxifloxacin and comparator antimicrobials. Patients and methods: Outpatients with moderate or severe COPD were recruited from respiratory clinics throughout Spain. Moxifloxacin was available in year 2, and was to be prescribed to 50% of patients in that period in a non-randomised allocation. Time to recovery was compared in successfully treated AE-COPD; cross-sectionally for all AE-COPD over 2 years, first AE-COPD and all AE-COPD in year 2, and longitudinally in patients receiving comparator antimicrobials for AE-COPD in year 1 and moxifloxacin in year 2. Results: 614 AE-COPD were treated in 441 patients over 2 years (mean age 66.7 ± 8.3 years, 98% males, mean forced expiratory volume in 1 second [FEV1] 35.9 ± 8.8%). Mean time to recovery overall was 4.6 days (SD 3.3) with moxifloxacin 400 mg/day for 5 days, and 5.8 days (SD 4.6) with comparators (p < 0.01), which were most frequently amoxicillin/clavulanic acid 500/125mg/8h, clarithromycin 500mg/12h and cefuroxime axetil 500mg/12h for 7–10 days. Longitudinal analysis showed that 27 patients treated with moxifloxacin in the second year of the study recovered in a mean of 3.7 days (SD 3.1), and the same patients treated with comparator antimicrobials in year one recovered in a mean of 6.8 days (SD 4.6) [p = 0.02]. In contrast, in 66 patients treated with comparator antimicrobials in both years, mean time to recovery was 7.4 days (SD 7.3) in year one and 5.5 days (SD 3.5) in year two (p = 0.24). All subgroup analyses showed a statistically significant reduction of 18–25% in time to recovery with moxifloxacin compared with other antibiotics. Conclusions:Moxifloxacin significantly reduced time to recovery from AE-COPD in patients with moderate to severe disease by approximately 20% (>1 day) compared with other antimicrobials. Faster recovery should result in earlier return to work or normal activities, and to social and economic savings.