Doxycycline for outpatient-treated acute exacerbations of COPD: a randomised double-blind placebo-controlled trial.

BACKGROUND: Antibiotics do not reduce mortality or short-term treatment non-response in patients receiving treatment for acute exacerbations of COPD in an outpatient setting. However, the long-term effects of antibiotics are unknown. The aim of this study was to investigate if the antibiotic doxycycline added to the oral corticosteroid prednisolone prolongs time to next exacerbation in patients with COPD receiving treatment for an exacerbation in the outpatient setting. METHODS: In this randomised double-blind placebo-controlled trial, we recruited a cohort of patients with COPD from outpatient clinics of nine teaching hospitals and three primary care centres in the Netherlands. Inclusion criteria were an age of at least 45 years, a smoking history of at least 10 pack-years, mild-to-severe COPD (Global Initiative of Chronic Obstructive Lung Disease [GOLD] stage 1-3), and at least one exacerbation during the past 3 years. Exclusion criteria were poor mastery of the Dutch language, poor cognitive functioning, known allergy to doxycycline, pregnancy, and a life expectancy of shorter than 1 month. If a participant had an exacerbation, we randomly assigned them (1:1; with permuted blocks of variable sizes [ranging from two to ten]; stratified by GOLD stage 1-2 vs 3) to a 7 day course of oral doxycycline 100 mg daily (200 mg on the first day) or placebo. Exclusion criteria for randomisation were fever, admission to hospital, and current use of antibiotics or use within the previous 3 weeks. Patients in both groups received a 10 day course of 30 mg oral prednisolone daily. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary outcome was time to next exacerbation in all randomly allocated patients except for those incorrectly randomly allocated who did not meet the inclusion criteria or met the exclusion criteria. This trial is registered with the Netherlands Trial Register, number NTR2499. FINDINGS: Between Dec 22, 2010, and Aug 6, 2013, we randomly allocated 305 (34%) patients from the cohort of 887 patients to doxycycline (152 [50%]) or placebo (153 [50%]), excluding four (1%) patients (two [1%] from each group) who were incorrectly randomly allocated from the analysis. 257 (85%) of 301 patients had a next exacerbation (131 [87%] of 150 in the doxycycline group vs 126 [83%] of 151 in the placebo group). Median time to next exacerbation was 148 days (95% CI 95-200) in the doxycycline group compared with 161 days (118-211) in the placebo group (hazard ratio 1·01 [95% CI 0·79-1·31]; p=0·91). We did not note any significant differences between groups in the frequency of adverse events during the first 2 weeks after randomisation (47 [31%] of 150 in the doxycycline group vs 53 [35%] of 151 in the placebo group; p=0·54) or in serious adverse events during the 2 years of follow-up (42 [28%] vs 43 [29%]; p=1). INTERPRETATION: In patients with mild-to-severe COPD receiving treatment for an exacerbation in an outpatient setting, the antibiotic doxycycline added to the oral corticosteroid prednisolone did not prolong time to next exacerbation compared with prednisolone alone. These findings do not support prescription of antibiotics for COPD exacerbations in an outpatient setting. FUNDING: Netherlands Organization for Health Research and Development.

Effect of an Outpatient Pulmonary Rehabilitation Program on Exercise Tolerance and Asthma Control in Obese Asthma Patients.

PURPOSE: To compare the effects of an outpatient pulmonary rehabilitation (PR) program on exercise tolerance and asthma control in obese and nonobese patients with asthma. METHODS: Nonobese (body mass index [BMI] <30 kg/m) and obese (BMI ≥ 30 kg/m) patients with asthma who participated in a local multidisciplinary 12-week PR program were analyzed retrospectively. Effects of PR were assessed by changes in 6-minute walking distance (6MWD) and Asthma Control Questionnaire (ACQ). RESULTS: A total of 138 asthma patients were included: 53 (38.4%) obese and 85 (61.6%) nonobese. At baseline, obese patients with asthma had a lower level of exercise tolerance reflected by a lower 6MWD (525 m vs 621 m; P < .001). After PR, the 6MWD improved significantly in both groups (≥50 m in nonobese vs ≥45 m in obese; P < .001 in both groups). The improvement in 6MWD was clinically relevant in 71% of the nonobese and 60% of the obese patients. These patients had lower 6MWD (P = .024), higher usage of long-acting ß-agonist (P = .034) and oral corticosteroids (P = .033). Asthma control also improved in both groups (ΔACQ -0.3 in nonobese vs ΔACQ -0.4 in obese; P = .021 and P = .019, respectively). Clinically relevant improvement was achieved by 46.5% of nonobese and 51.9% of obese patients with asthma. The improvements between the groups were not statistically different. CONCLUSIONS: A standardized PR program is feasible in obese patients with asthma and they benefit as much as nonobese patients with asthma. However, there are still a large number of patients who show no clinically significant improvement. Patients with more severe asthma seem to benefit the most from PR.

Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma.

BACKGROUND: The pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether this improvement is the result of better mechanical properties of the airways or decreased systemic and bronchial inflammation remains unclear. METHODS: A longitudinal study in obese patients with asthma (bariatric surgery and asthma group (BS+A), n=27) and obese control (bariatric surgery without asthma group (BS-A), n=39) subjects undergoing bariatric surgery, and obese patients with asthma without intervention (no bariatric surgery and asthma group (NBS+A), n=12). Lung function, asthma control, cellular infiltrates in bronchial biopsies and circulating markers of systemic inflammation were measured during follow up at 3, 6 and 12 months. RESULTS: Bariatric surgery resulted in a profound weight loss at 12 months. In the BS+A group as well as the BS-A group FEV1, functional residual capacity, total lung capacity improved, whereas FEV1/FVC only improved in the BS-A group. In addition, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD20 improved in BS+A, whereas in the NBS+A group only ACQ improved. Small airway function R5-R20 improved in both surgery groups, however the change in the BS+A group was greater, resulting in a comparable R5-R20 between BS+A and BS-A at 12-month follow-up. Besides improvement of systemic inflammation (high sensitivity C-reactive protein, adiponectin and leptin) after BS, only a decrease in mast cell numbers was detectable in the BS+A group. CONCLUSIONS: Bariatric surgery improved small airway function, decreased systemic inflammation and number of mast cells in the airways. These effects could explain the improvement of asthma control, quality of life and lung function. Therefore bariatric surgery, in addition to all other positive effects, also improves asthma in subjects with morbid obesity. TRIAL REGISTRATION NUMBER: 3204.

Systemic inflammation and lung function impairment in morbidly obese subjects with the metabolic syndrome.

BACKGROUND: Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment. METHODS: This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria. RESULTS: A total of 452 patients were included. Patients with the metabolic syndrome (n = 293) had significantly higher blood monocyte (mean 5.3 versus 4.9, P = 0.044) and eosinophil percentages (median 1.0 versus 0.8, P = 0.002), while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P = 0.032). Blood eosinophils were associated with FEV1/FVC ratio (adj. B -0.113, P = 0.018). CONCLUSION: Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia.

Concerns about exercise are related to walk test results in pulmonary rehabilitation for patients with COPD.

BACKGROUND: Although international guidelines on pulmonary rehabilitation acknowledge that psychological factors contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD), the few empirical studies investigating this association have found inconsistent results. PURPOSE: The purpose of this study is to investigate whether negative affect and beliefs about exercise of patients with COPD would be related to baseline 6-min walk (6-MW) test results in a pulmonary rehabilitation setting, after correction for physical variables (sex, age, height, weight, and lung function). A second aim was to examine whether patients' beliefs are associated with treatment outcomes, as measured by an improvement in 6-MW distance. METHOD: A 12-week pulmonary rehabilitation program was completed by 166 patients. Beliefs (perceived necessity and concerns) about exercise and negative affect were assessed by a questionnaire. Clinical data were obtained from medical records. RESULTS: Baseline 6-MW distance was positively related to younger age, male gender, better pulmonary function, and having fewer concerns about exercise. After rehabilitation, patients had increased their walk distance by 12% (32 m), on average. Baseline physiological and psychological variables were unrelated to patients' response to treatment (increase in walk distance). However, subgroup analysis showed that for patients with mild to moderate airflow obstruction, concerns about exercise were negatively related to response to treatment. CONCLUSION: We conclude that patients' beliefs about the negative consequences of exercise are associated with baseline 6-MW test performance and response to treatment for patients with mild to moderate COPD. We recommend that patients' concerns about exercise are discussed and, if necessary, corrected during the intake phase.

Utility of nitric oxide for the diagnosis of asthma in an allergy clinic population.

Fractionated exhaled nitric oxide (FeNO) expression is increased in airway inflammation and several studies have suggested that FeNO measurement can be useful in patients with asthma. Atopic individuals have increased FeNO levels, indicating that atopy may be a codeterminant in FeNO production. The aim of this study was to determine the discriminative value of FeNO for asthma and other atopic conditions in the general allergy clinic. Patients referred to the outpatient allergy clinic were screened. A standardized questionnaire was taken and atopic status was assessed (skin-prick test or specific plasma IgE). FeNO level and spirometry were measured. If the patient's history was suspect for asthma, a provocative concentration causing a 20% decrease in forced expiratory volume in 1 second (PC(20)) histamine challenge followed. One hundred fourteen steroid-naive patients were included. Forty-two subjects were diagnosed as asthmatic patients and 72 were diagnosed as nonasthmatic patients, comprising patients with allergic rhinitis (n = 32), nonallergic rhinitis (n = 11), urticaria (n = 11), eczema (n = 7), and other (n = 11). Asthmatic patients had a higher FeNO level than nonasthmatic patients (44 ppb versus 17 ppb; p < 0.001). Receiver operating characteristic curve analysis revealed the optimal FeNO level to distinguish asthma from nonasthma at 27 ppb, with a sensitivity of 78%, specificity of 92%, a positive predictive value of 86%, and a negative predictive value of 87%. Increased FeNO was positively correlated with the presence of respiratory symptoms (p < 0.01), airflow reversibility (p < 0.001), total IgE (p < 0.001), and negatively correlated with PC(20) histamine (p = 0.019). Multivariate analysis revealed that atopy was not a significant predictor of FeNO in asthmatic patients. Measuring FeNO is a simple and useful test to differentiate new asthma patients from those with other atopic conditions in a general allergy clinic.

The dynamics of illness perceptions: testing assumptions of Leventhal's common-sense model in a pulmonary rehabilitation setting.

OBJECTIVES: Although Leventhal's common-sense model (CSM) is proposed to represent a dynamic system, limited research has been conducted to investigate whether and how illness perceptions change. This study tested two hypotheses from the CSM about the dynamics of illness perceptions of patients with chronic obstructive pulmonary disease (COPD) in a pulmonary rehabilitation setting. DESIGN AND METHODS: The study employed a longitudinal design. Patients with COPD (N=87) who took part in a pulmonary rehabilitation programme filled out the Illness Perception Questionnaire - Revised (IPQ-R) before and after treatment and rated the degree to which the rehabilitation had led to the achievement of desired outcomes. Clinical variables and quality of life (Chronic Respiratory Disease Questionnaire) data were obtained from medical records. RESULTS: In line with expectations, results showed that, at baseline, longer time since diagnosis was associated to perceptions corresponding with a chronic illness model (longer illness duration, more experienced consequences, less perceived personal controllability), after correction for clinical variables. After completion of the rehabilitation programme, patients who were more convinced that their participation had led to the achievement of desired outcomes were less concerned about the negative consequences of COPD, had stronger perceptions about the variability in symptoms (cyclical timeline) and had stronger perceptions of personal controllability Conclusions: We conclude that, in accordance with Leventhal et al.'s CSM, coping with an illness is a continuous process and the achievement of desired outcomes during treatment is likely to enable patients to adopt a more positive representation of their illness.

Drop-out and attendance in pulmonary rehabilitation: the role of clinical and psychosocial variables.

BACKGROUND: In spite of the well-demonstrated benefits for patients with COPD, pulmonary rehabilitation programmes show considerable drop-out and suboptimal attendance rates. The purpose of this prospective study is to examine causes for drop-out and non-attendance during a 12 week multidisciplinary pulmonary rehabilitation programme, and to investigate whether sociodemographic and medical factors as well as patients' perception of their illness are related to drop-out and non-attendance. METHODS: Two hundred and seventeen patients with COPD who were referred to a rehabilitation centre participated in this multicentre study. Prior to treatment, patients received a questionnaire, which included the Illness Perception Questionnaire-Revised. Clinical data were drawn from medical records. Drop-out and attendance were recorded during the programme. RESULTS: Fifty patients (23%) did not complete the rehabilitation course, of which half was due to medical reasons (e.g. exacerbations, hospitalisations). Non-completion could not be predicted by baseline sociodemographic, clinical or psychological variables. Patients who declined treatment did not differ from patients who dropped out due to medical reasons. On average, patients attended 92% of all scheduled appointments. Of all missed appointments, approximately 20% were accountable to factors beyond patients' control (e.g. absent therapists, hospitalisations). Smoking, living alone, a lower fat free mass and lower confidence in treatment increased the chance of patients not attending an appointment during rehabilitation. CONCLUSION: In general, adherence in rehabilitation is high. However, paying attention to patients' nutritional status and creating a positive expectation of treatment during referral and intake appear to be important if one aims to optimise patients' attendance during rehabilitation.

Inappropriate prescription of proton pump inhibitors on two pulmonary medicine wards.

OBJECTIVE: We recently noticed that proton pump inhibitor (PPI) use was high on a pulmonary medicine ward of a university clinic and reasons for this high usage were not clear. Our aim was to determine the indications for PPI use on two pulmonary medicine wards and to assess whether this use was appropriate. METHODS: We assessed prospectively the number of patients on PPIs and the indications for PPI use on two pulmonary medicine wards, one from a university and one from a regional clinic in The Netherlands. RESULTS: On admission, 88 of 300 (29%) patients already used PPIs. The use of PPIs was discontinued in three (1%) patients, whereas PPIs were initiated in 45 (15%) patients, resulting in 130 (43%) patients on PPIs during hospitalization. The most common indication for PPI use was the prevention of medication-associated complications. In 78 of 130 (60%) patients on PPIs, this medication was used for a registered indication, whereas in 52 (40%) patients a registered indication was not present (overuse). In contrast, 19 of 300 (6%) patients were not prescribed PPIs despite the presence of a registered indication for its use (underuse). No differences were found in prescription rate and indications for PPI use between the university and the regional clinic. CONCLUSION: PPI use was very common on two pulmonary medicine wards in the Netherlands. Forty percent of the patients used their PPIs for a nonregistered indication. As use of PPIs is costly and may be associated with side effects, hospital physicians should to be better educated on guidelines for its use.

Bronchiolitis obliterans organizing pneumonia (BOOP) after thoracic radiotherapy for breast carcinoma.

Common complications of thoracic radiotherapy include esophagitis and radiation pneumonitis. However, it is important to be aware of uncommon post-radiotherapy complications such as bronchiolitis obliterans organizing pneumonia (BOOP). We report on two patients with carcinoma of the breast who developed an interstitial lung disease consistent with BOOP. BOOP responds to treatment with corticosteroids and the prognosis is generally good despite of the need for long-term administration of corticosteroids as relapses can occur during tapering of steroids. This report provides guidelines for the evaluation and treatment of patients with pulmonary infiltrates after radiotherapy.