Heterogeneity of treatment response in bronchiectasis clinical trials.

BACKGROUND: Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QoL) and lung function are the most common end-points evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis. METHODS: We evaluated treatment response in three randomised clinical trials that evaluated mucoactive therapy (inhaled mannitol), an oral anti-inflammatory/antibiotic (azithromycin) and an inhaled antibiotic (aztreonam). Treatment response was defined by an absence of exacerbations during follow-up, an improvement of QoL above the minimum clinically important difference and an improvement in forced expiratory volume in 1 s (FEV1) of ≥100 mL from baseline. RESULTS: Cumulatively the three trials included 984 patients. Changes in FEV1, QoL and exacerbations were heterogeneous in all trials analysed. Improvements in QoL were not correlated to changes in FEV1 in the azithromycin and aztreonam trials (r= -0.17, p=0.1 and r=0.04, p=0.4, respectively) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QoL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV1 is not a responsive measure in bronchiectasis. CONCLUSIONS: Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV1 is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response, suggesting the need to develop biomarkers to identify responders.

Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Use of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin. OBJECTIVE: The primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety. MATERIALS/PATIENTS: IN THIS MULTICENTER RCT PATIENTS AGED ≥ 18-YEAR-OLD WERE INCLUDED WITH CONFIRMED BRONCHIECTASIS AND ≥ 2 EXACERBATIONS IN THE PRECEDING YEAR. PATIENTS WERE ASSIGNED (1:1) TO RECEIVE TIS OR PLACEBO OD FOR 1-YEAR.: RESULTS: 58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49-1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes. CONCLUSION: Long-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease. TRAIL REGISTRATION NUMBER: The BATTLE study was registered at Clinical trials.gov number: NCT02657473 . Date: 13 august 2016.

CRP-guided antibiotic treatment in acute exacerbations of COPD in hospital admissions.

The role of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (COPD) is controversial and a biomarker identifying patients who benefit from antibiotics is mandatory. We performed a randomised, controlled trial in patients with acute exacerbations of COPD, comparing C-reactive protein (CRP)-guided antibiotic treatment to patient reported symptoms in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, in order to show a reduction in antibiotic prescription.Patients hospitalised with acute exacerbations of COPD were randomised to receive antibiotics based either on the GOLD strategy or according to the CRP strategy (CRP ≥50 mg·L-1).In total, 101 patients were randomised to the CRP group and 119 to the GOLD group. Fewer patients in the CRP group were treated with antibiotics compared to the GOLD group (31.7% versus 46.2%, p=0.028; adjusted odds ratio (OR) 0.178, 95% CI 0.077-0.411, p=0.029). The 30-day treatment failure rate was nearly equal (44.5% in the CRP group versus 45.5% in the GOLD-group, p=0.881; adjusted OR 1.146, 95% CI 0.649-1.187, p=0.630), as was the time to next exacerbation (32 days in the CRP group versus 28 days in the GOLD group, p=0.713; adjusted hazard ratio 0.878, 95% CI 0.649-1.187, p=0.398). Length of stay was similar in both groups (7 days in the CRP group versus 6 days in the GOLD group, p=0.206). On day-30, no difference in symptom score, quality of life or serious adverse events was detected.Use of CRP as a biomarker to guide antibiotic treatment in severe acute exacerbations of COPD leads to a significant reduction in antibiotic treatment. In the present study, no differences in adverse events between both groups were found. Further research is needed for the generalisability of these findings.

Antibiotic treatment strategies for community-acquired pneumonia in adults.

BACKGROUND: The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy. METHODS: In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval. RESULTS: A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies. CONCLUSIONS: Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).

Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression.

BACKGROUND: Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium. METHODS: Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls. RESULTS: In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate < 0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA < 0.001). CONCLUSION: We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).

Atypical aetiology in patients hospitalised with community-acquired pneumonia is associated with age, gender and season; a data-analysis on four Dutch cohorts.

BACKGROUND: Microorganisms causing community-acquired pneumonia (CAP) can be categorised into viral, typical and atypical (Legionella species, Coxiella burnetii, Mycoplasma pneumoniae, and Chlamydia species). Extensive microbiological testing to identify the causative microorganism is not standardly recommended, and empiric treatment does not always cover atypical pathogens. In order to optimize epidemiologic knowledge of CAP and to improve empiric antibiotic choice, we investigated whether atypical microorganisms are associated with a particular season or with the patient characteristics age, gender, or chronic obstructive pulmonary disease (COPD). METHODS: A data-analysis was performed on databases from four prospective studies, which all included adult patients hospitalised with CAP in the Netherlands (N = 980). All studies performed extensive microbiological testing. RESULTS: A main causative agent was identified in 565/980 (57.7 %) patients. Of these, 117 (20.7 %) were atypical microorganisms. This percentage was 40.4 % (57/141) during the non-respiratory season (week 20 to week 39, early May to early October), and 67.2 % (41/61) for patients under the age of 60 during this season. Factors that were associated with atypical causative agents were: CAP acquired in the non-respiratory season (odds ratio (OR) 4.3, 95 % CI 2.68-6.84), age <60 year (OR 2.9, 95 % CI 1.83-4.66), male gender (OR 1.7, 95 % CI 1.06-2.71) and absence of COPD (OR 0.2, 95 % CI 0.12-0.52). CONCLUSIONS: Atypical causative agents in CAP are associated with respectively non-respiratory season, age <60 years, male gender and absence of COPD. Therefore, to maximise its yield, extensive microbiological testing should be considered in patients <60 years old who are admitted with CAP from early May to early October. TRIAL REGISTRATION: NCT00471640 , NCT00170196 (numbers of original studies).

Diagnostic accuracy of a serotype-specific antigen test in community-acquired pneumonia.

Our aim was to evaluate the diagnostic accuracy and clinical utility of a serotype-specific urinary antigen detection multiplex assay for identification of 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) in urine of patients with community-acquired pneumonia. Adult patients with clinical suspicion of community-acquired pneumonia were included. In addition to standard diagnostic procedures, a urine sample was collected to perform the urinary antigen detection test. Demographic, clinical, radiological and microbiological data were collected. Among 1095 community-acquired pneumonia patients Streptococcus pneumoniae was identified as causative pathogen in 257 (23%), when using conventional diagnostic methods and in 357 (33%) when urinary antigen detection was added. Of the 49 bacteraemic episodes caused by one of the 13 serotypes covered by the urinary antigen detection, 48 were detected by the urinary antigen detection, indicating a sensitivity of 98%. Of the 77 community-acquired pneumonia episodes with a "non-urinary antigen detection" causative pathogen, none had a positive urinary antigen detection result, indicating a specificity of 100%. Addition of the urinary antigen detection test to conventional diagnostic methods increased the prevalence of S. pneumoniae community-acquired pneumonia by 39%. Using bacteraemic episodes as reference sensitivity and specificity of the urinary antigen detection was 98% and 100%, respectively.

Transient impairment of reticulocyte hemoglobin content and hepcidin-25 induction in patients with community-acquired pneumonia.

INTRODUCTION: Patients with community-acquired pneumonia (CAP) often exhibit a declining hemoglobin (Hb) concentration. During inflammation pro-inflammatory cytokines and cells of the reticuloendothelial system induce disturbances in iron homeostasis. In this study inflammation markers and hepcidin-25 concentrations were monitored together with short-term alterations in reticulocyte hemoglobinization (RET-He). METHODS: A total of 25 patients with CAP participated in the study. The assay for serum hepcidin-25 is based on a combination of weak cation exchange chromatography and time-of-flight mass spectrometry. RESULTS: At hospital admission serum hepcidin-25 concentrations (14.6 ± 6.9 nMol/L, mean ± SD) were established in the upper level of the reference range (0.5-13.9 nMol/L). Results for C-reactive protein (CRP) and Interleukin-6 (IL-6) were obviously increased compared to the reference ranges. From admission until day 14 hepcidin-25, CRP and IL-6 steadily decreased towards the reference ranges. Hb concentrations declined from admission until day 4 from 8.1 ± 1.0 mMol/L to 7.4 ± 0.9 mMol/L. At admission Ret-He results were within the lower region of the reference range (1900-2300aMol) and results demonstrated a decline during admission from 1931 ± 241 aMol until 1845 ± 199 aMol (NS) at day 4. From a minimum Ret-He value at day 4 results increased towards 2129 ± 136 aMol at day14. CONCLUSION: A transient increase of cytokine-stimulated serum hepcidin-25 in combination with a temporary decrease of Hb and Ret-He is demonstrated in patients with CAP. Our results support the hypothesis that hepcidin-25 induces transient impairment of reticulocyte hemoglobin content (Ret-He).

Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial.

IMPORTANCE: Macrolide antibiotics have been shown beneficial in cystic fibrosis (CF) and diffuse panbronchiolitis, and earlier findings also suggest a benefit in non-CF bronchiectasis. OBJECTIVE: To determine the efficacy of macrolide maintenance treatment for adults with non-CF bronchiectasis. DESIGN, SETTING, AND PARTICIPANTS: The BAT (Bronchiectasis and Long-term Azithromycin Treatment) study, a randomized, double-blind, placebo-controlled trial conducted between April 2008 and September 2010 in 14 hospitals in The Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. INTERVENTIONS: Azithromycin (250 mg daily) or placebo for 12 months. MAIN OUTCOME MEASURES: Number of infectious exacerbations during 12 months of treatment. Secondary end points included lung function, sputum bacteriology, inflammatory markers, adverse effects, symptom scores, and quality of life. RESULTS: Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range [IQR], 0-1), compared with 2 (IQR, 1-3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 [95% CI, 0.16-0.51]). In a mixed-model analysis, change in forced expiratory volume in the first second of expiration (percent of predicted) over time differed between groups (F1,78.8 = 4.085, P = .047), with an increase of 1.03% per 3 months in the azithromycin group and a decrease of 0.10% per 3 months in the placebo group. Gastrointestinal adverse effects occurred in 40% of patients in the azithromycin group and in 5% in the placebo group (relative risk, 7.44 [95% CI, 0.97-56.88] for abdominal pain and 8.36 [95% CI, 1.10-63.15] for diarrhea) but without need for discontinuation of study treatment. A macrolide resistance rate of 88% was noted in azithromycin-treated individuals, compared with 26% in the placebo group. CONCLUSIONS AND RELEVANCE: Among adults with non-CF bronchiectasis, the daily use of azithromycin for 12 months compared with placebo resulted in a lower rate of infectious exacerbations. This could result in better quality of life and might influence survival, although effects on antibiotic resistance need to be considered. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00415350.

[A man with swollen eyelids]. / Een man met gezwollen oogleden.

A 74-old man developed severe periorbital emphysema after a video-assisted thoracoscopy for lung malignancy. Because of severe symptoms of pain and visual impairment, subcutaneous emphysema was evacuated by bilateral punctures and manual mobilisation of air through the puncture holes.

[A man with yellow nails]. / Een man met gele nagels.

A 60-year-old man was referred to the outpatient clinic due to dyspnea of effort and productive coughing and rhinorrhea. Physical examination revealed swollen ankles and yellow, hyperkeratotic nails. HRCT showed bronchiectasis. This triad of symptoms indicates yellow nail syndrome. Vitamin E improved the yellow nails, while optimal expiration techniques alleviated respiratory symptoms.

Treatment with inhaled antibiotics in bronchiectasis, side effects, and evaluation of the tolerance test; analysis from the BATTLE randomized controlled trial.

INTRODUCTION: Tobramycin inhalation solution (TIS) is a treatment option for patients with frequent exacerbations of bronchiectasis. A possible side effect of TIS is the development of chronic cough and bronchospasm, whereby the guidelines suggest a (in hospital) tolerance test with the first dose of TIS. However, data on respiratory adverse events are not consistent. In the present analysis from the BATTLE study (NCT02657473), we evaluated the added value of the tolerance test and aimed to observe the development of inhaled treatment related bronchial hyperreactivity. METHODS: Fifty-seven patients from the BATTLE study were analyzed. Patients were randomized to receive TIS or placebo OD for 1 year. A tolerance test was performed with spirometry measurements before and after the first dose and with a bronchodilator in advance. Adverse events were strictly monitored. RESULTS: Fifty-seven patients (100%) passed the tolerance test with no decrease in spirometry measurements or development of local intolerability. During the study treatment, a total of five TIS-treated patients (17.8%) withdrew due to airway hyperresponsiveness after a mean of 9.2 (SD13.9) weeks and one placebo-treated patient (3.5%) after 2 weeks (TIS vs. placebo; p = 0.66). The other TIS-related adverse events were not clinically significant. CONCLUSION: The use of inhaled medication is well tolerated in the heterogenous bronchiectasis population, without signs of airway hyperresponsiveness after the first dose of inhaled medication. From this observation, it can be concluded that there is no additional value for this advised tolerance test. However, closely monitoring on adverse effects during the first weeks after starting TIS is recommended.

Procalcitonin-Guided Antibiotic Prescription in Patients With COVID-19: A Multicenter Observational Cohort Study.

BACKGROUND: Despite the low rate of bacterial coinfection, antibiotics are very commonly prescribed in hospitalized patients with COVID-19. RESEARCH QUESTION: Does the use of a procalcitonin (PCT)-guided antibiotic protocol safely reduce the use of antibiotics in patients with a COVID-19 infection? STUDY DESIGN AND METHODS: In this multicenter cohort, three groups of patients with COVID-19 were compared in terms of antibiotic consumption, namely one group treated based on a PCT-algorithm in one hospital (n = 216) and two control groups, consisting of patients from the same hospital (n = 57) and of patients from three similar hospitals (n = 486) without PCT measurements during the same period. The primary end point was antibiotic prescription in the first week of admission. RESULTS: Antibiotic prescription during the first 7 days was 26.8% in the PCT group, 43.9% in the non-PCT group in the same hospital, and 44.7% in the non-PCT group in other hospitals. Patients in the PCT group had lower odds of receiving antibiotics in the first 7 days of admission (OR, 0.33; 95% CI, 0.16-0.66 compared with the same hospital; OR, 0.42; 95% CI, 0.28-0.62 compared with the other hospitals). The proportion of patients receiving antibiotic prescription during the total admission was 35.2%, 43.9%, and 54.5%, respectively. The PCT group had lower odds of receiving antibiotics during the total admission only when compared with the other hospitals (OR, 0.23; 95% CI, 0.08-0.63). There were no significant differences in other secondary end points, except for readmission in the PCT group vs the other hospitals group. INTERPRETATION: PCT-guided antibiotic prescription reduces antibiotic prescription rates in hospitalized patients with COVID-19, without major safety concerns.

[Current inpatient treatment options for COVID-19: an update]. / Medicamenteuze behandeling covid-19 in de tweede lijn.

In this article we provide an overview of the current treatment recommendations for COVID-19. These recommendations are made by the SWAB (StichtingWerkgroepAntibioticabeleid), in cooperation with the FMS (FederatieMedischSpecialisten (online: swab.nl/nl/covid-19.). Treatment options for patients in both ambulatory care and admitted to the hospital are listed. These treatment options include both antiinflammatory and antiviral therapy.

Relationship between biomarkers and findings on low-dose computed tomography in hospitalised patients with acute exacerbation of COPD.

Background: Acute exacerbations of COPD (AECOPD) and community acquired pneumonia (CAP) often coexist. Although chest radiographs may differentiate between these diagnoses, chest radiography is known to underestimate the incidence of CAP in AECOPD. In this exploratory study, we prospectively investigated the incidence of infiltrative changes using low-dose computed tomography (LDCT). Additionally, we investigated whether clinical biomarkers of CAP differed between patients with and without infiltrative changes. Methods: Patients with AECOPD in which pneumonia was excluded using chest radiography underwent additional LDCT-thorax. The images were read independently by two radiologists; a third radiologist was consulted as adjudicator. C-reactive protein (CRP), procalcitonin (PCT), and serum amyloid A (SAA) at admission were assessed. Results: Out of the 100 patients included, 24 had one or more radiographic abnormalities suggestive of pneumonia. The interobserver agreement between two readers (Cohen's κ) was 0.562 (95% CI 0.371-0.752; p<0.001). Biomarkers were elevated in the group with radiological abnormalities compared to the group without abnormalities. Median (interquartile range (IQR)) CRP was 76 (21.5-148.0) mg·L-1 compared to 20.5 (8.8-81.5) mg·L -1 (p=0.018); median (IQR) PCT was 0.09 (0.06-0.15) µg·L-1 compared to 0.06 (0.04-0.08) µg·L-1 (p=0.007); median (IQR) SAA was 95 (7-160) µg·mL-1 compared to 16 (3-89) µg·mL-1 (p=0.019). Sensitivity and specificity for all three biomarkers were moderate for detecting radiographic abnormalities by LDCT in this population. The area under the receiver operating characteristic curve was 0.66 (95% CI 0.52-0.80) for CRP, 0.66 (95% CI 0.53-0.80) for PCT and 0.69 (95% CI 0.57-0.81) for SAA. Conclusion: LDCT can detect additional radiological abnormalities that may indicate acute-phase lung involvement in patients with AECOPD without infiltrate(s) on the chest radiograph. Despite CRP, PCT and SAA being significantly higher in the group with radiological abnormalities on LDCT, they proved unable to reliably detect or exclude CAP. Further research is warranted.

The effect of maintenance azithromycin on radiological features in patients with bronchiectasis - Analysis from the BAT randomized controlled trial.

RATIONALE: Bronchiectasis (abnormal dilatation of bronchi) is usually diagnosed by high resolution computed tomography (HRCT) and radiological severity has been found to correspond with clinical outcome. A beneficial effect of macrolides maintenance treatment in frequent exacerbating bronchiectasis patients has been established in randomized trials. This study was undertaken to prospectively evaluate the effect of long-term azithromycin (AZM) on radiological features in patients with bronchiectasis. METHODS: The BAT randomized controlled trial (2008-2010) investigated the effect of 1 year of AZM (250 mg OD) in bronchiectasis with frequent exacerbations. Chest (HR)CT-scans at baseline and after one year of study treatment were obtained and scored by two radiologists according to the Brody - and the Bhalla scoring system. RESULTS: 77 (93%) patients conducted the BAT trial were evaluated in this post-hoc analysis. A significant improvement of the radiological features based on the Brody score was found after one year of AZM therapy as compared to placebo (p = 0.024), with a not significant improvement of the Bhalla score (p=0.071). Especially the consolidation (Bhalla) and parenchymal changes (Brody) sub scores significantly improved (both p=0.030), and even a radiological deterioration was seen on the Brody bronchiectasis sub score for the placebo treated patients (mean 14.5 (11.7) vs.15.7 (11.9)). CONCLUSIONS: The beneficial effect of long-term AZM treatment on radiological features was demonstrated in this randomized controlled trial. (HR)CT's can be used as an objective measure of treatment response in bronchiectasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT00415350.

Vitamin D supplementation in chronic obstructive pulmonary disease patients with low serum vitamin D: a randomized controlled trial.

BACKGROUND: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients. OBJECTIVES: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD. METHODS: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life. RESULTS: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes. CONCLUSIONS: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627.

Bacillus Calmette-Guérin vaccine to reduce healthcare worker absenteeism in COVID-19 pandemic, a randomized controlled trial.

OBJECTIVES: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Guérin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. METHODS: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). RESULTS: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication. CONCLUSIONS: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19.