Search

Objectives: It is unclear whether recurrent sputum culture with Pseudomonas aeruginosa from patients with chronic obstructive pulmonary disease (COPD) is caused by intermittent airway carriage by different P. aeruginosa lineages or persistent carriage by the same lineage, and whether lineages genetically adapt during carriage. Methods: Whole-genome sequencing was performed for P. aeruginosa isolates sampled longitudinally from sputum cultures in patients with COPD who were enrolled in an ongoing randomized controlled trial (clinicaltrials.gov: NCT03262142). Results: A total of 153 P. aeruginosa isolates were sequenced for 23 patients during 365 days of follow-up. Recurrent presence of P. aeruginosa was seen in 19 patients (83%) and was caused by persistence of the same clonal lineage in all but one patient. We identified 38 genes mutated in parallel in two or more lineages, suggesting positive selection for adaptive mutations. Mutational enrichment analysis revealed genes important in antibiotic resistance and chronic infections to be more frequently mutated. Discussion: Recurrent P. aeruginosa was common and carried for a prolonged time after initial detection in the airways of patients with COPD. Recurrence was caused by persistence of the same clonal lineage and was associated with genetic adaptation. Trial data on possible clinical benefits of attempting antibiotic eradication of P. aeruginosa in COPD are warranted.

Background Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. Methods This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20–365 from study allocation and (ii) days alive and without exacerbation within days 20–365 from the study allocation. Discussion This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. Trial registration ClinicalTrials.gov NCT03262142. Registered on August 25, 2017.

Objective Hydroxychloroquine has been proposed as a primary prophylactic agent against coronavirus disease 2019 (COVID-19). This study aimed to investigate if patients treated with hydroxychloroquine for a non-COVID-19 indication had a lower risk of verified infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared with matched controls. Methods A cohort comprising all persons in Denmark collecting hydroxychloroquine prescriptions in 2020 and 2019 (i.e., both during and before SARS-CoV-2 was confirmed in Denmark), matched by age and sex with controls, was studied. Data were collected using the Danish national registries, which contain complete information on patient health data, prescriptions and microbiological test results. The main outcome was microbiologically verified SARS-CoV-2 infection. Results In total, 5488 hydroxychloroquine users were matched with 54,486 non-users. At baseline, the groups differed in terms of diagnoses of pulmonary disease, cardiovascular disease, renal disease, gastrointestinal/metabolic disease and dementia, as well as treatment with antirheumatic drugs. The final model was adjusted for these potential confounders. Use of hydroxychloroquine for non-COVID-19 indications was not associated with any change in confirmed SARS-CoV-2 (hazard ratio 0.90, 95% confidence interval 0.76–1.07). This result was robust in the propensity-score-matched sensitivity analysis. Conclusion This study, which is the largest to date to investigate the primary prophylactic effect of hydroxychloroquine against SARS-CoV-2, does not support any prophylactic benefit of hydroxychloroquine in the prevention of infection with SARS-CoV-2.

Background: Pulmonary P. aeruginosa infections increase morbidity in COPD patients. While low resolution molecular typing has shown that the same clonal lineage can persist and adapt in the lungs, the prevalence of chronic infections in consistently sampled COPD cohorts remains unknown. Objective: The study aim was to determine the prevalence and genetic adaptation of persistent P. aeruginosa infections in patients with COPD. Methods: Whole-genome sequencing study of P. aeruginosa strains sampled longitudinally from sputum cultures in 23 patients enrolled in an ongoing randomized controlled trial in Denmark (clinicaltrials.gov: NCT03262142). Results: A total of 153 P. aeruginosa isolates were sequenced in 23 patients during 365 days of follow-up. Genome sequencing showed that 18 patients were infected with clonal lineages that persisted for at least 30 days (Figure 1). We identified 37 P. aeruginosa genes that were independently mutated in two or more lineages, suggesting a positive selection for adaptive mutations. Mutation in the same genes have previously been shown to be important for persistent infections in patients with genetically defined mucociliary clearance defects. Conclusion:P. aeruginosa persists and genetically adapts in patients with COPD. Thus, our results indicate parallelism to P. aeruginosa infections in patients with genetically defined mucociliary clearance defects.

Background: The impact of P. aeruginosa on long-term prognosis in COPD remains unknown. Objective: To determine whether P. aeruginosa is associated with increased risk of exacerbation or death in patients with COPD. Methods: Observational cohort study on 22.053 COPD outpatients (Fig.1). Time-dependent Cox proportional hazard regression model was used to estimate a) hospitalisation for exacerbation or all-cause mortality and b) all-cause mortality after 2 years. Results:P. aeruginosa was found in 4.1% of the patients. Hospital admissions (80% and 48%,p Conclusions:P. aeruginosa is associated with substantially worsened long-term prognosis in COPD. A randomized controlled trial is needed to conclude whether targeted antibiotic interventions can improve the prognosis in this highly vulnerable group of patients.

To provide an update on efficacy and safety of antibiotic treatments for stable non-cystic fibrosis (CF) bronchiectasis (BE). Systematic review based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was done. Twenty-six studies (1.898 patients) fulfilled the inclusion criteria. Studies of inhaled tobramycin have revealed conflicting results regarding quality of life (QoL), exacerbations and admissions, but may result in sputum cultures negative for Pseudomonas aeruginosa, whereas studies investigating the effect of inhaled gentamycin have shown positive effects on sputum bacterial density, decrease in sputum cultures positive for P. aeruginosa, QoL and exacerbation rate, but no improvement in forced expiratory volume in first second (FEV1). Oral azithromycin can reduce exacerbations, together with minor improvements in QoL and FEV1. Furthermore, oral erythromycin reduces exacerbations, but has no effect on lung function, symptoms or QoL. Inhaled ciprofloxacin may reduce P. aeruginosa in sputum cultures, but without changes in lung function, exacerbations or QoL. Although with limited evidence, inhaled colistin may have effects on P. aeruginosa density, exacerbations and QoL, whereas studies on aztreonam revealed no significant clinical improvements in the outcomes of interest, including exacerbation rate. Adverse events, including bronchospasm, have been reported in association with tobramycin and aztreonam. Several antibiotic treatment regimens have been shown to improve QoL and exacerbation rate, whereas findings regarding sputum production, lung function and admissions have been conflicting. Evidence-based treatment algorithms for antibiotic treatment of stable non-CF BE will have to await large-scale, long-term controlled studies.

Aim: Update on efficacy and safety of non-antibiotic therapy for stable non-cystic fibrosis (CF) bronchiectasis. Methods: Systematic review based on the PRISMA-guidelines. Results: Fifteen studies (1278 patients) fulfilled the inclusion criteria. Studies (n = 3) suggest that inhaled hypertonic saline may be beneficial in patients with non-CF BE, although possibly not superior to isotonic saline. The effect of hypertonic saline on QoL, lung function, and exacerbation rate has, at best, been inconsistent. Inhaled mannitol (n = 6) affects sputum characteristics, but with no significant effect on exacerbation rate, lung function, or sputum, although it may have an effect on QoL and time to first exacerbation. High-dose inhaled corticosteroids (ICS) (n = 4) reduce sputum volume and eosinophils, possibly due to concomitant asthma, but with no effect on sputum purulence and bacteriology, lung function and exacerbation rate, although it seems to have positive impact on QoL and respiratory symptoms. One study investigating add-on long-acting beta2-agonist to ICS (n = 40) reported an effect on QoL, but no effect on lung function or exacerbation rate. Conclusion: Airway clearing techniques, including hypertonic saline and mannitol, and asthma controller medication may have beneficial effects in patients with non-CF BE, but only limited evidence suggests an effect on lung function and exacerbation rate.

The purpose of this retrospective study was to outline the practical use and clinical value of the immunodiagnostic interferon-gamma release assay (IGRA) on suspicion of active Mycobacterium tuberculosis (TB) infection.A retrospective study of all patients (n=91) tested with IGRA (Quantiferon-TB-Gold, Celletis International, Australia) for M. tuberculosis infection from 1 January 2005 to the 31 December 2006 at a Danish regional hospital.In 74 patients suspected of active TB, the sensitivity of IGRA was 80% (8/10), the specificity was 85% (50/59), PPV was 47% (8/17) and NPV was 96% (50/52). The positive likelihood ratio (LR) was 5.3 and the negative LR was 0.24. Due to a suboptimal diagnostic setup, the diagnosis of lung cancer in one patient was delayed significantly by a positive IGRA.In the current study, IGRA had a high false-positive rate for diagnosing active TB and had a rather low sensitivity which is in line with recent meta analyses. The physicians' use and judgement of this new test seemed suboptimal, as the overwhelming use of IGRA for suspected active TB was not in concordance with international guidelines. IGRA does not differentiate between active and latent M. tuberculosis infection, and IGRA may seldomly be used as a supplementary evaluative tool (with many false negative and "false positive" results).

INTRODUCTION: We aimed to evaluate post-COVID-19 fatigue, change in functional capacity and health-related quality of life (HRQoL) eight months after discharge from hospital due to COVID-19.METHODS: A total of 83 patients (35 women) admitted to the Copenhagen University Hospital - North Zealand Hospital, Denmark, for COVID-19 during the period from March to June 2020 were evaluated eight months after discharge using validated questionnaires quantifying fatigue, HRQoL and post-COVID-19 functional status. Follow-up data were correlated with measures of pre-COVID-19 status (anthropometrics, comorbidities) and measures of severity of the acute infection.RESULTS: A total of 22 (65%) women and 12 (26%) men reported excessive fatigue. In all, 20 women (67%) and 17 men (37%) reported decreased physical function. Female sex was associated with fatigue. Loss of physical function was associated with pre-COVID-19 presence of heart disease and absence of lung disease. Severity of the acute COVID-19 infection was not associated with fatigue or change in functional status. Fatigue and functional status were correlated with both generic HRQoL and lung disease-specific HRQoL.CONCLUSIONS: Female sex was associated with a higher risk of fatigue eight months after hospitalisation with COVID-19 infection. Regarding loss of functional capacity after COVID-19, we found an apparently protective effect of pre-COVID-19 lung disease. Our findings underscore the urgent need for further research and the importance of evaluating those recovering from COVID-19 for symptoms of excessive fatigue and change in functional capacity irrespective of the severity of the initial infection.FUNDING: none.TRIAL REGISTRATION: not relevant.