Systemic antibiotics for Pseudomonas aeruginosa infection in outpatients with non-hospitalised exacerbations of pre-existing lung diseases: a randomised clinical trial.

BACKGROUND: The effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes. METHODS: Multicenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365. RESULTS: The trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27-0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6-1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3-4.5) in the control group, p = 0.037. CONCLUSIONS: Use of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03262142, registration date 2017-08-25.

Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC): can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial.

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.

Descriptive analysis of long COVID sequelae identified in a multidisciplinary clinic serving hospitalised and non-hospitalised patients.

BACKGROUND: There are emerging data of long-term effects of coronavirus disease 2019 (COVID-19) comprising a diversity of symptoms. The aim of this study was to systematically describe and measure pulmonary and extra-pulmonary post-COVID-19 complications in relation to acute COVID-19 severity. METHODS: Patients attending a standard of care 3 months post-hospitalisation follow-up visit and those referred by their general practitioner because of persistent post-COVID-19 symptoms were included. Patients underwent symptomatic, quality of life, pulmonary (lung function and high-resolution computed tomography (HRCT)), cardiac (high-resolution ECG), physical (1-min sit and stand test (1-MSTST), handgrip strength, cardiopulmonary exercise testing (CPET)) and cognitive evaluations. RESULTS: All 34 hospitalised and 22 out of 23 non-hospitalised patients had ≥1 complaint or abnormal finding at follow-up. Overall, 67% of patients were symptomatic (Medical Research Council (MRC) ≥2 or COPD assessment test (CAT) ≥10), with no difference between hospitalised versus non-hospitalised patients. Pulmonary function (forced expiratory volume in 1 s (FEV1) or diffusing capacity of the lung for carbon monoxide (D LCO)) <80% of predicted) was impaired in 68% of patients. D LCO was significantly lower in those hospitalised compared to non-hospitalised (70.1±18.0 versus 80.2±11.2% predicted, p=0.02). Overall, 53% had an abnormal HRCT (predominantly ground-glass opacities) with higher composite computed tomography (CT) scores in hospitalised versus non-hospitalised patients (2.3 (0.1-4.8) and 0.0 (0.0-0.3), p<0.001). 1-MSTST was below the 25th percentile in almost half of patients, but no signs of cardiac dysfunction were found. Cognitive impairments were present in 59-66% of hospitalised and 31-44% of non-hospitalised patients (p=0.08). CONCLUSION: Three months after COVID-19 infection, patients were still symptomatic and demonstrated objective respiratory, functional, radiological and cognitive abnormalities, which were more prominent in hospitalised patients. Our study underlines the importance of multidimensional management strategies in these patients.

12-months follow-up of pulmonary tele-rehabilitation versus standard pulmonary rehabilitation: A multicentre randomised clinical trial in patients with severe COPD.

Between March 2016 and October 2017, we randomised 134 patients with severe COPD from 8 hospitals in the Capital Region of Denmark to participate in either standardised, outpatient pulmonary rehabilitation (control group) or on-line, supervised and home-based tele-rehabilitation (intervention group). We found no difference between the groups in the primary outcome: six minutes walking distance (6MWD) after completion of the programme. The current study presents results from the 12-month follow-up with assessment of the 6MWD and analyses of hospitalisation and mortality. There were no significant differences between or within the groups in the 6MWD one year after completion of the programme.

NIV for acute respiratory failure in COPD: high in-hospital mortality is determined by patient selection.

Introduction: Hospital mortality among chronic obstructive pulmonary disease (COPD) patients receiving NIV for acute respiratory failure has shown to be significantly higher in clinical settings than in the randomized trials (RCTs) which clinical guidelines are based on. This may be due to the quality of care of NIV or patient selection. In daily clinical practice, we include patients with terminal pulmonary disease with a do-not-intubate (DNI) or a do-not-resuscitate (DNR) order with a high mortality risk compared to highly selected patients in RCTs. The aim of this study was to determine the role of patient selection for in-hospital mortality among patients receiving NIV for acute respiratory failure of COPD. Methods: We conducted a retrospective study including all patients receiving acute NIV due to acute respiratory failure at the respiratory wards in 2012-2013 at two hospitals in Greater Copenhagen. Results: Overall in-hospital mortality rate was 30%. In patients with a DNI/DNR order, mortality was 59% and in patients with no limitations in treatment 2%. Patients who fulfilled the exclusion criteria of the RCT by Plant et al. had a mortality of 41% compared to 25% in the remaining population. Conclusions: High overall in-hospital mortality reflects that patient selection in clinical practice is very different from RCT. Quality of acute NIV treatment seems acceptable in clinical practice for patients with less severe COPD and no limitations in treatment. Higher mortality in patients with DNI/DNR order may be due to inefficient NIV treatment for these patients with more severe COPD.

A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations - The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol.

BACKGROUND: The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome. METHODS: This is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 × 109 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV1, and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage. DISCUSSION: This will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02857842 , 02-august-2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016.

COPD: Mortality and Readmissions in Relation to Number of Admissions with Noninvasive Ventilation.

In severe COPD, patients having survived acute hypercapnic respiratory failure (AHRF) treated with noninvasive ventilation (NIV) have a high mortality and risk of readmissions. The aim was to analyze the prognosis for patients with COPD having survived AHRF and to assess whether previous admissions with NIV predict new ones.We conducted a retrospective follow-up analysis of 201 patients two years after NIV treatment of AHRF. Comparison of time-to-event in patients previously treated with NIV versus patients with no previous NIV treatment. We found a one-year mortality of 33.8% and high risks of: readmission (53.2%), any event (67.7%), and life-threatening events (49.8%). Patients with previous NIV treatments had an increased hazard ratio for life-threatening events: 1.60, p = 0.023 despite having lower in-hospital mortality than patients with no previous NIV treatment (18.9% vs. 33.1%, p = 0.043). We found that having survived one episode of AHRF considerably worsened the prognosis for the affected patients.The prognosis for patients having survived AHRF with NIV treatment is poor: the prognosis worsens with additional episodes of AHRF. Future research and treatment should focus on patients with repeated episodes of AHRF.

Home Non Invasive Ventilation (NIV) treatment for COPD patients with a history of NIV-treated exacerbation; a randomized, controlled, multi-center study.

BACKGROUND: In chronic obstructive pulmonary disease, the prognosis for patients who have survived an episode of acute hypercapnic respiratory failure due to an exacerbation is poor. Despite being shown to improve survival and quality-of-life in stable patients with chronic hypercapnic respiratory failure, long-term noninvasive ventilation is controversial in unstable patients with frequent exacerbations, complicated by acute hypercapnic respiratory failure. In an uncontrolled group of patients with previous episodes of acute hypercapnic respiratory failure, treated with noninvasive ventilation, we have been able to reduce mortality and the number of repeat respiratory failure and readmissions by continuing the acute noninvasive ventilatory therapy as a long-term therapy. METHODS: Multi-center open label randomized controlled trial of 150 patients having survived an admission with noninvasive ventilatory treatment of acute hypercapnic respiratory failure due chronic obstructive pulmonary disease. The included patients are randomized to usual care or to continuing the acute noninvasive ventilation as a long-term therapy, both with a one-year follow-up period. The primary endpoint is time to death or repeat acute hypercapnic respiratory failure; secondary endpoints are one-year mortality, number of readmissions and repeat acute hypercapnic respiratory failure, exacerbations, dyspnea, quality of life, sleep quality, lung function, and arterial gases. DISCUSSION: Though previous studies of long-term noninvasive ventilation have shown conflicting results, we believe the treatment can reduce mortality and readmissions when applied in patients with previous need of acute ventilatory support, regardless of persistent hypercapnia. TRIAL REGISTRATION: clinicaltrials.org: NCT01513655 16-Jan-2012.