Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial.

BACKGROUND: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). RESULTS: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14 versus 9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group versus two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group versus six patients receiving placebo (p=0.57). CONCLUSIONS: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.

Protocol for detecting unrecognized sleep apnea in patients with atrial fibrillation by a home-monitoring device: the DAN-APNO study.

BACKGROUND: Determining the presence of modifiable risk factors for atrial fibrillation (AF), such as sleep apnea is of clinical importance due to the potential impact targeting these risk factors can have on the progression and burden of AF. Using new digital-based technology is a promising solution to the underreporting of sleep apnea highlighted by academical societies in recent years. The aim of this study is to report the prevalence and severity of sleep apnea in patients with AF and, secondarily, assess the accuracy and feasibility of a new home-screening device for sleep apnea (NightOwl™ by Ectosense). METHODS: DAN-APNO is a cross-sectional study at the Department of Cardiology, Herlev-Gentofte Hospital recruiting patients with AF referred to anticoagulation initiation aged 18 to 90 years without known sleep apnea. At least 150 patients will be recruited and undergo medical history, clinical evaluation, several sleep-apnea questionnaires, and a sleep-recording evaluation for four nights with sleep apnea home-monitoring device NightOwl™. Additionally, the first 20 participants and participants with moderate-severe sleep apnea by screening are referred to cardio-respiratory monitoring (CRM). This clinical evaluation allows the comparison of standard evaluation method and the NightOwl™. Clinical measures include Apnea-Hypopnea Index (AHI), Oxygen Desaturation Index (ODI), pulse rate, as well as questionaries about sleep apnea assessment and the clinical feasibility of the NightOwl™ device. Main outcomes comprise analysis of the prevalence and severity of sleep apnea, and clinical and demographic predictors of moderate and severe sleep apnea. In addition, correlation analyses for accuracy measures between CRM and NightOwl™ will be conducted along with patient ease-of-use and satisfaction questionnaires. DISCUSSION: This study is limited by selection bias; only patients with atrial fibrillation from anticoagulation clinic is asked to participate, which could limit the generalizability of our results. However, this study aims to test whether a miniaturized simple home-monitoring device for detecting sleep apnea in patients with AF potentially can evaluate sleep apnea more conveniently and easier. Trial Registration The study is registered the 18-02-2021 at clinicaltrials.gov with registration number: NCT04760002.

Effect of different corticosteroid regimes for hospitalised patients with exacerbated COPD: pooled analysis of individual participant data from the REDUCE and CORTICO-COP trials.

BACKGROUND: Systemic corticosteroid administration for severe acute exacerbations of COPD (AECOPD) reduces the duration of hospital stays. Corticosteroid-sparing regimens have showed non-inferiority to higher accumulated dose regimens regarding re-exacerbation risk in patients with AECOPD. However, it remains unclear whether 14-day or 2-5-day regimens would result in shorter admission durations and changes in mortality risk. We explored this by analysing the number of days alive and out of hospital based on two randomised controlled trials with different corticosteroid regimens. METHODS: We pooled individual patient data from the two available multicentre randomised trials on corticosteroid-sparing regimens for AECOPD: the REDUCE (n = 314) and CORTICO-COP (n = 318) trials. In the 14-day regimen group, patients were older, fewer patients received pre-treatment with antibiotics and more patients received pre-treatment with systemic corticosteroids. Patients randomly allocated to the 14-day and 2-5-day regimens were compared, with adjustment for baseline differences. RESULTS: The number of days alive and out of hospital within 14 days from recruitment was higher for the 2-5 day regimen group (mean 8.4 days; 95% confidence interval [CI] 8.0-8.8) than the 14-day regimen patient group (4.2 days; 95% CI3.4-4.9; p < 0.001). The 14-day AECOPD group had longer hospital stays (mean difference, 5.4 days [standard error ± 0.6]; p < 0.0001) and decreased likelihood of discharge within 30 days (hazard ratio [HR] 0.5; 95% CI 0.4-0.6; p < 0.0001). Comparing the 14-day regimen and the 2-5 day regimen group showed no differences in the composite endpoint 'death or ICU admission' (odds ratio [OR] 1.4; 95% CI 0.8-2.3; p = 0.15), new or aggravated hypertension (OR 1.5; 95% CI 0.9-2.7; p = 0.15), or mortality risk (HR 0.8; 95% CI 0.4-1.5; p = 0.45) during the 6-month follow-up period. CONCLUSION: 14-day corticosteroid regimens were associated with longer hospital stays and fewer days alive and out of hospital within 14 days, with no apparent 6-month benefit regarding death or admission to ICU in COPD patients. Our results favour 2-5 day regimens for treating COPD exacerbations. However, prospective studies are needed to validate these findings.

Early detection of COPD in primary care: the Copenhagen COPD screening project.

OBJECTIVE: To evaluate the effectiveness of a screening programme for COPD in primary care. MATERIAL/METHODS: Subjects aged 65 years or older registered with a general practitioner in Copenhagen were asked to complete a questionnaire on smoking status and symptoms of COPD. If they were smokers or former smokers or if morning cough with sputum and/or dyspnoea was present, subjects were defined as "at risk of COPD" and were invited to undergo spirometric examination. RESULTS: Of the 7103 subjects who met the study criteria, 81.2% responded to the questionnaire. Of these, 58.5% were at risk of COPD. Of those at risk, 40% underwent a spirometric examination. COPD was classified as mild in 252 (42.3%), moderate in 258 (43.3%) and severe-very severe in 86 subjects (14.4%). The participation rate was significantly higher among subjects invited for spirometry at a healthcare centre compared to general practice. CONCLUSIONS: Our findings suggest that a questionnaire can be used as a screening tool to identify subjects at risk of COPD. Furthermore, the study shows that more than half the subjects aged 65 years and above were at risk of COPD and required clinical assessment. Willingness to undergo spirometric examination depends on the location of the screening.

Prevalence of sleep apnea in unselected patients with atrial fibrillation by a home-monitoring device: The DAN-APNO study.

Background: Sleep apnea (SA), a modifiable risk factor in - atrial fibrillation (AF), is associated with worse outcomes in AF. We aimed to assess the prevalence and severity of SA in patients with AF, and, subsequently, to assess the positive predictive value (PPV) of moderate to severe SA by a home-monitoring device in comparison to cardio-respiratory monitoring (CRM) in consecutive patients with AF. Methods: This cross-sectional study recruited unselected patients with AF without known SA from an out-patient clinic at Department of Cardiology, Herlev-Gentofte University Hospital. Participants underwent four consecutive nights of sleep-recording with the home-monitoring device NightOwl™ (NO). Moderate SA was defined as an Apnea-Hypopnea Index (AHI) of 15-29 and severe SA as ≥ 30 AHI. Participants with moderate to severe SA was offered CRM for validation of the diagnosis. Results: We included 126 patients with AF with a median age of 68 (interquartile range: 60-75) years, 42 (33 %) women, 70 (56 %) hypertension, 61 (48 %) hyperlipidemia and 49 (39 %) heart failure. NO detected severe SA in 36 (29 %) of patients with AF, moderate SA in 35 (28 %), mild SA in 45 (36 %) and no SA in 10 (8 %). Of 71 patients with moderate to severe SA by NO, 38 patients underwent CRM and the PPV of NO was 0.82 (31/38) to diagnose moderate SA and 0.92 (22/24) to diagnose severe SA by CRM. Conclusion: Moderate to severe SA by NO was highly prevalent in patients with AF without known SA. A home-monitoring device such as NO could be an easy and feasible SA screening tool in patients with AF.

Pulmonary rehabilitation for moderate COPD (GOLD 2)--does it have an effect?

BACKGROUND: Although pulmonary rehabilitation is an integrated part of standard care in patients with severe COPD, it is uncertain whether those with less severe COPD benefit from such treatment. The aim of the present survey was to evaluate the effect of rehabilitation in patients with moderate COPD and to determine their willingness to participate in rehabilitation. MATERIAL AND METHODS: In a single-centre, randomized, placebo-controlled, unblinded clinical trial, participants comprised 61 of 133 referred subjects with moderate COPD. Of the 61 participants, 35 were randomized to receive rehabilitation and 26 subjects to receive standard COPD care from their GP. After randomization 19 subjects dropped out. RESULTS: Effects of physical training were seen during the period of intervention. Compared with those receiving standard GP care, those receiving rehabilitation showed improvements in walking distance and leg strength as well as improvements in quality of life; however, the effect was temporary, and at 18 months' follow-up there was no significant difference between the groups. Only 61 subjects of the referred group of 133 with moderate COPD accepted the offer of rehabilitation. CONCLUSION: Although an effect was found of pulmonary rehabilitation in subjects with moderate COPD, it disappeared over 18 months. Only a minority of patients with moderate COPD referred for rehabilitation accepted and completed the treatment offer.

Systemic Corticosteroids and the Risk of Venous Thromboembolism in Patients with Severe COPD: A Nationwide Study of 30,473 Outpatients.

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated with long and short OCS regimens. In this nationwide cohort study of 30,473 COPD outpatients treated for AECOPD, we compared the risk of VTE hospitalisation and all-cause mortality within 6 months in OCS dose of >250 mg vs. ≤250 mg. A multivariable Cox proportional hazard regression was used to estimate the risk. The incidence of VTE hospitalisations was 0.23%. A long OCS treatment course was associated with an increased risk of VTE compared to a short course (hazard ratio (HR) 1.69, [95% confidence interval (CI) 1.05 to 2.72], p < 0.031). A higher risk of all-cause mortality was seen in the group of COPD patients treated with a long OCS course (HR 1.71, [95% CI 1.63 to 1.79], p < 0.0001). The risk of reported VTE hospitalisation was higher among AECOPD patients treated with long courses of OCS, but the absolute risk was low, suggesting under-reporting of the condition.

Asthma patients who smoke have signs of chronic airflow limitation before age 45.

BACKGROUND: The frequency of smokers among asthma patients often mirrors the frequency of smokers among healthy individuals. Smoking has been shown to increase the lung function decline in adult asthma patients and change the composition of the bronchial inflammation. OBJECTIVE: To examine the consequences of smoking in a large cohort of young asthma patients. METHODS: Seven hundred ninety-three asthma patients, aged 14 to 44, were examined using lung function measurements, bronchial provocations, clinical interviews, and questionnaires. RESULTS: Forty-five percent of participants were smokers; smokers had significantly lower forced expiratory volume in one second (FEV(1)), FEV(1) in percent of predicted value (FEV(1)% pred), and FEV(1)/forced vital capacity (FVC) values compared with nonsmokers, and there was a dose-response relationship between tobacco exposure and these lung function measures. Smoking seemingly affected the FEV(1) growth already in adolescence, and before the age of 45, significantly more smokers than nonsmokers had signs of airflow limitation, with FEV(1)/FVC ratios below 0.70. Smokers had more asthma symptoms despite receiving inhaled corticosteroid (ICS) treatment as frequently as did nonsmokers. CONCLUSION: The additive effect of smoking on lung function decline in asthma patients is detectable at early ages and leads to signs of airflow limitation before the age of 45 years.

Early detection of COPD in primary care--the Copenhagen COPD Screening Project.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is among the leading causes of death in the world, and further increases in the prevalence and mortality are predicted. Delay in diagnosing COPD appears frequently even though current consensus guidelines emphasize the importance of early detection of the disease. The aim of the present study is to evaluate the effectiveness of a screening programme in general practice. METHODS/DESIGN: Subjects aged 65 years and older registered with a General Practitioner (GP) in the eastern Copenhagen will receive a written invitation and a simple questionnaire focusing on risk factors and symptoms of COPD. Subjects who meet the following criteria will be encouraged to undergo spirometric testing at their GP: current smokers, former smokers, and subjects with no smoking history but who have dyspnea and/or chronic cough with sputum. DISCUSSION: The Copenhagen COPD Screening Project evaluates the effectiveness of a two-stage screening program for COPD in general practice and provides important information on how to organize early detection of COPD in general practice in the future.

Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN: This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS: 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA: • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR: Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS: Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

The use of COPD maintenance therapy following spirometry in General Practice.

BACKGROUND: Several studies have shown that the use of pulmonary medication is widespread and often initiated without initial spirometry. Early detection of chronic obstructive pulmonary disease (COPD) by spirometry in General Practice is essential for an early and correct implementation of medical treatment. AIM: The aim of the present study was to evaluate the use of regular therapy following diagnostic spirometry for COPD in General Practice from February 2008 to February 2009. METHOD: Spirometry data and results were linked through Statistics Denmark with information from the Register of Medicinal Product Statistics using the unique personal identification code. Data were analysed to evaluate the impact of screening on use of regular COPD therapy. Primary outcome was initiation of regular therapy following COPD diagnosis with spirometry. RESULTS: In a population of 3,376 individuals at risk, 1,458 underwent spirometric assessment with 631 being diagnosed with COPD; 110 of those received regular therapy before assessment with this figure increasing to 161 after spirometry. Of 827 participants not receiving a COPD diagnosis, 36 received regular therapy prior to assessment and 42 received regular therapy after spirometry despite no established COPD diagnosis. CONCLUSION: There is a significant chance of receiving regular therapy after being diagnosed with COPD. However, a large proportion of subjects diagnosed with COPD did not receive regular therapy following diagnosis. Efforts should be made to ensure correct diagnosis and correct medical treatment according to guidelines in individuals with COPD.