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To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. A total of 6112 participants with a median age of 69 years (interquartile range, 65–74) and median of 2 (interquartile range, 1–3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87–1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46–1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35–1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66–1.28). BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs. [ABSTRACT FROM AUTHOR]

We aimed at assessing the efficacy and safety on antibiotic exposure of a strategy combining a respiratory multiplex PCR (mPCR) with enlarged panel and daily procalcitonin (PCT) measurements, as compared with a conventional strategy, in adult patients who were critically ill with laboratory-confirmed SARS-CoV-2 pneumonia. This multicentre, parallel-group, open-label, randomized controlled trial enrolled patients admitted to 13 intensive care units (ICUs) in France. Patients were assigned (1:1) to the control strategy, in which antibiotic streamlining remained at the discretion of the physicians, or interventional strategy, consisting of using mPCR and daily PCT measurements within the first 7 days of randomization to streamline initial antibiotic therapy, with antibiotic continuation encouraged when PCT was >1 ng/mL and discouraged if < 1 ng/mL or decreased by 80% from baseline. All patients underwent conventional microbiological tests and cultures. The primary end point was antibiotic-free days at day 28. Between April 20th and November 23rd 2020, 194 patients were randomized, of whom 191 were retained in the intention-to-treat analysis. Respiratory bacterial co-infection was detected in 48.4% (45/93) and 21.4% (21/98) in the interventional and control group, respectively. The number of antibiotic-free days was 12.0 (0.0; 25.0) and 14.0 (0.0; 24.0) days, respectively (difference, −2.0, (95% CI, −10.6 to 6.6), p=0.89). Superinfection rates were high (51.6% and 48.5%, respectively). Mortality rates and ICU lengths of stay did not differ between groups. In severe SARS-CoV-2 pneumonia, the mPCR/PCT algorithm strategy did not affect 28-day antibiotics exposure nor the major clinical outcomes, as compared with routine practice. [ABSTRACT FROM AUTHOR]

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. 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). 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. During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19. [ABSTRACT FROM AUTHOR]

To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59–68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3–5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%–18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4–21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19. [ABSTRACT FROM AUTHOR]

We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir–interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. The intention-to-treat population included 583 participants—lopinavir/ritonavir (n = 145), lopinavir/ritonavir–IFN–β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)—among whom 418 (71.7%) were male, the median age was 63 years (IQR 54–71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55–1.26, p 0.39), lopinavir/ritonavir–IFN–β-1a versus control, aOR 0.69 (95%CI 0.45–1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62–1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir–IFN–β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens. [ABSTRACT FROM AUTHOR]