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BackgroundThe antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19. MethodsThis open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, [≥]18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with <14 days symptoms, considered suitable for initial ambulatory management. Patients were randomised (1:1) to azithromycin (500 mg daily orally for 14 days) or to standard care without macrolides. The primary outcome was the difference in proportion of participants with death or hospital admission from any cause over the 28 days from randomisation, assessed according to intention-to-treat (ITT). Trial registration: ClinicalTrials.gov, NCT04381962, Study closed. Findings298 participants were enrolled from 3rd June 2020 to 29th January 2021. The primary outcome was assessed in 292 participants. The primary endpoint was not significantly different between the azithromycin and control groups (Adjusted OR 0{middle dot}91 [95% CI 0{middle dot}43-1{middle dot}92], p=0{middle dot}80). Rates of respiratory failure, progression to pneumonia, all-cause mortality, and adverse events, including serious cardiovascular events, were not significantly different between groups. InterpretationIn patients with mild-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospitalisation or death. Our findings do not support the use of azithromycin in patients with mild-moderate COVID-19. FundingNIHR Oxford BRC, University of Oxford and Pfizer Inc. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE and the Cochrane Central register of Controlled Trials (CENTRAL) with the terms ("azithromycin") AND ("COVID" OR "COVID-19") AND ("clinical trials"), until March 25, 2021, with no language restrictions. We identified 42 studies, among which there were four completed randomised trials of azithromycin (with or without hydroxychloroquine) in hospitalised patients with severe disease, and three completed randomised trials of azithromycin in mild COVID-19 in primary care. The four trials in hospitalised patients randomised 8,988 participants to azithromycin or standard care or hydroxychloroquine and found no evidence of a difference in mortality, duration of hospital stay or peak disease severity. Of the three trials in primary care, these randomised participants with early disease to 3 or 5 days of therapy, of which only one assessed azithromycin as standalone therapy. This large, adaptive platform trial in the UK randomised 540 participants in primary care to 3 days treatment with azithromycin versus 875 to standard care alone and found no meaningful difference in time to first reported recovery, or of rates of hospitalisation (3% versus 3%) and there were no deaths. We did not identify any randomised trials in patients with COVID-19 managed in ambulatory care. Added value of this studyThe ATOMIC2 trial was uniquely-designed to assess azithromycin as a standalone therapy in those with mild-moderately COVID-19 presenting to emergency care, but assessed as appropriate for initial ambulatory management without hospital admission. ATOMIC2 also uniquely assessed high-dose, long-duration treatment to investigate the efficacy of putative anti-inflammatory effects. We found that azithromycin 500 mg daily for 14 days did not reduce the proportion of participants who died or required hospital admission from any cause over the 28 days from randomisation. Implications of all the available evidenceOur findings, taken together with existing data, suggest there is no evidence that azithromycin reduces hospitalisation, respiratory failure or death compared with standard care, either in early disease in the community, or those hospitalised with severe disease, or in those with moderate disease managed on an ambulatory pathway.
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BackgroundThe role of specific blood tests to predict poor prognosis in patients admitted with infection from SARS-CoV2 virus remains uncertain. During the first wave of the global pandemic, an extended laboratory testing panel was integrated into the local pathway to guide triage and healthcare resource utilisation for emergency admissions. We conducted a retrospective service evaluation to determine the utility of extended tests (D-dimer, ferritin, high-sensitivity troponin I, lactate dehydrogenase, procalcitonin) compared to the core panel (full blood count, urea & electrolytes, liver function tests, C-reactive protein). MethodsClinical outcomes for adult patients with laboratory-confirmed COVID-19 admitted between 17th March to 30st June 2020 were extracted, alongside costs estimates for individual tests. Prognostic performance was assessed using multivariable logistic regression analysis with 28-day mortality used as the primary endpoint, and a composite of 28-day intensive care escalation or mortality for secondary analysis. ResultsFrom 13,500 emergency attendances we identified 391 unique adults admitted with COVID-19. Of these, 113 died (29%) and 151 (39%) reached the composite endpoint. "Core" test variables adjusted for age, gender and index of deprivation had a prognostic AUC of 0.79 (95% Confidence Interval, CI: 0.67 to 0.91) for mortality and 0.70 (95% CI: 0.56 to 0.84) for the composite endpoint. Addition of "extended" test components did not improve upon this. ConclusionOur findings suggest use of the extended laboratory testing panel to risk stratify community-acquired COVID-19-positive patients on admission adds limited prognostic value. We suggest laboratory requesting should be targeted to patients with specific clinical indications.
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BackgroundHydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and small randomized studies. MethodsThe Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day mortality. Results1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia. ConclusionsIn patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death. FundingMedical Research Council and NIHR (Grant ref: MC_PC_19056). Trial registrationsThe trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
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AimIn addition to respiratory symptoms, COVID-19 can present with gastrointestinal complaints suggesting possible faeco-oral transmission. The primary aim of this review was to establish the incidence and timing of positive faecal samples for SARS-CoV-2 in patients with COVID-19. MethodsA systematic literature review identified studies describing COVID-19 patients tested for faecal virus. Search terms for Medline included clinical, faeces, gastrointestinal secretions, stool, COVID-19, SARS-CoV-2 and 2019-nCoV. Additional searches were done in AJG, Gastroenterology, Gut, Lancet Gastroenterology and Hepatology, The WHO Database, CEBM, NEJM, social media and the NICE, bioRxiv and medRxiv preprints. Data were extracted concerning the type of test, number and timing of positive samples, incidence of positive faecal tests after negative nasopharyngeal swabs and evidence of viable faecal virus or faeco-oral transmission of the virus. ResultsThere were 26 relevant articles identified. Combining study results demonstrated that 53{middle dot}9% of those tested for faecal RNA were positive. Duration of faecal viral shedding ranged from 1 to 33 days after a negative nasopharyngeal swab with one result remaining positive 47 days after onset of symptoms. There is insufficient evidence to suggest that COVID-19 is transmitted via faecally shed virus. ConclusionThere is a high rate of positive PCR tests with persistence of SARS-CoV-2 in faecal samples of patients with COVID-19. Further research is needed to confirm if this virus is viable and the degree of transmission through the faeco-oral route. This may have important implications on isolation, recommended precautions and protective equipment for interventional procedures involving the gastrointestinal tract.
