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Most studies investigating early risk predictors in coronavirus disease 19 (COVID-19) lacked comparison with controls. We aimed to assess and directly compare outcomes and risk predictors at time of emergency department (ED) presentation in COVID-19 and controls. Consecutive patients presenting to the ED with suspected COVID-19 were prospectively enrolled. COVID-19-patients were compared with (i) patients tested negative (overall controls) and (ii) patients tested negative, who had a respiratory infection (respiratory controls). Primary outcome was the composite of intensive care unit (ICU) admission and death at 30 days. Among 1081 consecutive cases, 191 (18%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 890 (82%) were tested negative (overall controls), of which 323 (30%) had a respiratory infection (respiratory controls). Incidence of the composite outcome was significantly higher in COVID-19 (23%) as compared with the overall control group (10%, adjusted-HR 2.45 (95%CI, 1.61–3.74), p &lt, 0.001) or the respiratory control group (10%, adjusted-HR 2.93 (95%CI, 1.66–5.17), p &lt, 0.001). Blood oxygen saturation, age, high-sensitivity troponin, c-reactive protein, and lactate dehydrogenase were identified as the strongest predictors of poor outcome available at time of ED presentation in COVID-19 with highly comparable prognostic utility in overall and respiratory controls. In conclusion, patients presenting to the ED with COVID-19 have a worse outcome than controls, even after adjustment for differences in baseline characteristics. Most predictors of poor outcome in COVID-19 were not restricted to COVID-19, but of comparable prognostic utility in controls and therefore generalizable to unselected patients with suspected COVID-19.

A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by nsp12-nsp7-nsp8) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting nsp12 (Tajima’s D = −2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic.

Older age and frailty are predictors of adverse outcomes in patients with COVID-19. In emergency medicine, patients do not present with the diagnosis, but with suspicion of COVID-19. The aim of this study was to assess the association of frailty and age with death or admission to intensive care in patients with suspected COVID-19. This single-centre prospective cohort study was performed in the Emergency Department of a tertiary care hospital. Patients, 65 years and older, with suspected COVID-19 presenting to the Emergency Department during the first wave of the pandemic were consecutively enrolled. All patients underwent nasopharyngeal SARS-CoV-2 PCR swab tests. Patients with a Clinical Frailty Scale (CFS) &gt, 4, were considered to be frail. Associations between age, gender, frailty, and COVID-19 status with the composite adverse outcome of 30-day-intensive-care-admission and/or 30-day-mortality were tested. In the 372 patients analysed, the median age was 77 years, 154 (41.4%) were women, 44 (11.8%) were COVID-19-positive, and 125 (33.6%) were frail. The worst outcome was seen in frail COVID-19-patients with six (66.7%) adverse outcomes. Frailty (CFS &gt, 4) and COVID-19-positivity were associated with an adverse outcome after adjustment for age and gender (frailty: OR 5.01, CI 2.56–10.17, p &lt, 0.001, COVID-19: OR 3.47, CI 1.48–7.89, p = 0.003). Frailty was strongly associated with adverse outcomes and outperformed age as a predictor in emergency patients with suspected COVID-19.