Highlights d The receptor-binding motif (RBM) is a highly variable region of SARS-CoV-2 spike d RBM mutation N439K has emerged independently in multiple lineages d N439K increases spike affinity for hACE2; viral fitness and disease are unchanged d N439K confers resistance to several mAbs and escapes some polyclonal responses

Background Coronavirus disease 2019 (COVID-19) has been associated to microvascular alterations. We screened the fundus of patients with COVID-19 to detect alterations of the retina and its vasculature and to assess possible correlations with clinical parameters. Methods Cross-sectional study. The presence of retinal alterations in patients with COVID-19 and subjects unexposed to the virus was assessed using fundus photographs and their prevalence was compared. Mean arteries diameter (MAD) and mean veins diameter (MVD) were compared between patients and unexposed subjects with multiple linear regression including age, sex, ethnicity, body mass index, smoking/alcohol consumption, hypertension, hyperlipidaemia, diabetes as covariates. The influence of clinical/lab parameters on retinal findings was tested in COVID-19 patients. Findings 54 patients and 133 unexposed subjects were enrolled. Retinal findings in COVID-19 included: haemorrhages (9·25%), cotton wools spots (7·4%), dilated veins (27·7%), tortuous vessels (12·9%). Both MAD and MVD were higher in COVID-19 patients compared to unexposed subjects (98·3 ± 15·3 µm vs 91·9 ± 11·7 µm, p = 0.006 and 138·5 ± 21·5 µm vs 123·2 ± 13·0 µm, p <0.0001, respectively). In multiple regression accounting for covariates MVD was positively associated with COVID-19 both in severe (coefficient 30·3, CI95% 18·1–42·4) and non-severe (coefficient 10·3, CI95% 1·6–19·0) cases compared to unexposed subjects. In COVID-19 patients MVD was negatively correlated with the time from symptoms onset (coefficient −1·0, CI 95% −1·89 to −0·20) and positively correlated with disease severity (coefficient 22·0, CI 95% 5·2–38·9). Interpretation COVID-19 can affect the retina. Retinal veins diameter seems directly correlated with the disease severity. Its assessment could have possible applications in the management of COVID-19. Funding None.

The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February-19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death. Forty-eight (20.6 %) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1 %) and their median age was 61 years (IQR 50-72). The timedependent probability of death was 19.7 % (95 % CI 14.6-24.9 %) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95 % CI 1.48−2.92 per ten years more) and obesity (aHR 3.04, 95 % CI 1.42−6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95 % CI 1.41−48.29), C-reactive protein levels (aHR 1.17, 95 % CI 1.02−1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95 % CI 1.37−4.87) upon admission. Case-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20 %. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.

BackgroundItaly was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe. MethodsThis prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the timedependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death. ResultsForty-eight (20.6%) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1%) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7% (95% CI 14.6-24.9%) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95% CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95% CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95% CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95% CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95% CI 1.37-4.87) upon admission. ConclusionsCase-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20%. Our study adds evidence to the notion that older age, obesity and All rights reserved. No reuse allowed without permission.was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. : medRxiv preprint more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.

Background Patients hospitalised with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2; coronavirus 2019 disease (COVID-19)] infection are frequently older with co-morbidities and receiving polypharmacy, all of which are known risk factors for drug–drug interactions (DDIs). The pharmacological burden may be further aggravated by the addition of treatments for COVID-19. Objective The aim of this study was to assess the risk of potential DDIs upon admission and during hospitalisation in patients with COVID-19 treated at our hospital. Methods We retrospectively analysed 502 patients with COVID-19 (mean age 61 ± 16 years, range 15–99) treated at our hospital with a proven diagnosis of SARS-CoV-2 infection hospitalised between 21 February and 30 April 2020 and treated with at least two drugs. Results Overall, 68% of our patients with COVID-19 were exposed to at least one potential DDI, and 55% were exposed to at least one potentially severe DDI. The proportion of patients experiencing potentially severe DDIs increased from 22% upon admission to 80% during hospitalisation. Furosemide, amiodarone and quetiapine were the main drivers of potentially severe DDIs upon admission, and hydroxychloroquine and particularly lopinavir/ritonavir were the main drivers during hospitalisation. The majority of potentially severe DDIs carried an increased risk of cardiotoxicity. No potentially severe DDIs were identified in relation to tocilizumab and remdesivir. Conclusions Among hospitalised patients with COVID-19, concomitant treatment with lopinavir/ritonavir and hydroxychloroquine led to a dramatic increase in the number of potentially severe DDIs. Given the high risk of cardiotoxicity and the scant and conflicting data concerning their efficacy in treating SARS-CoV-2 infection, the use of lopinavir/ritonavir and hydroxychloroquine in patients with COVID-19 with polypharmacy needs to be carefully considered.

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Background: Acute Hypoxemic Respiratory Failure (AHRF) is a common complication of Covid-19 related pneumonia, for which non-invasive ventilation (NIV) with Helmet Continuous Positive Airway Pressure (CPAP) is widely used. During past epidemics of SARS and MERS pneumomediastinum (PNM) and pneumothorax (PNX) were common complications (respectively 1.7-12% and 16,4%) either spontaneous or associated to ventilation. Methods: Aim of our retrospective study was to investigate the incidence of PNX/PNM in COVID-19 pneumonia patients treated with CPAP. Moreover, we examined the correlation between PNX/PNM and Positive end-expiratory pressure (PEEP) values. We collected data from patients admitted to Luigi Sacco University Hospital of Milan from 21/02/2020 to 06/05/2020 with COVID-19 pneumonia requiring CPAP. Results: One-hundred-fifty-four patients were enrolled. During hospitalization 3 PNX and 2 PNM occurred (3.2%). Out of these five patients 2 needed invasive ventilation after PNX, two died. In the overall population, 42 patients (27%) were treated with High-PEEP (>10 cmH2O), and 112 with Low-PEEP (≤10 cmH2O). All the PNX/PNM occurred in the High-PEEP group (5/37 vs 0/112, p<0,001). Conclusion: The incidence of PNX appears to be lower in COVID-19 than SARS and MERS, but their occurrence is accompanied by high mortality and worsening of clinical conditions. Considering the association of PNX/PNM with high PEEP we suggest using the lower PEEP as possible to prevent these complications.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 primarily affecting the respiratory system which can damage vessels walls virtually in any body district. Changes affecting retinal vessels are a good marker for systemic vascular alterations. This study investigated retinal vessels during the acute phase of COVID-19 and after patients recovery. Fifty-nine eyes from 32 COVID-19 patients and 80 eyes from 53 unexposed subjects were included. Mean arteries diameter (MAD) and mean veins diameter (MVD) were assessed through semi-automatic analysis on fundus color photos at baseline and 6 months later in patients and subjects unexposed to the virus. At baseline MAD and MVD were significantly higher in COVID-19 patients compared to unexposed subjects (p < 0.0001). Both MAD and MVD significantly decreased in COVID-19 patients at follow-up (from 97.5 ± 10.9 to 92.2 ± 11.4 µm, p < 0.0001 and from 133.1 ± 19.3 to 124.6 ± 16.1 µm, p < 0.0001, respectively). Despite this reduction vessels diameter remained significantly higher in severe COVID-19 patients compared to unexposed subjects. Transient retinal vessels dilation could serve a biomarker for systemic inflammation while long-lasting alterations seen in severe COVID-19 likely reflect irreversible structural damage to the vessels walls and should be further investigated for their possible effects on tissues perfusion and function.