An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients (preprint)

BackgroundWhilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. MethodsHere, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. ResultsOur analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61 - 0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. ConclusionsAlthough clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome.

Predictors of Mortality Using Machine Learning Decision Tree Algorithm in Critically Ill Adult Patients with COVID-19 Admitted to the ICU. (preprint)

Background:The Coronavirus Disease-19 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major cause of intensive care unit (ICU) admissions globally. Robust data of epidemiology, characteristics, and disease outcomes from different regions and populations showed considerable variations. However, limited number of reports addressed predictors of mortality utilizing machine learning methods. Herein, we aimed to describe the association and relationship of a predefined set of variables found to be predictive of 28–day ICU outcome among adults COVID-19 patients admitted to the ICU using a machine learning decision tree (DT) algorithm.Methods:This was a prospective/retrospective, multicenter cohort study from 14 hospitals in Saudi Arabia. We included critically ill COVID-19 patients admitted to the ICU between March 1, 2020, and October 31, 2020. The primary outcome was 28-day ICU mortality. Secondary outcomes were 90-day mortality and ICU length of stay. The predictors of mortality were identified using two predictive models, the conventional logistic regression and DT analysis.Results:A total of 1468 critically ill COVID-19 patients were included. The mean age was 55.9 (SD±15.1) years, with 74% of the patients were males. The 28-day ICU mortality was 540 (36.8%), while 90-day mortality was 600 (40.9%). The multivariable logistic regression model demonstrated that the PaO2/FiO2 ratio on ICU admission and the need for intubation or vasopressors could strongly predict 28-day ICU mortality. The DT algorithm identified five variables [need for intubation, need for vasopressors, age, gender, and PaO2/FiO2 ratio] provided in an algorithmic fashion to predict 28-day ICU outcome. Conclusion:Five clinical predictors of 28-day ICU outcome were identified using DT algorithmic analysis of COVID-19 patients admitted to ICU. The findings of this DT analysis may be used in ICU for early identification of critically ill COVID-19 patients who are at high risk of 28-day mortality.

Awake Prone Position in Hypoxemic Patients with Coronavirus Disease 19 (COVI-PRONE): A Study protocol and Statistical Analysis Plan for Randomized Clinical Trial (preprint)

BackgroundCoronavirus disease 2019 (COVID-19), may progress to respiratory failure requiring invasive mechanical ventilation. Due to ventilator shortage and healthcare systems strain, affordable interventions such as awake prone positioning has been used to improve oxygenation, however, the effect of this intervention on patient-important outcomes is uncertain. The COVI-PRONE trial aims to determine if awake prone positioning in hypoxemic COVID-19 patients reduces the need for invasive mechanical ventilation. Study designA pragmatic, multicenter, international, parallel-group, and stratified randomized controlled trial, aiming to enrol 400 hospitalized adults with COVID-19. ParticipantsThe target population is hospitalized adults with confirmed or suspected COVID-19, hypoxemia that requires [≥]40% oxygen or [≥] 5 L/min by nasal cannula, and abnormal chest x-ray. We will exclude patients with any of the following: immediate need for intubation; altered mental status; contraindication to prone positioning; hemodynamic instability; body mass index > 40 kg/m2; third trimester pregnancy; do not intubate status; previous enrolment or intubation within the same hospital admission; and prone positioning for more than one day prior to randomization. Study intervention and controlFollowing informed a priori or deferred consent, eligible patients will be centrally randomized to either the intervention arm (prone positioning) or standard of care (no prone positioning). Patients randomized to the prone position will be required to either self-prone or assist-prone for a total of eight to ten hours per day until they meet pre-specified stopping criteria. Study outcomesThe primary outcome is invasive mechanical ventilation at 30-days of randomization. Other outcomes include mortality at 60 days, invasive and non-invasive mechanical ventilation free days at 30 days, hospital length of stay at 60 days, days alive and outside of the hospital at 60 days, complications of proning, and serious adverse events.

Helmet noninvasive ventilation for COVID-19 patients (Helmet-COVID): study protocol for a multicenter randomized controlled trial (preprint)

IntroductionNoninvasive ventilation delivered by helmet is has been used for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. The aim of this study is to compare helmet noninvasive ventilation with usual care versus usual care alone to reduce the mortality. Methods and analysisThis is a multicenter, pragmatic, parallel, randomized controlled trial that compares helmet noninvasive ventilation with usual care to usual care alone in 1:1 ratio. A total of 320 patients will be enrolled in this study. The primary outcome is 28-day all-cause mortality. The primary outcome will be compared between the two study groups in the intention-to-treat and per-protocol cohorts. An interim analysis will be conducted for both safety and effectiveness. Ethics and disseminationApprovals are obtained from the Institutional Review Boards (IRBs) of each participating institution. Our findings will be published in peer-review journals and presented at relevant conferences and meetings. Trial registration numberNCT04477668 registered on July 20, 2020 Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis trial compares helmet NIV to usual care for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. C_LIO_LIThe trial is a multi-center, pragmatic, parallel randomized controlled trial. C_LIO_LIThe main limitation is the unblinded design due to the nature of the intervention. C_LI

Statistical Analysis Plan for the Helmet Non-Invasive Ventilation for COVID-19 Patients (Helmet-COVID) Randomized Controlled Trial (preprint)

Background and objective Noninvasive respiratory support is frequently needed for patients with acute hypoxemic respiratory failure due to coronavirus disease 19 (COVID-19). Helmet noninvasive ventilation having multiple advantages over other support modalities but data about effectiveness are limited. Methods In this multicenter randomized trial of helmet non-invasive ventilation for COVID-19 patients (Helmet-COVID), 320 adult ICU patients with suspected or confirmed COVID-19 and acute hypoxemic respiratory failure (with a ratio of arterial oxygen partial pressure to fraction (percent) of inspired oxygen (PaO2/FiO2) <200 despite supplemental oxygen with a partial/non-rebreathing mask at a flow rate >10 L/min or above) will be randomized to helmet-noninvasive ventilation with usual care or usual care alone. The primary outcome is death from any cause within 28 days after randomization. The trial has 80% power to detect a 15% absolute risk reduction from 40% to 25%. Conclusion Consistent with international guidelines, we developed a detailed plan to guide the analysis of the Helmet-COVID trial. This plan specifies the statistical methods for the evaluation of primary and secondary outcomes to facilitate unbiased analyses of clinical data.

Favipiravir and Hydroxychloroquine Combination Therapy in Patients with Moderate to Severe COVID-19 (FACCT): An Open-Label, Multicentre, Randomised, Controlled Trial (preprint)

Background: No antiviral drug has been proven effective for the treatment of patients with moderate-to-severe coronavirus disease 2019 (COVID-19). Favipiravir and hydroxychloroquine were introduced as potential antiviral agents to treat patients with COVID-19.Methods: We conducted an investigator-initiated, multicentre, open-label, randomised trial involving hospitalised patients with confirmed moderate-to-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at nine hospitals in Saudi Arabia. Eligible patients were adult with moderate-to-severe COVID-19 defined as oxygen saturation (Sao2) of 94% or less while breathing ambient air or significant clinical symptoms with chest X-ray changes requiring hospital admission. Randomisation was in a 1:1 ratio to receive standard care (control group) or standard care plus favipiravir and hydroxychloroquine. The favipiravir loading dose was 1800 mg twice daily on day 1, then 800mg twice daily for nine days and hydroxychloroquine as 400mg twice daily, followed by 200mg twice daily for days 2-5. The primary outcome was time to clinical improvement of two points (from the status at randomisation) on a seven-category ordinal scale or live discharge from the hospital within 14 days. Analyses were done in an intention-to-treat population of patients to assess the primary and secondary endpoints. The trial is registered at ClinicalTrials.gov (NCT04392973).Findings: From May 2020 to Jan 2021, 254 patients were enrolled; 129 were assigned to standard of care and 125 patients to the combination of favipiravir and hydroxychloroquine. The mean age was 52·65 ±13·06 years, 59·4% were men, and 229 (90·15%) required supplemental oxygen at randomisation (with or without non-invasive ventilation). The time to clinical improvement was not significantly different between the two groups; median of 9 days (95%CI: 8, 12) in the treatment group and 7 days (95%CI: 6, 10) in the control group (HR:0·845; 95% CI 0·617 to 1·157; p-value = 0·29). The median duration of hospitalisation among patients discharged on or before day 14 was 9 days (95%CI: 8, 12) for the treatment group and 8 days (95%CI: 7, 10) for the control group with a p-value of 0·42. The 28-day mortality was not significantly different between the two groups, 9 (7·63%) in the treatment group vs 13 (10·32%) in the control group; p-value=0·45. The most prevalent adverse events were headache, elevation in ALT, and the prolonged QTc interval in the treatment group.Interpretation: The combination of favipiravir and hydroxychloroquine did not result in a statistically significant clinical benefit in patients with moderate-to-severe COVID-19. No new safety signals were recognised for both medications.Trial Registration: This trial is registered with ClinicalTrials.gov, Identifier: NCT04392973, May 19, 2020.Funding Statement: King Abdullah International Medical Research Center, Saudi Arabia.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This trial was approved by the Saudi Food and Drug Authority (SFDA). Ethical approval was obtained from the Institutional Review Board (IRB) at the Ministry of National Guard-Health Affairs (MNGHA) and Ministry of Health (MOH). The trial was overseen by an independent data and safety monitoring board (DSMB). The trial was done according to the Declaration of Helsinki principles and the International Conference on Harmonization-Good Clinical Practice guidelines.

Extracorporeal Membrane Oxygenation in the Middle East and India During the COVID-19 Pandemic (preprint)

Background: Extracorporeal membrane oxygenation (ECMO) use for severe Coronavirus disease 2019 (COVID-19) patients has evolved during the course of the pandemic. Early uncertainty regarding the role of ECMO during the current pandemic was based on the suboptimal initial experiences. However, more recent data suggests favorable outcomes in COVID-19 patients receiving ECMO support. We aimed to explore the epidemiology and outcomes of ECMO for COVID-19 related cardiopulmonary failure and evaluate outcomes of new centers versus established ones.Methods: This is a retrospective, multicenter international, observational study conducted in (19) ECMO centers in five countries from March 1, 2020, to September 30, 2020. We included 307 patients with COVID-19 who received ECMO for refractory hypoxemia and severe respiratory acidosis with or without circulatory failure. Data collection included Patients characteristics, demographic data, ECMO-related specific data, pre-ECMO patient condition, 24 hours post-ECMO initiation data, and outcome. The primary outcome is survival to home discharge. Secondary outcomes include mortality during ECMO, survival to decannulation, and outcomes stratified by center type in which patients were treated.Findings: Three hundred and seven COVID-19 patients received ECMO support during the study period. The median age was 45 years (37-52 IQR), and 81% were men. 178 (58%) patients survived ECMO, of whom 138 (45%) patients were discharged home, and 40 patients (13%) died post-ECMO decannulation while 128 patients (41.7%) died during ECMO. Patient outcomes in the new centers developed in response to the pandemic were similar to those of established centers.Interpretation: During pandemics, ECMO may provide favorable outcomes in highly select patients as resources allow. Outcomes in ECMO centers established during the pandemic were comparable to existing centers.Funding Statement: None.Declaration of Interests: Kiran Shekar acknowledges research support from the Metro North Hospital and Health Service and the Prince Charles Hospital Foundation. Dr. Brodie receives research support from ALung Technologies. He has been on the medical advisory boards for Baxter, Abiomed, Xenios, and Hemovent and is the President-Elect of the Extracorporeal Life Support Organization (ELSO). Dr. Combes reported receiving grants and personal fees from Maquet, Xenios, and Baxter and serving as the recent past president of the EuroELSO organization. Other authors have no conflict of interest.Ethics Approval Statement: After the SWAAC ELSO steering committee's authorization, IRB approval was obtained from the coordinating center King Saud Medical City in Riyadh - Saudi Arabia. The country representatives obtained IRB approval for each participating center as well.

Nationwide Seroprevalence of SARS-CoV-2 in Saudi Arabia (preprint)

Background: Estimated seroprevalence of Coronavirus Infectious Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is a critical evidence for a better evaluation of the virus spread and monitoring the progress of the COVID-19 pandemic in a population. In the Kingdom of Saudi Arabia (KSA), SARS-CoV-2 seroprevalence has been reported in specific regions, but an extensive nationwide study has not been reported. Here, we report a nationwide study to determine the prevalence of SARS-CoV-2 in the population of KSA during the pandemic, using serum samples from healthy blood donors, non-COVID patients and healthcare workers (HCWs) in six different regions of the kingdom, with addition samples from COVID-19 patients.Methods: A total of 11703 serum samples were collected from different regions of the KSA including; 5395 samples from residual healthy blood donors (D); 5877 samples from non-COVID patients collected through residual sera at clinical biochemistry labs from non-COVID patients (P); and 400 samples from consented HCWs. To determine the seroprevalence of SARS-CoV-2, all serum samples, in addition to positive control sera from RT-PCR confirmed COVID-19 patients, were subjected to in-house ELISA with a sample pooling strategy, which was further validated by testing individual samples that make up some of the pools, with a statistical estimation method to report seroprevalence estimates.Results: Overall (combining D and P groups) seroprevalence estimate was around 11% in Saudi Arabia; and was 5.1% (Riyadh), 1.5% (Jazan), 18.4% (Qassim), 20.8% (Hail), 14.7% (ER; Alahsa), and 18.8% in Makkah. Makkah samples were only D group and had a rate of 24.4% and 12.8% in the cities of Makkah and Jeddah, respectively. The seroprevalence in Saudi Arabia across the sampled areas would be 12 times the COVID-19 infection rate. Among HCWs, 7.5% (4.95-10.16 CI 95%) had reactive antibodies to SARS-CoV-2 without reporting any previously confirmed infection. This was higher in HCWs with hypertension. The study also presents the demographics and prevalence of co-morbidities in HCWs and subset of non-COVID-19 population.Conclusion: Our study estimates the overall national serological prevalence of COVID-19 in Saudi Arabia to be 11%, with an apparent disparity between regions.Funding Statement: This study was funded by KAIMRC, Grant: RC20/180; PI: Naif K. Alharbi.Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: The study was approved by the IRB in KAIMRC (Ministry of National Guard Health Affairs) for project number RC20-180. Residual samples from blood banks and clinical laboratories were obtained after an IRB approval. COVID-19 patients and HCWs signed informed consents to give blood samples.

Critically ill patients with diabetes and Middle East respiratory syndrome: A multi-center observational study (preprint)

Background: Diabetes is a risk factor for infection with coronaviruses. This study describes the demographic, clinical data, and outcomes of critically ill patients with diabetes and Middle East Respiratory Syndrome (MERS). Methods: : This retrospective cohort study was conducted at 14 hospitals in Saudi Arabia (September 2012- January 2018). We compared the demographic characteristics, underlying medical conditions, presenting symptoms and signs, management and clinical course, and outcomes of critically ill patients with MERS who had diabetes compared to those with no diabetes. Multivariable logistic regression analysis was performed to determine if diabetes was an independent predictor of 90-day mortality. Results: : Of the 350 critically ill patients with MERS, 171 (48.9%) had diabetes. Patients with diabetes were more likely to be older, and have comorbid conditions, compared to patients with no diabetes. They were more likely to present with respiratory failure requiring intubation, vasopressors, and corticosteroids. The median time to clearance of MERS-CoV RNA was similar (23 days (Q1, Q3: 17, 36) in patients with diabetes and 21.0 days (Q1, Q3: 10, 33) in patients with no diabetes). Mortality at 90 days was higher in patients with diabetes (78.9% versus 54.7%, p<0.0001). Multivariable regression analysis showed that diabetes was an independent risk factor for 90-day mortality (odds ratio, 2.09; 95% confidence interval, 1.18-3.72). Conclusions: : Half of the critically ill patients with MERS have diabetes; which is associated with more severe disease. Diabetes is an independent predictor of mortality among critically patients with MERS.

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19 (preprint)

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

Furin cleaves SARS-CoV-2 spike-glycoprotein at S1/S2 and S2'for viral fusion/entry: indirect role for TMPRSS2 (preprint)

The Spike (S)-protein of SARS-CoV-2 binds host-cell receptor ACE2 and requires proteolytic 'priming' (S1/S2) and 'fusion-activation' (S2') for viral entry. The S-protein furin-like motifs PRRAR685{downarrow} and KPSKR815{downarrow} indicated that proprotein convertases promote virus entry. We demonstrate that furin and PC5A induce cleavage at both sites, ACE2 enhances S2' processing, and their pharmacological inhibition (BOS-inhibitors) block endogenous cleavages. S1/S2-mutations (S1/S2) limit S-protein-mediated cell-to-cell fusion, similarly to BOS-inhibitors. Unexpectedly, TMPRSS2 does not cleave at S1/S2 or S2', but it can: (i) cleave/inactivate S-protein into S2a/S2b; (ii) shed ACE2; (iii) cleave S1-subunit into secreted S1', activities inhibited by Camostat. In lung-derived Calu-3 cells, BOS-inhibitors and S1/S2 severely curtail 'pH-independent' viral entry, and BOS-inhibitors alone/with Camostat potently reduce infectious viral titer and cytopathic effects. Overall, our results show that: furin plays a critical role in generating fusion-competent S-protein, and indirectly, TMPRSS2 promotes viral entry, supporting furin and TMPRSS2 inhibitors as potential antivirals against SARS-CoV-2

SARS-CoV-2 protein ORF3a is pathogenic in Drosophila and causes phenotypes associated with COVID-19 post-viral syndrome (preprint)

The Coronavirus Disease 2019 (COVID-19) pandemic has caused millions of deaths and will continue to exact incalculable tolls worldwide. While great strides have been made toward understanding and combating the mechanisms of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, relatively little is known about the individual SARS-CoV-2 proteins that contribute to pathogenicity during infection and that cause neurological sequela after viral clearance. We used Drosophila to develop an in vivo model that characterizes mechanisms of SARS-CoV-2 pathogenicity, and found ORF3a adversely affects longevity and motor function by inducing apoptosis and inflammation in the nervous system. Chloroquine alleviated ORF3a induced phenotypes in the CNS, arguing our Drosophila model is amenable to high throughput drug screening. Our work provides novel insights into the pathogenic nature of SARS-CoV-2 in the nervous system that can be used to develop new treatment strategies for post-viral syndrome.

COVID-19 Critical Care Simulations: An International Cross-sectional Survey (preprint)

Background: Many healthcare systems initiated rapid training with COVID-19 simulations for their healthcare workers (HCWs) to build surge capacity and optimize infection control measures. This study aimed to describe COVID-19 simulation drills in international healthcare centers. Methods: This is a cross-sectional survey among simulation team leaders and HCWs, based on each center's debriefing reports from simulation centers from 30 countries in all WHO regions where COVID-19 simulation drills were conducted. The primary outcome measures were the COVID-19 simulations' characteristics, outcomes, facilitators, obstacles, and challenges encountered during the simulation sessions. Results: Invitation was sent to 500 simulation team leaders and HCWs, and 343 responded. Those who completed the study comprised 121 participants: 62.8% females; 56.2% physicians; 41.3% from East Mediterranean (EMRO) countries; 25.6% from Southeast Asian countries (SERO); and 12.4% from Europe. The frequency of simulation sessions was monthly (27.1%), weekly (24.8%), twice weekly (19.8%), or daily (21.5%). Among participants, 55.6% reported the team's full engagement in the simulation sessions. The average session length was 30–60 minutes. The most commonly reported debriefing leaders were ICU staff, simulation lab staff, and E.R. facilitators, and the least common were infection control staff. A total of 80% reported "a lot" to "a great improvement" in terms of clinical preparedness after simulation sessions, and 70% were satisfied with the COVID-19 simulation sessions and thought they were better than expected. Most of the perceived issues reported were related to infection control measures, followed by team dynamics, logistics, and patient transport issues. Conclusion: Simulation centers team leaders and HCWs reported positive feedback on COVID-19 simulation sessions. The presence of multiprofessional personnel during drills is warranted. These drills are a valuable tool for rehearsing safe dynamics of HCWs on the frontline of COVID-19.Trial registration: Not applicable.

Efficacy of Corticosteroids in COVID-19 Patients: A Systematic Review and Meta-Analysis (preprint)

BackgroundTo systematically review the literature about the effect of systemic corticosteroid therapy (CST) on outcomes of COVID-19 patients. MethodsWe searched Medline, Embase, EBM Reviews, Scopus, Web of Science, and preprints up to July 20, 2020. We included observational studies and randomized controlled trials (RCT) that assessed COVID-19 patients treated with CST. We pooled adjusted effect estimates of mortality and other outcomes using a random effect model, among studies at low or moderate risk for bias. We assessed the certainty of evidence for each outcome using the GRADE approach. ResultsOut of 1067 citations screened for eligibility, one RCT and 19 cohort studies were included (16,977 hospitalized patients). Ten studies (1 RCT and 9 cohorts) with 10,278 patients examined the effect of CST on short term mortality. The pooled adjusted RR was 0.92 (95% CI 0.69-1.22, I2=81.94 %). This effect was observed across all stages of disease severity. Four cohort studies examined the effect of CST on composite outcome of death, ICU admission and mechanical ventilation need. The pooled adjusted RR was 0.41(0.23-0.73, I2=78.69%). Six cohort studies examined the effect of CST on delayed viral clearance. The pooled adjusted RR was 1.47(95% CI 1.11-1.93, I2=43.38%). ConclusionHeterogeneous and low certainty cumulative evidence suggests that CST lacks efficacy in reducing short-term mortality while possibly delaying viral clearance in patients hospitalized with COVID-19. Because of the discordant results between the single RCT and observational studies, more research should continue to identify the clinical and biochemical characteristics of patients population that could benefit from CST.