Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease.

Favipiravir has antiviral activity against influenza, West Nile virus, and yellow fever virus and against flaviviruses. The objective of this pilot study was to compare three arms: favipiravir; hydroxychloroquine; standard care (no specific SARS-CoV-2 treatment) only, in symptomatic patients infected by SARS-CoV-2 in an open-labelled randomized clinical trial. The trial was registered with Bahrain National Taskforce for Combatting COVID-19 on the 7th of May 2020 (registration code: NCT04387760). 150 symptomatic patients with COVID-19 disease were randomized into one of three arms: favipiravir, hydroxychloroquine, or standard care only. The primary outcome was the clinical scale at the end of study follow up (day 14 or on discharge/death) based on a points scale. The secondary outcomes were viral clearance, biochemical parameter changes and mortality at 30-days. Baseline characteristics did not differ between groups. The proportion of patients who achieved a clinical scale < 2 did not differ between groups. The favipiravir-treated and hydroxychloroquine-treated group showed increased viral clearance (OR, 95%CI 2.38, 0.83-6.78, OR, 95%CI 2.15, 0.78-5.92, respectively) compared to standard care, but this was not significant. The biochemical profile did not differ between groups, except for the platelet count (P < 0.03) and uric acid (P < 0.004) that were higher with favipiravir-treatment. Primary or secondary outcome measures did not differ between favipiravir, hydroxychloroquine, and standard therapy for mild to moderate COVID-19 disease; therefore, whilst favipiravir therapy appeared safe with a trend to increased viral clearance, there was no superior therapeutic utility.Clinical trials registration. NCT04387760. Registration date: 07/05/2020.

Evaluation of Rapid Antigen Tests Using Nasal Samples to Diagnose SARS-CoV-2 in Symptomatic Patients.

INTRODUCTION: The best way to mitigate an outbreak besides mass vaccination is via early detection and isolation of infected cases. As such, a rapid, cost-effective test for the early detection of COVID-19 is required. METHODS: The study included 4,183 mildly symptomatic patients. A nasal and nasopharyngeal sample obtained from each patient was analyzed to determine the diagnostic ability of the rapid antigen detection test (RADT, nasal swab) in comparison with the current gold-standard (RT-PCR, nasopharyngeal swab). RESULTS: The calculated sensitivity and specificity of the RADT was 82.1 and 99.1%, respectively. Kappa's coefficient of agreement between the RADT and RT-PCR was 0.859 (p < 0.001). Stratified analysis showed that the sensitivity of the RADT improved significantly when lowering the cut-off RT-PCR Ct value to 24. CONCLUSION: Our study's results support the potential use of nasal swab RADT as a screening tool in mildly symptomatic patients, especially in patients with higher viral loads.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Influence of COVID-19 Pandemic on Cardiac Services in Bahrain: Building Cardiovascular Protocol for Future Pandemics.

BACKGROUND: There are different protocols initiated to maintain the workflow in cardiovascular units around the world. Variable responses were seen in different populations. We adapted certain protocols during coronavirus disease-2019 (COVID-19) pandemic because we want to know the key element that maintains an acceptable standard of cardiovascular care during future pandemics. METHODS: Four hundred and fifty-four cardiac patients were admitted during COVID-19 era. Patients from March to July 2020 were included in this study. Those patients were divided into two periods: strict-COVID-19 from March 19, 2020, to May 18, 2020 (132 patients) and mid-COVID-19 from May 19, 2020, to July 18, 2020 (322 patients). These were compared to admissions at the pre-COVID-19 era from January 19, 2020, to March 18, 2020 (600 patients). All patients' data were collected through the quality department from the electronic medical records. RESULTS: Throughout the COVID-19 pandemic, the admission number and ST-elevation myocardial infarction (STEMI) cases were dramatically reduced during the strict-COVID-19 time yet recovered back in the mid-COVID-19 period. The admission rate was reduced from 600 to 132, while the STEMI cases dropped from 91 in pre-COVID-19 to 41 in strict-COVID-19 and then back to 81 cases in mid-COVID 19 period (P > 0.05/P = 0.02 between pre and mid-COVID-19 periods). CONCLUSION: Our cardiac center continues to serve our population without a complete lockdown period due to multiple key elements adapted during this pandemic. The flexibility in the protocols of managing acute cardiac cases has maintained the mortality rate stable through all COVID-19 periods and return to working efficiently to near-normal levels.

Is glucose-6-phosphatase dehydrogenase deficiency associated with severe outcomes in hospitalized COVID-19 patients?

Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is known to suppress the antioxidant system and is likely to aggravate severity of COVID-19, which results in a pro-oxidant response. This possible association has not been explored adequately in human studies. In this research, we report that the occurrence of non-invasive ventilation, intubation or death-all of which are indicative of severe COVID-19, are not significantly different in hospitalized COVID-19 patients with and without G6PDd (4.6 vs. 6.4%, p = 0.33). The likelihood of developing any of these severe outcomes were slightly lower in patients with G6PDd after accounting for age, nationality, presence of comorbidities and drug interventions (Odds ratio 0.40, 95% confidence intervals 0.142, 1.148). Further investigation that extends to both, hospitalized and non-hospitalized COVID-19 patients, is warranted to study this potential association.

Association between RT-PCR Ct values and COVID-19 new daily cases: a multicenter cross-sectional study.

Proactive prediction of the epidemiologic dynamics of viral diseases and outbreaks of the type of COVID-19 has remained a difficult pursuit for scientists, public health researchers, and policymakers. It is unclear whether RT-PCR Cycle Threshold (Ct) values of COVID-19 - or any other virus - as indicator of viral load, could represent a possible predictor for underlying epidemiologic changes on a population level. The study objective is thus to investigate whether population-wide changes in SARS-CoV-2 RT-PCR Ct values over time are associated with the daily fraction of positive COVID-19 tests. In addition, this study analyses the factors that could influence RT-PCR Ct values. A retrospective cross-sectional study was conducted on 63,879 patients from May 4, 2020 to September 30, 2020, in all COVID-19 facilities in the Kingdom of Bahrain. Data collected included number of tests and newly diagnosed cases, as well as Ct values, age, sex nationality, and symptomatic status. Ct values were found to be negatively and very weakly correlated with the fraction of daily positive tests in the population r = -0.06 (CI 95%: -0.06; -0.05; p=0.001). The R-squared for the regression model (adjusting for age and number of daily tests) showed an accuracy of 45.3%. Ct Values showed an association with nationality (p=0.012). After the stratification, the association between Ct values and the fraction of daily positive cases was only maintained for the female sex and Bahraini-nationality. Symptomatic presentation was significantly associated with lower Ct values (higher viral loads). Ct values do not show any correlation with age (p=0.333) or sex (p=0.522). We report one of the first and largest studies to investigate the epidemiologic associations of Ct values with COVID-19. Although changes in Ct values showed a moderate association with daily cases, our results indicate that it may not be as predictive within a simple model. More population studies and models from global cohorts are necessary.

Is Atrial Fibrillation a Risk Factor for Worse Outcomes in Severe COVID-19 Patients: A Single Center Retrospective Cohort.

INTRODUCTION: New onset atrial fibrillation leads to worse outcomes in patients with sepsis. The association between new onset atrial fibrillation (AF) in COVID19 patients with COVID19 outcomes are lacking. This study aims to determine whether new onset atrial fibrillation in COVID19 patients admitted in the ICU is a risk factor for death or requirement of mechanical ventilation (MV). METHODS: This is a retrospective study conducted in a cohort of COVID-19 patients admitted to Bahrain Defence Force COVID19 Field ICU between April 2020 to November 2020. Data were extracted from the electronic medical records. The patients who developed new onset AF during admission were compared to patients who remained in sinus rhythm. Multivariate logistic regression models were used to control for confounders and estimate the effect of AF on the outcomes of these patients. RESULTS: Our study included a total of 492 patients out of which 30 were diagnosed with new onset AF. In the AF group, the primary outcome occurred in 66.7% of patients (n = 20). In the control group, 17.1% (n = 79) developed the primary outcome. Upon adjusting for the confounders in the multivariate regression model, AF had an odds ratio of 3.96 (95% CI: 1.05-14.98; p = 0.042) for the primary outcome. CONCLUSION: Our results indicate that new onset AF is a risk factor for worse outcomes in patients admitted with COVID19 in the ICU.

COVID-19 viral load not associated with disease severity: findings from a retrospective cohort study.

BACKGROUND: Being able to use COVID-19 RT-PCR Ct values as simple clinical markers of disease outcome or prognosis would allow for the easy and proactive identification and triaging of high-risk cases. This study's objective was thus to explore whether a correlation exists between COVID-19 viral loads, as indicated by RT-PCR Ct values, and disease severity, as indicated by respiratory indices. RESULTS: A multi-centre cross-sectional retrospective study was conducted, using data obtained from Bahrain's National COVID-19 Task force's centralised database. The study period ranged from May 2, 2020 to July 31, 2020. A multivariable logistic regression was used to assess for a correlation using data from a total of 1057 admitted COVID-19 cases. The covariates adjusted for included sex, age, presentation, and comorbidities. In our cohort, Ct value showed no statistical significance for an association with requirement for oxygenation on admission (Odds ratio 1.046; 95%CI 0.999 to 1.096, p = 0.054). CONCLUSION: Viral load, as indicated by Ct values, did not seem to be associated with requirement for oxygenation on admission in our cohort. We postulate however that time since onset of symptom may have acted as an unaccounted-for confounder. As such, RT-PCR Ct values may not be a useful prognostic clinical tool in isolation.

Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.

Convalescent plasma (CP) therapy in COVID-19 disease may improve clinical outcome in severe disease. This pilot study was undertaken to inform feasibility and safety of further definitive studies. This was a prospective, interventional and randomized open label pilot trial in patients with severe COVID-19. Twenty COVID-19 patients received two 200 ml transfusions of convalescent patient CP over 24-h compared with 20 who received standard of care. The primary outcome was the requirement for ventilation (non-invasive or mechanical ventilation). The secondary outcomes were biochemical parameters and mortality at 28 days. The CP group were a higher risk group with higher ferritin levels (p < 0.05) though respiratory indices did not differ. The primary outcome measure was required in 6 controls and 4 patients on CP (risk ratio 0.67, 95% CI 0.22-2.0, p = 0.72); mean time on ventilation (NIV or MV) did not differ. There were no differences in secondary measures at the end of the study. Two patients died in the control and one patient in the CP arm. There were no significant differences in the primary or secondary outcome measures between CP and standard therapy, although a larger definitive study is needed for confirmation. However, the study did show that CP therapy appears to be safe in hospitalized COVID-19 patients with hypoxia.Clinical trials registration NCT04356534: 22/04/2020.

Time Till Viral Clearance of Severe Acute Respiratory Syndrome Coronavirus 2 Is Similar for Asymptomatic and Non-critically Symptomatic Individuals.

Despite the modeled estimations of the burden of asymptomatic spread, the duration of viral positivity and infectiousness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains understudied. The objective of the present study was to estimate and compare the time till viral clearance of SARS-CoV-2 in asymptomatic and non-critical symptomatic individuals. We studied 184 SARS-CoV-2-positive participants, of whom 145 were asymptomatic. Our analysis uncovered that time till viral negativity is similar for subclinical [median time till viral clearance: 11 days, interquartile range (IQR): 8, 14] and overt infections (median: 11 days, IQR: 9, 14) after controlling for age and sex. This has implications in understanding the period of infectivity for SARS-CoV-2 in order to plan adequate public health measures to control the community spread.

Is sickle cell disease a risk factor for severe COVID-19 outcomes in hospitalized patients? A multicenter national retrospective cohort study.

Introduction: Studies that examine the association between sickle cell disease (SCD) and COVID-19 outcomes are lacking. This study aims to determine whether SCD is a risk factor for severe COVID-19 infection in regard to the requirement of noninvasive ventilation/high flow nasal cannula (NIV/HFNC), mechanical ventilation (MV), or death in hospitalized patients. Methods: Retrospective cohort study included COVID-19 patients admitted to four COVID-19 treatment facilities in Bahrain between February 24, 2020 and July 31, 2020. All SCD patients with COVID-19 were included and compared to a randomly selected sample of non-SCD patients with COVID-19. Data were collected from the medical records. Multivariate logistic regression models were used to control for confounders and estimate the effect of SCD on the outcomes. Results: 1792 patients with COVID-19 were included; 38 of whom were diagnosed with SCD as well. In the SCD group, one (2.6%) patient required NIV/HFNC, one (2.6%) required MV, and one (2.6%) death occurred. In comparison, 56 (3.2%) of the non-SCD patients required NIV/HFNC, 47 (2.7%) required MV, and death occurred in 58 (3.3%) patients. Upon adjusting for confounders, SCD had an odds ratio of 1.847 (95% CI: 0.39-8.83; p = 0.442). Conclusion: Our results indicate that SCD is not a risk factor for worse COVID-19 outcomes in hospitalized patients.

The effect of ABO blood group and antibody class on the risk of COVID-19 infection and severity of clinical outcomes.

The COVID-19 pandemic has affected more than 100 million cases and caused immense burdens on governments and healthcare systems worldwide. Since its emergence in December 2019, research has been focused on treating the infected, identifying those at risk and preventing spread. There is currently no known biological biomarker that predicts the risk of infection. Several studies emerged suggesting an association between ABO blood group and the risk of COVID-19 infection. In this study, we used retrospective observational data in Bahrain to investigate the association between ABO blood group and risk of infection, as well as susceptibility to severe ICU-requiring infection. We found a higher risk associated with blood group B, and a lower risk with blood group AB. No association was observed between blood group and the risk of a severe ICU-requiring infection. We extended the analysis to study the association by antibodies; anti-a (blood groups B and O) and anti-b (blood groups A and O). No association between antibodies and both risk of infection or susceptibility to severe infection was found. The current study, along with the variation in blood group association results, indicates that blood group may not be an ideal biomarker to predict risk of COVID-19 infection.

The high prevalence of asymptomatic SARS-CoV-2 infection reveals the silent spread of COVID-19.

PURPOSE: The COVID-19 pandemic has led to over 92 million cases and 1.9 million deaths worldwide since its outbreak. Public health responses have focused on identifying symptomatic individuals to halt spread. However, evidence is accruing that asymptomatic individuals are infectious and contributing to this global pandemic. METHODS: Observational data of 320 index cases and their 1289 positive contacts from the National COVID-19 Database in Bahrain were used to analyze symptoms, infectivity rate and PCR Cycle threshold (Ct) values. RESULTS: No significant difference (p = 1.0) in proportions of symptomatic (n = 160; 50.0%) and asymptomatic index cases (n = 160; 50.0%) were seen; however, SARS-CoV-2 positive contact cases were predominantly asymptomatic (n = 1127, 87.4%). Individuals aged 0-19 years constituted a larger proportion of positive contact cases (20.8%) than index cases (4.7%; p < 0.001). A total of 22% of the positive contacts were infected by symptomatic male index cases aged between 30-39 years. The total numbers of exposed contacts (p = 0.33), infected contacts (p = 0.81) and hence infectivity rate (p = 0.72) were not different between symptomatic and asymptomatic index cases. PCR Ct values were higher in asymptomatic compared to symptomatic index cases (p < 0.001), and higher in asymptomatic compared to symptomatic positive contacts (p < 0.001). No differences between the infectivity rates of index cases with Ct values <30 and values ≥30 were observed (p = 0.13). CONCLUSION: These data reveal that the high asymptomatic incidence of SARS-CoV-2 infection in Bahrain and subsequent positive contacts from an index case were more likely to be asymptomatic, showing the high "silent" risk of transmission and need for comprehensive screening for each positive infection to help halt the ongoing pandemic.

The prevalence of asymptomatic and symptomatic COVID-19 in a cohort of quarantined subjects.

BACKGROUND: The frequency of asymptomatic SARS-CoV-2 infection with viral spread is unclear. Asymptomatic SARS-CoV-2 infection development and progression was investigated in subjects undergoing mandatory quarantine on airport arrival. METHODS: 2714 subjects were tested for SARS-CoV-2 and all were quarantined for 2 weeks. Viral retesting was undertaken on symptom development and routinely at 14 days if asymptomatic. Asymptomatic, positive patients underwent viral testing every 2 days to determine viral clearance. RESULTS: 188/2714 (6.9%) patients became SARS-CoV-2 positive. On arrival, 136/188 tested positive, with 44/188 (23.4%) symptomatic and 92/188 (48.9%) asymptomatic. All 92 patients remained asymptomatic and were retested every 2 days until viral clearance. 2526 quarantined subjects remained virus free at 14 days. Viral clearance did not differ between symptomatic and asymptomatic patients (12.6 ± 1.0 days and 12.1 ± 0.4 days, respectively). Of the 52/188 (27.7%) testing negative on arrival, 27/52 subsequently became positive and developed symptoms 2-13 days after arrival. 25/188 (13.3%) remained asymptomatic and tested positive at day 14, with viral testing undertaken every 2 days in these subjects; of these, 24 remained asymptomatic, with viral clearance at 9.4 ± 0.7 days - less than for those who were asymptomatic on arrival (p < 0.002). CONCLUSION: Asymptomatic patients with COVID-19 were more prevalent than those exhibiting symptoms, and are an infection reservoir.

The Efficacy and Safety of Hydroxychloroquine in Patients with COVID-19: A Multicenter National Retrospective Cohort.

INTRODUCTION: Hydroxychloroquine (HCQ) is an antimalarial drug that received worldwide news and media attention in the treatment of patients with coronavirus disease 2019 (COVID-19). This drug was used on the basis of its antimicrobial and antiviral properties despite lack of definite evidence of clinical efficacy. In this study, we aim to assess the efficacy and safety of using HCQ in treatment of patients with COVID-19 who were admitted in acute care hospitals in Bahrain. METHODS: We conducted a retrospective cohort study on a random sample of patients admitted with COVID-19 between 24 February and 31 July 2020. The study was conducted in four acute care COVID-19 hospitals in Bahrain. Data was extracted from the medical records. The primary endpoint was the requirement of non-invasive ventilation, intubation, or death. Secondary endpoint was length of hospitalization for survivors. Three methods of analysis were used to control for confounding factors: logistic multivariate regression, propensity score adjusted regression, and matched propensity score analysis. RESULTS: A random sample of 1571 patients were included, 440 of whom received HCQ (treatment group) and 1131 did not receive it (control group). Our results showed that HCQ did not have a significant effect on primary outcomes due to COVID-19 infection when compared to controls after adjusting for confounders (OR 1.43, 95% CI 0.85-2.37, P = 0.17). Co-administration of azithromycin had no effect on primary outcomes (OR 2.7, 95% CI 0.82-8.85, P = 0.10). HCQ was associated with increased risk of hypoglycemia (OR 10.9, 95% CI 1.72-69.49, P = 0.011) and diarrhea (OR 2.8, 95% CI 1.4-5.5, P = 0.003), but not QT prolongation (OR 1.92, 95% CI 0.95-3.9, P = 0.06) or cardiac arrhythmia (OR 1.06, 95% CI 0.55-2.05, P = 0.85). CONCLUSION: Our results showed no significant beneficial effect of using hydroxychloroquine on the outcome of patients with COVID-19. Moreover, the risk of hypoglycemia due to hydroxychloroquine would possess a significant risk for out-of-hospital use.

Quarantining arriving travelers in the era of COVID-19: balancing the risk and benefits a learning experience from Bahrain.

The quarantine period imposed to travelers in many countries due to COVID19 is a major obstacle for any traveler. Lifting the quarantine period could lead to significant improvement in people's quality of life and any country's economy. Bahrain have used two quarantine models from arriving passengers. We report data about the incidence of COVID19 on arriving passengers at Bahrain International airport. Infection rates were reported on arrival, during quarantine and after leaving quarantine. Results showed that travelers had low incidence of COVID19 on arriving and during the quarantine period, while becoming at higher risk after leaving quarantine. We concluded that quarantine requirement maybe lifted for arriving travelers. Testing upon arrival with implementation of the public health preventative measures can minimize the risk of transmission.

COVID-19 and sickle cell disease in Bahrain.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is caused by a newly identified strain of the coronavirus family that has been shown to affect the hemoglobin beta chain, the same chain that has sickle cell disease (SCD) mutation. This study was undertaken to see if COVID-19 infection increased disease severity in patients with SCD. METHODS: Mass screening of the Bahraini population was undertaken between February and April 2020. RESULTS: A total of 38,092 Bahraini people were tested for COVID-19 during this period; 378 (1%) were SCD patients. Six patients with SCD had COVID-19 (1.6%): three remained asymptomatic, two had mild symptoms and one required oxygen therapy. The SCD patients had a similar average length of stay when compared with non-SCD COVID-19 patients (10.7 days). CONCLUSION: The infection rate, clinical course and viral clearance seen for the SCD patients with COVID-19 were no different to those without SCD.