Previous SARS-CoV-2 infection or a third dose of vaccine elicited cross-variant neutralizing antibodies in vaccinated solid organ transplant recipients (preprint)

The SARS-CoV-2 pandemic poses a great threat to global health, particularly in solid organ transplant recipients (SOTRs). Although a 3-dose mRNA vaccination protocol has been implemented for the majority of SOTRs, its effectiveness was still largely unknown. We analyzed 113 vaccinated SOTRs, and 30 healthy controls (HCs), some of whom had recovered from COVID, for their immune responses against the original vaccine strain and variants of concern (VOC), including the highly mutated-omicron variant. Here, we report that 3 doses of the mRNA vaccine had only a modest effect in eliciting anti-viral responses against all viral strains in the fully vaccinated SOTRs who did not contract the virus. Only 34.0% (16/47) of this group of patients demonstrated both detectable anti-RBD IgG and neutralization activities against alpha, beta, and delta variants, and only 8.5% (4/47) of them showed additional omicron-neutralizing capacities. In contrast, 79.5% (35/44) of the vaccinated recovered-SOTRs demonstrated both higher anti-RBD IgG levels and neutralizing activities against all VOC, including omicron. These findings illustrate a significant impact of previous infection on the development of anti-COVID immune responses in vaccinated SOTRs and highlight the need for alternative strategies to protect a subset of a lesser-vaccine responsive population.

COVID-19 ICU and Mechanical Ventilation Patient Characteristics and Outcomes - A Systematic Review and Meta-analysis (preprint)

Background To characterize COVID-19 ICU admissions, their outcome and associated features, as well as identify their regional discrepancies. Methods Scopus, Embase, preprint servers bioRvix and medRvix and the Intensive Care National Audit and Research Center (ICNARC) website was searched for reports through May 1st 2020  on COVID-19 ICU admissions and outcomes using pre-defined search terms and eligibility criteria.Relevant data was extracted and pooled using fixed or random effects meta-analysis depending on heterogeneity. Study quality was assessed by the NIH tool and heterogeneity was assessed by I2 and Q tests. Baseline patient characteristics, ICU and IMV outcomes were pooled and meta-analyzed. Pooled odds ratios (pOR) were calculated for clinical features against ICU, MV mortality. Subgroup analysis was carried out based on patient regions.Results Twenty-eight studies comprising 12,437 COVID-19 ICU admissions from seven countries were meta-analyzed. Pooled ICU admission rate was 21%[95% CI 0.12 to 0.34] and 69% of cases needed IMV[95% CI 0.61-0.75]. ICU and IMV mortality were 28.3%[95% CI 0.25 to 0.32], 43%[95% CI 0.29 to 0.58] and ICU, IMV duration was 7.78[95% CI 6.99 to 8.63] and 10.12[95% CI 7.08 to 13.16] days respectively. Besides confirming the significance of comorbidities and clinical findings of COVID-19, major correlates with ICU mortality were found to be IMV [pOR 16.46, 95% CI 4.37 to 61.96], acute kidney injury (AKI) [pOR 12.47, 95% CI 1.52 to 102.7], and acute respiratory distress syndrome (ARDS) [pOR 6.52, 95% CI 2.66 to 16.01]. Subgroup analyses confirm significant regional discrepancies in outcomes.Conclusions This is the most comprehensive systematic review and meta-analysis of COVID-19 ICU and IMV cases and associated outcomes to date and the only analysis to analyze and associate IMV with COVID-19 ICU mortality. The significant association of AKI, ARDS and IMV with mortality has implications for ICU resource planning for AKI and ARDS as well as research into optimal ventilation strategies for patients. Regional differences in outcome implies a need to develop region specific protocols for ventilatory support as well as overall treatment.Study Registration PROSPERO registration number CRD42020182482.

COVID-19 ICU and mechanical ventilation patient characteristics and outcomes - A systematic review and meta-analysis (preprint)

BackgroundInsight into COVID-19 intensive care unit (ICU) patient characteristics, rates and risks of invasive mechanical ventilation (IMV) and associated outcomes as well as any regional discrepancies is critical in this pandemic for individual case management and overall resource planning. Methods and FindingsElectronic searches were performed for reports through May 1 2020 and reports on COVID-19 ICU admissions and outcomes were included using predefined search terms. Relevant data was subsequently extracted and pooled using fixed or random effects meta-analysis depending on heterogeneity. Study quality was assessed by the NIH tool and heterogeneity was assessed by I2 and Q tests. Baseline patient characteristics, ICU and IMV outcomes were pooled and meta-analyzed. Pooled odds ratios (pOR) were calculated for clinical features against ICU, IMV mortality. Subgroup analysis was carried out based on patient regions. A total of twenty-eight studies comprising 12,437 COVID-19 ICU admissions from seven countries were meta-analyzed. Pooled ICU admission rate was 21% [95% CI 0.12-0.34] and 69% of cases needed IMV [95% CI 0.61-0.75]. ICU and IMV mortality were 28.3% [95% CI 0.25-0.32], 43% [95% CI 0.29-0.58] and ICU, IMV duration was 7.78 [95% CI 6.99-8.63] and 10.12 [95% CI 7.08-13.16] days respectively. Besides confirming the significance of comorbidities and clinical findings of COVID-19 previously reported, we found the major correlates with ICU mortality were IMV [pOR 16.46, 95% CI 4.37-61.96], acute kidney injury (AKI) [pOR 12.47, 95% CI 1.52-102.7], and acute respiratory distress syndrome (ARDS) [pOR 6.52, 95% CI 2.66-16.01]. Subgroup analyses confirm significant regional discrepancies in outcomes. ConclusionsThis is the most comprehensive systematic review and meta-analysis of COVID-19 ICU and IMV cases and associated outcomes to date and the only analysis to implicate IMVs associtaion with COVID-19 ICU mortality. The significant association of AKI, ARDS and IMV with mortality has implications for ICU resource planning for AKI and ARDS as well as research into optimal ventilation strategies for patients. Regional differences in outcome implies a need to develop region specific protocols for ventilatory support as well as overall treatment.

Repositioned chloroquine and hydroxychloroquine as antiviral prophylaxis for COVID-19: A protocol for rapid systematic review of randomized controlled trials (preprint)

Since the SARS-CoV-2 outbreak rapidly evolved into a pandemic, there is an urgent need for rapid development, identification and confirmation of efficacious antiviral prophylaxis. In this setting, the existing drugs chloroquine (CQ) and hydroxychloroquine (HCQ) which has suggestive evidence of efficacy against SARS-CoV-2 infection and COVID-19 disease has become prime candidates to be repositioned as therapeutic and preventative agents, and a growing number of clinical trials have been registered to study their preventative potential for at-risk populations using a range of dosing schemes and outcome measures. This rapid systematic review protocol aims to provide streamlined and timely synthesis on methodologies and results of randomized controlled trials assessing the efficacy of CQ and HCQ in hopes that this will constructively inform further research as well as public health policy.

Repositioning Chloroquine as Ideal Antiviral Prophylactic against COVID-19 - Time is Now (preprint)

The novel coronavirus 2019 (COVID-19) pandemic is rapidly advancing despite public health measures. Pharmaceutical prophylaxis is an established approach to potentially control infectious diseases and is one solution to the urgent public health challenge posed by COVID-19. Screening and development of new vaccines and antivirals is expensive and time consuming while the repositioning of available drugs should receive priority attention as well as international government and agency support. Here we propose an old drug chloroquine (CQ) to be urgently repositioned as an ideal antiviral prophylactic against COVID-19. CQ has ability to block viral attachment and entry to host cells. Its proven clinical efficacy against a variety of viruses including COVID-19 and its current deployment in COVID-19 therapeutic trials strengthens its potential candidacy as a prophylactic. Furthermore, CQ has a long safety record, is inexpensive and widely available. Here we reviewed CQ's antiviral mechanisms, its laboratory efficacy activity against COVID-19, as well as CQ's pharmacokinetics in its established use against malaria and autoimmune diseases to recommend safe and potentially efficacious dose regimens for protection against COVID-19: a pre-exposure prophylaxis of 250-500mg daily and post-exposure prophylaxis at 8mg/kg/day for 3 days. We recommend further urgent research on CQ for COVID-19 prevention and urge that the above regimens be investigated in parallel with mass deployment by relevant agencies in attempts to contain the pandemic without unnecessary regulatory delays as benefits far outweigh risks or costs.