The Saudi Critical Care Society Practice Guidelines on the Management of COVID-19 in the ICU: Therapy Section (preprint)

BackgroundThe rapid increase in coronavirus disease 2019 (COVID-19) cases during the subsequent waves in Saudi Arabia and other countries prompted the Saudi Critical Care Society (SCCS) to put together a panel of experts to issue evidence-based recommendations for the management of COVID-19 in the intensive care unit (ICU).MethodsThe SCCS COVID-19 panel included 51 experts with expertise in critical care, respirology, infectious disease, epidemiology, emergency medicine, clinical pharmacy, nursing, respiratory therapy, methodology, and health policy. All members completed an electronic conflict of interest disclosure form. The panel addressed 9 questions that are related to the therapy of COVID-19 in the ICU. We identified relevant systematic reviews and clinical trials, then used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach as well as the evidence-to-decision framework (EtD) to assess the quality of evidence and generate recommendations.ResultsThe SCCS COVID-19 panel issued 12 recommendations on pharmacotherapeutic interventions (immunomodulators, antiviral agents, and anticoagulants) for severe and critical COVID-19, of which 3 were strong recommendations and 9 were weak recommendations. ConclusionThe SCCS COVID-19 panel used the GRADE approach to formulate recommendations on therapy for COVID-19 in the ICU. The EtD framework allows adaptation of these recommendations in different contexts. The SCCS guideline committee will update recommendations as new evidence becomes available.

Combination of (Interferon beta-1b, Lopinavir-Ritonavir and Ribavirin) versus Favipiravir in Hospitalized Patients with Non-Critical COVID-19: A Cohort Study (preprint)

Objectives: Our study aims at comparing the efficacy and safety of INF-based therapy (lopinavir/ritonavir, ribavirin, and interferon β-1b) vs. favipiravir (FVP) in a cohort of hospitalized patients with non-critical COVID-19.Methods: Single center observational study comparing INF-based therapy (interferon β-1b, ribavirin, and lopinavir/ritonavir) vs. FVP in non-critical hospitalized COVID-19 patients. Allocation to either treatment group was non-random but based on changes to national treatment protocols rather than physicians’ selection (quasi-experimental). We examined the association between INF-based therapy and 28-day mortality using Cox regression model with treatment as a time-dependent covariate.Results: The study cohort included 222 patients, of whom 68 (28%) received IFN-based therapy. Antiviral therapy was started at a median of 5 days (3-6 days) from symptoms onset in the IFN group vs. 6 days (4-7 days) for the FVP group, P <0.0001. IFN-based therapy was associated with a lower 28-day mortality as compared to FVP (6 (9%) vs. 18 (12%)), adjusted hazard ratio [aHR] (95% Cl) = 0.22 (0.056-0.87)). No difference in hospitalization duration between the 2 groups, 9 (7-14) days vs. 9 (7-13) days, P=0.732 was found. IFN treated group required less use of systemic corticosteroids (57%) as compared to FVP (77%), P=0.023 after adjusting for disease severity and other confounders. Patients in the IFN treated group were more likely to have nausea and diarrhea as compared to FVP group (13%) vs. (3%), P=0.013 and (18%) vs. (3%), P<0.0001, respectively.Conclusion: Early INF-based triple therapy was associated with lower 28-days mortality and less need for systemic corticosteroids as compared to FVP in non-critical hospitalized COVID-19 patients.Funding Statement: None.Declaration of Interests: None.Ethics Approval Statement: KFMC Institutional Review Board (IRB) approved the study and waived the need for informed consent.

Elevated Expression Levels of Lung Complement Anaphylatoxin, Neutrophil Chemoattractant Chemokine IL-8, and RANTES in MERS-CoV-Infected Patients: Predictive Biomarkers for Disease Severity and Mortality (preprint)

The complement system represents an innate immune response consisting of a protein network. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement‐modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including Seven complement proteins including complement regulatory factors during MERS-CoV infection. We also measured the expression of lung neutrophil chemoattractant chemokine IL-8 (CXCL8) and RANTES (CCL5). Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a and C3a, was positively correlated with IL-8, RANTES and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P (properdin), suggesting positive regulation of the complement during MERS-CoV infection. In addition, we also demonstrated that a high viral load in all patients with MERS-CoV correlated with C5a and C3a levels. Pulmonary complement mediators, disease severity, and an increased fatality rate may be linked to the degree of complement activation against MERS-CoV. High levels of lung C5a, C3a, factor P, IL-8 and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8 and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the functional partners (protiens) prediction of highly expressed proteins (C5a, C3a, factor P, IL-8 and RANTES), the computational protein–protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.  

Severity of COVID-19 Infection in ACEI/ARB Users in Two Saudi Public Specialty Hospitals: Retrospective Cohort Study (preprint)

Background: The uncertainty about COVID-19 outcomes in angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) users continues with contradictory findings. The aim of this study was to determine the effect of ACEI/ARB use in patients with severe COVID-19. Methods: This retrospective cohort study was done in two Saudi public specialty hospitals designated as COVID-19 referral facilities. We included 354 patients with confirmed diagnosis of COVID-19 between April and June 2020, of which 146 were ACEI/ARB users and 208 were non-ACEI/ARB users. Controlling for confounders, we conducted a multivariate logistic regression and a sensitivity analyses using propensity score matching (PSM) and Inverse propensity score weighting (IPSW) for high risk patient subsets. Results: Compared to non-ACEI/ARB users, ACEI/ARB users had an eight-fold higher risk of developing critical or severe COVID-19 (OR=8.25, 95%CI=3.32-20.53); a nearly 7-fold higher risk of intensive care unit (ICU) admission (OR=6.76, 95%CI=2.88-15.89) and a nearly 5-fold higher risk of requiring noninvasive ventilation (OR=4.77,95%CI=2.15-10.55). Patients with diabetes, hypertension, and/or renal disease had a five-fold higher risk of severe COVID-19 disease (OR=5.40,95%CI=2.0-14.54]. These results were confirmed in the PSM and IPSW analyses. Conclusion: In general, but especially among patients with hypertension, diabetes, and/or renal disease, ACEI/ARB use is associated with a significantly higher risk of severe or critical COVID-19 disease, and ICU care.

Severity of COVID-19 Infection in ACEI/ARB Users in Two Saudi Public Specialty Hospitals; Retrospective Cohort Study (preprint)

The uncertainty about COVID-19 outcomes in angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) users continues with contradictory findings. The aim of this study was to determine the effect of ACEI/ARB use in patients with severe COVID-19. This retrospective cohort study done in two Saudi public specialty hospitals designated as COVID-19 referral facilities. We included 354 patients with confirmed diagnosis of COVID-19 between April and June 2020, of which 146 were ACEI/ARB users and 208 were non-ACEI/ARB users. Controlling for confounders, we conducted a multivariate logistic regression and a sensitivity analysis using propensity score matched (PSM) patients. Compared to non-ACEI/ARB users, ACEI/ARB users had an eight-fold higher risk of developing critical or severe COVID-19 (OR=8.25, 95%CI=3.32-20.53); a nearly 7-fold higher risk of intensive care unit (ICU) admission (OR=6.76, 95%CI=2.88-15.89) and a nearly 5-fold higher risk of requiring noninvasive ventilation (OR=4.77,95%CI=2.15-10.55). Patients with diabetes, hypertension, and/or renal disease had a five-fold higher risk of severe COVID-19 disease (OR=5.40,95%CI=2.0-14.54]. These results were confirmed in the PSM analysis. In general, but especially among patients with hypertension, diabetes, and/or renal disease, ACEI/ARB use is associated with a significantly higher risk of severe or critical COVID-19 disease, and ICU care.

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.