Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated Acute Kidney Injury.

Introduction: Neutrophil extracellular traps (NETs) release (i.e., NETosis) has been recently implicated in the pathomechanism underlying severe end-organ damage in Coronavirus Disease 2019 (COVID-19) and could present a novel therapeutic target. We aimed to determine whether circulating levels of cell-free DNA (cfDNA), a surrogate for NETosis, may be associated with the development of acute kidney injury (AKI), a major contributor to poor outcomes and mortality in COVID-19. Methods: Blood samples were collected prospectively from adult patients infected with SARS-CoV-2 presenting to the emergency department (ED). Circulating levels of cfDNA were quantified from patients' serum. Further assessment of correlations between cfDNA levels and markers of AKI (i.e., serum creatinine (SCr), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)), biomarkers of thrombotic microangiopathy and of inflammation in patients' serum was performed. Results: Fifty-one COVID-19 patients were enrolled. cfDNA levels were found to be significantly higher in those who developed severe AKI (p < 0.001) and those needing renal replacement therapy (p = 0.020). cfDNA positively correlated with ED SCr, NGAL, cystatin C, neutrophil count, neutrophil-to-lymphocyte ratio, C3a, C5a, Scb5-9, IL-6, IL-8, IL-10, TNF-α, LDH, CRP, ferritin, and fibrinogen and negatively correlated with ADAMTS13/von-Willebrand factor ratio and lymphocyte count. In a multivariate logistic regression, a one-unit increase in cfDNA value was associated with 4.6% increased odds of severe AKI (OR = 1.046; p = 0.040). Finally, cfDNA significantly correlated with established NETs components, myeloperoxidase, and neutrophil elastase. Conclusion: Intravascular NETosis could be an important contributing factor in the development of microthrombosis and COVID-19-associated AKI. Further research is urgently needed to understand the role of NETosis in COVID-19 and evaluate therapeutic avenues for targeting this process.

Tocilizumab in addition to standard of care in the management of COVID-19: a meta-analysis of RCTs.

OBJECTIVE: We performed a systematic review and meta-analysis for exploring clinical benefits and safety of tocilizumab in addition to standard of care (SOC) in treating patients with coronavirus disease 2019 (COVID-19). METHODS: An electronic search was carried out in PubMed, EMBASE, Cochrane Library, and Science Direct, as well as in medRxiv preprint server, to identify eligible studies. Only randomized Controlled Trials (RCTs) that compared mortality events and/or adverse events between a tocilizumab + SOC group and a SOC-only control group were included. The primary outcome was 28-day mortality. Secondary outcomes include progression to severe disease, defined as need for mechanical ventilation (MV) or intensive care unit (ICU) admission, and adverse events (AE). RESULTS: A total of nine studies (6,490 participants) could be included in this meta-analysis, with 3,358 participants in the tocilizumab + SOC group and 3,132 participants in the SOC-only group. The overall mortality rate was lower in the tocilizumab group compared to the SOC-only group, though the difference was not statistically significant (odds ratio [OR], 0.87; 95% CI, 0.73-1.04; I2, 15%). This finding was unaffected by subgroup analyses based on initial use of steroids or mechanical ventilation at baseline. Patients receiving tocilizumab were 26% less likely to progress to MV, and this difference was statistically significant (OR, 0.74; 95% CI, 0.64-0.86; I2, 0%). Among patients who were not in ICU at randomization, the tocilizumab group had 34 % lower rate of ICU admission compared to the SOC-only group (OR, 0.66; 95% CI, 0.40-2.14; I2, 29%). The occurrence of serious infections was lower in the tocilizumab group (OR, 0.57; 95% CI, 0.36-0.89; I2, 21%). CONCLUSION: Tocilizumab is generally well-tolerated in COVID-19. Although this drug does not appear to have a significant benefits on survival, it may have a role in preventing progression to intensive care and MV.

Early prediction of COVID-19-associated acute kidney injury: Are serum NGAL and serum Cystatin C levels better than serum creatinine?

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with a high risk of acute kidney injury (AKI), often requiring renal replacement therapy (RRT). Serum Cystatin C (sCysC) and serum Neutrophil Gelatinase-Associated Lipocalin (sNGAL) are emerging biomarkers for kidney injury, and were suggested to be superior to serum creatinine (sCr) in several clinical settings. Moreover, elevated sCysC is associated with disease severity and mortality in COVID-19. We aimed to assess the utility of sCysC and sNGAL for predicting COVID-19-associated AKI, need for RRT, and need for intensive care unit (ICU) admission, when measured at presentation to the emergency department (ED). METHODS: Patients presenting to the ED with laboratory-confirmed COVID-19 were included. The primary outcome was development of COVID-19-associated AKI, while the secondary outcomes were need for RRT and ICU admission. RESULTS: Among 52 COVID-19 patients, 22 (42.3%) developed AKI with 8/22 (36.4%) requiring RRT. Both sCr and sCysC demonstrated excellent performance for predicting AKI (AUC, 0.86 and 0.87, respectively) and need for RRT (AUC, 0.94 and 0.95, respectively). sNGAL displayed acceptable performance for predicting AKI (AUC, 0.81) and need for RRT (AUC, 0.87). CONCLUSIONS: SCr and sCysC measured at ED presentation are both highly accurate predictors of AKI and need for RRT, whereas sNGAL demonstrated adequate diagnostic performance. While sCyC was previously shown to be superior to sCr as a diagnostic biomarker of kidney injury in certain etiologies, our findings demonstrate that sCr is comparable to sCyC in the context of predicting COVID-19-associated AKI. Given the high sensitivity of these biomarkers for predicting the need for RRT, and as sCysC is associated with mortality in COVID-19 patients, we recommend their measurement for enabling risk stratification and early intervention.

Combined Cytokine Scores Assessed at Emergency Department Presentation Predicts COVID-19 Critical Illness.

N/A.

Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study.

BACKGROUND: The mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis. METHODS: Blood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65. RESULTS: A total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively). CONCLUSION: Necrosis appears to be the main driver of hospitalisation, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.

Laparoscopic surgery during the COVID-19 pandemic: detection of SARS-COV-2 in abdominal tissues, fluids, and surgical smoke.

BACKGROUND: There are still concerns over the safety of laparoscopic surgery in coronavirus disease 2019 (COVID-19) patients due to the potential risk of viral transmission through surgical smoke/laparoscopic pneumoperitoneum. METHODS: We performed a systematic review of currently available literature to determine the presence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in abdominal tissues or fluids and in surgical smoke. RESULTS: A total of 19 studies (15 case reports and 4 case series) comprising 29 COVID-19 patients were included. The viral RNA was positively identified in 11 patients (37.9%). The samples that tested positive include the peritoneal fluid, bile, ascitic fluid, peritoneal dialysate, duodenal wall, and appendix. Similar samples, together with the omentum and abdominal subcutaneous fat, tested negative in the other patients. Only one study investigated SARS-COV-2 RNA in surgical smoke generated during laparoscopy, reporting negative findings. CONCLUSIONS: There are conflicting results regarding the presence of SARS-COV-2 in abdominal tissues and fluids. No currently available evidence supports the hypothesis that SARS-COV-2 can be aerosolized and transmitted through surgical smoke. Larger studies are urgently needed to corroborate these findings.

Coronavirus Disease 2019 (COVID-19) set to increase burden of atherosclerotic cardiovascular disease in Kenya.

The coronavirus disease 2019 (COVID-19), first reported in Kenya on March 13, 2020, is spreading rapidly. As of 30th June 2020, over 6,190 cases had been reported with a case fatality of 3.2%. Previous Coronavirus outbreaks have been associated with a significant burden of Cardiovascular disease. For COVID-19, however, there has been no direct reference to potential long-term cardiovascular effects, especially in Africa where atherosclerotic diseases are an emerging challenge. This article, therefore, aims at describing possible long-term effects on the burden of atherosclerotic disease among Kenyans. Available data indicate that COVID-19 and cardiovascular disease share pathomechanisms and risk factors which include ACE2 receptor invasion and renin-angiotensin system signaling, oxidative stress, systemic inflammation, and endothelial dysfunction. Further, SAR-COV-2 infection causes dyslipidemia, dysglycemia, kidney, and liver disease. These mechanisms and diseases constitute risk factors for the initiation, progression, and complications of atherosclerosis. In Kenya, the common risk factors for atherosclerotic cardiovascular disease, and COVID-19 comprising Hypertension, Diabetes Mellitus, Obesity, Cigarette Smoking, Respiratory Tract Infections, Pulmonary Thromboembolism, Chronic Obstructive Pulmonary Disease, and Renal disease are not uncommon and continue to increase. In essence, the prevalence of the common risk factors/comorbidities, between COVID-19 and CVD occurrence of ACE2 receptors on the endothelium, and hence pathomechanisms of SARS-COV-2 infection imply that COVID-19 may increase the burden of atherosclerotic disease in Kenya. All due care should be taken, to prevent and effectively manage the disease, to avert an imminent epidemic of atherosclerotic disease.

Intracranial hemorrhage in coronavirus disease 2019 (COVID-19) patients.

BACKGROUND: Emerging evidence suggests that a subset of coronavirus disease 2019 (COVID-19) patients may present with or develop cerebrovascular disease during the course of hospitalization. Whereas ischemic stroke in COVID-19 patients has been well described, data on intracranial hemorrhage (ICH) in these patients is still limited. We, therefore, conducted a rapid systematic review of current scientific literature to identify and consolidate evidence of ICH in COVID-19 patients. METHODS: A systematic search of literature was conducted between November 1, 2019, and August 14, 2020, on PubMed and China National Knowledge Infrastructure (CNKI) to identify eligible studies. RESULTS: A total of 23 studies describing ICH in 148 COVID-19 patients were included. The pooled incidence of ICH in COVID-19 patients was 0.7% (95% CI 0.5-0.9), with low levels of inter-study heterogeneity observed (I2 = 33.6%, Cochran's Q = 12.05, p = 0.149). Most of the patients were elderly male patients (65.8%) with comorbidities, the most common being systemic hypertension (54%). Hemorrhage involving multiple cranial compartments was reported in 9.5% of cases. Single compartments were involved in the rest, with intraparenchymal hemorrhage (IPH) being the most common variety (62.6%) and intraventricular hemorrhage (IVH) the least common (1.4%). Half of these patients were on some form of anticoagulation. Overall, the mortality rate in the COVID-19 patients with ICH was about 48.6%. CONCLUSION: Although relatively uncommon among COVID-19 patients, ICH is associated with a high mortality rate. Early identification of patients at risk of developing ICH, particularly with comorbid conditions and on anticoagulant therapy, may be important to improve outcomes.

Arterial Thrombosis in Coronavirus Disease 2019 Patients: A Rapid Systematic Review.

BACKGROUND: Emerging evidence suggests that severe form of coronavirus disease 2019 (COVID-19) is mediated, in part, by a hypercoagulable state characterized by micro- and macro-vascular thrombotic angiopathy. Although venous thrombotic events in COVID-19 patients have been well described, data on arterial thrombosis (AT) in these patients is still limited. We, therefore, conducted a rapid systematic review of current scientific literature to identify and consolidate evidence of AT in COVID-19 patients. METHODS: A systematic search of literature was conducted between November 1, 2019, and June 9, 2020, on PubMed and China National Knowledge Infrastructure to identify potentially eligible studies. RESULTS: A total of 27 studies (5 cohort, 5 case series, and 17 case reports) describing arterial thrombotic events in 90 COVID-19 patients were included. The pooled incidence of AT in severe/critically ill intensive care unit-admitted COVID-19 patients across the 5 cohort studies was 4.4% (95% confidence interval 2.8-6.4). Most of the patients were male, elderly, and had comorbidities. AT was symptomatic in >95% of these patients and involved multiple arteries in approximately 18% of patients. The anatomical distribution of arterial thrombotic events was wide, occurring in limb arteries (39%), cerebral arteries (24%), great vessels (aorta, common iliac, common carotid, and brachiocephalic trunk; 19%), coronary arteries (9%), and superior mesenteric artery (8%). The mortality rate in these patients is approximately 20%. CONCLUSIONS: AT occurs in approximately 4% of critically ill COVID-19 patients. It often presents symptomatically and can affect multiple arteries. Further investigation of the underlying mechanism of AT in COVID-19 would be needed to clarify possible therapeutic targets.

Acute Kidney Injury is Associated with Worse Prognosis In COVID-19 Patients: A Systematic Review and Meta-analysis.

BACKGROUND: The association between acute kidney injury (AKI) and outcome of coronavirus disease 2019 (COVID-19) has not yet been conclusively established. Therefore, we conducted a meta-analysis of recent scientific literature to assess whether AKI may be associated with worse prognosis and increased mortality in COVID-19 patients. METHODS: A systematic search of literature was conducted between 1st November 2019 and 15th May 2020 on Medline (PubMed interface) and China National Knowledge Infrastructure (CNKI) to identify potentially eligible studies. Cohort or case-control studies reporting data on AKI in patients with or without severe COVID-19 were included. Studies were divided into separate cohorts for analysis based on two endpoints (severity [severe vs non-severe] and mortality [non-survivors vs survivors]). Data were pooled into a meta-analysis to estimate pooled odds ratio (OR) with 95% confidence interval (95% CI) for either outcome. RESULTS: A total of 15 studies (n= 5,832 patients) were included in the analysis. Overall, AKI was found to be associated with significantly increased odds of COVID-19 severity (OR= 18.5; 95% CI 8.99-38.08) and mortality (OR= 23.9; 95% CI 18.84-30.31). No heterogeneity was observed for both outcomes (Cochran's Q= 6.21, p=0.52, I2=0% and Cochran's Q= 4.56, p=0.47, I2=0% respectively). -Conclusion: According to current data, AKI seems to be associated with worse prognosis in COVID-19 -patients. -Further investigation of the underlying mechanism of renal disease in COVID-19 would be needed to clarify possible therapeutic targets. AKI could be used as a clinical characteristic in severity classification and risk -stratification.

Lymphopenia and neutrophilia at admission predicts severity and mortality in patients with COVID-19: a meta-analysis.

BACKGROUND: There is a compelling need to identify clinical and laboratory predictors of unfavorable clinical course and death in patients with coronavirus disease (COVID-19). A trend towards low lymphocyte count and high neutrophil counts in patients with poor outcomes has been reported by earlier studies. We aim to synthesize existing data evaluating the relationship between clinical outcomes and abnormal neutrophil and lymphocyte counts at admission in COVID-19 patients. METHODS: An electronic search was carried out in PubMed, China National Knowledge Infrastructure (CNKI) and Cochrane Central Register of Controlled Trials (CENTRAL) to identify eligible studies reporting frequency data on neutrophilia and lymphopenia at admission in hospitalization in COVID-19 patients. Pooled odds ratios of clinical outcomes for each parameter were calculated using Comprehensive Meta-Analysis. RESULTS: A total of 22 studies (4,969 patients) were included in this meta-analysis. Lymphopenia at admission was found to be significantly associated with increased odd of progression to severe disease (odds ratio [OR], 4.20; 95% confidence interval [95CI%], 3.46-5.09) and death (OR, 3.71; 95%CI, 1.63-8.44). Neutrophilia at admission was also found to be significantly associated with increased odd of progression to severe disease (OR, 7.99; 95%CI, 1.77-36.14) and death (OR, 7.87; 95%CI, 1.75-35.35). Subgroup analysis revealed that COVID-19 patients with severe lymphopenia (<0.5 x10×9/L) had 12-fold increased odds of in-hospital mortality. CONCLUSION: Admission lymphopenia and neutrophilia are associated with poor outcomes in patients with COVID-19. Regular monitoring and early and even more aggressive intervention shall hence be advisable in patients with low lymphocyte and high neutrophil counts. These variables may be useful in risk stratification models.

Cancer is associated with coronavirus disease (COVID-19) severity and mortality: A pooled analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly escalating pandemic that has spread to many parts of the world. As such, there is urgent need to identify predictors of clinical severity in COVID-19 patients. This may be useful for early identification of patients who may require life-saving interventions. In this meta-analysis, we evaluated whether malignancies are associated with a significantly enhanced odds of COVID-19 severity and mortality. METHOD: A systematic search of literature was conducted between November 1, 2019, to May 26th, 2020 on PubMed and China National Knowledge Infrastructure (CNKI) to identify studies reporting data on cancers in patients with or without severe COVID-19 were included. The primary outcome of interest was the association between malignancies and COVID-19 severity, while the secondary outcome was the association between malignancies and COVID-19 mortality. Data were pooled into a meta-analysis to estimate pooled odds ratio (OR) with 95% confidence interval (95% CI) for either outcome. RESULTS: A total of 20 studies (n = 4549 patients) were included. Overall, malignancies were found to be associated with significantly increased odds of COVID-19 severity (OR = 2.17; 95% CI 1.47-3.196; p < 0.001) and mortality (OR = 2.39; 95% CI 1.18-4.85; p = 0.016). No heterogeneity was observed for both outcomes (Cochran's Q = 6.558, p = 0.922, I2 = 0% and Cochran's Q = 2.91, p = 0.71, I2 = 0% respectively). CONCLUSION: Malignancies were significantly associated with a 2-fold increase in the odds of developing severe COVID-19 disease, as well as mortality. Larger studies are needed to corroborate these findings. These patients should be closely monitored for any signs of unfavorable disease progression.

Association of Cardiovascular Disease With Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis.

Observational studies have reported an association between underlying cardiovascular diseases (CVD) and worse prognosis in COVID-19 patients, but this still remains unclear. We conducted a meta-analysis of recent studies that reported the association of CVD with worse prognosis and increased mortality in COVID-19 patients. Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from November 1, 2019 to April 20, 2020. Inclusion criteria were observational case-control or cohort studies on COVID-19 patients with a history of CVD included, which reported outcomes of COVID-19 infection severity, clearly outlined the definition of "severe disease" and with sample size >10. Data were abstracted independently by 2 authors. Studies were divided into 2 separate cohorts for analysis: severity (severe vs nonsevere) and mortality (nonsurvivors vs survivors). Data was pooled into a meta-analysis to estimate pooled odds ratio (OR) with 95% confidence interval (95% CI) for each outcome. A total of 18 studies (n = 4858 patients) were included. Sixteen studies were from China, while 2 were from the United States. Pre-existing CVD was associated with a significantly increased risk of a severe form of COVID-19 (OR = 3.14; 95% CI 2.32-4.24; I2 = 0%; Q = 8.68, P= 0.73) and overall risk of COVID-19 all-cause mortality (OR = 11.08; 95% CI: 2.59-47.32; I2 = 55%; P = 0.11). However, this study did not find a significant association between previous history of CVD and mortality in severe COVID-19 disease (OR = 1.72; 95% CI: 0.97-3.06, I2 = 0%, P = 0.46). Pre-existing CVD is associated with worse outcomes among patients with COVID-19. Clinicians and policymakers need to take account of these findings in implementing risk stratification models.