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.

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.

Congenital Anomalies of the Tracheobronchial Tree: A Meta-Analysis and Clinical Considerations.

BACKGROUND: The aim of this study was to determine the prevalence and anatomic features of major tracheobronchial anomalies. METHODS: Major electronic databases were systematically searched to identify eligible studies. Data were extracted and pooled into a meta-analysis. The primary outcome was the prevalence of major tracheobronchial anomalies, specifically tracheal bronchus (TB) and accessory cardiac bronchus (ACB). Secondary outcomes included the origin and types of TB and ACB. RESULTS: A total of 27 studies (n = 119,695 patients) were included. A TB was present in 0.99% (95% confidence interval, 0.67 to 1.37) of patients, and an ACB was present in 0.14% (95% confidence interval, 0.09 to 0.20). The overall prevalence of TB was higher in imaging than in operative studies (1.81% vs 0.82%). It was also higher in pediatric (2.55%) than in adult studies (0.50%). Patients with other congenital anomalies were 15 times more likely to have a TB (odds ratio 14.89; 95% confidence interval, 7.09 to 31.22). The most common origin of TBs was from the trachea (81.42%), primarily from the right side (96.43%). The most common origin of ACBs was from the intermediate bronchus (74.32%). The ACBs terminated as blind-ending diverticulum in two thirds of cases. CONCLUSIONS: Major tracheobronchial anomalies are present in approximately 1% of the population, although the prevalence is higher among pediatric patients and patients with accompanying congenital anomalies. Although rare, major tracheobronchial anomalies can be associated with significant respiratory morbidities and present challenges during airway management in surgical and critical care patients. Establishing a preoperative diagnosis of these variations is essential for planning and implementing an appropriate airway management strategy to minimize attendant complications.

Laboratory abnormalities in children with mild and severe coronavirus disease 2019 (COVID-19): A pooled analysis and review.

Limited data exists to-date on the laboratory findings in children with COVID-19, warranting the conduction of this study, in which we pool the currently available literature data on the laboratory findings seen in children with mild and severe COVID-19. Following an extensive literature search, we identified 24 eligible studies, including a total of 624 pediatric cases with laboratory-confirmed COVID-19, which report data on 27 different biomarkers. We then performed a meta-analysis to calculate the pooled prevalence estimates (PPE) for these laboratory abnormalities in mild COVID-19. As data was too limited for children with severe COVID-19 to allow pooling, results were presented descriptively in a summary of findings table. Our data show an inconsistent pattern of change in the leukocyte index of mild and severe cases of COVID-19 in children. Specifically, changes in leukocyte counts were only observed in 32% of the mild pediatric cases (PPE: 13% increase, 19% decrease). In mild disease, creatine kinase-MB (CK-MB) was frequently elevated, with a PPE of 33%. In severe disease, c-reactive protein (CRP), procalcitonin (PCT), and lactate dehydrogenase (LDH) were frequently elevated. Based on data obtained from early COVID-19 studies, leukocyte indices in children appear inconsistent, differing from those reported in adults that highlight specific leukocyte trends. This brings into question the utility and reliability of such parameters in monitoring disease severity in the pediatric population. Instead, we suggest physicians to serially monitor CRP, PCT, and LDH to track the course of illness in hospitalized children. Finally, elevated CK-MB in mild pediatric COVID-19 cases is indicative of possible cardiac injury. This highlights the importance of monitoring cardiac biomarkers in hospitalized patients and the need for further investigation of markers such as cardiac troponin in future studies.

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.

Background As coronavirus disease 2019 (COVID-19) pandemic rages on, there is urgent need for identification of clinical and laboratory predictors for progression towards severe and fatal forms of this illness. In this study we aimed to evaluate the discriminative ability of hematologic, biochemical and immunologic biomarkers in patients with and without the severe or fatal forms of COVID-19. Methods An electronic search in Medline (PubMed interface), Scopus, Web of Science and China National Knowledge Infrastructure (CNKI) was performed, to identify studies reporting on laboratory abnormalities in patients with COVID-19. Studies were divided into two separate cohorts for analysis: severity (severe vs. non-severe and mortality, i.e. non-survivors vs. survivors). Data was pooled into a meta-analysis to estimate weighted mean difference (WMD) with 95% confidence interval (95% CI) for each laboratory parameter. Results A total number of 21 studies was included, totaling 3377 patients and 33 laboratory parameters. While 18 studies (n = 2984) compared laboratory findings between patients with severe and non-severe COVID-19, the other three (n = 393) compared survivors and non-survivors of the disease and were thus analyzed separately. Patients with severe and fatal disease had significantly increased white blood cell (WBC) count, and decreased lymphocyte and platelet counts compared to non-severe disease and survivors. Biomarkers of inflammation, cardiac and muscle injury, liver and kidney function and coagulation measures were also significantly elevated in patients with both severe and fatal COVID-19. Interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin were strong discriminators for severe disease. Conclusions Several biomarkers which may potentially aid in risk stratification models for predicting severe and fatal COVID-19 were identified. In hospitalized patients with respiratory distress, we recommend clinicians closely monitor WBC count, lymphocyte count, platelet count, IL-6 and serum ferritin as markers for potential progression to critical illness.