Neuropathogenesis and Neurological Manifestations of SARS-CoV-2

Neurological complications of COVID-19 contribute significantly to mortality in the intensive care unit (ICU). Preventive therapy, though discussed in literature, is limited for COVID-19 neurological manifestations and treatment algorithms continue to rely on evidence from previous pandemics. Thus, in this chapter we evaluate current in vitro, in vitro, histopathological studies to ascertain the most likely mechanisms of SARS-CoV-2 central nervous system entry. From this understanding, we determine probable mechanisms for neurological compilations observed in COVID-19 as relevant to the clinician. SARS-CoV-2 infection of nasal epithelium and the respiratory tract may allow for a systemic inflammatory response that results in neuroinflammation. While most neurological complications are inflammatory in etiology, rarely, SARS-CoV-2 may enter into the central nervous system and mediate neuronal damage. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Biomarkers of renal injury as early predictors of COVID-19 associated AKI: a prospective observational trial (BRICOAKI-trial)

Introduction: Early prediction by the use of serum and urinary biomarkers for the detection of acute kidney injury (AKI) may be very valuable to optimize the management and helps in improving the outcomes. This study aims to investigate whether daily measurement of urinary and plasma renal biomarkers have a role in earlier predicting COVID-19 associated AKI. Method(s): The study was conducted as a single-center, prospective, observational cohort study between August 2020 and December 2020 in hospitalized COVID-19 patients. A total of 65 moderate and severe COVID-19 positive adult (>= 18 years) patients were enrolled for this study. We measured serum creatinine, cystatin C, NGAL, KIM-1, Urine-Klotho, TIMP-2, IL-6 level, and urinary microalbumin/urinary creatinine on various days. The receiver operating characteristic curve (ROC) analysis was used to find the sensitivity and specificity of various markers to predict the incidence of AKI. Result(s): A total of 24 moderate and 41 severe COVID-19 patients were included. Out of which 47 patients developed (72.3%) acute kidney injury (AKI) over the course of COVID-19. Among these subjects, 18/47 (38.2%) developed severe AKI (KDIGO 2 + 3), and 5/47 (10.6%) required RRT. NGAL was found to be the best marker to predict the probability of AKI (Area under curve AUC of 0.713-0.786) with a sensitivity of 76-90% and specificity of 56-79% on different days of assessment from Day 1 to Day 7. IL-6 had moderate accuracy of prediction and cystatin C, KIM-1, Urine-Klotho, TIMP-2, IL-6 had poor accuracy for predicting the incidence of AKI. Conclusion(s): Urinary biomarkers like NGAL have good predictability for AKI.

ACUTE KINDEY INJURY OVER EXISTING CHRONIC KIDNEY DISEASE IN PATIENTS WITH SARS-CoV-2 INFECTION

Introduction: Patients with chronic kidney disease (CKD) and that have SARS-CoV-2 infection are at higher risk of developing acute kidney injury (AKI) and have higher mortality rates after hospital admission. Method(s): The study group included 120 patients: 70 with a history of CKD (eGFR rate of <60 mL/min);and 50 were within the control group with no history of kidney disease. Data on patients' gender, age, co-morbidities, and laboratory results from blood and urine samples, taken at admission into the ER, were collected. Laboratory values included calculated eGFR (by the CKD-EPI 2021 formula), highly sensitive inflammatory markers, D-dimer, blood-cell counts, and changes in urine parameters (hematuria, proteinuria). Co-morbidities included hypertension, obesity, diabetes mellitus, vascular disease, and CKD. All patients had been treated by the official protocol of the Republic of Bulgaria for SARS-CoV-2 treatment, but not all of them have received remdesivir. We also assessed which risk factors may have led to AKI with emphasis to the levels of specific biomarkers (IL-6, IL-18, KIM-1, NGAL, ACE2, SAA). Result(s): Overall median age of patients was 65.7 years;gender ratio was 50% M/F in both groups. Median duration of symptoms before hospitalization was 6 days. Of the 120 patients, 35% were febrile with temperatures >38oC Overall, creatinine level on admission was elevated in 58.3% of cases;eGFR was <60 mL/min/1.73 m2 in 50% of patients. Mean value of eGFR on admission was 82.3 mL/min/1.73 m2 for the non-CKD group and 49.5 mL/min/1.73 m2 for the CKD group. In total, three patients needed renal-replacement therapy: two patients from the CKD group and one from the non-CKD group. Urine samples showed 39 patients had proteinuria: of these, 87.1% had 1+ proteinuria and the others had >1+. Of the 22 cases of hematuria, 54.5% had only 1+ hematuria. Acute kidney injury occurred in 38 patients (31.6%) of whom 31 had CKD (44.3% of CKD patients). Overall, within our cohort of 120 patients, in-hospital mortality was 19.1% (23 patients): of these, 66.6% had AKI (19 patients). Overall, 100% of patients that did not survive Covid-19 also had CKD. We also analyzed risk factors that may have led to AKI. Logistic regression for risk factors for AKI showed that, the factors significantly linked with the incidence of AKI were an eGFR of >=60 mL/min/1.73m2, having symptoms for >=6 or more days before hospitalization, and not having received remdesivir as a treatment. Also, the levels of IL-6, SAA, and KIM-1 were significantly higher for patients that had AKI. Conclusion(s): We found that CKD was not a risk factor for COVID-19-related AKI. Conversely, we found that developing AKI was significantly associated with in-hospitalization death, which was linked with renal inflammatory processes and injury caused by SARS-CoV-2. No conflict of interestCopyright © 2023

Utility of urinary biomarkers for diagnosis of acute kidney injury (AKI) in COVID-19

Introduction: Incidence of AKI reported varies from 0.5% to 37%.These incidence cannot be extrapolated in our patients as the severity of COVID-19 infection, the ethnicity of the patients l, the clinical profile and the healthcare delivery system is different.The aim of this study was to explore whether urinary cell cycle arrest markers and other renal biomarkers have a role in predicting AKI in critically ill patients with COVID-19 and acute respiratory disease Methods: This prospective, longitudinal cohort study included critically ill COVID-19 patients without AKI at study entry. Patients aged more than 18 years with moderate or severe respiratory disease as defined by Berlin criteria were subsequently recruited from November 2020 to May 2021. Urine samples were collected on admission to critical care areas for determination of KIM1, NGAL, IL-18,IGF-BP-7, TIMP -2 at the time point of study inclusion, 12h, 24h, 48h, after inclusion. The demographic information, comorbidities, clinical, and laboratory data were recorded. The study outcomes were the development of AKI and mortality during hospitalization. Result(s): [Formula presented] ROC analysis was done to determine the diagnostic performance of the various urinary biomarkers;AUC was 0.655 for normalised IL-18, 0.685 for normalised NGAL, 0.658 for normalised TIM-1, and so on Conclusion(s): AKI was common in critically ill COVID-19 patients. Raised values of urinary biomarkers with clinical information, are useful for the identification of AKI in critically ill COVID-19 patients. No conflict of interestCopyright © 2023

URINARY BIOMARKERS TO PREDICT ACUTE KIDNEY DAMAGE AND MORTALITY IN COVID-19

BACKGROUND AND AIMS: Acute kidney injury (AK) is a frequent condition in patients hospitalized for COVID-19. There are only few reports on the use of urinary biomarkers in COVID-19 and no data comparing the prognostic use of individual biomarkers in the prediction of adverse outcome so far. METHOD: We performed a prospective monocentric study on the value of urinary biomarkers to predict the composite endpoint of a transfer to the intensive care unit (ICU), the need for renal replacement therapy (RRT), mechanical ventilation and in-hospital mortality. A total of 41 patients hospitalized for COVID-19 were enrolled in this study. Urine samples were obtained shortly after admission in order to assess neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), calprotectin and vanin-1. RESULTS: We identified calprotectin as a predictor of a severe course of the disease, requiring intensive care treatment (AUC 0.728, P = .016). Positive and negative predictive values were 78.6% and 76.9%, respectively, using a cut-off concentration of 127.8 ng/mL. NGAL tended to predict COVID-19 associated AKI without reaching statistical significance (AUC 0.669, P = .053). The best parameter in the prediction of in-hospital mortality was NGAL as well (AUC 0.674, P = .077). KIM-1 and vanin-1 did not reach significance for any of the investigated endpoints. CONCLUSION: While KIM-1 and vanin-1 did not provide prognostic clinical information in the context of COVID-19, this study shows that urinary calprotectin and NGAL concentrations are independent predictors of an adverse course of the disease. Calprotectin and NGAL may thereby constitute helpful adjuncts in the identification of patients at increased risk who may benefit from upcoming antiviral agents to SARS-CoV-2.

Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26)

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.