Pathological changes in COVID-19 pneumonia on limited post-mortem sampling of lung: A saga of inflammation and thrombosis.

We describe three postmortem open lung-biopsy findings among patients with COVID-19 pneumonia who were on anticoagulant therapy. The spectrum of histopathological findings included lung inflammation in the form of diffuse alveolar damage (DAD) in exudative and organizing phases, with or without pulmonary artery thrombosis in different stages of evolution. This spectrum of inflammation and thrombosis may be indicative of a natural history of severe COVID-19 pneumonia or demonstrative of variation in therapeutics.

Organ Involvement in COVID-19: A Molecular Investigation of Autopsied Patients.

Precise reasons for severe manifestation of SARS-CoV-2 remain unanswered, and efforts have been focused on respiratory system management. Demonstration of unequivocal presence of SARS-CoV-2 in vital body organs by cadaver autopsy was the only way to prove multi-organ involvement. Hence, the primary objective of the study was to determine presence of the SARS-CoV-2 in various organs of patients succumbing to SARS-CoV-2 infection. A total of 246 samples from different organs of 21 patients who died due to severe COVID-19 illness were investigated by qRT-PCR, and SARS-CoV-2 was detected in 181 (73.57%) samples and highest positivity of SARS-CoV-2 being (expectedly) found in nasopharynx (90.4%) followed by bilateral lungs (87.30%), peritoneal fluid (80%), pancreas (72.72%), bilateral kidneys (68.42%), liver (65%) and even in brain (47.2%). The deceased patients were categorized to three subgroups based upon the extent of organs in which SARS-CoV-2 was detected by qRT-PCR (high intensity ≥80%, intermediate intensity = 65-80% and low intensity ≤65% organs involvement). It was conclusively established that SARS-CoV-2 has the property of invasion beyond lungs and even crosses the blood-brain barrier, resulting in multi-system disease; this is probably the reason behind cytokine storm, though it is not clear whether organ damage is due to direct injury caused by the virus or result of inflammatory assault. Significant inverse correlation was found between the Ct value of lung samples and number of organs involved, implying that higher viral load in lungs is directly proportionate to involvement of extrapulmonary organs and patients with higher viral load in respiratory secretions should be monitored more closely for any warning signs and the treatment strategies should also address involvement of other organs for better outcome, because lungs, though the primary site of infection, are not the only organ system responsible for pathogenesis of systemic illness.

Natural and genetically-modified animal models to investigate pulmonary and extrapulmonary manifestations of COVID-19.

Coronavirus disease-19 (COVID-19), a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is a primarily respiratory tract disease. Suitable animal models for COVID-19 are required to study various aspects of pathogenesis, drug discovery, effective and safe vaccine development. Several laboratory animals including, non-human primates, hamsters, ferrets, transgenic mice, and zebrafish, have been used and proven their significance experimentally. Currently available animal models of SARS-CoV-2 can be broadly classified into two categories 1) natural animal models 2) genetically-modified that exhibit different degrees of susceptibility of SARS-CoV-2, tissue damage in respiratory and other organ systems. Not all the available animal models mimic COVID-19-like phenotype completely. Therefore, understanding various aspects of COVID-19 requires different animal models. In this review article, we provide an update on the immune response and clinical manifestations observed in naturally occurring and genetically-modified animals of COVID-19. We then review the transmission, viral replication, lung pathology, immunological aspects, and extrapulmonary phenotypes observed in various animal models. In the end, we put forth our perspective on the anticipated uses, disadvantages, and limitations of each type of animal model.

SARS-CoV-2 infected individuals can experience a range of clinical features ranging from no symptoms to critical illness associated with respiratory failure, septic shock, and multi-organ failure. Additionally, SARS-CoV-2 infection is not restricted to the respiratory tract due to the multi-organ expression of ACE2. Further, the emergence of SARS-CoV-2 variants-of-concern demands continuous research on host transmission, evasion from host immune response, and development of effective and durable vaccines. A better understanding of the pathogenesis, severity, incubation period, scorable symptoms, effective treatment modalities with the least side effects, and boosting of the immune system can reduce the disease obstacles for the society as well as an individual person. Therefore, to investigate various aspects of SARS-CoV-2 infection and COVID-19 requires suitable animal models. Several laboratory animals including, non-human primates (NHPs), hamsters, ferrets, transgenic mice, zebrafish, guinea pigs, minks, have been considered and proven their significance experimentally. Currently available animal models of COVID-19, either natural host or genetically modified, exhibit different degrees of susceptibility of SARS-CoV-2 tissue damage in respiratory and other organ systems. Not all the available animal models mimic the COVID-19 like phenotype completely. Therefore, understanding different aspects of COVID-19 will require different animal models. In the proposed article, we have reviewed the immunological and clinical manifestations observed in various natural, and genetically-modified animal models of numerous COVID-19 studies. We also summarized the up-to-date laboratory findings on available on significant COVID-19 animal models, and put forth our perspective for the objective dependent usage of animal models.

Clinical, Virological, and Pathological Profile of Patients Who Died of COVID-19: An Autopsy-Based Study From India.

Background and objective Ever since its emergence in December 2019, coronavirus disease 2019 (COVID-19) has affected more than 220 million people worldwide, resulting in more than 45 million deaths. The present autopsy-based study was undertaken to understand the pathophysiology of the disease and correlate the histopathological and virological findings with the antemortem clinical and biochemical determinants. Methods In this prospective observational study, autopsies were carried out on 21 reverse transcription-polymerase chain reaction (RT-PCR)-proven COVID-19 patients who had died of the disease. The histopathological findings of tissue samples from lungs, liver, and kidneys collected during the autopsy were graded based on their presence or absence; if present, they were graded as either focal or diffuse. The findings were correlated with antemortem clinical and biochemical findings. Postmortem tissue RT-PCR analysis was conducted, and findings were compared with postmortem histopathological findings. Results There was multisystem involvement with the COVID-19 cases. The involvement of lungs was observed in most of the cases (90.4%). The presence of viral RNA was observed in all the organs including the liver (57.1%) and kidney (66.6%). An association was observed between antemortem biochemical parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT)] and the histopathological features in the liver. No correlation between the Sequential Organ Failure Assessment (SOFA) score recorded clinically and lung histopathology was observed; nor was there any correlation between blood urea-creatinine levels and kidney histopathology. Conclusions Our study shows that COVID-19 is a multisystemic disease and the mortality associated with it is likely to be multifactorial. Despite the presence of amplifiable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in various organs, no association could be established between the clinical and histopathology findings. Neither the duration of hospitalization nor the duration of mechanical ventilation showed any correlation with the severity of histopathological findings in the lungs at autopsy.

Adequate Antithrombin III Level Predicts Survival in Severe COVID-19 Pneumonia.

Critically ill patients with COVID-19 are at an increased thrombotic risk, hence thromboprophylaxis with heparin is considered mandatory. Antithrombin III (ATIII) is the most potent endogenous anticoagulant and is required for the clinical efficacy of heparin. Profound hypercoagulable and inflammatory state associated with COVID-19 can result in decreased ATIII levels and ineffective heparin treatment resulting in increased mortality. The present study evaluated ATIII levels in critically ill patients of COVID-19 and correlated them with other coagulation parameters and disease outcomes. A retrospective review of those critically ill COVID-19 patients was performed who were on a therapeutic dose of low molecular weight heparin (LMWH) and had serial measurements of ATIII, anti-factor Xa (antiFXa) assay and other routine coagulation parameters. A total of 27 critically ill COVID-19 patients were identified, out of these, 12 survived and 15 had disease-induced mortality. ATIII levels were found to be significantly lower in non-survivors on the third day of serial measurement along with worsening of other coagulation parameters. AntiFXa levels were found to be higher in non-survivors as compared to survivors. Further studies are required to establish ATIII as a prognostic marker and to determine the utility of monitoring antiFXa levels in COVID-19 patients on LMWH therapy.

Evolution of pathology teaching for MBBS students during COVID-19 pandemic lockdown: Moving from a real to a virtual classroom.

BACKGROUND: The COVID-19 pandemic lockdown has forced university hospitals to forego traditional classes and embrace online teaching platforms as the sole modality of medical education. Herein, we describe our experience of shifting from the arena of a real to a virtual classroom during the lockdown phase. Materials and. METHODS: The institutional subscription of G-suite was used for creating a virtual Google classroom. Google Calendar, Google Meet, and Google Forms were used for notification of schedules, conducting theory and practical classes, and conducting assessments, respectively. The learner-centric SNAPPS model was adapted for an interactive case-based learning (CBL) program using multimedia tools. Students' perspective on online education was assessed based on their responses to a validated questionnaire. RESULTS: The conduction of online classes, particularly the live practical classes and the CBL program got the maximum affirmative (up to 85%) responses. Students of the same batch also performed better in a test following the online CBL (77.03% vs 73.3%, P = 0.03, paired t-test statistically significant) compared to a test before it. However, access to laptops and poor Internet connectivity were significant causes of concern for nearly 40% of students. CONCLUSION: The use of virtual classroom has proved to be an efficient method for continuing teaching of Pathology to MBBS students in times of lockdown when face-to-face conventional teaching was not possible. The experience indicated that in the future a judicious mixture of traditional and online classes may be a more effective educational design for teaching Pathology to MBBS students.