Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.

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Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.

Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series.

A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice.

A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with substantial morbidity and mortality. Although much has been learned in the first few months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation, and many patients with anosmia show no or only minor respiratory symptoms1. Studies in animals infected experimentally with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, provide opportunities to study aspects of the disease that are not easily investigated in human patients. Although the severity of COVID-19 ranges from asymptomatic to lethal2, most experimental infections provide insights into mild disease3. Here, using K18-hACE2 transgenic mice that were originally developed for SARS studies4, we show that infection with SARS-CoV-2 causes severe disease in the lung and, in some mice, the brain. Evidence of thrombosis and vasculitis was detected in mice with severe pneumonia. Furthermore, we show that infusion of convalescent plasma from a recovered patient with COVID-19 protected against lethal disease. Mice developed anosmia at early time points after infection. Notably, although pre-treatment with convalescent plasma prevented most signs of clinical disease, it did not prevent anosmia. Thus, K18-hACE2 mice provide a useful model for studying the pathological basis of both mild and lethal COVID-19 and for assessing therapeutic interventions.

/pdf/covid-19-treatments-and-pathogenesis-including-anosmia-in-53zej1m44p.pdf

COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. Methods In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. Findings The median age of our cohort was 73·5 years (range 42–84; IQR 67·5–77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. Interpretation The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. Funding None.

Keywords:forensic science;suicide;carbon monoxide;charcoal;briquette;automobile;exhaust
Abstract: Carbon monoxide (CO) inhalation is one of the leading methods of suicide in the United States. A sharp increase in suicide by inhaling the CO produced from burning charcoal has been reported in parts of Asia; however, the incidence of this method has not been determined in a U.S. population. Thus, we determined trends of CO suicide in the ethnically diverse population of King County, Washington, U.S.A. During the period 1996�2009, we identified 158 cases of suicide by CO poisoning, with 125 because of automotive exhaust, 26 because of charcoal burning, and seven from other CO sources. While historical U.S. data indicate >99% of CO suicides in the United States occurring by automobile exhaust inhalation, in the most recent years analyzed, c. 40% of CO-related suicides in King County, Washington, were because of charcoal burning, indicating a possible shift in suicide trends that warrants further scrutiny in additional populations.

Trends in Suicide by Carbon Monoxide Inhalation in King County, Washington: 1996–2009

Suicide by burning is an extreme act that is uncommon in the United States and throughout the Western world. The characteristics of people who complete such acts are not well understood. To address this issue, we examined the death records of the King County Medical Examiner's Office in Washington State over the 13 years from 1996 to 2009. Twenty-five cases of suicide by burning were identified and used to characterize decedent demographics, circumstances of death, and motivating factors. Compared to other methods of suicide, burning demonstrated a significant overrepresentation of decedents who were women, 40-59 years of age, and Asian/Pacific Islander. They also tended to have previous psychiatric illness and/or substance abuse issues. Self-burning predominantly occurred at the decedent's residence with the intent of suicide given. There was no unifying theme in motivating factors. Together, these data represent the characteristics of people whose death is because of suicide by burning in King County, Washington. Language: en

Case Series of Completed Suicides by Burning Over a 13-Year Period

Diabetes mellitus type 1 and type 2 are diseases characterized by impaired regulation of blood glucose due to decreased insulin production and insulin resistance, respectively. Management of diabetes mellitus often requires injection of exogenous insulin. Continuous subcutaneous insulin infusion (CSII or insulin pump) is a diabetes treatment modality utilizing a device to aid in regulation of glycemic control. Malfunctions in device components can have rare fatal consequences. Described in this report are six fatalities due to one such malfunction, the failure of plastic cannulas of CSII devices to penetrate the skin and deliver insulin, resulting in fatal diabetic ketoacidosis (DKA). The cases derive from four different death investigation systems. For each case, scene and autopsy findings are presented, as well as selected toxicology and histology findings. These cases illustrate the importance of careful examination of CSII devices in death investigations and introduce a discussion on discrepant manner of death classifications.

Timothy L. Williams

Papers

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

Trends in Suicide by Carbon Monoxide Inhalation in King County, Washington: 1996–2009

Case Series of Completed Suicides by Burning Over a 13-Year Period

Fatalities Due to Failure of Continuous Subcutaneous Insulin Infusion Devices: A Report of Six Cases.