A case-control autopsy series of liver pathology associated with novel coronavirus disease (COVID-19).

BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19. METHODS: Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA. RESULTS: 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue. CONCLUSIONS: The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.

Suicide by Gaseous Displacement of Atmospheric Oxygen With Carbon Dioxide From Dry Ice Sublimation.

ABSTRACT: Deaths from gaseous substances can occur from exposure to toxic gases or from accumulation of nontoxic gases that displace oxygen. We present a 38-year-old man with no known medical history, who was found deceased in a small bathroom with blankets and towels shoved under the door from the inside.At autopsy, the decedent was found to be in a moderate state of decomposition. There was mild pulmonary congestion, with no other significant findings. Standard postmortem toxicology on femoral blood was noncontributory.A search of the decedent's cell phone revealed statements and internet searches regarding carbon dioxide (CO 2 ) and asphyxia using dry ice. A journal entry also outlined a suicide plan using large amounts of dry ice, which was enacted by placing a laundry basket of dry ice into a bathtub containing water. Based on the investigation, the cause of death was determined to be asphyxia from displacement of oxygen with CO 2 .Dry ice sublimates into gaseous CO 2 , which quickly accumulates, with concentrations of 10% or more, rapidly becoming life-threatening. There are no pathognomonic autopsy findings seen in CO 2 -related asphyxia. In these circumstances, scene investigation is the most important factor in determining cause of death.

Expression of Immune Checkpoint Receptors in Placentae With Infectious and Non-Infectious Chronic Villitis.

Pregnancy is an immunological paradox whereby maternal immunity accepts a genetically unique fetus (or fetuses), while maintaining protective innate and adaptive responses to infectious pathogens. This close contact between the genetically diverse mother and fetus requires numerous mechanisms of immune tolerance initiated by trophoblast cell signals. However, in a placental condition known as villitis of unknown etiology (VUE), there appears to be a breakdown in this tolerance allowing maternal cytotoxic T-cells to traffic into the placenta to destroy fetal villi. VUE is associated with several gestational complications and an increased risk of recurrence in a subsequent pregnancy, making it a significant obstetrical diagnosis. The cause of VUE remains unclear, but dysfunctional signaling through immune checkpoint pathways, which have a critical role in blunting immune responses, may play an important role. Therefore, using placental tissue from normal pregnancy (n=8), VUE (n=8) and cytomegalovirus (CMV) infected placentae (n=4), we aimed to identify differences in programmed cell death 1 (PD-1), programmed death ligand-1 (PD-L1), LAG3 and CTLA4 expression between these etiologies by immunohistochemistry (IHC). Results demonstrated significantly lower expression of PD-L1 on trophoblast cells from VUE placentae compared to control and CMV infection. Additionally, we observed significantly higher counts of PD-1+ (>100 cells/image) and LAG3+ (0-120 cells/image) cells infiltrating into the villi during VUE compared to infection and control. Minimal CTLA4 staining was observed in all placentae, with only a few Hofbauer cells staining positive. Together, this suggests that a loss of tolerance through immune checkpoint signaling may be an important mechanism leading to the activation and trafficking of maternal cells into fetal villi during VUE. Further mechanistic studies are warranted to understand possible allograft rejection more clearly and in developing effective strategies to prevent this condition from occurring in utero.

Acute Kidney Injury in Severe COVID-19 Has Similarities to Sepsis-Associated Kidney Injury: A Multi-Omics Study.

OBJECTIVE: To compare coronavirus disease 2019 (COVID-19) acute kidney injury (AKI) to sepsis-AKI (S-AKI). The morphology and transcriptomic and proteomic characteristics of autopsy kidneys were analyzed. PATIENTS AND METHODS: Individuals 18 years of age and older who died from COVID-19 and had an autopsy performed at Mayo Clinic between April 2020 to October 2020 were included. Morphological evaluation of the kidneys of 17 individuals with COVID-19 was performed. In a subset of seven COVID-19 cases with postmortem interval of less than or equal to 20 hours, ultrastructural and molecular characteristics (targeted transcriptome and proteomics analyses of tubulointerstitium) were evaluated. Molecular characteristics were compared with archived cases of S-AKI and nonsepsis causes of AKI. RESULTS: The spectrum of COVID-19 renal pathology included macrophage-dominant microvascular inflammation (glomerulitis and peritubular capillaritis), vascular dysfunction (peritubular capillary congestion and endothelial injury), and tubular injury with ultrastructural evidence of mitochondrial damage. Investigation of the spatial architecture using a novel imaging mass cytometry revealed enrichment of CD3+CD4+ T cells in close proximity to antigen-presenting cells, and macrophage-enriched glomerular and interstitial infiltrates, suggesting an innate and adaptive immune tissue response. Coronavirus disease 2019 AKI and S-AKI, as compared to nonseptic AKI, had an enrichment of transcriptional pathways involved in inflammation (apoptosis, autophagy, major histocompatibility complex class I and II, and type 1 T helper cell differentiation). Proteomic pathway analysis showed that COVID-19 AKI and to a lesser extent S-AKI were enriched in necroptosis and sirtuin-signaling pathways, both involved in regulatory response to inflammation. Upregulation of the ceramide-signaling pathway and downregulation of oxidative phosphorylation in COVID-19 AKI were noted. CONCLUSION: This data highlights the similarities between S-AKI and COVID-19 AKI and suggests that mitochondrial dysfunction may play a pivotal role in COVID-19 AKI. This data may allow the development of novel diagnostic and therapeutic targets.

Cerebral Vascular Thrombosis Associated With Ulcerative Colitis and Primary Sclerosing Cholangitis.

ABSTRACT: We report a case of a sudden death of a 23-year-old man with a history of ulcerative colitis and primary sclerosing cholangitis due to cerebral vascular thrombosis. He was found supine in bed with no signs of trauma or drug use. Three days before being found, he had complained of fever and excessive diarrhea. At autopsy, the brain was markedly edematous with diffuse subarachnoid hemorrhage over the left cerebral hemisphere. The vessels at the base of the brain were unremarkable, and there was no significant hemorrhage over the inferior surfaces. On sectioning, clotted blood was identified in the left frontal lobe and lateral ventricles. Microscopically, the left cerebral hemisphere showed extensive intraparenchymal hemorrhage, necrosis, and numerous thrombosed leptomeningeal vessels. Sections of the transverse and descending colon showed changes consistent with the history of ulcerative colitis.Cerebral venous and sinus thrombosis represents approximately 1% of all strokes and is a known rare complication associated with inflammatory bowel disease (IBD). Symptoms of cerebral venous thrombosis are highly variable and may manifest as headache, focal neurological deficits, seizure, or encephalopathy. In addition to acquired hypercoagulability risk factors patients develop during active disease flares (eg, dehydration), studies suggest that IBD itself represents an independent risk factor for thrombosis. It is important for the forensic pathologist to consider thrombotic complications, particularly those in the cerebral venous system, as potential manifestations of known or undiagnosed IBD.

The Spectrum of Histopathologic Findings in Lungs of Patients With Fatal Coronavirus Disease 2019 (COVID-19) Infection.

CONTEXT.­: Respiratory failure appears to be the ultimate mechanism of death in most patients with severe coronavirus disease 2019 (COVID-19) infection. Studies of postmortem COVID-19 lungs largely report diffuse alveolar damage and capillary fibrin thrombi, but we have also observed other patterns. OBJECTIVE.­: To report demographic and radiographic features along with macroscopic, microscopic, and microbiologic postmortem lung findings in patients with COVID-19 infections. DESIGN.­: Patients with confirmed COVID-19 infection and postmortem examination (March 2020-May 2020) were included. Clinical findings were abstracted from medical records. Lungs were microscopically reviewed independently by 4 thoracic pathologists. Imaging studies were reviewed by a thoracic radiologist. RESULTS.­: Eight patients (7 men, 87.5%; median age, 79 years; range, 69-96 years) died within a median of 17 days (range, 6-100 days) from onset of symptoms. The median lung weight was 1220 g (range, 960-1760 g); consolidations were found in 5 patients (62.5%) and gross thromboemboli were noted in 1 patient (12.5%). Histologically, all patients had acute bronchopneumonia; 6 patients (75%) also had diffuse alveolar damage. Two patients (25%) had aspiration pneumonia in addition. Thromboemboli, usually scattered and rare, were identified in 5 patients (62.5%) in small vessels and in 2 of these patients also in pulmonary arteries. Four patients (50%) had perivascular chronic inflammation. Postmortem bacterial lung cultures were positive in 4 patients (50%). Imaging studies (available in 4 patients) were typical (n = 2, 50%), indeterminate (n = 1, 25%), or negative (n = 1, 25%) for COVID-19 infection. CONCLUSIONS.­: Our study shows that patients infected with COVID-19 not only have diffuse alveolar damage but also commonly have acute bronchopneumonia and aspiration pneumonia. These findings are important for management of these patients.

COVID-19-Associated Nonocclusive Fibrin Microthrombi in the Heart.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. METHODS: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. RESULTS: Male sex was more common in the COVID-19 group (P=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (P=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (P=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (P=0.69, P=1.00, P=0.46, P=0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. CONCLUSIONS: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

Mechanisms of vascular dysfunction in the interleukin-10-deficient murine model of preeclampsia indicate nitric oxide dysregulation.

Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

Maternal T Cells in the Human Placental Villi Support an Allograft Response during Noninfectious Villitis.

During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR ß-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis-placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.

Suicidal Carbon Monoxide Poisoning by Formic and Sulfuric Acids.

In 1987, a case report was published in the German journal Archiv für Kriminologie describing an apparently novel method of suicide in which the decedent produced a lethal amount of carbon monoxide by mixing formic acid and sulfuric acid. This method of chemical suicide remained obscure until 2003, when Dr. Philip Nitschke, a vocal supporter of assisted suicide, began promoting a homemade carbon monoxide generator which utilized this same chemical reaction. In 2006, he coauthored The Peaceful Pill Handbook, which provided further details about how the device worked. Pro-voluntary euthanasia organizations and online forums continue to provide information about this method, promoting it as painless and efficient. There have been nine case reports of suicides and attempted suicides using this chemical reaction, with five reported in Europe, three in the United States, and one in Taiwan. Two additional cases were reported in news articles that did not correspond to known case reports, indicating that this method of suicide is more common than the scientific literature would suggest. We present the case of a 44-year-old male who learned about this method of chemical suicide online and filmed the suicidal act while verbally recording carbon monoxide levels prior to losing consciousness.

Child Death Review: Past, Present, and Future.

This article describes the current state of child death reviews (CDR) in the United States. The CDR process has evolved over almost 40 years from informal local meetings to a coordinated effort involving all 50 states. Child death review programs across the country vary in the level of financial and administrative support, legislation, and review processes. While there is still a long way to go in standardizing the practice between states, great strides have been made in data collection, education, and prevention initiatives.

Certification of Vehicular Hyperthermia Deaths in the Pediatric Population.

The investigation of vehicular hyperthermia deaths in infants and children requires coordination between the autopsy, clinical history, and scene investigation. Unfortunately, autopsy findings can be limited or nonspecific, clinical history may be unavailable, and details concerning ambient temperature and vehicular temperature may be vague. In cases where hyperthermia is established as the cause of death, the certification of manner of death can be challenging and inconsistent among medical examiners. This article provides an overview of vehicular hyperthermia deaths and the certification of cause and manner of death in these cases.

An unusual suicidal death by automobile antenna: a case report.

Worldwide, over one million people commit suicide every year. In the United States, the majority of these cases consist of gunshot wounds, hangings, and drug overdoses. Nevertheless, on rare occasions will individuals exhibit extraordinary creativity in how they decide to end their lives. A decomposing white male was found lying beside his vehicle; blood was noted on the hood. Beneath the deceased's head was a copious amount of blood, and clutched within his right hand was a vehicle radio antenna. A search of a nearby storage shed uncovered drug paraphernalia and in the decedent's bedroom were two handwritten suicide notes. At autopsy, a defect was discovered in the right posterior oropharnyx. Immediately posterior to this injury were fractures of the right transverse processes and interarticular portions of the C2 and C3 vertebrae, with perforation of the right vertebral artery. No other injuries were noted externally. Radiographs of the head and neck showed no evidence of a projectile, and no corresponding exit defect was identified. Postmortem toxicology was positive for cocaine and methamphetamine. We present a case report of a man under the influence of cocaine and methamphetamine employing a car antenna to cause self-inflicted, intraoral penetrating trauma to the cervical spine and right vertebral artery, resulting in exsanguination and his subsequent death.

Acute myocardial infarction in sickle cell anemia.

Cardiovascular dysfunction consistent with ischemia has been observed during episodes of painful crisis and following periods of heavy physical exertion in individuals with sickle cell disease. Similar findings have been observed in other individuals while taking the alpha-adrenergic agonist pseudoephedrine. However, acute myocardial infarction is extremely rare. The authors describe a case of sudden death in a child with sickle cell disease due to acute myocardial infarction and suggest that heavy exertional stress and use of pseudoephedrine may have precipitated the event.

Suicidal hangings in jail using telephone cords.

In a three month period of 2000, three suicide hanging deaths involving the use of telephone cords occurred in Texas jails and were autopsied at the Southwestern Institute of Forensic Sciences in Dallas. In each case, the telephone was located within the cell, allowing the prisoners unhindered access at any time. Because of these incidents, two of the jails shortened their receiver cords to a total length of 6-8 in. The telephones were otherwise unaltered, and are still in the same locations. The third jail replaced their entire phone with a cordless telephone. Despite the attention that these cases received, standards have not been set regarding the type or placement of telephones used within jail cells, and a fourth incident in 2002 underscores this ongoing problem. These three incidents highlight the need to provide telephones that, if placed within holding cells or other jail cells, do not provide a possible means of suicide.

Exsanguination by subclavian-esophageal fistula associated with a left subclavian aneurysm.

Aortic aneurysms are a common autopsy finding, but aneurysms confined exclusively to the subclavian arteries are rare. When found, they are typically associated with trauma, surgery, or aberrant vessel distribution. Subclavian-esophageal fistula formation is also rare, with the vast majority being related to aberrant vessel distribution or esophageal foreign bodies. Dicle et al. first reported a subclavian-esophageal fistula associated with a non-aberrant subclavian artery aneurysm in 1999 (1). The following case would mark the second report of that phenomenon, and the first in the setting of a forensic autopsy.