Increased Angiotensin-Converting Enzyme 2 and Loss of Alveolar Type II Cells in COVID-19-related Acute Respiratory Distress Syndrome.

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.

Serum uric acid, disease severity and outcomes in COVID-19.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. METHODS: In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. RESULTS: The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50-168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6-7.8, P < 0.001) or competing risks (adjusted hazard ratio 20.8, 95% confidence interval 10.4-41.4, P < 0.001) models. At the structural level, kidneys from patients with COVID-19 showed a major reduction in urate transporter URAT1 expression in the brush border of proximal tubules. CONCLUSIONS: Among patients with COVID-19 requiring hospitalization, low serum levels of uric acid are common and associate with disease severity and with progression to respiratory failure requiring invasive mechanical ventilation.

The Liver in COVID-19-Related Death: Protagonist or Innocent Bystander?

INTRODUCTION: The coronavirus disease 2019 (COVID-19) infection, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), involves several organs through participation of angiotensin-conversion enzyme 2 (ACE2) receptors. The presence of ACE2 receptors in the liver renders this organ a potential target for the novel coronavirus. METHODS: We performed 14 complete autopsies of patients infected with SARS-CoV-2. In each case we stained liver tissue sections with haematoxylin/eosin, Masson blue trichrome stain, periodic acid-Schiff (PAS), Perls, and performed cytokeratin-7 (CK7) immunochemistry. RESULTS: Macroscopically, livers were pale and yellowish in 8 of 14 (57%) patients, and had a nutmeg appearance in the other 6 cases (42%). Histologically, centrolobular necrosis was observed in 12 cases (86%), and was associated with discreet to moderate lobular or portal inflammation. Steatosis was seen in 8 cases (57%), but fibrosis was rare. Cholestasis and discrete bile duct proliferation was observed in 5 cases (36%). DISCUSSION/CONCLUSION: The main histological changes can be explained by the hypoxic status as a result of severe hypoxemic pneumonia leading to death. Drug toxicity may also play a role in certain cases. Other histological changes may be explained by previous hepatic conditions or underlying hepatic diseases. We concluded that COVID-19 infection was not associated with a specific histopathological pattern of the liver.

SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.

Postmortem diagnosis of hyponatremia: case report and literature review.

Hyponatremia is defined as a plasma sodium concentration less than 135 or 130 mEq/L (or mmol/L) and may be responsible for life threatening symptoms that can be observed in a variety of medical conditions. Cases of fatal hyponatremia have been reported in both clinical and forensic literature in situations of water intoxication due to psychogenic polydipsia, amphetamine derivative drug intake, high-endurance exercise, iatrogenic causes, and exceptional cases of child abuse by forced water intoxication. Vitreous sodium levels have been determined to be relatively stable during the early postmortem period and similar to levels found in normal serum of living subjects. Nevertheless, there are relatively few cases of fatal hyponatremia described in literature that underwent exhaustive postmortem biochemical investigations. A case of fatal water intoxication in a psychiatric patient who underwent medicolegal investigations, including postmortem biochemistry, was chosen as a starting point to a literature review of deaths by hyponatremia that may be encountered in the forensic setting.

Bupropion Overdose Resulted in a Pharmacobezoar in a Fatal Bupropion (Wellbutrin® ) Sustained-release Overdose: Postmortem Distribution of Bupropion and its Major Metabolites.

Bupropion (BUP) overdose commonly causes generalized seizures and central nervous system depression. The case of a 28-year-old woman who died from a massive lethal overdose with sustained-release bupropion (Wellbutrin® 300 mg) is herein presented. The autopsy revealed the presence of a pharmacobezoar consisting of at least 40 tablets in the stomach. Determination of bupropion and its active metabolites (hydroxybupropion, threobupropion, erythrobupropion) was achieved by a liquid chromatographic mass spectrometry (LC-MS/MS) method. Postmortem concentrations for bupropion, hydroxybupropion, threobupropion, and erythrobupropion were obtained in intracranial blood, urine, bile, liver, kidney, and vitreous humor. In this case, intracranial blood level of the parent drug was 1.9 mg/L. Threobupropion was the most abundant metabolite in both blood and urine, 59.3 and 890.6 mg/L. Tissue distribution showed the highest concentration in the liver, 12.3 mg/kg. The 0.8 bupropion concentration ratio vitreous/blood suggested that vitreous could be a valuable specimen for toxicological analysis should postmortem blood be unavailable.

Diagnosis of myocardial ischemia combining multiphase postmortem CT-angiography, histology, and postmortem biochemistry.

PURPOSE: The aim of this study was to assess whether the identification of pathological myocardial enhancement at multiphase postmortem computed tomography angiography was correlated with increased levels of troponin T and I in postmortem serum from femoral blood as well as morphological findings of myocardial ischemia. We further aimed to investigate whether autopsy cases characterized by increased troponin T and I concentrations as well as morphological findings of myocardial ischemia were also characterized by pathological myocardial enhancement at multiphase postmortem computed tomography angiography. MATERIALS AND METHODS: Two different approaches were used. In one, 40 forensic autopsy cases that had pathological enhancement of the myocardium (mean Hounsfield units ≥95) observed at postmortem angiography were retrospectively selected. In the second approach, 40 forensic autopsy cases that had a cause of death attributed to acute myocardial ischemia were retrospectively selected. RESULTS: The preliminary results seem to indicate that the identification of a pathological enhancement of the myocardium at postmortem angiography is associated with the presence of increased levels of cardiac troponins in postmortem serum and morphological findings of ischemia. Analogously, a pathological enhancement of the myocardium at postmortem angiography can be retrospectively found in the great majority of autopsy cases characterized by increased cardiac troponin levels in postmortem serum and morphological findings of myocardial ischemia. CONCLUSIONS: Multiphase postmortem computed tomography angiography is a useful tool in the postmortem setting for investigating ischemically damaged myocardium.

Philemon and Baucis deaths: case reports and postmortem biochemistry contribution.

The death of a person as a reaction to the death of another is known as Philemon and Baucis death and may represent a difficult challenge for pathologists, especially due to the decompositional changes that often characterized these situations. In this article, we describe two cases of Philemon and Baucis deaths, the first concerning a married couple and the second concerning a father and son. Postmortem investigations including radiology and biochemistry were performed. Based on the results of all investigations, deaths were attributed to natural causes. Third-party involvement could be excluded in both situations. In one case, biochemical analysis results revealed potentially contributing causes of death. The reported cases emphasize the importance of correlating findings from different postmortem investigations to identify causes of death, precipitating conditions and predisposing disorders, thus allowing the conclusion of natural death to be reached and third-party involvement to be excluded.