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Post-mortem viral dynamics and tropism in COVID-19 patients in correlation with organ damage.

ABSTRACT: The persistence of SARS-CoV-2 after death of infected individuals is unclear. The aim of this study was to investigate the presence of SARS-CoV-2 RNA in different organs in correlation with tissue damage and post-mortem viral dynamics in COVID-19 deceased. Twenty-eight patients (17 males, 11 females; age 66-96 years; mean 82.9, median 82.5 years) diagnosed with COVID-19 were studied. Swabs were taken post-mortem during autopsy (N = 19) from the throat, both lungs, intestine, gallbladder, and brain or without autopsy (N = 9) only from the throat. Selective amplification of target nucleic acid from the samples was achieved by using primers for ORF1a/b non-structural region and the structural protein envelope E-gene of the virus. The results of 125 post-mortem and 47 ante-mortem swabs were presented as cycle threshold (Ct) values and categorized as strong, moderate, and weak. Viral RNA was detected more frequently in the lungs and throat than in the intestine. Blood, bile, and the brain were negative. Consecutive throat swabs were positive up to 128 h after death without significant increase of Ct values. All lungs showed diffuse alveolar damage, thrombosis, and infarction and less frequently bronchopneumonia irrespective of Ct values. In 30% the intestine revealed focal ischemic changes. Nucleocapsid protein of SARS-CoV-2 was detected by immunohistochemistry in bronchial and intestinal epithelium, bronchial glands, and pneumocytes. In conclusion, viral RNA is still present several days after death, most frequently in the respiratory tract and associated with severe and fatal organ damage. Potential infectivity cannot be ruled out post-mortem.

SUBMITTER: Skok K

PROVIDER: S-EPMC7438212 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSevere COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19.MethodsIn this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients.FindingsThe median age at death of our cohort of ten patients was 73 years (IQR 52-79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients.InterpretationOur series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19.FundingImperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.

Project description:(1) Background: The current outbreak of COVID-19 infection is an ongoing challenge and a major threat to public health that requires surveillance, prompt diagnosis, as well as research efforts to understand the viral pathogenesis. Despite this, to date, very few studies have been performed concerning autoptic specimens. Therefore, this study aimed: (i) to reiterate the importance of the autoptic examination, the only method able to precisely define the cause of death; (ii) to provide a complete post-mortem histological and immunohistochemical investigation pattern capable of diagnosing death from COVID-19 infection. (2) Methods: In this paper, the lung examination of two subjects who died from COVID-19 are discussed, comparing the obtained data with those of the control, a newborn who died from pneumonia in the same pandemic period. (3) Results: The results of the present study suggest that COVID-19 infection can cause different forms of acute respiratory distress syndrome (ARDS), due to diffuse alveolar damage and diffuse endothelial damage. Nevertheless, different patterns of cellular and cytokine expression are associated with anti-COVID-19 antibody positivity, compared to the control case. Moreover, in both case studies, it is interesting to note that COVID-19, ACE2 and FVIII positivity was detected in the same fields. (4) Conclusions: COVID-19 infection has been initially classified as exclusively interstitial pneumonia with varying degrees of severity. Subsequently, vascular biomarkers showed that it can also be considered a vascular disease. The data on Factor VIII discussed in this paper, although preliminary and limited in number, seem to suggest that the thrombogenicity of Sars-CoV2 infection might be linked to widespread endothelial damage. In this way, it would be very important to investigate the pro-coagulative substrate both in all subjects who died and in COVID-19 survivors. This is because it may be hypothesized that the different patterns with which the pathology is expressed could depend on different individual susceptibility to infection or a different personal genetic-clinical background. In light of these findings, it would be important to perform more post-mortem investigations in order to clarify all aspects of the vascular hypothesis in the COVID-19 infection.

Project description:BackgroundProminent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS.MethodsIn this post-mortem case series, we investigated the neuropathological features in the brains of patients who died between March 13 and April 24, 2020, in Hamburg, Germany. Inclusion criteria comprised a positive test for SARS-CoV-2 by quantitative RT-PCR (qRT-PCR) and availability of adequate samples. We did a neuropathological workup including histological staining and immunohistochemical staining for activated astrocytes, activated microglia, and cytotoxic T lymphocytes in the olfactory bulb, basal ganglia, brainstem, and cerebellum. Additionally, we investigated the presence and localisation of SARS-CoV-2 by qRT-PCR and by immunohistochemistry in selected patients and brain regions.Findings43 patients were included in our study. Patients died in hospitals, nursing homes, or at home, and were aged between 51 years and 94 years (median 76 years [IQR 70-86]). We detected fresh territorial ischaemic lesions in six (14%) patients. 37 (86%) patients had astrogliosis in all assessed regions. Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 34 (79%) patients. SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem. The presence of SARS-CoV-2 in the CNS was not associated with the severity of neuropathological changes.InterpretationIn general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included.FundingGerman Research Foundation, Federal State of Hamburg, EU (eRARE), German Center for Infection Research (DZIF).

Project description:BackgroundMajor organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls.ObjectiveExamine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls.Data sourcesMEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021.Study eligibility criteriaEnglish language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text.Study appraisal and synthesis methodsStudy quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised.ResultsOf 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%-94% male and 48%-78% White race; 10%-40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls.LimitationsApplicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown.Conclusions and implications of key findingsPostacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps.Prospero registration numberCRD42020204788.

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Post-mortem viral dynamics and tropism in COVID-19 patients in correlation with organ damage.

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