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A study published in EBioMedicine shows unique characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may explain why patients suffer from severe, prolonged coronavirus disease 2019 (COVID-19).
Rossana Bussani, MD, University of Trieste,Trieste, Italy, and colleagues analysed the organs of 41 patients who died of COVID-19 at the University Hospital of Trieste. The researchers took lung, heart, liver, and kidney samples to examine the behaviour of the virus. Of the 41 patients, 6 required intensive care, while 35 were hospitalised in either other hospital units or local nurseries until death. The average age of patients was 77 and 84 years for males and females, respectively. Hypertension, chronic cardiac disease, dementia, diabetes and cancer were the most common comorbidities. All patients eventually died of clinical acute respiratory distress syndrome.
At pathological examination, the researchers found that all cases exhibited lung damage and the lungs appeared congested at macroscopic examination. Meanwhile, histological analysis of all cases revealed gross destruction of the normal lung architecture, consistent with a condition of diffuse alveolar damage with edema, intra-alveolar fibrin deposition with hyaline membranes and hemorrhage. This was accompanied by occlusion of alveolar spaces due to cell delamination. Loss of cellular integrity was also confirmed by the presence of nuclear dust, indicative of ongoing cellular death.
In addition, the researchers reported numerous abnormalities in the pulmonary macro- and micro-vasculature in COVID-19 patients. Alterations of the pulmonary vasculature were concomitant with extensive lung vessel thrombosis, which was detected in 5 (83%) of 6 patients in intensive care and 16 (46%) of 35 non-intensive care patients. Thrombi were hetero-synchronous, showed different stages of organization, with some thrombi still infiltrated by inflammatory cells and others in an advanced, fibrotic stage. The researchers said this is suggestive of endogenous thrombosis in the lung, although repeated embolic episodes cannot be excluded. Sporadic lung thrombosis was also present in additional 8 of 35 of the non-intensive care patients, for a total of 29 (71%) of all the patients that were analysed.
Further, in situ RNA hybridisation for the detection of the SARS-CoV-2 genome indicated that the alterations in the lung were concomitant with persistent viral infection of pneumocytes and endothelial cells. RNA-positive pneumocytes were found to be largely present in the lungs of 10 of 11 tested individuals. The authors said presence of abundant cytoplasmic RNA signals and expression of the Spike protein in the lungs after 30-40 days from diagnosis in the study suggests ongoing replication and postulates a continuous pathogenetic role of viral infection.
The researchers also noted the presence of anomalous epithelial cells among the cases which were characterised by abnormally large cytoplasm and, very commonly, by the presence of bi- of multi-nucleation. Presence of these dysmorphic cells was detected in 87% of patients. They added that the dysmorphic cells very often showed features of syncytia, characterised by several nuclei with an ample cytoplasm surrounded by a single plasma membrane. Most of these syncytia-forming, dysmorphic cells were bona fide pneumocytes.
Meanwhile, despite occasional detection of virus-positive cells, no overt signs of viral infection were detected in other organs, which showed non-specific alterations.
“COVID-19 is a unique disease characterised by extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, along with the presence of infected cell syncytia,” the authors wrote. “Several of COVID-19 features might be consequent to the persistence of virus-infected cells for the duration of the disease.”
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