Systemic Analysis of the Hallmarks of Advanced COVID-19 Pathology

Doctor looks at X-ray images of lungs
Study authors provided a systemic analysis of to identify key characteristics of extensive and advanced COVID-19.

Extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, and infected cell syncytia are hallmark signs of advanced coronavirus disease 2019 (COVID-19), according to a study published in EBioMedicine. Virus-infected cells persisting weeks after the initial diagnosis may have an important role in symptoms and severity of COVID-19.

Study authors conducted a post-mortem analysis on the lungs, brains, hearts, livers, and kidneys of 41 consecutive patients who died of COVID-19 at the University Hospital in Trieste, Italy. Of these, 6 patients required intensive care (IC). Immunohistochemistry staining was performed on all tissue samples. In situ hybridization to detect the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome was performed in tissue samples from the IC patients and 5 non-IC patients who met specific criteria.

At baseline, the most common comorbidities were hypertension (n=17), chronic cardiac disease (n=13), dementia (n=13), diabetes (n=12), and cancer (n=12).

Of the 11 samples that underwent in situ hybridization, 10 showed numerous SARS-CoV-2-infected cells expressing viral Spike protein in lung tissue. Study results showed extensive lung vessel thrombosis in the micro- and macro-vasculature in 5 IC patients (83%) and 16 non-IC patients (46%). These thrombi exhibited different stages of organization, suggesting an endogenous ongoing thrombotic process in the lung.

A total of 29 patients (71%) in the study had a sporadic lung thrombosis and 10 patients (24%) had ongoing vasculitis in the lung micro- and macro-vasculature. Dysmorphic cells, often showing syncytia, were present in pneumocytes of 20 patients (50%), including all 6 IC patients.

The presence of SARS-CoV-2 RNA in lung cells weeks after initial diagnosis challenges the theory that COVID-19 follows a biphasic course, with an initial phase of viral replication followed by a second phase of hyperinflammation in which viral replication is less relevant.

“Presence of abundant cytoplasmic RNA signals and expression of the Spike protein in the lungs after 30-40 days from diagnosis in our study suggests ongoing replication and postulates a continuous pathogenic role of viral infection,” investigators noted. Other hallmark signs of COVID-19 were massive lung thrombosis and endothelial dysfunction, and both were directly linked to the persistence of these virus-infected cells.


Bussani R, Schneider E, Zentilin L, et al. Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine. 2020;61(103104). doi: 10.1016/j.ebiom.2020.103104