SARS-CoV-2 viral liver aggregates and scarce parenchymal infection implicate systemic disease as a driver of abnormal liver function

Background: Liver function tests (LFTs) are elevated in > 50% of hospitalized individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), with increased enzyme levels correlating with a more severe COVID-19 course. Despite these observations, evaluations of viral presence within liver parenchyma and viral impact on liver function remain controversial. Methods and Results: Our work is a comprehensive immunopathological evaluation of liver tissue from 33 patients with severe, and ultimately fatal, cases of SARS-CoV-2 infection. Coupled with clinical data, we reveal the absence of SARS-CoV-2 infection in cholangiocytes and hepatocytes despite dramatic systemic viral presence. Critically, we identify significant focal viral sinusoidal aggregates in 2/33 patients and single viral RNA molecules circulating in the hepatic sinusoids of 15/33 patients. Utilizing co-immunofluorescence, focal viral liver aggregates in patients with COVID-19 were colocalized to platelet and fibrin clots, indicating the presence of virus-containing sinusoidal microthrombi. Furthermore, this patient cohort, from the initial months of the COVID-19 pandemic, demonstrates a general downtrend of LFTs over the course of the study timeline and serves as a remarkable historical time point of unattenuated viral replication within patients. Conclusions: Together, our findings indicate that elevated LFTs found in our patient cohort are not due to direct viral parenchymal infection with SARS-CoV-2 but rather likely a consequence of systemic complications of COVID-19. This work aids in the clinical treatment considerations of patients with SARS-CoV-2 as therapies for these patients may be considered in terms of their direct drug hepatotoxity rather than worsening hepatic function due to direct infection.