SARS-COV-2 ENDOTHELIAL DYSFUNCTION CAN CAUSE ERECTILE DYSFUNCTION: HISTOPATHOLOGICAL, IMMUNOHISTOCHEMICAL AND ULTRASTRUCTURAL STUDY OF THE HUMAN PENIS

ABSTRACT

OBJECTIVE: To describe the histopathological features of penile tissue of patients who recovered from symptomatic COVID-19 infection and subsequently developed severe erectile dysfunction (ED). MATERIALS AND METHODS: After providing informed consent, penile tissue was collected from patients undergoing surgery for inflatable penile prosthesis due to severe ED under an IRB approved protocol. Two specimens were obtained from men with a history of COVID-19 infection and two specimens were obtained from men with no history of infection (all men tested negative immediately before surgery). Tissue from COVID-19 (+) and COVID-19 (-) specimens were imaged with transmission electron microscopy (TEM). The tissue was analyzed for viral RNA using polymerase chain reaction (PCR) and viral spike protein. Formalin-fixed paraffinembedded tissues were stained with hematoxylin and eosin (H&E) and subjected to immunohistochemical analysis for endothelial Nitric Oxide Synthase (eNOS) expression (marker of endothelial function). Endothelial progenitor cells (EPC) function was assessed ex vivo by determination of endothelial colony forming units from blood samples collected from the COVID-19 (+) and COVID (-) men with severe ED. RESULTS: TEM revealed extracellular viral particles ∼100 nm in diameter, with prominent peplomers (spikes), and electron-dense dots of the nucleocapsid inside the particles near penile vascular endothelial cells of the COVID-19 (+) patients. Notably, viral particles were not detected in tissue obtained from COVID-19 (-) men. COVID-19 RNA was detected in both the penis biopsy samples from men with a history of COVID, but not in the samples from COVID-19 (-) men. There were no significant differences in H&E staining between COVID-19 (+) and COVID-19 (-) men and viral spike protein was not detected. Immunohistochemistry showed decreased eNOS expression in the corpus cavernosum of COVID-19 (+) men compared to COVID-19 (-) men, consistent with endothelial dysfunction. COVID-19 spike protein-positive cells could not be detected by immunofluorescence despite positive COVID-19 PCR. EPC levels from the COVID-19 (+) men were 0 cell/well and 1.167 cell/well respectively compared to mean EPCs from 34 COVID-19 (-) men with severe ED (4.04 cells/well), suggesting impaired endothelial function. CONCLUSIONS: Our study is the first to demonstrate the presence of COVID-19 virus in the penis long after the initial infection in humans. Our study also suggests that widespread endothelial cell dysfunction from COVID-19 infection can contribute to resultant erectile dysfunction. Future studies will evaluate novel molecular mechanisms of how COVID-19 infection leads to ED. IMPACT STATEMENT COVID-19 can linger in the penis long after initial infection and can contribute to erectile dysfunction.