Reply.

We thank Mr Ng for his insightful remarks related to COVID-19, liver injury, and regeneration in our recent article. These additional comments will help to open up commentary on the possible long-term consequences with COVID-19 in liver transplant (LT) recipients, particularly in the setting of severe disease and/or reinfection. However, it is hoped that widespread and early use of COVD-19 vaccines in these patients may preclude some of these concerns. ,

In our own work, we investigated patterns of liver injury, vascular involvement, and regeneration in 60 patients who died of COVID-19 pneumonia, along with 13 patients who died of non-COVID fatal pneumonia (serving as disease control subjects). There are other autopsy studies where COVID-19 has been likewise significantly associated with liver involvement and thromboembolic complications. Additional recent publications indicate that the presence of underlying liver disease can provoke worse outcomes in COVID-19 disease.

COVID-19 in LT recipients results in higher numbers of intensive care unit admission and rates of mechanical ventilation. , LT patients with COVID-19 do exhibit a higher risk of acute liver injury, which may mirror the histopathologic findings we have noted in nontransplant patients. We might postulate, that direct damage of liver cells by SARS-CoV-2 and changes of immunometabolic responses might provoke severe liver injury especially in immunosuppressed LT recipients with coexistent metabolic syndrome, as noted previously.

Our data on regenerative responses in fatal COVID-19 revealed increased frequency of hepatic stem/progenitor cells. The relevance of such histopathologic changes of hepatic repair for patients in the course of LT or other concomitant pathophysiological scenarios of the liver in COVID-19 remains unclear.

We agree that adverse possibilities may be afforded by SARS-CoV-2 “long-haul” outcomes, reinfection, and emergence of variant viruses. These do raise the spectra of irreversible graft disease, which might increase risks of retransplantation. This area of clinical endeavor requires further research with elucidation of pathogenic mechanisms and better determination of risk to help answer the provocative questions raised by Mr. Ng.