Discussion
In this observational prospective multicentre study, we report the characteristics, early outcome and management of the COVID-19 outbreak on the largest European cohort of liver transplant patients with confirmed SARS-CoV-2 infection up to date. Case fatality rate of the overall study population was 12% (95% CI 5% to 24%), whereas that of the hospitalised patients was 17% (95% CI 7% to 32%). This latter is in line with that of the general population, as reported by most of the largest studies, where the in-hospital case fatality rate ranges from 15% to 22%.1 25 26 All the patients who died, except one, were men. CV disease, obesity, arterial hypertension, diabetes mellitus and chronic kidney disease, although well represented in our population, were not over-represented in the group with adverse outcomes. A clinical history of neoplasia, especially an active cancer at the moment of the diagnosis, was frequently found in the group with a worse prognosis. Recently transplanted patients presented with less fever and respiratory-related symptoms than patients who were transplanted for more than 1 and 5 years, respectively. Among laboratory data, lymphocytopenia and thrombocytopenia were more frequent in patients who died. Alteration in liver enzymes was mild and rarely observed, although mostly found in hospitalised patients. Whether the immunosuppression was decreased or left unchanged had no impact on outcome.
Our study suggests that, despite well-described risk factors for poor outcome of COVID-19 infection are highly represented in our cohort, COVID-19 liver transplant patients show a clinical course not necessarily more severe to that observed in non-liver transplant patients affected by COVID-19.25–27 Publications pooling patients with different organ transplanted reported worse outcomes (in-hospital case fatality rate 24%–27%).11 13 Another publication merging surveys from European and American centres with a smaller sample than our prospective study reported 9 deaths among 39 liver transplant patients.28 Like others, we find that male patients are more prone to develop ARDS29 and have a more severe outcome.25 Although highly frequent in our cohort, CV and metabolic comorbidities were not over-represented in patients with poor outcomes.25 26 History of previous or active cancer, such as being transplanted for HCC or having cancer at the moment of the COVID-19 diagnosis, was associated with a poor outcome. This is in agreement with a national Chinese report on over 2000 confirmed COVID-19 cases with a history of cancer, showing them having higher risk to contract COVID-19 and poorer outcome than individuals without cancer.30 31
Concerning clinical presentation, patients transplanted for less than 5 years exhibited less frequently fever and dyspnoea. This may suggest higher immunosuppression attenuates COVID-19 typical clinical symptoms. GI manifestations were common (33%) in our series, which is in line with the 29% reported in solid organ transplant recipients in Spain.11
Lymphopenia has been reported to be predictive of poor outcome in non-transplanted COVID-19 patients.29 32 A similar trend was found also in our cohort of liver transplant patients.
One of the key questions in the management of liver transplant patients affected with COVID-19 concerns the management of the immunosuppression.33 In our cohort, the immunosuppression was reduced in 39% of the patients and discontinued in 7%. Mycophenolate mofetil was the most discontinued therapy. The majority of the patients with COVID-19 who did not need a hospitalisation were kept on their usual immunosuppressive regimen. Although some reports want to suggest a potential positive role of tacrolimus as antiviral in the treatment of human coronaviruses,34 since 88% of our patients were treated with CNIs, it was not possible to assess any specific effect of this therapy.
Our study has limitations. All the participating centres are European. It will be important to have similar prospective studies from other continents. We limited our analysis to the patients with a positive reverse transcription PCR for SARS-CoV-2. We did not include patients with typical presentation but without a microbiological confirmation due to lack of testing capacity. On the other hand, the NAAT assay as the recommended confirmatory test has a sensitivity in the order of 71%,35 and this could be lower in immunosuppressed population.13 Moreover, although liver transplant patients were generally well instructed to contact their transplant centre as far as COVID-like symptoms appeared, we cannot exclude a global underestimation of the total number of COVID-19 infections in this population.
Our study has strengths. It is, at the time of writing, the largest prospective study of liver recipient patients affected by COVID-19. It is by design not a survey but a prospective acquisition of data approved by local ethics committees.
In conclusion, in this European multicentre prospective study of liver transplant recipients, COVID-19 is associated with an overall and in-hospital case fatality rate of 12% (95% CI 5% to 24%) and 17% (95% CI 7% to 32%), respectively. Patients infected early after liver transplantation did not have a worse outcome and tend to have less symptoms. A history of cancer was more frequent in patients with poorer outcome.