Reply to: “Age and comorbidity are central to the risk of death from COVID-19 in liver transplant recipients”
Authors: Manuel Rodríguez-Perálvarez, Jordi Colmenero, Magdalena Salcedo
Journal: Journal of Hepatology (2021)

Age and comorbidity are central to the risk of death from COVID-19 in liver transplant recipientsJournal of HepatologyVol. 75Issue 1PreviewOur understanding of the impact of COVID-19 on liver transplant recipients has recently advanced significantly. In August 2020 Colmenero et al. published data on behalf of the Spanish Liver Transplant Society (SETH) in the Journal of Hepatology.1 The authors reported data on 111 LT recipients with SARS-CoV-2 infection and concluded that these patients were at no greater risk of severe COVID-19 than the general population. Furthermore, within LT recipients, comorbidity, male sex, and mycophenolate mofetil (MMF) use were reported as associated with severe disease. Full-Text PDF Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patientsJournal of HepatologyVol. 74Issue 1PreviewThe incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate. Full-Text PDF We read with great interest the letter by G. J. Webb et al.1Webb G.J. Moon A.M. Barnes E. Barritt A.S. Marjot T. Age and comorbidity are central to the risk of death from COVID-19 in liver transplant recipients.J Hepatol. 2021; 75: 226-228Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar regarding our recent nationwide study promoted by the Spanish Society of Liver Transplantation (SETH), which evaluated the incidence and outcomes of coronavirus disease 2019 (COVID-19) in liver transplant (LT) patients.2Colmenero J. Rodríguez-Perálvarez M. Salcedo M. Arias-Milla A. Munoz-Serrano A. Graus J. et al.Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.J Hepatol. 2021; 74: 148-155Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar The authors merged the SETH data with their own international cohort (COVID-Hep/SECURE-Cirrhosis)3Webb G.J. Marjot T. Cook J.A. Aloman C. Armstrong M.J. Brenner E.J. et al.Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.Lancet Gastroenterol Hepatol. 2020; 5: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar resulting in 258 LT patients with COVID-19. The combined data analysis allowed them to highlight the importance of age and comorbidities as key factors influencing outcomes. We completely agree with this conclusion, which may also be true for non-transplant patients with COVID-19. However, some statements require further clarification. Firstly, Webb et al. used overall mortality as the only outcome in the analysis. Although mortality is the true hard outcome, there are some patients with severe acute respiratory distress syndrome who will not ultimately die but who will require mechanical ventilation and prolonged stay in the intensive care unit, with important physical and cognitive sequelae.4Hosey M.M. Needham D.M. Survivorship after COVID-19 ICU stay.Nat Rev Dis Primers. 2020; 6: 60Crossref PubMed Scopus (143) Google Scholar As these survivors are mostly young individuals without previous comorbidities, neglecting them in the primary outcome would increase the relative weight of older age and comorbidities as prognostic factors in the multivariate analysis. A composite endpoint including mechanical ventilation, admission to the intensive care unit and/or death (whatever occurred first) would be more appropriate to capture the true severity of COVID-19, independently of age and comorbidities. This composite endpoint has been used in large cohort studies evaluating clinical features and outcomes in COVID-19.5Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20519) Google Scholar An important limitation of the COVID-Hep/SECURE-Cirrhosis study3Webb G.J. Marjot T. Cook J.A. Aloman C. Armstrong M.J. Brenner E.J. et al.Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.Lancet Gastroenterol Hepatol. 2020; 5: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar was that the interval from diagnosis to outcome was not recorded. This is why the authors had to use multivariate logistic regression for the merged database analysis. Since both mortality and the composite event are time-dependent outcomes, this statistical approach may not be optimal, particularly in clinical situations in which the time of follow-up varies among patients, as in this case. As a consequence, and also influenced by the reduction in statistical power associated with the outcome modification, the statistical significance of mycophenolate mofetil to increase the risk of severe COVID-19 found in our study (relative risk [RR] 3.94; 95% CI 1.59–9.74; p = 0.003)2Colmenero J. Rodríguez-Perálvarez M. Salcedo M. Arias-Milla A. Munoz-Serrano A. Graus J. et al.Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.J Hepatol. 2021; 74: 148-155Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar was lost in the analysis by Webb et al. regarding mortality3Webb G.J. Marjot T. Cook J.A. Aloman C. Armstrong M.J. Brenner E.J. et al.Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.Lancet Gastroenterol Hepatol. 2020; 5: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar (odds ratio [OR] 3.15; 95% CI 0.94–10.53; p = 0.063). However, the deleterious effect of mycophenolate mofetil on COVID-19 severity seems consistent and clinically relevant with a similar RR and OR, respectively, in both analyses, and it is a matter of sample size and statistical approach to obtain significant results. In our study using Kaplan-Meier curves and Cox's regression analysis, we showed a dose-dependent relationship between mycophenolate mofetil at baseline and development of severe COVID-19 during follow-up (p = 0.003). In addition, among those patients receiving the full dose of mycophenolate (i.e. 2,000 mg per day), a complete drug withdrawal upon admission had a trend towards reduced severity of COVID-19.2Colmenero J. Rodríguez-Perálvarez M. Salcedo M. Arias-Milla A. Munoz-Serrano A. Graus J. et al.Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.J Hepatol. 2021; 74: 148-155Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Indeed, there is a plausible physiopathological mechanism underlying these clinical observations consisting of a synergic and deleterious effect of mycophenolate and SARS-CoV-2 on depleting lymphocytes, which ultimately results in worse outcomes.5Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20519) Google Scholar,6Wang F. Nie J. Wang H. Zhao Q. Xiong Y. Deng L. et al.Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.J Infect Dis. 2020; 221: 1762-1769Crossref PubMed Scopus (272) Google Scholar Regarding other immunosuppressants, we found a protective role of tacrolimus against severe COVID-19 in the initial multivariate model (RR 0.19; 95% CI 0.05–0.68; p = 0.011), but its significance was lost in the final model. In a more recent international cohort including data from 243 LT patients with COVID-19 from 9 European countries, tacrolimus was found to reduce the risk of mortality after controlling for age and comorbidities in the multivariate analysis (hazard ratio 0.55; 95% CI 0.31–0.99; p = 0.049).7Belli L.S. Fondevila C. Cortesi P.A. Conti S. Karam V. Adam R. et al.Protective role of tacrolimus, deleterious role of age and comorbidities in liver transplant recipients with Covid-19: results from the ELITA/ELTR multi-center European study.Gastroenterology. 2021; 160: 1151-1163Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar The role of mTOR inhibitors could not be adequately analyzed in these studies since they were seldom used in the included patients but the merged database analysis of Webb et al. again provided interesting results with a trend towards reduced risk of mortality in patients receiving everolimus after controlling for age and comorbidities (OR 0.31; 95% CI 0.08–1.11; p = 0.071).1Webb G.J. Moon A.M. Barnes E. Barritt A.S. Marjot T. Age and comorbidity are central to the risk of death from COVID-19 in liver transplant recipients.J Hepatol. 2021; 75: 226-228Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Finally, corticosteroids have been demonstrated to improve survival in immunocompetent patients with COVID-19 in well-designed randomized controlled trials.8Group R.C. Horby P. Lim W.S. Emberson J.R. Mafham M. Bell J.L. et al.Dexamethasone in hospitalized patients with covid-19.N Engl J Med. 2021; 384: 693-704Crossref PubMed Scopus (7056) Google Scholar In conclusion, age and comorbidities are crucial determinants of the severity of COVID-19 infection (and of mortality) among LT patients. However, the immunosuppression protocol may be the only true modifiable risk factor. Taken together, the available series, each with inherent strengths and limitations, point in the same direction: modifications of baseline immunosuppression could be helpful to ameliorate the severity COVID-19. In the absence of randomized controlled trials in LT patients, the current evidence calls for the consideration of a dose reduction or withdrawal of mycophenolate and maintenance or initiation of other immunosuppressants, such as corticosteroids, tacrolimus or everolimus, in LT patients with confirmed COVID-19. The Spanish Society of Liver Transplantation (SETH) was the only funding agent. All authors contributed equally to this work. JC has received lecture fees from Chiesi, Astellas and Novartis. Advisory to Chiesi. MR-P has received lecture fees from Astellas, Novartis and Intercept Pharma. MS has received lecture fees from Astellas, Novartis, and Chiesi. Advisory to Jazz and Novartis. JP has received lecture fees by Astellas, Chiesi, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.17 MB) Help with pdf files Multimedia component 1