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We read with great interest the COVID-LT study by C Becchetti et al,1 which included 57 liver transplant (LT) patients from 12 European institutions who were diagnosed with coronavirus disease 2019 (COVID-19). Simultaneously, the Spanish Society of Liver Transplantation (SETH) has conducted a nationwide prospective study including 22 transplant institutions and 111 LT patients with COVID-19.2 Since there were only nine overlapped cases, both cohorts add up to 159 LT patients and taken together their close analysis (table 1) may derive in practical conclusions.
The crude incidence of COVID-19 was increased in the SETH study as compared with the COVID-LT study (0.84% vs 0.48%), even with a shorter recruitment period. This could be explained because the SETH study was performed during the outbreak period in Spain, one of the toughest in Europe.3 The SETH study allowed to calculate standardised incidence ratio (SIR) and found that LT patients may have doubled risk of acquiring COVID-19 within an epidemic scenario (SIR 191.2; 95% CI 190.3 to 192.2) as compared with age-matched and gender-matched general population.2 Although LT patients could have been tested more frequently for COVID-19 given their lifelong clinical surveillance, this may have had limited influence in the SETH cohort as 93.7% of patients were symptomatic and there was no differential testing protocol for immunosuppressed or fragile patients according to the Spanish national authorities. Therefore, the increased SIR in LT patients claim for a stricter social distancing and to consider an earlier access to vaccination whenever available.
Clinical features and outcomes were much alike in both cohorts (table 1). The COVID-LT investigators hypothesised that the clinical course of COVID-19 in LT patients, despite increased comorbidities,4 may not be more severe to that observed in non-liver transplant cohorts.1 The results of the SETH study confirmed that mortality rates are actually lower in LT patients as compared with age-matched and gender-matched general population (standardised mortality ratio 95.5; 95% CI 94.2 to 96.8).2 Noteworthy, no death was registered among LT patients younger than 50 years old in both cohorts.
The role of immunosuppression in COVID-19 could not be explored in depth by the COVID-LT investigators as the primary endpoint (ie, death) only occurred in seven patients. The SETH study used severe COVID-19 as a composite main endpoint, which comprised mechanical ventilation, admission to intensive care unit and/or death. Although death alone may be considered a harder outcome, severe COVID-19 may better capture the most severe forms of the disease and it was used in the original report of COVID-19 in China.5 This composite endpoint allowed to analyse independent predictors of worse outcomes, including immunosuppression. Both cohorts showed that complete discontinuation of immunosuppression after COVID-19 diagnosis had no benefit. Regarding calcineurin inhibitors, in vitro studies have shown antiviral properties against coronaviruses.6 7 In the COVID-LT study, the continuation on calcineurin inhibitor therapy after COVID-19 diagnosis was increased among survivors (64% vs 42.8%).1 In the SETH study, baseline immunosuppression containing tacrolimus had a trend towards reduced risk of severe COVID-19 in the univariate analysis (relative risk (RR)=0.54; p=0.08). More importantly the SETH study showed that baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (RR=3.94; p=0.003), particularly at doses higher than 1000 mg/day. Complete withdrawal of mycophenolate at COVID-19 diagnosis ameliorated the risk of severe COVID-19 (41.7% vs 69.2%; p=0.16).2 The relationship between mycophenolate and severe COVID-19 could be explained by a synergic effect (viral and pharmacological) on depleting T-lymphocytes, with an increase in CD4+/CD8+ ratio, being both features strongly associated with worse outcomes.8
Taken together, the COVID-LT and the SETH cohorts suggest that chronic immunosuppression could exert a protective effect against the most severe forms of COVID-19 and complete withdrawal of immunosuppression may not be useful. Unlike calcineurin inhibitors, mycophenolate could be deleterious for COVID-19 successful resolution, thus providing a rationale to modulate immunosuppression in transplant patients with COVID-19. Further studies, randomised if possible, are required.
Contributors MRP drafted the manuscript; MS, JC and JAP critically reviewed the manuscript for important intellectual content. All authors have approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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