key: cord-1007871-3llo88jo authors: Pearson, Meredith M.; Limaye, Ajit P.; Biggins, Scott W. title: Tacrolimus: Unlikely harmful and perhaps helpful in liver transplant recipients with COVID-19 date: 2020-12-30 journal: Gastroenterology DOI: 10.1053/j.gastro.2020.12.050 sha: 4e4ed1802426bb1c5329cfdb510f5cbeb40d62be doc_id: 1007871 cord_uid: 3llo88jo nan Now almost one year into the COVID-19 pandemic, medical recommendations for patients infected with its causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continue to evolve. The impact and management of chronic immunosuppressive medications, such as those required after liver transplantation (LT), has been one such topic of deliberation. Experts recommend consideration of lowering the overall level of immunosuppression, as is the recommendation for managing severe infections in general. 1 A contrasting consideration has been the hypothesis that COVID-19 can cause dysregulated, excessive inflammatory activity, in which immunomodulators could potentially be beneficial. To complicate things further, this "cytokine storm" association has been called into question as studies have shown lower levels of key inflammatory cytokines in cohorts with COVID-19 compared to those with acute respiratory distress syndrome, 2, 3 and in a randomized, placebo-controlled trial, the interleukin (IL)-6 inhibitor tocilizumab failed to improve outcomes in patients with COVID-19. 4 Compared to the general population, solid organ transplant recipients appear to have higher rates of SARS-CoV-2 infection, but of those hospitalized, short-term outcomes are similar. [5] [6] [7] [8] This also seems to be true in non-transplant populations on immunosuppressive medications; in a large cohort of patients with inflammatory bowel disease and COVID-19, chronic treatment with TNF antagonists was not a risk factor for severe COVID-19. 9 However, all immunosuppressants are equal. Mycophenolate-containing immunosuppression has been found to be a predictor of severe COVID-19, an effect not observed with calcineurin inhibitors or mTOR inhibitors. 6 This may be related to its potential to cause lymphopenia, which has been found to be predictive of poor outcomes in those with COVID-19. 10 J o u r n a l P r e -p r o o f cyclosporine, mycophenolate mofetil, and mTOR inhibitors. On initial analysis, advanced age (older than 70 years) was the only factor independently associated with increased mortality, but given the association between increasing age and comorbidities, a second model excluding age, showed diabetes and chronic kidney disease as independent risk factors for mortality as well. This study may be the first to show an independent association between tacrolimus and improved survival in patients with COVID-19. Tacrolimus, a calcineurin inhibitor, exerts its immunosuppressive effect by inhibiting transcriptional activation of multiple cytokine genes, including those for IL-2 and tumor necrosis factor (TNF)-alpha. Tacrolimus and cyclosporine have also been shown to inhibit coronavirus replication in vitro, 11, 12 so perhaps the benefit is due to a direct antiviral effect rather than an immunomodulatory one; however, an antiviral effect has not yet been confirmed in vivo. While this observed association between tacrolimus and survival is certainly intriguing, more studies are needed before recommending switching LT recipients with severe COVID-19 to tacrolimus. It must be interpreted, like all observational studies, with caution. In the early days of the pandemic, hydroxychloroquine was promoted as a treatment for COVID-19, and even gained emergency approval from the United States Food and Drug Administration, based on very limited data from observational studies. This led to widespread use of a medication that was ultimately found to have no mortality benefit once more thoroughly evaluated in randomized trials. 13 But with appropriate caution, this study by Belli et al does provide rationale for further investigation into the impact of calcineurin inhibitors in COVID-19. Relatedly, a recent pilot study found a mortality benefit in patients (without a history of transplantation) hospitalized with COVID-19 and hypoxemia or elevated inflammatory markers who were treated with cyclosporine and steroids as compared to steroids alone. 14 The work by Belli et al also strengthens the case that older age and chronic comorbidities, such as diabetes, chronic kidney disease, and obesity, are the most important determinants of short-term outcomes in COVID-19. This has been observed previously in transplant recipients and in the general population. [5] [6] [7] [8] [9] 15 Clinical insights for hepatology and liver transplant providers during the COVID-19 pandemic Is a "Cytokine Storm" Relevant to COVID-19? Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions Efficacy of Tocilizumab in Patients Hospitalized with Covid-19 Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy COVID-19 in solid organ transplant: A multi-center cohort study But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry Predictive factors for disease progression in hospitalized patients with coronavirus disease 2019 in Wuhan Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506 The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19 Cyclosporine A plus low-dose steroid treatment in COVID-19 improves clinical outcomes in patients with moderate to severe disease. A pilot study Clinical Characteristics of Coronavirus Disease 2019 in China