key: cord-0715772-u961samd authors: Parente, Alessandro; Manzia, Tommaso Maria; Angelico, Roberta; Tirotta, Fabio; Muiesan, Paolo; Tisone, Giuseppe; Framarino dei Malatesta, Marialuisa title: COVID‐19, liver transplant, and immunosuppression: Allies or foes? date: 2020-07-31 journal: Transpl Infect Dis DOI: 10.1111/tid.13417 sha: bc61919c04a65d9cba511b50f94fa5111d12bbbb doc_id: 715772 cord_uid: u961samd Liver transplant (LT) recipients are considered at a particularly high risk for developing critical COVID‐19 infection. To date, available data are heterogeneous and scarce and mortality in LT recipients seems to be higher compared to normal population, but whether this is caused by altered immunological status, immunosuppression (IS), or underlying comorbidities has not yet been fully clarified. Some evidences show that IS might play a role in the pathophysiology of this new disease. We searched all available data regarding LT recipients infected by COVID‐19, focusing on the role of IS. To date, 244 LT recipients have been reported as COVID‐19‐positive. Trends among transplant physicians are to reduce overall IS, especially antimetabolite drugs, but the current available observations are still not enough to build strong evidences for recommendation and IS should be meticulously tailored case by case. AND "liver transplant" from November 2019 until June 10, 2020. The electronic bibliographic database included MEDLINE-PubMed, EMBASE, Cochrane Library, and Web of Science. All original articles, letters to the editor, correspondence, case reports, clinical randomized controlled trials, non-randomized controlled trials, reviews, consensus articles, and protocol studies were included. Only papers published in English were reviewed. Data extraction, using the text, tables, and figures of the original available articles, was performed out independently by two researchers (AP and FT). The quality of the data selected was evaluated independently by two researchers (RA and TMM). As of June 10, 2020, there are 244 reported cases of LT infected by COVID-19, 3-21 including 240 adult and 4 pediatric LT recipients (Table 1) . So far, the available data are scarce, not homogeneous, and based mainly on case reports, correspondences, and letters to the editors; thus, the analysis and the interpretation of data must be cautious. Among the largest series, 9, 12, 19 the overall mortality of LT recipients infected with SARS-CoV-2 ranged from 16% to 29%. Of the 244 LT patients with COVID-19 reported, 41 (16.8%) died. The ELTR registry reported the largest cohort so far with 103 cases. 19 Out of these, 76 (74%) were male and 27 (26%) were female with a median age of 65 years (range 11-82). Comorbidities were common and included hypertension (51%), diabetes (41%), chronic renal impairment (15%), and history of smoking (13%). As expected, most patients (85%) received CNIs-based IS, but, unfortunately, information on the management of IS during the SARS-CoV-2 infection is unavailable. Notably, in this large case series the mortality rate was higher among patients with a follow-up ≥2 years from LT. 19 This trend is confirmed by other reports, 4, 18 but the underlying reasons remain unclear. One potential explanation could be the longer exposure to IS therapy, a known risk factor for developing IS-related complications such as hypertension or diabetes that might play a role in increasing the mortality risk for COVID-19. On the other hand, other publications are discordant reporting a greater mortality rate among patients transplanted within the last 2 years. 9 Calcineurin inhibitors (CNIs) are the mostly used IS drugs after LT and are considered the mainstay in IS maintenance regimens. CNIs, namely cyclosporine and FK506 (tacrolimus), acquire activity after binding the cyclophilin or FKBP-12. Their interaction with calcineurin blocks the transfer of the nuclear factor of activated T lymphocytes (NFAT) in the nucleus. NFAT is necessary for the induction of the cytokine gene expression, like the interleukin-2 (IL-2). The blockage of NFAT dephosphorylation leads to the no response of T lymphocytes to specific antigenic stimuli. Thus, the IL-2-dependent growth and differentiation is blocked. 22 Looking specifically into the SARS-CoV family, experimental studies demonstrated molecular interactions between calcineurin/NFAT pathway, CNIs, and CoV non-structural protein 1 (Nsp1). In particular, both cyclosporine and FK506 blocked the replication of human and animal SARS-CoV in vitro. [23] [24] [25] [26] [27] Even though these are experimental models, in vitro evidences showed that both cyclosporin and tacrolimus might have a potential role in inhibiting SARS-CoV replication. Antimetabolites drugs, such as mycophenolate mofetil (MMF), mycophenolic acid (MPA), and azathioprine (AZA), are also commonly used after LT. They work by disrupting the making of RNA and DNA, thus hindering the replication of T and B lymphocytes. In COVID-19 patients, the significant decrease in total number of B cells, T cells, and NK cells leads to the dysregulation of immune response. Notably, these patients show a pronounced lymphopenia and low counts of CD3+ and CD4+ cells and memory helper T, while the percentage of naïve helper T cells seems to be increased. 28 In this scenario, antimetabolite drugs have an inherent potential to cause lymphopenia and/or impair lymphocyte function, thus overlapping with COVID-19 effects of inducing lymphopenia, with a potential additional risk for LT recipients. With this report, we would like to make a request to all the physicians dealing with LT to document in detail all COVID-19 cases, with particular attention to the IS management. Only gathering uniform and comparable data, we will better understand whether these indispensable drugs could be our friends or our foes during these uncharted times. All the authors declare that there is no conflict of interest regarding the publication of this manuscript. MFDM and AP conceived the study. AP and RA designed the study. 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