key: cord-0949154-d9ed1jx9 authors: Colmenero, Jordi; Rodríguez-Perálvarez, Manuel; Salcedo, Magdalena; Arias-Milla, Ana; Muñoz-Serrano, Alejandro; Graus, Javier; Nuño, Javier; Gastaca, Mikel; Bustamante-Schneider, Javier; Cachero, Alba; Lladó, Laura; Caballero, Aránzazu; Fernández-Yunquera, Ainhoa; Loinaz, Carmelo; Fernández, Inmaculada; Fondevilla, Constantino; Navasa, Miquel; Iñarrairaegui, Mercedes; Castells, Lluis; Pascual, Sonia; Ramírez, Pablo; Vinaixa, Carmen; González-Dieguez, María Luisa; González-Grande, Rocío; Hierro, Loreto; Nogueras, Flor; Otero, Alejandra; Álamo, José María; Blanco-Fernández, Gerardo; Fábrega, Emilio; García-Pajares, Fernando; Montero, José Luis; Tomé, Santiago; De la Rosa, Gloria; Pons, José Antonio title: Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients. date: 2020-08-01 journal: J Hepatol DOI: 10.1016/j.jhep.2020.07.040 sha: ce5fd807861bef0beb70ae9e86840c68c7f0340e doc_id: 949154 cord_uid: d9ed1jx9 BACKGROUND & AIMS: The incidence and outcomes of coronavirus disease 2019 (Covid-19) in immunocompromised patients are a matter of debate. METHODS: Prospective nationwide study including a consecutive cohort of liver transplant patients with Covid-19 recruited during the Spanish outbreak from February 28(th) to April 7(th), 2020. The primary outcome was severe Covid-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardized incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe Covid-19 among hospitalized patients were analyzed using multivariate Cox regression. RESULTS: A total of 111 liver transplant patients were diagnosed with Covid-19 (SIR=191.2 [95%CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. Twelve patients were admitted to the ICU (10.8%). The mortality rate was 18%, being lower compared to the matched general population (SMR=95.5 [95%CI 94.2-96.8]). Thirty-five patients (31.5%) met criteria of severe Covid-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe Covid-19 (RR=3.94; 95%CI 1.59-9.74; p=0.003), particularly at doses higher than 1,000 mg/day (p=0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. CONCLUSIONS: Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring Covid-19 but their mortality rates are lower than matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe Covid-19. However, complete immunosuppression withdrawal should be discouraged. Rodríguez-Perálvarez -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. -MG has received speaker fees from and/or acted as advisor for Astellas, Novartis, Chiesi, Baxter, and Medtronic. -MN has received lecture fees from Astellas Pharma. -MI has received lecture fees from BMS. -CV has received lecture fees from Novartis, Abbie, and Gilead. -AC has received lecture fees from Astellas Pharma. -GB-F has received lecture fees from Bayer and Astellas. -JLM as received lecture fees from Bayer and Gilead. -JP has received lecture fees by Astellas, Chiesi, and Gilead. G, LH, FN, AO, JA, EF, FG-P, ST and GDR have no conflict of interest to disclose regarding the present manuscript. The Spanish Society of Liver Transplantation (SETH) was the only funding agent and covered the fee of an expert English language reviewer. A raw data set underpinning the present research publication may be found in the following repository: http://dx.doi.org/10.17632/5ssscvfmxn.2 -Jordi Colmenero*: Study design, statistical analysis and manuscript preparation. According to data on previous coronaviruses (MERS-CoV and SARS-CoV), it has been hypothesized that Covid-19 has an earlier phase of viral replication and a later phase characterized by viral clearance due to immune response. This second phase may eventually trigger a deregulation of CD4+ T cells, activation of CD8+ T cells and macrophages, and a cytokine storm [3, 4] , ultimately producing the most severe forms of Covid-19. Immunomodulatory agents could ameliorate this harmful immune response [4] but this could lead to an increase in viral load and delayed disease recovery. Interestingly, the most frequently used immunosuppressive agents in LT recipients, namely calcineurin inhibitors [5] , have shown intriguing capacities to inhibit the replication of coronaviruses [6] . Therefore, baseline immunomodulation could protect LT patients against the most severe clinical forms of Covid-19 [7] . In this prospective nationwide study, we aimed to analyze the epidemiological pattern, clinical features and outcomes of LT patients diagnosed with Covid-19 as compared with those observed in the general Spanish population. This is a prospective nationwide study promoted by the Spanish Society of Liver Patients receiving a LT in Spain undergo lifelong surveillance by the transplant team and they are instructed to contact for any health-related issue. All LT recipients with known Covid-19 were prospectively enrolled in the registry up to April 7 th , 2020, when the national authorities informed that the epidemiological curve had reached a plateau. There were no exclusion criteria. LT patients with Covid-19 were declared to the SETH registry using an anonymized online platform. The transplant institution was responsible for declaring cases as soon as they were aware of them. Nurse transplant coordinators actively searched for Covid-19 patients by telephone contact. Covid-19 was confirmed by a real-time reverse transcriptase polymerase chain reaction assay (PCR) of nasal and pharyngeal swab specimens [8] . In Spain, patients admitted to the hospital were tested onsite within the first 24 hours, while outpatients with mild symptoms were tested at home or at "drive-thru" testing sites within the next 72 hours after contacting a dedicated phone number. All clinical information was extracted by experienced transplant physicians from reliable electronic medical data sources. Demographic data, comorbidities (Charlson comorbidity index [9] ), clinical features, laboratory parameters and transplant-related information including baseline immunosuppression (drugs and trough concentrations) were recorded. Chest X-rays were reported by a single member of the radiology department at each center. Modifications of immunosuppression therapy were registered as well as specific drugs prescribed for Covid-19. Management protocols for Covid-19 were broadly similar within the national territory according to the SETH and the Ministry of Health recommendations. Patients were admitted to hospital if they had hypoxemia (arterial oxygen partial pressure <70 mmHg) and/or radiological chest X-ray abnormalities. Patients with significant co-morbidities or over the age of 60 were also admitted at the discretion of the responsible clinician even if they did not fulfill the above referred criteria. Patients could be treated with oral hydroxychloroquine and/or azithromycin for 5-7 days. In patients with moderate-severe Epidemiological curves in general and LT populations were broadly similar (figure 1). Therapy with hydroxychloroquine and/or azithromycin at hospital admission did not decrease the risk of severe Covid-19 (p=0.64 and p=0.45, respectively). In the general population, a total of 21,717 deaths were registered by April conclusions. Whereas some studies report aggressive Covid-19 with fatal outcomes [10, 11] , other authors suggest that severe respiratory disease may be anecdotical [12] . Since transplant patients have more comorbidities than the general population [13] , the The relationship of immunosuppression and Covid-19 outcomes is frequently referred to as a double-edged sword [14] . Too much immunosuppression could result in increased viral load and delayed recovery whereas a competent immune system could be responsible for the most severe forms of the disease [15] . In the transplant setting, many authors advocate the potential benefit of immunosuppression in Covid-19 based on personal experiences or on uncontrolled clinical observations [12, [16] [17] [18] [19] . In the present study, the vast majority of patients were receiving calcineurin inhibitors (tacrolimus or cyclosporine), mTOR inhibitors (everolimus), and/or mycophenolate. Whereas calcineurin and mTOR inhibitors were not associated with worse outcomes, at least not with their usual trough concentrations, mycophenolate therapy at baseline was an independent predictor of severe Covid-19 in a dose-dependent manner. This interesting observation may be explained by the different mechanisms of action. Mycophenolate produces a cytostatic effect on activated lymphocytes [20] . In Covid-19, the virus SARS-CoV-2 has a direct cytotoxic effect on lymphocytes, particularly CD8+ [3, 21] , thereby explaining the association between lymphopenia and worse outcomes [2] . Therefore, mycophenolate and SARS-CoV-2 may exert a synergic and deleterious effect on depleting peripheral lymphocytes, which would be responsible for an aberrant immune reconstitution as demonstrated with other viruses [22] . In contrast, mTOR inhibitors increase the quality and functionality of memory T cells and reduce the replication of a myriad of viruses including cytomegalovirus, herpes virus-8, Epstein-Barr, and human immunodeficiency virus [23] . Regarding calcineurin inhibitors, some studies have shown antiviral effects in vitro against coronaviruses [6] and they could also ameliorate the cytokine storm [15] . A randomized controlled trial with calcineurin inhibitors and/or mTOR inhibitors in immunocompetent individuals could be of great interest. An algorithm proposal to modify baseline immunosuppression in LT patients diagnosed with Covid-19 according to the study findings is presented in figure 4 . Given the lack of solid scientific evidence, the therapeutic approach against Covid-19 varied among participating institutions and usually included a combination of hydroxychloroquine, azithromyzin, antivirals, corticosteroids, and/or monoclonal antibodies in a stepwise process. In the only randomized trial published hitherto, antiviral therapy with lopinavir/ritonavir failed to reduce mortality in patients with severe Covid-19 [24] . In our cohort, hydroxychorloquine and/or azithromyzin were started early after diagnosis but we did not observe a clear benefit. Antivirals (lopinavir/ritonavir, remdesivir, and interferon), boluses of corticosteroids, and monoclonal antibodies (tocilizumab) were prescribed mainly in unresponsive cases in the present cohort and it is hard to extract valid conclusions. Caution should be taken in the absence of well-designed randomized trials [25] . ** These therapies were started at Covid-19 diagnosis. Other therapies against Covid-19 were not included as they were initiated selectively in unresponsive cases and would confound the analysis. disease during the Spanish epidemics from February 20, until April 7, 2020. Cumulative incidence of the general population was adjusted according to age and gender to match the liver transplant population. Clinical Characteristics of Coronavirus Disease 2019 in China Dysregulation of immune response in patients with COVID-19 in Wuhan, China COVID-19: consider cytokine storm syndromes and immunosuppression Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis Suppression of coronavirus replication by cyclophilin inhibitors Immunosuppression drug-related and clinical manifestation of Coronavirus disease 2019: A therapeutical hypothesis Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China A new method of classifying prognostic comorbidity in longitudinal studies: development and validation Pneumonia in Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan, China Covid-19 and Kidney Transplantation Coronaviruses and immunosuppressed patients. The facts during the third epidemic Timevarying impact of comorbidities on mortality after liver transplantation: a national cohort study using linked clinical and administrative data Immunosuppression for hyperinflammation in COVID-19: a double-edged sword? COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm? How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review Early Description of Coronavirus 2019 Disease in Kidney Transplant Recipients in New York Determining risk factors for mortality in liver transplant patients with COVID-19 COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy Mycophenolate mofetil and its mechanisms of action Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials The Role of mTOR Inhibitors in the Management of Viral Infections: A Review of Current Literature A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Chloroquine and hydroxychloroquine in covid-19 HIGHLIGHTS • The incidence of Covid-19 is increased in liver transplant patients • Mortality rates are lower than those observed in matched general population • Immunosuppression withdrawal may not be justified • Mycophenolate may increase the risk of severe Covid-19 in a dose dependentmanner • Calcineurin inhibitors and everolimus are not deleterious for Covid-19 We greatly appreciate the endeavor of the nurse transplant coordinators in attending transplant recipients and for providing continuous support to their families. We thank Ms. Paloma Bellés from AOPC for her contribution in secretariat and logistic aspects.We also acknowledge Ms. Donna Pringle for professional English language polishing.