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Jordi Colmenero, PhD, Manuel Rodríguez-Perálvarez, PhD, Magdalena Salcedo, PhD, Ana Arias-Milla, MD, Alejandro Muñoz-Serrano, MD, Javier Graus, MD, Javier Nuño, MD, Mikel Gastaca, MD, Javier Bustamante-Schneider, MD, Alba Cachero, MD, Laura Lladó, MD, Aránzazu Caballero, MD, Ainhoa Fernández-Yunquera, MD, Carmelo Loinaz, MD, Inmaculada Fernández, MD, Constantino Fondevilla, PhD, Miquel Navasa, MD, Mercedes Iñarrairaegui, PhD, Lluis Castells, MD, Sonia Pascual, MD, Pablo Ramírez, PhD, Carmen Vinaixa, MD, María Luisa González- Dieguez, MD, Rocío González-Grande, MD, Loreto Hierro, MD, Flor Nogueras, MD, Alejandra Otero, PhD, José María Álamo, MD, Gerardo Blanco-Fernández, PhD, Emilio Fábrega, MD, Fernando García-Pajares, MD, José Luis Montero, PhD, Santiago Tomé, PhD, Gloria De la Rosa, MD, José Antonio Pons, PhD PII: S0168-8278(20)30521-3 DOI: https://doi.org/10.1016/j.jhep.2020.07.040 Reference: JHEPAT 7884 To appear in: Journal of Hepatology Received Date: 8 May 2020 Revised Date: 23 July 2020 Accepted Date: 27 July 2020 Please cite this article as: Colmenero J, Rodríguez-Perálvarez M, Salcedo M, Arias-Milla A, Muñoz- Serrano A, Graus J, Nuño J, Gastaca M, Bustamante-Schneider J, Cachero A, Lladó L, Caballero A, Fernández-Yunquera A, Loinaz C, Fernández I, Fondevilla C, Navasa M, Iñarrairaegui M, Castells L, Pascual S, Ramírez P, Vinaixa C, González-Dieguez ML, González-Grande R, Hierro L, Nogueras F, Otero A, Álamo JM, Blanco-Fernández G, Fábrega E, García-Pajares F, Montero JL, Tomé S, De la Rosa G, Pons JA, Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients., Journal of Hepatology (2020), doi: https://doi.org/10.1016/j.jhep.2020.07.040. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. TITLE PAGE Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients. List of authors and affiliations On behalf of the Spanish Society of Liver Transplantation (SETH) Order Name/Surname Degree Affiliations Address 1. Jordi Colmenero PhD - Liver Transplant Unit, Hospital Clínic, Villarroel St., 170, 08036, IDIBAPS, University of Barcelona (Spain) Barcelona, Spain - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 2. Manuel PhD - Department of Hepatology and Liver Menéndez Pidal Av., 14004, Rodríguez- Transplantation, Hospital Universitario Reina Córdoba, Spain. Perálvarez sofía, IMIBIC, Córdoba (Spain). - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 3. Magdalena PhD - Hepatology and Liver Transplantation Unit, Doctor Esquerdo St., 7, Salcedo Hospital General Universitario Gregorio 28009, Madrid, Spain. Marañón, Universidad Complutense, Madrid (Spain). - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 4. Ana Arias-Milla MD Hepatology and Liver Transplant Unit, Manuel de Falla St., 1, Hospital Puerta de Hierro, IDIPHIMSA, 28222, Majadahonda Universidad Autónoma de Madrid (Spain). Madrid, Spain. 5. Alejandro MD Hepatology and Liver Transplant Unit, Manuel de Falla St., 1, Muñoz-Serrano Hospital Puerta de Hierro, IDIPHIMSA, 28222, Majadahonda Universidad Autónoma de Madrid (Spain). Madrid, Spain. 6. Javier Graus MD - Department of Digestive Diseases, Hospital Colmenar Viejo Rd., 607 - Ramón y Cajal, IRYCIS, Madrid (Spain). 09100, 28034, Madrid, - Centro de Investigación Biomédica en Red Spain. de Enfermedades Hepáticas y Digestivas (CIBERehd). 1 7. Javier Nuño MD Hepatobiliary and Liver Transplantation Unit, Colmenar Viejo Rd., 607 - Hospital Universitario Ramón y Cajal, Madrid 09100, 28034, Madrid, (Spain). Spain. 8. Mikel Gastaca MD Liver Transplantation Unit, Cruces University Plaza de Cruces, 12, 48903, Hospital, University of the Basque Country, San Vicente de Barakaldo, Biocruces Bizkaia Health Research Institute, Vizcaya, Spain. Bilbao (Spain) 9. Javier MD Liver Transplantation Unit, Cruces University Plaza de Cruces, 12, 48903, Bustamante- Hospital, University of the Basque Country, San Vicente de Barakaldo, Schneider Biocruces Bizkaia Health Research Institute, Vizcaya, Spain. Bilbao (Spain) 10. Alba Cachero MD Liver Transplant Unit, Hospital Universitari de Avinguda de la Granvia de Bellvitge, IDIBELL, L'Hospitalet de l'Hospitalet, 146, 08907, Llobregat, Barcelona (Spain). L'hospitalet de Llobregat, Spain. 11. Laura Lladó MD Liver Transplant Unit, Hospital Universitari de Avinguda de la Granvia de Bellvitge, IDIBELL, L'Hospitalet de l'Hospitalet, 146, 08907, Llobregat, Barcelona (Spain). L'hospitalet de Llobregat, Spain. 12. Aránzazu MD - Hepatology and Liver Transplantation Unit, Doctor Esquerdo St., 7, Caballero Hospital General Universitario Gregorio 28009, Madrid, Spain. Marañón, Universidad Complutense, Madrid (Spain). - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 13. Ainhoa MD - Hepatology and Liver Transplantation Unit, Doctor Esquerdo St., 7, Fernández- Hospital General Universitario Gregorio 28009, Madrid, Spain. Yunquera Marañón, Universidad Complutense, Madrid (Spain). - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 14. Carmelo Loinaz MD Department of Hepatology/HPB- Av de Córdoba, s/n, 28041, surgery/Transplantation, Hospital Madrid, Spain. Universitario 12 de Octubre, Madrid (Spain). 15. Inmaculada MD Department of Hepatology/HPB- Av de Córdoba, s/n, 28041, Fernández surgery/Transplantation, Hospital Madrid, Spain. Universitario 12 de Octubre, Madrid (Spain). 16. Constantino PhD - Liver Transplant Unit, Hospital Clínic, Villarroel St., 170, 08036, Fondevilla IDIBAPS, University of Barcelona (Spain) Barcelona, Spain - Centro de Investigación Biomédica en Red 2 de Enfermedades Hepáticas y Digestivas (CIBERehd). 17. Miquel Navasa MD - Liver Transplant Unit, Hospital Clínic, Villarroel St., 170, 08036, IDIBAPS, University of Barcelona (Spain) Barcelona, Spain - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 18. Mercedes PhD - Liver Unit, Clínica Universidad de Navarra, Pío XII Av., 36, 31008, Iñarrairaegui IDISNA, Pamplona (Spain). Pamplona, Navarra, Spain. - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 19. Lluis Castells MD - Department of Internal Medicine, Liver Unit, Passeig de la Vall d'Hebron, Hospital Universitari Vall d’Hebron, 119-129, 08035, Barcelona, Universitat Autònoma de Barcelona (Spain). Spain. - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 20. Sonia Pascual MD Liver Unit, Hospital General Universitario de Pintor Baeza St., nº 12, Alicante (Spain). 03010, Alicante, Spain. 21. Pablo Ramírez PhD Liver Transplantation Unit. Liver Unit. N-301 Madrid-Cartagena Department of Surgery. IMIB, Hospital Rd., 30331, Murcia, Spain. Universitario Virgen de la Arrixaca, Murcia, Spain 22. Carmen Vinaixa MD - Department of Hepatology and Liver Fernando Abril Martorell Transplantation, Hospital Universitario y Av, 106, 46026, Valencia, Politécnico La Fe, Valencia (Spain). Spain. - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 23. María Luisa MD Liver Unit and Division of Gastroenterology & Emilio Rodríguez Vigil St., González- Hepatology, Hospital Universitario Central de 2, 33006, Oviedo Asturias, Dieguez Asturias, Oviedo (Spain). Spain. 24. Rocío González- MD Department of Liver Transplantation, Hospital Carlos de Haya Av., s/n, Grande Regional Universitario de Málaga (Spain). 29001, Málaga, Spain. 25. Loreto Hierro MD Department of Paediatric Hepatology and Paseo de la Castellana, 261, Liver Transplantation, Hospital Universitario 28046, Madrid, Spain. La Paz, Madrid (Spain). 26. Flor Nogueras MD Department of Hepatology and Liver Avenida de las Fuerzas Transplantation, Hospital Virgen de las Armadas, 2, 18014, Nieves, Granada (Spain). Granada, Spain. 27. Alejandra Otero PhD Liver Transplant Unit, Hospital de A Coruña Jubias de Arriba 82, 15006, 3 (Spain). A Coruña, Spain 28. José María MD Liver Transplant Unit, Hospital Virgen del Avda. Manuel Siurot, s/n, Álamo Rocío, Seville (Spain). 41013, Sevilla, Spain. 29. Gerardo Blanco- PhD Department of HPB surgery and Liver Elvas Av., s/n, 06080, Fernández Transplantation, Complejo Hospitalario Badajoz, Spain. Universitario de Badajoz, Spain. 30. Emilio Fábrega MD - Department of Digestive Diseases, IDIVAL, Valdecilla Av., 25, 39008, Hospital Universitario Marqués de Valdecilla, Santander, Spain. Santander (Spain). - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 31. Fernando García- MD Department of Liver Transplantation, Hospital Paseo Arco Ladrillo, 64, Pajares Río Hortega de Valladolid (Spain). 47008, Valladolid, Spain. 32. José Luis PhD - Department of Hepatology and Liver Menéndez Pidal s/n, Postal Montero Transplantation, Hospital Universitario Reina code 14004, Córdoba, sofía, IMIBIC, Córdoba (Spain). Spain. - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). 33. Santiago Tomé PhD Department of Liver Transplantation, Hospital Rúa Choupana s/n, 15706, Universitario de Santiago (Spain). Santiago de Compostela, Spain 34. Gloria De la MD Registro Español de Trasplante hepático Sinesio delgado St., 4 - 8, Rosa (RETH) y Organización Nacional de Madrid, Spain. Trasplantes (ONT), (Spain) 35. José Antonio PhD Liver Transplantation Unit. Liver Unit. N-301 Madrid-Cartagena Pons Department of Surgery. IMIB, Hospital Rd., 30331, Murcia, Spain. Universitario Virgen de la Arrixaca, Murcia, Spain. Contact author information: Manuel Luis Rodríguez-Perálvarez, MD, PhD. Hospital Universitario Reina Sofía. Avda. Menéndez Pidal s/n, Postal code 14004, Córdoba, Spain. Phone: +34 617854692 E-mail: ropeml@hotmail.com; manuell.rodriguez.sspa@juntadeandalucia.es 4 Keywords: Covid-19; SARS-CoV-2; pneumonia; epidemiology; transplantation; immunosuppression; mycophenolate; calcineurin inhibitors; tacrolimus; everolimus; standardized incidence; standardized mortality. Electronic word count: 3,268 words (up to the acknowledgement section). Number of tables: 2; Number of figures: 4; Supplem. tables: 2. Conflict of interest statement - 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. 5 AA-M, AM-S, JG, JN, JB-S, AC, LL, AC, AF-Y, CL, IF, CF, LC, SP, PR, MG-D, RG- G, LH, FN, AO, JA, EF, FG-P, ST and GDR have no conflict of interest to disclose regarding the present manuscript. Financial support The Spanish Society of Liver Transplantation (SETH) was the only funding agent and covered the fee of an expert English language reviewer. Data availability statement A raw data set underpinning the present research publication may be found in the following repository: http://dx.doi.org/10.17632/5ssscvfmxn.2 Authors contributions - Jordi Colmenero*: Study design, statistical analysis and manuscript preparation. - Manuel L. Rodríguez-Perálvarez*: Study design, statistical analysis and manuscript preparation. - M. Salcedo: literature review, data recording and manuscript draft review for important intellectual content. - A. Arias-Milla, A. Muñoz-Serrano, J. Graus, J. Nuño, M. Gastaca, J. Bustamante- Schneider, A. Cachero, L. Lladó, A. Caballero, A. Fernández-Yunquera, C. Loinaz, I. Fernández, C. Fondevila, M. Navasa, M. Iñarrairaegui L. Castells, S. Pascual, P. Ramírez, C. Vinaixa, M.L. González-Dieguez, R. González-Grande, L. Hierro, F. 6 Nogueras, A. Otero, J.M. Álamo, G. Blanco-Fernández, E. Fábrega, F. García-Pajares, J.L. Montero and S. Tome: identification and inclusion of patients, data recording and manuscript draft review for important intellectual content. - G. De la Rosa: provided and analyzed data from the Spanish Liver Transplant Registry. - J.A. Pons: Original concept, study design, literature review, and manuscript draft review for important intellectual content. * These two authors contributed equally to the present work and may be considered co- first authors. 7 ABSTRACT 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 28th to April 7th, 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. 8 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. LAY SUMMARY: In liver transplant patients, chronic immunosuppression increases the risk of acquiring Covid-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalized patients. Abbreviations: - Covid-19: coronavirus disease 2019 - CI: confidence interval - ICU: intensive care unit - IQR: interquartile range - LT: liver transplantation - PCR: real-time reverse transcriptase polymerase chain reaction assay. - RR: relative risk - SETH: Spanish liver transplant society, Sociedad Española de Trasplante Hepático. 9 INTRODUCTION Spain has registered the fastest spread of coronavirus disease 2019 (Covid-19) in Europe with 210,773 cases detected by April, 28th, 2020, and case-fatality rate of 11.3%[1], being much higher than those observed in China, the origin of the pandemic[2]. The liver transplantation (LT) network in Spain is composed by 25 institutions in which more than 13,000 alive LT patients are surveilled. Transplant recipients are considered by some authors as a high-risk sub-population for Covid-19 as they receive lifelong immunosuppressive therapy. 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. 10 PATIENTS AND METHODS This is a prospective nationwide study promoted by the Spanish Society of Liver Transplantation (SETH), which was launched after the outbreak of Covid-19 in Spain on February 28th, 2020. The study was performed according to the principles of the declaration of Helsinki and the European Union regulation 2016/679. The study was approved by the research ethics committee of the Hospital Clínic Barcelona (HCB 2020/0384) and the research protocol was registered at ClinicalTrials.gov (NCT04361591). Oral informed consent to participate in the study was obtained from all patients/relatives, and written informed consent was retrieved after viral clearance. Identification and characterization of LT patients with Covid-19. 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 7th, 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. 11 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 Covid-19, antiviral therapy with lopinavir/ritonavir or remdesivir was allowed as compassionate use. Patients with acute distress respiratory syndrome could receive boluses of steroids and/or tocilizumab. Regarding immunosuppression, Covid-19 protocols encouraged clinicians to reduce, but not to withdraw immunosuppression in LT patients. Patients were followed until April 21st, 2020, thereby ensuring a minimum of 2 weeks of follow-up for clinical outcomes. Study definitions and outcomes. The main outcome evaluated was severe Covid-19, which was a composite endpoint including need for mechanical ventilation, admission to the intensive care unit (ICU), and/or death. This endpoint was used in a previous study describing the clinical features of Covid-19 in China[2]. Secondary outcomes were: respiratory insufficiency (arterial oxygen partial pressure <60 mmHg), need for mechanical ventilation, admission to the 12 ICU and liver allograft dysfunction (conventionally defined as raising bilirubin >4 times from baseline values or international normalized ratio>1.4). Patients were considered cured of Covid-19 when discharged from the hospital or after two consecutive PCR- negative results separated by more than 48 hours, whichever occurred first. Data sources, calculation of standardized ratios and statistical analysis. Data regarding populations at risk were obtained from the National Statistics Institute (general population) and from the Spanish Liver Transplant Registry (LT population), both updated in 2019. The incidence and outcomes of Covid-19 epidemics in the general Spanish population were retrieved from the official publication of the Ministry of Health, which is updated on a daily basis (https://www.mscbs.gob.es/). To obtain the cumulative incidence of Covid-19, data was accessed on 7th April, 2020, whereas mortality data were obtained on 21st, April 2020, aligning with the periods of recruitment and surveillance respectively of LT patients. Relative risks of Covid-19 (incidence and mortality) in LT patients as compared with the general population were expressed as standardized incidence and mortality ratios, which result from the ratio of the observed to the expected events. Expected incidence and outcomes in LT patients were obtained from the numbers observed in the general population, after balancing for age and gender. Ninety-five percent confidence intervals (95%CI) were calculated under the assumption that the number of cases observed followed a Poisson distribution. Continuous variables were reported as mean and standard deviations or as median and interquartile range (IQR), as appropriate. Categorical variables were summarized as counts and percentages. Among hospitalized patients, independent predictors of severe Covid-19 were identified using Cox regression analysis. Patients were censored when discharged or on April 21st. Variables available at Covid-19 onset showing a p≤0.30 in 13 the univariate analysis entered the initial multivariate model. Non-significant co-variates were removed from the model in a backward stepwise process, commencing by those with the highest p value. All possible interactions were tested. A confounding factor was confirmed when its removal from the model motivated >15% variation in the remaining β coefficients. The statistical analysis was performed using SPSS version 22.0 (IBM Corp, Armonk, NY). Every hypothesis tested was two-tailed and considered significant if p <0.05. RESULTS Standardized incidence of Covid-19 in LT patients. Epidemiological curves in general and LT populations were broadly similar (figure 1). Peaks of new cases occurred between March 25th and April 1st, with subsequent stabilization, and incipient decline at database closure. The geographical distribution of Covid-19 in the general population and in LT recipients overlapped widely (figure 2). The autonomous regions with the highest absolute number of confirmed cases were Madrid and Catalonia, both in the general population and in the LT population. Within the study period, 146,690 persons were diagnosed with Covid-19 in Spain (cumulative incidence 311.93 cases/105 habitants). Cumulative incidence was increased in older people, particularly beyond 60 years old (supplementary table 1). On the other hand, the alive LT population in Spain comprises 13,255 patients, among whom there were 111 confirmed cases of Covid-19 (cumulative incidence 837.41 cases/105 patients). After adjusting for age and gender, the number of observed cases almost doubled the expected number of cases (suppl. table 1) thus resulting in a standardized incidence ratio of 14 191.22 (95%CI 190.28-192.16). In the subset of patients older than 60, the standardized incidence ratio was even higher (206.48; 95%CI 205.45-207.52). Clinical characteristics and outcomes of LT patients with Covid-19. A total of 111 LT patients with Covid-19 were included (table 1). The mean age was 65.34±10.96 and there was a male predominance (71.2%). The median interval from transplantation was 105 months (IQR 35-168). None of the patients had been infected by the liver donor. The most frequent comorbidity was hypertension (57.7%). The vast majority of patients (n=109; 98.2%) were receiving chronic immunosuppression: Calcineurin inhibitors were the predominant immunosupressants, either alone (n=34; 30.6%), or in combination with mycophenolate (n=29; 26.1%) or everolimus (n=9; 8.1%). The remaining 37 patients (33.3%) received calcineurin inhibitors-free immunosuppression, based on mycophenolate and/or everolimus (table 1). Covid-19 was symptomatic in 93% of patients. The most frequent symptoms were fever (74.8%) and cough (70.3%). Asymptomatic patients (n=7) were tested for Covid-19 because of incidental radiological findings (n=2) or after a high-risk contact (n=5). Regarding laboratory parameters, the absolute lymphocyte count was 670/µl (IQR 430-1,040) and D dimer was 600 ng/mL (IQR 345-1,630). The chest X-ray showed abnormalities in 78.4% of patients, with a bilateral diffuse pattern in 58.6% of patients. The median follow-up after the diagnosis of Covid-19 was 23 days, with a minimum of 15 days for the last included patient. Ninety-six patients (86.5%) were admitted to hospital according to the following criteria: 18 patients (18.8%) had hypoxemia, 81 patients (84.4%) had radiological chest abnormalities, 77 patients (80.2%) were older than 60 years, and 51 patients (53.1%) had significant comorbidities (Charlson >3). Most of admitted patients met more than one criterion: 11 patients (11.5%) met 2 criteria, 32 patients (33.3%) met 3 criteria and 36 patients (37.5%) met 4 criteria. Only 6 15 patients did not meet any of the recommendations described above and the reason for hospital admission was the presence of severe clinical symptoms. There was a significant elevation of transaminases (doubled nadir) in 16 patients (14.7%). Three patients developed liver graft dysfunction (2.7%) but none of them had graft loss. Respiratory insufficiency occurred in 44 patients (39.6%). Twenty-two patients (19.8%) required respiratory support after a median of 5 days (IQR 1.75-9.5) after hospital admission, being non-invasive in 13 patients and invasive 9 patients. Twelve patients were admitted to the ICU (10.8%). The mortality rate was 18% with a median interval from hospital admission of 7 days (IQR 5-9.75). At database closure, 81 patients (73%) had been discharged or remained asymptomatic at home, and 10 patients (9%) were still in-hospital. After a median of 17 days (IQR 13-27.5), a PCR-negative result for Covid- 19 was confirmed in 18 patients. Thirty-five patients (31.5%) met criteria of severe Covid-19 (table 1). These patients were characterized by older age (p=0.038), more frequent dyspnea (p<0.001) and a reduced PaO2/FiO2 ratio (p=0.044) on admission. During hospital stay, severe Covid- 19 patients presented reduced lymphocyte counts (p=0.013), increased D dimer (p=0.032) and increased serum ferritin (p=0.004). Regarding management, severe Covid-19 patients received more frequently tocilizumab (p<0.001) and boluses of corticosteroids (p=0.007). Patients receiving mycophenolate or attempting a complete withdrawal of immunosuppression were more prevalent in the severe Covid-19 group (p=0.014, and p=0.016 respectively). Conversely, tacrolimus-containing immunosuppression was more frequent in the non-severe Covid-19 group, although without statistical significance (p=0.113). 16 Risk factors of severe Covid-19 among hospitalized patients. Baseline risk factors of severe Covid-19 among hospitalized patients (n=96) were screened using Cox regression analysis (table 2). The multivariate analysis identified the following independent predictors: Charlson comorbidity index (relative risk [RR]=1.28 (95%CI 1.05-1.56), male gender (RR=2.49; 95%CI 1.14-5.41), dyspnea at diagnosis (RR=7.25; 95%CI 2.95-17.82), and baseline immunosuppression containing mycophenolate (RR=3.94; 95%CI 1.59-9.74). Age, estimated glomerular filtration rate and complete withdrawal of immunosuppression upon hospital admission were not significant, but they were kept in the analysis to be controlled as potential confounding factors. Kaplan-Meier curves illustrate the negative prognostic impact of mycophenolate, particularly at doses higher than 1,000 mg/day (figure 3). Among patients receiving full-dose of mycophenolate at baseline (ie. 2,000 mg/day), complete drug withdrawal had a trend towards reduced severe Covid-19 (41.7% vs 69.2%; p=0.16). Interestingly, baseline therapy with calcineurin inhibitors, mTOR inhibitors (everolimus), and maintenance corticosteroids, independently of their trough concentrations/doses, were not associated with increased risk of severe Covid-19. 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). Standardized mortality ratio of Covid-19 in LT patients. In the general population, a total of 21,717 deaths were registered by April 21st. Overall mortality rates were 14.8%, but were as high as 27.9% in patients older than 60 years (supplementary table 2). Among the LT population, 20 patients with Covid-19 died during the study period (mortality rate 18%). After adjusting for age and gender, the number of observed deaths among LT patients was slightly lower than the expected number of deaths (suppl. table 2), thus resulting in a standardized mortality ratio of 17 95.55 (95%CI 94.25-96.85). When evaluating subgroups according to age strata, no death was registered among LT patients younger than 60. Adjusted mortality rates in patients older than 60 were similar in LT recipients and in the general population (standardized mortality ratio=100.29; 95%CI 98.93-101.66). DISCUSSION This is the first nationwide study evaluating the incidence and outcomes of Covid-19 in immunosuppressed patients as compared with age and gender-matched counterparts from the general population. Despite a similar epidemiological pattern, LT patients had almost doubled standardized incidence rates of Covid-19. Chronic exposure to immunosuppressive agents did not increase standardized mortality rates but our findings suggest that mycophenolate, particularly at doses higher than 1,000 mg/day, could increase the risk of severe Covid-19 among hospitalized LT patients. Since other immunosuppressants such as calcineurin inhibitors (tacrolimus and cyclosporine) and mTOR inhibitors (everolimus) did not show this association, the present study provides key evidence to modulate immunosuppression in order to improve outcomes in LT patients with Covid-19. A similar epidemiological curve and geographical distribution of Covid-19 were observed between LT recipients and the general population. Despite routine recommendations given to LT patients regarding social distancing, they had almost doubled risk of developing Covid-19 as compared with age and gender-matched general population. The most plausible explanations are chronic immunosuppression and increased comorbidities, which would make them more vulnerable. Precautions should be intensified within a context of epidemy to prevent transmission. Regarding 18 outcomes, patients had a minimum of 2 weeks of surveillance to ensure that the need for intensive care and mortality were adequately captured, as previous studies reported that these outcomes may occur earlier[2]. The current evidence of Covid-19 in solid organ transplant recipients is based on short and uncontrolled case-series with contradictory 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 expected severity of Covid-19 would be increased. Although standardized rates of severe Covid-19 could not be calculated (due to unreliable data from the general population), we demonstrated that standardized mortality rates were actually lower in LT patients as compared with the general population. The clinical features associated with severe Covid-19 were similar to those previously reported[2]: older age, male gender, increased co-morbidities, raised D dimer, serum ferritin and decreased absolute lymphocyte count. PaFiO2 and dyspnea at admission were also associated with an increased risk of severe Covid-19, but only the latter variable was included in the final multivariate model due to missing PaFiO2 information in 22 patients. Noteworthy, the interval from LT until SARS-CoV-2 infection had no impact on the risk of evolving to severe Covid-19. However, the number of patients diagnosed of Covid-19 within the first year after LT was limited (n=15) and further studies are required to confirm this finding. 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 19 on personal experiences or on uncontrolled clinical observations[12, 16-19]. 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 20 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]. Some limitations of the present study should be highlighted. Underdiagnosing of Covid- 19 could be an issue given the suboptimal sensitivity of PCR of nasal and pharyngeal swab specimens and the limited access to diagnostic tests at some timepoints during the Covid-19 epidemy in Spain. The true cumulative incidence of Covid-19 may have been underestimated, although in a similar proportion in LT patients and in the general population, thus making standardized incidence ratio equally reliable. Under-reporting is another potential limitation in prospective registries but we believe it had a limited impact in the present study because LT patients/relatives are tightly connected by phone with the nurse transplant coordinator at each center to report any intercurrent health issue. The limited sample size may have weakened some analyses and results marginally not significant should be carefully interpreted as some could be clinically meaningful. Finally, the present study was neither designed nor powered to evaluate the effect of specific therapies against Covid-19 and no solid conclusion may be derived in this regard. In conclusion, being chronically immunosuppressed and with increased co-morbidities, LT patients are more likely to develop Covid-19 within an outbreak scenario and therefore social distancing and other preventative measures should be enhanced in these 21 patients. Mortality rates were lower than those observed in age- and gender-matched general population, thereby suggesting that chronic immunosuppression could exert a certain protective effect against the most severe forms of Covid-19. A complete immunosuppression withdrawal after the diagnosis of Covid-19 may not be justified. However, in patients receiving mycophenolate, dose reduction or temporary conversion to calcineurin inhibitors or everolimus may be considered until complete recovery from Covid-19. ACKNOWLEDGEMENTS 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. 22 TABLES Table 1. Clinical characteristics of 111 liver transplant recipients with coronavirus-19 disease (Covid-19) included in the Spanish Society of Liver Transplantation (SETH) registry. Severe Covid-19 was defined as need for mechanical ventilation, admission to intensive care unit and/or death. VARIABLE Covid-19 SETH Non-severe Severe Covid-19 p registry Covid-19 N=35 N=111 N=76 Age 65.34 ± 10.96 63.88 ± 11.94 68.51 ± 7.70 0.038 Gender (Women); % (n) 28.8% (32) 25% (19) 37.1% (13) 0.189 Previous medical history Diabetes; % (n) 47.7% (53) 43.4% (33) 57.1% (20) 0.179 Hypertension; % (n) 57.7% (64) 59.2% (45) 54.3% (19) 0.626 ACE inhibitors; % (n) 29.7% (33) 31.6% (24) 25.7% (9) 0.530 Cardiomyopathy; % (n) 19.8% (22) 17.1% (13) 25.7% (9) 0.290 Bronchopulmonary; % (n) 11.7% (13) 11.8% (9) 11.4% (4) 0.850 Charlson comorbidity index; median (IQR) 4 (2-6) 3 (2-4.7) 5 (4-7) 0.002 Interval since transplantation Months; median (IQR) 105 (35-168) 97.5 (30-160) 127 (57-208) 0.197 <12 months; % (n) 13.5% (15) 11.8% (9) 17.1% (6) 0.448 Aetiology of liver disease Alcohol; % (n) 30.6% (34) 28.9% (22) 35.3% (12) 0.571 Hepatitis C; % (n) 28.8% (32) 30.3% (23) 25.7% (9) 0.623 Hepatitis B; % (n) 10.8% (12) 11.8% (9) 8.6% (3) 0.750 Autoimmune; % (n) 8.1% (9) 6.6% (5) 11.4% (4) 0.459 Clinical presentation of Covid-19 Fever; % (n) 74.8% (83) 75% (57) 74.3% (26) 0.936 Dyspnea; % (n) 41.4% (46) 25% (19) 77.1% (27) <0.001 Cough; % (n) 70.3% (78) 67.1% (51) 77.1% (27) 0.282 Gastrointestinal; % (n) 34.2% (38) 36.8% (28) 28.6% (10) 0.394 Asymptomatic; % (n) 6.3% (7) 9.2% (7) 0% (0) 0.095 Laboratory parameters in hospitalized patients (n=96); median (IQR) PaO2/FiO2 ratio (onset)* 400 (309-436) 403 (333-444) 328 (279-420) 0.044 Lymphocyte (onset)-count/µl 670 (430-1,040) 715 (415-1,000) 600 (430-1,200) 0.449 Lymphocyte count (min)-count/µl 455 (275-755) 500 (380-840) 310 (200-500) 0.013 D dimer (onset)-ng/mL 600 (345-1,630) 540 (340-1,010) 1,100 (450-2,796) 0.127 D dimer (max)-ng/mL 1,050 (517-3,299) 800 (390-2,543) 2,229 (809-4,290) 0.032 Ferritin (max)-ng/mL 847 (376-1975) 511 (256-1,663) 1,459 (770-2,264) 0.004 Estimated glomerular filtration rate - 62.5 (41.3-79.7) 63.2 (43.5-82.5) 53.3 (39-74) 0.396 ml/min** Chest X-ray abnormalities Normal; % (n) 21.6% (24) 31.6% (24) 0% (0) 0.002 23 Unilateral; % (n) 19.8% (22) 18.4% (14) 22.8% (8) Bilateral; % (n) 58.6% (65) 50% (38) 77.1% (27) Covid-19 specific therapy in hospitalized patients (n=96) Azithromycin; % (n) 62.5% (60) 63.9% (39) 60% (21) 0.702 Hydroxychloroquine; % (n) 91.7% (88) 90.2% (55) 94.3% (33) 0.482 Lopinavir/ritonavir; % (n) 41.7% (40) 36.1% (22) 51.4% (18) 0.142 Remdesivir; % (n) 1% (1) 0% (0) 2.9% (1) 0.365 Interferon beta; % (n) 3.1% (3) 1.6% (1) 5.7% (2) 0.552 Tocilizumab; % (n) 15.6% (15) 4.9% (3) 34.3% (12) <0.001 Boluses of corticosteroids; % (n) 12.5% (12) 4.9% (3) 25.7% (9) 0.007 Immunosuppression at baseline (drugs) Tacrolimus; % (n) 59.5% (66) 64.5% (49) 48.6% (17) 0.113 Cyclosporine; % (n) 5.4% (6) 5.3% (4) 5.7% (2) 0.922 Mycophenolate; % (n) 51.4% (57) 43.4% (33) 68.6% (24) 0.014 Everolimus; % (n) 20.7% (23) 22.4% (17) 17.1% (6) 0.528 Corticosteroids (maintenance); % (n) 21.8% (24) 18.7% (14) 28.6% (15) 0.241 Immunosupression (combinations); % (n) CNI 30.6% (34) 32.9% (25) 25.7% (9) 0.374 CNI + mycophenolate 26.1% (29) 27.6% (21) 22.9% (8) CNI + everolimus 8.1% (9) 9.2% (7) 5.7% (2) Mycophenolate +/- everolimus 33.3% (37) 27.6% (21) 45.7% (16) None 1.8% (2) 2.6% (2) 0% (0) Immunosuppression baseline (dose- mg) Tacrolimus (n=66); median (IQR) 2.5 (1.5-5) 2.5 (1.7-5) 2 (1-4.25) 0.986 Cyclosporine (n=6); median (IQR) 75 (50-150) 125 (62.5-150) 125 (75-150) 0.400 Mycophenolate (n=57); median (IQR) 1,000 (1,000-2,000) 1,000 (1000-1,500) 1,500 (1,000-2,000) 0.056 Everolimus (n=23); median (IQR) 2 (1-2.1) 2 (1.1-2.4) 2 (0.87-2.25) 1 Corticosteroids (maintenance) (n=24); 10 (5-20) 5 (4.7-16.2) 10 (8.7-30) 0.673 median (IQR) Immunosuppression (trough concentrations onset- ng/mL) Tacrolimus (n=66); median (IQR) 4.95 (3.32-6.92) 5 (4-6.7) 4.2 (2.7-6.9) 0.772 Cyclosporine (n=6); median (IQR) 99 (51.5-148.6) 99 (88.5-125) 85.1 (25-145.2) 1 Everolimus (n=23); median (IQR) 3.5 (2.9-5.5) 3.5 (2.9-5.4) 3.5 (1.6-6.4) 1 * PaO2/FiO2 was not available in 22 patients. ** Estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease-4 (MDRD-4); IQR: interquartile range. 24 Table 2. Clinical predictors of severe Covid-19 among patients admitted into the hospital (n=96). Severe Covid-19 was defined as requirement of respiratory support, admission in intensive care unit and/or death. Univariate and multivariate Cox´s regression analyses were used. VARIABLES UNIVARIATE ANALYSIS MULTIVARIATE MULTIVARIATE ANALYSIS ANALYSIS (INITIAL MODEL) (FINAL MODEL) RR (95% CI) P RR (95% CI) P RR (95% CI) P Age 1.05 (1.01-1.10) 0.017 1.05 (0.98-1.13) 0.166 1.03 (0.98-1.09) 0.182 Gender (male) 1.56 (0.77-3.17) 0.212 7.66 (2.20-26.69) 0.001 2.49 (1.14-5.41) 0.021 Diabetes 1.59 (0.80-3.17) 0.181 0.26 (0.10-0.68) 0.006 Hypertension 0.93 (0.47-1.84) 0.838 ACE inhibitors 0.23 (0.34-1.56) 0.414 Charlson comorbidity 1.25 (1.11-1.40) <0.001 1.34 (1.02-1.76) 0.031 1.28 (1.05-1.56) 0.015 Interval since liver transplantation (>12 1 (0.99-1) 0.466 months) Dyspnea 4.19 (1.89-9.30) <0.001 15.91 (4.17-60.73) <0.001 7.25 (2.95-17.82) <0.001 Cough 0.96 (0.43-2.15) 0.934 Fever 0.73 (0.34-1.58) 0.429 Gastrointestinal 0.72 (0.34-1.52) 0.392 symptoms PaFiO2 0.99 (0.99-0.99) 0.038 0.99 (0.99-0.99) 0.012 Lymphocyte count 1 (0.99-1) 0.418 D Dimer 1 (1-1) 0.409 Estimated glomerular 0.99 (0.98-1.01) 0.249 1.01 (0.99-1.04) 0.171 1.01 (0.98-1.03) 0.077 filtration rate Tacrolimus* 0.54 (0.29-1.07) 0.079 0.19 (0.05-0.68) 0.011 Cyclosporine* 0.76 (0.18-3.22) 0.708 Trough concentrations 1.01 (0.93-1.10) 0.762 (tacrolimus)* Trough concentrations 1.04 (0.92-1.19) 0.485 (cyclosporine)* Mycophenolate* 2.62 (1.25-5.49) 0.011 5.32 (1.60-17.69) 0.006 3.94 (1.59-9.74) 0.003 Everolimus* 0.77 (0.32-1.88) 0.575 Trough concentrations 0.86 (0.59-1.32) 0.490 (everolimus)* Corticosteroids* 1.53 (0.72-3.22) 0.262 1.77 (0.59-5.27) 0.303 Withdrawal of 2.03 (0.91-4.51) 0.083 0.34 (0.08-1.51) 0.155 0.58 (0.24-1.40) 0.229 immunosuppression** Hydroxychlorochine** 0.64 (0.33-5.88) 0.640 Azithromycin** 0.77 (0.38-1.53) 0.454 * These variables pertain to active immunosuppression therapy at Covid-19 diagnosis; ** 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. 25 FIGURE LEGENDS Figure 1. Epidemiological curve of Covid-19 in Spain from February 28th, 2020 until the registry closure on April 7th, 2020. Absolute number of cases are shown for the whole Spanish population and for the liver transplant population. Figure 2. Geographical distribution of Covid-19 among autonomous regions in Spain. Absolute number of cases are shown for the whole Spanish population and for the liver transplant population. Figure 3. Kaplan Meier curves showing the impact of mycophenolate-containing immunosuppression (upper panel) and increased doses (lower panel) on the development of severe Covid-19. P values are from Log rank test. Figure 4. Proposed algorithm to modify immunosuppression in liver transplant patients with Covid-19 according to the findings of the present study. The recommendations should be adapted to each patient taking into account the interval from liver transplantation and the individualized risk of rejection. SUPPLEMMENTARY MATERIAL Supplementary table 1. Calculation of standardized incidence ratio of coronavirus-19 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. Supplementary table 2. Calculation of standardized mortality ratio of coronavirus-19 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. 26 REFERENCES [1] Ministerio de Sanidad. Gobierno de España. Accessed on April 21st, 2020. Updated information available at https://www.mscbs.gob.es/en/profesionales/saludPublica/ccayes/alertasActual/nCov- China/situacionActual.htm. [2] Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020;382:1708- 1720. [3] Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020 (in press). [4] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-1034. [5] Rodriguez-Peralvarez M, Guerrero-Misas M, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis. Cochrane Database Syst Rev 2017;3:CD011639. [6] Tanaka Y, Sato Y, Sasaki T. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses 2013;5:1250-1260. [7] Romanelli A, Mascolo S. Immunosuppression drug-related and clinical manifestation of Coronavirus disease 2019: A therapeutical hypothesis. Am J Transplant 2020 (In press). [8] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. 27 [9] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-383. [10] Zhu L, Gong N, Liu B, Lu X, Chen D, Chen S, et al. Coronavirus Disease 2019 Pneumonia in Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan, China. Eur Urol 2020;77:748-754. [11] Akalin E, Azzi Y, Bartash R, Seethamraju H, Parides M, Hemmige V, et al. Covid-19 and Kidney Transplantation. N Engl J Med 2020 (In press). [12] D'Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl 2020;26:832-834. [13] Tovikkai C, Charman SC, Praseedom RK, Gimson AE, van der Meulen J. Time- varying impact of comorbidities on mortality after liver transplantation: a national cohort study using linked clinical and administrative data. BMJ Open 2015;5:e006971. [14] Ritchie AI, Singanayagam A. Immunosuppression for hyperinflammation in COVID-19: a double-edged sword? Lancet 2020;395:1111. [15] Willicombe M, Thomas D, McAdoo S. COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm? J Am Soc Nephrol 2020;31:1145-1146. [16] Minotti C, Tirelli F, Barbieri E, Giaquinto C, Dona D. How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review. J Infect 2020 (In press). [17] Columbia University Kidney Transplant P. Early Description of Coronavirus 2019 Disease in Kidney Transplant Recipients in New York. J Am Soc Nephrol 2020;31:1150-1156. 28 [18] Webb GJ, Moon AM, Barnes E, Barritt AS, Marjot T. Determining risk factors for mortality in liver transplant patients with COVID-19. Lancet Gastroenterol Hepatol 2020 (In press). [19] Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy. Lancet Gastroenterol Hepatol 2020;5:532-533. [20] Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85-118. [21] Wang 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;221:1732-1769. [22] Brennan DC, Legendre C, Patel D, Mange K, Wiland A, McCague K, et al. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant 2011;11:2453-2462. [23] Bowman LJ, Brueckner AJ, Doligalski CT. The Role of mTOR Inhibitors in the Management of Viral Infections: A Review of Current Literature. Transplantation 2018;102:S50-S59. [24] Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir- Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020;382:1787- 1799. [25] Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ 2020;369:m1432. 29 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 dependent- manner. • Calcineurin inhibitors and everolimus are not deleterious for Covid-19.