Ann Liver Transplant.  2021 Nov;1(2):129-134. 10.52604/alt.21.0022.

Immunosuppression for liver transplant recipients during the COVID-19 pandemic

• Park JI
• Jung BH

• KMID: 2560862
• DOI: http://doi.org/10.52604/alt.21.0022

Abstract

SARS-CoV-2 infection has resulted in a pandemic with serious consequences for worldwide health care system. Liver transplant recipients manifest immunosuppressed status and are theoretically more vulnerable to infection, suggesting the need to modify the immunosuppressive regimens according to the patient status and the treatments used. This study intended to present the action mechanisms of immunosuppressive agents and show the balance between immunosuppressive effects and antiviral agents in relation to immunosuppressive treatment in patients with COVID-19 infection. In the absence of robust evidence to support general recommendations, experience with other viral infections suggests the benefit of management of immunosuppression without mycophenolate mofetil or mammalian target of rapamycin inhibitors. It is also important to consider the possible drug interactions, especially in the case of tacrolimus, with a few antiviral treatments in the context of COVID-19. The immunosuppressive effect of immunomodulating drugs administered to patients with severe lung disease also should be taken into account. The present study reviews the mechanisms of action of the different immunosuppressive agents, as well as their potential effect on SARS-CoV-2 infection. Guidelines for the management of immunosuppression in liver transplant recipients are suggested.

Keyword

SARS-CoV-2; Immunosuppression; Immunomodulation; Cytokines; Pneumonia; Liver transplantation

Reference

1. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. 2020; Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30:269–271. DOI: 10.1038/s41422-020-0282-0. PMID: 32020029. PMCID: PMC7054408.

2. de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, et al. 2020; Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 117:6771–6776. DOI: 10.1073/pnas.1922083117. PMID: 32054787. PMCID: PMC7104368.

3. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. Washington State 2019-nCoV Case Investigation Team. 2020; First case of 2019 novel coronavirus in the United States. N Engl J Med. 382:929–936. DOI: 10.1056/NEJMoa2001191. PMID: 32004427. PMCID: PMC7092802.

4. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. 2020; Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 11:222. DOI: 10.1038/s41467-019-13940-6. PMID: 31924756. PMCID: PMC6954302.

5. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. 2020; A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 382:1787–1799. DOI: 10.1056/NEJMoa2001282. PMID: 32187464. PMCID: PMC7121492.

6. Gao J, Tian Z, Yang X. 2020; Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 14:72–73. DOI: 10.5582/bst.2020.01047. PMID: 32074550.

7. Li G, De Clercq E. 2020; Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 19:149–150. DOI: 10.1038/d41573-020-00016-0. PMID: 32127666.

8. Dong L, Hu S, Gao J. 2020; Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 14:58–60. DOI: 10.5582/ddt.2020.01012. PMID: 32147628.

9. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. 2020; Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 56:105949. DOI: 10.1016/j.ijantimicag.2020.105949. PMID: 32205204. PMCID: PMC7102549.

10. Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W. 2020; Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol. 38:10–18.

11. Li X, Geng M, Peng Y, Meng L, Lu S. 2020; Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. 10:102–108. DOI: 10.1016/j.jpha.2020.03.001. PMID: 32282863. PMCID: PMC7104082.

12. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. China Medical Treatment Expert Group for Covid-19. 2020; Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 382:1708–1720. DOI: 10.1056/NEJMoa2002032. PMID: 32109013. PMCID: PMC7092819.

13. Peiris JS, Yuen KY, Osterhaus AD, Stöhr K. 2003; The severe acute respiratory syndrome. N Engl J Med. 349:2431–2441. DOI: 10.1056/NEJMra032498. PMID: 14681510.

14. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. 2020; SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 181:271–280.e8. DOI: 10.1016/j.cell.2020.02.052. PMID: 32142651. PMCID: PMC7102627.

15. Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. 2020; COVID-19: immunology and treatment options. Clin Immunol. 215:108448. DOI: 10.1016/j.clim.2020.108448. PMID: 32353634. PMCID: PMC7185015.

16. Lessler J, Reich NG, Brookmeyer R, Perl TM, Nelson KE, Cummings DA. 2009; Incubation periods of acute respiratory viral infections: a systematic review. Lancet Infect Dis. 9:291–300. DOI: 10.1016/S1473-3099(09)70069-6.

17. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration, UK. 2020; COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 395:1033–1034. DOI: 10.1016/S0140-6736(20)30628-0.

18. Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. 2018; MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 104:8–13. DOI: 10.1016/j.cyto.2018.01.025. PMID: 29414327. PMCID: PMC7129230.

19. Prompetchara E, Ketloy C, Palaga T. 2020; Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 38:1–9.

20. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, et al. 2004; Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 136:95–103. DOI: 10.1111/j.1365-2249.2004.02415.x. PMID: 15030519. PMCID: PMC1808997.

21. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. 2020; The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 20:363–374. DOI: 10.1038/s41577-020-0311-8. PMID: 32346093. PMCID: PMC7187672.

22. Shokri S, Mahmoudvand S, Taherkhani R, Farshadpour F. 2019; Modulation of the immune response by Middle East respiratory syndrome coronavirus. J Cell Physiol. 234:2143–2151. DOI: 10.1002/jcp.27155. PMID: 30146782. PMCID: PMC7166610.

23. Shin HS, Kim Y, Kim G, Lee JY, Jeong I, Joh JS, et al. 2019; Immune responses to Middle East respiratory syndrome coronavirus during the acute and convalescent phases of human infection. Clin Infect Dis. 68:984–992. DOI: 10.1093/cid/ciy595. PMID: 30060038. PMCID: PMC7108191.

24. Zhao J, Zhao J, Mangalam AK, Channappanavar R, Fett C, Meyerholz DK, et al. 2016; Airway memory CD4(+) T cells mediate protective immunity against emerging respiratory coronaviruses. Immunity. 44:1379–1391. DOI: 10.1016/j.immuni.2016.05.006. PMID: 27287409. PMCID: PMC4917442.

25. Kikkert M. 2020; Innate immune evasion by human respiratory RNA viruses. J Innate Immun. 12:4–20. DOI: 10.1159/000503030. PMID: 31610541. PMCID: PMC6959104.

26. de Wit E, van Doremalen N, Falzarano D, Munster VJ. 2016; SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 14:523–534. DOI: 10.1038/nrmicro.2016.81. PMID: 27344959. PMCID: PMC7097822.

27. Hermann-Kleiter N, Baier G. 2010; NFAT pulls the strings during CD4+ T helper cell effector functions. Blood. 115:2989–2997. DOI: 10.1182/blood-2009-10-233585. PMID: 20103781.

28. Li CK, Wu H, Yan H, Ma S, Wang L, Zhang M, et al. 2008; T cell responses to whole SARS coronavirus in humans. J Immunol. 181:5490–5500. DOI: 10.4049/jimmunol.181.8.5490. PMID: 18832706. PMCID: PMC2683413.

29. Liu W, Fontanet A, Zhang PH, Zhan L, Xin ZT, Baril L, et al. 2006; Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 193:792–795. DOI: 10.1086/500469. PMID: 16479513. PMCID: PMC7109932.

30. Castells L, Baliellas C, Bilbao I, Cantarell C, Cruzado JM, Esforzado N, et al. 2014; [Early detection, prevention and management of renal failure in liver transplantation]. Gastroenterol Hepatol. 37:480–491. Spanish. DOI: 10.1016/j.gastrohep.2013.11.006. PMID: 25060591.

31. Serrano Aulló MT, Parra Moncasi E, Lorente Pérez S. 2011; [Immunosuppression in liver transplantation: renoprotective regimens]. Gastroenterol Hepatol. 34:422–427. Spanish. DOI: 10.1016/j.gastrohep.2010.12.009. PMID: 21458889.

32. Moini M, Schilsky ML, Tichy EM. 2015; Review on immunosuppression in liver transplantation. World J Hepatol. 7:1355–1368. DOI: 10.4254/wjh.v7.i10.1355. PMID: 26052381. PMCID: PMC4450199.

33. Taylor AL, Watson CJ, Bradley JA. 2005; Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol. 56:23–46. DOI: 10.1016/j.critrevonc.2005.03.012. PMID: 16039869.

34. D'Antiga L. 2020; Coronaviruses and immunosuppressed patients: the facts during the third epidemic. Liver Transpl. 26:832–834. DOI: 10.1002/lt.25756. PMID: 32196933.

35. Zhao M. 2020; Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. Int J Antimicrob Agents. 55:105982. DOI: 10.1016/j.ijantimicag.2020.105982. PMID: 32305588. PMCID: PMC7161506.

36. Pfefferle S, Schöpf J, Kögl M, Friedel CC, Müller MA, Carbajo-Lozoya J, et al. 2011; The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog. 7:e1002331. DOI: 10.1371/journal.ppat.1002331. PMID: 22046132. PMCID: PMC3203193.

37. Membreno FE, Espinales JC, Lawitz EJ. 2013; Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis. 17:129–139. DOI: 10.1016/j.cld.2012.09.008. PMID: 23177289.

38. Badri PS, Parikh A, Coakley EP, Ding B, Awni WM, Dutta S, et al. 2016; Pharmacokinetics of tacrolimus and cyclosporine in liver transplant recipients receiving 3 direct-acting antivirals as treatment for hepatitis C infection. Ther Drug Monit. 38:640–645. DOI: 10.1097/FTD.0000000000000315. PMID: 27310199.

39. Morrey JD, Smee DF, Sidwell RW, Tseng C. 2002; Identification of active antiviral compounds against a New York isolate of West Nile virus. Antiviral Res. 55:107–116. DOI: 10.1016/S0166-3542(02)00013-X.

40. Sebastian L, Madhusudana SN, Ravi V, Desai A. 2011; Mycophenolic acid inhibits replication of Japanese encephalitis virus. Chemotherapy. 57:56–61. DOI: 10.1159/000321483. PMID: 21282947.

41. Leyssen P, Balzarini J, De Clercq E, Neyts J. 2005; The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. J Virol. 79:1943–1947. DOI: 10.1128/JVI.79.3.1943-1947.2005. PMID: 15650220. PMCID: PMC544097.

42. Kaur P, Chu JJ. 2013; Chikungunya virus: an update on antiviral development and challenges. Drug Discov Today. 18:969–983. DOI: 10.1016/j.drudis.2013.05.002. PMID: 23684571. PMCID: PMC7108317.

43. Pan Q, de Ruiter PE, Metselaar HJ, Kwekkeboom J, de Jonge J, Tilanus HW, et al. 2012; Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C virus infection in vitro and in vivo. Hepatology. 55:1673–1683. DOI: 10.1002/hep.25562. PMID: 22213147.

44. Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, et al. 2013; Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 67:606–616. DOI: 10.1016/j.jinf.2013.09.029. PMID: 24096239. PMCID: PMC7112612.

45. A long and winding sTORy. 2017; Nat Cell Biol. 19:1131. DOI: 10.1038/ncb3624. PMID: 28960201.

46. Wang CH, Chung FT, Lin SM, Huang SY, Chou CL, Lee KY, et al. 2014; Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit Care Med. 42:313–321. DOI: 10.1097/CCM.0b013e3182a2727d. PMID: 24105455.

47. Forns X, Navasa M. 2020; Liver transplant immunosuppression during the Covid-19 pandemic. Gastroenterol Hepatol. 43:457–463. DOI: 10.1016/j.gastrohep.2020.06.003. PMID: 32646657. PMCID: PMC7290227.