COVID-19 in solid organ transplantation patients: A systematic review

Abstract

Coronavirus disease (COVID-19) rapidly progresses to severe acute respiratory syndrome. This review aimed at collating available data on COVID-19 infection in solid organ transplantation (SOT) patients.

We performed a systematic review of SOT patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MEDLINE and PubMed databases were electronically searched and updated until April 20, 2020. The MeSH terms used were “COVID-19” AND “Transplant.”

Thirty-nine COVID-19 cases were reported among SOT patients. The median interval for developing SARS-CoV-2 infection was 4 years since transplantation, and the fatality rate was 25.64% (10/39). Sixteen cases were described in liver transplant (LT) patients, and the median interval since transplantation was 5 years. The fatality rate among LT patients was 37.5% (6/16), with death occurring more than 3 years after LT. The youngest patient who died was 59 years old; there were no deaths among children. Twenty-three cases were described in kidney transplant (KT) patients. The median interval since transplantation was 4 years, and the fatality rate was 17.4% (4/23). The youngest patient who died was 71 years old. Among all transplant patients, COVID-19 had the highest fatality rate in patients older than 60 years : LT, 62.5% vs 12.5% (p=0.006); KT 44.44% vs 0 (p=0.039); and SOT, 52.94% vs 4.54% (p=0.001).

This study presents a novel description of COVID-19 in abdominal SOT recipients. Furthermore, we alert medical professionals to the higher fatality risk in patients older than 60 years. (PROSPERO, registration number=CRD42020181299)

Liver Transplantation; Systematic Review; COVID-19; Humans; Liver Diseases; SARS-CoV-2; 2019-nCoV; Solid Organ Transplant Recipient


INTRODUCTION

Coronavirus disease 2019 (COVID-19) is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (11. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. https://doi.org/10.1001/jama.2020.1585
https://doi.org/10.1001/jama.2020.1585...
,22. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020. https://doi.org/10.1002/jmv.25757
https://doi.org/10.1002/jmv.25757...
). The first case of this disease was reported in Wuhan, Hubei province, China, in December 2019 (33. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33. https://doi.org/10.1056/NEJMoa2001017.
https://doi.org/10.1056/NEJMoa2001017...
). Since March 2020, COVID-19 has spread worldwide and has become a public health emergency and a pandemic of international concern (44. World Health Organization. WHO Characterizes COVID-19 as A Pandemic. Available from: https://www.paho.org/hq/index.php?option=com_content&view=article&id=15756:who-characterizes-covid-19-as-a-pandemic&Itemid=1926&lang=en
https://www.paho.org/hq/index.php?option...
).

COVID-19 is extremely contagious and, in certain cases, may rapidly progress to severe acute respiratory syndrome. An unexpectedly high rate of SARS-CoV-2 infection has been observed worldwide. An age gradient in the risk of death was identified, and patients older than 60 years were reported to have a higher mortality rate (55. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020. pii: S1473-3099(20)30243-7. https://doi.org/10.1016/S1473-3099(20)30243-7
https://doi.org/10.1016/S1473-3099(20)30...
,66. Glynn JR. Protecting workers aged 60-69 years from COVID-19. Lancet Infect Dis. 2020. pii: S1473-3099(20)30311-X. https://doi.org/10.1016/S1473-3099(20)30311-X
https://doi.org/10.1016/S1473-3099(20)30...
), with a case fatality rate close to 8-10% (55. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020. pii: S1473-3099(20)30243-7. https://doi.org/10.1016/S1473-3099(20)30243-7
https://doi.org/10.1016/S1473-3099(20)30...
,66. Glynn JR. Protecting workers aged 60-69 years from COVID-19. Lancet Infect Dis. 2020. pii: S1473-3099(20)30311-X. https://doi.org/10.1016/S1473-3099(20)30311-X
https://doi.org/10.1016/S1473-3099(20)30...
). Moreover, the presence of comorbidities results in increased mortality, with multiorgan dysfunction (11. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. https://doi.org/10.1001/jama.2020.1585
https://doi.org/10.1001/jama.2020.1585...
,22. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020. https://doi.org/10.1002/jmv.25757
https://doi.org/10.1002/jmv.25757...
).

Data on COVID-19 in solid organ transplant (SOT), liver transplant (LT), and kidney transplant (KT) patients are scarce (77. Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15929
https://doi.org/10.1111/ajt.15929...
). Mazzafero et al. (88. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients?: preliminary experience from an Italian transplant center in Lombardy. Lancet Gastroenterol Hepatol. 2020. pii: S2468-1253(20)30116-3. https://doi.org/10.1016/S2468-1253(20)30116-3
https://doi.org/10.1016/S2468-1253(20)30...
) reported a novel experience with several COVID-19 cases at an Italian transplant center in Lombardy (88. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients?: preliminary experience from an Italian transplant center in Lombardy. Lancet Gastroenterol Hepatol. 2020. pii: S2468-1253(20)30116-3. https://doi.org/10.1016/S2468-1253(20)30116-3
https://doi.org/10.1016/S2468-1253(20)30...
). Another case series from Italy showed that children who had received LTs were not at a higher risk for severe SARS-CoV-2 infection despite being immunosuppressed (99. D’Antiga L. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplant. 2020. https://doi.org/10.1002/lt.25756
https://doi.org/10.1002/lt.25756...
).

Transplant societies and guidelines were initially established to decrease the risk of infection and protect health care professionals. Recipients and donors may be at risk of being carriers of SARS-CoV-2 or contracting active COVID-19 through contact with patients who have COVID-19 or through exposure to SARS-CoV-2 (1010. Wang J, Li X, Cao G, Wu X, Wang Z, Yan T. COVID-19 in a Kidney Transplant Patient. Eur Urol. 2020. pii: S0302-2838(20)30211-6. https://doi.org/10.1016/j.eururo.2020.03.036
https://doi.org/10.1016/j.eururo.2020.03...
).

Insufficient data on infected SOT recipients are available, particularly data regarding the management of immunosuppressants and fatality rates. This review aimed to collate the available data that address the management of COVID-19 infection in abdominal SOT patients.

METHODS

Study identification

A systematic review of the literature on COVID-19 and transplantation was carried out. The MEDLINE and PubMed databases (http://www.ncbi.nlm.nih.gov/pubmed) were electronically searched and updated until April 20, 2020. The MeSH terms used were “COVID-19” (entire related MeSH terms: 2019 novel coronavirus, SARS-CoV-2 infection, 2019-nCoV infection) AND “transplant.” The electronic bibliographic database included MEDLINE-PubMed, EMBASE, Cochrane Library, and Web of Science.

The terms and MeSH terms for the PubMed database search were developed with the PICO structure: patient, intervention, comparison or control, and outcome (PICO). The terms for each group were combined with the “OR” operator. The results of the search terms forming the “P” (Patients) group were combined with those of search terms forming the “I” (Intervention) group, with “AND,” and for exclusion terms, with “NOT.”

Participants/population: Adults and children who were abdominal organ recipients and were diagnosed as having COVID-19. Intervention(s), exposure(s): Adults and children who were abdominal SOT recipients and tested positive for COVID-19 that progressed to severe acute respiratory syndrome. Comparator(s)/control: The control group was selected from the group of patients who were not exposed to SARS-CoV-2. We evaluated other groups of LT and KT patients and various epidemiologic groups such as those matched for age, sex, and comorbidities. Context Main outcome(s): Survival after SARS-CoV-2 infection and outcomes related to medical management, as a potential therapy to this infection in this population; establishing guidelines and programs to better treat this population.

This systematic review was registered in the international database of prospectively registered systematic reviews (PROSPERO, registration number=CRD42020181299). The review protocol can be accessed online via the PROSPERO website (https://www.crd.york.ac.uk/prospero/). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist was adhered to when preparing this manuscript (1111. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. https://doi.org/10.1371/journal.pmed.1000100
https://doi.org/10.1371/journal.pmed.100...
,1212. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
https://doi.org/10.1371/journal.pmed.100...
,1313. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, et al. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157. https://doi.org/10.1136/bmj.i157
https://doi.org/10.1136/bmj.i157...
). The review methodology followed the recommendations published by PRISMA (1111. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. https://doi.org/10.1371/journal.pmed.1000100
https://doi.org/10.1371/journal.pmed.100...
,1212. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
https://doi.org/10.1371/journal.pmed.100...
,1313. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, et al. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157. https://doi.org/10.1136/bmj.i157
https://doi.org/10.1136/bmj.i157...
).

Study selection

Inclusion and exclusion criteria

Selection criteria were used within the research question of the PICO structure. All studies evaluated were written in English.

Case reports, letters to the editor, clinical randomized controlled trials, non-randomized controlled trials, reviews, consensus articles, and protocol studies were included. Studies on organs other than the liver and kidneys, those on tissues transplants, those on a novel therapy for COVID-19, those on the impact of COVID-19 on the transplant system, those on vaccine research, those involving patients on hemodialysis, those on the clinical manifestation of COVID-19, epidemiologic studies, those on elective or non-transplant surgical procedures, and those on immunosuppression protocols that were unrelated to abdominal SOT and COVID-19 were excluded.

Study data extraction

Data extraction was carried out independently by two researchers, using the text, tables, and figures of the original published articles. The quality of the studies selected and the selection methods were evaluated by two independent researchers (LSN and LYZ). In the case of a disagreement, the researchers held a consensus meeting to reach a final decision.

Statistical analysis

Quantitative and qualitative variables were presented as number and percentage, median and range, or mean and standard deviation. The COVID-19 prevalence and fatality rates of patients who were older than 60 years were calculated and compared. A Mann-Whitney U test was used to compare independent samples, and p<0.05 was considered significant. All tests were performed using IBM SPSS 25 software, with α=0.05 and a 95% confidence interval.

The data were generated using Review Manager Version 5.3 software provided by the Cochrane Collaboration (RevMan; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark).

RESULTS

Study selection

The literature search revealed 113 articles, of which 24 articles were selected and analyzed in this review. Figure 1 depicts the flow diagram of the systematic literature search, according to the PRISMA statement, and the selection criteria for the articles.

Figure 1
Flow diagram of the systematic literature search according to the PRISMA statement. *Kidney transplant (KT) and liver transplant (LT).

We did not find well-designed randomized control trials, cohorts, or prospective or retrospective studies. Most articles were case series, letters to the editor, and editorials.

Data extraction and synthesis were performed specifically using articles on SOT with COVID-19 infection, that is, 24 articles. There were 11 articles regarding Liver transplantation (Table 1), 14 articles on Kidney transplantation (Table 2), and one article on SOT as presented with liver and KT.

Table 1
COVID-19 infection in liver transplant patients.
Table 2
COVID-19 infection in kidney transplant patients.

Solid organ transplant patients

Twenty-four articles on SOT patients were selected. Thirty-nine cases were related to SOT and COVID-19 infection. The median interval since transplantation to COVID-19 infection was 4 years (range, 0.01 - 30.10). The overall fatality rate in solid organ transplant patients was 25.64% (10/39), and the fatality rate was 52.94% in patients older than 60 years (p=0.001; Table 3).

Table 3
COVID-19 infection in SOT, LT, and KT patients. Overall parameters and prevalence/fatality rate in COVID-19 in SOT, liver and kidney patients.

Liver transplant patients

From the 11 articles included in the analysis of LT patients infected by SARS-CoV-2, seven were case reports/correspondences (88. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients?: preliminary experience from an Italian transplant center in Lombardy. Lancet Gastroenterol Hepatol. 2020. pii: S2468-1253(20)30116-3. https://doi.org/10.1016/S2468-1253(20)30116-3
https://doi.org/10.1016/S2468-1253(20)30...
,99. D’Antiga L. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplant. 2020. https://doi.org/10.1002/lt.25756
https://doi.org/10.1002/lt.25756...
,), 3 were consensuses (1919. Liu H, He X, Wang Y, Zhou S, Zhang D, Zhu J, et al. Management of COVID-19 in patients after liver transplantation: Beijing working party for liver transplantation. Hepatol Int. 2020. https://doi.org/10.1007/s12072-020-10043-z
https://doi.org/10.1007/s12072-020-10043...

20. Saigal S, Gupta S, Sudhindran S, Goyal N, Rastogi A, Jacob M, et al. Liver transplantation and COVID-19 (Coronavirus) infection: guidelines of the liver transplant Society of India (LTSI). Hepatol Int. 2020. https://doi.org/10.1007/s12072-020-10041-1
https://doi.org/10.1007/s12072-020-10041...
-2121. Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC, et al. Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement. Hepatology. 2020. https://doi.org/10.1002/hep.31281
https://doi.org/10.1002/hep.31281...
), and one article was a case series on overall SOT (77. Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15929
https://doi.org/10.1111/ajt.15929...
). The LT group included a total of 16 cases, with a median interval since transplantation of 5.95 years (range, 0.01-26.5). These cases involved transplants in pediatric and adult patients, with no reported deaths in children. Tacrolimus administration was discontinued in two cases, with satisfactory evolution of these patients; however, therapy with methylprednisolone was maintained (Table 1). The LT case fatality rate was 37.5% (6/16). Six patients evolved to death, more than 3 years after LT, with the youngest being 59 years of age (Table 1 and Table 3).

Kidney transplant patients

Fourteen articles were included in the analysis of KT patients with COVID-19. Among these, six were case reports/case series (2222. Bussalino E, De Maria A, Russo R, Paoletti E. Immunosuppressive therapy maintenance in a kidney transplant recipient SARS-CoV-2 pneumonia: A case report. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15920
https://doi.org/10.1111/ajt.15920...

23. Bartiromo M, Borchi B, Botta A, Bagalè A, Lugli G, Tilli M, et al. Threatening drug-drug interaction in a kidney transplant patient with Coronavirus Disease 2019 (COVID-19). Transpl Infect Dis. 2020. https://doi.org/10.1111/tid.13286
https://doi.org/10.1111/tid.13286...

24. Ning L, Liu L, Li W, Liu H, Wang J, Yao Z, et al. Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: Case report. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15897
https://doi.org/10.1111/ajt.15897...

25. Zhang H, Chen Y, Yuan Q, et al. Identification of Kidney Transplant Recipients with Coronavirus Disease 2019. Eur Urol. 2020. pii: S0302-2838(20)30205-0. https://doi.org/10.1016/j.eururo.2020.03.030
https://doi.org/10.1016/j.eururo.2020.03...

26. Chen S, Yin Q, Shi H, Du D, Chang S, Ni L, et al. A familial cluster, including a kidney transplant recipient, of Coronavirus Disease 2019 (COVID-19) in Wuhan, China. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15903
https://doi.org/10.1111/ajt.15903...
-2727. Seminari E, Colaneri M, Sambo M, Gallazzi I, Di Matteo A, Roda S, et al. SARS Cov2 infection in a renal- transplanted patient: A case report. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15902
https://doi.org/10.1111/ajt.15902...
28. Marx D, Moulin B, Fafi-Kremer S, Benotmane I, Gautier G, Perrin P, et al. First case of COVID-19 in a kidney transplant recipient treated with belatacept. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15919
https://doi.org/10.1111/ajt.15919...
29. Gandolfini I, Delsante M, Fiaccadori E, Zaza G, Manenti L, Degli Antoni A, et al. COVID-19 in kidney transplant recipients. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15891
https://doi.org/10.1111/ajt.15891...
30. Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient?: Does immunosuppression alter the clinical presentation? 2020. https://doi.org/10.1111/ajt.15874
https://doi.org/10.1111/ajt.15874...
31. Martino F, Plebani M, Ronco C. Kidney transplant programmes during the COVID-19 pandemic. Lancet Respir Med. 2020;8(5):e39. https://doi.org/10.1016/S2213-2600(20)30182-X
https://doi.org/10.1016/S2213-2600(20)30...
), five were correspondences (1010. Wang J, Li X, Cao G, Wu X, Wang Z, Yan T. COVID-19 in a Kidney Transplant Patient. Eur Urol. 2020. pii: S0302-2838(20)30211-6. https://doi.org/10.1016/j.eururo.2020.03.036
https://doi.org/10.1016/j.eururo.2020.03...
,), one was a guideline (3232. The Renal Association. Guidance on the management of transplant recipients diagnosed with or suspected of having COVID19. Updated 25th March. Available from: https://bts.org.uk/wp-content/uploads/2020/03/Clinical_management_transplant_recipients.pdf
https://bts.org.uk/wp-content/uploads/20...
), one an editorial (3333. Haberal M. COVID-19 UPDATE. Exp Clin Transplant. 2020;18(2):139-40. https://doi.org/10.6002/ect.2020.000e.
https://doi.org/10.6002/ect.2020.000e...
), and one was a case series on SOT (77. Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15929
https://doi.org/10.1111/ajt.15929...
). Twenty-three KT cases were described. The median interval since transplantation was 4 years (range, 0.25-30.1). The fatality rate among KT patients was 17.4% (4/23), and the youngest patient who died was 71 years. Immunosuppressive therapy was reduced or suspended in 13 cases, with good clinical evolution in eight patients (Table 2 and 3).

DISCUSSION

The transplant society’s recommendations and guidelines during the COVID-19 pandemic, with insufficient evidence, consider LT and KT as safe procedures. The transplant team should discuss the real risks and benefits of the procedure and of immunosuppression therapy. On the basis of the scarce data on SARS-CoV-2 infection, it is suggested that therapy for COVID-19 patients be individualized. This review provided data on SOT and COVID-19 infection.

In their study, Mazzafero et al. (88. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients?: preliminary experience from an Italian transplant center in Lombardy. Lancet Gastroenterol Hepatol. 2020. pii: S2468-1253(20)30116-3. https://doi.org/10.1016/S2468-1253(20)30116-3
https://doi.org/10.1016/S2468-1253(20)30...
) reported that three patients with severe COVID-19 among 111 long-term LT survivors (who had undergone transplantation more than 10 years ago) died. The post-transplant course had been uneventful for all three patients, and their immunosuppressive regimen had been tapered gradually, with very low trough concentrations of calcineurin inhibitors (two patients receiving ciclosporin and one receiving tacrolimus) (88. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients?: preliminary experience from an Italian transplant center in Lombardy. Lancet Gastroenterol Hepatol. 2020. pii: S2468-1253(20)30116-3. https://doi.org/10.1016/S2468-1253(20)30116-3
https://doi.org/10.1016/S2468-1253(20)30...
).

D’Antiga et al. (99. D’Antiga L. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplant. 2020. https://doi.org/10.1002/lt.25756
https://doi.org/10.1002/lt.25756...
) reported a case series from a single center in Italy, wherein children who received LTs were not at increased risk for severe SARS-CoV-2 infection compared with the general population despite being immunosuppressed (99. D’Antiga L. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplant. 2020. https://doi.org/10.1002/lt.25756
https://doi.org/10.1002/lt.25756...
). Nevertheless, this series was biased as it involved the study of a population of children, which has a lower incidence rate of SARS-CoV-2 infection.

The American Association for the Study of Liver Diseases suggests that immunosuppression should not be reduced or stopped in asymptomatic LT recipients (2121. Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC, et al. Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement. Hepatology. 2020. https://doi.org/10.1002/hep.31281
https://doi.org/10.1002/hep.31281...
). Immunosuppression, despite its immunomodulatory effect, did not seem to increase the risk of severe COVID-19 disease in transplantation patients. Given that a reactive innate immune response might be responsible for the severe clinical manifestations of SARS-CoV-2 infection, immunosuppression might be protective against COVID-19; however, this needs further clarification.

Unrecognized COVID-19 infection among transplantation recipients largely increases the potential of development of severe immune suppression and postsurgical infection, which may lead to multisystem organ damage or death. A donor with unidentified COVID-19 infection may also spread the virus to multiple recipients. The therapeutic paradox is compelling in such patients: insufficient immunosuppression results in graft loss due to rejection, whereas excessive immunosuppression results in severe infection. Strict screening protocols for organ transplant recipients and donors, aimed at identifying carriers of SARS-CoV-2, must be developed to aid in reducing further transmission (1414. Qin J, Wang H, Qin X, Zhang P, Zhu L, Cai J, et al. Perioperative Presentation of COVID-19 Disease in a Liver Transplant Recipient. Hepatology. 2020. https://doi.org/10.1002/hep.31257
https://doi.org/10.1002/hep.31257...
15. Lagana SM, De Michele S, Lee MJ, Emond JC, Griesemer AD, Tulin-Silver SA, et al. COVID-19 Associated Hepatitis Complicating Recent Living Donor Liver Transplantation. Arch Pathol Lab Med. 2020. https://doi.org/10.5858/arpa.2020-0186-SA
https://doi.org/10.5858/arpa.2020-0186-S...
16. Zhong Z, Zhang Q, Xia H, Wang A, Liang W, Zhou W, et al. Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15928
https://doi.org/10.1111/ajt.15928...
17. Huang JF, Zheng KI, George J, Gao HN, Wei RN, Yan HD, et al. Fatal outcome in a liver transplant recipient with COVID-19. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15909
https://doi.org/10.1111/ajt.15909...
18. Liu B, Wang Y, Zhao Y, Shi H, Zeng F, Chen Z. Successful treatment of severe COVID-19 pneumonia in a liver transplant recipient. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15901
https://doi.org/10.1111/ajt.15901...
). However, the scarce data must be better analyzed with more prolonged follow-up, and evaluations should be carried out in recipients with COVID-19 infection.

Fernandez-Ruiz et al. (77. Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15929
https://doi.org/10.1111/ajt.15929...
) reported on 18 SOT recipients with COVID-19. The majority of patients were KT recipients (44.4% [8/18]), followed by LT (33.3% [6/18]) and heart transplant recipients (22.2% [4/18]). The median patient age was 71.0±12.8 years, with a predominance of male patients (77.8% [14/18]), and the median interval since transplantation was 9.3 years. The case fatality rate was 27.8% (5/18). Their study suggests that SARS-CoV-2 infection had a severe course in SOT recipients (77. Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15929
https://doi.org/10.1111/ajt.15929...
). Moreover, this finding differs from those of other publications, which report similar results in non-transplanted patients with COVID-19 infection. However, the current study, which analyzed overall SOT cases, found that the median interval from transplantation to COVID-19 infection was 4 years, and the case fatality rate was 25.64% (10/39). Therefore, we demonstrated that SOT populations have a higher mortality risk than that in non-transplanted populations.

Moreover, Verity et al. (55. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020. pii: S1473-3099(20)30243-7. https://doi.org/10.1016/S1473-3099(20)30243-7
https://doi.org/10.1016/S1473-3099(20)30...
) demonstrated an age gradient in the risk of death in a COVID-19-infected population, which showed that early estimates indicate the fatality ratio (55. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020. pii: S1473-3099(20)30243-7. https://doi.org/10.1016/S1473-3099(20)30243-7
https://doi.org/10.1016/S1473-3099(20)30...
). According to their findings, there was an increase in the severity of COVID-19 with age in patients older than 60 years, along with a higher fatality rate (66. Glynn JR. Protecting workers aged 60-69 years from COVID-19. Lancet Infect Dis. 2020. pii: S1473-3099(20)30311-X. https://doi.org/10.1016/S1473-3099(20)30311-X
https://doi.org/10.1016/S1473-3099(20)30...
). Moreover, in this study, we observed a significant increase in fatality risk among SOT patients older than 60 years.

The main limitations of this study were that only case series and editorials on the topic were found in the literature. To the best of our knowledge, the number of cases with patients who had undergone SOT and were infected with COVID-19 is considerably low. Further, only this review was registered in the PROSPERO database (https://www.crd.york.ac.uk/prospero/). However, there are several ongoing clinical trials on COVID-19 (https://clinicaltrials.gov/ct2/results?cond=COVID-19). Further data is warranted for more definitive recommendations. The main contributions of this systematic review are the novel description of COVID-19 infection in SOT recipients (LT and KT), especially in terms of the management of the disease and immunosuppression therapy, and the fact that it alerts medical professionals to the higher fatality risk in SOT patients older than 60 years.

CONCLUSION

This study presents a novel description of COVID-19 infection in abdominal SOT recipients. Furthermore, we alert medical professionals to the higher fatality risk in the population of patients older than 60 years.

REFERENCES

  • 1
    Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. https://doi.org/10.1001/jama.2020.1585
    » https://doi.org/10.1001/jama.2020.1585
  • 2
    Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020. https://doi.org/10.1002/jmv.25757
    » https://doi.org/10.1002/jmv.25757
  • 3
    Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33. https://doi.org/10.1056/NEJMoa2001017
    » https://doi.org/10.1056/NEJMoa2001017
  • 4
    World Health Organization. WHO Characterizes COVID-19 as A Pandemic. Available from: https://www.paho.org/hq/index.php?option=com_content&view=article&id=15756:who-characterizes-covid-19-as-a-pandemic&Itemid=1926&lang=en
    » https://www.paho.org/hq/index.php?option=com_content&view=article&id=15756:who-characterizes-covid-19-as-a-pandemic&Itemid=1926&lang=en
  • 5
    Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020. pii: S1473-3099(20)30243-7. https://doi.org/10.1016/S1473-3099(20)30243-7
    » https://doi.org/10.1016/S1473-3099(20)30243-7
  • 6
    Glynn JR. Protecting workers aged 60-69 years from COVID-19. Lancet Infect Dis. 2020. pii: S1473-3099(20)30311-X. https://doi.org/10.1016/S1473-3099(20)30311-X
    » https://doi.org/10.1016/S1473-3099(20)30311-X
  • 7
    Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15929
    » https://doi.org/10.1111/ajt.15929
  • 8
    Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients?: preliminary experience from an Italian transplant center in Lombardy. Lancet Gastroenterol Hepatol. 2020. pii: S2468-1253(20)30116-3. https://doi.org/10.1016/S2468-1253(20)30116-3
    » https://doi.org/10.1016/S2468-1253(20)30116-3
  • 9
    D’Antiga L. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplant. 2020. https://doi.org/10.1002/lt.25756
    » https://doi.org/10.1002/lt.25756
  • 10
    Wang J, Li X, Cao G, Wu X, Wang Z, Yan T. COVID-19 in a Kidney Transplant Patient. Eur Urol. 2020. pii: S0302-2838(20)30211-6. https://doi.org/10.1016/j.eururo.2020.03.036
    » https://doi.org/10.1016/j.eururo.2020.03.036
  • 11
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. https://doi.org/10.1371/journal.pmed.1000100
    » https://doi.org/10.1371/journal.pmed.1000100
  • 12
    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
    » https://doi.org/10.1371/journal.pmed.1000097
  • 13
    Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, et al. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157. https://doi.org/10.1136/bmj.i157
    » https://doi.org/10.1136/bmj.i157
  • 14
    Qin J, Wang H, Qin X, Zhang P, Zhu L, Cai J, et al. Perioperative Presentation of COVID-19 Disease in a Liver Transplant Recipient. Hepatology. 2020. https://doi.org/10.1002/hep.31257
    » https://doi.org/10.1002/hep.31257
  • 15
    Lagana SM, De Michele S, Lee MJ, Emond JC, Griesemer AD, Tulin-Silver SA, et al. COVID-19 Associated Hepatitis Complicating Recent Living Donor Liver Transplantation. Arch Pathol Lab Med. 2020. https://doi.org/10.5858/arpa.2020-0186-SA
    » https://doi.org/10.5858/arpa.2020-0186-SA
  • 16
    Zhong Z, Zhang Q, Xia H, Wang A, Liang W, Zhou W, et al. Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15928
    » https://doi.org/10.1111/ajt.15928
  • 17
    Huang JF, Zheng KI, George J, Gao HN, Wei RN, Yan HD, et al. Fatal outcome in a liver transplant recipient with COVID-19. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15909
    » https://doi.org/10.1111/ajt.15909
  • 18
    Liu B, Wang Y, Zhao Y, Shi H, Zeng F, Chen Z. Successful treatment of severe COVID-19 pneumonia in a liver transplant recipient. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15901
    » https://doi.org/10.1111/ajt.15901
  • 19
    Liu H, He X, Wang Y, Zhou S, Zhang D, Zhu J, et al. Management of COVID-19 in patients after liver transplantation: Beijing working party for liver transplantation. Hepatol Int. 2020. https://doi.org/10.1007/s12072-020-10043-z
    » https://doi.org/10.1007/s12072-020-10043-z
  • 20
    Saigal S, Gupta S, Sudhindran S, Goyal N, Rastogi A, Jacob M, et al. Liver transplantation and COVID-19 (Coronavirus) infection: guidelines of the liver transplant Society of India (LTSI). Hepatol Int. 2020. https://doi.org/10.1007/s12072-020-10041-1
    » https://doi.org/10.1007/s12072-020-10041-1
  • 21
    Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC, et al. Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement. Hepatology. 2020. https://doi.org/10.1002/hep.31281
    » https://doi.org/10.1002/hep.31281
  • 22
    Bussalino E, De Maria A, Russo R, Paoletti E. Immunosuppressive therapy maintenance in a kidney transplant recipient SARS-CoV-2 pneumonia: A case report. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15920
    » https://doi.org/10.1111/ajt.15920
  • 23
    Bartiromo M, Borchi B, Botta A, Bagalè A, Lugli G, Tilli M, et al. Threatening drug-drug interaction in a kidney transplant patient with Coronavirus Disease 2019 (COVID-19). Transpl Infect Dis. 2020. https://doi.org/10.1111/tid.13286
    » https://doi.org/10.1111/tid.13286
  • 24
    Ning L, Liu L, Li W, Liu H, Wang J, Yao Z, et al. Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: Case report. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15897
    » https://doi.org/10.1111/ajt.15897
  • 25
    Zhang H, Chen Y, Yuan Q, et al. Identification of Kidney Transplant Recipients with Coronavirus Disease 2019. Eur Urol. 2020. pii: S0302-2838(20)30205-0. https://doi.org/10.1016/j.eururo.2020.03.030
    » https://doi.org/10.1016/j.eururo.2020.03.030
  • 26
    Chen S, Yin Q, Shi H, Du D, Chang S, Ni L, et al. A familial cluster, including a kidney transplant recipient, of Coronavirus Disease 2019 (COVID-19) in Wuhan, China. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15903
    » https://doi.org/10.1111/ajt.15903
  • 27
    Seminari E, Colaneri M, Sambo M, Gallazzi I, Di Matteo A, Roda S, et al. SARS Cov2 infection in a renal- transplanted patient: A case report. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15902
    » https://doi.org/10.1111/ajt.15902
  • 28
    Marx D, Moulin B, Fafi-Kremer S, Benotmane I, Gautier G, Perrin P, et al. First case of COVID-19 in a kidney transplant recipient treated with belatacept. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15919
    » https://doi.org/10.1111/ajt.15919
  • 29
    Gandolfini I, Delsante M, Fiaccadori E, Zaza G, Manenti L, Degli Antoni A, et al. COVID-19 in kidney transplant recipients. Am J Transplant. 2020. https://doi.org/10.1111/ajt.15891
    » https://doi.org/10.1111/ajt.15891
  • 30
    Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient?: Does immunosuppression alter the clinical presentation? 2020. https://doi.org/10.1111/ajt.15874
    » https://doi.org/10.1111/ajt.15874
  • 31
    Martino F, Plebani M, Ronco C. Kidney transplant programmes during the COVID-19 pandemic. Lancet Respir Med. 2020;8(5):e39. https://doi.org/10.1016/S2213-2600(20)30182-X
    » https://doi.org/10.1016/S2213-2600(20)30182-X
  • 32
    The Renal Association. Guidance on the management of transplant recipients diagnosed with or suspected of having COVID19. Updated 25th March. Available from: https://bts.org.uk/wp-content/uploads/2020/03/Clinical_management_transplant_recipients.pdf
    » https://bts.org.uk/wp-content/uploads/2020/03/Clinical_management_transplant_recipients.pdf
  • 33
    Haberal M. COVID-19 UPDATE. Exp Clin Transplant. 2020;18(2):139-40. https://doi.org/10.6002/ect.2020.000e
    » https://doi.org/10.6002/ect.2020.000e

Publication Dates

  • Publication in this collection
    03 June 2020
  • Date of issue
    2020

History

  • Received
    5 May 2020
  • Accepted
    8 May 2020
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