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

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)


' INTRODUCTION
Coronavirus disease 2019  is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (1,2). The first case of this disease was reported in Wuhan, Hubei province, China, in December 2019 (3). Since March 2020, COVID-19 has spread worldwide and has become a public health emergency and a pandemic of international concern (4).
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 (5,6), with a case fatality rate close to 8-10% (5,6). Moreover, the presence of comorbidities results in increased mortality, with multiorgan dysfunction (1,2).
Data on COVID-19 in solid organ transplant (SOT), liver transplant (LT), and kidney transplant (KT) patients are scarce (7). Mazzafero et al. (8) reported a novel experience with several COVID-19 cases at an Italian transplant center in Lombardy (8). 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 (9).
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 (10).
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. 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 (11,12,13). The review methodology followed the recommendations published by PRISMA (11,12,13).

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 nontransplant 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 po0.05 was considered significant. All tests were performed using IBM SPSS 25 software, with a=0.05 and a 95% confidence interval.
The data were generated using Review Manager Version 5.3 software provided by the Cochrane Collaboration (Rev-Man; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark).

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.
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.

Solid organ transplant patients
Twenty-four articles on SOT patients were selected. Thirtynine 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).

Liver transplant patients
From the 11 articles included in the analysis of LT patients infected by SARS-CoV-2, seven were case reports/correspondences (8,9,(14)(15)(16)(17)(18), 3 were consensuses (19)(20)(21), and one article was a case series on overall SOT (7). 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).

' 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. (8) 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) (8).
D'Antiga et al. (9) 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 (9). 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 (21). 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 (14). 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. (7)  Their study suggests that SARS-CoV-2 infection had a severe course in SOT recipients (7). 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 nontransplanted populations.