Safe use of Liver Grafts from Syphilis-Positive Donors in Liver Transplantation and Review of the Literature

Background: The growing disparity between organ availability and the number of candidates for organ transplantation has urged the use of marginal grafts including grafts from syphilis-positive donors. However, few knowledges could be acknowledged about this due to the rare data from case reports. Therefor we evaluate our data and summarize our experience of the management of liver grafts from syphilis-positive donors. Methods: From January 2015 to December 2019, 22 adult patients received liver transplantation from syphilis-positive donors while 873 patients got liver transplantation from syphilis-negative donors at our center. Given the imbalance in several baseline variables, propensity score matching was used. The outcomes were compared including complications, hospital stay, recovery of liver function and survival of the two groups and the management of the recipients was reviewed. Results: There were no differences in complications and hospital stay of the recipients after transplantation. And it showed similar trends in the liver function recovery. Patient and graft survivals were comparable to that of syphilis-negative grafts. And benzathine penicillin is effective to protect the recipients from syphilis. Conclusions: The use of liver grafts from syphilis-positive donors does not to increase the morbidity and mortality of the recipients. Also, the prophylactic theory of benzathine penicillin is helpful. results Disease; RPR,Rapid Plasma Reagin; TPPA,Treponema Pallidum Particle Agglutination.


Introduction
To date there is no better therapeutic options for patients with end-stage liver disease except for liver transplantation. Nevertheless, the shortage of liver donors does not match the increasing demand for liver grafts, which has led to broadening of acceptance criteria for potential organ donor candidates 1 , in other words, utilizing marginal grafts regardless of the risk of transmission of infection 2 .
Syphilis, caused by Treponema pallidum, has a worldwide distribution. The risk of syphilis in organ donors should not be neglected, and Gibel et al 3 estimate it to be about 0.15%. Unfortunately, the prevalence of syphilis in organ donors should have increased with the substantially growing incidence of syphilis over the past decades [4][5][6][7] .
Although syphilis is mainly transmitted by sexual contract and is infrequent in other ways 8 , it theoretically has the transmission possibility via organ transplantation. In fact, there are two reports documented describing this phenomenon, one after kidney transplantation 9 and the other after liver transplantation 10 . Serologic testing of organ donors for syphilis is recommended but evidence of donor syphilis infection is not considered a contraindication for using organs if prophylactic antibiotics are administered to the recipient 11 . However, no cohort study of liver grafts from syphilis-positive donors in liver transplantation has been reported, as the possibility of syphilitic hepatitis after liver transplantation that may result in poor prognosis.
Hence, we report our promising results on the clinical outcome of liver transplantation using syphilis-positive liver grafts within our monocenter experience. In addition, we performed the useful prophylactic theory of penicillin.

Materials And Methods
From January 2015 to December 2019, 22 adult patients had liver transplantation from syphilis-positive donors at our center while 873 patients underwent liver grafts from syphilis-negative donors. Given the imbalance in several baseline variables, 1:4 propensity score matching was used. Here we reviewed the outcomes of these 22 recipients and took those 88 patients as control in this study. Before transplantation all patients received syphilis-positive liver grafts were noti ed of potential poor prognosis and the possibility of infection.

Syphilis-positive Donors
Age, sex, and serum features of the syphilis-positive donors are listed in Table 1

Follow-up after transplantation
After transplantation all patients were monitored intensively until they were stable. The evaluation included clinical symptoms, biochemical tests and image surveillance. Serology test for syphilis was monitored at day 5, then month 1, 3, 6 and 12. The evaluation of follow-up after discharge mainly concentrated on liver function, complications, and survival. Computed tomography was conducted every half a year while ultrasound monthly.
Propensity score matching The R language 3.5.1 was used to match the patients as 1:4 pairing through the propensity score matching (PSM). The matching variables included gender, age, BMI of donors and recipients, making the baseline data of these two groups comparable.

Statistics
The statistical software SPSS 25.0(SPSS, Inc., Chicago, IL) was used to analyze the data. The mean value and standard deviation of the data were then presented. Statistical analysis methods included Chi-square test, Student's t test and Kaplan-Meier method with log-rank test. It was considered statistically signi cant when P < 0.05.  (Table 2). Post-transplantation results showed there were no differences between these two groups concerning hospital stay (21 vs. 21 day p = 0.90) and post-transplant complications, such as primary non-function (4.5% vs. 3.4%, P = 1.00), biliary complications (13.6% vs. 15.9%, P = 1.00) and renal failure (4.5% vs. 12.5%, P = 0.49) ( Table 3). As for the liver function recovery after liver transplantation, no signi cant differences were observed in these two groups. The trends of the mean value of serum liver function markers, for example alanine transaminase, aspartate aminotransferase, international normalized ratio and total bilirubin were similar in both groups after liver transplantation (Fig. 1). No syphilis hepatitis was observed in any patient. What was more, there were no differences between these two groups in patient and graft survival (Fig. 2). All these results above demonstrated that syphilis-positive grafts did not result in poor prognosis or increase the morbidity and mortality.

Conclusions
The use of liver grafts from syphilis-positive donors does not to increase the morbidity and mortality of the recipients which can relatively alleviate the shortage of donor liver. And the prophylactic theory of benzathine penicillin for recipients is helpful.

Discussion
During the last 2 decades, the growing disparity between organ availability and the number of candidates for organ transplantation has compelled the use of sub-optimal or marginal donors. Extensive donor test is recommended to prevent transmission of disease by transplantation. Traditionally, syphilis screening involves a nontreponemal anticardiolipin serological test (eg, Rapid Plasma Reagin [RPR] or Venereal Disease Research Laboratory [VDRL]). Subsequently positive results are con rmed by a speci c treponemal test (eg, TPPA) 12 . Nowadays, it has the trend to use treponemal-speci c EIA for syphilis screening and a nontreponemal test will be taken on positive results 13,14 . As we can see in Table 1, we would miss syphilis positivity if we tested our donors in the traditional way. However, the latter method also has its limitation with about 17% of EIA results false-positives and discordant test results as reported 14 . Hence, it is recommended that discordant results should be tested using the TPPA test 15 . So, we use EIA as the initial screening method, and positive results will be con rmed by TPPA and RPR.
The EIA test was negative in all recipients before transplantation. One recipient (case 13) had positive EIA and TPPA at day 5 but his TPPA results was negative and EIA remained positive afterwards. An explanation of this phenomenon may be the passive transmission of antibodies from donor at transplantation or transmission of lymphocytes with the grafts, which has been described already in kidney transplantation 16,17 . Case 10 had negative EIA at day 5 but had positive EIA and PRP (1:1) at month 1, it was considered that he was infected with syphilis in the past, but had been cured and was not infectious. Afterwards, his PRP became negative and EIA remained positive 18 . With this recipient (case 10), we should be aware of the possibility of syphilitic hepatitis. It is uncommon in immunocompetent individuals 10 while it has been depicted in immunocompromised patients, such as those infected with human immunode ciency virus (HIV) 19 . In syphilitic hepatitis, there would be a notable increase in alkaline phosphatase and a modest increase in aspartate aminotransferase, alanine transaminase and bilirubin along with clinical symptoms including rash and hepatomegaly 10  Summarily, our cohort study illustrates that syphilis-positive liver grafts did not result in poor prognosis or increase the morbidity and mortality of the recipients after liver transplantation. Benzathine penicillin is effective to protect recipients from transmission of syphilis. Furthermore, we summarize and share our experience in the management of recipients with syphilis-positive liver grafts. With the increasing disparity between donors and recipients, it is vital to be aware that syphilis-positive liver grafts are safe for recipients as long as prophylactic antibiotics are administered to the recipients. Availability of data and materials The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests Funding Not applicable.
Authors' contributions TL and XB conceived of the study, and participated in its design and coordination and helped to draft the manuscript. WZ and MZ participated in the design of the study and collected the data and built the datasets. XD and YS conceived of the study and performed the statistical analysis. LY and CQ performed the statistical analysis and helped to draft the manuscript. All authors read and approved the nal manuscript.