Orthotopic liver transplantation from a donor with Schistosoma japonicum

To the Editor:

Despite of the rapid increase of donation after cardiac death (DCD) in China, the shortage of organs continues to be a major problem. Every organ procured is so valuable that it should never be discarded easily, especially a liver that could save a patient’s life in an emergency. This leads to the use of grafts from donors with unrecognized and unusual diseases, including schistosomiasis.[1]Here, we reported a case of orthotopic liver transplantation (OLT) from a donor withSchistosoma japonicumto a patient with end-stage cirrhosis due to HBV infection.

A 44-year-old male patient was admitted to our center because of jaundice for 20 days. He had a history of cirrhosis due to 20 years HBV infection, and presented with jaundice, ascites, lower extremity edema as well as liver, kidney and coagulation dysfunction. Laboratory results were as follows: white blood count 7.8×109/L, hemoglobin 101 g/L, platelets 47×109/L, alanine aminotransferase (ALT) 175 U/L (9-50), aspartate aminotransferase (AST) 297 U/L (15-40), alkaline phosphatase (ALP) 233 U/L (45-125), total bilirubin 796.7 μmol/L (0-22.0), direct bilirubin 522 μmol/L (0-6.0), albumin 32.2 g/L, serum creatinine 131 μmol/L and international normalized ratio (INR) 2.99. The score of model for end-stage liver disease (MELD)-Na was 37, which indicated a high mortality rate without immediate liver transplantation. On July 3rd 2016, the patient underwent OLT from a DCD donor. This was permitted by the Ethics Committee of our hospital, and the liver was attributed by the China Organ Transplant Response System. The appearance of the donor liver was normal. However, frozen biopsy during operation showed a number of degenerated foreign bodies with lymphocytic and eosinophilic infiltration within the portal areas, suggestingSchistosomaeggs (Fig. 1A). Nevertheless, the liver parenchyma showed no signs of architectural change. The donor was from the endemic region ofSchistosoma japonicum, but remained asymptomatic and had a normal liver function. This was considered an incidental pathologic finding. Concerning all factors mentioned above, the decision was made to perform the operation, as the patient would have little chance to survive otherwise.

The operation was successful, and the postoperative course was uneventful. The patient’s liver function recovered rapidly and his symptoms relieved gradually. His immunosuppressant regimen consisted of steroids, tacrolimus (initiated with 2 mg/d, adjusted by drug concentration ranging from 6-10 ng/mL) and mycophenolate mofetil (500 mg every 12 hours). Hepatitis B prophylaxis with telbivudine and intravenous hepatitis B immune globulin was administrated postoperation, and the HBV DNA test showed negative (less than 1×103copies) on postoperative day 45. No extra anti-parasite treatment was given. The patient was discharged at day 20 postoperation, and maintained good liver function in the 6 months’ follow-up. The recent biopsy of the allograft at two points showed no signs of rejection or fibrosis, and noSchistosomaeggs was found (Fig. 1B and C).

Schistosomiasis is a worldwide epidemic disease, effecting at least 200 million people worldwide.[2]Human beings can be infected by five species ofSchistosoma, includingSchistosoma haematobium,Schistosoma mansoni,Schistosoma japonicum,Schistosoma intercalatum, andSchistosoma mekongi. In China, onlySchistosoma japonicumis epidemic. Even with the great efforts made by the Chinese government, schistosomiasis caused bySchistosoma japonicumhas not been eliminated, and in fact appears to resurge in some areas.[3]Schistosomiasis is acquired after contact with water contaminated bySchistosomacercariae, and can present acute clinical signs including fever, chill, weakness, headache, diarrhea, nausea, eosinophilia, etc. Most patients become asymptomatic as the infection progresses to the chronic phase, and the hepatocellular synthetic function may be preserved in the early stage.[2]As the number of donationafter citizens’ death grows, a certain amount of potential donors may be infected by schistosomiasis, and can only be diagnosed with preoperative biopsy. Whether to utilize the liver with histological finding ofSchistosomaeggs and normal liver function to expand the donation pool becomes a dilemma for transplant surgeons.

Fig. 1. Pathologic biopsy of the graft. A: Degenerated Schistosoma eggs with lymphocytic and eosinophilic infiltration in the liver frozen section biopsy during the operation (Hematoxylin eosin staining, original magnification ×200); B: Biopsy of the graft six months postliver transplantation (Hematoxylin eosin staining, original magnification ×200); C: Biopsy of the graft six months post-liver transplantation (Masson staining, original magnification ×200).

Schistosomaeggs may cause hepatic fibrosis and portal hypertension, but allograft biopsy at six months posttransplantation showed no signs of fibrosis or rejection, and no eggs were found in our case. Before our work, five articles including 13 patients receiving liver transplantation from donors withSchistosoma mansonihave been reported (Table).[1,2,4-6]SinceSchistosoma mansonimatures and unites in the portal venous system after the acute phase, and resides in the mesenteric vein, only eggs migrate to the liver. Therefore, the liver from infected donor is unlikely to contain adult worms ofSchistosoma mansoniand transmit schistosomiasis.[6]Without continuous production and deposition of eggs in the graft of the recipient, hepatic schistosomiasis is self-limited, while hepatic fibrosis may also be reduced over time if reinfection is avoided.[2]It was reported that no evidence of schistosomiasis was found in patients’ follow-up biopsies,[1,2]and in one patient, no eggs or fibrosis was seen at six months post-transplantation,[5]which was in consistent with our result. Based on these facts, the simple presence ofSchistosomaeggs with normal liver function is not considered a contraindication for liver donation.[2,4,6]SinceSchistosoma japonicumhas similar characteristics and life cycle withSchistosoma mansoni,[7]we support this viewpoint, and report success in the case of liver transplantation from a donor withSchistosoma japonicum.

There is no consensus on the treatment ofSchistosomafor recipients in this situation. Praziquantel is the most effective drug for the treatment to schistosomiasis, and can be used for post-transplantation patients due to mild side-effects and very low toxicity.[2,7]Part of the recipients from the reported articles were given praziquantel post-transplantation and showed no sign of recurrence.[1,5]However, praziquantel can only kill adult worms and has little effect on eggs or immature worms.[2]Thus some scholars suggest that donors should receive the treatment of praziquantel while recipients need not. Recipients of such organs had good prognosis.[2,4,6]With that, we decided not to give praziquantel treatment, and six months’ follow-up of the patient showed no sign of schistosomiasis.

Due to the existence of allograft and the effect of immunosuppressant regimen, the immune microenvironment in the recipient is quite complicated. WithSchistosomaeggs, it becomes even more complicated. Helminth parasites, includingSchistosoma, play an important role in immunoregulation by causing a shift in T helper cell phenotype, inducing regulatory cells, and affecting innate cells like mast cells and eosinophils.[8]With these abilities, helminth parasites escape the attack of the host’ simmune system and survive. When helminth parasites encounter organ transplantation, such immunoregulation effects may help induce tolerance.[9]The patient in this report showed a significant increase of eosinophils in peripheral blood post-liver transplantation (Fig. 2), which was considered a result induced by theSchistosomaeggs. Moreover, he maintained stable homeostasis with relatively low dosage of immunosuppressant (prednisone 5 mg/d, tacrolimus 0.027 mg/kg/d, concentration ranging from 5 to 7 ng/mL). Researchers have proved that Th2-eosinophils could suppress the autoimmune inflammation like arthritis.[10]Whether eosinophilia in this patient helped protect allograft from rejection requires further research.

Table. Summary the available data about the use of liver grafts infected with schistosomiasis

Fig. 2. The eosinophils in peripheral blood of the patient postliver transplantation.

In summary, incidental finding ofSchistosoma japonicumeggs with normal liver function should not be considered as contraindication for liver donation, and it is donors (especially living donors) that should receive anti-parasite treatment rather than recipients. The longterm prognosis of recipients who received a liver withSchistosomaeggs remains to be observed, and the immunoregulation effects and mechanism ofSchistosomaeggs in the setting of transplantation requires further study.

Bo Peng, Xing-Guo She, Ke Cheng, Hong Liu, Ying Niu and Ying-Zi Ming

The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha 410013, China; Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha 410013, China (Peng B, She XG, Cheng K, Liu H, Niu Y and Ming YZ)

Contributors:PB and MYZ proposed the study. PB wrote the first draft. SXG collected the clinical data. PB and SXG contributed equally to this study. All authors contributed to the design and interpretation of the study and to further drafts. MYZ is the guarantor.

Funding:This study was supported by a grant from the Wu Jieping Medical Foundation (320.6750.15070).

Ethical approval:The study was approved by the Ethics Committee of the Third Xiangya Hospital.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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3 Gray DJ, Li YS, Williams GM, Zhao ZY, Harn DA, Li SM, et al. A multi-component integrated approach for the elimination of schistosomiasis in the People’s Republic of China: design and baseline results of a 4-year cluster-randomised intervention trial. Int J Parasitol 2014;44:659-668.

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6 Andraus W, Pugliese V, Pecora R, D’Albuquerque LA. Intentional use of Schistosoma mansoni-infected grafts in living donor liver transplantation. Liver Transpl 2012;18:867-868.

7 Ross AG, Bartley PB, Sleigh AC, Olds GR, Li Y, Williams GM, et al. Schistosomiasis. N Engl J Med 2002;346:1212-1220.

8 Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites--masters of regulation. Immunol Rev 2004;201:89-116.

9 Johnston CJ, McSorley HJ, Anderton SM, Wigmore SJ, Maizels RM. Helminths and immunological tolerance. Transplantation 2014;97:127-132.

10 Chen Z, Andreev D, Oeser K, Krljanac B, Hueber A, Kleyer A, et al. Th2 and eosinophil responses suppress inflammatory arthritis. Nat Commun 2016;7:11596.

Published online May 23, 2017.

Ying-Zi Ming (Email: myz_china@ aliyun.com)

10.1016/S1499-3872(17)60023-7)