Herpes simplex in a liver transplant recipient

Abstract

Fatal hepatitis is a rare complication of disseminated herpes simplex virus (HSV) 1 and 2 infections. In adult transplant recipients, most cases of HSV hepatitis occur with reactivation but may be seen with primary infection.1-6 Herein, we present a case of a 57-year-old white female with end-stage liver disease from hepatitis C who underwent transplant of a right lobe of the liver from her daughter and died after contracting HSV 2 hepatitis. Her immunosuppressive regimen included rapamycin, tacrolimus, and prednisone. Due to elevated liver function tests (total bilirubin 14.1, aspartate aminotransferase 287, alanine aminotransferase 138, and alkaline phosphatase 1,246), an abdominal computed tomography scan was performed on day 7 after transplant, showing multiple hepatic microabscesses (Fig. 1). A presumptive diagnosis of disseminated candidiasis was made, and treatment with fluconazole was initiated. Blood cultures were negative for yeast. Due to worsening liver tests, a transjugular liver biopsy was obtained on day 22 after transplant and found to be immunostain-positive for HSV 2 within a necrotizing granuloma with evidence of viral cytopathic changes (Fig. 2). Cultures of the liver tissue were positive for HSV. Serum HSV qualitative polymerase chain reactions were also positive for HSV. The patient was promptly started on intravenous acyclovir 10 mg/kg every 12 hours with dosing adjusted due to concomitant development of acute renal failure. Her liver function tests improved over the next few days, with no further progression of her renal failure. The patient had no cutaneous or genital HSV lesions and, on review of records, did not undergo pretransplant screening for HSV 1 or 2. Her daughter was subsequently found to have antibodies to HSV1 and 2, with no history of HSV genital, mucous membrane, or cutaneous lesions. The patient subsequently required surgical debridement of a wound infection in the operating room. The liver was noted to have numerous vesicles uniformly distributed throughout its surface (Fig. 3). An intraoperative biopsy of the liver was immunostain-positive for herpes simplex within a necrotizing granuloma with no further viral cytopathic changes, consistent with resolving infection. No other manifestations of HSV infection were identified. However, she subsequently developed worsening liver function tests and partial disruption of the bile duct anastomosis due to a multiresistant Pseudomonas aeruginosa infection and ultimately succumbed to persistent Pseudomonas aeruginosa sepsis. At the request of the family, no autopsy was performed. Multiple hepatic microabscesses. Innumerable, subcentimeter, hypovascular foci scattered throughout the hepatic allograft are shown by computed tomography during the portal-venous phase of intravenous contrast enhancement. Intraoperative appearance of herpes simplex vesicles overlying the surface of the transplanted liver. Initial liver biopsy. (A) Liver with zonal necrosis (right side) contains hepatocytes showing nuclear inclusions indicating viral cytopathic effect (arrowheads). The virally infected cells show multinucleated cells with molded nuclei and eosinophilic nuclear inclusions with chromatin margination. These cells are seen at the border of the residual viable area (lower left corner). Hemotoxylin & eosin original magnification ×100. (B) Immunohistochemical staining for HSV antigens was strongly positive in the zone of virally infected cells, whereas stains for cytomegalovirus and adenovirus were negative. Original magnification ×100. HSV hepatitis should be considered an infectious disease emergency. Left untreated, HSV hepatitis has a mortality rate of 86%.7 With acyclovir therapy, the mortality rate dropped to 33% in one study,2 and empiric therapy should be considered if HSV hepatitis is suspected.6 Symptoms have been reported as early as 5 days after transplantation, compared with 30-40 days for cytomegalovirus hepatitis,2, 8, 9 and may include fever, fatigue, myalgias, progressive transaminase elevation, abdominal pain, and coagulopathy, although skin lesions are uncommon.4 HSV hepatitis may result in nonspecific hepatic microabscesses on computed tomography scan.10, 11 At imaging, innumerable small hepatic foci measuring less than 2 cm in diameter are termed microabscesses when infectious in etiology12 and probably represent confluent foci of necrosis. Microabscesses are likely the intrahepatic equivalent of the superficial herpetic vesicles noted at surgery (Fig. 3). Typically, these lesions are distributed evenly throughout the liver.13 Microabscesses are commonly fungal in origin, most commonly due to Candida albicans in immunocompromised patients,12, 13 although Aspergillus sp, Histoplasma capsulatum, Cryptococcus neoformans, and mucormycosis may be considered. Bacterial causes include Staphylococcus aureus, Mycobacterium tuberculoum, and Mycobacterium avium-intracellulare. Most bacterial liver abscesses present as one or a few well-demarcated lesions greater than 2 cm in diameter and are often solitary and large (3-5 cm). Noninfectious lesions may sometimes mimic hepatic microabscesses, including multiple metastases, lymphoma, Kaposi's sarcoma, sarcoidosis, and widespread focal fatty infiltration.12, 13 In liver allograft recipients, post-transplant lymphoproliferative disease and recurrent hepatocellular carcinoma would be considerations. An additional issue is the use of prophylactic acyclovir for HSV immunoglobulin G “mismatches” (i.e., HSV immunoglobulin G–negative recipients of HSV immunoglobulin G–positive organs).14 We are unaware of our patient's HSV status pretransplant; her daughter was seropositive. It is possible that primary HSV infection could be avoided with prophylactic acyclovir.4 HSV, herpes simplex virus.