Neonatal Liver Transplantation for Fulminant Hepatitis Caused by Herpes Simplex Virus Type 2

Neonatal herpes simplex virus (HSV) infection can cause skin disease or disseminated infection, resulting in hepatitis, pneumonitis, intravascular coagulopathy, or encephalitis (1). It is usually acquired perinatally, with a high mortality rate in disseminated disease (1–3). We describe a 12-day-old girl with fulminant hepatitis and fulminant hepatic failure (FHF) secondary to HSV type 2 infection who underwent a successful liver transplantation (LT). CASE REPORT A female infant was delivered at 39 weeks of gestation by emergency caesarean section for fetal distress, weighing 2.6 kg and subsequently breast-fed. She became ill at 8 days of age. Her mother had vaginal thrush antenatally, but there was no history of primary herpetic lesion or other perinatal problems. The parents were healthy and nonconsanguineous. Two older siblings from the mother's previous marriage were healthy. The infant was admitted within hours in a collapsed state, apneic, unresponsive, with capillary refill longer than 10 seconds, and with unrecordable serum blood glucose. No oral or vesicular skin lesions were noted. The liver was palpable at 2 cm, the spleen not palpable, and there was no ascites. The patient was resuscitated and required ventilation and inotropic support. Treatment with broad-spectrum antibiotics and acyclovir was started. Initial investigations showed the white cell count was 10.5 × 109/L with neutropenia (1.3 × 109/μL), thrombocytopenia (platelet count, 19 × 109/L), hypoglycemia (blood glucose, 1.1 mmol/L), and coagulopathy (blood initially noncoagulable; prothrombin time >100 seconds; reference range, 9–13 seconds; activated partial thromboplastin time, 80 seconds; reference range, 26–35 seconds). Liver function test results showed the following serum concentrations: total bilirubin, 83 μmol/L; conjugated bilirubin, 34 μmol/L; albumin, 26 g/L; aspartate aminotransferase, 6106 U/L; alanine aminotransferase, 1764 U/L; gamma-glutamyltransferase, 182 U/L, and ammonia, 202 μmol/L. The patient had lactic acidosis (lactate, 5.6 μmol/L). Serum ferritin was markedly increased (19,530 μg/L; normal range, 110–503 μg/L); serum iron was 27.3 μmol/L (5–25 μmol/L), iron-binding capacity was 25.9 μmol/L, and iron saturation was 100%. Galactosemia, fructose intolerance, and tyrosinemia were excluded. Hepatitis A, B, and C virus; Epstein-Barr virus; and cytomegalovirus infections were excluded using virologic or serologic methods. A putative diagnosis of FHF secondary to neonatal hemochromatosis (NH) was made. Intravenous dextrose, N-acetylcysteine, desferrioxamine, and selenium infusions; prostaglandin E1; α-tocopherol; and blood products were administered. Antibiotics and acyclovir were continued. The patient was referred for further treatment. At transfer, she had fluid overload, with pulmonary edema and oliguria. Cranial ultrasound showed no abnormality. An electroencephalograph showed diffuse metabolic encephalopathy. Carnitine and sodium benzoate therapy was added. She was too unstable for abdominal magnetic resonance imaging. Lip salivary glands biopsy tissue showed no hemosiderin deposit. Ventilation and inotropic support were continued, and she remained neurologically and hemodynamically stable with improved urine output. Her multiorgan involvement probably was primarily due to FHF and thought to be potentially reversible. She underwent LT on day 12 of life, still with a working diagnosis of NH. She received a monosegment 2 liver graft from a donor weighing 65 kg. The inferior vena cava anastomosis was achieved using the triangular piggyback technique. The recipient portal vein was anastomosed to the left portal vein of the donor. The donor hepatic artery was anastomosed to the infrarenal aorta using an arterial conduit. Biliary drainage was through a Roux-en-Y loop. The explanted liver showed small yellow nodules and irregular green areas. Histologically, there was widespread panacinar necrosis, hemorrhage, congestion, and focal infiltration by neutrophils. Surviving hepatocytes showed severe cholestasis, patchy ballooning, and moderate steatosis (Fig. 1). There were mild iron stores (2+). Bacterial and viral culture results of the explanted liver were negative, but immunohistochemical staining for HSV was positive (Fig. 2). Small bowel biopsy taken during LT did not show hemosiderin. Herpes simplex virus 2 was isolated from a nasopharyngeal swab taken at the referring hospital, but this result only became available 2 days after LT. Maternal vaginal culture at this time was negative for HSV, but subsequently she had specific HSV IgG antibody. With this information, perinatally acquired HSV 2 infection was considered to be the cause of the FHF, rather than NH.FIG. 1.: Histology of explanted liver, showing widespread panacinar necrosis. The surviving parenchyma showed steatosis (magnification, ×1300).FIG. 2.: Immunohistochemical staining of the explanted liver for HSV was positive (magnification, ×1300).The postoperative course was difficult and was complicated by acute renal failure, requiring hemofiltration for 15 days, and acute respiratory distress syndrome, requiring high-frequency oscillatory ventilation for 15 days. The patient also experienced left ventricular dysfunction that necessitated noradrenaline and dobutamine infusions. A wound hematoma that became infected with Mycoplasma hominis required debridement. Intravenous ganciclovir was given for 2 weeks (for suspected cytomegalovirus infection), followed by oral acyclovir (40 mg/kg four times daily) for 3 months. Prednisolone (initial dose, 1.5 mg/kg daily, with gradual reduction to discontinuation at 3 months after transplantation) and low-dose cyclosporine (target through level, 100–125 μmol/L for first 3 months, and subsequently 50–100 μmol/L) were given for immunosupression. The patient was discharged 40 days after admission. Five months after LT, she experienced vesicular eruption of both hands and feet. Culture of this vesicular fluid isolated HSV 2. The lesions responded to oral acyclovir. Another episode of herpetic lesions developed 1 month later, and acyclovir prophylaxis was continued for 1 year without further skin eruption. Currently, 25 months after the LT, the patient is well, has normal liver and renal function, but has moderate global developmental delay, walking with support and saying single words. DISCUSSION The knonwn causes of FHF in the neonate include hemophagocytic lymphohistiocytosis; metabolic, toxic, infective, autoimmune, and ischemic causes; and NH (4,5). Neonatal hemochromatosis is a disorder of intrauterine onset, manifested within the first hours or days after birth, and is associated with extrahepatic deposits of hemosiderin that spare the reticuloendothelial cells in the spleen, bone marrow, and lymph nodes (6). Demonstrating hemosiderin deposit in biopsy tissue of lip salivary glands has been suggested to be of diagnostic value (7). The serum ferritin concentration usually is increased markedly in NH, but also is a nonspecific finding in various forms of end-stage liver disease in both neonates and adults (6,8). Decreased serum transferrin concentration and supersaturation of iron-binding capacity are more specific (6). In this case, hyperferritinemia and supersaturation of iron were noted, but total iron-binding capacity was within the normal range. This demonstrates that iron-binding capacity can be fully saturated in liver failure due to HSV hepatitis and that this finding is not specific to NH. The diagnosis of NH continues to depend on the demonstration of extrahepatic siderosis, which as this case shows can be difficult in a critically ill infant (6). Neonatal HSV infection, although rare, has a significant mortality and morbidity (2,3). It often is transmitted vertically from mother to newborn, although the maternal infection can go unrecognized (1,3,9). Infection also can occur without the typical herpetic skin, eye, or oral lesions (3,10). The histologic features usually seen in hepatitis in HSV infection are necrosis with hepatocytes that contain eosinophilic intranuclear inclusions (3,11). Immunoperoxidase staining may demonstrate viral antigens in the nucleus, cytoplasm, and cell membrane of affected hepatocytes (12). Herpes simplex virus has been isolated from the nasopharyngeal and cervical fluids of patients with HSV hepatitis (13). It may be difficult to differentiate FHF caused by HSV hepatitis from NH, as both may cause increased serum ferritin level. Furthermore, maternal history of primary herpes and postnatal herpetic cutaneous lesions may be absent in the affected newborns (1,3). In this case, the diagnosis of HSV infection was established only after LT by the isolation of HSV 2 from nasopharyngeal secretions obtained before LT, and after positive immunohistochemical staining of the explanted liver. However, high-dose intravenous acyclovir had been started immediately on presentation, perhaps explaining the relatively good neurodevelopmental outcome in this child. The management of neonatal FHF usually presents a challenging clinical problem. Infants with FHF usually are very ill and may have coagulopathy, hypoglycaemia, electrolyte imbalance, cerebral edema, cardiorespiratory instability, and renal failure (5). Supportive measures such as ventilatory and inotropic supports, correction of coagulopathy, and prevention of hypoglycemia and electrolyte imbalances are necessary. Exchange transfusion may be beneficial. Rapid neurologic deterioration and progressive multiple organ failure often means that a decision to perform transplantation occurs before the cause of FHF can be firmly established (5). When NH is a possibility, an antioxidant cocktail that includes N-acetylcysteine, selenium, α-tocopherol, vitamin C, prostaglandin E1, and desferrioxamine should be started (14). However, this should not delay listing for transplantation, because in the neonatal period, even with innovative surgical solutions, the major risk in liver failure is death while awaiting LT. Survival after neonatal LT is much shorter than in later infancy, with a high risk for technical and infective complications. When a liver graft becomes available, an experienced team should review the clinical situation to determine whether a reasonable prognosis for good quality survival exists with transplantation. The current case demonstrates the potential of this treatment option. Antibiotics and acyclovir should be prescribed until a liver graft is available. Conventional wisdom dictates that LT is contraindicated in HSV fulminant hepatitis as neonatal HSV infection is a disseminated infection, leading to multiorgan failure (2,3,15–17), and because fatal HSV hepatitis may recur, especially with high immunosuppression (18,19). Only been a few reports describe successful LT in FHF secondary to HSV hepatitis (13,20). Hattori et al. (20) described a 2-month-old infant with FHF who underwent a successful living-related LT. The infant experienced no neurologic deficit 25 months after LT. Shanley et al. (13) described a 32-year-old woman who had FHF secondary to HSV 2 infection during the third trimester of pregnancy and subsequently underwent a successful LT, as in our case. The diagnosis of HSV 2 infection was established only after LT. After surgery, the patient received high-dose acyclovir, with no recurrence of HSV infection up to 10 months after LT. The authors concluded that the combination of high-dose acyclovir therapy with liver transplantation was lifesaving. This case report illustrates the difficulty in managing neonatal FHF when the decision to proceed with LT often is made without establishing the cause of FHF. Nevertheless, neonatal FHF caused by perinatally acquired HSV infection should not be considered an absolute contraindication to LT, and LT may be successful with proper management. Posttransplant acyclovir prophylaxis is necessary to prevent recurrence of HSV infection, as observed in this case, and should be given for a prolonged time.