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Rare and Deadly

      Presentation

      An ordinary virus might have proved lethal had vague signs not been swiftly identified. A 44-year-old woman, recently returned from a trip to Las Vegas, was admitted to our university hospital after 2 days of fever, chills, photophobia, pain in the right upper quadrant and back, dysuria, and subsequent altered mental status. Her past medical history was notable for cervical dysplasia, which had been treated by hysterectomy, and breast augmentation.

      Assessment

      On examination, the patient was lethargic with stable vital signs. Her eyes were anicteric, and her liver margin was palpated 4 cm below the right costal margin. On hospital day 3, she had about 10 discrete vesicles, 3-5 mm in size, on an erythematous base. These were scattered on the dorsal and palmar surfaces of both hands and on the dorsal feet (Figure 1). A few vesicles were found on her shins; 1 was on her left hip. She had no oral mucosal or genital lesions.
      Figure thumbnail gr1
      Figure 1The patient had a few scattered discrete vesicles in a predominantly acral distribution. A, The patient's dorsal hand served as 1 site. B, The patient's ankle also was affected.
      Laboratory results revealed markedly elevated hepatic enzymes, with aspartate aminotransferase peaking at 9020 U/L and alanine aminotransferase reaching 4820 U/L. The patient had an international normalized ratio of 2.4, a platelet count of 68,000/mm3, and a slightly elevated creatinine of 1.3 mg/dL. Blood and urine cultures were negative. No acetaminophen was detected in her serum. Tests for hepatitis A, B, and C, human immunodeficiency virus, antinuclear antibodies, anti-smooth muscle antibody, anti-liver-kidney antibody, and pregnancy were negative. Iron studies and a ceruloplasmin level were normal. Computed tomography and magnetic resonance imaging scans displayed ascites and bilateral pleural effusions.
      A transjugular liver biopsy was performed, and a vesicle on the patient's skin was biopsied as well. The liver biopsy demonstrated confluent coagulative necrosis without significant inflammation, and numerous hepatocytes had smudged nuclei and marginated chromatin, consistent with viral inclusions. Immunohistochemical staining of the liver specimen was positive for herpes simplex virus (HSV) type 2. The skin biopsy disclosed an intraepidermal vesicle with keratinocyte necrosis, ghosts of multinucleated giant cells, and overall changes suggestive of herpes infection. A skin biopsy specimen sent for a viral fluorescent antibody test was positive for HSV-2, and a skin tissue culture grew HSV-2.

      Diagnosis

      The presence of isolated skin vesicles coupled with histological and immunohistochemical findings of HSV-associated hepatitis led to a diagnosis of disseminated HSV manifesting as fulminant hepatic failure—a disorder that has now been identified in 2 immunocompetent patients treated at our institution. Both presented with very similar skin findings (Figure 2). These cases illustrate that patients frequently have 10 or fewer scattered distinct vesicles or pustules, predominantly in an acral distribution. It has been estimated that 44% of patients with HSV-associated hepatitis have a herpetic rash, although more detailed descriptions of the skin findings rarely are found in the medical literature. We did not see the grouped vesicles that are typical of localized herpes infection.
      Figure thumbnail gr2
      Figure 2Two patients were treated for fulminant hepatitis associated with herpes simplex virus at our institution. Composite data are shown here.
      IV, intravenous; PO, oral; d, days.
      Fulminant hepatic failure is defined clinically as acute hepatitis and encephalopathy in a patient with no history of liver disease.
      • Trey C.
      • Lipworth L.
      • Chalmers T.C.
      • et al.
      Fulminant hepatic failure Presumable contribution to halothane.
      The most common causes are acetaminophen toxicity, drug reaction, hepatitis B, ischemia, hepatitis A, and autoimmune hepatitis; 27% of cases are of undetermined etiology.
      • Ostapowicz G.
      • Fontana R.J.
      • Schiødt F.V.
      • et al.
      Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.
      Despite high HSV seroprevalence in the population (62% for type 1 and 17% for type 2), HSV is a rare source of fulminant hepatic failure, accounting for only 1% of all cases or 25-50 cases per year in the United States.
      • Xu F.
      • Sternberg M.R.
      • Kottiri B.J.
      • et al.
      Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States.
      • Schiødt F.V.
      • Davern T.J.
      • Shakil A.O.
      • McGuire B.
      • Samuel G.
      • Lee W.M.
      Viral hepatitis-related acute liver failure.
      • Graham B.B.
      • Kaul D.R.
      • Saint S.
      • Janssen W.J.
      Clinical problem-solving Kiss of death.
      It is rarer still to see this condition in an immunocompetent patient. Classic risk factors for HSV-related fulminant hepatic failure include pregnancy and immunosuppression.
      • Graham B.B.
      • Kaul D.R.
      • Saint S.
      • Janssen W.J.
      Clinical problem-solving Kiss of death.
      In 1 series, only 24% (33/137) of afflicted patients were apparently immunocompetent.
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      Proposed mechanisms for this peculiar HSV manifestation in an immunocompetent host include overwhelmingly high inoculation and viremia, latent virus reactivation after reinfection by a second HSV strain, infection with specific hepatovirulent strains of HSV, and occult defects in host T-cell immunity.
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      We suspect that our patient had a primary genital HSV-2 infection induced by an unusually powerful viral strain. Aside from the aforementioned tests, an HSV serologic analysis was performed in this patient—low level antibody detection by Western blot assay was indeterminate for HSV. Antibody profiles to HSV can take 12-16 weeks to develop, especially if the patient is undergoing antiviral therapy. In addition, HSV serologies are difficult to interpret, because IgM can be detected in both primary and recurrent infections.
      • Morrow R.
      • Friedrich D.
      Performance of a novel test for IgM and IgG antibodies in subjects with culture-documented genital herpes simplex virus-1 or -2 infection.
      The most common signs of HSV-induced fulminant hepatic failure include fever (98%), coagulopathy (96.5%), and acute renal failure (65.3).
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      Of the 44% of patients that exhibit a herpetic rash, 61% have mucocutaneous lesions and 39% have a disseminated presentation.
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      HSV hepatitis can be readily diagnosed when liver biopsy demonstrates characteristic findings of focal necrosis with minimal surrounding inflammation. Intranuclear inclusion bodies are often found, and immunohistochemical analysis can confirm the presence of viral antigens in tissue sections from skin and liver (Figure 3). Polymerase chain reaction for serum HSV DNA is sensitive and specific, but it can take up to 5 days for results to become available.
      • Saeed K.
      • Pelosi E.
      Comparison between turnaround time and cost of herpes simplex virus testing by cell culture and polymerase chain reaction from genital swabs.
      Figure thumbnail gr3
      Figure 3These microscopic findings come from a similar case (patient 2). A, A hematoxylin and eosin stain of a skin biopsy demonstrated an intraepidermal vesicle and characteristic viral cytopathic changes in adjacent keratinocytes (arrow). B, A hematoxylin and eosin stain of a liver biopsy demonstrated an area of necrosis with minimal surrounding inflammation (arrow). C, Immunohistochemical staining for herpes simplex virus confirmed the presence of viral antigens in the liver specimen.
      Prognosis is generally poor. In the largest available series, 74% of cases were fatal.
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      Factors portending a particularly poor prognosis include coagulopathy, a platelet count under 75,000/mm3, encephalopathy, alanine aminotransferase levels exceeding 5000 U/L, male gender, age older than 40 years, and an immunocompromised state.
      We encourage clinicians to hold a high index of suspicion for disseminated HSV infection in any patient presenting with fulminant hepatic failure of unknown etiology. Careful skin examination should be performed, and strong consideration should be given to empiric acyclovir therapy until this entity has been excluded. Acyclovir is a safe drug, and the potential cost of missing this diagnosis can be devastating. In a recent series, patients treated with acyclovir had a mortality rate of 51% compared with 88% in patients who did not receive acyclovir.
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      In this same series, a delay in treatment was also significantly associated with a need for liver transplant and with death.

      Management

      Our patient, despite no identifiable risk factors, presented with a rare and deadly manifestation of a common viral infection. The patient's specific cutaneous findings, scattered discrete vesicles, were an important clue to the diagnosis. Lifesaving treatment with systemic acyclovir was administered early in the course of disease. In 57.6% of cases, diagnosis of HSV hepatitis is made at autopsy.
      • Norvell J.P.
      • Blei A.T.
      • Jovanovic B.D.
      • Levitsky J.
      Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.
      This might, in part, be due to treatment delays if subtle but important signs on the patient's skin are missed.
      Our patient received intravenous acyclovir, 600 mg 3 times a day, early in the disease process. Her symptoms and liver function gradually improved. On hospital day 8, the patient was discharged on oral valacyclovir, 1 g twice a day, for a total of 15 days after discharge. At a follow up visit 2 weeks later, her liver function tests had normalized and symptoms had resolved.

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