Klaff, Lindy S. MD; Kim, H Nina MD, MS; Marrazzo, Jeanne M. MD, MPH
From the Department of Medicine, University of Washington, Seattle, Washington
Correspondence: Lindy S. Klaff, MD, Harborview Medical Center, Department of Medicine, 325 Ninth Avenue, Mailbox 359782, Seattle, WA 98104. E-mail: firstname.lastname@example.org
Received for publication November 16, 2005, and accepted May 18, 2006.
A PREVIOUSLY HEALTHY, SEXUALLY ACTIVE 17-year-old girl was transferred from a hospital in Alaska for evaluation of fever, abdominal pain, rash, and liver lesions. Ten days before transfer, the patient presented to a primary care clinic with a 4-day history of increased vaginal discharge, lower abdominal pain, nausea, and headache. Nucleic acid amplification tests for Neisseria gonorrhoeae and Chlamydia trachomatis were negative, and she was treated with oral metronidazole for presumed bacterial vaginosis. The next day, she returned to the clinic with an additional complaint of dysuria and was prescribed trimethoprim/sulfamethoxazole for presumed bacterial cystitis, although urine cultures ultimately yielded no growth. Two days later, the patient presented to an emergency department with fever, worsening abdominal pain, dysuria, and hematuria. Examination revealed severe bilateral flank pain, cervical motion tenderness, and numerous warts at the vaginal introitus. Laboratory evaluation revealed pancytopenia, particularly in the white cell line (white blood cell count 1.2 k/μL, hematocrit 34, platelets 123 K), and moderate elevation in aminotransferases (alanine transaminase 453 U/L, aspartate transaminase 355 U/L). At that point, the patient was admitted and treated with parenteral metronidazole, levofloxacin, and gentamicin for coverage of presumed pelvic inflammatory disease, although a diagnosis of appendicitis was also considered. A pregnancy test was negative.
A contrast-enhanced computed tomography scan of the abdomen was performed and revealed multiple liver lesions and a small amount of peritoneal fluid. An exploratory laparoscopy, performed on the day of admission to evaluate persistent, severe lower abdominal pain, demonstrated multiple yellow pustules measuring 2 to 3 mm on the capsule of the liver (Fig. 1). Bacterial cultures of these lesions yielded no growth; viral cultures were not obtained. A small amount of bloody pelvic fluid was noted, and cell count of this material revealed 31,350 red blood cells/high-power field and 62 white blood cells/high-power field, of which 95% were monocytes. Multiple blood cultures remained sterile. On hospital day 3, the patient remained febrile and developed a rash consisting of discrete, scattered pustular and vesicular lesions, all on an erythematous base, that first appeared on her back and face and subsequently spread to her arms, legs, and trunk. A skin biopsy was performed, but the results were unavailable at the time of transfer to our tertiary care hospital 4 days later. Because of the patient’s pancytopenia, bone marrow biopsy was performed and showed a hypocellular marrow with normal cell lineages and no abnormal forms. Viral hepatitis serologies, serum test for heterophile antibodies (monospot), and antinuclear antibody test were negative, HIV antibodies were not present, and a PPD was nonreactive. Repeated testing for C. trachomatis and N. gonorrhoeae using nucleic acid amplification testing were negative.
The patient had been healthy before the current episode, had not recently received any immunizations, had not traveled outside of Alaska, and had never eaten any wild game or uncooked meat. She reported having had 4 lifetime male sex partners and had been sexually active with her current partner for 4 months; they did not use condoms regularly. Her mother reported that she had had chickenpox as a young child.
What Is Your Diagnosis?
Answer: Disseminated primary infection with herpes simplex virus type 2 (HSV-2) in an immunocompetent host seronegative for antibody to HSV type 1.
On hospital day 7, the girl was transferred to our hospital. Antinuclear antibody, cytomegalovirus serologies, and a rapid plasma reagin (RPR) assay were sent and were negative. Skin biopsy of a cutaneous vesicle was performed on arrival. Direct fluorescent antibody testing and viral culture of the skin biopsy material were diagnostic of HSV-2.1 Serum polymerase chain reaction testing for HSV-2 was negative; testing of serum for HSV type-specific antibodies by Western blot2 revealed the presence of antibodies to HSV-2 and absence of antibodies to HSV-1. Acyclovir (500 mg intravenously 3 times a day) was initiated. The patient’s elevated aminotransferases improved over the course of the next 3 days, and on discharge her aspartate transaminase was 68 U/L and alanine transaminase was 217 U/L. She defervesced and her leukopenia also improved, with a white blood cell count on discharge of 3.35 k/μL.
Although HSV-2 is typically transmitted through genital sexual contact, most infected persons do not report a history of genital ulcers or a discrete initial outbreak.3 When initial infection with HSV-2 is symptomatic, the typical appearance is that of discrete vesicles clustered on the external genitalia. In our patient’s case, however, the only genital lesions noted were warts. Our case is important for 3 reasons.
First, disseminated HSV with hepatitis in an immunocompetent host is a rare but well-described entity4; however, to our knowledge, no previous intraoperative images documenting the hepatic capsular lesions seen in our patient have been published. Similar lesions have been reported in patients with disseminated infection resulting from varicella zoster virus,5 another herpesvirus that can cause a similar clinical picture and was the main alternative diagnosis in our patient. HSV hepatitis, caused by an unspecified type but presumably HSV-1, was initially reported in 1969 in an adult undergoing concomitant corticosteroid therapy.6 Since that time, there have been multiple reports of HSV hepatitis in the setting of pregnancy, solid organ transplantation, and other immunocompromised states.7,8 Most of these reports are of patients with HSV-1 or with type unspecified, but some implicate HSV-2, primarily in immunocompromised hosts.9,10 In a review of 52 patients with HSV hepatitis, 44 of whom were significantly immunocompromised, a mortality rate of greater than 80% was seen. Additionally, leukopenia was seen in 43% of the patients and 82% had fever,11 similar to our patient. Only 31% of patients reviewed had genital lesions documented at the time of presentation.9 The treatment of choice for disseminated HSV, including hepatitis, is parenteral acyclovir. Given the high fatality rate of this disease, antiviral chemotherapy should be initiated when disseminated HSV is suspected. Despite the delay in administering appropriate therapy in our patient, she ultimately recovered without sequelae.
Second, patients with no detectable antibody to HSV-1 are more likely to have a severe symptomatic initial infection with HSV-2; this is termed “primary infection.” This is particularly true for women compared with men, probably because of the relatively larger surface area initially infected in the female genital tract and resultant involvement of more dorsal ganglia.12 Primary infection in women may involve not only the central nervous system, presenting with lymphocyte-predominant meningitis, radiculopathy, and urinary retention, but may involve the abdominal and pelvic viscera as well. The latter likely accounted for our patient’s persistent abdominal and pelvic pain and for the hemorrhagic peritonitis seen at laparoscopy.
Third, genital herpes was not suspected in our patient, despite unprotected sex with a new partner, a presentation consistent with disseminated viral disease, and evaluation by multiple providers. If the correct diagnosis had been suspected, she likely would have avoided both a bone marrow biopsy and laparoscopy, and parenteral acyclovir would likely have been administered earlier in her course. Other diagnostic considerations at that time should have also included hepatitis A and B, Epstein-Barr virus, varicella zoster virus, and cytomegalovirus as well as toxic ingestions and autoimmune hepatitis. Our patient had positive HSV-2 antibodies 10 days from the onset of her symptoms, which can occur in 20% of individuals with primary HSV-2 infection.13 Serum antibody to HSV is often undetectable during the initial phase of illness; serology is not reliable for the diagnosis during this period.
Because over 45 million persons in the United States are estimated to be infected with HSV-2,14 this common infection should be a primary diagnostic consideration in young, sexually active patients at risk who present with compatible—if uncommon—presentations.
1.Sanders C, Nelson C, Hove M, Woods GL. Cytospin-enhanced direct immunofluorescence assay versus cell culture for detection of herpes simplex virus in clinical specimens. Diagn Microbiol Infect Dis 1998; 32:111–113.
2.Ashley R, Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 & 2 in human sera. J Clin Microbiol 1988; 26:662–667.
3.Wald A, Koutsky L, Ashley RL, Corey L. Genital herpes in a primary care clinic. Demographic and sexual correlates of herpes simplex type 2 infections. Sex Transm Dis 1997; 24:149–155.
4.Czartoski T, Liu C, Koelle DM, Schmechel S, Kalus A, Wald A. Fulminant, acyclovir-resistant, herpes simplex virus type 2 hepatitis in an immunocompetent woman. J Clin Microbiol 2006; 44:1584–1586.
5.Cohen J, Brunell P, Straus S, Krause P. Recent advances in varicella-zoster virus infection. Ann Intern Med 1999; 130:922–932.
6.Diderholm H, Sternram U, Tegner KB, Willen R. Herpes simplex hepatitis in an adult. Acta Med Scand 1969; 186:151–155.
7.King A, Graves CR. Herpes simplex hepatitis in pregnancy: A case report and review of the literature. Obstet Gynecol Surv 1999; 54:463–468.
8.Bissig K, Zimmerman A, Bernasch D, Furrer H, Dufour J. Herpes simplex hepatitis 4 years after liver transplantation. J Gastroenterol 2003; 38:1005–1008.
9.McCalmont T, McLeod D, Kerr R, Hopkins M, Geisinger K. Fatal disseminated herpesvirus infection with hepatitis. Arch Pathol Lab Med 1994; 118:566–567.
10.Fahy R, Crouser E, Pacht E. Herpes simplex type 2 causing fulminant hepatic failure. South Med J 2000; 93:1212–1216.
11.Kaufman B, Gandhi SA, Louie E, Rizzi R, Illei P. Herpes simplex virus hepatitis: Case report and review. Clin Infect Dis 1997; 24:334–338.
12.Holmes K, et al. Sexually Transmitted Diseases, 3rd ed. New York: McGraw-Hill, Health Professions Division, 1999:289–291.
13.Ashley-Morrow R, Krantz E, Wald A. Time course of seroconversion by HerpeSelect ELISA after acquisition of genital herpes simplex virus type 1 (HSV-1) or HSV-2. Sex Transm Dis 2003; 30:310–314.
14.Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines. MMWR Morb Mortal Wkly Rep 2002;51.