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Kiss of Death
Brian B. Graham, M.D., Daniel R. Kaul, M.D., Sanjay Saint, M.D., M.P.H., and William J. Janssen, M.D.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows.
From the Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver (B.B.G., W.J.J.); the Division of Infectious Disease (D.R.K.), Department of Internal Medicine (S.S.), and Department of Veterans Affairs Health Services Research and Development Center of Excellence and Department of Medicine (S.S.) all at the University of Michigan, Ann Arbor; and the Department of Medicine, National Jewish Medical and Research Center, Denver (W.J.J.). Address reprint requests to Dr. Graham at the University of Colorado Health Sciences Center, 4200 E. 9th Ave., Box C-272, Denver, CO, 80262, or at brian. graham@uchsc.edu. N Engl J Med 2009;360:2564-8.
Copyright 2009 Massachusetts Medical Society.

A 23-year-old South African man presented to an emergency department with a 2-day history of fever, mild dyspnea, headache, nausea, and myalgias. His symptoms had begun 5 days after he had traveled to Colorado to ski with friends. He was thought to have a viral illness, was treated with intravenous fluids, and was discharged with a prescription for acetaminophenhydrocodone. After 2 days, his symptoms worsened and he returned to the emergency department. A chest radiograph was clear, and he was treated with intravenous fluids and ibuprofen, again without relief. The following day, he returned to the emergency department with vomiting, dyspnea, and photophobia. He was admitted to the hospital for further evaluation and treatment. This active young patient presents with nonspecific symptoms that have not improved with treatment. The fever suggests an infectious cause, and the presence of photophobia raises a concern about meningitis. Bacterial meningitis, however, would be expected to progress more rapidly. Travelers on crowded airplanes may be exposed to various pathogens (e.g., influenza virus and other viruses), and resulting infections may not improve rapidly. Pulmonary embolism should be considered, given the patients recent travel and dyspnea, but this condition would not generally result in photophobia, myalgias, or vomiting. Altitude sickness can cause headaches, nausea, and malaise, but it generally occurs within 24 hours after ascent. At this point, the patient has undergone three evaluations in the emergency department, and his condition is worsening. I agree with the decision to admit him to the hospital. The patient had previously been healthy, took no medications, and had no known drug allergies. Several of his family members had hypertension. His father had recently recovered from African tick-bite fever. The patient reported that he did not smoke and did not use recreational drugs. He drank alcohol socially and reported intermittent binge drinking. He was sexually active and had had more than 15 sexual partners in his lifetime. The patient was born and lived on the west coast of South Africa. He worked as a consultant and had traveled extensively the preceding year, with trips to Mozambique, the United Arab Emirates, Canada, and Japan. He had recently driven across South Africa in an uncovered vehicle. The patients drive across South Africa, in particular, exposed him to a number of agents that might lead to a febrile illness. Among vectorborne diseases, malaria may have an extended incubation period (as long as 3 months for Plasmodium falciparum malaria) and typically presents as an undifferentiated febrile illness. Rickettsial diseases such as murine typhus and diseases caused by Rickettsia conorii and R. africae tend to have a shorter incubation period (usually 7 to 14 days) and may be difficult to distinguish clinically from malaria with the exception that R. conorii and R. africae

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infections may present with a rash or a black eschar (tache noire) at the bite site. Dengue and tickborne relapsing fever should also be considered, since the patient may have been infected with a pathogen just before traveling to the United States. Typhoid fever, which is not always characterized by diarrhea, is another possibility. The patients sexual history mandates testing for the human immunodeficiency virus (HIV), since acute HIV infection or later-stage disease complicated by an opportunistic infection could explain his presentation. Although the patient does not report a sore throat, acute infection with cytomegalovirus (CMV) or EpsteinBarr virus (EBV) is common in young people and should be considered. The patient appeared ill. He had a temperature of 38.8C, a blood pressure of 96/50 mm Hg, and a heart rate of 104 beats per minute. The respiratory rate was 16 breaths per minute, and the oxygen saturation was 95% while the patient was breathing ambient air. His conjunctiva were injected but without icterus. There was mild oropharyngeal erythema, but no oral ulcers or lesions were present. He had no nuchal rigidity. His chest was clear on auscultation. The abdomen was soft and nontender, without hepatosplenomegaly. No rash or edema was observed. The remainder of the physical examination was normal.

liter; aspartate aminotransferase level, 354 U per liter (normal range, 0 to 47); alanine aminotransferase level, 197 U per liter (normal range, 0 to 47); alkaline phosphatase level, 73 U per liter (normal range, 39 to 117); and total bilirubin level, 0.7 mg per deciliter (12.0 mol per liter; normal range, 0.0 to 1.3 mg per deciliter [0.0 to 22.2 mol per liter]). The international normalized ratio (INR) was 1.0. A lumbar puncture showed 1 white cell per cubic millimeter (a lymphocyte) and 2 red cells per cubic millimeter; the glucose level was 57 mg per deciliter (3.2 mmol per liter), and the protein level was 56 mg per deciliter. Blood cultures were obtained.

The left shift suggests infection. The absence of reactive lymphocytes makes infection with CMV or EBV unlikely. The elevated aminotransferase levels may be caused by a rickettsial infection, a viral infection, or malaria, although the normal bilirubin level makes malaria unlikely. The protein level is slightly elevated, but the results of cerebrospinal fluid analysis are otherwise normal. In this patient, disease acquired in Africa as well as more routine causes of infection must be considered. Further testing should include blood smears to rule out malaria, blood cultures to rule out Staphylococcus aureus infection and typhoid fever, a nasopharyngeal swab to rule out respiratory viral infections such as influenza, and seroSepsis appears to be likely, although dehydration logic tests for CMV infection, EBV infection, from fever and vomiting could also explain some rickettsial diseases, and viral hepatitis. of the patients symptoms. Blood cultures should be obtained, and broad-spectrum antibiotics The patient was given intravenous fluids and antishould be considered. The absence of nuchal rigid- pyretic agents. The next day, he remained episodiity makes bacterial meningitis unlikely; neverthe- cally febrile, with temperatures as high as 38.9C. less, it seems reasonable to perform a lumbar punc- The creatinine level decreased to 1.3 mg per deciliture, given the patients photophobia. Although ter (115 mol per liter), but the aspartate amina rash may be absent in some cases of rickettsial otransferase level increased to 701 U per liter and diseases, an eschar is typically seen at the site of the alanine aminotransferase level increased to inoculation; the absence of an eschar in this pa- 326 U per liter. The platelet count decreased to tient makes infection with R. conorii or R. africae 76,000 per cubic millimeter, and the white-cell unlikely. count decreased to 3000 per cubic millimeter. The blood cultures obtained at admission were negaNo previous laboratory-test results were available. tive, and a blood smear was negative for plasmoThe patients white-cell count was 9100 per cubic dium organisms. Empirical antimicrobial therapy millimeter. A manual differential cell count re- with doxycycline was initiated. Urinary toxicologic vealed 50% polymorphonuclear cells, 42% bands, screening was negative for alcohol and drugs, and 4% lymphocytes, and 4% monocytes. The hemo- a serum acetaminophen level was undetectable. globin level was 16.7 g per deciliter, and the plate- Tests for hepatitis C antibody, hepatitis B surface let count was 123,000 per cubic millimeter. The antigen, hepatitis B core antibody, and hepatitis A serum creatinine level was 1.4 mg per deciliter antibody were negative, as were tests for antibod(124 mol per liter); albumin level, 3.9 g per deci- ies against CMV and HIV types 1 and 2 and seron engl j med 360;24 nejm.org june 11, 2009

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logic tests for leptospirosis, EBV, Rocky Mountain spotted fever, typhus, and Q fever. On day 5 of the patients hospitalization, the antibiotic regimen was broadened to include levofloxacin, vancomycin, and acyclovir. Liver-function values continued to increase; on hospital day 6, the aspartate aminotransferase level was 13,280 U per liter; the alanine aminotransferase level, 2920 U per liter; the bilirubin level, 4.0 mg per deciliter (68.4 g per liter); and the INR, 2.4. The patients mental status declined. He had a generalized tonicclonic seizure that responded to lorazepam. He underwent orotracheal intubation for airway protection and was transferred to a tertiary care hospital for further evaluation and possible liver transplantation. The patient appears to have fulminant hepatic failure. The development of encephalopathy is of great concern, and coupled with the increasing INR, it may necessitate urgent liver transplantation. Acute liver failure is most commonly due to infection (usually hepatitis A or B infection) or drugs or other toxins (with acetaminophen being the most common). Less common causes of acute liver failure include Wilsons disease, autoimmune hepatitis, and ischemic injury. The hepatitis E virus, which is either waterborne or foodborne, causes more severe inflammation than the hepatitis A virus, but it is more common in Asia than in southern Africa. Herpesviruses can also cause fulminant hepatic failure. The tests for CMV and EBV are negative, but infection with herpes simplex virus (HSV) or varicellazoster virus (VZV) is possible. These infections can occur in immunocompetent patients, and skin lesions may be few or absent. At this point, I would perform serologic tests for hepatitis E virus, HSV, and VZV, and I would carefully examine the skin for any lesions suggestive of HSV or VZV infection. A liver biopsy should be considered, although the short interval between the development of acute liver failure and the development of severe coagulopathy can complicate the timing of the procedure. In VZV and HSV infection, nonspecific necrosis is often observed; however, inclusion bodies with positive immunostaining for HSV or VZV antigens would be diagnostic. It is reasonable to continue treatment with acyclovir, since HSV is a cause of fulminant hepatic failure, albeit a rare one. After the patients transfer to the tertiary care hospital, his renal function deteriorated. Continuous
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renal-replacement therapy was initiated. Computed tomographic imaging of the brain showed cerebral edema. The coagulopathy and thrombocytopenia worsened (INR, 3.1; platelet count, 25,000 per cubic milliliter), precluding liver biopsy. Upper gastrointestinal bleeding and hypotension developed in the patient, and there were chest radiographic findings that were consistent with the acute respiratory distress syndrome, with diffuse infiltrates (Fig. 1). The patient required vasopressor support, an increasing fraction of inspired oxygen, and positive end-expiratory pressure. Evaluation for liver transplantation was initiated. The patients renal failure and encephalopathy and the presence of alveolar infiltrates are consistent with fulminant hepatic failure. The most likely causes at this point include HSV infection, hepatitis E, or a metabolic or inflammatory disease such as autoimmune hepatitis. Very rare causes not yet mentioned include syphilis, adenovirus infection, and hemorrhagic fever (although the short incubation period makes hemorrhagic fever unlikely). On the third day after the patients transfer to the tertiary care hospital, a qualitative polymerasechain-reaction (PCR) assay for HSV type 2 (HSV-2) from blood obtained on day 5 of the hospitalization was positive, indicating at least 100 viral copies per milliliter. The next day, an HSV PCR assay from a bronchial aspirate was also positive. IgG levels for HSV type 1 (HSV-1) were elevated, and IgG levels for HSV-2 were negative. HSV IgM

Figure 1. Chest Radiograph Obtained 1 Day after the Patients Transfer to the Tertiary Care Hospital. Diffuse alveolar infiltrates are present, a finding that is RETAKE 1st ICM consistent AUTHOR acute respiratory distress syndrome. with the Graham
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was not tested. Despite continued treatment with acyclovir, progressive hepatic failure with coagulopathy, lactic acidosis, and hypoglycemia developed in the patient. Superinfection with Candida albicans in the blood also developed, and he was treated with caspofungin. After 12 days of multiorgan failure from overwhelming sepsis, the patients family decided to withdraw supportive care. The patient died shortly thereafter. The family declined an autopsy in order to expedite the return of the patients body to South Africa. After repeated questioning, the patients friends revealed that he had left a nightclub with a female companion several days before he became ill. She was noted to have a perioral vesicular lesion, which was consistent with herpes labialis. This unfortunate young man had a rare but welldescribed complication of what presumably was primary infection with a very common virus. The laboratory data suggest an acute infection with HSV-2 and previous infection with HSV-1. Patients with fulminant hepatic failure are at high risk for superinfection, which occurred in this patient. The decision regarding liver transplantation is difficult in an infected patient with fulminant hepatic failure. Transplantation may be the only lifesaving therapy available, but immunosuppression after transplantation may exacerbate the infection.

C om men ta r y
Fulminant hepatic failure is most often defined as the development of acute hepatitis and encephalopathy (within 2 to 8 weeks after initial symptoms) in a person with no history of liver disease.1 A prospective multicenter study in the United States showed that fulminant hepatic failure in adults was most often caused by an overdose of acetaminophen (in 39% of patients), followed by idiosyncratic drug reactions (13%), acute hepatitis B virus infection (7%), ischemic liver injury (6%), hepatitis A (4%), and autoimmune hepatitis (4%); the cause was unknown in 27% of patients.2 No cases of HSV were identified. The incidence of acetaminophen overdosing is lower in many other countries, perhaps because of differences in the selection of medication or in the prevalence of alcohol abuse (which lowers the threshold for acetaminophen overdosing).3 Rapid determination of the cause of fulminant hepatic failure is critical, since prompt initiation of therapy can be lifesaving. Serologic and
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antigen tests can be used in the diagnosis of hepatitis A, B, and E and acute EBV or CMV infection; serologic testing for HSV and VZV is less helpful because of the high seroprevalence of these viruses. PCR can detect HSV and VZV DNA in the serum, but there may be a considerable delay before the results are available. HSV PCR assays have excellent specificity (99%) and good sensitivity (at least 90%), particularly when the viral load is more than 500 copies per milliliter.4 Liver biopsy can be used to rapidly diagnose HSV and VZV infection. The histopathological features of HSV and VZV hepatitis include focal areas of necrosis with minimal surrounding inflammation. Intranuclear inclusion bodies are often present. Immunohistochemical analysis can be used to detect viral antigens in tissue sections. Empirical treatment with antiviral therapy early in the course of the disease may be indicated in enigmatic cases of fulminant hepatic failure. Acyclovir is the first choice, since it is effective against both HSV and VZV infections, although a response may take several days. The treatment of other viral infections (e.g., intravenous immune globulin for hepatitis A infection) is generally not initiated until a specific diagnosis has been made. HSV is common worldwide but is a rare cause of fulminant hepatic failure. In the United States, among people between 14 and 49 years of age, the estimated seroprevalence of HSV-2 is 17%, and the estimated seroprevalence of HSV-1 is 62%.5 Most HSV-1 and HSV-2 infections are subclinical. HSV-1 is typically transmitted during childhood by nonsexual contact with oral mucosa; symptomatic infections are usually limited to the perioral area. HSV-2 is acquired through sexual contact and most commonly causes recurrent, painful anogenital vesicular lesions, but it may cause oral lesions. HSV is the cause of less than 1% of cases of fulminant hepatic failure,6 resulting in 25 to 50 cases per year in the United States (40% are caused by HSV-1 and 60% are caused by HSV-2).7 Fulminant hepatic failure from HSV occurs primarily in immunosuppressed persons (particularly organ-transplant recipients), pregnant women, and children (particularly newborns). Pregnant women are at greatest risk during the third trimester, when the virus crosses the placental membrane and is associated with a high risk of death for both the mother and the fetus.8 However, fulminant hepatic failure from HSV can also occur in immunocompetent pernejm.org june 11, 2009

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sons; in one recent series, 24% of patients with fulminant hepatic failure due to HSV were characterized as being immunocompetent.7 A high index of suspicion is necessary to diagnose fulminant hepatic failure due to HSV, particularly in immunocompetent hosts.9 The physical examination may reveal cutaneous lesions in the perioral or anogenital regions, but the absence of these lesions does not rule out the diagnosis.7,10 The interval between primary exposure and the development of cutaneous lesions ranges from 3 to 7 days. Unfortunately, a common theme in the literature is the diagnosis of HSV infection at autopsy. In one series of patients with fulminant hepatic failure due to HSV, the correct diagnosis was made before death in only 23% of patients.11 Fulminant hepatic failure caused by HSV is potentially treatable. The survival rate among patients who receive acyclovir is higher than the rate among those who do not receive this drug (88% vs. 51% in one series),7 and patients who receive it sooner do better than those who receive delayed treatment. Unfortunately, because of the delay in the diagnosis, immunocompetent patients may be less likely than patients who are not immunocompetent to receive acyclovir initially.10 Liver transplantation is a potential therapeutic option, although there is concern that immunosuppression may worsen the infection in the post-transplantation period. Patients with cryptogenic hepatic failure who have undergone transplantation and in whom HSV infection was diagnosed by
References
1. Trey C, Lipworth L, Chalmers TC, et al.

analysis of the explanted organ have been successfully treated with acyclovir during the postoperative period.12 Because of the rapid course of fulminant hepatic failure, there may be a short interval between illness that is severe enough to warrant transplantation and illness that has progressed to the point that the patient would not survive the operation. Our patient had a rare complication of a common infection. He probably acquired the infection by oral contact with the woman with whom he was seen, who was reported to have evidence of active HSV infection. Why the patient died as a consequence of this usually benign infection is unknown, but proposed mechanisms of severe HSV infection in immunocompetent hosts include an overwhelming inoculation of virus, latent virus reactivation after reinfection by a second HSV strain, infection with specific HSV strains with increased virulence, and defects in host T lymphocytes or macrophages, resulting in an inability to respond to or process unique HSV antigens.13,14 Diagnosing HSV infection at the time of the patients initial presentation would have been difficult unless a particularly careful history taking had revealed his female acquaintance with the perioral lesion. Earlier treatment with acyclovir could have been lifesaving, however, rendering the presumed kiss less than lethal.
Supported by an Advanced Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs (to Dr. Saint). No potential conflict of interest relevant to this article was reported.

Fulminant hepatic failure: presumable contribution to halothane. N Engl J Med 1968; 279:798-801. 2. Ostapowicz G, Fontana RJ, Schidt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-54. 3. Chan TY. Fulminant hepatic failure due to acetaminophen poisoning may be less common in Hong Kong. J Toxicol Clin Toxicol 2001;39:175-7. 4. Stcher M, Leb V, Bozic M, et al. Parallel detection of five human herpes virus DNAs by a set of real-time polymerase chain reactions in a single run. J Clin Virol 2003;26:85-93. 5. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296:964-73.

6. Schidt FV, Davern TJ, Shakil AO,

McGuire B, Samuel G, Lee WM. Viral hepatitis-related acute liver failure. Am J Gastroenterol 2003;98:448-53. 7. Norvell JP, Blei AT, Jovanovic BD, Levitsky J. Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases. Liver Transpl 2007;13: 1428-34. 8. Avgil M, Ornoy A. Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection. Reprod Toxicol 2006;21:436-45. 9. Abbo L, Alcaide ML, Pano JR, Robinson PG, Campo RE. Fulminant hepatitis from herpes simplex virus type 2 in an immunocompetent adult. Transpl Infect Dis 2007;9:323-6. 10. Farr RW, Short S, Weissman D. Fulminant hepatitis during herpes simplex virus infection in apparently immunocompetent

adults: report of two cases and review of the literature. Clin Infect Dis 1997;24:1191-4. 11. Kaufman B, Gandhi SA, Louie E, Rizzi R, Illei P. Herpes simplex virus hepatitis: case report and review. Clin Infect Dis 1997;24:334-8. 12. Montalbano M, Slapak-Green GI, Neff GW. Fulminant hepatic failure from herpes simplex virus: post liver transplantation acyclovir therapy and literature review. Transplant Proc 2005;37:4393-6. 13. Miyazaki Y, Akizuki S, Sakaoka H, Yama moto S, Terao H. Disseminated infection of herpes simplex virus with fulminant hepatitis in a healthy adult: a case report. APMIS 1991;99:1001-7. 14. Dix RD, McKendall RR, Baringer JR. Comparative neurovirulence of herpes simplex virus type 1 strains after peripheral or intracerebral inoculation of BALB/c mice. Infect Immun 1983;40:103-12.
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