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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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clinical problem-solving

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.

liter; aspartate aminotransferase level, 354 U per

liter (normal range, 0 to 47); alanine amino
transferase 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 seroThe 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.

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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 immuno
competent 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 thrombocyto
penia 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. Eval
uation 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
Graham
RETAKE
1st
AUTHOR
ICM
consistent
with the acute
respiratory distress
syndrome.
REG F

FIGURE

CASE

TITLE

EMail

fig 1

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ARTIST: mleahy
FILL

2nd
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SIZE
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clinical problem-solving

was not tested. Despite continued treatment with

acyclovir, progressive hepatic failure with coagu
lopathy, 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 multi
organ 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

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 per-

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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 diag
nosis.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

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 anti
gens.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.

References
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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
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3. Chan TY. Fulminant hepatic failure due
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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
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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.
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McGuire B, Samuel G, Lee WM. Viral

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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,
Yamamoto 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.
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Copyright 2009 Massachusetts Medical Society.

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