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Volume 360:2564-2568
June 11, 2009
Number 24
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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.
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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
acetaminophen–hydrocodone. 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.
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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 patient's 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 patient's 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 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 patient's sexual history mandates
testing for the human immunodeficiency virus (HIV), since acute HIV infection or laterstage 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 Epstein–Barr virus (EBV) is common in young people and should be
considered.
The patient appeared ill. He had a temperature of 38.8°C, 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.
Sepsis appears to be likely, although dehydration from fever and vomiting could also
explain some of the patient's symptoms. Blood cultures should be obtained, and broadspectrum antibiotics should be considered. The absence of nuchal rigidity makes bacterial
meningitis unlikely; nevertheless, it seems reasonable to perform a lumbar puncture,
given the patient's photophobia. Although a rash may be absent in some cases of
rickettsial diseases, an eschar is typically seen at the site of inoculation; the absence of an
eschar in this patient makes infection with R. conorii or R. africae unlikely.
No previous laboratory-test results were available. The patient's white-cell count
was 9100 per cubic millimeter. A manual differential cell count revealed 50%
polymorphonuclear cells, 42% bands, 4% lymphocytes, and 4% monocytes. The
hemoglobin level was 16.7 g per deciliter, and the platelet count was 123,000 per
cubic millimeter. The serum creatinine level was 1.4 mg per deciliter (124 µmol per
liter); albumin level, 3.9 g per deciliter; 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 µmol per liter; normal range, 0.0
to 1.3 mg per deciliter [0.0 to 22.2 µmol 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 serologic tests for CMV infection, EBV infection,
rickettsial diseases, and viral hepatitis.
The patient was given intravenous fluids and antipyretic agents. The next day, he
remained episodically febrile, with temperatures as high as 38.9°C. The creatinine
level decreased to 1.3 mg per deciliter (115 µmol per liter), but the aspartate
aminotransferase level increased to 701 U per liter and the alanine aminotransferase
level increased to 326 U per liter. The platelet count decreased to 76,000 per cubic
millimeter, and the white-cell count decreased to 3000 per cubic millimeter. The
blood cultures obtained at admission were negative, and a blood smear was negative
for plasmodium organisms. Empirical antimicrobial therapy with doxycycline was
initiated. Urinary toxicologic screening was negative for alcohol and drugs, and a
serum acetaminophen level was undetectable. Tests for hepatitis C antibody,
hepatitis B surface antigen, hepatitis B core antibody, and hepatitis A antibody were
negative, as were tests for antibodies against CMV and HIV types 1 and 2 and
serologic tests for leptospirosis, EBV, Rocky Mountain spotted fever, typhus, and Q
fever.
On day 5 of the patient's 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 µg per liter); and the INR, 2.4. The patient's mental status
declined. He had a generalized tonic–clonic 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 Wilson's
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 varicella–zoster 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 patient's transfer to the tertiary care hospital, his renal function
deteriorated. Continuous 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 (Figure 1). The
patient required vasopressor support, an increasing fraction of inspired oxygen, and
positive end-expiratory pressure. Evaluation for liver transplantation was initiated.
Figure 1. Chest Radiograph Obtained 1 Day after the Patient's
Transfer to the Tertiary Care Hospital.
Diffuse alveolar infiltrates are present, a finding that is
consistent with the acute respiratory distress syndrome.
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The patient's 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 patient's transfer to the tertiary care hospital, a
qualitative polymerase-chain-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 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 patient's family decided to
withdraw supportive care. The patient died shortly thereafter. The family declined
an autopsy in order to expedite the return of the patient's body to South Africa.
After repeated questioning, the patient's 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 well-described 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.
Commentary
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 persons; 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 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 patient's 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.
Source Information
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 [email protected] .
References
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acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med
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hepatitis-related acute liver failure. Am J Gastroenterol 2003;98:448453. [ISI][Medline]
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10. Farr RW, Short S, Weissman D. Fulminant hepatitis during herpes simplex virus
infection in apparently immunocompetent adults: report of two cases and review
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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. [ISI][Medline]
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;37:4393-4396. [CrossRef][ISI][Medline]
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;99:1001-1007. [ISI][Medline]
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;40:103-112. [Free Full Text]
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