Keywords
herpes hepatitis - fulminant herpes - pregnancy herpes - disseminated herpes
Fulminant herpes simplex virus (HSV) hepatitis with disseminated extrahepatic involvement
is a rare complication of herpes virus infection, traditionally described in significantly
immunocompromised hosts.[1] The immunosuppressive effects of pregnancy make pregnant women the second most common
population to suffer from disseminated disease.[2] Humoral and cell-mediated immunity are most depressed in the third trimester, as
demonstrated by decreased T-cell count and altered B-/T-cell ratios.[2] Disseminated disease is life-threatening, with maternal mortality risk reported
to be as high as 39%.[2] The current treatment recommendation for fulminant HSV hepatitis in pregnancy is
intravenous (IV) acyclovir, with the addition of foscarnet for acyclovir-resistant
cases.[3] We present a case refractory to both acyclovir and foscarnet, the first of its kind
reported in the literature.[4] Ultimately, only delivery resulted in resolution of maternal hepatic and neurologic
dysfunction.
Case Report
The patient was a 24-year-old gravida 1 with no significant medical history who presented
to our hospital as a transfer of care at 272/7 weeks' gestation with fever of unknown origin, hepatic failure, and leukopenia. She
presented to the outside facility 7 days prior with vague complaints of fever, nausea,
abdominal pain, malaise, and anorexia. At the outside hospital, she was noted to have
mild transaminitis (alanine transaminase [ALT] 205 U/L, aspartate transaminase [AST]
357 U/L) and persistent fevers. Empiric broad-spectrum antimicrobial coverage was
initiated, including azithromycin, piperacillin/tazobactam, and acyclovir. Initial
laboratory evaluation included negative blood cultures and hepatitis panel. Additionally,
antibody testing was negative for rapid plasma reagin (RPR), human immunodeficiency
virus, rubella, toxoplasma, streptococcus pneumovirus, influenza A/B, respiratory
syncytial virus (RSV), parainfluenza, legionella, chlamydia, gonorrhea, and antinuclear
antibody (ANA). Epstein-Barr virus testing was consistent with remote infection. Due
to continued fevers, hypoxemia, a new chest consolidation, and worsening liver failure
with associated coagulopathy, the patient was transferred to the medical intensive
care unit (MICU) at our facility on hospital day 7.
Upon arrival to our MICU, physical exam was significant for mild jaundice and a few
very small shallow, friable ulcerations on the labia. We obtained HSV cultures and
continued broad-spectrum antibiotics with IV acyclovir from the outside facility.
Despite supportive care and appropriate antiviral therapy, the patient's hepatic dysfunction
worsened (AST 2290 U/L, ALT 783 U/L, lactate dehydrogenase 6551 U/L, and total bilirubin
7.5 mg/dL) with associated coagulopathy (international normalized ratio [INR] 1.9).
On hospital day 8, she developed significant pancytopenia, hypotension requiring dual-agent
pressor therapy, and acute respiratory failure requiring intubation. She had significantly
altered mental status concerning for hepatic encephalopathy versus herpetic encephalitis.
We diagnosed disseminated extrahepatic HSV 2 with associated fulminant hepatitis by
polymerase chain reaction (PCR) in genital, liver, bronchoalveolar, blood, and cerebral
spinal fluid samples. Given the lack of clinical response to acyclovir and a plateau
in maternal serum HSV PCR cycles, the consulting infectious disease specialists recommended
the addition of foscarnet as second-line therapy for treatment of acyclovir-resistant
HSV hepatitis on hospital day 21.
Of note, initial fetal anatomic survey at the outside hospital was consistent with
an isolated open-lipped schizencephaly. After extensive counseling by the maternal
fetal medicine providers there, the patient opted for palliative care with no fetal
monitoring or intervention. The fetal diagnosis was confirmed via ultrasound at our
institution. Prior to intubation and mental status change, the patient had again confirmed
her strong desire for no intervention on behalf of the fetus.
On hospital day 24, the patient remained neurologically impaired, intubated with increasing
ventilator requirements, hypotensive, and coagulopathic. Given the lack of response
to dual-agent antiviral therapy, rising maternal serum lactate levels (11.2 mmol/L),
and very guarded prognosis, we held a multidisciplinary conference to discuss the
potential therapeutic benefit of delivery. Due to the prenatal diagnosis of schizencephaly
and desire for no fetal intervention, as well as worsening maternal status, we made
the decision to proceed with prostaglandin induction via misoprostol (50 μg every
6 hours). In planning for induction, we performed a fetal paracentesis due to a new
finding of fetal ascites and concern for abdominal dystocia during delivery. HSV PCR
on the fetal fluid returned negative. On hospital day 25, a female fetus was delivered
vaginally with no signs of life weighing 1,878 g. Fetal autopsy was declined by the
patient's health care surrogate.
The patient's immediate postpartum course was complicated by transient hypofibrinogenemia
concerning for disseminated intravascular coagulopathy. We placed an intrauterine
balloon for 36 hours secondary to postpartum hemorrhage, which was thought to be due
to coagulopathy and not related to uterine atony. The coagulopathy was resolved with
factor replacement and red cell transfusion. Within 4 days of delivery, the patient
was successfully extubated, weaned off pressor support, and had significant improvement
in hepatic function marked by normalizing transaminases, total bilirubin, and INR.
Her encephalopathy resolved more slowly, but normal mental status was noted before
final discharge to home on hospital day 44. Repeat HSV PCR from blood sampling remained
positive at time of discharge, but continued to trend downward. She remained on acyclovir
for the duration of her hospital course and will need a prolonged outpatient course
per recommendations from infectious disease specialists.
Discussion
Fulminant herpes hepatitis is rare, with the disease burden heavily concentrated among
neonates and severely malnourished children. In 1969, Thomas Henry Flewett, a prominent
British pathologist, and colleagues reported the first adult case in a female patient
at 28 weeks' gestation who developed hepatic dysfunction following primary herpetic
stomatitis.[5] Since that time, 34 more cases of herpes hepatitis in pregnancy have been reported
in the literature, with a mortality rate of 39% reported by Kang and Graves in 1999,
but only 9% among the subsequent 11 cases reported from 2000 to present.[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] This is in stark contrast to the 74.4% mortality rate for herpes hepatitis in the
general population reported by Norvell et al in 2007 and may reflect the underlying
disease state that made the nonpregnant patients vulnerable to disseminated herpes.[15]
The nomenclature used to describe variations of systemic herpes infections is applied
inconsistently throughout the literature. For the purpose of our work, disseminated herpes refers to HSV documented by culture or PCR in a nongenital or mucosal fluid or tissue.
Herpes hepatitis is more specific and describes patients with seropositive active herpes viremia (usually
measured via serum PCR) and associated transaminitis. Fulminant herpes hepatitis includes HSV-seropositive patients with true liver failure (as evidenced by decreased
albumin, elevated INR, and severe transaminitis) in critical condition. Our case describes
a patient with fulminant herpes hepatitis, the most severe form of the infection.
The clinical presentation of febrile abdominal pain and anicteric hepatic dysfunction
in pregnancy should prompt immediate consideration of the diagnosis of herpes hepatitis
and separates this disorder from the other common etiologies of nonfebrile hepatic
failure in pregnancy: acute fatty liver, preeclampsia/HELLP (hemolysis, elevated liver
enzymes, and low platelets), and intrahepatic cholestasis. Clinical symptoms concerning
for disseminated herpes can be nonspecific, including fever, malaise, abdominal pain,
and nausea. Laboratory findings, too, can be subtle in the early stages, including
mild transaminitis, leukopenia, and elevated INR. The gold standard for the diagnosis
of herpes hepatitis remains liver biopsy with histopathology, electron microscopy,
and culture. The classic finding of hemorrhagic necrosis, inflammation, and enlarged
ground glass nuclei with marginalized chromatin is pathognomonic.[16] However, percutaneous liver biopsy in the setting of maternal coagulopathy can be
associated with significant bleeding-related morbidity, making alternative definitive
diagnostic modalities desired. Basic serology carries a well-known risk of false negative
result; PCR assay from a maternal serum sample should be performed in such cases where
the diagnosis remains suspected.[12]
[14] If the testing is positive, clinicians can follow serial PCR amplification crossing
points, which correlate with viral load (the higher the cycle number, the lower the
viral quantity), to determine the persistence and strength of viremia ([Fig. 1]).
Fig. 1 Qualitative HSV PCR trending. HSV PCR cycle interpretation: The higher the cycle
number, the lower the viral quantity. A change of 3.32 cycles is approximately equivalent
to a change of 1 log in copies per milliliter. Abbreviations: AST, aspartate aminotransferase;
HSV, herpes simplex virus; PCR, polymerase chain reaction.
Though no antiviral agent has been proven effective in randomized trials, intravenous
acyclovir is standard first-line therapy for presumed disseminated disease. In cases
of drug-resistant herpetic infection, intravenous foscarnet is the agent of choice
but carries with it a significant risk of toxicity to the renal tubules. A pyrophosphate
analogue that selectively inhibits viral polymerase, foscarnet is primarily used to
treat cytomegalovirus when ganciclovir is contraindicated, as well as acyclovir-resistant
herpes virus or varicella zoster.[17]
[18] Though no adverse events have been reported with foscarnet use in pregnancy, the
data are sparse, and current recommendations are for use only in the setting of a
high risk of maternal mortality without treatment.[19]
Despite intensive supportive care and treatment with both acyclovir and foscarnet,
our patient experienced progressive multiorgan dysfunction and persistent stable viremia
as measured by serum qualitative HSV PCR, the first case of dual-agent resistance
to be reported. When traditional intravenous antiviral therapies failed and prognosis
appeared very poor, a multidisciplinary team offered the patient's family the option
of therapeutic induction of labor, with the caveat that literature is sparse regarding
delivery to improve innate cell-mediated immune function. Fulminant herpes hepatitis
is very rarely diagnosed in immunocompetent patients, and pregnant women represent
a particularly vulnerable group. Though the precise mechanism for increased susceptibility
has not been proven in vitro, it is well established that pregnant women have significantly
depleted cell-mediated immunity as measured by helper T-cell count, which nadirs in
the third trimester.[20] This nadir mirrors the gestational age during which the vast majority of the aforementioned
37 cases of herpes hepatitis in pregnancy have been diagnosed. In our case, delivery
occurred on hospital day 27, with significant clinical and laboratory improvement
seen within 3 days postpartum.
In summary, the diagnosis of herpes hepatitis and empiric treatment with intravenous
acyclovir should be strongly considered in any case of febrile hepatic dysfunction
in pregnancy. We recommend consideration be given to therapeutic delivery in the setting
of antiviral-resistant disease with concern for maternal mortality; we also suggest
that HSV qualitative PCR be used to trend disease burden.
