Case Reports and Series

Herpes simplex virus hepatitis in immunocompetent

Q1Q2 sexually active patient: Case report

i The corrections made in this section will be reviewed and approved by a journal production editor.

Johny Salema, Johny.salem@std.balamand.edu.lb, Ali Hamdana, Samia Mitria, Ayman Tabchehb, Pierre Hanib,⁎,
Q3 Drpierrehani@gmail.com

a
Department of Internal Medicine, Faculty of Medicine, University of Balamand, Dekweneh-Beirut 1003, Lebanon
b
Department of Gastroenterology, Faculty of Medicine, University of Balamand, Dekweneh-Beirut 1003, Lebanon

⁎ Corresponding author.

Abstract
Introduction : Herpes simplex virus (HSV) is a highly prevalent infection, which on rare occasions can
become disseminated and be responsible for serious complications including significant neurological,
gastrointestinal and even cardiac morbidity. This article presents a case of rare but yet potentially fatal
complication of HSV which is hepatitis in an immunocompetent patient.Case.22 years-old Caucasian
female who presented to a peripheral hospital with fever and dysuria. She was admitted to a peripheral
hospital and treated for presumptive diagnosis of urinary tract infection without any amelioration in
symptoms after multiple days of antibiotics. Deterioration in clinical status triggered transfer to our
institution, where further workup yielded the diagnosis of herpes hepatitis which was successfully treated
with good patient outcome.
Discussion : Hepatitis secondary to HSV is a rare diagnosis that can rapidly progress to fulminant liver
failure. Early recognition and treatment within the first 72 h from onset are essential. Yet despite initiation of
appropriate antiviral therapy, morbidity and mortality remain high. As a consequence, empiric antiviral
therapy should be considered by providers for patients that have such characteristics as the latter ones or
have history of HSV in order to avoid the possibly fatal outcomes.
Conclusion : HSV hepatitis is difficult to diagnose, it carries a high mortality rate, thus emphasizing on the
importance of early diagnosis and treatment to prevent the development of acute liver failure. It should be
considered in the differential diagnosis of any case of severe hepatitis.

Keywords:

Hepatitis, Herpes simplex virus, Acute liver failure

Introduction
Q4 Herpes simplex virus (HSV) infection is a high concern among the population due to its high prevalence (Looker et al.
2015,; Looker et al. 2015) as well as due to its associated complications that were largely described in the literature (
Berger and Houff, 2008). It is the second most common sexually transmitted disease (STD) with a prevalence rate of
21.9 % (Satterwhite et al., 2013). Classic manifestations of symptomatic HSV infection include Herpes labialis which is
a cutaneous manifestation predominantly caused by HSV type 1 (HSV-1), as well as herpes genitalis that is
predominantly caused by HSV type 2 (HSV-2) (Noor et al., 2018). On rare occasions, HSV can become disseminated
and be responsible for serious complications including significant neurological, gastrointestinal and even cardiac
morbidity (Berger and Houff, 2008; Yamamoto et al., 2018). A rare but potentially fatal complication of HSV is
hepatitis, which could have a spectrum of manifestations ranging from mild hepatitis to acute liver failure and possibly
death (Norvell et al., 2007). HSV hepatitis represents less than 1 % of all cases of acute liver failure (ALF) (Schiodt et
al., 2003). It occurs primarily in patients with impaired immunity (Ahmed et al., 2020; Kang and Graves, 1999; Ahmed
et al. 2022), but cases were reported among immunocompetent patients in fewer instances (Lakhan and Harle, 2008;
Ngo et al. 2020; Phadke et al., 2016; Farr et al., 1997; Inthasot et al. 2018).

This article reports an additional case of severe HSV induced hepatitis that occurred in an immunocompetent sexually
active young female patient.

Case
The presented case pertains to a 22 years-old Caucasian female who presented to a peripheral hospital with fever and
dysuria. Past medical history is unremarkable and does not take any chronic treatment. She is of middle eastern
descent, more specifically Lebanese. She is sexually active but has no history of IV drug use or recent ill contacts; she
does not disclose any unprotected sexual encounters.

In the first institution, a urinalysis taken upon presentation showed presence of abundant white blood cells (WBC)
along with 6–8 red blood cells (RBC), otherwise negative. Consequently, she was started on Augmentin antibiotic
therapy, but subsequently transitioned to a broader regimen of Ciprofloxacin and Vancomycin due to clinical status
worsening while waiting for results of urine culture (unremitting fever). Throughout her hospitalization, the patient
experienced symptoms of nausea, epigastric pain, and intermittent fever accompanied by occasional bouts of diarrhea.
Her C-reactive protein (CRP) levels remained persistently elevated (ranging from 150 to 200), and her white blood cell
count (WBC) exhibited a mild decline to 2900 (normal range N: 4000–10000), while the percentage of lymphocytes
progressively increased to 31 % (N: 20–40 %). A thorough analysis and culture of her stool samples corroborated the
presence of 15–20 WBC. Tests for Salmonella and Brucella yielded negative results. Notably, her alanine
aminotransferase (ALT) levels exhibited a progressive elevation, escalating to 295 initially and subsequently reaching
544 (N: 0–55), accompanied by an elevated lactate dehydrogenase (LDH) of 837 (N: 125–220), gamma-glutamyl
transferase (GGT) at 75 (N: 9–36), and total bilirubin at 0.4 (N: 0.1–1.2) (with direct bilirubin at 0, N: 0–0.3). An
abdominal and pelvic ultrasound did not yield any diagnostic findings. Furthermore, the hepatitis B surface antigen
(HbsAg) assay returned negative results. As well, the urine culture result was negative.

Following a five-day hospitalization period, the patient was transferred to our institution for further evaluation and
management. Upon admission to our emergency department, she exhibited a temperature of 38.7 degrees Celsius,
blood pressure of 114/77 mmHg, heart rate of 124 beats per minute, and oxygen saturation of 99 % while breathing
room air. The patient continued experiencing persistent epigastric pain, along with nausea, and diarrhea. Her physical
exam was not significant for any findings, including any rashes, lymphadenopathy, or genital lesions.

Notable laboratory values included a WBC count of 2.11 k with 24.5 % lymphocytes, hemoglobin level of 12 (N: 12–
15), a platelet count of 125,000 (N: 150–500), CRP at 150 (N: 0–5), prothrombin time (PT) at 17.4 (N: 11–15),
international normalized ratio (INR) at 1.35 (N: 1), activated partial thromboplastin time (aPTT) at 39.5 (N: 25–40),
creatinine at 0.6, sodium at 141 (N: 135–145), potassium at 3.3 (N: 3.4–4.5), AST at 1205 (N: 0–55), ALT at 1102,
GGT at 80, alkaline phosphatase at 64 (N: 40–150), total bilirubin at 0.41 with direct bilirubin at 0.22, albumin at 3.2
(N: 3.6–5.3), and lipase at 30 (N: 8–78).

A computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast enhancement disclosed
hepatomegaly with a midclavicular axis measurement of 19 cm (N: 6–12) (Fig. 1), characterized by a smooth contour
and uniform density. Additionally, periportal and pericholecystic edema were noted, and the gallbladder was suitably
distended with evidence of wall thickening (Fig. 2), likely indicative of an inflammatory process through contiguity. No
evidence of intrahepatic or extrahepatic biliary dilatation was observed. Minor intrahepatic fluid accumulation was
detected in the right parieto-colic gutter, accompanied by mild pelvic ascites. The spleen also appeared enlarged,
measuring 14.2 cm in the coronal plane (N: 6–13).

i Images may appear blurred during proofing as they have been optimized for fast web viewing. A high quality version
will be used in the final publication. Click on the image to view the original version.

Fig. 1

Computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast enhancement respectively showing changes
associated with hepatitis including hepatomegaly as well as periportal, pericholecystic edema and gallbladder wall thickening
without evidence of intrahepatic or extrahepatic biliary dilatation or obstruction.

i Images may appear blurred during proofing as they have been optimized for fast web viewing. A high quality version
will be used in the final publication. Click on the image to view the original version.

Fig. 2

Computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast enhancement respectively showing changes
associated with hepatitis including hepatomegaly as well as periportal, pericholecystic edema and gallbladder wall thickening
without evidence of intrahepatic or extrahepatic biliary dilatation or obstruction.
In-hospital investigative assays encompassed assessments for Brucella, salmonella, HIV types 1 and 2, Hepatitis A,
Hepatitis B, Hepatitis C, cytomegalovirus, Parvovirus, Epstein-Barr virus, urinalysis, repeat urine culture, stool
analysis, and vaginal culture. All these investigations returned unremarkable results. However, herpes type 2
immunoglobulin G (IgG) exhibited a positive result at 80 (N: <0.9), as well as positive IgM at 5.59 (N: <0.9), while
herpes simplex virus type 1 (HSV-1) testing returned negative results. Notably, a blood polymerase chain reaction
(PCR) assay on blood sample confirmed the presence of HSV2 with 3,352,000 copies/ml (N: <50) and, consequently,
intravenous Acyclovir therapy was promptly initiated at a dose of 250 mg every 8 h. This intervention correlated with a
progressive decline in ALT levels and a reduction in the frequency and severity of febrile episodes, as demonstrated in
Graphs 1 and 2, respectively.

Patient was eventually discharged after one week of IV acyclovir treatment, afebrile, with subsiding levels of LTFs
more specifically ALT; clinically and hemodynamically stable, with continuation of therapy and follow up as
outpatient.

Discussion
Herpes simplex virus (HSV) infection can often present with nonspecific flu-like symptoms including fever, myalgias,
and abdominal pain (Norvell et al., 2007; Ahmed et al., 2020) thus potentially delaying diagnosis in a large number of
cases. Hepatitis secondary to HSV is a rare diagnosis that can rapidly progress to fulminant liver failure (Natu et al.,
2017), and late diagnosis in such cases should be avoided especially since most cases of such nature are unfortunately
diagnosed on autopsy (Norvell et al., 2007); at a much late and fatal stage. At such stages, fatal severe complications
include renal failure, disseminated intravascular coagulopathy (DIC), but most importantly encephalopathy if seen,
indicates worst prognosis (Natu et al., 2017).

HSV hepatitis most commonly affects patients with impaired immunity such as pregnancy, malignancy,
immunosuppression, or post inhalational anesthetics, though literature reports have reported up to 25 % of cases in yet
immunocompetent individuals (Natu et al., 2017).

This case presented as a typical specimen of non-specific symptoms, more specifically fever with preliminary focus of
urinary tract infection. As the case progressed, non-response to antibiotics with continuous deterioration of clinical
status necessitated transfer to a central institution. On review with the patient, she noted in retrospect the concomitant
presence of vaginal pruritis a few days after admission to the other institution, even though her physical exam was
normal upon transfer to our institution. Typical HSV related lesions are “multiple vesicular lesions appearing on an
erythematous base” at the cutaneous site of infection, but in some cases “mucosal HSV infection can appear as
urethritis or pharyngitis without cutaneous lesions” (Bennett et al., 2020). In such cases, appropriate diagnosis should
include laboratory confirmation of the infection in the association with the right clinical context. Ideally, if the liver is a
site of involvement, liver biopsy (Ahmed et al., 2020) would also be an important option. In fact, this patient had
leukopenia, mild thrombocytopenia, coagulopathy and the associated transaminases elevation 100–1000 fold with a
normal bilirubin termed as “anicteric hepatitis” (Ahmed et al., 2020). These laboratory findings associated with both
PCR confirmation and clinical suspicion are enough to prompt the initiation of antiviral treatment (Natu et al., 2017).
Optimally, liver biopsy could have been done for diagnosis confirmation, but unfortunately was not done due to
financial restraints of the patient. 3 important facts were also to be noted: (1) no testing for hepatitis E was done due to
lack of availability at the time in Lebanon, (2) no partner testing was done at the time due to the fact that the patient
preferred to keep the partner anonymous, (3) white blood cells noted on stool analysis were not considered to be
significant due the absence of clinical symptoms.

There is no standardized treatment data for HSV hepatitis. Acyclovir, an acyclic nucleoside analogue that is a substrate
for HSV-specific thymidine kinase, was the first antiviral agent clearly demonstrated to be effective against HSV
infections. This latter is a well proven potent medication in vitro and in vivo against HSV-1, HSV-2, and VZV, with
partial activity against CMV (Bennett et al., 2020). Initial IV treatment with acyclovir should be started promptly,
ideally within 72 h of symptom onset, for an approximate duration of 2–7 days at the dose of 5–10 mg/kg every 8 h or
until clinical improvement is observed (Natu et al., 2017). One should bear in mind that a notable side effect of
intravenous acyclovir is transient renal insufficiency secondary to crystallization of the compound in the renal
parenchyma. This adverse reaction can be avoided if the medication is given slowly over 1 h and the patient is well
 hydrated. Then, if clinically and serologic amelioration occurs, discharge can be done and therapy continues with oral
antiviral therapy. Ideally 10 days oral therapy is needed (for a total of 14 days of IV plus oral therapy), with slight
preference towards valacyclovir due to its higher bioavailability. Adjunctive treatment for HSV-2 infection induced
symptoms include sitz baths (for dysuria in female patients) and intermittent or indwelling bladder catheterization (if
urinary retention develops) (Bennett et al., 2020).

Our patient was treated with acyclovir 250 mg every 8 h for 7 days, and transitioned to oral acyclovir 400 mg 5 times
daily for 10 days (due to the unavailability of valacyclovir in Lebanon at the time). Follow-up testing as outpatient,
showed normalization of her liver enzymes, white blood cells count, platelets count and INR after completing the
aforementioned therapy.

Antiviral has shown promise in a yet poor prognosis predominant disease as stated in many studies (Norvell et al.,
2007; Bennett et al., 2020; Klein et al., 1991; Lagrew et al., 1984). Yet despite initiation of appropriate antiviral
therapy, morbidity and mortality remain high. Variables that were associated with a poorer prognosis included male sex,
increased age, immunosuppression, and/or presentation with significant liver dysfunction (Norvell et al., 2007). As a
consequence, empiric antiviral therapy should be considered by providers for patients that have such characteristics or
even have a history of previous HSV infection.

Conclusion
HSV hepatitis is difficult to diagnose, it carries a high mortality rate, thus emphasizing on the importance of early
diagnosis and treatment with Acyclovir to prevent the development of acute liver failure. It should be considered in the
differential diagnosis of any case of severe hepatitis. Careful monitoring is needed even after the resolution of acute
liver failure.

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have
given his/her/their consent for his/her/their images and other clinical information to be reported in the case.

Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our
research.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have
Q5 appeared to influence the work reported in this paper.

References

i The corrections made in this section will be reviewed and approved by a journal production editor. The newly
added/removed references and its citations will be reordered and rearranged by the production team.

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Highlights
• Herpes simplex virus (HSV) is a highly prevalent infection, which on rare occasions can become disseminated and be
responsible for serious complications.

• This article presents a case of rare but yet potentially fatal complication of HSV which is hepatitis in an immunocompetent
patient.

• Hepatitis secondary to HSV is a rare diagnosis that can rapidly progress to fulminant liver failure.

• Empiric antiviral therapy should be considered by providers in order to avoid the possibly fatal outcomes.

• HSV hepatitis is difficult to diagnose and carries a high mortality rate, thus emphasizing on the importance of early diagnosis
and treatment to prevent the development of acute liver failure.

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