Logo American Journal of Case Reports

Call: 1.631.629.4328
Mon-Fri 10 am - 2 pm EST

Contact Us

Logo American Journal of Case Reports Logo American Journal of Case Reports Logo American Journal of Case Reports

03 August 2021: Articles  USA

Disseminated Herpes Simplex Virus-2 (HSV-2) as a Cause of Viral Hepatitis in an Immunocompetent Host

Challenging differential diagnosis

Dushyanth Srinivasan1ABCDEF*, Christina M. Kaul2EF, Amna B. Buttar3E, Fatima I. Nottingham1E, Jeffrey B. Greene2E

DOI: 10.12659/AJCR.932474

Am J Case Rep 2021; 22:e932474

0 Comments

Abstract

BACKGROUND: Herpes simplex virus-2 (HSV-2) affects nearly 1 in 5 adults in the United States. Complications such as viral hepatitis and dissemination are rare in immunocompetent hosts. In this report, we describe a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent patient with recurrent fevers and elevated aminotransferases.

CASE REPORT: A 57-year-old man with a history of type 2 diabetes and hypertension was admitted with a right index finger lesion concerning for an abscess. He underwent successful incision and drainage and was started on ampicillin-sulbactam. On Day 2 of hospitalization, he developed recurrent fevers and elevated aminotransferases and inflammatory markers. An extensive infectious, rheumatologic, and malignancy workup were pursued without immediate findings. Imaging demonstrated cirrhotic morphology of the liver and splenomegaly, but lab markers were intact for liver synthetic function. On Day 7 of hospitalization, fever frequency decreased, and HSV-2 titers resulted, with positive IgM and negative IgG. He subsequently developed erythematous, raised lesions in multiple dermatomes. Nucleic acid amplification testing of biopsied lesions was positive for HSV-2, confirming viral hepatitis secondary to disseminated HSV-2. He was started on intravenous acyclovir and discharged on valacyclovir following improvement in symptoms.

CONCLUSIONS: We report a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent host. Up to 25% of cases occur in immunocompetent hosts and many patients do not develop characteristic skin lesions. Early diagnosis and treatment of viral hepatitis secondary to disseminated HSV remains vital to minimize morbidity and mortality.

Keywords: Hepatitis, Herpes Simplex, Leukopenia, acyclovir, Adult, Antiviral Agents, Diabetes Mellitus, Type 2, Hepatitis, Viral, Human, Herpesvirus 2, Human, Middle Aged

Background

Herpes simplex virus-2 (HSV-2) is a common sexually transmitted disease known to cause genital lesions. It is estimated that nearly 1 in 5 adults in the United States has HSV-2, with an annual incidence of one million cases per year [1,2]. Seroprevalence rates are estimated near 16% in those aged 14–49 [3]. Despite the prevalence of HSV-2, complications such as viral hepatitis and dissemination remain rare in immuno-competent hosts. In this report, we describe a rare case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent patient with recurrent fevers and elevated aminotransferases. Disseminated HSV-2 was diagnosed following positive IgM serologies and interval development of vesicular lesions.

Case Report

A 57-year-old man with past medical history of hypertension and diabetes mellitus type 2 presented to the emergency room (ER) with right index finger pain. Three days prior to admission, the patient cut his right index finger while sorting ballots. In the following days, he noted worsening swelling and pain in the finger causing him to present to the ER. At the time of presentation, he was afebrile, with a heart rate of 87 beats per minute, respiratory rate of 16 breaths per minute, blood pressure of 143/82 mmHg, and oxygen saturation of 97% on room air. The physical exam was notable for a 1-cm raised lesion over the dorsal aspect of the distal interphalangeal joint on the index finger (Figure 1). Complete blood cell count demonstrated a platelet count of 91×103 cells/µL and the basic metabolic panel was unremarkable. The patient was evaluated by the orthopedics team, who performed a bedside incision and drainage. Purulent drainage was expressed and sent for culture. The patient was started on ampicillin-sulbactam and admitted to the orthopedic service for further care.

On Day 2 of hospitalization, he developed multiple fevers daily, up to 39.5°C, despite continuation of ampicillin-sulbactam. White blood cell count and platelet count were reduced to 3.4×103 cells/µL and 80×103 platelets/µL, respectively, while the aminotransferases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated (AST: 270 U/L, ALT: 332 U/L). The inflammatory markers C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and ferritin were also elevated to 108.3 mg/L, 83 mm/h, and 517 ng/ mL, respectively. Given elevated inflammatory markers and multiple fevers daily, our infectious diseases (ID) team was consulted, and the patient was transferred to our hospitalist service for further workup. Upon further questioning, the patient noted he had experienced intermittent night sweats 2 days prior to admission. He denied any known sick contacts, recent cough, shortness of breath, abdominal pain, diarrhea, dysuria, joint pain, lymphadenopathy, known sick contacts, or other rashes/lesions. The patient had no history of recurrent infections, immunodeficiency, known allergies to medication, or previous steroid use. He worked in local government and had no recent travel history. The patient consumed alcohol 3 to 5 times per week, 3 drinks at a time, and was sexually active with 2 female partners, intermittently using barrier protection. Family history was significant for inflammatory bowel disease and multiple sclerosis in his 2 sisters, but no history of malignancy was noted.

At the time of transfer to the hospitalist service, the patient’s ampicillin-sulbactam had been discontinued. He was subsequently transitioned to doxycycline empirically to cover potential atypical infections, including tick-borne illnesses. Viral and further infectious workup was thus far negative, including SARS-CoV-2 PCR, Borrelia IgG/IgM, Anaplasma IgG, Babesia IgG, Ehrlichia IgG, West Nile Virus IgM, Rickettsia IgG, HIV, Procalcitonin, Hepatitis A IgM, Hepatitis B surface antigen, Hepatitis C antibody, QuantiFERON-Plus for tuberculosis, urine Streptococcus pneumoniae and Legionella antigen, wound cultures, and blood cultures. Due to inconclusive diagnostic tests and lack of clinical improvement, doxycycline was discontinued. A computed tomography (CT) scan of the chest, abdomen, and pelvis was obtained to assess for malignancy or localized infectious etiology. Findings were notable for cirrhotic morphology of the liver, an enlarged spleen concerning for portal hypertension, and splenic lesions, of which the largest was 22.7 mm (Figure 2). Multiple indeterminant enhancing splenic lesions were also noted that were read as possible hemangiomas or hematomas. Inflammatory markers and aminotransferases continued to rise with CRP, ferritin, AST, and ALT peaking at 131.9 mg/L, 4391 ng/mL, 377 U/L, and 515 U/L, respectively.

Given the complexity of the case, a multi-disciplinary approach was taken, with the involvement of the hospitalist, ID, hepatology, rheumatology, and hematology teams. Hemophagocytic lymphohistiocytosis (HLH) was considered, given the constellation of his symptoms; however, he only met 3 of the necessary 5 criteria needed for diagnosis (fever, splenomegaly, and elevated ferritin). Rheumatologic work-up was also negative, including antinuclear antibody, complement factor 3, complement factor 4, myeloperoxidase, and proteinase 3. A broad workup for his transaminitis was pursued, including viral etiologies such as cytomegalovirus (CMV), Epstein-Barr virus, and HSV. Finally, a whole-body gallium scan was obtained to assess for any potential source of infection given findings of splenic lesions on CT. The abdomen gallium scan results demonstrated no areas of localized uptake.

On Day 7 of hospitalization, the patient’s frequency of fevers decreased to 1 to 2 times a day. He was also found to have new erythematous, raised lesions on his right wrist (Figure 3), right medial thigh (Figure 4), left triceps (Figure 5), suprapubic area (Figure 6), and right posterior auricular region. At this time, HSV-2 titers were detected, with positive IgM and negative IgG, consistent with acute primary infection. Nucleic acid amplification testing from biopsied skin lesions was positive for HSV-2. The patient was placed on contact precautions and started on intravenous acyclovir 400 mg every 8 h. Inflammatory markers, including ferritin, CRP, ESR, and liver enzymes continued to downtrend with subsequent improvement in his fever curve as well. He was discharged home on valacyclovir 1000 mg 3 times per day by mouth and instructed not to return to work or have close contact with other individuals for 5 to 7 days, given that the lesions had not scabbed over. He was seen in the ID outpatient clinic 1 week after hospital discharge and noted improvement in his symptoms. HSV-2-related lesions had scabbed over and valacyclovir was reduced to 1000 mg twice a day with planned completion of a total antiviral course of 14 days. Followup HSV-2 serum titers confirmed seroconversion with positive HSV-2 IgG titers and falling IgM titers, further validating a primary HSV-2 infection.

Discussion

Our case highlights the importance of considering disseminated HSV as a differential diagnosis for recurrent fevers and elevated aminotransferases, even in patients without classic skin findings. HSV-2 remains a common sexually transmitted disease in the United States, and most often presents with genital lesions. Primary infection occurs when an individual is exposed to another who is actively shedding the virus from their skin or secretions. Following initial exposure, the virus typically has a 4-7-day incubation period that may be accompanied by itching or burning at the exposure site prior to development of classic vesicular lesions [1,4]. It is important, however, to note that many patients may not develop characteristic lesions following primary infection. In a survey of New York City residents performed in 2004 to determine HSV-2 seroprevalence, Schillinger et al found that nearly 28% of surveyed individuals were infected with HSV-2, of which 88.4% had no prior knowledge of diagnosis [5]. Our patient presented with a lesion on the right index finger, which was initially thought to be an abscess based upon history and notable purulent drainage. In hindsight, the lesion was likely a herpetic whitlow and representative of an acute herpetic process. However, lack of assessment of this lesion by the primary team and the absence of other cutaneous signs of herpes infection delayed the consideration of disseminated HSV by more than 6 days.

Our case is of particular interest given the rarity of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent host. Viral hepatitis accounts for only 1–2% of all viral causes of acute liver failure [6–10]. Risk factors for disseminated disease include immunodeficiency, immunocompromised state, post-transplantation, and pregnancy (primarily in the third trimester); however, up to 25% of cases occur in immunocompetent patients [8]. HSV hepatitis remains difficult to diagnose given the nonspecific nature of presenting signs and symptoms. Most commonly, patients present in an anicteric state with elevated aminotransferases, low bilirubin, leukopenia, and thrombocytopenia with concurrent fever or abdominal pain [9–14]. Although peak aminotransferases are often greater than 1000, values less than 1000 can be seen [15]. The constellation of these signs and symptoms can also mimic other rare cytokine-induced states, such as HLH, and can lead to a broad workup as seen in our patient. Disseminated HSV-2 has been shown to cause HLH-like syndromes, and differentiating between them remains important, as empiric high-dose immunosuppression could worsen HSV-2 [16]. Our patient met 3 of the necessary 5 criteria for HLH, and steroids were not given. We also highlight that only 30–50% of patients present with, or develop, characteristic herpetic lesions, further emphasizing that clinicians should not rely on classic cutaneous findings in diagnosing disseminated HSV [9]. Early diagnosis and treatment with intravenous acyclovir remains essential as 74% of cases progress to acute liver failure, with mortality rates as high as 90% [7–10,12,13,17].

Cases of viral hepatitis secondary to disseminated HSV in immunocompetent patients have been described in the literature [18–29], many of which resulted in acute liver failure. The patho-physiology driving dissemination of HSV in immunocompetent hosts remains unclear. In their case report, Miyazaki et al proposed 4 possible mechanisms for dissemination in the immuno-competent host: 1) host immunological defenses overwhelmed by HSV viremia at initial infection, 2) occult defects in T cell and macrophage processing of HSV antigens, 3) reinfection by a second strain of HSV, and 4) heterogeneity in HSV strains [21].

Although no primary immunodeficiencies were noted in our patient, CT of the abdomen did demonstrate a cirrhotic morphology of the liver. This may suggest an acquired immunodeficient state, as cirrhosis can be associated with several abnormalities in both innate and adaptive immune response due to underlying changes in the liver architecture. This can impact the function of circulating immune cells, leading to decreases in naïve, memory T helper cells, and cytotoxic T cells even in the early stages of cirrhosis [30–33]. These findings, however, are much more heightened and prevalent in a decompensated state, which was not evident in our patient [31]. It remains unclear whether our patient had true cirrhosis versus late-stage fibrosis, given that markers of liver synthetic function were not deranged, aminotransferases continued to downtrend as he underwent followup as an outpatient, and acuity of the disseminated HSV-2 may have contributed to the cirrhotic morphologic appearance on imaging. Further work-up, however, would be required to confirm cirrhosis diagnosis and substantiate if this may have played a role in developing the disseminated HSV-2 in our patient.

Conclusions

Early diagnosis and treatment of viral hepatitis secondary to disseminated HSV remains vital to minimize morbidity and mortality. Although signs and symptoms can be nonspecific, HSV hepatitis must be considered in those with recurrent fevers, elevated aminotransferases, leukopenia, and thrombocytopenia. The constellation of these findings was crucial for the diagnosis in our patient, and early treatment with acyclovir likely improved the outcome. It is also important to highlight the need for a high index of suspicion given that most patients develop characteristic mucocutaneous lesions late in their presentation. Many patients will not develop skin lesions at all, and up to 25% of cases occur in immunocompe-tent hosts. Similarly, in our patient, cutaneous lesions were a late finding in our patient’s presentation, and the workup for primary immunodeficiency was negative. The incidental finding of cirrhosis may have represented an acquired immunodeficient state in our patient; however, further studies are needed to validate such correlations.

References:

1.. Groves MJ, Genital herpes: A review: Am Fam Physician, 2016; 93(11); 928-34

2.. Satterwhite CL, Torrone E, Meites E, Sexually transmitted infections among US women and men: Prevalence and incidence estimates, 2008: Sex Transm Dis, 2013; 40(3); 187-93

3.. Bradley H, Markowitz LE, Gibson T, McQuillan GM, Seroprevalence of herpes simplex virus types 1 and 2 – United States, 1999–2010: J Infect Dis, 2014; 209(3); 325-33

4.. Gnann JW, Whitley RJ, Clinical practice. Genital Herpes: N Engl J Med, 2016; 375(7); 666-74

5.. Schillinger JA, McKinney CM, Garg R, Seroprevalence of herpes simplex virus type 2 and characteristics associated with undiagnosed infection: New York City, 2004: Sex Transm Dis, 2008; 35(6); 599-606

6.. Chung AB, Fas N, Successful acyclovir treatment of herpes simplex type 2 hepatitis in a patient with systemic lupus erythematosus: a case report and meta analysis: Am J Med Sci, 1998; 316(6); 404-7

7.. Ichai P, Roque Afonso AM, Sebagh M, Herpes simplex virus-associated acute liver failure: A difficult diagnosis with a poor prognosis: Liver Transpl, 2005; 11(12); 1550-55

8.. 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(10); 1428-34

9.. Poley RA, Snowdon JF, Howes DW, Herpes simplex virus hepatitis in an immunocompetent adult: A fatal outcome due to liver failure: Case Rep Crit Care, 2011; 2011; 138341

10.. Riediger C, Sauer P, Matevossian E, Herpes simplex virus sepsis and acute liver failure: Clin Transplant, 2009; 23(Suppl.21); 37-41

11.. Kang AH, Graves CR, Herpes simplex hepatitis in pregnancy: A case report and review of the literature: Obstet Gynecol Surv, 1999; 54(7); 463-68

12.. Peters DJ, Greene WH, Ruggiero F, McGarrity TJ, Herpes simplex-induced fulminant hepatitis in adults: A call for empiric therapy: Dig Dis Sci, 2000; 45(12); 2399-404

13.. Pinna AD, Rakela J, Demetris AJ, Fung JJ, Five cases of fulminant hepatitis due to herpes simplex virus in adults: Dig Dis Sci, 2002; 47(4); 750-54

14.. Shanley CJ, Braun DK, Brown K, Fulminant hepatic failure secondary to herpes simplex virus hepatitis. Successful outcome after orthotopic liver transplantation: Transplantation, 1995; 59(1); 145-49

15.. Natu A, Iuppa G, Packer CD, Herpes simplex virus hepatitis: A presentation of multi-institutional cases to promote early diagnosis and management of the disease: Case Reports Hepatol, 2017; 2017; 3180984

16.. Liew JW, Jones BL, Hunter AJ, Disseminated herpes simplex masquerading as hemophagocytic lymphohistiocytosis: A case report: Perm J, 2019; 23; 18-202

17.. Fink CG, Read SJ, Hopkin J, Acute herpes hepatitis in pregnancy: J Clin Pathol, 1993; 46(10); 968-71

18.. Glas M, Smola S, Pfuhl T, Fatal multiorgan failure associated with disseminated herpes simplex virus-1 infection: A case report: Case Rep Crit Care, 2012; 2012; 359360

19.. Lattanzio N, Bell S, Lorenzo C, Wiese-Rometsch W, Gordillo M, A case report of disseminated herpes simplex hepatitis masquerading as spinal headache: J Community Hosp Intern Med Perspect, 2020; 10(3); 273-74

20.. McMinn PC, Lim IS, McKenzie PE, Disseminated herpes simplex virus infection in an apparently immunocompetent woman: Med J Aust, 1989; 151(10); 588-90

21.. Miyazaki Y, Akizuki S, Sakaoka H, Disseminated infection of herpes simplex virus with fulminant hepatitis in a healthy adult. A case report: APMIS, 1991; 99(11); 1001-7

22.. Rimawi BH, Meserve J, Rimawi RH, Disseminated herpes simplex virus with fulminant hepatitis: Case Reports Hepatol, 2015; 2015; 463825

23.. Velasco M, Llamas E, Guijarro-Rojas M, Ruiz-Yague M, Fulminant herpes hepatitis in a healthy adult: A treatable disorder?: J Clin Gastroenterol, 1999; 28(4); 386-89

24.. Inthasot V, Goushchi A, Lazzaroni S, Fatal septic shock associated with herpes simplex virus hepatitis: A case report: Eur J Case Rep Intern Med, 2018; 5(12); 000982

25.. Ono A, Hayes CN, Akamatsu S, Retrospective identification of herpes simplex 2 virus-associated acute liver failure in an immunocompetent patient detected using whole transcriptome shotgun sequencing: Case Reports Hepatol, 2017; 2017; 4630621

26.. Yamamoto T, Kenzaka T, Matsumoto M, A case report of myocarditis combined with hepatitis caused by herpes simplex virus: BMC Cardiovasc Disord, 2018; 18(1); 134

27.. Abbo L, Alcaide ML, Pano JR, Fulminant hepatitis from herpes simplex virus type 2 in an immunocompetent adult: Transpl Infect Dis, 2007; 9(4); 323-26

28.. Ak O, Uygur Bayramicli O, Ozer S, Yilmaz B, A case of herpes simplex hepatitis with hepatic nodules in an immunocompetent patient: Turk J Gastroenterol, 2007; 18(2); 115-18

29.. Down C, Mehta A, Salama G, Herpes simplex virus hepatitis in an immunocompetent host resembling hepatic pyogenic abscesses: Case Reports Hepatol, 2016; 2016; 8348172

30.. Albillos A, Hera Ad Ade L, Reyes E, Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: Amelioration with norfloxacin: J Hepatol, 2004; 40(4); 624-31

31.. Albillos A, Lario M, Alvarez-Mon M, Cirrhosis-associated immune dysfunction: Distinctive features and clinical relevance: J Hepatol, 2014; 61(6); 1385-96

32.. McGovern BH, Golan Y, Lopez M, The impact of cirrhosis on CD4+ T cell counts in HIV-seronegative patients: Clin Infect Dis, 2007; 44(3); 431-37

33.. Morita K, Fukuda Y, Nakano I, Peripheral lymphocyte subsets vary with stage of hepatitis C virus-associated liver disease: Hepatogastroenterology, 2005; 52(66); 1803-8

SARS-CoV-2/COVID-19

04 July 2022 : Case report  Italy

Interleukin-6 Is a Promising Marker of COVID-19 in Children: A Case Series of 2 Brothers with Severe COVID-...

Am J Case Rep In Press; DOI: 10.12659/AJCR.934468  

29 June 2022 : Case report  USA

A Clinical Case of COVID-19 Vaccine-Associated Guillain-Barré Syndrome

Am J Case Rep In Press; DOI: 10.12659/AJCR.936896  

16 June 2022 : Case report  Ecuador

Multidrug-Resistant Klebsiella pneumoniae in a Patient with SARS-Cov-2 Pneumonia in an Intensive Care Unit ...

Am J Case Rep In Press; DOI: 10.12659/AJCR.936498  

13 June 2022 : Case report  Japan

Stenotrophomonas maltophilia Infection Associated with COVID-19: A Case Series and Literature Review

Am J Case Rep In Press; DOI: 10.12659/AJCR.936889  

In Press

05 Jul 2022 : Case report  Saudi Arabia

Osteolytic Lesion of the Maxilla in an Undiagnosed Multiple Myeloma Patient Identified Incidentally by Cone...

Am J Case Rep In Press; DOI: 10.12659/AJCR.936585  

05 Jul 2022 : Case report  USA

Histiocytic Disorder Mimicking a Brain Tumor: A Report of 2 Rare Cases

Am J Case Rep In Press; DOI: 10.12659/AJCR.935885  

05 Jul 2022 : Case report  Greece

Solitary Soft-Tissue Metastasis of a Pancreatic Adenocarcinoma 2 Years After Curative Resection: Report of ...

Am J Case Rep In Press; DOI: 10.12659/AJCR.934951  

05 Jul 2022 : Case report  Switzerland

Degenerated Serous Cystic Tumor of the Pancreas: Case Report and Literature Review of an Aggressive Present...

Am J Case Rep In Press; DOI: 10.12659/AJCR.936165  

Most Viewed Current Articles

23 Feb 2022 : Case report  USA

Penile Necrosis Associated with Local Intravenous Injection of Cocaine

DOI :10.12659/AJCR.935250

Am J Case Rep 2022; 23:e935250

17 Feb 2022 : Case report  Oman

Myocarditis, Pulmonary Hemorrhage, and Extensive Myositis with Rhabdomyolysis 12 Days After First Dose of P...

DOI :10.12659/AJCR.934399

Am J Case Rep 2022; 23:e934399

06 Dec 2021 : Case report  Brazil

Lipedema Can Be Treated Non-Surgically: A Report of 5 Cases

DOI :10.12659/AJCR.934406

Am J Case Rep 2021; 22:e934406

09 Feb 2022 : Case report  Saudi Arabia

Extensive Cerebral Venous Sinus Thrombosis (CVST) After the First Dose of Pfizer-BioNTech BNT162b2 mRNA COV...

DOI :10.12659/AJCR.934744

Am J Case Rep 2022; 23:e934744

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923