Liver transplantation has become the gold standard for the treatment of end-stage liver disease [1]. Although immunosuppressive agents after liver transplantation are essential for maintaining graft function, they also increase the incidence of various opportunistic infections [2]. Strenuous efforts have been made to detect opportunistic infections earlier and optimize immunosuppressant usage to counterbalance acute rejection and infectious complications [3]. However, infectious complications remain one of the leading causes of mortality after liver transplantation [4].

Herpes simplex virus (HSV) infection, categorized into HSV types 1 and 2, is ubiquitous and contagious in adults [5]. The clinical manifestations of HSV infection primarily present as orofacial, genital, or anal disease and are confined to a cutaneous lesion. However, it can occur in various tissues of the body [6]. HSV-induced hepatitis is a rare complication of HSV infection, often leading to severe liver failure [7]. While HSV infection is lifelong and can recur in immunocompetent patients, it is usually not fatal and is treatable with antiviral agents [8]. We report a case of rare but fatal systemic HSV infection with atypical clinical manifestations early after living donor liver transplantation.

A 45-year-old female patient who suffered repeated large-volume paracentesis and recurrent esophageal variceal bleeding due to alcoholic liver cirrhosis with uncontrolled portal hypertension, underwent living donor liver transplantation using a left liver graft from an ex-spouse. The model for end-stage liver disease score prior to transplantation was 7, and the Child-Pugh grade was B at the time of transplantation. For immunosuppression, 20 mg of basiliximab and 500 mg of methylprednisolone were administered during the operation. After surgery, the total bilirubin level and prothrombin time normalized rapidly, and the patient was transferred to the general ward on postoperative day (POD) 5. Triple regimen immunosuppressive agents consisting of tacrolimus, mycophenolate mofetil, and a steroid were administered. The trough tacrolimus level was maintained between 6–8 ng/mL during the postoperative period.

Mild erythematous erosive patches developed on both palms and soles on POD 12. The lesions were suspected to be hand-foot eczema or a skin reaction. Thus, topical desonide was applied based on the dermatologist’s opinion. However, the extent and severity of skin lesions gradually worsened. Consequently, erythematous vesicles and papules with severe itching were increasingly scattered on the neck, arms, and trunk. The lesion did not respond to various topical steroids and antihistamines, so we decided to perform a skin biopsy. At the same time, aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels, which had normalized, increased rapidly. Since the CT scan could not reveal the specific cause of liver dysfunction, such as hemodynamic abnormalities in the allograft and bile duct dilatation, we also performed a sonography-guided liver biopsy.

Despite intensive empirical antibiotic treatment while awaiting the biopsy results, the patient rapidly deteriorated and was transferred to the intensive care unit. A skin biopsy showed very distinctive features compatible with HSV infection (Fig. 1A). The liver biopsy also showed extensive confluent coagulative necrosis and viral cytopathic effects in the bile duct with positive immunohistochemical staining for HSV (Fig. 1B). The patient’s HSV IgG assay was positive before liver transplantation. Although high-dose intravenous acyclovir (10 mg/kg daily during continuous renal replacement therapy) was administered immediately after the diagnosis, serious erosion and rash accompanied by severe pain covered the skin of the entire body (Fig. 2). Finally, the patient died due to multiorgan failure on POD 28.

Figure 1. (A) A skin biopsy showed acantholysis and multinucleated giant cells with ground-glass intranuclear viral inclusions and chromatin margination (x400, hematoxylin-eosin stain). (B) A liver biopsy demonstrated necrotic hepatocytes with viral cytopathic changes (x400, hematoxylin-eosin stain). The yellow arrow indicates multinucleated giant cells with ground-glass intranuclear viral inclusions and chromatin margination.

Figure 2. Severe erosion and rash covered all body skin on postoperative day 28.

HSV infection is widespread worldwide. Although there are some regional differences, the prevalence of HSV-1 and HSV-2 was reported to be 66% and 12%, respectively, of the total population [9]. It primarily affects the skin and mucus membranes, irrespective of the type. For most immunocompetent hosts, an HSV infection is temporary and resolves without detrimental sequelae [8]. However, there have been several reports on visceral involvement in HSV infections [10,11]. In particular, HSV hepatitis can cause fatal acute liver failure even in immunocompetent hosts if it is not diagnosed in time [7]. Compromised cellular immunity after transplantation is a major risk factor for reinfection with and the recurrence of HSV [12]. One study reported that 42% of patients with positive HSV IgG before transplantation experienced changes of HSV polymerase chain reaction from negative to positive early after liver transplantation [13]. However, clinical manifestations of them were confined to oral mucosa and treated easily. In this case report, HSV infection might have resulted from the reactivation of a previous virus infection, considering that her HSV IgG assay was positive. It is unclear whether the origin site of the disseminated HSV infection was the skin or liver. However, considering the clinical course, in which liver failure occurred several days after the aggravation of skin lesions, HSV hepatitis was thought to be secondary visceral dissemination. Further, the HSV infection in our case report was likely to involve other organs as well as the skin and liver because the typical clinical presentations of HSV hepatitis are anicteric hepatitis without skin lesions [12].

There have been few reports on lethal HSV hepatitis in immunosuppressed hosts early after solid organ transplantation [10,14]. They have been reported the mortality rate of HSV hepatitis to 50% or more even with antiviral treatment. Most importantly, only the early detection and diagnosis of HSV infection can improve its prognosis. However, serologic analysis to detect antibodies has a limited role in diagnosing HSV infections because of its significant false-positive rate [15]. The most definite diagnostic modality is viral culture and pathologic diagnosis through biopsy. Histologic findings of HSV infection are very distinctive. It could be diagnosed when there are key features such as acanthosis with solitary keratinocytes and multinucleated giant cells with ground-glass intranuclear viral inclusions, suggesting viral cytopathic effects, even without immunohistochemistry [16]. In our case, we did not readily consider an HSV infection because the skin lesions initially appeared on the extremities, not on the orolabial, genital, or perianal area, where it typically begins. Patients with atypical skin lesions early after liver transplantation need to consult a dermatologist to discern suspected herpetic skin infection because atypical skin lesions are more frequent in immunosuppressed patients [17]. Furthermore, we should keep in mind the possibility of HSV infection when atypical skin lesions occurring in the early posttransplant period do not respond to topical steroids and antihistamines. In addition, if progressive aminotransferase elevations with coagulopathy occur in the early postoperative period without other problems, HSV hepatitis should be included in the differential diagnosis.

Transplant recipients have been reported to have severe clinical manifestations with visceral involvement and a slower response to antiviral treatment [18]. The urgent administration of high-dose acyclovir can avoid life-threatening outcomes. The empirical administration of acyclovir has to be considered for patients with symptoms suspicious of an HSV infection even before a definite diagnosis. In terms of prevention, many centers have implemented cytomegalovirus prevention protocols for high-risk patients using ganciclovir, acyclovir, valacyclovir, and valganciclovir [19]. These antiviral agents also have prophylactic effects against HSV replication. A previous study reported that severe HSV hepatitis disappeared after using prophylactic acyclovir [7]. According to the American Society of transplantation infectious disease community of practice guidelines, HSV‐specific antiviral prophylaxis should be administered for HSV-seropositive transplant recipients who are not receiving cytomegalovirus prophylaxis [18]. Further, it also could be considered when HSV-seronegative patients undergo liver transplantation with grafts from seropositive donors. Acyclovir at a dose of 200 mg three or four times a day is effective in HSV prophylaxis.

In conclusion, our case report presents a fatal and atypical HSV infection with systemic involvement early after living donor liver transplantation. We should consider HSV as a source of severe opportunistic infections and make efforts for prevention and an early diagnosis.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: HSJ, PJP, DSK. Data curation: HSJ, PJP, WJK. Formal analysis: HSJ, PJP, YDY, DSK. Investigation: HSJ, PJP, WJK, HJH, YDY. Methodology: HJH, YDY. Project administration: DSK. Resources: PJP, WJK. Supervision: DSK. Writing - original draft: HSJ, PJP, WJK, HJH, YDY. Writing - review & editing: All.