Unusual oral presentation of HSV-1 lesions in an adult liver transplant recipient

Abstract

Herpes Simplex Virus (HSV) hepatitis in liver transplant patients is a rarely reported infective complication of HSV with severe consequences, often leading to fulminant hepatitis if left untreated. The clinical signs are often atypical, leading to under-reporting in the literature and potential delays in treatment. Our case report describes such atypical mucocutaneous lesions in a liver transplant recipient. We highlight the need for further reports, especially those with images, in order to aid the diagnosis of HSV infection, and to allow prompt treatment to prevent complications such as HSV hepatitis.

Background 

HSV-1 and 2 represent rare causes of hepatitis, which if left untreated, often lead to fulminant hepatitis and death. Clinical manifestations of HSV hepatitis are often non-specific, with mucocutaneous lesions only presenting in 27% of cases. Furthermore, recognition of HSV reactivation is often hindered by the atypical systemic manifestations. Not only does this lead to under-reporting in the literature, but may also lead to delays in treatment. Case reports and clinical images, such as ours, are important in aiding the early detection of HSV reactivation, thereby allowing treatment to be delivered in a prompt manner in order to resolve or prevent HSV hepatitis.

Case presentation

A 40-year-old woman was referred to our hospital with fulminant hepatitis, jaundice, hyperbilirubinaemia (total bilirubin 30 mg/dL), peripheral oedema, mild increase in serum transaminases and prolongation of coagulation time (International normalised ratio (INR) 8.9). No neurological deficit was found. Discussion with family members revealed a history of increased alcohol intake over several years. She was not being followed up by hepatology and no other disease was reported.

She was admitted to the intensive care unit (ICU) and resuscitated with stat fresh frozen plasma transfusions, with correction of volemia and electrolyte imbalance. Total body CT scan was performed, revealing hepatosplenomegaly with no other significant alterations. Two days later, with no sign of hepatic improvement, she was registered to the National Liver Transplant Recipient List with priority A, model for end stage liver disease score 36; receiving an orthotopic liver transplantation (OLTx) July 2018 from a deceased donor the day after.

The donor was a female in her early 80s, who was declared brain dead 2 days after admission (confirmed on electroencephalogram (EEG) after traumatic head and thoracic injuries. A pre-transplantation viral screen was performed during declaration of brain death, with results available before transplantation (see – investigations).

The postoperative recovery period was initially undertaken in ICU with evidence of coagulation time correction, persistence of mildly elevated liver transaminases and little sign of improvement in cholestasis. Immunosuppression was introduced with a tapered steroid regimen (from intravenous methylprednisolone 1 g once daily (OD) on the day of OLTx, to per os (PO) 20 mg OD on postoperative day (POD) 7), intravenous basiliximab on POD 0 and POD 4, PO calcineurin inhibitor (Tacrolimus) starting from POD 7 and PO mycophenolate motefil 500 mg twice daily (BD) from POD 4, then 1 g BD from POD 6 onwards.

On POD 4 she was transferred to the surgical transplant ward. On POD 10, a liver biopsy was performed showing acute rejection, with no signs of viral hepatitis (RAI 9); she was therefore treated with a high dose-steroid regimen (intravenous methylprednisolone 1 g OD for 3 days) lasting from POD 12 to POD 15.

After the first steroid administration on POD 12, while serum transaminases, gamma glutamyltransferase  (GGT), white blood cell, slowly decreased (figure 1), she began to complain of dysphagia and the appearance of greenish-black lesions were noted on the lips and oral cavity (figure 2). No skin lesions were present. No fever, coagulopathy, leucopenia or signs of viral hepatitis or renal failure were noted. On review by the dermatology specialist, oral erythema multiforme (EM) was suggested as a potential cause. While on consultation with the infectious disease specialist, uncertainties were drawn on the diagnosis and thus further exams were carried out.

Figure 1.

Biochemical and immunosuppression data after liver transplant. Legend – glutamic oxaloacetic transaminase (GOT) (IU/L), glutamatic pyruvate transaminase (GPT) (IU/L), gamma glutamyltransferase (GGT) (IU/L), alkaline phosphatase (ALP) (IU/L). Total bilirubin (T bil) (mg/dL). White blood cell count (WBC) (cells/microliter). Tacrolimus (ng/ml).

Figure 2.

Greenish-black HSV-1 lesions in the oral cavity, day 12 after liver transplant.

Investigations

Blood samples were taken from the donor for pre-transplantation viral screens. Samples were obtained from a central venous catheter 2 h into our declaration of death protocol, with results available after 21 h. Both nucleic acid amplification tests (NAATs) and serological tests were performed. NAATs were negative for HBV, HCV and HIV 1/2. Serological tests were negative for HBs Ab, HBc Ab, HCV Ab, HIV Ab and Ag (p24). HBV RNA and HCV RNA tests were not performed as NAATs were negative. Serology for HSV showed that donor serostatus was negative for HSV-2 IgG and positive for HSV-1 IgG.

The serostatus of the recipient, on investigations performed 2 days prior to OLTx, was found to be positive for HBsAb and negative for HBsAg, HBcAb, HBV DNA, HCV ab, HCV RNA and HIV Ab. The recipient was IgG negative for HSV-2, and positive for HSV-1, Cytomegalovirus (CMV), and Varicellar Zoster Virus (VZV); Ebstein Barr Virus (EBV) serostatus was not tested.

On POD 14, repeat serological tests demonstrated that the recipient was positive for HSV-1 IgG and negative for HSV-1 IgM, however a direct wound swab taken from the oral mucosal lesions on POD 14 was demonstrated to be positive for HSV-1 DNA (4969 copies/mL) and negative for HSV 2 DNA using the real-time PCR method.

On POD 15, serum HSV-1 DNA levels were found to be 5041 copies/mL (with levels over 250 copies/mL considered positive).

Differential diagnosis

The differential diagnoses considered in our case included oral manifestations of CMV, EM, erythroplakia, erosive lichen planus, syphilis of the oral cavity and atrophic glossitis from vitamin deficiency.

Treatment

The patient was started on intravenous Acyclovir therapy 600 mg BD on POD 14, with improvement of the mucosal lesions and evidence of complete mucosal healing (figure 3) after 8 days of antiviral therapy (continued for 14 days in total). Serum HSV 1 DNA levels were 4869 copies/mL on POD 17 and undetectable by POD 36.

Figure 3.

Lesions after acyclovir treatment, day 21 after liver transplant.

Outcome and follow-up

Due to the persistent high levels of bilirubinemia and normal coagulation results, the patient underwent treatment with three series of Molecular Adsorbent Recirculation System (MARS).

Graft function improved concomitantly with decreasing levels of serum bilirubin. However, as bilirubin levels are still abnormal, the patient is under observation within our unit, but in an otherwise good state of health.

Discussion

In our patient, there was an initial degree of uncertainty regarding the diagnosis. Our case presented with oral well-demarcated brown oval patches with pale borders, with some demonstrating a central ulceration. Our case is unusual considering the presence of darkly discoloured patches, likely explained by the high serum levels of bilirubin (>30 mg/dL). Moreover, the distribution of these apthous-like ulcerative lesions were predominantly on the tongue. This is opposed to the classic presentation of gingivostomatitis with vesicles and ulcerations.

EM was considered as a potential differential diagnosis due to the appearance of ulcerative ‘target-like lesions’ present on the oral mucosa as is common with EM. Moreover, herpes simplex virus is implemented in the immune-reactive pathogenesis of EM and indeed, regular testing for HSV is warranted in the diagnostic workup. However, as there were no concomitant lesions at other body sites, and as the patient had already been on a strong immunosuppressive regime prior to the manifestation of symptoms, we felt this diagnosis was highly unlikely.¹

DNA PCR demonstrating elevated levels of HSV viral levels and resolution of oral lesions on acyclovir was strongly suggestive of HSV infection. Other diagnoses, such as erythroplakia, would have likely persisted despite anti-viral therapy.

HSV infections in liver transplant recipients usually occur early during the course of recovery (in our case, lesions were noted on POD 12).² Due to the short interval between transplantation and HSV infection, reactivation is the likely source,³ caused either by the immunosuppressive regimen or donor-acquired primary infection, rather than a community-acquired primary infection.⁴ Moreover, with over 90% of the worldwide population expected to have had HSV-1 or HSV-2, and more than half of the European population demonstrating HSV-1 seropositivity, diagnosis of HSV lesions should be based on direct methods such as wound swabbing for HSV DNA or viral cultures.^{5 6}

Risk factors for reactivation include stay in critical care as suggested by the prevalence of HSV reactivation in critical care patients, as well as a high level of immunosuppression.⁷ For example, as described in the literature, use of mycophenolate mofetil in OLTx has shown an increased risk of HSV reactivation.^{4 8} Anti-viral prophylaxis is often recommended to prevent reactivation of common viral infections such as CMV after solid organ transplants, which in turn prevents HSV and VZV. However, serological screening within a pre-emptive approach is an acceptable alternative.⁹

Similarities can be drawn to the case report by Burke et al,¹⁰ which documented the HSV presentation as plaques on the tongue of a patient after liver transplant. The true prevalence of atypical HSV dermatological presentations in liver transplant patients is unknown. It is likely that such atypical presentations have led to under-recognition, and as such, under-reporting in the literature, as well as delays in the treatment and prevention of HSV complications.¹¹

One of the most feared complications is HSV viral hepatitis.¹² HSV reaches target organs predominantly through vascular dissemination from focal sites, such as mucocutaneous lesions.¹³ In some cases, HSV infection of organs has been hypothesised to arise from contiguous spread.¹⁴ HSV dissemination in immunocompetent hosts is thought to occur after large viral load inoculations overwhelming the immune defences, secondary strain infections leading to increased HSV virulence, or due defects in innate and adaptive immune systems.¹⁵ In solid organ transplant recipients, vascular dissemination is largely consequential to the post-transplant immunosuppressive regime.^16–18 The majority of HSV cases after liver transplants are secondary to HSV reactivation, and less commonly due to primary infection. Although rare, HSV transmission has also been documented through the transplantation of HSV-infected donor organs.¹⁹ This rare yet severe complication has only been reported in short case series or case reports.

Both HSV-1 and HSV-2 have been found to cause viral hepatitis with poor outcomes, often leading to fulminant hepatitis and death when left untreated.²⁰ Systemic symptoms are often non-specific such as fever, rise in transaminases, coagulopathy, with only 27% of patients presenting concomitantly with mucocutaneous lesions.¹⁵ HSV hepatitis infection should be considered as an infectious diseases emergency, which when left untreated yields a mortality rate of 86%. With acyclovir therapy, however, the mortality rate drops to 33%²¹; thus, empirical therapy should be considered whenever suspected.³

Despite evidence that antiviral prophylaxis prevents disease recurrence,²² the practice of which has to be carefully considered in accordance with various healthcare systems.

At our Liver Transplant Centre, we manage common viral infections with strict monitoring and a pre-emptive strategy. We therefore do not provide prophylactic treatment for HSV or other viral infections such as CMV and VZV. We believe that other solid organ transplant centres under national healthcare models have similar local policies. However, we acknowledge that there have been no recent studies or surveys into the differences between local practice regarding HSV prophylaxis. Further cost/benefit studies are needed to guide the potential introduction of universal prophylaxis for HSV.

Future studies should take into account the changes in immunosuppressive regimens and introduction of monoclonal antibodies over past decades, such as Basiliximab used with our patient. Further studies are required in order to comprehensively evaluate the risks, clinical manifestations and outcomes of HSV reactivation after liver transplant.

Learning points.

• HSV is a common viral infection in immunosuppressed patients such as liver transplant recipients, virological testing (for HSV, CMV, VZV and EBV) prior to transplantation should be performed.

• HSV infections can lead to severe complications such as pulmonary lesions, encephalitis and hepatitis.

• HSV presentation in liver transplant patients can be atypical.

• Atypical mucocutaneous lesions, combined with the unspecific clinical manifestations in complications such as HSV hepatitis, hinders the diagnosis and delays treatment.

• Case reports such as ours, documenting the atypical mucocutaneous lesions are important in aiding recognition.

• Antiviral prophylaxis is recommended, however further studies are needed prior to the introduction of universal HSV prophylaxis.