Human herpesvirus 6B encephalitis in a liver transplant recipient: A case report and review of the literature

Abstract Human herpesvirus 6B (HHV‐6B) encephalitis in a liver transplant recipient is rarely reported. In this report, we presented a case of HHV‐6B encephalitis in a liver transplant recipient and reviewed the relevant literature. A 56‐year‐old man was admitted to the intensive care unit (ICU) with an acute headache and intermittent convulsion 17 days after liver transplantation. Next‐generation sequencing (NGS) of the cerebrospinal fluid (CSF) revealed 30691 sequence reads of HHV‐6B and real‐time polymerase chain reaction (real‐time PCR) of the CSF detected HHV‐6B DNA at 12 000 copies/mL, so the patient was diagnosed with HHV‐6B encephalitis and received ganciclovir treatment promptly. The condition of the patient improved well and returned to the general ward with no neurologic deficits. This case indicated that adequate awareness, early diagnosis, and timely treatment are crucial to a good prognosis of HHV‐6B encephalitis after liver transplantation.


| L ABOR ATORY E X AMINATIONS
Additional laboratory values included the following: C-reactive protein 7 mg/L, ALT 46 IU/L, AST 30 IU/L, 46 μmol/L, blood ammonia 46 μmol/L, and BNP <100 pg/mL. Imaging of the brain by CT scanning and magnetic resonance imaging (MRI) demonstrated no other abnormalities except for cerebral ischemia, and the electroencephalogram was abnormal due to the continuous electrographic seizures.

| TRE ATMENT AND D IAG NOS IS
On admission, the patient was diagnosed with epilepsy of unknown cause and was treated with mechanical ventilatory support and antiepileptic drugs. Then, tacrolimus and sirolimus were discontinued, and glucocorticoid was initiated. Various B vitamins were supplemented to improve neurologic symptoms. Simultaneously, a next-generation sequencing assay was performed to identify central nervous system infection. Two days later, next-generation sequencing (NGS) of CSF showed 30691 sequence reads of HHV-6B with 98.59% coverage of the HHV-6B genome ( Figure 1) and realtime polymerase chain reaction (real-time PCR) of the CSF detected HHV-6B DNA at 12 000 copies/mL, so the patient was diagnosed with HHV-6B encephalitis and received intravenous ganciclovir (250 mg daily) immediately. MRI scan of the brain showed symmetric hyperintense signal distributed in the frontal lobe and temporal lobe on the fourth day of ICU admission ( Figure 2). 2 weeks after starting ganciclovir, the patient's clinical manifestations markedly improved with the stable neurologic status, and real-time PCR of HHV-6B were all negative (blow 1000 copies/mL) for CSF and blood.
The patient was weaned from the ventilator on the next day. After ganciclovir administration for four weeks, CSF pressure returned to 80 mmH 2 O. From this day onwards, the dosage of ganciclovir decreased to 150 mg/d. Thirty-seven days after admission, he was discharged to the organ transplant ward for further treatment, with no obvious neurologic deficits. The clinical course was summarized in

| D ISCUSS I ON
Human herpesvirus 6 is a widespread virus that primarily infects most children in the first 2 years of age. 2 Seroprevalence of HHV-6 in healthy adulthood is up to 90%, so most HHV-6 infections in transplantation recipients are thought to be caused by virus reactivation. The prevalence of HHV-6 reactivation among liver transplantation recipients varies widely from 4.3% to 53.7%, partly due to differences in study size and diagnostic assays for HHV-6. NGS, known as high-throughput sequencing, can detect unexpected pathogens in a single application. NGS has been proved to be a promising method to identify abundant and transplant-related pathogens. 14 In this case, NGS found sequence reads of HHV-6B in the patient's CSF, which facilitated the timely diagnosis of HHV-6B encephalitis and contributed to a favorable prognosis of the patient.
Human herpesvirus 6 has a unique ability to integrate its genome into telomeres of the human host. This phenomenon, commonly called inherited chromosomally integrated HHV-6 (ciHHV-6), occurs in 2% of liver transplants patients. 3 Recognition of ciHHV-6 is vital for clinical strategy. ciHHV-6-induced HHV-6 infection after liver transplant has been reported to be associated with liver rejection and mortality. 15,16 On the other hand, misdiagnosis of ciHHV-6 as HHV-6 reactivation will result in unnecessary and potentially toxic antiviral therapy. 17 Thus, it has been recommended to examine donated organs and organ recipients for ciHHV-6. If HHV-6 load in whole blood is above 5.5 log10 copies/mL or persistently at a high level under appropriate antiviral treatment, ciHHV-6 should be assumed and further confirmed by quantitative PCR of HHV-6 on fingernails or hair follicles. 18 In this case, quantitative PCR of HHV-6 revealed 12 000 copies/mL (4.08 log10 copies/mL) in CSF and negative results in whole blood, which excluded the possibility of ciHHV-6 and indicated that the encephalitis might be caused by endogenous reactivation of HHV-6B strain. However, we did not determine ciHHV-6 status in the donor, which is the inadequacy of this case report.

| CON CLUS ION
In summary, HHV-6 infection should be considered if liver transplant recipients develop confusion or epileptic seizures. The prompt early diagnosis and the timely application of antiviral therapy are of great significance for improving the patient's prognosis.

CO N FLI C T O F I NTE R E S T
There are no conflicts of interest.