This is the case of a 70-year-old man who presented to the emergency department with sudden confusion and agitation of 1 day duration. In the initial assessment, vital signs were significant for fever (38.8 C). Physical examination revealed a drowsy elderly patient who was easily arousable and oriented to person. He was able to move all extremities against gravity and no nuchal rigidity was noted. His reflexes were +2 throughout and Babinski sign was negative bilaterally. No rashes or skin lesions were appreciated. Suddenly, while under evaluation in the emergency department, the patient had a generalized tonic-clonic seizure lasting a few minutes.
Initial blood work showed a normal complete blood count (CBC) with differential counts, and an unremarkable comprehensive metabolic panel including globulin levels. Urinalysis was negative for pyuria and bacteriuria. Urine drug screen was also negative. His HIV test was negative. Computed tomography (CT) scan of the head was negative for any acute process. CT angiography of the head and neck was negative for stenosis, occlusion, aneurysm, arteriovenous malformation or dissection. Magnetic resonance imaging (MRI) of the brain showed advanced cerebral atrophy with extensive chronic microvascular ischaemic changes, no evidence of haemorrhage and nonspecific micro-haemorrhages mainly over the deep structure consistent with the sequelae of traumatic brain injury (TBI).
Blood cultures were drawn and the patient underwent a lumbar puncture. He was then started on empiric antibiotics (vancomycin, ampicillin and ceftriaxone) in addition to acyclovir. Cerebrospinal fluid (CSF) profile showed elevated glucose of 161 mg dl-1 (normal range 40-70 mg dl-1), elevated protein of 71 mg dl-1 (normal range 15-45 mg dl-1), WBC count of 2 (normal range <10 per cm3) with 63% lymphocytes. The CSF sample was positive for HHV-6 on the BioFire FilmArray Meningitis/Encephalitis (ME) Panel (bioMerieux; Marcy-l'Etoile, France). The patient was intubated, transferred to the ICU and was switched to ganciclovir for treatment of suspected HHV-6 encephalitis. Antibiotics were discontinued.
There was no significant improvement in the patient's mentation despite ganciclovir therapy. Five days later, his HHV-6 quantitative PCR (qPCR) performed on plasma, showed 5.1 log10 copies/ml (116 000 copies/ml) of HHV-6B DNA in the plasma and 4.5 log10 copies/ml (29 700 copies/ml) in the CSF. A repeat plasma HHV-6 PCR remained elevated at 5.7 log10 copies/ml (487 000) copies after 12 days of treatment, raising concern for treatment failure. Although the persistent high viral load could also be explained by iciHHV-6, no HHV-6 mRNA testing was available at the time to determine whether the patient had both ciHHV-6 and an active infection; therefore, the decision was made to continue treatment based on his clinical symptoms and ganciclovir was changed to foscarnet. The patient's mentation improved to baseline per his family and a repeat HHV-6 plasma PCR showed improvement with 4.6 log10 copies/ml (38 000 copies/ml) detected. He received a total of 14 days of foscarnet therapy and was discharged to home.
A few weeks after his discharge, the patient presented again to the emergency room in a postictal state. He was nonadherent to his antiepileptic regimen and had a breakthrough seizure. At that time, the infectious disease specialist did not recommend any further workup for encephalitis. Three months later, the patient was admitted again for altered mental status. According to his family, he was slower to respond and more lethargic than usual. HHV-6 plasma PCR was repeated and showed persistent DNAemia with 4.7 log10 copies/ml (54 300 copies/ml) detected. Despite this result and his encephalopathy, the patient was haemodynamically stable without systemic signs of infection. Infectious disease specialists discussed his case and agreed that his multiple admissions for encephalopathy were unlikely secondary to HHV-6 encephalitis given the lack of correlation of viral load or antiviral treatment with his symptoms. Their decision was to send an HHV-6 chromosomal integration assay and hold further treatment pending the result. Meanwhile, the patient's mentation improved, and he was discharged home. Following discharge, the result of the chromosomal integration assay performed through whole blood qPCR at the University of Washington's Department of Laboratory Medicine was received; the HHV-6 virus-to-cell ratio was approximately 1:1, confirming our suspicion for iciHHV-6.