HHV-6 reactivations in immunocompetent patients with psychiatric disorders: visual hallucinations or possible interactions?

To the Editor, Human herpesvirus 6 (HHV-6) comprises two double-stranded DNA viruses, HHV-6A and HHV-6B, which are distinguished based on antibody reactivity, T-cell clone reactivity, and restriction banding patterns.[1] The International Committee on Taxonomy of Viruses has recently classified these as two distinct viral species.[2] HHV-6B is the primary causative agent of roseola infantum, while the pathogenic mechanisms of HHV-6A remain less well understood. Serological studies indicate that over 95% of adults are seropositive for one or both HHV-6 variants, which establish latency following primary infection. These viruses persist primarily in T-cells and bone marrow progenitor cells.[3]In vitro studies have demonstrated HHV-6B latency in astrocytes, while HHV-6A has been shown to remain latent in oligodendrocytes.[4] Both viral types are capable of modulating the immune system, promoting immunosuppressive effects and chronic inflammatory pathways.[3,4] HHV-6B is the primary agent responsible for the reactivation of viral infections in both immunocompetent and immunocompromised individuals, presenting with a wide clinical spectrum ranging from asymptomatic reactivation to severe conditions associated with high morbidity and mortality, including encephalitis, hepatitis, and pneumonitis.[3,4] In recent years, HHV-6-associated neuroinflammation during early life has been increasingly implicated in the pathogenesis of various mood disorders, such as bipolar disorder and major depressive disorder.[5] We present two cases of suspected HHV-6 reactivation in patients with pre-existing psychiatric disorders hospitalized at Cardinal Massaia Hospital in Asti, Italy in 2022-2023. Oral consent was obtained from the patients and documented in their medical records prior to the publication of this report. The first case involves a 42-year-old woman with a history of major depressive disorder and compulsive personality disorder, who was undergoing chronic therapy with fluoxetine and delorazepam. The patient reported no recent travel or sexual activity and was employed as a waitress at a rural agricultural establishment. In June 2022, the patient was hospitalized due to fever and a maculopapular rash, which a dermatologist diagnosed as erythema multiforme minor, along with decreased platelet count and elevated transaminase levels (Table 1). A full-body CT scan was performed, with no pathological findings detected. Empirical therapy with ciprofloxacin (500 mg every 12 h) and doxycycline (100 mg every 12 h) was initiated. Comprehensive microbiological analyses excluded the presence of other viral, bacterial, protozoan, or fungal infections. Serological testing for HHV-6 revealed positive immunoglobulin G (IgG) but negative immunoglobulin M (IgM) (IFA, Vidia Ltd., Czech Republic). Quantitative analysis of HHV-6 DNA in blood showed a high viral load of 46,000,000 cp/mL. Despite the mild clinical presentation, treatment with orally administered valacyclovir (1 g every 8 h for 7 days) was initiated due to the elevated HHV-6 DNA viral load, persistent leukopenia, and mildly elevated transaminase levels. Empiric antibiotic treatment was dismissed after 7 days. This intervention led to the complete resolution of laboratory abnormalities and a significant decrease in HHV-6 DNA levels. A hair follicle examination, conducted to assess HHV-6 chromosomal integration, yielded a positive result. The patient underwent follow-up evaluations over a six-month period, which demonstrated a gradual but consistent decline in HHV-6 DNA levels in the blood. Table 1 - Laboratory and virological characteristics at baseline and at the end of follow-up Variables Patient 1 Patient 2 Patient 1 (3 month FUP) Patient 2 (3 month FUP) WBC (109/L) 4.2 5.0 8.2 6.2 Hgb (g/dL) 13.3 11.0 13.0 12.0 PLTS (109/L) 91 132 256 351 GOT (U/L) 117 90 22 42 GPT (U/L) 81 150 25 40 Total Bilirubin (mg/dL) 1.3 2.0 1.2 1.3 Creatinine (g/dL) 0.70 0.86 0.70 0.70 LDH (U/L) 560 576 451 400 CRP (g/dL) 22.00 9.00 0.05 0.10 PCT (ng/dL) 0.02 0.16 0.02 0.02 HHV-6 DNA blood (cp/mL) 46,000,000 2,975,000 5,700,000 350,000 HHV-6 DNA CSF (cp/mL) NA 2,365,000 NA NA HHV-6 DNA (hair follicle integration) Positive Positive NA NA WBC: White blood cell; RBC: Red blood cell; PLTS: Platelets; GOT: Glutamate-oxaloacetate transaminases; GPT: Glutamate-pyruvate transaminases; LDH: Lactate dehydrogenases; CRP: C-reactive protein; PCT: Procalcitonin; HHV-6: Human herpesvirus 6; CSF: Cephalorachidian fluid; FUP: Follow-up; NA: Not available. The second patient was a 50-year-old woman with a history of paranoid schizophrenia diagnosed in early adulthood. At the time of admission, she was receiving chronic therapy with risperidone. Her prior medical records did not reveal any significant findings. The patient was admitted to the hospital in August 2023 due to symptoms including fever, disorientation, restlessness, and mutism. A CT scan of the brain showed no abnormalities, and a lumbar puncture revealed cerebrospinal fluid (CSF) with minor mononuclear cellularity (5 cells/mm3), alongside normal levels of glycorrhachia and proteinorrhachia. FilmArray analysis of the CSF was positive for HHV-6. Viral DNA was subsequently extracted and purified using a silica-based nucleic acid purification technique, and real-time quantitative PCR confirmed HHV-6 DNA viral loads of 2,975,000 cp/mL in the blood and 2,365,000 cp/mL in the CSF (QIAsymphony®, QIAGEN). Given the compatible clinical presentation, severity of the condition, and central nervous system involvement, intravenous ganciclovir (5 mg/kg every 12 h) was initiated, and neurological HHV-6 reactivation was suspected. A magnetic resonance imaging scan performed 14 days after the initial presentation showed no signs of encephalitic involvement. Following 14 days of ganciclovir therapy, the treatment was transitioned to oral valganciclovir (900 mg every 12 h) for an additional 7 days. Clinical improvement was observed within 7–10 days of treatment, and subsequent hair follicle testing confirmed HHV-6 DNA integration. Follow-up over a three-month period demonstrated a gradual reduction in HHV-6 DNA levels in blood samples. Symptomatic HHV-6 reactivation in immunocompetent individuals has been documented in the literature. Increasing evidence suggests the presence of HHV-6 in cerebral cells of patients with psychiatric disorders, supporting the hypothesis of cellular latency in this population. Niebuhr et al.[5] conducted a pivotal case–control study involving 180 patients with schizophrenia and their respective controls to measure IgG antibody levels to HHV-6 in both pre- and post-diagnosis specimens. Their findings revealed a significant association between HHV-6 seropositivity and schizophrenia, with a hazard ratio of 1.17 (95% confidence interval [CI] = 1.04, 1.32).[5] Further evidence was provided by Prusty et al.[6] in a recent post-mortem study, which confirmed viral latency in the cerebellar Purkinje cells of 50 bipolar and schizophrenic patients and 15 patients with major depressive disorder. HHV-6A and HHV-6B late proteins (indicating active infection) and viral DNA were detected more frequently (P < 0.001 for each virus) in the cerebellum of patients with major depressive disorder and bipolar disorder compared to controls.[6] Although clinical reports of HHV-6 reactivation in psychiatric populations remain rare, Deshpande et al.[6] described a noteworthy case of a new diagnosis of schizophrenia accompanied by concomitant HHV-6 reactivation, where the patient required both antipsychotic and antiviral therapy for complete clinical resolution. More recently, Bayturan et al.[7] analyzed IgG seropositivity for Herpesviridae, including HHV-6, in patients diagnosed with depressive disorder according to DSM-5 criteria and in healthy volunteers aged 11 to 18 years.[8] HHV-6 IgG levels were significantly higher in the mood disorder group (P < 0.001),[8] with a significant positive correlation observed between HHV-6 antibody levels and scores on the DSM-5 Level 2 Somatic Symptom Scale.[7] Although case–control and genetic studies have suggested potential links between HHV-6 infection and psychiatric disorders, there is still a lack of clinical data regarding the impact and optimal management of HHV-6 reactivation in these patients. This report highlights the need for further investigations to elucidate the potential correlation between HHV-6 reactivation and psychiatric disorders. Funding None Author Contributions Tommaso Lupia and Marco Casarotto contributed to the collection of clinical data, conceptualization and writing of the manuscript. Francesco Giuseppe De Rosa contributed to the design and revision of the paper. All authors read and approved the final manuscript. Conflicts of Interest None