To our knowledge, this study presents for the first time a series of severe HHV-7-related encephalitis in immunocompetent pediatric patients and provides additional information about the prognoses of these patients to assist with clinical decision-making. Previous studies have shown that the prognosis of HHV-7-related encephalitis is good [6, 16,17,18,19,20,21,22,23]. However, this study’s results revealed that older pediatric patients exhibited more severe symptoms and were more likely to experience serious or even life-threatening adverse events.

HHV-7-related encephalitis is rare in immunocompetent pediatric patients. In 1996, Torigoe et al. first described the association between HHV-7 and neurological symptoms as febrile seizures, hemiplegia, and loss of consciousness. [24] In this study, the most common manifestations of HHV-7-related encephalitis were fever, seizures, and altered consciousness, similar to those observed in other forms of encephalitis. Febrile seizures are common in early childhood. Schwarz et al. detected HHV-7 DNA in the cerebrospinal fluid of 57 out of 2972 hospitalized pediatric patients in 2014 [24], and Chan et al. emphasized that delayed primary infection of HHV-7 in older children and adolescents may lead to more severe neurological complications [8], as the more mature immune system tends to induce exaggerated inflammatory responses during initial infection. Alternatively, Ongradi et al. postulated that HHV-7 infection in early childhood establishes lifelong latency, with potential reactivation under immunocompromised conditions, potentially contributing to severe neurological manifestations [23]. In this study, two 9-year-old patients exhibited poor clinical outcomes, which were speculated may be attributed to either delayed primary HHV-7 infection or virus reactivation. However, the limited sample size in this study necessitates further investigation to determine whether advanced age serves as a risk factor for poor prognosis.

In this study, HHV-7 was detected using mNGS of CSF samples; a positive result confirmed HHV-7-related encephalitis. mNGS is an identification method that can detect approximately all pathogens in a sample and exhibits higher sensitivity and specificity for HHV-7 detection than traditional diagnostic methods such as culture and serology. Nonetheless, this technology cannot differentiate between a primary infection and viral reactivation in immunocompetent pediatric patients. Schwartz et al. proposed that HHV-7 DNA in the CSF alone is insufficient to indicate an etiological association. Hence, since confirmatory CSF PCR or serological testing (e.g., HHV-7 IgM/IgG assays) was not performed for these cases, the etiological association between HHV-7 and encephalitis remains uncertain. Notably, the inability to serologically confirm primary infection may compromise the certainty of HHV-7-encephalitis correlation. Future studies should prioritize the development of an integrated multimodal diagnostic framework combining mNGS, PCR, and serological assays to enhance the diagnostic specificity of HHV-7-associated encephalitis [3, 25,26,27,28,29].

Yamamoto et al. demonstrated that MRI and EEG abnormalities are present in the brain of patients with HHV-7-related encephalitis, particularly in the temporal lobe, and encompass slow-wave activity during primary HHV-7 infection-related encephalitis. [29] In this study, a possible decrease in background rhythm, slightly higher levels of theta wave activity, and an increase in fast-wave frequency were observed, all of which corroborated the above-mentioned observations.

For patients with ciHHV-6, ganciclovir and foscarnet are recommended as first-line therapy, whereas cidofovir is considered a second-line option [23]. However, the optimal treatment for pediatric patients with HHV-7 remains unclear. Acyclovir was administered in most of the reviewed cases; however, the difference was that immunosuppression and plasma exchange therapy were added to the severe cases. In previous case reports and series, pediatric patients diagnosed with HHV-7-related encephalitis almost completely recovered [17,18,19,20,21], whereas, in this study, one patient died, and one was paralyzed and went into a coma; such cases have not been previously reported. More patients are needed to identify the risk factors associated with HHV-7-related encephalitis in pediatric patients and determine the most effective diagnostic and treatment approaches.

This study has several limitations at the methodological level, as follows: Firstly, in terms of etiological diagnosis, although cerebrospinal fluid samples were detected using mNGS and the genetic material of HHV-7 was successfully identified, due to the limitations of clinical sample preservation conditions, we failed to comprehensively carry out serological antibody detection and dynamic monitoring of quantitative PCR. Secondly, mNGS technology has its inherent limitations in determining the infection phase. This technique cannot accurately distinguish between the initial infection, latent activation, or re-infection of the virus, and such critical differentiation usually relies on the analysis of serological conversion patterns. More importantly, our understanding of the specific role of genetic factors in the disease process is still superficial. Currently, our knowledge mainly comes from retrospective studies and case reports, lacking systematic in-depth research. Additionally, due to the failure to obtain cerebrospinal fluid specimens from patients during the recovery period for virus load verification, we cannot clarify the temporal sequence correlation between the number of HHV-7 nucleic acid copies and the outcome of clinical symptoms.