Persistent hyponatremia as a distinctive feature of HHV-6B encephalitis in pediatric hematopoietic stem cell transplant recipients: A case series Free

Background: Electrolyte imbalances are a common complication in the context of transplantation, generally presenting as mild and responding well to timely symptomatic management. However, we have observed several instances of hyponatremia that exhibit significant resistance to treatment, even with intravenous sodium supplementation, and persist for extended durations. Our findings indicate that HHV-6B encephalitis can be a causative factor for this persistent hyponatremia.

Methods: A retrospective analysis was conducted on pediatric patients who underwent hematopoietic stem cell transplantation (HSCT) at our center from January 2022 to July 2025 who experienced hyponatremia, defined as serum sodium levels below 135 mmol/L, which persisted for more than two weeks despite the implementation of corrective interventions.

Results: Within a cohort of 350 pediatric patients undergoing HSCT, five cases with refractory hyponatremia were identified. This group comprised two male and three female patients, with ages ranging from 4.5 to 10.1 years. The initial diagnoses included T-cell acute lymphoblastic leukemia (T-ALL) (n=2), juvenile myelomonocytic leukemia (JMML) (n=2), and myelodysplastic syndrome with increased blasts (MDS-IB) (n=1). The sources of donor cells were unrelated cord blood (n=3) and haploidentical donors (n=2). Hyponatremia was observed in four patients between 13 and 22 days post-transplant, typically occurring after neutrophil engraftment. The other patient with T-ALL experienced a relapse after HSCT and subsequently underwent CD7 CAR-T cell therapy, developing hyponatremia 17 days after the CAR-T cell infusion. All five patients exhibited significant hyponatremia, with a median level of 118.5 mmol/L (range: 115.8–128.2 mmol/L), following a rapid decline from normal sodium levels within an average of 1.6 days (range: 0.6–8 days). The most severe decrease was observed in one patient whose sodium level dropped from normal to 118.5 mmol/L within 15 hours, showing no response to treatment with 3% hypertonic saline. Neurological symptoms were present in all patients: one exhibited hyperexcitability and hand tremors; two experienced headaches and vomiting, with one also suffering from persistent intractable vulvar pruritus; and two developed seizures. Cerebrospinal fluid (CSF) analysis using next-generation sequencing (NGS) consistently detected HHV-6B exclusively, with a median viral load of 35,264 copies/mL (range: 24,972–59,433 copies/mL). Peripheral blood (PB) testing confirmed HHV-6B positivity in all cases (NGS in 3 cases, PCR in 2 cases). Neuroimaging assessments were performed on four patients: two computed tomography scans and one magnetic resonance imaging (MRI) scan with contrast yielded normal results, and one non-contrast MRI demonstrated multiple intracranial signal abnormalities. Importantly, none of the patients had a history of hypothyroidism, Addison's disease, or renal disorders. It is noteworthy that among the cohort of encephalitis cases subjected to NGS testing, three patients diagnosed with Streptococcus mitis meningitis concurrently tested positive for HHV-6B; however, they did not present with refractory hyponatremia. All five patients were administered antiviral therapy comprising ganciclovir, foscarnet, and intravenous immunoglobulin. Four patients underwent testing for PB within 10 days, which confirmed the clearance of HHV-6B. However, hyponatremia persisted for an extended period. For a patient with persistent hyponatremia for one month, a subsequent CSF analysis performed on day 31 verified the absence of HHV-6B. Sodium levels were restored to normal by day 64. The patient exhibiting vulvar pruritus, who initially presented with the mildest form of hyponatremia, achieved normalization of sodium levels by day 39. However, the vulvar pruritus persisted for a longer duration. A CSF test conducted on day 40 confirmed the clearance of HHV-6B. Two patients achieved sodium normalization by days 51 and 143, respectively. No subsequent CSF tests were performed. At the time of this report, the final patient had been experiencing severe hyponatremia for 72 days, though CSF analysis on day 60 confirmed the absence of HHV-6B. Importantly, no patients succumbed to these complications.

Conclusion: Persistent hyponatremia may act as a distinctive clinical indicator of HHV-6B encephalitis in pediatric patients undergoing HSCT. The underlying mechanisms require further investigation.