Varicella and varicella zoster virus meningoencephalitis in a diffuse large B-cell lymphoma patient after chimeric antigen receptor-T-cell therapy

Varicella is predominantly caused by the primary infection of a susceptible individual with the varicella zoster virus (VZV). Antiviral prophylaxis, especially for VZV, has emerged as a critical component of the standard of care for patients undergoing chimeric antigen receptor (CAR)-T cell therapy, resulting in lower occurrences of infections.1 Currently, there is limited literature reporting VZV infections following CAR-T therapy, with sporadic case reports such as VZV-induced retinitis and another detailing a refractory verrucous VZV infection.2,3 However, no reports describing varicella meningoencephalitis have been identified to date. This report describes VZV-induced varicella and meningoencephalitis in a diffuse large B-cell lymphoma (DLBCL) patient after CAR-T cell therapy. In view of the rarity and critical condition of this patient, a report was conducted. A middle-aged man with relapsed DLBCL underwent R-CHOP, multiple salvage regimens, autologous haematopoietic stem cell transplantation and CD19/CD20 CAR-T therapy. In February 2025, the patient presented with fever, delirium and diffuse rashes. The rashes first appeared on the trunk and subsequently disseminated, presenting as scattered erythematous macules, papules and vesicles throughout the body. Some vesicles had progressed to crust formation, and central umbilication was observed in a subset of lesions (Figure 1a). Dermatologic evaluation confirmed varicella; cranial MRI revealed meningoencephalitic changes (Figure 1c). Peripheral blood metagenomic next-generation sequencing (mNGS) detected VZV with a sequence count of 4032 (5 February 2025). Acyclovir and intravenous immunoglobulin were initiated. CSF was yellow and turbid, with white blood cell count 854 × 106/L (lymphocyte predominant), protein 7540.5 mg/L and lactate dehydrogenase 245 U/L. Following antiviral therapy, skin lesions, fever and neuropsychiatric symptoms resolved (Figure 1b and d). On 19 March 2025, MRI showed marked improvement, VZV mNGS reads fell to 7 (19 March 2025) and CSF parameters normalized, confirming successful treatment of VZV. Changes in skin manifestations and cranial MRI findings in this patient before and after anti-VZV treatment. (a) The patient exhibited prominent lesions on the skin of the chest, abdomen and lower limbs. (b) After anti-VZV treatment, the skin lesions of the patient improved significantly compared with pretreatment findings, but scars remained. (c) a–f: abnormal signal detected in the right cerebellar hemisphere, characterized by hypointensity on T1-weighted images and hyperintensity on T2-weighted and T2-FLAIR sequences. Abnormal band-like hyperintensity was observed in the ependyma of the posterior horns of the bilateral lateral ventricles on T2-FLAIR sequences. (d) g–l: the re-examination results for the patient indicated that the abnormal signal was relieved. Infection remains one of the major complications of CAR-T therapy. A study of non-relapse mortality (NRM) associated with CAR-T has demonstrated that infection is the predominant factor contributing to NRM, accounting for approximately 50% of NRM cases across various diseases.4 Reactivation of the herpes virus, manifesting as a delayed response, often occurs over 6–12 months following the infusion of CD19 CAR-T cells.5 Additionally, in a study of large B-cell lymphoma, delayed restoration of CD4+ T cells in patients treated with CD19-directed CAR-T cells remains at risk of opportunistic infections for more than 1 year after CAR-T therapy.1 At 1 year, more than 50% of patients exhibited cell counts below 200 cells/mm3. The CD4+ T lymphocyte count in this patient consistently remained above 200 cells/mm3. This phenomenon indicates that relying solely on specific immune indicators may not be sufficient for accurately assessing the risk of infection. Currently, the incidence of VZV infection among patients undergoing CAR-T therapy remains unclear. There is a lack of consensus regarding the specific strategies of prophylactic treatment for VZV, as well as whether preventive treatment should be implemented. A meta-analysis evaluating the risk of infection in patients undergoing CAR-T therapy revealed that, among studies detailing antiviral prophylaxis regimens, 66.7% reported the administration of acyclovir or valacyclovir from the initiation of lymphodepletion until CD4+ T-cell count recovery or for a minimum duration of 3–12 months post-CAR-T-cell infusion.6 The patient described in this report underwent prophylactic treatment with valacyclovir dispersible tablets at a dosage of 300 mg once daily for approximately 5 months following CAR-T therapy. This case took place over 10 months after the discontinuation of antiviral treatment. For this patient, VZV meningoencephalitis is a late toxicity that also warrants attention. The LDH in the patient’s CSF showed a substantial increase. The specific cause remains unclear and may be related to brain parenchymal damage. Meanwhile, MRI revealed abnormal signals and a small number of ischaemic foci. For patients with compromised immune function, it is recommended to avoid using live vaccines due to the potential for these vaccines to introduce an unpredictable infection risk.7 Thus, it is imperative to thoroughly examine whether patients undergoing CAR-T therapy require VZV vaccination prophylaxis, the optimal timing for initiating preventive measures and the duration for which these measures should be maintained. In summary, this case report describes a rare instance of VZV infection following CAR-T therapy, characterized by meningoencephalitis with concurrent varicella. This case serves as an important alert for clinical physicians: patients undergoing CAR-T therapy are at risk of late toxicity associated with VZV activation. In addition, complications such as meningoencephalitis pose a potentially fatal risk. Therefore, heightened vigilance throughout the diagnostic and differential diagnostic process is essential, as early recognition of atypical symptoms and signs, aided by advanced techniques such as mNGS, plays a critical role. Furthermore, it is advisable to implement long-term follow-up monitoring for these patients, encompassing viral infection markers, lymphocyte subsets and counts, and immunoglobulin levels. Timely antiviral prophylactic treatment should be administered based on individual patient conditions. We are grateful to the patient of this report and all members of the Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. This work was supported by the National Natural Science Foundation of China (No. 81974005), the Beijing Xisike Clinical Oncology Research Foundation (Y-SYBLD2022MS-0055), and the Natural Science Foundation of Hubei Province (2025AFD777). The authors have no conflict of interest to declare. The data that support the findings of this study are available from the corresponding author upon reasonable request.