EBMT Issues Harmonised Guidelines for Viral CNS Infections After Cell Therapy

Viral encephalitis, meningitis, and myelitis constitute rare yet devastating infectious complications following allogeneic hematopoietic cell transplantation and chimeric antigen receptor T-cell therapy. While the global incidence of viral encephalitis in the general population ranges from approximately five to ten cases per one hundred thousand individuals annually, incidence figures and case-fatality rates rise markedly among severely immunocompromised recipients. Profound and prolonged T-cell dysfunction, the disruption of the protective blood-brain barrier, and exposure to intensive conditioning or maintenance immunosuppressive regimens strongly predispose vulnerable hosts to opportunistic central nervous system viral invasion. Over one hundred distinct viral agents possess the capacity to trigger neurotropic inflammation, but clinical evidence is concentrated among pathogens that frequently reactivate following cell therapy. To resolve widespread diagnostic delays, under-recognition, and heterogeneous reporting across centers, the Infectious Diseases Working Party and the Practice Harmonization and Guidelines Committee of the European Society for Blood and Marrow Transplantation established comprehensive, syndrome-oriented recommendations.

The consensus guidelines were formulated by an international multidisciplinary panel comprising four hematology experts, three infectious disease specialists, one clinical microbiologist, four pediatricians, and four members of the Practice Harmonization and Guidelines Committee. The panel conducted a structured literature search within PubMed spanning January 2000 through September 2025, synthesizing registry analyses, cohort investigations, systematic reviews, and small case series across adult and pediatric populations. Because randomized controlled trials and comparative observational studies are entirely absent for the majority of diagnostic and therapeutic interventions in these rare cohorts, the committee deliberately refrained from formal grading of evidence or recommendation strength. Instead, panel members conducted a narrative synthesis, iteratively refining clinical recommendations during a dedicated two-day workshop. Final recommendations were unanimously approved to provide practicing hematologists, infectious disease specialists, and neurologists with practical guidance covering disease definitions, early empirical and pathogen-directed antiviral interventions, structured laboratory workflows, and objective treatment response criteria.

Across allogeneic stem-cell transplant recipients, the overall incidence of viral encephalitis ranges between 0.5 percent and 1.5 percent, resulting almost exclusively from the reactivation of latent viruses under intensive post-transplant immunosuppression. Human herpesvirus 6, predominantly human herpesvirus 6B, represents the primary causative organism, accounting for 70 percent to 80 percent of documented encephalitis cases. Large registry analyses indicate an overall human herpesvirus 6 encephalitis incidence of 0.45 percent, with risk varying substantially by graft source, reaching 2.14 percent after cord-blood transplantation, 0.68 percent following unrelated-donor transplants, and 0.51 percent in haploidentical recipients, compared to 0.06 percent in matched sibling donor procedures. Symptom onset typically clusters between post-transplant days twenty and forty, presenting classically as limbic encephalitis accompanied by acute confusion, amnesia, refractory seizures, and bilateral hippocampal hyperintensity on neuroimaging. Other documented viral pathogens include cytomegalovirus, herpes simplex virus types 1 and 2, varicella-zoster virus, Epstein-Barr virus, adenovirus, and polyomaviruses JC and BK.

In patients receiving chimeric antigen receptor T-cell therapies, central nervous system viral infections remain exceedingly rare and are largely documented within case series, even when cerebrospinal fluid assessments are conducted systematically. Clinical recognition has nonetheless expanded, especially regarding human herpesvirus 6 and JC polyomavirus, which arise during protracted immune reconstitution deficits. Although human herpesvirus 6 reactivation or viral genomic detection has been identified during ex vivo T-cell expansion and manufacturing, published evidence demonstrates that this laboratory finding does not indicate viral transmission through the infused cell product or establish a causative link with subsequent post-infusion encephalitis. Specific predisposing risk factors in the cellular immunotherapy setting include prolonged severe cytopenias exceeding thirty days, persistent B-cell aplasia with hypogammaglobulinemia, receipt of B-cell maturation antigen-directed products, prior allogeneic stem-cell transplantation, and intensive exposure to corticosteroids or tocilizumab administered to manage concurrent immune effector cell-associated neurotoxicity syndrome.

Diagnostic standardization relies on updated definitions adapted from the International Encephalitis Consortium criteria to account for the unique physiology of cellular therapy recipients. Viral encephalitis is defined by a compatible acute or subacute neurological syndrome persisting for at least twenty-four hours, paired with supportive parenchymal neuroimaging and verified viral involvement. Probable cases require viral nucleic acid identification in cerebrospinal fluid without brain biopsy, provided alternative etiologies are thoroughly investigated. Importantly, because severe immunosuppression attenuates typical neuroinflammatory cascades, genuine viral invasion may occur in the complete absence of cerebrospinal fluid pleocytosis or characteristic radiologic lesions, meaning negative baseline surrogates cannot exclude active disease.

The recommended diagnostic algorithm outlines a flexible six-step workflow integrating clinical suspicion, biochemical screening, neuroimaging, lumbar puncture, virological correlation, and ancillary testing. Magnetic resonance imaging represents the primary imaging modality, leveraging pathogen-specific patterns such as temporal necrotizing lesions for herpes simplex virus, ventriculitis or ependymal enhancement for cytomegalovirus, and progressive multifocal leukoencephalopathy patterns for JC virus. Lumbar puncture incorporates rapid multiplex polymerase chain reaction testing for core neurotropic viruses, supplemented by metagenomic next-generation sequencing in unresolved, progressive presentations. Parallel plasma testing quantifies viral replication but cannot replace cerebrospinal fluid analysis, because peripheral viremia can represent unrelated systemic reactivation, while negative plasma tests do not exclude isolated central nervous system replication. Clinicians must also evaluate cellular integration to rule out inherited chromosomally integrated human herpesvirus 6.

Because clinical outcomes deteriorate rapidly when treatment is delayed, empiric antiviral therapy should be initiated immediately based on clinical and radiological suspicion while diagnostic confirmatory tests remain pending. In the early post-transplant period between weeks two and six, in patients with profound lymphopenia, limbic symptoms, or preceding syndrome of inappropriate antidiuretic hormone secretion, empiric foscarnet at a dosage of ninety milligrams per kilogram every twelve hours or sixty milligrams per kilogram every eight hours is strongly indicated. Foscarnet delivers essential coverage against human herpesvirus 6B while maintaining activity against herpes simplex virus and varicella-zoster virus, including thymidine kinase-mutant strains that break through standard acyclovir prophylaxis. Conversely, when clinical presentation points toward herpes simplex virus or varicella-zoster virus in patients whose prophylaxis was interrupted or discontinued, intravenous acyclovir at ten milligrams per kilogram every eight hours remains the empiric regimen of choice, with renal function and myelosuppression guiding adjustments.

Pathogen-directed antiviral therapy requires careful consideration of agent-specific central nervous system penetration, individual organ toxicities, and ongoing immunosuppressive burdens, continuing for at least three weeks or until documented virological clearance. Confirmed human herpesvirus 6 and cytomegalovirus encephalitis require treatment with intravenous foscarnet or ganciclovir, reserving combination regimens for severe refractory infections due to cumulative nephrotoxicity and bone marrow suppression. Newer anti-cytomegalovirus agents such as letermovir and maribavir demonstrate poor blood-brain barrier penetration and are explicitly not recommended for active central nervous system infection. Herpes simplex virus and varicella-zoster virus infections respond to intravenous acyclovir, supplemented by short courses of corticosteroids for varicella-zoster vasculopathy. In cases of acyclovir-resistant herpes simplex virus, foscarnet or compassionate-use helicase-primase inhibitors represent viable rescue options. Epstein-Barr virus post-transplant lymphoproliferative disorder involving the central nervous system requires rituximab, systemic chemotherapy, or adoptive allogeneic cytotoxic T lymphocytes such as tabelecleucel.

The evaluation of therapeutic response is structured into standardized categories assessed by a multidisciplinary team at two to eight weeks following treatment initiation or upon unexpected clinical deterioration. Complete response without neurological sequelae is defined as full clinical resolution of symptoms, requiring no mandatory repeat lumbar puncture or neuroimaging. For patients exhibiting persistent residual neurological deficits, complete response with sequelae requires sustained clinical stabilization for more than four weeks, clearance of baseline neuroimaging and electroencephalogram abnormalities, and negative viral polymerase chain reaction results in cerebrospinal fluid or plasma sampled at least seven days apart. Cases exhibiting unyielding viral loads, advancing symptoms, or expanding lesions are categorized as progressive disease, prompting immediate reassessment of resistance and treatment modification.

Despite modern supportive care, post-transplant viral central nervous system infections carry a grave prognosis, with overall published cohort case-fatality rates ranging between 30 percent and 60 percent. In the European Society for Blood and Marrow Transplantation cohort of ninety-seven human herpesvirus 6 encephalitis cases, thirty-day mortality reached 27 percent, and six-month overall survival stood at 62 percent. Cytomegalovirus and adenovirus encephalitis demonstrate mortality rates between 40 percent and 70 percent, whereas promptly managed herpes simplex virus and varicella-zoster virus infections exhibit lower mortality rates below 20 percent. Adverse prognostic predictors include haploidentical or umbilical cord graft sources, severe graft-versus-host disease, high baseline viral loads, and delays in starting antiviral therapy exceeding 1.5 days. Furthermore, an unvalidated prognostic scoring tool incorporates Glasgow Coma Scale scores below nine, severe thrombocytopenia under twenty thousand platelets per microliter, and involvement of more than three brain lobes, stratifying six-month mortality between 11 percent and 80 percent.

Viral myelitis represents an exceptionally rare yet distinct manifestation of central nervous system viral disease following hematopoietic cell transplantation and cellular immunotherapy. Clinically characterized by spinal cord inflammation, viral myelitis presents with acute or subacute limb weakness, flaccid paralysis, hyporeflexia, sensory ataxia, band-like truncal paresthesias, and autonomic bowel or bladder dysfunction. Human herpesvirus 6 accounts for the majority of reported post-transplant viral myelitis cases, predominantly developing within sixty days of cord-blood or haploidentical transplantation, followed by cytomegalovirus, varicella-zoster virus, and human parvovirus B19. Diagnostic confirmation requires contrast-enhanced spinal magnetic resonance imaging, which frequently demonstrates longitudinally extensive transverse myelitis spanning three or more vertebral segments, combined with cerebrospinal fluid molecular testing. Therapeutic management mirrors encephalitis algorithms, utilizing intravenous foscarnet or ganciclovir for human herpesvirus 6 and cytomegalovirus, high-dose intravenous acyclovir and corticosteroids for varicella-zoster virus, and intravenous immunoglobulins for parvovirus B19.

Long-term secondary prevention requires a balanced approach that combines pathogen-specific surveillance, targeted pharmacological prophylaxis, and safe restoration of endogenous cellular immunity. For patients recovering from herpes simplex virus or varicella-zoster virus central nervous system infections, secondary prophylaxis with oral acyclovir or valacyclovir should continue for at least six to twelve months, provided graft-versus-host disease has resolved and systemic immunosuppression has ceased. Following cytomegalovirus encephalitis, secondary prophylaxis with oral letermovir accompanied by routine plasma viral load monitoring may be considered for a minimum of three months in high-risk patients. Conversely, secondary antiviral prophylaxis is explicitly discouraged for human herpesvirus 6, adenovirus, BK virus, and JC polyomavirus, as routine pharmacotherapy fails to prevent central nervous system recurrence. Ultimately, careful tapering of immunosuppressive agents and the investigational administration of virus-specific adoptive T-cell therapies remain the most promising strategies to restore lasting protective immunity against neurotropic viral disease.

Subject of Research: Clinical guidelines for viral encephalitis, meningitis, and myelitis after hematopoietic cell transplantation and CAR T-cell therapy

Article Title: Syndrome-oriented CNS infectious complications after hematopoietic stem-cell transplantation and CAR T-cell therapy, part 1—viral encephalitis, meningitis, and myelitis: recommendations from the Practice Harmonization & Guidelines Committee of the EBMT

Article References: Piñana, J. L., Cesaro, S., Styczynski, J., Schmidt-Hieber, M., Mikulska, M., Neofytos, D., Baccelli, F., Navarro, D., Onida, F., Ruggeri, A., Sanchez-Ortega, I., Camara, R. D. L., Averbuch, D., Yakoub-Agha, I., & Ljungman, P. (2026). Syndrome-oriented CNS infectious complications after hematopoietic stem-cell transplantation and CAR T-cell therapy, part 1—viral encephalitis, meningitis, and myelitis: recommendations from the Practice Harmonization & Guidelines Committee of the EBMT. eClinicalMedicine, 101, Article 104312. https://doi.org/10.1016/j.eclinm.2026.104312

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104312

Keywords: Viral Encephalitis, Hematopoietic Stem Cell Transplantation, CAR T-Cell Therapy, EBMT Guidelines, Human Herpesvirus 6, Cytomegalovirus, Viral Myelitis, Neurotropic Viruses, Antiviral Prophylaxis, Syndrome-oriented, infectious, complications