CDC Warns B-Cell–Depleting Therapies May Increase Risk of Severe Arboviral Neuroinvasive Disease

The CDC is warning clinicians that patients receiving B-cell–depleting or B-cell–modulating medications, particularly anti-CD20 monoclonal antibodies, may be at increased risk for severe and potentially fatal arboviral neuroinvasive disease.¹ The Health Alert Network (HAN) advisory comes amid an early and strong start to the US West Nile virus season, with several weeks of peak mosquito and tick activity still remaining.¹

Although most arboviral infections are asymptomatic, symptomatic infections may cause febrile illness or neurologic complications, including aseptic meningitis, encephalitis, and acute flaccid myelitis.¹ Patients who are immunocompromised may experience longer incubation periods, atypical presentations, prolonged infection, and more severe outcomes.¹˒²

Anti-CD20 Therapy Linked to Severe and Fatal Disease

B-cell–depleting therapies are widely used across hematology, oncology, neurology, and rheumatology. Anti-CD20 monoclonal antibodies currently approved in the United States include rituximab (Rituxan; Genentech, Biogen) and its biosimilars, ocrelizumab (Ocrevus; Genentech), ofatumumab (Kesimpta; Novartis), ublituximab (Briumvi; TG Therapeutics), obinutuzumab (Gazyva; Genentech), and ibritumomab tiuxetan (Zevalin; Acrotech, Spectrum).¹

According to the CDC, published case reports involving patients receiving anti-CD20 therapy who subsequently developed arboviral neuroinvasive disease have demonstrated an overall mortality rate of approximately 40%, with long-term neurologic sequelae reported among most survivors.¹ West Nile virus has been the most frequently identified pathogen, although severe infections involving eastern equine encephalitis virus, Powassan virus, Jamestown Canyon virus, La Crosse virus, Cache Valley virus, and Potosi virus have also been documented.¹

Earlier literature underscores the potential severity of infection in this population. A review of 21 patients receiving recent rituximab therapy who developed arboviral disease found neuroinvasive disease in all patients, with molecular testing required to establish the diagnosis in 20 of 21 cases.³ Disease duration ranged from 12 days to 1 year, illustrating the potential for unusually prolonged infection.³

Chronic Neurodegenerative Encephalitis Raises New Concern

Of particular concern is an unusual form of chronic neurodegenerative encephalitis associated with orthobunyavirus infection in patients receiving rituximab. The CDC reported that this presentation has now been described in at least 5 patients, with neurologic deterioration developing over months to years following infection with Jamestown Canyon, Cache Valley, or Potosi viruses. All 5 patients died.¹

Delayed recognition and the involvement of rare or unexpected pathogens contributed to diagnostic difficulties in these cases.¹

One previously published case involved a 56-year-old patient with mantle cell lymphoma receiving maintenance rituximab who developed progressive neurologic symptoms after initially experiencing fatigue, arthralgia, and weight loss. The patient's condition progressed to rapidly progressive dementia, and metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid ultimately identified Jamestown Canyon virus. Despite treatment, the patient deteriorated and died approximately 1 year after suspected symptom onset. Notably, serologic testing was negative despite evidence of ongoing infection, highlighting an important diagnostic challenge associated with B-cell depletion.⁴

Molecular Testing May Be Critical for Diagnosis

Because anti-CD20 antibodies impair humoral immune responses, affected patients may have delayed or absent virus-specific antibody production, potentially limiting the sensitivity of standard serologic testing.¹˒² The CDC therefore recommends preferential use of molecular testing, including reverse transcription polymerase chain reaction (RT-PCR) or mNGS, when arboviral infection is suspected in patients receiving B-cell–depleting monoclonal antibodies.¹

Potential specimens include serum, plasma, cerebrospinal fluid, whole blood, and tissue, depending on the clinical presentation and laboratory capabilities.¹ Clinicians should also consider prolonged viremia and obtain a detailed history of travel and mosquito or tick exposure, even when illness develops outside the typical May-through-November arbovirus season.¹

Prevention Becomes Particularly Important

There are currently no approved treatments, prophylactic agents, or human vaccines for the arboviral diseases endemic to the United States highlighted in the advisory, making prevention particularly important for patients with impaired B-cell function.¹

The CDC recommends counseling patients beginning B-cell–depleting or other immunosuppressive therapies about mosquito and tick precautions, including use of Environmental Protection Agency–registered insect repellents, protective clothing, permethrin-treated clothing and gear, mosquito control around the home, and routine tick checks after outdoor exposure.¹˒²

For pharmacists involved in oncology, hematology, neurology, or rheumatology care, medication counseling may provide an opportunity to reinforce these preventive measures and to increase awareness that fever, confusion, persistent headache, weakness, imbalance, or other neurologic symptoms in a patient receiving B-cell–depleting therapy may warrant prompt evaluation for an arboviral infection.¹

References

1. Centers for Disease Control and Prevention. Risk of Severe Arboviral Disease in Patients Receiving B Cell-Depleting or Modulating Medications. Health Alert Network; CDCHAN-00532. Published August 11, 2026. Accessed August 13th, 2026. https://www.cdc.gov/han/php/notices/han00532.html

2. Centers for Disease Control and Prevention. Clinical Guidance for Vector-Borne Viral Diseases in People Who Are Immunocompromised. Updated June 12, 2026. https://www.cdc.gov/vector-borne-diseases/hcp/clinical-guidance-immunocompromised/index.html

3. Kapadia RK, Staples JE, Gill CM, et al. Severe Arboviral Neuroinvasive Disease in Patients on Rituximab Therapy: A Review. Clin Infect Dis. 2023;76(6):1142-1148. doi:10.1093/cid/ciac766

4. Solomon IH, Ganesh VS, Yu G, et al. Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. Emerg Infect Dis. 2021;27(1):238-242. doi:10.3201/eid2701.203448