Fatal Avian Orthoavulavirus-1 Encephalitis Driven by Host-Mediated Hypermutation During Cancer Immunotherapy

Unprecedented measles-like RNA hypermutation in a common avian virus has triggered a fatal case of neuroinvasive encephalitis in a cancer patient, according to a study published in Acta Neuropathologica.

The 70-year-old patient, who was enrolled in the phase two MajesTEC-5 clinical trial for multiple myeloma, presented with a rapidly progressive infection of the brainstem and cerebellum. Researchers conducting metagenomic RNA sequencing discovered that the pathogen responsible was avian orthoavulavirus-1—historically known as Newcastle disease virus—which had undergone extensive host-mediated nucleotide substitution.

While human infections by this virus are typically self-limiting and restricted to mild ocular surface irritation, this specific case revealed an intraparenchymal viral load where roughly one percent of all generated sequencing reads aligned directly to the viral genome.

Following frontline teclistamab-based induction and autologous stem cell transplantation, the patient received maintenance therapy consisting of teclistamab, daratumumab, and lenalidomide, targeting B-cell maturation antigen and CD3.

Researchers Sequenced Cerebellar Biopsy Tissue to Identify the Pathogen

Bioengineers and medical researchers utilized stranded total RNA libraries prepared from a fresh cerebellar biopsy specimen, sequencing them via Element Biosciences AVITI and Illumina NextSeq 2000 platforms. Computational pathogen discovery pipelines identified the infectious agent as avian orthoavulavirus-1 isolate AOaV-1 SMP60/HH/2025. Histopathological evaluation of the cerebellar biopsy tissue revealed preserved parenchymal cytoarchitecture alongside intense, multifocal neuroinflammatory responses.

This molecular signature corresponds directly to host adenosine deaminase acting on RNA, known as ADAR enzymes.

Bioinformatic reconstruction using strainline revealed that a day-twenty-seven urine specimen harbored a single, minimally mutated viral sequence designated haplotype H0, representing the putative ancestral strain. Haplotype H1.1 exhibited almost exclusive uridine-to-cytidine transitions, reflecting ADAR-mediated deamination on the negative-sense genomic RNA template.

Avian Orthoavulavirus-1 Undergoes Extreme Genetic Changes in Immunocompromised Hosts

• Unusual Zoonotic Pathogen: Avian orthoavulavirus-1, normally found in birds and previously known to cause only mild eye irritation in humans, can undergo extreme genetic changes inside an immunocompromised host.
• Immunotherapy Context: The patient was undergoing specialized T-cell-redirecting cancer immunotherapy for multiple myeloma, a treatment regimen that heavily alters immune surveillance.
• Parallels to Measles: The severe brain inflammation mirrors subacute sclerosing panencephalitis, a fatal late complication driven by persistent viral mutation in measles infections.

Despite aggressive antiviral administration alongside maximum supportive neurocritical care, the patient experienced relentless clinical deterioration. Post-mortem examination was subsequently performed following formal authorization from the patient’s legally appointed representative.

Viral Haplotype	Primary Specimen Source	Dominant Mutation Type	Mechanistic Origin
H1.1	Cerebellar Biopsy	Uridine-to-cytidine transitions	ADAR deamination on negative-sense template
H2.1	Cerebellar Biopsy	Adenosine-to-guanosine transitions	ADAR deamination on positive-sense intermediate

Standard Panel Testing May Fail to Detect Hypermutating Pathogens

Standard panel testing may fail to detect neuroinvasive zoonotic pathogens undergoing profound within-host hypermutation.

As detailed in Acta Neuropathologica, this fatal presentation broadens our understanding of how host RNA editing enzymes can inadvertently drive lethal neurotropic disease variants during targeted cancer therapies.

References

• Krueger, C., Schaefers, C., Guenther, T., et al. (2026). Acta Neuropathologica, 152(1), Article 68.
• PubMed Central (PMC). National Library of Medicine.