Transfusion-Transmitted Cache Valley Virus Infection in a Kidney Transplant Recipient With Meningoencephalitis

Abstract

Background: Cache Valley virus (CVV) is a mosquito-borne virus that is a rare cause of disease in humans. In the fall of 2020, a patient developed encephalitis 6 weeks following kidney transplantation and receipt of multiple blood transfusions.

Methods: After ruling out more common etiologies, metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) was performed. We reviewed the medical histories of the index kidney recipient, organ donor, and recipients of other organs from the same donor and conducted a blood traceback investigation to evaluate blood transfusion as a possible source of infection in the kidney recipient. We tested patient specimens using reverse-transcription polymerase chain reaction (RT-PCR), the plaque reduction neutralization test, cell culture, and whole-genome sequencing.

Results: CVV was detected in CSF from the index patient by mNGS, and this result was confirmed by RT-PCR, viral culture, and additional whole-genome sequencing. The organ donor and other organ recipients had no evidence of infection with CVV by molecular or serologic testing. Neutralizing antibodies against CVV were detected in serum from a donor of red blood cells received by the index patient immediately prior to transplant. CVV neutralizing antibodies were also detected in serum from a patient who received the co-component plasma from the same blood donation.

Conclusions: Our investigation demonstrates probable CVV transmission through blood transfusion. Clinicians should consider arboviral infections in unexplained meningoencephalitis after blood transfusion or organ transplantation. The use of mNGS might facilitate detection of rare, unexpected infections, particularly in immunocompromised patients.

Keywords: Cache Valley virus; blood transfusion; kidney transplant; meningoencephalitis; transfusion-transmitted infection.

Figure 1.

Index kidney recipient magnetic resonance imaging of brain with and without contrast 2 months post-transplantation. Multifocal and regionally confluent areas of abnormally increased T2 fluid-attenuated inversion recovery signal within subcortical, deep, and periventricular cerebral hemispheric white matter bilaterally. No pathologic enhancement of the brain or the meninges on post-contrast scans. A small chronic lacunar infarct is seen within the right cerebellum.

Figure 2.

Index kidney recipient magnetic resonance imaging of brain with and without contrast 3 months post-transplantation. Interval subtle increase in fluid-attenuated inversion recovery hyperintensity at the left greater than right thalami; moderate central volume loss is similar to prior examination.

Figure 3.

Index kidney recipient magnetic resonance imaging of brain with and without contrast 4 months post-transplantation. Advanced widespread abnormal fluid-attenuated inversion recovery signal in the periventricular white matter, thalami, and brain stem.

Figure 4.

Metagenomic next-generation sequencing (mNGS) results for the index patient. A, Heat map of viral reads identified in the mNGS sequencing run. Each column of the heat map represents an individual patient cerebrospinal fluid sample, and the individual cells are color-coded based on viral read counts from green (minimum) to red (maximum), with gray denoting zero reads. The column corresponding to the index patient is highlighted with an arrow, and the read count data for the Orthobunyavirus (Cache Valley virus [CVV]) detection is displayed in a pop-up window. The highlighted cell shows that 3936 mNGS reads from the trisegmented bunyavirus genome are detected. Each row of the heat map represents taxonomic identification at the family (left), genus (middle), and species (right) levels, with asterisks denoting either the absence of a taxonomic designation in the reference database (eg, Agaricus bisporus virus X at the genus and family levels) or a read that is not specific at a given taxonomic level (eg, Gammaretrovirus at the species level). B, Coverage map of the bunyavirus reads from the index patient mapped to the closest identified viral reference sequence in the National Center for Biotechnology Information GenBank database (CCV MNZ-92011). A total of 775 nucleotides mapped CVV reads out of 3936 are observed to span the estimated 6871 bp L (large) segment. Automated heat and coverage maps were generated using the SURPI+ bioinformatics pipeline for pathogen identification [6, 9]. Abbreviations: NCBI, The National Center for Biotechnology Information; nt, nucleotide.

Figure 5.

Bayesian phylogenetic inference of transfusion-associated CVV and select Orthobunyaviruses. Maximum credibility trees depicting the nucleotide open reading frames of the small (A), medium (B), and large (C) genomic segments. The virus sequenced in this study is highlighted in blue text. Viruses are labeled with virus name, isolate designation, and GenBank accession numbers. Strains corresponding to lineage I or II are grouped with brackets. Posterior probabilities are indicated on each branch, and the scale bar depicts nucleotide substitutions per site. Abbreviation: CVV, Cache Valley virus.

Figure 6.

Index kidney recipient magnetic resonance imaging of brain with and without contrast 8 months post-transplantation. Progression of abnormalities particularly within the deep aspects of the cerebral hemispheres bilaterally as well as the basal ganglia and thalami and capsules, with new areas of diffusion restriction and enhancement compared with prior examination from 4 months post-transplantation.