Transmission of yellow fever vaccine virus through blood transfusion and organ transplantation in the USA in 2021: report of an investigation

Abstract

Background: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients.

Methods: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor.

Findings: We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation.

Interpretation: This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains.

Funding: US Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority, and the CDC Epidemiology and Laboratory Capacity Cooperative Agreement for Infectious Diseases.

Figure 1:

Timeline of events related to the transmission of yellow fever vaccine virus through blood transfusion and solid organ transplantation

Figure 2:. Initial detection of yellow fever virus by clinical metagenomic next-generation sequencing of CSF from a kidney recipient

One yellow fever virus read out of 14 608 788 reads in the RNA metagenomic library was detected. Multiple sequence alignment of the read from the recipient of the right kidney (YFV-single-read) along with 29 representative strains of yellow fever virus and two related flaviviruses (Wesselsbron virus and Sepik virus) was done using multiple alignment using fast Fourier transform. The alignment shows that the read was identical across 106 base pairs to the live attenuated 17D yellow fever vaccine strain. CSF=cerebrospinal fluid. SEPV=Sepik virus. WSLV=Wesselsbron virus. YFV=yellow fever virus.

Figure 3:. Comparison of gene expression profiles from solid organ and tissue recipients with those from patients with autoimmune or non-infectious encephalitis or viral meningoencephalitis

Heat map showing hierarchical clustering of differentially expressed genes (y axis) by sample (x axis). Normalised RNA gene expression levels, shown as Z scores and visualised using a colour bar gradient, reflect gene overexpression (yellow or orange) and underexpression (blue or black). Data from a cohort of 117 patients with autoimmune or non-infectious encephalitis and 117 patients with viral meningoencephalitis were used. Differentially expressed genes specific for autoimmune or non-infectious encephalitis (n=33) or viral meningoencephalitis (n=12) were selected for use in a machine learning-based classifier model. The genes shown (n=48) were selected using a classifier model and corresponding to either a cell signalling-associated pathway or an immune or inflammatory pathway, with subcategories assigned on the basis of known function. The asterisks denote genes that have been previously reported to be overexpressed in association with yellow fever vaccination or infection with non-yellow-fever flaviviruses.

Figure 4:. Evidence of yellow fever viral encephalitis in the brain tissue of the heart transplant recipient on autopsy

Left: perivascular lymphocytic inflammation (arrow) and glial proliferation and activation in an area of neuronal degeneration, 100×; middle: degenerating neurons (arrows) and neuronal processes (arrowheads), 400×; right: yellow fever virus RNA staining (in red) within inflammatory focus by in-situ hybridisation, 100×.