In March 2016, approximately one year after Zika virus (ZIKV) infections were reported in the United States, the U.S. Food and Drug Administration (FDA) recommended that states and territories convert from mini-pool screening to individual-unit screening to minimize the risk of ZIKV transmission through blood components.
In an investigational screening study published in The New England Journal of Medicine, researchers noted that the use of one such testing method – an individual transcription-mediated amplification (TMA) for RNA testing – is costly and provides a low yield. This assay, although highly accurate for testing for ZIKV, may not be economically feasible in the real-world setting, compared with the standard practice of screening donors with risks of ZIKV infection based on geographic areas with the greatest risk.
Of more than 4 million samples analyzed in the study, “ZIKV RNA was detected for the nine donors whose infection came from a mosquito bite and was present in plasma and red cells for long periods of time,” lead author Susan L. Stramer, PhD, vice president of scientific affairs at the American Red Cross, told ASH Clinical News. “Importantly, of the nine confirmed positives, the three donations that were most likely to result in transmission were detected by mini-pool nucleic acid testing, as well as individual donation nucleic acid testing.”
To evaluate the accuracy and feasibility of individual nucleic acid testing, researchers at the American Red Cross screened a total of 4,325,889 blood donations from five southeastern states considered high risk for ZIKV development (Alabama, Florida, Georgia, Mississippi, and South Carolina) between June 2016 and September 2017.
They retested initial reactive donations to establish ZIKV presence, then confirmed ZIKV presence using repeat TMA, TMA testing in exploratory mini-pools, real-time reverse-transcriptase polymerase chain reaction, immunoglobulin (IgM) serologic testing, and red-cell TMA.
Of the donations individually tested during the 15-month study period, investigators identified 160 samples as initially reactive (n=160) and 4,325,729 samples as non-reactive.
Six of the initially reactive donations were also reactive on repeat TMA, with four donations confirmed as IgM-negative. Of the 154 samples that registered as non-reactive on repeat testing, three were later confirmed IgM-positive, for a total of nine confirmed positive samples.
That translated to a “confirmed-positive rate” of one for every 480,654 samples, with a positive predictive value of 5.6 percent and a specificity of 99.9 percent.
Transmission of the virus in nine donors was likely attributable to:
- locally transmitted infections in Florida (n=2)
- travel to ZIKV-active areas (n=6)
- receiving an experimental ZIKV vaccine (n=1)
In the ZIKV-positive samples, the levels of ZIKV RNA varied depending upon where they were detected:
- red cells: 40-800,000 copies/mL up to 154 days following donation
- plasma: 12-20,000 copies/mL up to 80 days following donation
Overall, the authors calculated that the costs of identifying eight mosquitoborne ZIKV infections through individual screening was $5.3 million per ZIKV RNA–positive donation, making it economically unfeasible.
“Clinicians should know that blood is safe and no transfusiontransmitted ZIKV infections have occurred in the U.S.,” she noted. “In fact, only four recipients have been documented to have been infected from transfusion (all in Brazil), and these four recipients were transfused with blood products from three infected donors.” Following transfusion, said Dr. Stramer, none of these recipients developed symptoms associated with ZIKV RNA.
Based on these results, she believes that “the conversion to mini-pool nucleic acid testing from individual donation nucleic acid testing, as required by the FDA today, would be a better use of resources with equivalent patient safety.”
However, this analysis was limited by the lack of a comparator group, which could have been used to determine superiority over other testing modalities. In October 2017, the FDA approved the cobas Zika test to screen for ZIKV, which analyzes RNA and plasma from individual donors.
The findings should also inform the blood-screening recommendations for other transfusion-transmitted risks. “Clinicians should be educated about the mitigation of other viruses through transfusion, particularly from Babesia microti, a red cell parasite transmitted by the same tick as Lyme disease,” Dr. Stramer said. Screening is not yet required for this virus, despite it posing “a far more significant threat in parts of the U.S. where the ticks are common, represented by more than 200 transfusion transmissions.”
“Tests that detect a broad range of mosquito-borne agents are needed, and clinicians should be aware that there are other mitigation methods besides testing, such as pathogen inactivation,” she concluded.
The American Red Cross and Grifols Diagnostic Solutions supported this study.
The authors report financial support from the American Red Cross.
Saá P, Proctor M, Foster G, et al. Investigational testing for Zika virus among U.S. blood donors. N Engl J Med. 2018;378:1778-88.