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Continuous improvement has led to a very high degree of microbial safety of transfusion. Four issues are likely to impact the future of this safety. There will be further advances in the efficacy and efficiency of donation testing and pathogen reduction, increasing safety and hopefully eliminating unnecessary procedures. While system failures have been essentially eliminated, there will be ongoing, unpredictable issues that are inevitable. Emerging infections are likely the greatest concern and will continue, although advances in science and technology will permit increasingly rapid responses to outbreaks. Finally, the practice of transfusion may eventually impact safety as usage of blood is reduced and perhaps as alternatives to conventional blood components are developed.

In 2019, the Food and Drug Administration revised the requirement for further testing of anti-HCV-reactive donations testing nucleic acid (NAT)-nonreactive via routine mini-pool (MP)-NAT. Individual donation (ID)-HCV NAT was required as a supplemental test prior to a second FDA-licensed anti-HCV assay; if ID-HCV-NAT is reactive, no further testing is required. This study investigated the rate of low-level RNA in anti-HCV-reactive donation samples prior to and following the implementation of supplemental ID-HCV NAT.A retrospective analysis was conducted on frozen plasma unit samples from 1161 anti-HCV confirmed-positive/HCV-NAT-nonreactive donations collected from December 2014 to January 2020. Samples were tested by multiple replicates on the Grifols Procleix Ultrio Elite (UE) assay and corresponding discriminatory HCV (dHCV) assay on the Procleix Panther System. Prospectively, the prevalence of low-level RNA in 2912 anti-HCV-reactive donations detected through routine screening from April 2020 through March 2021 was determined.In retrospective analyses, 10 (0.86%) of 1161 plasma samples were UE reactive, of which four (0.34%) were dHCV reactive (in all replicates of UE and dHCV). Of 2912 anti-HCV-reactive donation samples testing NAT-nonreactive via routine MP-NAT, three (0.1%; 95% CI: 0.04-0.30) were dHCV reactive; 37% of the remaining samples were reactive by a second anti-HCV assay and thus serologically confirmed.Retrospective and prospective analysis in comparison to earlier studies revealed that low-level HCV-RNA reactivity is decreasing over time. The very low HCV-RNA rates may be due to the widespread use of highly effective, direct-acting anti-viral treatments for those diagnosed with HCV infection.

Background Blood donors were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); resulting antibody levels were monitored over time. Methods Donors reactive to anti-SARS-CoV-2 spike protein (S1-total antibodies) participated in a follow-up study of 18 months. Testing for nucleocapsid antibodies distinguished between vaccination and infection. Vaccination and symptom information were collected for anti-S1-reactive donors by completing a survey. Results The majority of 249 followed donors were over 60 years old (54%), White (90%), and female (58%); 83% had not been vaccinated at enrollment, but by study completion, only 29% remained nonvaccinated. Of the 210 (84%) anti-N-reactive donors, 138 (66%) reported vaccination, whereas 37 (95%) of donors vaccinated and anti-N negative at enrollment remained uninfected. Vaccinated (2 doses) and infected donors showed a steady increase in anti-S1 that increased markedly for vaccinated donors after a booster and infected donors after vaccination (slightly higher for those with hybrid immunity), whereas anti-N levels declined. Most surveyed nonvaccinated donors (65%) reported symptoms, whereas 85% of vaccinated donors were asymptomatic. A coronavirus disease 2019 (COVID-19) diagnosis was reported by 48 (31%) nonvaccinated and 3 (8%) vaccinated donors. Of asymptomatic donors, 38% never tested diagnostically for COVID-19, and 35% tested negative, suggesting an absence of knowledge of the infection. Conclusions Healthy blood donors were vaccinated at high rates and remained mostly asymptomatic and noninfected, whereas approximately two thirds of infected donors reported symptoms. Anti-S1 levels increased while anti-N decreased over 18 months but remained comparable between vaccinated and hybrid immune individuals with dramatic anti-S1 increases after vaccination or boosting.

In the United States, many blood collection organizations initiated programs to test all blood donors for antibodies to SARS-CoV-2, as a measure to increase donations and to assist in the identification of potential donors of COVID-19 convalescent plasma (CCP). As a result, it was possible to investigate the characteristics of healthy blood donors who had previously been infected with SARS-CoV-2. We report the findings from all blood donations collected by the American Red Cross, representing 40% of the national blood supply covering 44 States, in order to characterize the seroepidemiology of SARS-CoV-2 infection among blood donors in the United States, prior to authorized vaccine availability. We performed an observational cohort study from June 15th to November 30th, 2020 on a population of 1.531 million blood donors tested for antibodies to the S1 spike antigen of SARS-CoV-2 by person, place, time, ABO group and dynamics of test reactivity, with additional information from a survey of a subset of those with reactive test results. The overall seroreactivity was 4.22% increasing from 1.18 to 9.67% (June 2020 - November 2020); estimated incidence was 11.6 per hundred person-years, 1.86-times higher than that based upon reported cases in the general population over the same period. In multivariable analyses, seroreactivity was highest in the Midwest (5.21%), followed by the South (4.43%), West (3.43%) and Northeast (2.90%). Seroreactivity was highest among donors aged 18-24 (Odds Ratio 3.02 [95% Confidence Interval 2.80-3.26] vs age >55), African-Americans and Hispanics (1.50 [1.24-1.80] and 2.12 [1.89-2.36], respectively, vs Caucasian). Group O frequency was 51.5% among nonreactive, but 46.1% among seroreactive donors (P< .0001). Of surveyed donors, 45% reported no COVID-19-related symptoms, but 73% among those unaware of testing. Signal levels of antibody tests were stable over 120 days or more and there was little evidence of reinfection. Evaluation of a large population of healthy, voluntary blood donors provided evidence of widespread and increasing SARS-CoV-2 seroprevalence and demonstrated that at least 45% of those previously infected were asymptomatic. Epidemiologic findings were similar to those among clinically reported cases.

Background The Transfusion-Transmissible Infections Monitoring System (TTIMS) combines data from four US blood collection organizations including approximately 60% of all donations to monitor demographic and temporal trends in infectious disease markers and policy impacts. Study design and methods Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) consensus-positive definitions combined serology and nucleic acid testing results. These along with donor and donation characteristics were assembled into a single data set. Overall donation prevalence and demographic subsets were compared pre- and post-implementation of the 2015 change in men who have sex with men (MSM) deferral policy, among other prevalence comparisons. Results From October 2015 to September 2019, there were 712 HIV-, 1735 HBV-, and 5217 HCV-positive samples identified from approximately 27.5 million donations (>9.4 million donors). Prevalences per 100 000 donations were 2.6 (HIV), 6.3 (HBV), and 19.0 (HCV), and the highest for all three agents were in donations from first-time male donors. Two slight but significant increases in HIV prevalence were observed, both for comparisons of Year 1 (pre-MSM policy change) versus Year 4 (post-MSM policy change) for first-time males and first-time females; in contrast, similar comparisons demonstrated decreases in HCV prevalence (all donors and general trends for males and females). Except for HIV, prevalence increased with age; for all agents, prevalence was markedly higher in the south. Conclusions No major trends were observed over 4 years covering the MSM policy change from indefinite to a 12-month deferral, but ongoing monitoring is warranted. Demographic trends are consistent with those observed in other donor studies and community trends.

Background Hepatitis C virus (HCV) infection rates among US blood donors have been well characterized; however, few studies evaluated HCV genotypes among blood donors. Monitoring trends in disease and demographic patterns contributes to understanding the safety of the blood supply. We examined the demographic characteristics and distribution of HCV genotypes/subgenotypes for nearly a 16-year period among blood donors confirmed positive for HCV RNA but antibody negative (defined as nucleic acid testing [NAT] yield). Methods A retrospective assessment of demographic characteristics and testing data was used to determine temporal trends and geographical distribution of HCV genotypes/subgenotypes among American Red Cross blood donors confirmed positive as HCV-NAT yield. Results From 2003–2018, 343 donors (0.38/100 000 donations; 95% CI, .35–.43) were confirmed positive as HCV-NAT–yield cases. Temporal analysis revealed a significant increase in HCV-NAT–yield cases of 54.1% between 2009 and 2014 (P = .014), followed by a significant decline of 31.4% between 2015 and 2018 (P = .002). Significantly more HCV-NAT–yield cases were detected among first-time donors, non-Hispanic Whites, donors aged 20–29 years, equally likely to be males as females, with the highest frequency in the South (0.52/100 000 donations). Subgenotype 1a (49.6%) was most frequent, followed by 3a (18.7%), 2b (12.5%), 1b (8.5%), and 2a (1.7%). Conclusions Voluntary nonremunerated blood donors are at low risk for HCV infection. Since 2015, the frequency of HCV-NAT–yield cases decreased despite an increase in acute HCV infection in the general population. HCV subgenotypes 1a and 3a continue to remain predominant among US blood donors with recent HCV infection.

BACKGROUND Babesia is an intraerythrocytic parasite responsible for hundreds of cases of transfusion-transmitted babesiosis in the past 50 years. In May of 2020, blood testing for Babesia was implemented at the American Red Cross (ARC) for all donations in endemic areas of the northeastern and midwestern regions of the United States. METHODS Between May 2020 and May 2021, 1,816,669 donations from 13 states and DC were tested for Babesia by the ARC. Testing was performed in pools of 16 whole blood lysates using a licensed nucleic acid test (NAT) targeting Babesia 18S rRNA. Reactive donations were tested for B. microti antibody by immunoglobulin G immunofluorescence. Suspected cases of transfusion-transmitted babesiosis (TTB) were investigated if reported. RESULTS The first 13 months of Babesia screening identified 365 NAT-reactive donations. Antibodies for B. microti were detected in 79% (287) of reactive donations; negative serology samples were prevalent between May and July. Follow-up donations were collected from 142 donors, and 86% (122), collected up to 74 days after index, remained NAT reactive. Reactive donations were mainly collected in MA (77), CT (68), NY (49), NJ (47), and PA (44), but were identified in all states except Delaware. Most reactive blood donors were male (65%) aged between 40 and 80 years. Since the beginning of Babesia testing, no case of TTB was identified. CONCLUSIONS The absence of TTB cases since implementation of Babesia screening for blood donations collected in endemic areas suggests testing is an effective strategy to eliminate TTB.

Background Babesia microti, a red blood cell (RBC) parasite transmitted naturally to vertebrate hosts by ixodid ticks, is endemic to the northeastern and upper midwestern United States, with the geographic range of infected ticks expanding. B. microti is a blood safety issue with >200 transfusion-transmissions reported. Methods The American Red Cross's Hemovigilance program investigated hospital-reported transfusion-transmitted babesiosis (TTB) cases. Follow-up samples from involved donors were tested for B. microti antibodies and parasite DNA, the latter by real-time polymerase chain reaction (PCR). Test-positive donors were permanently deferred from future donations. Results B. microti-positive donors were implicated in 77 of 143 suspect TTB cases investigated from 2010 through 2017. In four cases, two positive donors were identified for a total of 81 positive donors. In three cases, a RBC unit was split and components transfused multiple times to the same pediatric recipient. RBCs were the transmitting product in all cases. At follow-up, all involved donors were antibody positive; 25 donors were also PCR positive. Positive donations were collected throughout the year, peaking in the summer. Most donors (78) were resident of, or traveled to (2), an endemic state. One donor resided in a non-endemic state without relevant travel history. One fatality listed babesia as a contributing factor. No implicated donation was screened by an investigational protocol. Conclusions Babesiosis remains a blood safety issue. Prior to FDA-licensed screening test availability and final FDA Guidance, blood collectors in endemic states investigationally tested none, a portion, or all collections. Future expanded testing will reduce the frequency of TTB cases.

From December 2020 to June 2021, 1654487 blood donors were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S1 protein, and 1028547 (62.17%) were reactive. A rapid increase in prevalence was due to vaccination. Among a subset of 1567446 donors, 729771 (46.56%) reported SARS-CoV-2 vaccination, of whom 633769 (86.84%) were S1-antibody reactive only in response to vaccination and 68269 (9.35%) were reactive to both S1 and nucleocapsid in response to prior infection; the remainder were not reactive to either antibody. Among the 837675 (53.44%) donors who did not report vaccination, 210022 (25.07%) had reactivity to both antibodies and 29446 (3.52%) to S1 only.

Background In December 2015, the men who have sex with men (MSM) deferral was reduced to 12 months in the United States. We compared human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) incidence and residual risk before and after this policy change using data from >50% of the US blood supply. Study design and methods Three estimation intervals from the Transfusion-Transmissible Infections Monitoring System were compared: 15-months pre- and two consecutive, nonoverlapping 15-month post-MSM deferral implementation. Repeat, first-time, and weighted all-donor incidences were estimated. Residual risk was calculated for all incidence estimates using the incidence/window-period method. Results HIV repeat donor incidence was 1.57 per 100 000 person-years (phtpy) in the second 15-month post change and not significantly different from pre-MSM incidence of 2.19 phtpy. Similar values were seen for HCV (1.49 phtpy vs 1.46 phtpy) and HBV (1.14 phtpy vs 0.97 phtpy). In some cases, higher estimated incidence, but without significant change from pre-MSM to the second post change period occurred for males and first-time donors (eg, first-time donors, second post change period: 6.12 phtpy HIV, 6.41 phtpy HCV and 5.34 phtpy HBV). Estimated per donation residual risk was 1:1.6 million for HIV, 1:2.0 million for HCV and 1:1.0 million for HBV based on weighted incidence for all donors. Conclusions Repeat, first-time, and overall donor incidence did not vary significantly comparing pre-MSM to either of the post-MSM estimation intervals. Residual risk estimates vary by study, but all yield residual risks in the United States of ≤1 per million, and thus far have not shown increasing risk with the 12-month MSM policy change.

Background Chinese blood centers use Hepatitis B surface antigen (HBsAg) rapid test (RT) in pre-donation and two rounds of screening with different enzyme-linked immunosorbent assays in post-donation. Nucleic acid testing (NAT) on screening non-reactive (SC-) donations has been gradually implemented since 2010. Yet RT+ and SC-/NAT+ donors are seldom included in hepatitis B virus (HBV) positive rate estimates in Chinese blood donors. Methods We performed HBsAg neutralization test (NT) on whole blood (WB) with pre-donation RT+ results and post-donation screening reactive (SC+) samples from Mianyang and Chongqing in 2015. The annual totals of pre- and post-donation NT+ donors were combined with the annual totals of SC-/NAT+ donors to derive the estimated HBV positive rates. Result In Mianyang and Chongqing, 59.4% and 68.2% of RT+ donors in Jan-Aug 2015 contributed for NT, 95.5% and 97.2% of which were NT+ respectively. In 2015, 422 and 667 donors from Mianyang and Chongqing respectively were HBsAg RT+, yielding estimated 403 and 648 pre-donation RT+/NT+ deferrals. 411 and 668 post-donation SC+ samples were NT tested from Mianyang and Chongqing, of which 249 and 323 were NT+ respectively. An estimated 63 donors in Mianyang and 88 donors in Chongqing were SC-/NAT+. The estimated HBV confirmed positive rate in blood donors are 1.59% in Mianyang and 1.01% in Chongqing. Conclusion Pre-donation HBsAg RT effectively intercepts donations from HBV infected donors. Using NT confirmatory results from RT+, SC+ and SC-/NAT+ donors, this study provides a model for more accurate estimation for HBV positive rates in China.

The Transfusion-Transmissible Infections Monitoring System (TTIMS) combines data from four US blood collection organizations including approximately 60% of all donations to monitor demographic and temporal trends in infectious disease markers and policy impacts.Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) consensus-positive definitions combined serology and nucleic acid testing results. These along with donor and donation characteristics were assembled into a single data set. Overall donation prevalence and demographic subsets were compared pre- and post-implementation of the 2015 change in men who have sex with men (MSM) deferral policy, among other prevalence comparisons.From October 2015 to September 2019, there were 712 HIV-, 1735 HBV-, and 5217 HCV-positive samples identified from approximately 27.5 million donations (9.4 million donors). Prevalences per 100 000 donations were 2.6 (HIV), 6.3 (HBV), and 19.0 (HCV), and the highest for all three agents were in donations from first-time male donors. Two slight but significant increases in HIV prevalence were observed, both for comparisons of Year 1 (pre-MSM policy change) versus Year 4 (post-MSM policy change) for first-time males and first-time females; in contrast, similar comparisons demonstrated decreases in HCV prevalence (all donors and general trends for males and females). Except for HIV, prevalence increased with age; for all agents, prevalence was markedly higher in the south.No major trends were observed over 4 years covering the MSM policy change from indefinite to a 12-month deferral, but ongoing monitoring is warranted. Demographic trends are consistent with those observed in other donor studies and community trends.

BACKGROUND US blood donors are tested for Trypanosoma cruzi antibodies only at their first presentation, based on studies, reviewed here, demonstrating the absence of incident infections. Reports of autochthonous human transmissions of the parasite in Texas have raised concern about the safety of one-time testing. METHODS Positive donation frequencies were evaluated among first-time blood donations from 2007 to 2015. Rates and their temporal changes were evaluated in an area of high T. cruzi infection and compared with rates elsewhere. Donors with positive results were surveyed for risk factors and relevant demographic characteristics. RESULTS Data from 9.1 million first-time donations were analyzed; 585 (1:15,544) were confirmed positive by radioimmunoprecipitation assay (RIPA) or concordantly positive with a second screening test/licensed assay. Seroprevalence in first-time donors in Southern California (an area of high endemicity) was 1:2,747, or 5.7-fold higher than the overall rate. Rates did not change over time nationally but showed a nonsignificant consistent downward trend in Southern California. The majority (92%) of donors who responded to a questionnaire had one or more T. cruzi endemic-area risk factors. Five donors with likely autochthonous infection were identified (2007-2013); nine additional donors had RIPA false positivity. CONCLUSION T. cruzi seroprevalence among donors nationally and in an area of high enzootic infection were stable or declining. Almost all interviewed seropositive donors had known risk factors indicating likely infection years earlier while residing in T. cruzi-endemic areas. In the United States, there was no evidence of increased T. cruzi prevalence among first-time donors.

Background Babesia microti, an intraerythrocytic parasite endemic in the Northeast and upper Midwest United States, is responsible for over 200 reported cases of transfusion-transmitted babesiosis (TTB). The American Red Cross has prospectively screened donations in endemic areas for B. microti since 2012. Methods Blood donation samples from Massachusetts, Connecticut, Minnesota, and Wisconsin were tested by arrayed fluorescence immunoassay and real-time polymerase chain reaction. Donors with reactive results by any test were deferred and invited to participate in a follow-up study. Results Screening of 506,540 donations (June 2012-May 2018) yielded 1299 reactives, 177 of which were DNA and antibody positive and 25 DNA positive only. During the same time, 23 unscreened RBC units collected in Connecticut and Massachusetts were involved in TTB cases, making the risk of transmitting the infection from an unscreened donation in these two states 15.6-times greater than from a Babesia-negative unit. B. microti screening in Connecticut and Massachusetts has been associated with a reduction in TTB cases; none reported from blood donors residing in Connecticut since 2016. The positive donor rate has also decreased in Connecticut from 0.67% in 2013 to 0.23% in 2017. Ongoing follow-up testing has shown that only 10% of antibody-positive donors serorevert within 1 year, while 94% of polymerase chain reacton-positive donors become negative within 12 months. Conclusions Blood donation screening for B. microti in endemic areas effectively mitigates TTB risk. Screening should be considered for all areas demonstrating ongoing risk defined as clinical cases or positive blood donors including those associated with TTB cases.

Background In the United States, blood donor testing for hepatitis B surface antigen (HBsAg) was initiated in the early 1970s. More recently, testing for antibody to hepatitis B core antigen (anti-HBc) and hepatitis B virus (HBV) DNA have been added. The incidence of hepatitis B has been declining. This study reviews the current status of testing and questions the need for continuation of HBsAg testing. Study design and methods From July 2011 to June 2015, a total of 22.4 million donations were serologically tested for HBsAg and anti-HBc and for HBV-DNA by nucleic acid testing (NAT). All reactive results were evaluated and a subset of donations that were either potential NAT yield (seronegative) or serologically positive but nonreactive by HBV NAT in minipools (MPs) of 16 were further evaluated by individual donation (ID)-NAT. Samples with detectable HBV DNA were defined as actively infected and considered potentially infectious. Results Routine testing plus supplemental ID-NAT identified 2035 samples representing active infection including 1965 with anti-HBc, 1602 with HBsAg, and 1453 with HBV DNA by MP-NAT, for respective rates per hundred-thousand donations of 9.10, 8.78, 7.16, and 6.50, continuing the downward trend previously observed. There were 29 HBV DNA-yield samples (1:771,389), 35 HBsAg-yield samples (anti-HBc nonreactive), and 404 with occult hepatitis B infection. There were six samples with HBsAg and HBV DNA detectable only by ID-NAT in the absence of anti-HBc; additional testing was consistent with extremely low or negligible levels of DNA. Conclusions Point estimates of HBV infection rates among blood donors continue to decline, as do those for incidence and residual risk. Elimination of HBsAg screening would have negligible impact, with a risk less than 1 per 4 million donations.

Because of the potential severe clinical consequences of Zika virus (ZIKV) infection, the large numbers of asymptomatic travelers returning from ZIKV-active areas, the detection of ZIKV nucleic acid in blood, and reports of transmission of ZIKV through transfusion, in 2016 the Food and Drug Administration released recommendations for individual-unit nucleic acid testing to minimize the risk of transmission of ZIKV through blood transfusions.The American Red Cross implemented investigational screening of donated blood for ZIKV RNA by means of transcription-mediated amplification (TMA). Confirmatory testing of reactive donations involved repeat TMA, TMA testing in exploratory minipools, real-time reverse-transcriptase polymerase chain reaction, IgM serologic testing, and red-cell TMA. Viral loads in plasma and red cells were estimated by means of end-point TMA. The costs of interdicting a donation that was confirmed to be positive were calculated for the 15-month period between June 2016 and September 2017.Of the 4,325,889 donations that were screened, 393,713 (9%) were initially tested in 24,611 minipools, and no reactive donations were found. Of the 3,932,176 donations that were subsequently tested individually, 160 were initially reactive and 9 were confirmed positive (a 1:480,654 confirmed-positive rate overall; positive predictive value, 5.6%; specificity, 99.997%). Six (67%) of the confirmed-positive donations were reactive on repeat TMA, of which 4 were IgM-negative; of these 4, all 3 that could be tested were reactive on minipool TMA. Two confirmed-positive donors had infections that had been transmitted locally (in Florida), 6 had traveled to ZIKV-active areas, and 1 had received an experimental ZIKV vaccine. ZIKV RNA levels in red cells ranged from 40 to 800,000 copies per milliliter and were detected up to 154 days after donation, as compared with 80 days of detection in plasma at levels of 12 to 20,000 copies per milliliter. On the basis of industry-reported costs of testing and the yield of the tests in our study, the cost of identifying 8 mosquito-borne ZIKV infections through individual-unit nucleic acid testing was $5.3 million per ZIKV RNA-positive donation.Screening of U.S. blood donations for ZIKV by individual-donation TMA was costly and had a low yield. Among the 9 confirmed ZIKV-positive donations, only 4 were IgM-negative; of these donations, all 3 that were tested were reactive on minipool TMA. (Funded by the American Red Cross and Grifols Diagnostic Solutions.).

BACKGROUND Blood donation screening detecting only antibodies fails to identify donors in the earliest stage of infection, before a detectable immunologic response, that is, the “window period” (WP). We present data on WP donations identified during prospective screening for Babesia microti, a transfusion-transmissible parasite of increasing concern in the United States. STUDY DESIGN AND METHODS Blood donations collected in Connecticut, Massachusetts, Minnesota, and Wisconsin were screened using polymerase chain reaction (PCR) and arrayed fluorescence immunoassay (AFIA) to detect B. microti DNA and antibodies, respectively. Parasite loads were estimated using quantitative PCR. Red blood cell (RBC) samples were inoculated into hamsters to assess infectivity. Donors screening reactive were indefinitely deferred, tested by supplemental methods, and followed to assess DNA and antibody clearance. Demographic data from WP donors (i.e., those screening PCR positive and AFIA negative) were compared to data from other positive donors. RESULTS Of 220,479 donations screened from June 2012 to August 2016, a total of 700 were positive, of which 15 (2% of positive donations or 1 per 14,699 screened donations) were confirmed WP donations. The median estimated parasite load in WP donations was 350 parasites/mL, no different than AFIA-positive and PCR-positive donors. Parasite loads in RBC samples from WP units ranged from 14 to 11,022 parasites/mL; RBC samples from three of 10 (30%) WP donations infected hamsters. The mean age of WP donors was 48 years (range, 17-75 years); three (20%) were female. WP donor demographics did not differ significantly from demographics of other donors. CONCLUSIONS We report one per 15,000 B. microti WP infections in blood donors in endemic areas, demonstrating the importance of nucleic acid testing to mitigate the risk of transfusion-transmitted babesiosis.

BACKGROUND Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States. STUDY DESIGN AND METHODS Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD. RESULTS To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized. CONCLUSION From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical.

Prevalence, incidence and residual risk of HIV, HCV and HBV are critical indicators of the safety of the blood supply. The American Red Cross routinely monitors these markers. Herein the results of testing over 58 million donations from 2007 to 2016 are reported. The prevalence and incidence of these infections has declined or remained essentially stable over the 7.5 to 10-year period. In 2015 to 2016, the prevalence of HIV, HCV and HBV were respectively: 1.65, 11.47 and 5.85 per hundred thousand (pht) donations with a significant decrease over the 10-year study only for HCV. Weighted incidence rates for all positives were 1.98 pht person years (py) for HIV, 2.20 pht py for HCV and 1.25 pht py for HBV. Estimates of residual risk using these incidence rates were: HIV, 1:2.3 million; HCV, 1:2.6 million; and HBV, 1:1.5 million donations, reflecting very low risk to recipients. There have been increases in the safety of the blood supply compared to prior published estimates. Demographic factors were shown to be associated with variations in infection prevalence and incidence. Continuing changes in the structure of the donor population or changes in policy could impact these measures of safety.

Background Risk assessments of transfusion‐transmitted emerging infectious diseases (EIDs) are complicated by the fact that blood donorsʼ demographics and behaviors can be different from the general population. Therefore, when assessing potential blood donor exposure to EIDs, the use of general population characteristics, such as U.S. travel statistics, may invoke uncertainties that result in inaccurate estimates of blood donor exposure. This may, in turn, lead to the creation of donor deferral policies that do not match actual risk. Study Design and Methods This article reports on the development of a system to rapidly assess EID risks for a nationally representative portion of the U.S. blood donor population. To assess the effectiveness of this system, a test survey was developed and deployed to a statistically representative sample frame of blood donors from five blood collecting organizations. Donors were directed to an online survey to ascertain their recent travel and potential exposure to Middle East respiratory syndrome coronavirus (MERS‐CoV). Results A total of 7128 responses were received from 54 256 invitations. The age‐adjusted estimated total number of blood donors potentially exposed to MERS‐CoV was approximately 15 640 blood donors compared to a lower U.S. general population‐based estimate of 9610 blood donors. Conclusion The structured donor demographic sample–based data provided an assessment of blood donorsʼ potential exposure to an emerging pathogen that was 63% larger than the U.S. population–based estimate. This illustrates the need for tailored blood donor–based EID risk assessments that provide more specific demographic risk intelligence and can inform appropriate regulatory decision making.

Background Rare transfusion-transmitted West Nile virus (WNV) cases usually occur due to gaps in testing involving converting to more sensitive nucleic acid testing (NAT) formats (referred to as triggering). Using data from 2014 to 2018, we investigated a strategy used to increase detection early in the triggering period and reviewed its yield as the individual donation (ID)-NAT geographic area was decreased. Methods Mini-pool-NAT transitioned to ID-NAT following triggering based on one WNV NAT-reactive donation (having an elevated signal, repeat reactive, or in an area with WNV ongoing activity). ID-NAT-triggered geographic areas included an entire state (2014-2017) or collections within a 50-mile radius of the triggering donor's residential zip code (2018). During the MP- to ID-NAT transition, donation samples were retrieved and tested by ID-NAT for those with results not yet released (referred to as in-process testing). Reactive sample confirmation was performed by repeat NAT of an independent sample or antibody testing. Results ID-NAT included 3.2 million donations of more than 25 million tested year-round, resulting in 684 confirmed positives; all confirmed-positive donations occurred from June to December (0.64/10,000). Overall, 52% (358/684) required ID-NAT for detection, including 68 (19%) antibody negatives. Ten of 19 (53%) identified in-process were ID-NAT-only detectable, including four antibody negatives, or approximately 1 per year (2.8% of ID-NAT-only detectable). With reduced triggering geography, 12 of 19 (63%) were not identified (including 6/10 ID-NAT-only detectable, and 2/4 ID-NAT-only detectable/antibody negative). Conclusion WNV NAT's utility is between June-December; however, abandoning testing outside of this time may increase risk. While in-process testing identified approximately one ID-NAT-only detectable (antibody-negative) donation per year, reducing the geographic triggered area decreased its effectiveness.

BACKGROUND Transfusion-transmitted West Nile virus (WNV) infection is infrequent as a result of minipool (MP) and individual-donation (ID) nucleic acid testing (NAT) of blood donations. ID-NAT is triggered on the basis of local WNV activity identified by MP-NAT. STUDY DESIGN AND METHODS A 78-year-old male patient who was treated for cardiac disease received 14 blood components from 30 donors in August 2016. He was discharged 7 days after aortic valve replacement and coronary bypass surgery, but was re-admitted on Day 12 with symptoms of viral infection, and eventually was diagnosed with aseptic meningitis. The patent died on Day 51. RESULTS The patient was positive for WNV-immunoglobulin M (IgM) antibodies in his cerebrospinal fluid on Day 14 and was positive for WNV-IgM (on Days 14 and 16) and WNV-IgG antibodies (on Day 16) in his serum. All associated donations were nonreactive by MP-NAT or ID-NAT. However, one MP-NAT was noted to have an elevated (but negative) signal-to-cutoff ratio, and one donor from that MP was subsequently found positive for WNV-IgM and IgG antibodies; the donor was diagnosed with a WNV-like viral syndrome that had an onset 3 to 5 days postdonation. The donor's plasma was transfused 12 days before the patient's onset of WNV-meningoencephalitis. Conversion to ID-NAT was triggered for the region 7 days after the implicated donation, which was associated with the region's first human WNV case. CONCLUSION Despite the possibility of mosquito-borne transmission, this was considered to be a case of transfusion-transmitted WNV infection from an MP-NAT–nonreactive donation collected just before triggering conversion to ID-NAT; a rare event recognized once in 84 million donations.

BACKGROUND The incidence of human immunodeficiency virus (HIV) in repeat blood donors has been estimated using seven methods. Although incidence is always calculated as cases per person-time, approaches to selecting cases and calculating person-time vary. Incidence estimates have not been compared among methods. STUDY DESIGN AND METHODS The seven methods were compared in a simulation study. Because three methods used information from donations made before an estimation interval, 8 years of donation and infection history were simulated, and Years 7 and 8 were treated as the estimation interval for all methods. An exponential random variate was assigned to each donor to simulate the time to infection. Infection risk was constant over 8 years in one scenario but increased at various rates in seven other scenarios. The infection risk scenarios were combined with four mixes of donation frequency to generate 32 test conditions. RESULTS Three methods produced biased estimates under all conditions. Three other methods were biased under most conditions. Bias from most methods increased as donation frequency declined. The single method that consistently produced unbiased estimates was the only method that involved the standard epidemiological approach of tabulating all interdonation intervals (IDIs) within the estimation interval. Bias was eliminated from one of the consistently biased methods by a simple modification that involved the average IDI in a sample of donors. CONCLUSION The standard epidemiological approach is recommended if required data are available. Otherwise, the modified method involving the estimated average IDI should be considered. Investigators should use caution when comparing incidence estimates among studies that use different estimation methods or donation frequencies.

BACKGROUND The frequency of positive test results for transfusion-transmitted infections (TTIs) among blood donors is an important index of safety; thus, appropriate monitoring is critical, particularly when there are changes in policies affecting donor suitability. STUDY DESIGN AND METHODS Testing algorithms from three large blood systems were reviewed and consensus definitions for a surveillance-positive result for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human T-cell lymphotropic virus (HTLV) established. In addition, information on each donation, including donor demographics and location, was collected. Combined data were analyzed to characterize the epidemiology of TTIs by person, place, and time. RESULTS Data from 14.8 million donations were collected for 2011 to 2012, representing more than 50% of the US blood supply. Surveillance-positive rates per 10,000 donations were as follows: HBV, 0.76; HCV, 2.0; HIV, 0.28; and HTLV 0.34. Rates did not vary between the 2 years, although there was variation within a year. With the exception of HTLV, rates were higher among males, and all rates were higher among first-time donations. Window-period donations (those positive only in nucleic acid tests) were infrequent (HBV, 13; HCV, 60; HIV, 14) during the 2-year period. Frequencies of surveillance-positive results varied by donor age and residence location. CONCLUSIONS We demonstrated that standardized data from multiple major US blood systems can be combined and analyzed for change. However, TTI frequencies are low, impacting their sensitivity to change. Furthermore, observed fluctuations in TTI frequencies may be secondary to changes in blood donor demographics rather than necessarily reflecting the immediate impact of policy modification.

Blood has been shown to contain disease-associated misfolded prion protein (PrP(TSE)) in animals naturally and experimentally infected with various transmissible spongiform encephalopathy (TSE) agents, and in humans infected with variant Creutzfeldt-Jakob disease (vCJD). Recently, we have demonstrated PrP(TSE) in extracellular vesicle preparations (EVs) containing exosomes from plasma of mice infected with mouse-adapted vCJD by Protein Misfolding Cyclic Amplification (PMCA). Here we report the detection of PrP(TSE) by PMCA in EVs from plasma of mice infected with Fukuoka-1 (FU), an isolate from a Gerstmann-Sträussler-Scheinker disease patient. We used Tga20 transgenic mice that over-express mouse cellular prion protein, to assay by intracranial injections the level of infectivity in a FU-infected brain homogenate from wild-type mice (FU-BH), and in blood cellular components (BCC), consisting of red blood cells, white blood cells and platelets, plasma EVs, and plasma EVs subjected to multiple rounds of PMCA. Only FU-BH and plasma EVs from FU-infected mice subjected to PMCA that contained PrP(TSE) transmitted disease to Tga20 mice. Plasma EVs not subjected to PMCA and BCC from FU-infected mice failed to transmit disease. These findings confirm the high sensitivity of PMCA for PrP(TSE) detection in plasma EVs and the efficiency of this in vitro method to produce highly infectious prions. The results of our study encourage further research to define the role of EVs and, more specifically exosomes, as blood-borne carriers of PrP(TSE).

BACKGROUND Differences in motivating factors that contribute to the decision to donate blood between infected and uninfected donors may help to identify areas for improving donor education. STUDY DESIGN AND METHODS As part of a risk factor study, confirmed-positive donors (cases) based on serology-only (human T-lymphotropic virus [HTLV]) or serology and nucleic acid testing (NAT) or NAT-only (human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV]), and serology-unconfirmed, NAT-negative false-positive donors (controls) were asked about motivations and opinions toward blood donation. “Test seeking” was inferred if a donor answered “yes” to “I wanted to get my test results” and one of the following: “blood center testing is confidential,” “free,” “more accurate than other test centers,” or “tests will identify problems with my blood.” Cases were compared to controls using descriptive and multivariable analyses. RESULTS Whether a case or control, the most common donation reason was “to help someone in need” (>90% in each group). After adjusting for demographic characteristics, test seeking was not significantly associated with infection status. Test seeking was more common in first-time, younger males and nonwhite, non-Hispanic donors. Of donors with HIV, 13% considered selection policies to be unfair, compared with 1, 2, 0.5, and 6% of donors with HBV, HCV, and HTLV and controls, respectively (adjusted odds ratio for HIV cases vs. controls, 3.9; 95% confidence interval, 2.3-6.7). CONCLUSIONS Most donors give to help those in need, including HIV-positive donors. Our results establish a baseline from which additional studies can be compared focused on alternate ways to reduce noncompliance and improved messaging to ensure that high-risk potential donors understand the reasons for blood donor screening policies.

Background Human T-lymphotropic virus (HTLV) blood donation screening has used a dual-testing algorithm beginning with either a chemiluminescent immunoassay or enzyme-linked immunosorbent screening assay (ELISA). Before the availability of a licensed HTLV supplemental assay, repeat-reactive (RR) samples on a first assay (Assay 1) were retested with a second screening assay (Assay 2). Donors with RR results by Assay 2 were deferred from blood donation and further tested using an unlicensed supplemental test to confirm reactivity while nonreactive (NR) donors remained eligible for donation until RR on a subsequent donation. This "dual-test" algorithm was replaced in May 2016 with the requirement that all RRs by Assay 1 be further tested by a licensed HTLV supplemental test (Western blot [WB]). In this study, we have requalified the dual-test algorithm using the available licensed HTLV WB. Study design and methods We tested 100 randomly selected HTLV RRs on screening Assay 1 (Abbott PRISM chemiluminescent immunoassay) but NR on screening Assay 2 (Avioq ELISA) by a Food and Drug Administration-licensed WB (MP Biomedicals) to ensure that no confirmed positives were among those that were RR by Assay 1 but NR by Assay 2. Results Of the 100 samples evaluated, 79 of 100 were WB seronegative, 21 of 100 indeterminate, and 0 of 100 seropositive. Of the 79 of 100 seronegative specimens, 73 of 79 did not express any bands on WB. Conclusions We demonstrated that none of the 100 samples RR on Assay 1 but NR on Assay 2 were confirmed positive. This algorithm prevents such donors from requiring further testing and from being deferred.

BACKGROUND: Characteristics of US blood donors with recent (RBI) or occult (OBI) hepatitis B virus (HBV) infection are not well defined. METHODS: Donors with RBI and OBI were identified by nucleic acid and serologic testing among 34.4 million donations during 2009–2015. Consenting donors were interviewed and their HBV S-gene sequenced. RESULTS: The overall rate of HBV-infected donors was 7.95 per 100,000; of these, 0.35 per 100,000 and 1.70 per 100,000 were RBI and OBI, respectively. RBI (n = 120) and OBI (n = 583) donors constituted 26% of all HBV-infected (n = 2735) donors. Detection of HBV DNA in 92% of OBI donors required individual donation nucleic acid testing. Donors with OBI compared to RBI were older (mean age, 48 vs 39 years; p < 0.0001) with lower median viral loads (9 vs. 529 IU/mL; p < 0.0001). A higher proportion of OBI than RBI donors were born or resided in an endemic country (39% vs. 5%; p= 0.0078). Seventy-seven percent of all RBI and OBI donors had multiple sex partners, an HBV-riskfactor. Of 40 RBI and 10 OBI donors whose S gene was sequenced, 33 (83%) and 6 (60%), respectively, carried HBV subgenotype A2; 18 (55%) and 2 (33%), respectively, shared an identical sequence. Infection with 1 or more putative HBV-immune-escape mutants was identified in 5 (50%) of OBI but no RBI donors. CONCLUSION: RBI and OBI continue to be identified at low rates, confirming the importance of comprehensive HBV DNA screening of US blood donations. HBV-infected donors require referral for care and evaluation and contact tracing; their HBV strains may provide important information on emergent genotypes.

West Nile virus appeared in the Americas for the first time in 1999 and spread rapidly in the following years. Although an acute infection, it was found to be transfusion-transmissible in 2002, and donor testing for WNV RNA was initiated throughout the United States by the summer of 2003. Testing in minipools was not adequately sensitive, and mechanisms were developed for rapid implementation of individual donation testing in times and areas of high incidence of human infection. Overall, the response has been very effective and may offer lessons for managing future outbreaks of acute, transfusion-transmissible infections.

The transmission of infectious disease by blood transfusion has been a major problem since the middle of the twentieth century. Since about 1960, there has been a concerted and prolonged effort to reduce or eliminate this outcome; the efforts have been successful, but new challenges continue to appear, mostly in the form of emerging infectious diseases. This chapter reviews two relevant issues: the possibility of predicting microbial threats to blood safety and the interventions that may be used to reduce the risks of transfusion transmission. While there are only limited opportunities to predict relevant infections, there are effective measures to enhance blood safety. These involve appropriate selection of donors, implementation of effective tests, and development and implementation of pathogen reduction.

US blood donors are tested for Trypanosoma cruzi antibodies only at their first presentation, based on studies, reviewed here, demonstrating the absence of incident infections. Reports of autochthonous human transmissions of the parasite in Texas have raised concern about the safety of one-time testing.Positive donation frequencies were evaluated among first-time blood donations from 2007 to 2015. Rates and their temporal changes were evaluated in an area of high T. cruzi infection and compared with rates elsewhere. Donors with positive results were surveyed for risk factors and relevant demographic characteristics.Data from 9.1 million first-time donations were analyzed; 585 (1:15,544) were confirmed positive by radioimmunoprecipitation assay (RIPA) or concordantly positive with a second screening test/licensed assay. Seroprevalence in first-time donors in Southern California (an area of high endemicity) was 1:2,747, or 5.7-fold higher than the overall rate. Rates did not change over time nationally but showed a nonsignificant consistent downward trend in Southern California. The majority (92%) of donors who responded to a questionnaire had one or more T. cruzi endemic-area risk factors. Five donors with likely autochthonous infection were identified (2007-2013); nine additional donors had RIPA false positivity.T. cruzi seroprevalence among donors nationally and in an area of high enzootic infection were stable or declining. Almost all interviewed seropositive donors had known risk factors indicating likely infection years earlier while residing in T. cruzi-endemic areas. In the United States, there was no evidence of increased T. cruzi prevalence among first-time donors.

Transmissible spongiform encephalopathies (TSEs) are untreatable, fatal neurologic diseases affecting mammals. Human disease forms include sporadic, familial and acquired Creutzfeldt-Jakob disease (CJD). While sporadic CJD (sCJD) has been recognized for near on 100 years, variant CJD (vCJD) was first reported in 1996 and is the result of food-borne transmission of the prion of bovine spongiform encephalopathy (BSE, ‘mad cow disease’). Currently, 230 vCJD cases have been reported in 12 countries, the majority in the UK (178) and France (27). Animal studies demonstrated highly efficient transmission of natural scrapie and experimental BSE by blood transfusion and fuelled concern that sCJD was potentially transfusion transmissible. No such case has been recorded and case–control evaluations and lookback studies indicate that, if transfusion transmission occurs at all, it is very rare. In contrast, four cases of apparent transfusion transmission of vCJD infectivity have been identified in the UK. Risk minimization strategies in response to the threat of vCJD include leucodepletion, geographically based donor deferrals and deferral of transfusion recipients. A sensitive and specific, high-throughput screening test would provide a potential path to mitigation but despite substantial effort no such test has yet appeared. The initial outbreak of vCJD appears to be over, but concern remains about subsequent waves of disease among those already infected. There is considerable uncertainty about the size of the infected population, and there will be at least a perception of some continuing risk to blood safety. Accordingly, at least some precautionary measures will remain in place and continued surveillance is necessary.

BACKGROUND Hepatitis E virus (HEV) is a nonenveloped emerging virus of increasing worldwide interest. Antibody prevalence, RNA frequencies, and transfusion transmissions have been reported. We investigated the HEV RNA and antibody frequencies in US blood donors. STUDY DESIGN AND METHODS Individual-donation HEV RNA testing was performed on 18,829 donations from six US geographic regions using a CE-marked nucleic acid test (95% limit of detection, 7.9 IU/mL). Repeat-reactive donations were confirmed by in-house, real-time polymerase chain reaction (PCR; 10.3 IU/mL). Total HEV seroprevalence in a randomly selected subset of donations (n = 4499) was assessed by a direct, double-antigen sandwich assay; reactives were further tested for immunoglobulin (Ig)G and IgM. As part of the total antibody confirmatory algorithm, the cutoff was adjusted. RESULTS Two donations tested confirmed-positive for RNA (PCR not quantifiable, IgM/IgG positive; and 14 IU/mL, antibody negative) for a frequency of 1 in 9500 (95% confidence interval [CI], 1:2850-1:56,180) and 99.96% specificity (95% CI, 99.92%-99.98%); both donors were from the Midwest United States. Antibody prevalence was 9.5% (95% CI, 8.7-10.5) before the cutoff adjustment and 7.7% (95% CI, 7.0%-8.5%) after adjustment; 0.58% (95% CI, 0.39%-0.85%) were IgM positive. CONCLUSIONS We confirmed comparatively low rates and low viral loads of HEV RNA in US blood donors indicating the need for individual-donation testing if screening is implemented. Antibody prevalence rates were comparable to those reported by one US study using a different assay, but lower than those reported in another study using yet a third assay. We did not answer the question of whether US blood donation screening is warranted. Selective strategies involving providing HEV-negative blood to severely immunosuppressed patients at risk of developing hepatitis may be considered.