Strategies for testing blood donors for West Nile virus.
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Blood Donors↗
Biomedical subjects
Michael P Busch
Publications and source records attributed to Michael P Busch.
Immunoglobulin G avidity in differentiation between early and late antibody responses to West Nile virus.
In 1999 West Nile virus (WNV) surfaced in the United States in the city of New York and spread over successive summers to most of the continental United States, Canada, and Mexico. Because WNV immunoglobulin M (IgM) antibodies have been shown to persist for up to 1 year, residents in areas of endemicity can have persistent WNV IgM antibodies that are unrelated to a current illness with which they present. We present data on the use of IgG avidity testing for the resolution of conflicting data arising from the testing of serum or plasma for antibodies to WNV. Thirteen seroconversion panels, each consisting of a minimum of four samples, were used. All samples were tested for the presence of WNV IgM and IgG antibodies, and the avidity index for the WNV IgG-positive samples was calculated. Panels that exhibited a rise in the WNV IgM level followed by a sequential rise in the WNV IgG level were designated "primary." Panels that exhibited a marked rise in the WNV IgG level followed by a sequential weak WNV IgM response and that had serological evidence of a prior flavivirus infection were designated "secondary." All samples from the "primary" panels exhibited low avidity indices (less than 40%) for the first 20 to 30 days after the recovery of the index sample (the sample found to be virus positive). All of the "secondary" samples had elevated WNV IgG levels with avidity indices of > or =55%, regardless of the number of days since the recovery of the index sample. These data demonstrate that it is possible to differentiate between recent and past exposure to WNV or another flavivirus through the measurement of WNV IgG avidity indices.
Antibodies, Viral↗
Tracking microchimeric DNA in plasma to diagnose and manage organ transplant rejection.
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Biomarkers↗
West Nile virus infections projected from blood donor screening data, United States, 2003.
National blood donor screening for West Nile virus (WNV) RNA using minipool nucleic acid amplification testing (MP-NAT) was implemented in the United States in July 2003. We compiled national NAT yield data and performed WNV immunoglobulin M (IgM) testing in 1 WNV-epidemic region (North Dakota). State-specific MP-NAT yield, antibody seroprevalence, and the average time RNA is detectable by MP-NAT were used to estimate incident infections in 2003. WNV donor screening yielded 944 confirmed viremic donors. MP-NAT yield peaked in August with >0.5% of donations positive for WNV RNA in 4 states. Peak IgM seroprevalence for North Dakota was 5.2% in late September. The average time viremia is detectable by MP-NAT was 6.9 days (95% confidence interval [CI] 3.0-10.7). An estimated 735,000 (95% CI 322,000-1,147,000) infections occurred in 2003, with 256 (95% CI 112-401) infections per neuroinvasive case. In addition to preventing transfusion-transmitted WNV infection, donor screening can serve as a tool to monitor seasonal incidence in the general population.
Blood Donors↗
Seroconversion following nonoccupational postexposure prophylaxis against HIV.
BACKGROUND: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. CONCLUSIONS: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.
Anti-HIV Agents↗
The cost-effectiveness of screening the U.S. blood supply for West Nile virus.
BACKGROUND: The spread of West Nile virus across North America and evidence of transmission by transfusion prompted the U.S. Food and Drug Administration to encourage the development of methods to screen the blood supply. OBJECTIVE: To assess the cost-effectiveness of nucleic acid amplification testing for West Nile virus in the U.S. blood supply. DESIGN: Markov cohort simulation. DATA SOURCES: Outcome probabilities estimated from nucleic acid testing done for West Nile virus in 2003, data from the Centers for Disease Control and Prevention, and published literature. Costs were taken from an economic study of West Nile virus infection and from estimated test costs. TARGET POPULATIONS: Transfusion recipients, 60 years of age or older, with and without underlying immunocompromise. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: The authors compared 6 strategies, taking into consideration minipool (pools of 6 to 16 donations) versus individual donation testing, and the geographic and seasonal nature of West Nile virus activity. OUTCOME MEASURES: Costs and effects of each strategy based on the prevention of transfusion-transmitted West Nile virus. RESULTS OF BASE-CASE ANALYSIS: The cost-effectiveness of annual, national minipool testing was 483,000 dollars per quality-adjusted life-year (QALY), whereas the cost-effectiveness of annual, national individual donation testing was 897,000 dollars/QALY. The cost-effectiveness of targeted individual donation testing in an area experiencing an outbreak coupled with minipool testing elsewhere was 520,000 dollars/QALY. RESULTS OF SENSITIVITY ANALYSIS: In 1-way analyses, the most important influences were the prevalence of West Nile virus and the cost of minipool testing and individual donation testing. The 95% range of results from probabilistic sensitivity analysis for targeted individual donation testing was 256,000 dollars to 1,044,000 dollars/QALY. LIMITATIONS: The outcomes of West Nile virus infection were based on data from the general population rather than from the population who received transfusions. The results are most useful in the context of geographically focused outbreaks of West Nile virus infection. CONCLUSIONS: Using targeted individual donation testing to interdict blood donations that are positive for the West Nile virus is relatively cost-effective but is highly dependent on West Nile virus prevalence.
Blood Transfusion↗
Nucleic acid amplification testing for diagnosis of acute HIV infection: has the time come?
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Acute Disease↗
Screening the blood supply for West Nile virus RNA by nucleic acid amplification testing.
BACKGROUND: The use of nucleic acid amplification tests of "minipools" of 16 samples to screen blood donors for West Nile virus RNA began in July 2003. We report the yield and characteristics of positive donations and the incremental yield and safety of nucleic acid amplification tests of individual donations. METHODS: Reactive minipools were analyzed to identify the individual reactive donations. For the regions with the highest yield on minipool testing, retrospective nucleic acid amplification testing was performed on individual donations that were negative on minipool testing. Reactive donations were confirmed by alternative nucleic acid amplification tests and IgM and IgG tests, and donors were followed to document seroconversion. RESULTS: From July 1 through October 31, 2003, 677,603 donations were prospectively screened for West Nile virus by minipool testing, yielding 183 confirmed viremic donations (0.027 percent, or 1 in 3703 donations). Retrospective individual testing of 23,088 donations from high-prevalence regions that were negative on minipool testing yielded 30 additional units with a low level of viremia, with 14 additional viremic units detected by prospective testing of individual donations late in the 2003 transmission season. Of all the viremic units detected, 5 percent were detected only by individual testing and were negative for IgM antibody, 29 percent were detected by individual testing after IgM seroconversion, and 66 percent were detected by minipool testing. West Nile virus infection was confirmed in both recipients of IgM-negative units that were reactive on individual testing, whereas neither recipient of antibody-positive blood components that were reactive on individual testing was infected. In 2004, prospective testing of individual donations in regions that yielded donations that were reactive on minipool testing resulted in a 32 percent incremental yield of units with a low level of viremia that would have been missed by minipool testing. CONCLUSIONS: Although nucleic acid amplification testing of minipools of blood donations prevented hundreds of cases of West Nile virus infection in 2003, it failed to detect units with a low level of viremia, some of which were antibody-negative and infectious. These data support the use of targeted nucleic acid amplification testing of individual donations in high-prevalence regions, a strategy that was implemented successfully in 2004.
Antibodies, Viral↗
Hepatitis C virus infection among prisoners in the California state correctional system.
BACKGROUND: Incarcerated populations are at high risk for hepatitis C virus (HCV) infection, yet prisoners are not routinely screened or treated for HCV infection. Understanding the risk factors of HCV infection among prisoners could help improve HCV interventions. METHODS: Prevalence and risk of HCV infection among 469 prisoners entering California State correctional facilities were assessed using HCV antibody screening, HCV RNA measurement, and structured interviews. Multivariate logistic regression analysis was used to identify independent correlates of HCV infection. RESULTS: The prevalence of HCV infection was 34.3% overall (95% confidence interval [CI], 30%-38%) and was 65.7% among those with a history of injection drug use (IDU), compared with 10.2% among those with no history of IDU (odds ratio [OR], 17.24; 95% CI, 10.52-28.25). Significant differences in HCV antibody positivity were found in association with age at first detention but not with the nature of the crime. Independent correlates of HCV infection included age, history of IDU, cumulative time of incarceration, biological sex (OR for females subjects compared with males subjects, 0.35; 95% CI, 0.13-0.96), and a history of having sex with a male IDU (OR, 4.42; 95% CI, 1.46-13.37). We identified significant differences in risk factors between male and female subjects--notably, that the risk of HCV infection was significantly elevated among female non-IDUs who reported having sexual partners with a history of IDU. Among non-IDUs, correlates of HCV infection included history of receipt of blood products and cumulative years of incarceration. CONCLUSIONS: HCV infection is pervasive among the California prison population, including prisoners who are non-IDUs and women with high-risk sexual behavior. These results should promote consideration of routine HCV antibody screening and behavioral interventions among incarcerated men and women.
Adult↗
Intermittent low-level viremia in very early primary HIV-1 infection.
Serial samples from source plasma donors with confirmed new HIV infection were investigated for low-level viremia (LLV) (ie, < 100 genome copies [cp]/mL) at time points preceding the period of steadily rising viremia above 100 cp/mL (ramp-up viremia). Fifteen of 44 plasma donor panels previously studied for the dynamics of HIV viremia during primary infection contained 70 samples with undetectable HIV-1 RNA by quantitative polymerase chain reaction (PCR). On retesting with a sensitive qualitative reverse transcriptase PCR assay (95% detection at 4 cp/mL), we identified LLV in 13 of 15 panels and 23 of 69 retested samples. In 6 panels, a total of 11 samples (1-3 per panel) were consistent with LLV before ramp-up viremia. These samples preceded the first sample with >100 cp/mL HIV by 9 to 25 days (median = 18 days) and were separated from the latter by at least 1 sample with undetectable viremia by the qualitative PCR assay. We conclude that LLV is not uncommon during the very early period of primary HIV infection preceding ramp-up viremia. It is not known if blood is infectious during this period; however, given the low viral concentrations and transient nature of the observed viremic "blips," the risk of infectivity can be assumed to be small.
Blood Donors↗
Acute-phase hepatitis C virus infection: implications for research, diagnosis, and treatment.
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Acute Disease↗
Viral and host factors in early hepatitis C virus infection.
Since 1980, the Transfusion-transmitted Viruses Study (TTVS) (1974-1980) has continued to maintain its computerized database and stored sera to enable ongoing study of new transfusion events since the 1970s. Most recently, we have used this resource to study parameters of acute hepatitis C virus (HCV) infection among 94 donor-recipient pairs in which there was transmission. In addition, frequent recipient observations permitted further characterization of the early phase of the infection's course. Donor RNA load ranged from 3.7 to 3,160,000 IU/mL. Onset of recipient viremia was judged from a total of 67 sera collected during the 4th through 8th days posttransfusion; only 2 of the 67 sera were still RNA nonreactive by that time. The recipients' latent periods to an alanine aminotransferase (ALT) elevation of > or =90 IU/L ranged from 6 to 112 days (median, 46 days) and was shorter with higher donor RNA levels. Descriptors of the recipient's illness showed several strongly positive and negative correlations. The latent period tended to be shorter in the 37% of cases that were clinically overt. Attributes of donors with genotypes 1 and non-1 and subtypes 1a and 1b did not differ significantly. Recipients with genotype 1 strains had shorter latent intervals than non-1 strains. On multivariate analysis, latent period was significantly associated (negatively) only with the highest ALT level during the first 120 days of follow-up (P = .014). In conclusion, host factors are more important determinants of acute HCV infection dynamics than virus-associated factors.
Adult↗
HIV-1 superinfection is not a common event.
Evidence for human immunodeficiency virus type 1 (HIV-1) superinfection was investigated among a group of four previously HIV-1 infected transfusion recipients (and the four implicated HIV-1 infected donors) identified by the Transfusion Safety Study, and two groups of 4 and 5 Brazilian injection drug users, who consistently injected themselves using shared paraphernalia. To probe these cases for possible superinfection we used heteroduplex mobility analysis (HMA) of HIV-1 tat, a technique which is a reliable for establishing epidemiologic linkages and searching for minor strains in mixed infection settings. In all these cases with established, untreated HIV-1 infections, we were unable to detect HIV-1 superinfection, even though the involved individuals were at high risk for second strain acquisition. We therefore conclude that although superinfection can occur in a few cases, it is a rare event, and the vast majority of recombinant HIV-1s characterized to date resulted from acute coinfections, rather than superinfection.
Brazil↗
Potential herpesvirus interaction during HIV type 1 primary infection.
One hundred twenty-three subjects with documented HIV-1 primary infection were followed for over a year; 96 received highly active antiretroviral therapy (HAART) at recruitment; 27 declined treatment. Fifty uninfected subjects served as baseline controls. HIV-1 viral load, CD4 and CD8 T cell numbers, and serologic changes to Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human herpesvirus 8 (HHV-8), and cytomegalovirus (CMV) were monitored. Although responses to HAART varied, herpesvirus reactivation frequencies did not differ relative to HIV-1 virologic responses. Forty-seven subjects had reactivations to a single herpesvirus type and 12 subjects to > or =2 types; no single herpesvirus dominated. Antibody seroprevalence to EBV, HHV-6, and CMV were similar but HHV-8 infection was twice as prevalent in HIV-1-infected vs. uninfected individuals. Notably, lower HIV-1 viremia (7,313 vs. 55,548 geometric mean RNA copies/ml) at baseline was significantly associated with HHV-8 seropositivity (p < 0.004).
Antiretroviral Therapy, Highly Active↗
Microchimerism in transfused trauma patients is associated with diminished donor-specific lymphocyte response.
BACKGROUND: Blood transfusion can result in long-term survival of donor leukocyte subpopulations, or microchimerism, in the peripheral blood of injured patients. Neither injury severity nor the number of transfusions is associated with its occurrence. We sought to determine whether changes in general or antigen-specific lymphocyte activation may be associated with the subsequent development of microchimerism. METHODS: We evaluated 63 transfused trauma patients, which we compared with 10 non-transfused trauma patients and 10 healthy control subjects. Of the 63 transfused patients, 31 were known to have evidence of microchimerism at hospital discharge with real-time quantitative PCR for non-recipient HLA DR alleles. We assessed lymphocyte response to phytohemagglutinin (PHA) using blood sampled upon arrival to the hospital (before transfusion) and at discharge. We performed one-way mixed leukocyte cultures (MLC) with pre-transfusion recipient specimens to assess recipient lymphocyte response to mitomycin-C treated donor cells and vice versa. RESULTS: Lymphocyte response to PHA in microchimeric transfusion recipients was lower at admission (before transfusion) and discharge than in non-microchimeric recipients. Lymphocytes from microchimeric patients had less response to donor cells than did lymphocytes from non-microchimeric patients. Microchimeric patients also more frequently had diminished lymphocyte response to a single blood donor on MLC. CONCLUSIONS: Transfusion-associated microchimerism is correlated with diminished response to mitogen challenge as well as to specific alloantigenic challenges. This microchimerism is predated by diminished lymphocyte response to a specific blood donor in many instances. The blood donor associated with this diminished alloantigenic lymphocyte response may be the source of microchimeric cells present in the recipient.
Adult↗
A new strategy for estimating risks of transfusion-transmitted viral infections based on rates of detection of recently infected donors.
BACKGROUND: Estimates for human immunodeficiency virus (HIV)-1 and hepatitis C virus (HCV) transfusion-transmitted risks have relied on incidence derived from repeat donor histories and imprecise estimates for infectious, preseroconversion window periods (WPs). STUDY DESIGN AND METHODS: By use of novel approaches, WPs were estimated by back-extrapolation of acute viral replication dynamics. Incidence was derived from the yield of viremic, antibody-negative donations detected by routine minipool nucleic acid testing (MP-NAT) of 37 million US donations (1999-2002) or from sensitive/less-sensitive HIV-1 enzyme immunoassay (S/LS-EIA) results for seropositive samples from 6.5 million donations (1999). Incidences and WPs were combined to calculate risks and project yield of individual donation (ID)-NAT. RESULTS: The HIV-1 WP from presumed infectivity (1 copy/20 mL) to ID-NAT detection was estimated at 5.6 days, and the periods from ID to MP-NAT detection and from MP-NAT to p24 detection at 3.4 and 6.0 days, respectively; corresponding estimates for HCV were 4.9, 2.5, and 50.9 days (the latter represents period from MP-NAT to HCV antibody detection). The HIV-1 incidence projected from MP-NAT yield or from S/LS-EIA data was 1.8 per 100,000 person-years, resulting in a corresponding HIV-1 transfusion-transmitted risk of 1 in 2.3 million. The HCV incidence from MP-NAT yield was 2.70 per 100,000 person-years with a corresponding risk of 1 in 1.8 million donations. Conversion from MP-NAT to ID-NAT was projected to detect two to three additional HIV-1 and HCV infectious units annually. CONCLUSIONS: MP-NAT yield and S/LS-EIA rates can accurately project transfusion risks. HCV and HIV-1 risks, currently estimated at 1 per 2 million units, could be reduced to 1 in 3 to 4 million units by ID-NAT screening.
Acute Disease↗
High-level long-term white blood cell microchimerism after transfusion of leukoreduced blood components to patients resuscitated after severe traumatic injury.
BACKGROUND: Long-term white blood cell (WBC) microchimerism (MC), of at least 2 years, has been reported in trauma patients receiving fresh nonleukoreduced (non-LR) blood. It is unknown, however, whether this occurs with LR blood products that are nearly devoid of WBCs. Twenty-seven patients transfused with LR and non-LR blood products were studied after severe traumatic injury. A secondary aim was to explore donor-recipient mixed lymphocyte reactivity in vitro. STUDY DESIGN AND METHODS: To quantify MC, allele-specific real-time polymerase chain reaction assays were developed targeting HLA Class II sequence polymorphisms. Extensive validation showed that these assays reliably detect a single copy of target sequence in a complex allogeneic background without false positivity. RESULTS: At a median follow-up of 26 months (range, 24-39 months), long-term MC was observed in 3 of 20 patients (15%) who received non-LR blood products and 2 of 7 (29%) who received LR blood products. The maximum MC ranged from 0.40 to 4.90 percent of circulating WBCs and appeared, by Class II genotype analysis, to be attributable to a single donor. CONCLUSION: It is concluded that robust levels of long-term MC, apparently traceable to a single donor, occur at similar frequency despite leukoreduction of transfused blood products. Exploratory analysis of donor-recipient mixed lymphocyte reactivity suggests that long-term MC may require a state of bidirectional tolerance before transfusion.
Blood Component Transfusion↗
Yield of hepatitis C virus nucleic acid testing among antibody-reactive or confirmed-positive samples.
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Antibodies, Viral↗