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1.  Prevalence of Serological Markers for Hepatitis B and C Viruses in Brazilian Blood Donors, and Incidence and Residual Risk of Transfusion-Transmission of Hepatitis C Virus 
Transfusion  2012;53(4):827-834.
Background
We evaluate the current prevalence of serological markers for HBV and HCV in blood donors and estimated HCV incidence and residual transfusion-transmitted risk at three large Brazilian blood centers.
Material and Methods
Data on whole blood and platelet donations were collected from January through December 2007 and analyzed by center, donor type (replacement vs. community), age, sex, donation status (first-time vs. repeat), and serological results for HBsAg, anti-HBc and anti-HCV. HBV (HBsAg+/anti-HBc+) and HCV (anti-HCV) prevalence rates were calculated for all first time donations. HCV incidence was derived including inter-donation intervals that preceded first repeat donations given during the study and HCV residual risk was estimated for transfusions derived from repeat donors.
Results
There were 307,354 donations from January through December 2007. Overall prevalence of concordant HBsAg and anti-HBc reactivity was 289 per 100,000 donations and of anti-HCV confirmed reactivity 191 per 100,000 donations. There were significant associations between older age and hepatitis markers, especially for HCV. HCV incidence was 3.11 (95% CI 0.77-7.03) per 100,000 person-years, and residual risk of HCV window-phase infections was estimated at 5.0 per million units transfused.
Conclusion
Improvement in blood donor selection, socioeconomic conditions and preventive measures, implemented over time, may have helped to decrease prevalence of hepatitis B and C viruses, relative to previous reports. Incidence and residual risk of HCV are also diminishing. Ongoing monitoring of hepatitis B and C viral markers among Brazilian blood donors should help guide improved recruitment procedures, donor selection, laboratory screening methods and counseling strategies.
doi:10.1111/j.1537-2995.2012.03840.x
PMCID: PMC3499633  PMID: 22882510
Blood donors; Brazil; Residual Risk; Hepatitis B; Hepatitis C; Prevalence; Incidence
2.  Frequent Longitudinal Sampling of Hepatitis C Virus Infection in Injection Drug Users Reveals Intermittently Detectable Viremia and Reinfection 
Defining clear hepatitis C virus (HCV) infection outcomes, including reinfection and viral intercalation after clearance of infection, requires ongoing, frequent follow-up, most importantly with longitudinal viral sequencing. Patients who have cleared HCV infection may demonstrate sustained viral clearance despite ongoing HCV exposure.
Background. Detection of hepatitis C virus (HCV) reinfection and intercalation (ie, intermittent recurrent bouts of viremia with homologous virus interspersed with aviremic periods) requires extensive and frequent evaluation and viral sequencing.
Methods. HCV infection outcomes were studied prospectively in active injection drug users with recurrent HCV RNA–positive tests after serial negative results. HCV viremia and viral sequences (Core/E1) were assessed from monthly blood samples.
Results. Viral clearance, reinfection, and intercalating infection were all detected. Among 44 participants with apparently resolved HCV (26 incident HCV clearers and 18 enrolled with already resolved infection), 36 (82%) remained persistently HCV RNA negative, but 8 demonstrated intermittent recurrent viremia. Four of these (50%) had confirmed reinfection with a heterologous virus; 3 demonstrated viral intercalation, and 1 was not classifiable as either. Estimated incidence of first reinfection was 5.4 per 100 person-years (95% confidence interval, 2.0–14.5). Six (75%) participants, including 3 of 4 with reinfection, demonstrated sustained viral clearance for a median of 26 months since last HCV RNA test.
Conclusions. These results show that frequent monitoring and viral sequencing are required to correctly assess HCV outcomes and estimate incidence of reinfection (which was previously overestimated). Sustained clearance may take many months and occur after episodes of reinfection and viral intercalation. Three of 4 subjects who had confirmed reinfection showed evidence of long-term clearance. Viral intercalation occurs with significant frequency. Further studies of these events, especially immunological, are needed to inform HCV clinical care and vaccine development.
doi:10.1093/cid/cis921
PMCID: PMC3540042  PMID: 23090930
hepatitis C virus; viral sequencing; reinfection; intercalation; young IDU
3.  Pegylated Interferon Alfa-2a Monotherapy Results in Suppression of HIV Type 1 Replication and Decreased Cell-Associated HIV DNA Integration 
The Journal of Infectious Diseases  2012;207(2):213-222.
Background. Antiretroviral therapy (ART)–mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication.
Methods. A total of 23 HIV type 1 (HIV-1)–infected, virologically suppressed subjects receiving ART (CD4+ T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg–interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, ≥400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed.
Results. At week 12 of Peg–interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P < .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P = .0046; arm B, P = .0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P = .0313) but increased residual viral loads (P = .0078), compared with subjects who experienced end-point failure.
Conclusions. Peg–interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication.
Clinical Trials Registration. NCT00594880.
doi:10.1093/infdis/jis663
PMCID: PMC3532820  PMID: 23105144
HIV-1; interferon-alpha; viral integration; immunotherapy
4.  Transfusion Associated Microchimerism: The Hybrid Within 
Transfusion medicine reviews  2012;27(1):10-20.
Microchimerism, the coexistence of genetically disparate populations of cells in a receptive host, is well described in both clinical and physiological settings, including transplantation and pregnancy. Microchimerism can also occur following allogeneic blood transfusion in traumatically injured patients, where donor cells have been observed decades after transfusion. To date, transfusion-associated microchimerism (TA-MC) appears confined to this clinical subset, most likely due to the immune perturbations that occur following severe trauma that allow foreign donor cells to survive. TA-MC appears to be unaffected by leukoreduction and has been documented following transfusion with an array of blood products. The only significant predictor of TA-MC to date is the age of red cells, with fresher units associated with higher risk. Thus far, no adverse clinical effect has been observed in limited studies of TA-MC. There are, however, hypothesized links to transfusion-associated graft vs. host disease (TA-GvHD) that may be unrecognized and consequently under-reported. Microchimerism in other settings has gained increasing attention due to a plausible link to autoimmune diseases, as well as its diagnostic and therapeutic potential vis-a-vis ante-natal testing and adoptive immunotherapy, respectively. Furthermore, microchimerism provides a tool to further our understanding of immune tolerance and regulation.
doi:10.1016/j.tmrv.2012.08.002
PMCID: PMC3518667  PMID: 23102759
Microchimerism; transfusion; chimerism; trauma; immunity; immune tolerance
5.  TRANSFUSION-TRANSMISSION OF HCV, A LONG BUT SUCCESSFUL ROAD MAP TO SAFETY 
Antiviral therapy  2012;17(7 0 0):1423-1429.
Improved blood banking practices and the development and implementation of increasingly sensitive serological and nucleic acid amplification technology (NAT) assays for screening donors for HCV over the past few decades have helped minimize the residual risk from transfusion-transmitted HCV in the developed world. Furthermore, studies of transfusion-transmitted infections and of donors identified as infected by routine screening have provided significant insights into HCV transmission, epidemiology and pathogenesis. However, transfusion-transmission of HCV is still a significant route of infection in the developing world. Key preventive mechanisms to ensure safe blood include elimination of paid donors and development of national donor pools comprised of volunteer repeat blood donors, combined with implementation of standardized and maximally sensitive screening assays for HCV. There is also a need to develop up-to-date data on HCV disease burden on a global scale, in part derived from systematic screening of donors for HCV. We suggest the creation of blood donor databases and specimen repositories, both at national and international levels, to facilitate epidemiological surveillance and pathogenesis and treatment studies in the future.
doi:10.3851/IMP2459
PMCID: PMC3725987  PMID: 23322562
6.  Cancer Incidence and Mortality in a Cohort of US Blood Donors: A 20-Year Study 
Journal of Cancer Epidemiology  2013;2013:814842.
Blood donors are considered one of the healthiest populations. This study describes the epidemiology of cancer in a cohort of blood donors up to 20 years after blood donation. Records from donors who participated in the Retroviral Epidemiology Donor Study (REDS, 1991–2002) at Blood Centers of the Pacific (BCP), San Francisco, were linked to the California Cancer Registry (CCR, 1991–2010). Standardized incidence ratios (SIR) were estimated using standard US 2000 population, and survival analysis used to compare all-cause mortality among donors and a random sample of nondonors with cancer from CCR. Of 55,158 eligible allogeneic blood donors followed-up for 863,902 person-years, 4,236 (7.7%) primary malignant cancers were diagnosed. SIR in donors was 1.59 (95% CI = 1.54,1.64). Donors had significantly lower mortality (adjusted HR = 0.70, 95% CI = 0.66–0.74) compared with nondonor cancer patients, except for respiratory system cancers (adjusted HR = 0.93, 95% CI = 0.82–1.05). Elevated cancer incidence among blood donors may reflect higher diagnosis rates due to health seeking behavior and cancer screening in donors. A “healthy donor effect” on mortality following cancer diagnosis was demonstrated. This population-based database and sample repository of blood donors with long-term monitoring of cancer incidence provides the opportunity for future analyses of genetic and other biomarkers of cancer.
doi:10.1155/2013/814842
PMCID: PMC3893810  PMID: 24489545
7.  Performance of Rapid Point-of-Care and Laboratory Tests for Acute and Established HIV Infection in San Francisco 
PLoS ONE  2013;8(12):e80629.
Background
Current laboratory and point-of-care tests for HIV detect different analytes and use different sample types. Some have fast turnaround times (<1 hour). We investigated how HIV test choice could impact case finding by testing programs.
Methods
We analyzed 21,234 consecutive HIV tests with venous blood obtained by San Francisco HIV testing programs from 2003 to 2008. For a subset, oral fluid (n = 6446) or fingerstick blood (n = 8127) samples were also obtained for rapid testing. In all cases, HIV status was determined using an HIV antibody-plus-RNA test algorithm. We assessed how the screening antibody tests performed individually versus the gold standard of the full algorithm. We then evaluated the potential ability of other tests (including new tests) to detect more cases, by re-testing all specimens that had negative/discrepant antibody results on initial screening.
Findings
The antibody-RNA algorithm identified 58 acute and 703 established HIV infection cases. 1st-generation (Vironostika) and 3rd-generation (Genetic Systems) immunoassays had 92 and 96 percent sensitivity, respectively. The Oraquick rapid test had clinical sensitivity of only 86 percent on oral fluid samples, but 92 percent on finger-stick blood. Newer 4th-generation, antigen-antibody combo rapid immunoassay (ARCHITECT) detected HIV in 87 percent of all the acute cases that had been missed by one of the previous screening assays. A point-of-care 4th generation antigen-antibody combo rapid test (Determine) detected about 54 percent of such acute cases.
Conclusions
Our study suggests that some rapid antibody blood tests will give similar case detection to laboratory antibody tests, but that oral fluid testing greatly reduces ability to detect HIV. New 4th-generation combo tests can detect the majority of acute infections detectable by HIV RNA but with rapid results. Using these tests as a primary screening assay in high-risk HIV testing programs could reduce or eliminate the need for HIV RNA testing.
doi:10.1371/journal.pone.0080629
PMCID: PMC3861178  PMID: 24349007
8.  Distinct roles of trauma and transfusion in induction of immune modulation post-injury 
Transfusion  2012;52(12):2533-2550.
BACKGROUND
Trauma and transfusion can both alter immunity, and while transfusions are common among traumatically injured patients, few studies have examined their combined effects on immunity.
STUDY DESIGN AND METHODS
We tracked the plasma levels of 41 immunomodulatory proteins in 56 trauma patients from time of injury up to 1 year later. In addition, a murine model was developed to distinguish between the effects of transfusion and underlying injury and blood loss.
RESULTS
Thirty-one of the proteins had a statistically significant change over time after traumatic injury, with a mixed early response that was predominantly anti-inflammatory followed by a later increase in proteins involved in wound healing and homeostasis. Results from the murine model revealed similar cytokine responses to humans. In mice, trauma/hemorrhage caused early perturbations in a number of the pro- and anti-inflammatory mediators measured, and transfusion blunted early elevations in IL-6, IL-10, MMP-9, and IFN-γ. Transfusion caused or exacerbated changes in MCP-1, IL-1α, IL-5, IL-15, and soluble E-selectin. Finally, trauma/hemorrhage alone increased KC and IL-13.
CONCLUSIONS
This work provides a detailed characterization of the major shift in the immunological environment in response to trauma and transfusion and clarifies which immune mediators are affected by trauma/hemorrhage and which by transfusion.
doi:10.1111/j.1537-2995.2012.03618.x
PMCID: PMC3392528  PMID: 22452342
Allogeneic Transfusion; Trauma/Hemorrhage; Mouse model; Cytokines; Immune Dysregulation
9.  Genome Wide Association Study (GWAS) of Chagas Cardiomyopathy in Trypanosoma cruzi Seropositive Subjects 
PLoS ONE  2013;8(11):e79629.
Background
Familial aggregation of Chagas cardiac disease in T. cruzi–infected persons suggests that human genetic variation may be an important determinant of disease progression.
Objective
To perform a GWAS using a well-characterized cohort to detect single nucleotide polymorphisms (SNPs) and genes associated with cardiac outcomes.
Methods
A retrospective cohort study was developed by the NHLBI REDS-II program in Brazil. Samples were collected from 499 T. cruzi seropositive blood donors who had donated between1996 and 2002, and 101 patients with clinically diagnosed Chagas cardiomyopathy. In 2008–2010, all subjects underwent a complete medical examination. After genotype calling, quality control filtering with exclusion of 20 cases, and imputation of 1,000 genomes variants; association analysis was performed for 7 cardiac and parasite related traits, adjusting for population stratification.
Results
The cohort showed a wide range of African, European, and modest Native American admixture proportions, consistent with the recent history of Brazil. No SNPs were found to be highly (P<10−8) associated with cardiomyopathy. The two mostly highly associated SNPs for cardiomyopathy (rs4149018 and rs12582717; P-values <10−6) are located on Chromosome 12p12.2 in the SLCO1B1 gene, a solute carrier family member. We identified 44 additional genic SNPs associated with six traits at P-value <10-6: Ejection Fraction, PR, QRS, QT intervals, antibody levels by EIA, and parasitemia by PCR.
Conclusion
This GWAS identified suggestive SNPs that may impact the risk of progression to cardiomyopathy. Although this Chagas cohort is the largest examined by GWAS to date, (580 subjects), moderate sample size may explain in part the limited number of significant SNP variants. Enlarging the current sample through expanded cohorts and meta-analyses, and targeted studies of candidate genes, will be required to confirm and extend the results reported here. Future studies should also include exposed seronegative controls to investigate genetic associations with susceptibility or resitance to T. cruzi infection and non-Chagas cardiomathy.
doi:10.1371/journal.pone.0079629
PMCID: PMC3854669  PMID: 24324551
10.  A Randomized, Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection 
Objectives
To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated, HIV-infected individuals.
Design
Randomized, double-blinded, placebo-controlled study.
Methods
Fifty-six subjects with treatment-mediated viral suppression for at least one year were randomized to add raltegravir 400 mg twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function (as assessed by flow-mediated vasodilation of the brachial artery [FMD]) from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.
Results
At baseline, the median CD4+ T cell count was 498 cells/mm3, nadir CD4+ T cell count was 191 cells/mm3, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group +0.032% per week, placebo group +0.023% per week; p=0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4+ T cell count and current abacavir use were associated with lower hyperemic velocity.
Conclusions
The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).
doi:10.1097/QAI.0b013e31826e7d0f
PMCID: PMC3480968  PMID: 22918156
HIV; raltegravir intensification; endothelial function; flow-mediated vasodilation
11.  The NHLBI Retrovirus Epidemiology Donor Studies (REDS and REDS-II): Twenty years of research to advance blood product safety and availability 
Transfusion medicine reviews  2012;26(4):281-304.e2.
The Retrovirus Epidemiology Donor Study (REDS), conducted from 1989–2001, and the Retrovirus Epidemiology Donor Study-II (REDS-II), conducted from 2004–2012, were National Heart Lung and Blood Institute (NHLBI) funded multicenter programs focused on improving blood safety and availability in the United States. REDS-II also included international study sites in Brazil and China. The three major research domains of REDS/REDS-II have been infectious disease risk evaluation, blood donation availability, and blood donor characterization. Both programs have made significant contributions to transfusion medicine research methodology by the use of mathematical modeling, large-scale donor surveys, innovative methods of repository sample storage, and establishing an infrastructure that responded to potential emerging blood safety threats such as XMRV. Blood safety studies have included protocols evaluating epidemiologic and/or laboratory aspects of HIV, HTLV I/II, HCV, HBV, WNV, CMV, HHV-8, B19V, malaria, CJD, influenza, and T. cruzi infections. Other analyses have characterized: blood donor demographics, motivations to donate, factors influencing donor return, behavioral risk factors, donors’ perception of the blood donation screening process, and aspects of donor deferral. In REDS-II, two large-scale blood donor protocols examined iron deficiency in donors and the prevalence of leukocyte antibodies. This review describes the major study results from over 150 peer-reviewed articles published by these two REDS programs. In 2011, a new seven year program, the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III), was launched. REDS-III expands beyond donor-based research to include studies of blood transfusion recipients in the hospital setting, and adds a third country, South Africa, to the international program.
doi:10.1016/j.tmrv.2012.04.004
PMCID: PMC3448800  PMID: 22633182
blood safety; transfusion-transmitted infections; blood availability; blood donors
12.  Dengue in the context of “safe blood” and global epidemiology: to screen or not to screen? 
Transfusion  2012;52(8):1634-1639.
doi:10.1111/j.1537-2995.2012.03747.x
PMCID: PMC3509801  PMID: 22882092
13.  Detection of host immune responses in acute phase sera of spontaneous resolution versus persistent hepatitis C virus infection 
The Journal of General Virology  2012;93(Pt 8):1673-1679.
Prior to the identification of hepatitis C virus (HCV), transfusion-transmission was common. Viral transmission in subjects with a known date of infection allows the study of the immune responses to acute HCV infection. We analysed 39 soluble immune factors in serum samples from subjects with transfusion-transmitted HCV. Dynamic expression kinetics of interferon gamma-induced protein 10 (IP-10), tumour necrosis factor-alpha and interleukin (IL)-10 were observed during acute HCV infection. Serum IP-10 was the only analyte that was significantly elevated in HCV resolvers compared with uninfected controls. In individuals who progressed to chronic HCV elevated levels of IP-10 and IL-10 coincided with first significant alanine aminotransferase elevation and remained elevated during the first year of acute HCV infection. In addition to monitoring lack of reduction in viral load, serum levels of IP-10 and IL-10 expression during acute HCV infection may be useful biomarkers to predict the progress to chronic HCV.
doi:10.1099/vir.0.041277-0
PMCID: PMC3541758  PMID: 22535775
14.  HCV RNA Levels in a Multi-Ethnic Cohort of Injection Drug Users: Human Genetic, Viral and Demographic Associations 
Hepatology (Baltimore, Md.)  2012;56(1):86-94.
In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV EIA were tested for HCV viremia by a bDNA assay. HCV genotype was determined by sequencing the HCV NS5B region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). HIV-1 prevalence was 13.9%. The overall median HCV RNA level was 6.45 log10 copies/ml. In unadjusted analyses, higher levels were found with older age, male gender, African American ancestry, HBV infection, HIV-1 infection and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotype 3 or genotype 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype and IL28B rs12979860 genotype were all independently associated with HCV RNA. Conclusion: The level of HCV viremia is influenced by a large number of demographic, viral and human genetic factors.
doi:10.1002/hep.25652
PMCID: PMC3369001  PMID: 22331649
epidemiology; genetics; HCV; IL28B; viremia
16.  ALTERATIONS IN MATERNAL-FETAL CELLULAR TRAFFICKING AFTER FETAL SURGERY 
Journal of Pediatric Surgery  2012;47(6):1089-1094.
Background/Purpose
Bi-directional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking.
Methods
Cellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n=5), MMC patients who had routine postnatal repair (n=6), and normal term patients (n=9). As a control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment (EXIT) procedure (n=6). Microchimerism in maternal and cord blood was determined using quantitative real-time PCR for non-shared alleles.
Results
Maternal-to-fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared to normal controls, postnatal MMC repair, and EXIT patients. There were no differences in fetal-to-maternal cell trafficking between groups.
Conclusion
Patients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor.
doi:10.1016/j.jpedsurg.2012.03.012
PMCID: PMC3377979  PMID: 22703775
Fetal surgery; myelomeningocele; spina bifida; maternal-fetal cellular trafficking; microchimerism; preterm labor; EXIT
17.  Lower-Sensitivity and Avidity Modifications of the Vitros Anti-HIV 1+2 Assay for Detection of Recent HIV Infections and Incidence Estimation 
Journal of Clinical Microbiology  2012;50(12):3968-3976.
Recent-infection testing assays/algorithms (RITAs) have been developed to exploit the titer and avidity of HIV antibody evolution following seroconversion for incidence estimation. The Vitros Anti-HIV 1+2 assay (Ortho-Clinical Diagnostics) was approved by the FDA to detect HIV-1 and HIV-2 infections. We developed a less-sensitive (LS) and an avidity-modified version of this assay to detect recent HIV infection. Seroconversion panels (80 subjects, 416 samples) were tested to calculate the mean duration of recent infection (MDR) for these assays. A panel from known long-term (2+ years) HIV-infected subjects on highly active antiretroviral therapy (HAART) (n = 134) and subjects with low CD4 counts (AIDS patients [n = 140]) was used to measure the false-recent rate (FRR) of the assays. Using a signal-to-cutoff ratio of 20 and the LS-Vitros assay gave a RITA MDR of 215 days (95% confidence interval [95% CI], ±65 days) and using an avidity index (AI) of 0.6 gave an MDR of 170 days (±44 days), while a combination of the two assays yielded a MDR of 146 days (±38.6) and an FRR of 8%. Misclassifying subjects with known long-term infection as recently infected occurred in 14% of AIDS patients and 29% (95% CI, 22, 38) of HAART subjects and 3% (95% CI, 0.8, 7.2) and 42% (95% CI, 33, 51), respectively, for the LS- and avidity-modified Vitros assays, with a misclassification rate of 15% (95% CI, 11, 20) overall using a dual-assay algorithm. Both modified Vitros assays can be used to estimate the length of time since seroconversion and in calculations for HIV incidence. Like other RITAs, they are subject to high FRR in subjects on HAART or with AIDS.
doi:10.1128/JCM.01454-12
PMCID: PMC3503010  PMID: 23035182
18.  BMI and obesity in US blood donors: a potential public health role for the blood centre 
Public health nutrition  2012;15(6):964-971.
Objective
According to the 2007–2008 National Health and Nutrition Examination Survey, the prevalence of obesity in the US population was 33·8 %; 34·3 % and 38·2 %, respectively, in middle-aged men and women. We asked whether available blood donor data could be used for obesity surveillance.
Design
Cross-sectional study of BMI and obesity, defined as BMI ≥ 30·0 kg/m2. Adjusted odds ratios (aOR) were calculated with logistic regression.
Setting
A network of six US blood centres.
Subjects
Existing data on self-reported height and weight from blood donors, excluding persons deferred for very low body weight.
Results
Among 1 042 817 donors between January 2007 and December 2008, the prevalence of obesity was 25·1 %; 25·7 % in men and 24·4 % in women. Obesity was associated with middle age (age 50–59 years v. <20 years: aOR =1·92 for men and 1·81 for women), black (aOR =1·57 for men and 2·35 for women) and Hispanic (aOR =1·47 for men and 1·49 for women) race/ethnicity compared with white race/ethnicity, and inversely associated with higher educational attainment (college degree v. high school or lower: aOR =0·56 for men and 0·48 for women) and double red cell donation and platelet donation.
Conclusions
Obesity is common among US blood donors, although of modestly lower prevalence than in the general population, and is associated with recognized demographic factors. Blood donors with higher BMI are specifically recruited for certain blood collection procedures. Blood centres can play a public health role in obesity surveillance and interventions.
doi:10.1017/S1368980011003405
PMCID: PMC3518631  PMID: 22230364
BMI; Obesity; Blood donors; Prevalence; United States; Continental population groups; Age; Educational status
19.  Absence of Transfusion-Associated Microchimerism in Pediatric and Adult Recipients of Leukoreduced and Gamma Irradiated Blood Components 
Transfusion  2011;52(5):936-945.
BACKGROUND
Transfusion-associated microchimerism (TA-MC), the persistence of significant levels of donor leukocytes in blood recipients for prolonged periods, has been demonstrated following non-leukoreduced and leukoreduced transfusion to patients with severe traumatic injury. Development of TA-MC has not been rigorously studied in settings that do not involve massive trauma where the blood is leukoreduced and irradiated.
STUDY DESIGN AND METHODS
A cohort of 409 prospectively followed medical and surgical adult and pediatric female recipients of leukoreduced and mostly irradiated allogeneic red blood cell and platelet transfusions were evaluated to determine development of TA-MC. Four and eight-week post-transfusion samples were analyzed using quantitative real-time polymerase chain reaction (RT-PCR) for Y-chromosome sequences in leukocyte DNA, the marker for microchimeric cells in female blood recipients. Repeat testing was performed on Y-chromosome positive samples to confirm microchimerism (MC), and subsequent post-transfusion samples were tested to investigate persistence of MC.
RESULTS
On initial testing, forty of 207 (19%) adult and forty-four of 202 (22%) pediatric female blood recipients demonstrated low level MC. On repeat testing of these and additional specimens, twelve (3%) recipients demonstrated low level transient MC, but none had persistent TA-MC similar to that seen in transfused trauma patients.
CONCLUSION
Persistence of MC was not demonstrated in adult and pediatric recipients of leukoreduced and mostly irradiated blood components. The risk of TA-MC appears to be dependent on the clinical setting and is rare other than in patients sustaining severe traumatic injury.
doi:10.1111/j.1537-2995.2011.03366.x
PMCID: PMC3257351  PMID: 21981710
microchimerism; transfusion; irradiation; pediatric; blood recipients
20.  Number of Recent Sexual Partners among Blood Donors in Brazil: Associations with Donor Demographics, Donation Characteristics and Infectious Disease Markers 
Transfusion  2011;52(1):151-159.
BACKGROUND
Brazilian blood centers ask candidate blood donors about the number of sexual partners in the last 12 months. Candidates who report a number over the limit are deferred. We studied the implications of this practice on blood safety.
STUDY DESIGN AND METHODS
We analyzed demographic characteristics, number of heterosexual partners, and disease marker rates among 689,868 donations from three Brazilian Centers between July 2007 and December 2009. Donors were grouped based on maximum number of partners allowed in the last 12 months for each center. Chi-square and logistic regression analysis were conducted to examine associations between demographic characteristics, number of sex partners, and individual and overall positive markers rates for HIV, HTLV-1/2, HBV, HCV, and syphilis.
RESULTS
First-time, younger and more educated donors were associated with a higher number of recent sexual partners, as was male gender in São Paulo and Recife (p <0.001). Serologic markers for HIV, syphilis and overall were associated with multiple partners in São Paulo and Recife (p<0.001), but not in Belo Horizonte (p= 0.05, 0.94, 0.75, respectively). In logistic regression analysis, number of recent sexual partners were associated with positive serologic markers (AOR=1.2–1.5) especially HIV (AOR=1.0–4.4).
CONCLUSIONS
Number of recent heterosexual partners was associated with HIV positivity and overall rates of serological markers of sexually transmitted infections. The association was not consistent across centers, making it difficult to define the best cut-off value. These findings suggest the use of recent heterosexual contacts as a potentially important deferral criterion to improve blood safety in Brazil.
doi:10.1111/j.1537-2995.2011.03248.x
PMCID: PMC3607364  PMID: 21756264
21.  Genetic Diversity of Recently Acquired and Prevalent HIV, Hepatitis B Virus, and Hepatitis C Virus Infections in US Blood Donors 
The Journal of Infectious Diseases  2012;205(6):875-885.
(See the editorial commentary by Katz, on pages 867–9 and see the article by Stramer et al, on pages 886–94.)
Background. Genetic variations of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) can affect diagnostic assays and therapeutic interventions. Recent changes in prevalence of subtypes/genotypes and drug/immune-escape variants were characterized by comparing recently infected vs more remotely infected blood donors.
Methods. Infected donors were identified among approximately 34 million US blood donations, 2006–2009; incident infections were defined as having no or low antiviral antibody titers. Viral genomes were partially sequenced.
Results. Of 321 HIV strains (50% incident), 2.5% were non-B HIV subtypes. Protease and reverse transcriptase (RT) inhibitor resistance mutations were found in 2% and 11% of infected donors, respectively. Subtypes in 278 HCV strains (31% incident) yielded 1a>1b>3a>2b>2a>4a>6d, 6e: higher frequencies of 3a in incident cases vs higher frequencies of 1b in prevalent cases were found (P = .04). Twenty subgenotypes among 193 HBV strains (26% incident) yielded higher frequencies of A2 in incident cases and higher frequencies of A1, B2, and B4 in prevalent cases (P = .007). No HBV drug resistance mutations were detected. Six percent of incident vs 26% of prevalent HBV contained antibody neutralization escape mutations (P = .01).
Conclusions. Viral genetic variant distribution in blood donors was similar to that seen in high-risk US populations. Blood-borne viruses detected through large-scale routine screening of blood donors can complement molecular surveillance studies of highly exposed populations.
doi:10.1093/infdis/jir862
PMCID: PMC3282564  PMID: 22293432
22.  Sensitive Detection Assays for Influenza RNA Do Not Reveal Viremia in US Blood Donors 
The Journal of Infectious Diseases  2012;205(6):886-894.
(See the article by Delwart et al, on pages 875–85, and see the editorial commentary by Katz, on pages 867–9.)
Background. There have been anecdotal reports of influenza viremia since the 1960s. We present an assessment of the prevalence of seasonal and 2009 H1N1 influenza viremia (via RNA testing) in blood donor populations using multiple sensitive detection assays.
Methods. Several influenza RNA amplification assays, including transcription-mediated amplification (TMA) and 2 reverse-transcription polymerase chain reaction (RT-PCR) assays, were evaluated and used to test donor samples. Retrospective samples from 478 subjects drawn at sites with high influenza activity were tested. Prospective samples were collected from 1004 blood donors who called their donation center within 3 days of donation complaining of influenza-like illness (ILI). The plasma collected on the day of donation for these subjects was tested.
Results. Of the repository samples, 2 of 478 plasma samples were initially reactive but not repeat reactive by influenza TMA. Of blood donors reporting ILI symptoms postdonation, 1 of 1004 samples was TMA initially reactive but not repeat reactive; all samples were nonreactive by RT-PCR testing.
Conclusions. Targeting blood donor populations most likely to have influenza infection, we failed to detect influenza RNA in 1482 donor samples, with most tested by 3 different RNA assays. Seasonal influenza does not appear to pose a significant contamination threat to the blood supply.
doi:10.1093/infdis/jir863
PMCID: PMC3282565  PMID: 22293429
23.  Distribution of Parvovirus B19 DNA in Blood Compartments and Persistence of Virus in Blood Donors 
Transfusion  2011;51(9):1896-1908.
Introduction
Because the receptor for Parvovirus B19 (B19V) is on erythrocytes, we investigated B19V distribution in blood by in-vitro spiking experiments and evaluated viral compartmentalization and persistence in natural infection.
Methods
Two whole blood protocols (ultracentrifugation and a rapid RBC lysis/removal protocol) were evaluated using quantitative real-time PCR. Whole blood (WB) was spiked with known concentrations of B19V and recovery in various blood fractions was determined. The rapid RBC lysis/removal protocol was then used to compare B19V concentrations in 104 paired whole blood and plasma samples collected longitudinally from 43 B19V infected donors with frozen specimens in the REDS Allogeneic Donor and Recipient Repository (RADAR).
Results
In B19V spiking experiments, ~one-third of viral DNA was recovered in plasma and two-thirds was loosely bound to erythrocytes. In the IgM positive stage of infection in blood donors when plasma B19V DNA concentrations were > 100 IU/mL, median DNA concentrations were ~30-fold higher in WB than in plasma. In contrast, when IgM was absent and when the B19V DNA concentration was lower, the median whole blood to plasma ratio was ~1. Analysis of longitudinal samples demonstrated persistent detection of B19V in WB but declining ratios of WB/plasma B19V with declining plasma VL levels and loss of IgM-reactivity.
Conclusions
The WB/plasma B19V DNA ratio varies by stage of infection. Further study is required to determine if this is related to the presence of circulating DNA-positive erythrocytes derived from B19V infected erythroblasts, B19V-specific IgM mediated binding of virus to cells, or other factors.
doi:10.1111/j.1537-2995.2010.03035.x
PMCID: PMC3591477  PMID: 21303368
24.  The frequency and specificity of Human Neutrophil Antigen Antibodies in a blood donor population 
Transfusion  2010;51(4):820-827.
BACKGROUND
Transfusion related acute lung injury (TRALI) has been associated with both HLA and HNA antibodies. HNA antibody frequency, specificity, and demographic associations have not been well defined in the blood donor population.
METHODS
A subset of 1171 donors (388 non-transfused males, 390 HLA antibody negative females with three or more pregnancies, and 393 HLA antibody positive females with three or more pregnancies) from a larger leukocyte antibody prevalence study (LAPS) was tested for IgG and IgM HNA antibody using a granulocyte immunofluorescence flow cytometry assay. Additional testing on selected samples included monoclonal antibody immobilization of granulocyte antigen – flow cytometry and granulocyte genotyping.
RESULTS
Eight samples were HNA antibody positive (prevalence 0.7% [95% CI, 0.3 - 1.3%]). Three HNA antibodies (one IgG and two IgM) were found in non-transfused males (prevalence 0.8% [95% CI, 0.2 - 2.2%]); all were pan-reactive or non-specific. One HLA antibody negative previously pregnant female had an IgG HNA antibody with HNA-1a specificity (prevalence 0.3% [95% CI, 0.01-1.4%]). Four HLA antibody positive previously pregnant females demonstrated HNA antibodies, three IgG and one IgM (prevalence 1% [95% CI, 0.3 - 2.6%]). Two of these were HNA-1a specific, one HNA-4a specific, and one non-specific.
CONCLUSION
HNA antibodies occur with low frequency in the donor population and are present in both male and female donors. Despite the implementation of TRALI reduction strategies, HNA antibodies are still present in donor blood products. Though our data do not create a case for urgent implementation of donor HNA antibody testing, future new developments for high throughput HNA antibody screening, including for HNA-3a, may warrant reconsideration.
doi:10.1111/j.1537-2995.2010.02913.x
PMCID: PMC3583295  PMID: 20977484
25.  Increased Frequency of Tim-3 Expressing T Cells Is Associated with Symptomatic West Nile Virus Infection 
PLoS ONE  2014;9(3):e92134.
More than a decade after West Nile virus (WNV) entered North America, and despite a significant increase in reported cases during the 2012 and 2013 seasons, no treatment or vaccine for humans is available. Although antiviral T cells contribute to the control of WNV, little is known about their regulation during acute infection. We analyzed the expression of Tim-3 and PD-1, two recently identified T cell negative immune checkpoint receptors, over the course of WNV infection. Symptomatic WNV+ donors exhibited higher frequencies of Tim-3+ cells than asymptomatic subjects within naïve/early differentiated CD28+/–CD57–CD4+ and differentiated CD28–CD57–CD8+ T cells. Our study links Tim-3-expression on T cells during acute WNV infection with the development of symptomatic disease, suggesting Tim-3 and its ligands could be targeted therapeutically to alter anti-WNV immunity and improve disease outcome.
doi:10.1371/journal.pone.0092134
PMCID: PMC3958446  PMID: 24642562

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