ABSTRACT
BACKGROUND
Some people rapidly develop iron deficiency anemia following blood donation, while others can repeatedly donate without becoming anemic.
METHODS
Two cohorts of blood donors were ...studied. Participants (775) selected from a 2‐year longitudinal study were classified into six analysis groups based on sex, donation intensity, and low hemoglobin deferral. Associations with iron supplement use, cigarette smoking, and four genetic variants of iron metabolism were examined at enrollment and with longitudinal regression models. An unbiased assessment of genetic variability and ability to repeatedly donate blood without experiencing low hemoglobin deferral was conducted on participants (13,403) in a cross‐sectional study who were examined by genome wide association (GWA).
RESULTS
Behaviors and genetic variants were associated with differences in hemoglobin and ferritin change following repeated donation. At least weekly iron supplement use was associated with improved status in first‐time donors, while daily use was associated with improved status in high‐intensity donors. Cigarette smoking was associated with 0.5 g/dL increased hemoglobin in high‐intensity donors. A736V in TMPRSS6 was associated with a rapid drop in hemoglobin and ferritin in first‐time females following repeated donation. Conversely, the protective TMPRSS6 genotype was not enriched among high‐intensity donors. H63D in HFE was associated with increased hemoglobin in female high‐intensity donors. However, no differences in genotype between first‐time and high‐intensity donors were found in GWA analyses.
CONCLUSION
Behavioral and genetic modifiers contributed to first‐time donor hemoglobin and iron status, while iron supplement use was more important than underlying genetics in high‐intensity donors.
It is unknown whether the reduction in HIV-1 reservoirs seen after allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 ...remission.
To characterize HIV-1 reservoirs in blood and tissues and perform analytic antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained, antiretroviral-free HIV-1 remission.
Case report with characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption.
Tertiary care center.
Two men with HIV with undetectable HIV-1 after allogeneic HSCT for hematologic tumors.
Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption.
No HIV-1 was detected from peripheral blood or rectal mucosa before analytic treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 and 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia within 2 weeks of the most recent negative viral load measurement and developed symptoms consistent with the acute retroviral syndrome. One patient developed new efavirenz resistance after reinitiation of antiretroviral therapy. Reinitiation of active therapy led to viral decay and resolution of symptoms in both patients.
The study involved only 2 patients.
Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. The definition of the nature and half-life of such reservoirs is essential to achieve durable antiretroviral-free HIV-1 remission.
Foundation for AIDS Research and National Institute of Allergy and Infectious Diseases.
BACKGROUND
Following transfusion, donor white blood cells (WBCs) can persist long‐term in the recipient, a phenomenon termed transfusion‐associated microchimerism (TA‐MC). Prior studies suggest TA‐MC ...is limited to transfusion following traumatic injury, and is not prevented by leukoreduction.
STUDY DESIGN AND METHODS
We conducted a prospective cohort study at a major trauma center to evaluate TA‐MC following injury. Index samples were collected upon arrival, prior to transfusion. Follow‐up samples were collected at intervals up to one year, and beyond for those testing positive for TA‐MC. TA‐MC was detected by real‐time quantitative allele‐specific polymerase chain reaction assays at the HLA‐DR locus and several polymorphic insertion deletion sites screening for non‐recipient alleles.
RESULTS
A total of 378 trauma patients were enrolled (324 transfused cases and 54 non‐transfused controls). Mean age was 42 ± 18 years, 74% were male, and 80% were injured by blunt mechanism. Mean Injury Severity Score was 20 ± 12. Among transfused patients, the median (interquartile range) number of red cell units transfused was 6 (3,12), and median time to first transfusion was 9 (0.8,45) hours. Only one case of long‐term TA‐MC was confirmed in our cohort. We detected short‐term TA‐MC in 6.5% of transfused subjects and 5.6% on non‐transfused controls.
CONCLUSIONS
In contrast to earlier studies, persistent TA‐MC was not observed in our cohort of trauma subjects. Short‐term TA‐MC was detected, but at a lower frequency than previously observed, and rates were not significantly different than what was observed in non‐transfused controls. The reduction in TA‐MC occurrence may be attributable to changes in leukoreduction or other blood processing methods.
See editorial on page 3291–3292, in this issue
Background. CD4⁺/CD8⁺ T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation ...predicts early death and blunted CD4⁺ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence. Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (< 6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologie suppression; at-risk HIV-negative persons were controls. We measured CD4⁺/CD8⁺ T-cell activation (percent CD38⁺/HLA-DR⁻) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels). Results. In unadjusted analyses, early ART predicted lower on-therapy CD8⁺ T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4⁺ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035). Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.
Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been ...implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor-α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL.
Background. Studies aimed at defining the association between host immune responses and human immunodeficiency virus (HIV) persistence during therapy are necessary to develop new strategies for cure. ...Methods. We performed a comprehensive assessment of ultrasensitive plasma HIV RNA levels, cell-associated HIV RNA levels, proviral HIV DNA levels, and T cell immunophenotyping in a cohort of 190 subjects in whom HIV levels were suppressed by highly active antiretroviral therapy. Results. The median CD4 + T cell count was 523 cells/mm 3 , and the median duration of viral suppression was 31 months. Cell-associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4 + and CD8 + T cells expressing markers of T-cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or programmed cell death protein 1 PD-1) (P < .05). Having a low CD4 + T-cell count despite receipt of virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (P < .01) and higher frequencies of CD4 + T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (P < .0001). Conclusions. Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1—expressing CD4 + T cells. Treated patients with a low CD4 + T-cell count had higher frequencies of PD-1—expressing CD4 + T cells and cell-based measures of viral persistence, suggesting that HIV infection in these individuals may be more difficult to cure and may require unique interventions.
The effectiveness of anti-parasite treatment with benznidazole in the chronic Chagas disease (ChD) remains uncertain. We evaluated, using data from the NIH-sponsored SaMi-Trop prospective cohort ...study, if previous treatment with benznidazole is associated with lower mortality, less advanced cardiac disease and lower parasitemia in patients with chronic ChD.
The study enrolled 1,959 ChD patients and abnormal electrocardiogram (ECG) from in 21 remote towns in Brazil. A total of 1,813 patients were evaluated at baseline and after two years of follow-up. Those who received at least one course of benznidazole were classified as treated group (TrG = 493) and those who were never treated as control group (CG = 1,320). The primary outcome was death after two-year follow-up; the secondary outcomes were presence at the baseline of major ChD-associated ECG abnormalities, NT-ProBNP levels suggestive of heart failure, and PCR positivity.
Mortality after two years was 6.3%; it was lower in the TrG (2.8%) than the CG (7.6%); adjusted OR: 0.37 (95%CI: 0.21;0.63). The ECG abnormalities typical for ChD and high age-adjusted NT-ProBNP levels suggestive of heart failure were lower in the TrG than the CG, OR: 0.35 CI: 0.23;0.53. The TrG had significantly lower rates of PCR positivity, OR: 0.35 CI: 0.27;0.45.
Patients previously treated with benznidazole had significantly reduced parasitemia, a lower prevalence of markers of severe cardiomyopathy, and lower mortality after two years of follow-up. If used in the early phases, benznidazole treatment may improve clinical and parasitological outcomes in patients with chronic ChD.
ClinicalTrials.gov, Trial registration: NCT02646943.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Previous reports of West Nile virus (WNV) RNA persistence in blood compartments have raised concerns around the remaining risk of WNV transfusion transmission. This study characterized the ...dynamics of WNV viremia in blood compartments in a longitudinal cohort of 54 WNV‐infected blood donors.
Study Design and Methods
Blood samples were collected throughout the year after WNV RNA–positive blood donation (index) and characterized for WNV immunoglobulin (Ig)M and IgG antibodies and for WNV RNA by real‐time reverse transcription–polymerase chain reaction. WNV viral loads were compared in plasma and whole blood samples and correlated with blood groups and clinical outcomes.
Results
WNV RNA persisted in the red blood cell (RBC) compartment up to 3 months postindex in 42% of the donors. Donors with the highest WNV RNA levels in plasma at index maintained the highest WNV RNA levels in whole blood over the 3 months postindex. Blood group A donors maintained higher postindex WNV viral load in whole blood than blood group O individuals (p = 0.027). Despite a trend for WNV RNA to persist longer in whole blood from symptomatic subjects, no significant association was found between WNV RNA levels in whole blood and disease outcome.
Conclusion
This study confirmed that WNV RNA persists in the RBC fraction in whole blood and further suggested that the level of persistence in whole blood may be a reflection of initial viral burden in plasma. The association with blood groups suggests that WNV adherence to RBCs may be mediated by molecules overrepresented at the surface of blood group A RBCs.
Characterisation of the dynamics of Zika virus persistence following acute infection is needed to inform blood donor and diagnostic testing policies and understand the natural history of Zika virus ...infection. We aimed to characterise the natural history, persistence, and clinical outcomes of Zika virus infection through a prospective study in initially asymptomatic Zika virus RNA-positive blood donors.
Zika virus-infected blood donors identified through Zika virus nucleic acid amplification test (NAAT) screening at three blood collection organisations in the USA were enrolled into a 1-year follow-up study, with blood and body fluid samples and detailed symptom data collected at up to seven visits. All samples were tested for Zika virus RNA by real-time PCR (rtPCR); follow-up plasma, whole blood, and urine were also tested by replicate NAAT. Plasma was tested for flavivirus-specific IgM and IgG by ELISA. Zika virus RNA persistence for each assay or sample type and plasma antibody persistence from estimated date of plasma NAAT-detectable infection were calculated from follow-up data using survival statistical methods.
Between July 6, 2016 and March 7, 2017, we enrolled 53 participants. From the estimated date of plasma NAAT-detectable infection, Zika virus RNA was detectable in plasma for 9·9 days (95% CI 8·1–12·0), in red blood cells for 95·4 days (62·8–129·1), and in whole blood for 73·5 days (39·8–107·5). Replicate NAATs (one or more of eight replicates positive) extended detection of Zika virus RNA in plasma to 34·8 days (19·9–56·2) and in whole blood (at least one of two tests positive) to 104·8 days (76·7–129·9). Urine was rtPCR reactive up to 14·5 days (10·5–20·3) and saliva up to 26·4 days (19·7–38·7). Zika virus IgM persisted for 237·7 days (128·7–459·5) from estimated time since plasma NAAT-detectable infection. Zika virus RNA fell below detectable limits more rapidly in the saliva of participants with pre-existing dengue virus IgG than in those without. Of 25 donors identified pre-seroconversion with symptom data at the first or second study visit, 16 (64%) developed multiple Zika virus-related symptoms after asymptomatic index donations, compared with nine (36%) of 25 donors detected after seroconversion.
Determination of viral marker persistence is enhanced by follow-up of blood donors who are pre-symptomatic or asymptomatic, Zika virus RNA-positive, and antibody negative. Zika virus RNA persists in red blood cells for several months following clearance from plasma and body fluids, and replicate, highly sensitive NAATs extend RNA detection in all compartments. Whole blood testing can extend detection of acute infection for diagnostics and monitoring of pregnant women, sexual partners, and travellers.
National Heart, Lung, and Blood Institute, Biomedical Advanced Research and Development Authority.
BACKGROUND
Babesia microti is a parasite that infects red blood cells (RBCs) in mammals. It is transmitted to humans by tick bites, transfusion, organ transplantation, and congenital acquisition. ...Although the Babesia natural history and seroprevalence in donors have been well described, gaps in knowledge relevant to transfusion remain.
STUDY DESIGN AND METHODS
Mice were infected with dilutions of parasitized blood to address the minimal infectious dose and the kinetics of parasitemia by quantitative polymerase chain reaction (qPCR) and of antibodies by enzyme immunoassay.
RESULTS
In immunocompetent DBA/2 mice infected with 100 parasitized RBCs (pRBCs) and in immunodeficient NSG mice infected with 63 pRBCs, parasitemia was detectable in five of five mice each. Peak parasitemia up to 2 × 107 pRBCs/mL at 2 to 3 weeks or 5 × 108 pRBCs/mL at 6 weeks was observed for DBA/2 and NSG mice, respectively. Protracted fluctuating parasitemia was observed for 8 months in DBA/2 mice, whereas NSG mice exhibited a high‐plateau parasitemia. Antibody titers continued to increase until 6 to 18 weeks in DBA/2 mice and remained high through 6 months. This study also investigated the analytical performance of Babesia assays that detect parasite DNA or RNA using a blinded panel. A Babesia assay targeting parasite RNA was approximately 10‐fold more sensitive compared to qPCR targeting DNA.
CONCLUSION
The mice in this study were highly susceptible to Babesia infection using as few as 1 to 2 log pRBCs and maintained chronic parasitemia. If the infectious dose in human transfusion recipients is comparably low, a highly sensitive assay targeting parasite RNA may safeguard the blood supply, particularly before antibody detection.
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