Evaluation of the efficacy and safety of amustaline/glutathione pathogen-reduced RBCs in complex cardiac surgery: the Red Cell Pathogen Inactivation (ReCePI) study-protocol for a phase 3, randomized, controlled trial.

BACKGROUND: Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. METHODS: ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. DISCUSSION: RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Longitudinal analysis of annual national hemovigilance data to assess pathogen reduced platelet transfusion trends during conversion to routine universal clinical use and 7-day storage.

BACKGROUND: France converted to universal pathogen reduced (PR; amotosalen/UVA) platelets in 2017 and extended platelet component (PC) shelf-life from 5- to 7-days in 2018 and 2019. Annual national hemovigilance (HV) reports characterized longitudinal PC utilization and safety over 11 years, including several years prior to PR adoption as the national standard of care. METHODS: Data were extracted from published annual HV reports. Apheresis and pooled buffy coat [BC] PC use was compared. Transfusion reactions (TRs) were stratified by type, severity, and causality. Trends were assessed for three periods: Baseline (2010-14; ~7% PR), Period 1 ([P1] 2015-17; 8%-21% PR), and Period 2 ([P2] 2018-20; 100% PR). RESULTS: PC use increased by 19.1% between 2010 and 2020. Pooled BC PC production increased from 38.8% to 68.2% of total PCs. Annual changes in PCs issued averaged 2.4% per year at baseline, -0.02% (P1) and 2.8% (P2). The increase in P2 coincided with a reduction in the target platelet dose and extension to 7-day storage. Allergic reactions, alloimmunization, febrile non-hemolytic TRs, immunologic incompatibility, and ineffective transfusions accounted for >90% of TRs. Overall, TR incidence per 100,000 PCs issued declined from 527.9 (2010) to 345.7 (2020). Severe TR rates declined 34.8% between P1-P2. Forty-six transfusion-transmitted bacterial infections (TTBI) were associated with conventional PCs during baseline and P1. No TTBI were associated with amotosalen/UVA PCs. Infections with Hepatitis E (HEV) a non-enveloped virus resistant to PR, were reported in all periods. DISCUSSION: Longitudinal HV analysis demonstrated stable PC utilization trends with reduced patient risk during conversion to universal 7-day amotosalen/UVA PCs.

Funding blood safety in the 21st century.

BACKGROUND: Since 2000, there has been an historic increase in international development assistance, including blood safety projects. The result has been increased blood donations and infectious disease screening in many beneficiary countries. A comprehensive examination of international development assistance for blood safety has yet to be completed. STUDY DESIGN AND METHODS: This report examines publicly available information, including donor agency websites and databases and data from the 2008 and 2012 World Health Organization Global Database on Blood Safety. RESULTS: Between 2000 and 2015, from $602.4 million to $2.1 billion in international development assistance was allocated to blood safety programs worldwide, mostly as part of the global response to the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic. The US President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria were responsible for the majority of blood safety funding, which peaked in 2010 and declined through 2015. CONCLUSION: Between 2000 and 2015, countries with high burdens of human immunodeficiency virus/acquired immunodeficiency syndrome received funding and technical assistance to improve national laboratories, increase blood component production, and strengthen clinical practice. Global trends in international development assistance at large, including aid for blood safety, suggest that funding will not rebound.

The contribution of unsafe blood transfusion to human immunodeficiency virus incidence in sub-Saharan Africa: reexamination of the 5% to 10% convention.

BACKGROUND: Historical estimates have attributed 5% to 10% of new human immunodeficiency virus (HIV) infections in sub-Saharan Africa (SSA) to unsafe blood transfusions. Although frequently cited, the validity of this statistic is uncertain or outdated. Recent estimates suggest blood transfusion's contribution to new HIV infections in the region may be much lower. STUDY DESIGN AND METHODS: We searched the peer-reviewed and gray literature for quantitative estimates of the specific contribution of unsafe blood transfusion to the proportion of new HIV infections occurring in SSA. The sources and methods used to generate attribution estimates were evaluated against published country-specific HIV prevalence data. RESULTS: Despite multiple secondary citations, a primary published source attributing 5% to 10% of new HIV infections to blood transfusions in SSA could not be established for the current era. The United Nations Programme on HIV and AIDS (UNAIDS) modes of transmission (MOT) reports representing 15 countries suggest that between 0 and 1.1% of new HIV infections per year (median, 0.2% or approx. two out of 1000 new infections each year) may be attributable to blood transfusions. CONCLUSION: Recent modeled estimates suggest that blood transfusions account for a very low proportion of new HIV infections in SSA, likely an order of magnitude lower than 5% to 10%. Direct quantification of risk is challenging given the paucity of data on the variables that impact transfusion-associated HIV. Specifically, data on HIV incidence in blood donors, blood bank laboratory test performance, and posttransfusion surveillance are lacking. Findings suggest an urgent need for improved surveillance and modeling of transfusion-associated HIV transmission in the region.

Progress Toward Strengthening National Blood Transfusion Services - 14 Countries, 2011-2014.

Blood transfusion is a life-saving medical intervention; however, challenges to the recruitment of voluntary, unpaid or otherwise nonremunerated whole blood donors and insufficient funding of national blood services and programs have created obstacles to collecting adequate supplies of safe blood in developing countries (1). Since 2004, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) has provided approximately $437 million in bilateral financial support to strengthen national blood transfusion services in 14 countries in sub-Saharan Africa and the Caribbean* that have high prevalence rates of human immunodeficiency virus (HIV) infections. CDC analyzed routinely collected surveillance data on annual blood collections and HIV prevalence among donated blood units for 2011-2014. This report updates previous CDC reports (2,3) on progress made by these 14 PEPFAR-supported countries in blood safety, summarizes challenges facing countries as they strive to meet World Health Organization (WHO) targets, and documents progress toward achieving the WHO target of 100% voluntary, nonremunerated blood donors by 2020 (4). During 2011-2014, overall blood collections among the 14 countries increased by 19%; countries with 100% voluntary, nonremunerated blood donations remained stable at eight, and, despite high national HIV prevalence rates, 12 of 14 countries reported an overall decrease in donated blood units that tested positive for HIV. Achieving safe and adequate national blood supplies remains a public health priority for WHO and countries worldwide. Continued success in improving blood safety and achieving WHO targets for blood quality and adequacy will depend on national government commitments to national blood transfusion services or blood programs through increased public financing and diversified funding mechanisms for transfusion-related activities.

Namibia's transition from whole blood-derived pooled platelets to single-donor apheresis platelet collections.

BACKGROUND: Few African countries separate blood donations into components; however, demand for platelets (PLTs) is increasing as regional capacity to treat causes of thrombocytopenia, including chemotherapy, increases. Namibia introduced single-donor apheresis PLT collections in 2007 to increase PLT availability while reducing exposure to multiple donors via pooling. This study describes the impact this transition had on PLT availability and safety in Namibia. STUDY DESIGN AND METHODS: Annual national blood collections and PLT units issued data were extracted from a database maintained by the Blood Transfusion Service of Namibia (NAMBTS). Production costs and unit prices were analyzed. RESULTS: In 2006, NAMBTS issued 771 single and pooled PLT doses from 3054 whole blood (WB) donations (drawn from 18,422 WB donations). In 2007, NAMBTS issued 486 single and pooled PLT doses from 1477 WB donations (drawn from 18,309 WB donations) and 131 single-donor PLT doses. By 2011, NAMBTS issued 837 single-donor PLT doses per year, 99.1% of all PLT units. Of 5761 WB donations from which PLTs were made in 2006 to 2011, a total of 20 (0.35%) were from donors with confirmed test results for human immunodeficiency virus or other transfusion-transmissible infections (TTIs). Of 2315 single-donor apheresis donations between 2007 and 2011, none of the 663 donors had a confirmed positive result for any pathogen. As apheresis replaced WB-derived PLTs, apheresis production costs dropped by a mean of 8.2% per year, while pooled PLT costs increased by an annual mean of 21.5%. Unit prices paid for apheresis- and WB-derived PLTs increased by 9 and 7.4% per year on average, respectively. CONCLUSION: Namibia's PLT transition shows that collections from repeat apheresis donors can reduce TTI risk and production costs.

Blood component use in a sub-Saharan African country: results of a 4-year evaluation of diagnoses associated with transfusion orders in Namibia.

National blood use patterns in sub-Saharan Africa are poorly described. Although malaria and maternal hemorrhage remain important drivers of blood demand across Africa, economic growth and changes in malaria, HIV/AIDS, and noncommunicable disease epidemiology may contribute to changes in blood demand. We evaluated indications for blood use in Namibia, a country in southern Africa, using a nationally representative sample and discuss implications for the region. Clinical and demographic data related to the issuance of blood component units in Namibia were reviewed for a 4-year period (August 1, 2007-July 31, 2011). Variables included blood component type, recipient age and sex, and diagnosis. Diagnoses reported by clinicians were reclassified into International Statistical Classification of Diseases, 10th Revision categories. Multiple imputation methods were used to complete a data set missing age, sex or diagnosis data. Descriptive analyses were conducted to describe indications for transfusions and use of red blood cells (RBCs), platelets, and plasma. A total of 39,313 records accounting for 91,207 blood component units were analyzed. The median age of Namibian transfusion recipients was 45 years (SD, ±19). A total of 78,660 RBC units were issued in Namibia during the study period. Red blood cells transfused for "unspecified anemia" accounted for the single largest category of blood issued (24,798 units). Of the overall total, 38.9% were for diseases of the blood and blood-forming organs (D50-D89). Infectious disease (A00-B99), pregnancy (O00-O99), and gastrointestinal (K20-K93) accounted for 14.8%, 11.1%, and 6.1% of RBC units issued, respectively. Although a specific diagnosis of malaria accounted for only 2.7% of pediatric transfusions, an unknown number of additional transfusions for malaria may have been categorized by requesting physicians as unspecified anemia and counted under diseases of blood forming organs. During the study period, 9751 units of fresh-frozen plasma were issued. Nearly one-quarter of these units (23.1%) were issued for gastrointestinal (K20-K93) diagnoses. Malignant neoplasms (C00-C97) accounted for 38.1% of 2978 platelet units issued. Blood use in Namibia reflects changes in the health care system due to economic development, improvement in HIV/AIDS and malaria epidemiology, high rates of health care facility-based childbirth, and access to noncommunicable disease treatment. However, better documentation of the indications for transfusion is needed to confirm these observations. Changing patterns of health care will result in changing demands for blood components. Improved methods to evaluate blood use patterns in sub-Saharan Africa may help set realistic national blood collection goals.

The impact of external donor support through the U.S. President's Emergency Plan for AIDS Relief on the cost of red cell concentrate in Namibia, 2004-2011.

BACKGROUND: External assistance can rapidly strengthen health programmes in developing countries, but such funding can also create sustainability challenges. From 2004-2011, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) provided more than $ 8 million to the Blood Transfusion Service of Namibia (NAMBTS) for supplies, equipment, and staff salaries. This analysis describes the impact that support had on actual production costs and the unit prices charged for red cell concentrate (RCC) units issued to public sector hospitals. MATERIAL AND METHODS: A costing system developed by NAMBTS to set public sector RCC unit prices was used to describe production costs and unit prices during the period of PEPFAR scale-up (2004-2009) and the 2 years in which PEPFAR support began to decline (2010-2011). Hypothetical production costs were estimated to illustrate differences had PEPFAR support not been available. RESULTS: Between 2004-2006, NAMBTS sold 22,575 RCC units to public sector facilities. During this time, RCC unit prices exceeded per unit cost-recovery targets by between 40.3% (US$ 16.75 or N$ 109.86) and 168.3% (US$ 48.72 or N$ 333.28) per year. However, revenue surpluses dwindled between 2007 and 2011, the final year of the study period, when NAMBTS sold 20,382 RCC units to public facilities but lost US$23.31 (N$ 170.43) on each unit. DISCUSSION: PEPFAR support allowed NAMBTS to leverage domestic cost-recovery revenue to rapidly increase blood collections and the distribution of RCC. However, external support kept production costs lower than they would have been without PEPFAR. If PEPFAR funds had not been available, RCC prices would have needed to increase by 20% per year to have met annual cost-recovery targets and funded the same level of investments as were made with PEPFAR support. Tracking the subsidising influence of external support can help blood services make strategic investments and plan for unit price increases as external funds are withdrawn.

Estimation of the prevalence and rate of acute transfusion reactions occurring in Windhoek, Namibia.

BACKGROUND: Acute transfusion reactions are probably common in sub-Saharan Africa, but transfusion reaction surveillance systems have not been widely established. In 2008, the Blood Transfusion Service of Namibia implemented a national acute transfusion reaction surveillance system, but substantial under-reporting was suspected. We estimated the actual prevalence and rate of acute transfusion reactions occurring in Windhoek, Namibia. METHODS: The percentage of transfusion events resulting in a reported acute transfusion reaction was calculated. Actual percentage and rates of acute transfusion reactions per 1,000 transfused units were estimated by reviewing patients' records from six hospitals, which transfuse >99% of all blood in Windhoek. Patients' records for 1,162 transfusion events occurring between 1(st) January - 31(st) December 2011 were randomly selected. Clinical and demographic information were abstracted and Centers for Disease Control and Prevention National Healthcare Safety Network criteria were applied to categorize acute transfusion reactions. RESULTS: From January 1 - December 31, 2011, there were 3,697 transfusion events (involving 10,338 blood units) in the selected hospitals. Eight (0.2%) acute transfusion reactions were reported to the surveillance system. Of the 1,162 transfusion events selected, medical records for 785 transfusion events were analysed, and 28 acute transfusion reactions were detected, of which only one had also been reported to the surveillance system. An estimated 3.4% (95% confidence interval [CI]: 2.3-4.4) of transfusion events in Windhoek resulted in an acute transfusion reaction, with an estimated rate of 11.5 (95% CI: 7.6-14.5) acute transfusion reactions per 1,000 transfused units. CONCLUSION: The estimated actual rate of acute transfusion reactions is higher than the rate reported to the national haemovigilance system. Improved surveillance and interventions to reduce transfusion-related morbidity and mortality are required in Namibia.

Comparison of HIV-1 detection in plasma specimens and dried blood spots using the Roche COBAS Ampliscreen HIV-1 test in Kisumu, Kenya.

The World Health Organization recommends screening donor blood for HIV in centralized laboratories. This recommendation contributes to quality, but presents specimen transport challenges for resource-limited settings which may be relieved by using dried blood spots (DBS). In sub-Saharan Africa, most countries screen donor blood with serologic assays only. Interest in window period reduction has led blood services to consider adding HIV nucleic acid testing (NAT). The U.S. Food and Drug Administration (FDA) mandates that HIV-1 NAT blood screening assays have a 95% detection limit at or below 100 copies/ml and 5000 copies/ml for pooled and individual donations, respectively. The Roche COBAS Ampliscreen HIV-1 test, version 1.5, used for screening whole blood or components for transfusion, has not been tested with DBS. We compared COBAS Ampliscreen HIV-1 RNA detection limits in DBS and plasma. An AIDS Clinical Trials Group, Viral Quality Assurance laboratory HIV-1 standard with a known viral load was used to create paired plasma and DBS standard nine member dilution series. Each was tested in 24 replicates with the COBAS Ampliscreen. A probit analysis was conducted to calculate 95% detection limits for plasma and DBS, which were 23.8 copies/ml (95% CI 15.1-51.0) for plasma and 106.7 copies/ml (95% CI 73.8-207.9) for DBS. The COBAS Ampliscreen detection threshold with DBS suggests acceptability for individual donations, but optimization may be required for pooled specimens.