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We performed a risk-benefit analysis for implementation of pathogen-inactivated ( PI) apheresis platelets ( APs) in the United States, focusing on the amotosalen/ultraviolet- A system. Risks and benefits were quantified per patient assuming a mean of 6 AP units per treatment cycle and using available clinical data, mathematical modeling, and observational studies. Current risks associated with AP transfusion can be divided into known partially addressed risks, known well-addressed risks, and unknown risks associated with acute or chronic emerging infectious agents ( EIAs). Bacterial contamination dominates the first category, at a per-patient rate of 1:250, which correlates with an estimated septic transfusion reaction rate of 1:1000. Quantitation of per-patient EIA risk was modeled to be between 1:370 (acute) and 1:667 (chronic). Due to its broad range of action PI is expected to reduce or eliminate these infectious risks and also to reduce the rate of febrile transfusion reactions and possibly alloimmunization. These benefits are weighed against 1) concerns for excess bleeding, 2) an apparent increase in acute respiratory distress syndrome in the initial report of the SPRINT clinical trial, and 3) the possible toxicity associated with the introduction of a new chemical into platelet ( PLT) units. However, transfusion of an estimated 100,000 patients with PI PLTs worldwide has occurred without reported serious adverse effects. We conclude that evidence indicates a favorable risk-benefit profile for the implementation of PLT PI and argues for a path forward toward US regulatory approval. [ABSTRACT FROM AUTHOR]

Background: With an increasing number of recognized transfusion-transmitted (TT) babesiosis cases, Babesia microti is the most frequently TT parasite in the United States. We evaluated the inactivation of B. microti in red blood cells (RBCs) prepared in Optisol (AS-5) using amustaline and glutathione (GSH) and in platelet components (PCs) in 100% plasma using amotosalen and low-energy ultraviolet A (UVA) light.Study Design and Methods: Individual RBCs and apheresis PCs were spiked with B. microti-infected hamster RBCs (iRBCs) to a final concentration of 106 iRBCs/mL and treated with the respective inactivation systems according to the manufacturer's instruction. Samples were collected before (control) and after (test) each treatment. Dilutions of the control samples to 10-6 were inoculated into hamsters, while the test samples were inoculated neat or at 10-1 dilution. At 3 and 5 weeks postinoculation, hamsters were evaluated for B. microti infection by microscopic observation of blood smears and 50% infectivity titers (ID50 ) were determined. Log reduction was calculated as control log ID50 minus test log ID50 .Results: Parasitemia was detected in hamsters injected with as low as 100,000-fold diluted control samples, while no parasites were detectable in the blood smears of any hamsters receiving neat test samples. Mean log reduction was more than 5 log/mL by amustaline/GSH for RBCs and more than 4.5 log/mL by amotosalen/UVA for PCs.Conclusion: B. microti was inactivated to the limit of detection in RBCs and PCs after the respective inactivation treatment. Complete inactivation of B. microti was achieved in this animal infectivity model, and pathogen reduction treatment inhibited transmission of infection. [ABSTRACT FROM AUTHOR]

Background: Concerned over the risk of Zika virus (ZIKV) transfusion transmission, public health agencies recommended the implementation of mitigation strategies for its prevention. Those strategies included the use of pathogen inactivation for the treatment of plasma and platelets. The efficacy of amotosalen/ultraviolet A to inactivate ZIKV in plasma had been previously demonstrated, and the efficacy of inactivation in platelets with the same technology was assumed. These studies quantify ZIKV inactivation in platelet components using amotosalen/ultraviolet A.Study Design and Methods: Platelet components were spiked with ZIKV, and ZIKV infectious titers and RNA loads were measured by cell culture-based assays and real-time polymerase chain reaction in spiked platelet components before and after photochemical treatment using amotosalen/ultraviolet A.Results: The mean ZIKV infectivity titers and RNA loads in platelet components before inactivation were either 4.9 log10 plaque forming units per milliliter, or 4.4 log10 50% tissue culture infective dose per milliliter and 7.5 log10 genome equivalents per milliliter, respectively. No infectivity was detected immediately after amotosalen/ultraviolet A treatment. No replicative virus remained after treatment, as demonstrated by multiple passages on Vero cell cultures; and ZIKV RNA was not detected from the first passage after inactivation. Additional experiments in this study demonstrated efficient inactivation to the limit of detection in platelets manufactured in 65% platelet additive solution, 35% plasma, or 100% plasma.Conclusion: As previously demonstrated for plasma, robust levels of ZIKV inactivation were achieved in platelet components. With inactivation of higher levels of ZIKV than those reported in asymptomatic, RNA-reactive blood donors, the pathogen-inactivation system using amotosalen/ultraviolet A offers the potential to mitigate the risk of ZIKV transmission by plasma and platelet transfusion. [ABSTRACT FROM AUTHOR]

Background and Objectives Blood Centre logistics, staffing and donor scheduling may be optimized if pathogen inactivation ( PI) of platelets can be delayed until Day 1, but bacteria may rapidly grow during this time. This study evaluates bacterial PI performed 24 and 30 h after collection. Materials and Methods PAS-3 platelet units were collected on the Amicus and subsequently inoculated (3-53 CFU/unit) with 1of 5 transfusion relevant bacterial species ( n = 3/organism). Units were then stored for either 24 ± 0·3 or 30 ± 0·3 h at 20-24°C with agitation, subsequently treated with amotosalen and UVA, and stored for 7 days. Samples were taken before and after inactivation, on Days 2, 5 and 7 for BacT/ ALERT testing, and on Days 5 and 7 for plate counts. Results All samples from units taken prior to inactivation either demonstrated positive plate culture counts, or, in untreated positive controls, were culture-positive during storage. All contaminated units treated with amotosalen and UVA 24 after inoculation were culture-negative on all days tested. With inactivation performed 30 h following inoculation, one of 15 units (1-of-3 replicates) was culture-positive with Klebsiella pneumonia (1 × 109 CFU/ml) by Day 5. Conclusion Photochemical treatment did not inactivate 1 of 15 units to sterility in apheresis platelets stored in PAS with a 30-h delay between contamination and treatment, but did inactivate 15 of 15 units with a 24-h delay. [ABSTRACT FROM AUTHOR]

Background: Pathogen inactivation methods are increasingly used to reduce the risk of infections after transfusion of blood products. Photochemical treatment (PCT) of platelets (PLTs) and plasma with amotosalen and ultraviolet A (UVA) light inactivates pathogens and white blood cells through formation of adducts between amotosalen and nucleic acid that block replication, transcription, and translation. The same adducts block the amplification of nucleic acids using polymerase chain reaction (PCR) in a manner that correlates with the number of adducts formed, providing a direct quality control (QC). Current QC measures for PCT rely on indirect methods that measure the delivered UVA dose or percent residual amotosalen after illumination, rather than directly measuring nucleic acid modification.Study Design and Methods: Endogenous mitochondrial DNA (mtDNA), which is detectable in PLT and plasma units, was chosen as a target for the quantification of photochemically induced modifications. DNA was extracted from untreated or amotosalen and UVA-treated PLTs or plasma, and mtDNA fragments of variable lengths were quantified using a real-time PCR inhibition assay.Results: PCT induced increasing real-time PCR inhibition of mtDNA amplification for larger amplicon sizes. Amplification was unaffected by treatment with amotosalen or UVA alone, whereas up to 3 log inhibition was observed after PCT. Blinded PCR testing of a panel of 110 samples each, from PLT or plasma components prepared for routine use within a blood center, allowed 100% discrimination between untreated and treated units.Conclusion: Our initial findings indicate that an adequately sensitive, quantitative real-time PCR inhibition assay targeting mtDNA could provide a valuable tool to confirm and monitor PCT. [ABSTRACT FROM AUTHOR]

Background: Pathogen inactivation (PI) is a new approach to blood safety that may introduce additional costs. This study identifies costs that could be eliminated, thereby mitigating the financial impact.Study Design and Methods: Cost information was obtained from five institutions on tests and procedures (e.g., irradiation) currently performed, that could be eliminated. The impact of increased platelet (PLT) availability due to fewer testing losses, earlier entry into inventory, and fewer outdates with a 7-day shelf life were also estimated. Additional estimates include costs associated with managing (1) special requests and (2) test results, (3) quality control and proficiency testing, (4) equipment acquisition and maintenance, (5) replacement of units lost to positive tests, (6) seasonal or geographic testing, and (7) health department interactions.Results: All costs are mean values per apheresis PLT unit in USD ($/unit). The estimated test costs that could be eliminated are $71.76/unit and a decrease in transfusion reactions corresponds to $2.70/unit. Avoiding new tests (e.g., Babesia and dengue) amounts to $41.80/unit. Elimination of irradiation saves $8.50/unit, while decreased outdating with 7-day storage can be amortized to $16.89/unit. Total potential costs saved with PI is $141.65/unit. Costs are influenced by a variety of factors specific to institutions such as testing practices and the location in which such costs are incurred and careful analysis should be performed. Additional benefits, not quantified, include retention of some currently deferred donors and scheduling flexibility due to 7-day storage.Conclusions: While PI implementation will result in additional costs, there are also potential offsetting cost reductions, especially after 7-day storage licensing. [ABSTRACT FROM AUTHOR]

BACKGROUND: The human erythrovirus B19 (B19) is a small (18- to 26-nm) nonenveloped virus with a single-stranded DNA genome of 5.6 kb. B19 is clinically significant and is also generally resistant to pathogen inactivation methods. Photochemical treatment (PCT) with amotosalen and ultraviolet A (UVA) inactivates viruses, bacteria, and protozoa in platelets (PLTs) and plasma prepared for transfusion. In this study, the capacity of PCT to inactivate B19 in human PLT concentrates was evaluated. STUDY DESIGN AND METHODS: B19 inactivation was measured by a novel enzyme-linked immunosorbent spot (ELISPOT) erythroid progenitor cell infectivity assay and by inhibition of long-range (up to 4.3 kb) polymerase chain reaction (PCR), under conditions where the whole coding region of the viral genome was amplified. B19-infected plasma was used to test whether incubation of amotosalen with virus before PCT enhanced inactivation compared to immediate PCT. RESULTS: Inactivation of up to 5.8 log of B19 as measured by the infectivity assay, or up to 6 logs as measured by PCR inhibition can be achieved under non-limiting conditions. Inactivation efficacy was found to increase with incubation prior to UVA illumination. Without incubation prior to illumination 2.1 +0.4 log was inactivated as determined by infectivity assay. When measured by PCR inhibition, inactivation varied inversely with amplicon size. When primers that spanned the entire coding region of the B19 genome were used, maximum inhibtion of PCR amplification was demonstrated. CONCLUSION: Under defined conditions, PCT with amotosalen combined with UVA light can be used to inactivate B19, a clinically significant virus that can be transmitted through blood transfusion, and heretofore has been demonstrated to be refractory to inactivation. [ABSTRACT FROM AUTHOR]