Health Economic Aspects of Platelet Concentrates: Comparing Cost and Reimbursement of Pathogen Inactivated and Conventional Platelet Concentrates in a German Comprehensive Cancer Center.

INTRODUCTION: Pathogen inactivation (PI) utilizing amotosalen and UVA light (INTERCEPT® Blood System) is a well-established method for the production of safer platelet concentrates (PCs). While many studies describe clinical and logistical benefits of PI, the implications and potential challenges from a hospital management perspective have not yet been analyzed - health economic analyses considering reimbursement of PI are lacking. The objective of this analysis was to examine the real-life inpatient treatment costs from a hospital perspective and to assess the economic impact of PI-PC versus conventional PC (CONV-PC) administration in Germany. METHODS: Real-life cost data for inpatient cancer cases from 2020 of the University Hospital Cologne were identified by operating and procedure codes. The German diagnosis-related groups, extra fees, case mix index (CMI), length of stay (LOS), and average resource consumption of PC were evaluated from a micro-management perspective. The potential economic impact of implementing PI-treated PCs was modeled retrospectively. RESULTS: In total, 951 inpatient cases were analyzed (CMI [median 4.7-9.9], LOS [median 26 days], number of cases in intensive care units [38%]). The median DRG fee was between EUR 13,800 and EUR 26,400. According to our model, the use of PI-PC compared to CONV-PC would result in savings between EUR 184 and EUR 306 per case. CONCLUSION: From a hospital management perspective, oncological cases requiring PC transfusion are associated with a high CMI (reimbursement per DRG flat fee) and moderate costs with sufficient add-on payment for PI on a case level. Investment and process costs for PI implementation can be analyzed for site-specific scenarios.

Characterization of pathogen-inactivated COVID-19 convalescent plasma and responses in transfused patients.

BACKGROUND: Efficacy of donated COVID-19 convalescent plasma (dCCP) is uncertain and may depend on antibody titers, neutralizing capacity, timing of administration, and patient characteristics. STUDY DESIGN AND METHODS: In a single-center hypothesis-generating prospective case-control study with 1:2 matched dCCP recipients to controls according to disease severity at day 1, hospitalized adults with COVID-19 pneumonia received 2 × 200 ml pathogen-reduced treated dCCP from 2 different donors. We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 convalescent plasma donors and recipients using multiple antibody assays including a Coronavirus antigen microarray (COVAM), and binding and neutralizing antibody assays. Outcomes were dCCP characteristics, antibody responses, 28-day mortality, and dCCP -related adverse events in recipients. RESULTS: Eleven of 13 dCCPs (85%) contained neutralizing antibodies (nAb). PRT did not affect dCCP antibody activity. Fifteen CCP recipients and 30 controls (median age 64 and 65 years, respectively) were enrolled. dCCP recipients received 2 dCCPs from 2 different donors after a median of one hospital day and 11 days after symptom onset. One dCCP recipient (6.7%) and 6 controls (20%) died (p = 0.233). We observed no dCCP-related adverse events. Transfusion of unselected dCCP led to heterogeneous SARS CoV-2 antibody responses. COVAM clustered dCCPs in 4 distinct groups and showed endogenous immune responses to SARS-CoV-2 antigens over 14-21 days post dCCP in all except 4 immunosuppressed recipients. DISCUSSION: PRT did not impact dCCP anti-virus neutralizing activity. Transfusion of unselected dCCP did not impact survival and had no adverse effects. Variable dCCP antibodies and post-transfusion antibody responses indicate the need for controlled trials using well-characterized dCCP with informative assays.

Is pathogen reduction an acceptable alternative to irradiation for risk mitigation of transfusion-associated graft versus host disease?

Transfusion-associated graft versus host disease (TA-GVHD) is a highly morbid and often fatal adverse event associated with transfusion of cellular blood products [platelets, red blood cells (RBCs) and whole blood] and more rarely with never-frozen plasma products. It is caused by residual viable donor T-lymphocytes that proliferate and actively target recipient tissues. Selective or universal irradiation of blood components using gamma-irradiation and more recently, X-ray irradiation, are the most commonly applied interventions and have been validated by the demonstration of in vitro T-lymphocyte inactivation, in murine models of TA-GVHD and by years of clinical experience. Irradiation, however, has multiple limitations including a sharp dose-response curve that renders quality control of dosage critically important, the use of radioactive radiation sources that are a terrorism risk, and selective implementation in many countries that leads to inadvertent omission and patient risk exposure. Certain pathogen reduction technologies (PRT) for platelets have been approved by regulatory authorities and endorsed by professional societies as an alternative to irradiation for reducing the risk of TA-GVHD, and PRT for RBCs and whole blood are in development. While the mechanism of action of T-lymphocyte inactivation differs from gamma/X-ray irradiation, the impact on T-lymphocyte inactivation for PRT is equivalent or superior to that of irradiation as demonstrated by sensitive in vitro lymphocyte proliferation assays and in vivo mouse models that approximate human TA-GVHD. Clinical trials and cumulative routine-use experience attest to the efficacy of PRT when used as an alternative to irradiation. While T-lymphocyte inactivation efficacy varies between PRT platforms, the implementation of PRT for platelets increases blood safety for patients beyond the mitigation of TA-GVHD, by decreasing the risk of transfusion transmitted infections with known viruses, bacteria and parasites as well as emerging pathogens.

Analysis of SARS-CoV-2 antibodies in COVID-19 convalescent blood using a coronavirus antigen microarray.

The current practice for diagnosis of COVID-19, based on SARS-CoV-2 PCR testing of pharyngeal or respiratory specimens in a symptomatic patient at high epidemiologic risk, likely underestimates the true prevalence of infection. Serologic methods can more accurately estimate the disease burden by detecting infections missed by the limited testing performed to date. Here, we describe the validation of a coronavirus antigen microarray containing immunologically significant antigens from SARS-CoV-2, in addition to SARS-CoV, MERS-CoV, common human coronavirus strains, and other common respiratory viruses. A comparison of antibody profiles detected on the array from control sera collected prior to the SARS-CoV-2 pandemic versus convalescent blood specimens from virologically confirmed COVID-19 cases demonstrates near complete discrimination of these two groups, with improved performance from use of antigen combinations that include both spike protein and nucleoprotein. This array can be used as a diagnostic tool, as an epidemiologic tool to more accurately estimate the disease burden of COVID-19, and as a research tool to correlate antibody responses with clinical outcomes.

Inactivation of a broad spectrum of viruses and parasites by photochemical treatment of plasma and platelets using amotosalen and ultraviolet A light.

BACKGROUND: The INTERCEPT Blood System pathogen reduction technology (PRT), which uses amotosalen and ultraviolet A light treatment (amotosalen/UV-PRT), inactivates pathogens in plasma and platelet components (PCs). This review summarizes data describing the inactivation efficacy of amotosalen/UVA-PRT for a broad spectrum of viruses and parasites. METHODS: Twenty-five enveloped viruses, six nonenveloped viruses (NEVs), and four parasites species were evaluated for sensitivity to amotosalen/UVA-PRT. Pathogens were spiked into plasma and PC at high titers. Samples were collected before and after PRT and assessed for infectivity with cell cultures or animal models. Log reduction factors (LRFs) were defined as the difference in infectious titers before and after amotosalen/UV-PRT. RESULTS: LRFs of ≥4.0 log were reported for 19 pathogens in plasma (range, ≥4.0 to ≥7.6), 28 pathogens in PC in platelet additive solution (PC-PAS; ≥4.1-≥7.8), and 14 pathogens in PC in 100% plasma (PC-100%; (≥4.3->8.4). Twenty-five enveloped viruses and two NEVs were sensitive to amotosalen/UV-PRT; LRF ranged from >2.9 to ≥7.6 in plasma, 2.4 or greater to greater than 6.9 in PC-PAS and >3.5 to >6.5 in PC-100%. Infectious titers for four parasites were reduced by >4.0 log in all PC and plasma (≥4.9 to >8.4). CONCLUSION: Amotosalen/UVA-PRT demonstrated effective infectious titer reduction for a broad spectrum of viruses and parasites. This confirms the capacity of this system to reduce the risk of viral and parasitic transfusion-transmitted infections by plasma and PCs in various geographies.

Pathogen inactivation with amotosalen plus UVA illumination minimally impacts microRNA expression in platelets during storage under standard blood banking conditions.

BACKGROUND: To reduce the risk of transfusion transmission infection, nucleic acid targeted methods have been developed to inactivate pathogens in PCs. miRNAs have been shown to play an important role in platelet function, and changes in the abundance of specific miRNAs during storage have been observed, as have perturbation effects related to pathogen inactivation (PI) methods. The aim of this work was to investigate the effects of PI on selected miRNAs during storage. STUDY DESIGN AND METHODS: Using a pool and split strategy, 3 identical buffy coat PC units were generated from a pool of 24 whole blood donors. Each unit received a different treatment: 1) Untreated platelet control in platelet additive solution (C-PAS); 2) Amotosalen-UVA-treated platelets in PAS (PI-PAS); and 3) untreated platelets in donor plasma (U-PL). PCs were stored for 7 days under standard blood banking conditions. Standard platelet quality control (QC) parameters and 25 selected miRNAs were analyzed. RESULTS: During the 7-day storage period, differences were found in several QC parameters relating to PI treatment and storage in plasma, but overall the three treatments were comparable. Out of 25 miRNA tested changes in regulation of 5 miRNA in PI-PAS and 3 miRNA U-PL where detected compared to C-PAS. A statistically significant difference was observed in down regulations miR-96-5p on Days 2 and 4, 61.9% and 61.8%, respectively, in the PI-PAS treatment. CONCLUSION: Amotosalen-UVA treatment does not significantly alter the miRNA profile of platelet concentrates generated and stored using standard blood banking conditions.

Clinical impact of amotosalen-ultraviolet A pathogen-inactivated platelets stored for up to 7 days.

BACKGROUND: Universal pathogen inactivation of platelet concentrates (PCs) using amotosalen/ultraviolet A with 7-day storage was implemented in Switzerland in 2011. Routine-use data were analyzed at the University Hospital Basel, Switzerland. STUDY DESIGN: A retrospective two-cohort study of patient and PC characteristics, component usage, patient outcomes, count increments (CIs), and adverse events were analyzed for two consecutive 5-year periods with either 0- to 5-day-old conventional PC (C-PC) (n = 14,181) or 0- to 7-day-old pathogen-inactivated PC (PI-PC) (n = 22,579). RESULTS: In both periods, PCs were issued for transfusion on a "first in, first out" basis. With 7-day PI-PC, wastage was reduced from 8.7% to 1.5%; 16.6% of transfused PI-PCs were more than 5 days old. Transfusion of PI-PC more than 5 days old compared with 5 days old or less did not increase platelet and RBC use on the same or next day as an indirect measure of hemostasis and did not increase transfusion reactions. Mean corrected count increments (CCIs) for PI-PC stored for 5 days or less were 22.6% lower than for C-PC (p < 0.001), and declined with increasing storage duration for both, although the correlation was weak (r2 = 0.005-0.014). Mean number of PCs used per patient and duration of PC support were not different for hematology/oncology, allogeneic and autologous hematopoietic stem cell transplant (HSCT), and general medical/surgical patients, who used the majority (~92.0%) of PI-PCs. Five-year treatment-related mortality in allogeneic HSCT was unchanged in the PI-PC period. CONCLUSIONS: PI-PCs with 7-day storage reduced wastage and did not increase PC or red blood cell utilization or adverse reactions compared with fresh PI-PC or a historical control group, demonstrating preserved efficacy and safety.

Update on pathogen inactivation treatment of plasma, with the INTERCEPT Blood System: Current position on methodological, clinical and regulatory aspects.

After the INTERCEPT Blood System for pathogen inactivation (PI) of plasma was locally validated and approved and is now in routine use in Portugal, a conference was arranged in Portugal, by the IPST, in Coimbra, on 19th November 2014. One of the presentations informed about the current status of the INTERCEPT technology for plasma and a subsequent round table discussion, focused on the methodological and logistical aspects as well as on the experience from clinical studies and routine therapeutic use of INTERCEPT treated plasma units. Moreover, in view of current interests, both the global regulatory issues and hemovigilance data obtained were highlighted. This manuscript provides a brief summary of what has been discussed during presentations and the Q/A round table session. It was agreed between speaker and the moderator of the session to report a consensus opinion on the importance of INTERCEPT to improve the safety of plasma products in a standardized way in terms of quality indicators of hemostasis and the clinical effectiveness as well as the reliability of the technology for plasma pathogen inactivation, to be reported as part of a theme section from Portugal and to be published in Transfusion Apheresis Science in early 2015. The session started showing the beneficial advantages of the INTERCEPT technology, which has already become the standard of practice in Portugal and in more than 20 other countries, and then highlighted some of the methodological and global quality/clinical aspects, which are not usually discussed. We hope the topic discussed here would be of interest to readers of Transfusion Apheresis Science.

Pathogen-inactivation of platelet components with the INTERCEPT Blood System ™: a cohort study.

INTRODUCTION: INTERCEPT treatment is used to reduce platelet transfusion associated bacterial infections. Limited data are available in Switzerland. PATIENTS AND METHODS: Patients with thrombocytopenia or thrombocyte dysfunction requiring platelet transfusions were enrolled in a prospective cohort study on safety (primary endpoint) and efficacy (secondary endpoint) of INTERCEPT treated platelets (I-PLTs). I-PLTs were produced from double-dose apheresis products. Data on safety were actively recorded for each transfusion. RESULTS: A total of 551 I-PLT units (mean platelet dose: 2.6 ± 0.4 × 10(11)/unit) were transfused to 46 patients (mean number of platelet transfusions per patient: 12 ± 12.5). Fifty-one (9%) transfusions were associated with adverse events and 12 (2%) with acute transfusion reactions. Eleven serious adverse events were observed, none considered as related to the administration of I-PLT. Mean 1-4h and 16-24h CCIs were 10.1 ± 8.1 and 3.6 ± 6.6, respectively. CONCLUSION: The transfusion of I-PLT was associated with a good safety profile and adequate platelet count increments at 1-4h.

Pathogen Inactivation of Platelet and Plasma Blood Components for Transfusion Using the INTERCEPT Blood System™

BACKGROUND: The transmission of pathogens via blood transfusion is still a major threat. Expert conferences established the need for a pro-active approach and concluded that the introduction of a pathogen inactivation/reduction technology requires a thorough safety profile, a comprehensive pre-clinical and clinical development and an ongoing hemovigilance program. MATERIAL AND METHODS: The INTERCEPT Blood System utilizes amotosalen and UVA light and enables for the treatment of platelets and plasma in the same device. Preclinical studies of pathogen inactivation and toxicology and a thorough program of clinical studies have been conducted and an active he-movigilance-program established. RESULTS: INTERCEPT shows robust efficacy of inactivation for viruses, bacteria (including spirochetes), protozoa and leukocytes as well as large safety margins. Furthermore, it integrates well into routine blood center operations. The clinical study program demonstrates the successful use for very diverse patient groups. The hemovigilance program shows safety and tolerability in routine use. Approximately 700,000 INTERCEPT-treated products have been transfused worldwide. The system is in clinical use since class III CE-mark registration in 2002. The safety and efficacy has been shown in routine use and during an epidemic. CONCLUSION: The INTERCEPT Blood System for platelets and plasma offers enhanced safety for the patient and protection against transfusion-transmitted infections.

Safety and clinical efficacy of platelet components prepared with pathogen inactivation in routine use for thrombocytopenic patients.

This study was conducted to evaluate the safety and efficacy of platelet concentrates (PC) after photochemical treatment (PCT) with the INTERCEPT Blood System™ and transfused in routine use in a population of patients suffering from a variety of hematological diseases. This was an observational, single-arm, open-label study of pooled buffy-coat PC (n=298) or apheresis PC (n=262) treated with INTERCEPT™ and transfused to 51 thrombocytopenic hematology patients. PCT replaced CMV screening and gamma irradiation, and made optional bacterial testing obsolete. The primary study endpoint was the incidence of acute transfusion reactions (ATR). Secondary endpoints included bleeding assessment, platelet count increments, and adverse events (AE). For the 553 transfusions, a total of 55 AE were observed regardless of relationship to platelet transfusion. Ten AE associated with nine transfusions met the criteria for ATR (1.6%). All ATRs were grade 1. Twelve serious AE were reported in 10 patients, none was related to platelet transfusion. Mean 24-h CI and CCI were 10.9 × 10(9) and 6.6 × 10(3)/L, respectively. No bleeding complications were attributable to the INTERCEPT-treated PC. This study confirms safety and efficacy of pathogen inactivated PC for support of thrombocytopenia and demonstrated that INTERCEPT technology can easily be implemented in routine operations.

An unbalanced translocation involving chromosome 14 is the probable cause for loss of potentially functional rearranged immunoglobulin heavy chain genes in the Epstein-Barr virus-positive Hodgkin's lymphoma-derived cell line L591.

In the vast majority of cases, Hodgkin-Reed Sternberg (H-RS) cells, the malignant cells in Hodgkin's lymphoma (HL), are derived from germinal centre B cells. In some cases, somatic mutations within the rearranged immunoglobulin heavy (IgH) chain genes were detected, rendering potentially functional gene rearrangements non-functional. In these H-RS cells the expression of high-affinity B-cell receptors (BCR) was prevented. As in other cases only one non-productive IgH chain gene rearrangement was amplified from H-RS cells, it was speculated whether, in these cases, the functionally rearranged IgH chain genes were lost. An alternative explanation might be that the rearranged genes could not be amplified owing to a high load of somatic mutations within the primer binding sites. Here, we showed that, in the HL-derived Epstein-Barr virus (EBV)-positive cell line L591, only one non-functional somatically mutated IgH gene rearrangement could be detected. The other potentially functional IgH gene rearrangement was lost as a result of an unbalanced translocation affecting the long arm of chromosome 14. Moreover, L591 cells express the EBV latent membrane proteins LMP1 and LMP2A, which might have contributed to the 'escape' of these cells from apoptosis within the germinal centre. We conclude that, apart from the introduction of 'crippling mutations' into the rearranged VDJ genes rearrangement, deletions of the IGH locus may be regarded as another mechanism to prevent the expression of a BCR in H-RS cells.