1 Introduction
Blood components and transfusions are critical to ensuring successful lifesaving and costly medical treatments and procedures, including surgeries, trauma care, chemotherapy, and stem cell and organ transplants. In the US, blood centers collect, process, and supply blood components to hospitals. Most hospitals purchase blood products from blood center suppliers and often supplement their supply through in-house collections. In 2013, approximately 14.2 million units of blood products were collected in the US, with 13.2 million transfused [
1]. Of these components, approximately 2.28 million platelet units were transfused [
1], predominantly for hematology and oncology patients (34%), followed by surgery (18%), general medicine (17%), and intensive care units (12%) [
2]. Platelets present certain challenges due to their limited shelf life (5 days post-collection). They are highly susceptible to bacterial contamination due to room temperature storage, often resulting in septic reactions when contaminated units are transfused [
3‐
8].
Screening for certain blood-borne pathogens has been implemented to improve blood safety. However, residual infectious risks still threaten patients, largely due to bacteria [
3‐
8] and emerging pathogens [
9‐
14]. Bacterial contamination is the leading infectious risk associated with platelet transfusion, occurring in approximately 1 in 1500 apheresis platelet components (PCs) [
3‐
8]. Primary bacterial culture, a screening method used for almost all platelets in the US supply, fails to detect more than half of bacterial contaminations [
3‐
8]. Furthermore, because no active system for adverse event reporting exists in the US, bacterial contamination of platelets and resulting sepsis are underrecognized and underreported [
15,
16]. Recent publications suggest that the rate of transfusion-associated (TA) septic reactions determined via active reporting is approximately tenfold that identified by passive reporting [
15]. In a 7-year multicenter study, Hong et al. reported a 1:2500 and 1:10,288 risk in bacterially contaminated and septic reactions, respectively, with active surveillance, when using platelets previously screened and found negative by bacterial culture [
16]. However, despite improvements in detection through active reporting, the linkage between a contaminated platelet and sepsis remains difficult to confirm in clinical settings as patients receiving platelets are often medically complex with underlying issues that can predispose them to infection [
16,
17].
Emerging pathogens, such as Zika, chikungunya, and dengue viruses, as well as Babesia, pose another risk to the blood supply [
9‐
14]. Challenges to a reactive testing strategy arise during these outbreaks: test development and pursuant regulatory approvals may require several years to complete, and continual addition of tests becomes increasingly costly for blood centers and hospitals [
18]. Even in the presence of testing, infectious outbreaks can adversely impact blood product availability [
18].
The US FDA has historically published formal guidance documents to address risks pertaining to transfusion-transmitted infections (TTIs). In March 2016, the FDA published a draft guidance on platelet bacterial contamination mitigation to improve platelet safety through implementation of specific measures, including pathogen reduction (PR) and secondary rapid bacterial testing (RT) of platelets [
3]. In addition, the FDA published a separate final guidance in August 2016 in response to the Zika virus outbreak, recommending the use of either PR or nucleic acid testing (NAT) prior to releasing all three blood components (platelets, red blood cells, plasma) for transfusion [
9].
The INTERCEPT
® Blood System (Cerus Corporation) is currently the only FDA-approved PR system for apheresis platelets. Viruses, bacteria, parasites, and white blood cells, including T cells, are inactivated during the PR process, thus reducing the risk for TTIs, including sepsis and TA graft-versus-host disease (TA-GVHD) [
19]. PR of platelets replaces both primary and secondary bacterial detection, cytomegalovirus (CMV) serology testing, irradiation, and Zika NAT [
3,
9,
19,
20].
Secondary RT is an alternate measure also included in the FDA draft guidance. The Pan Genera Detection (PGD) test (Verax Biomedical) is FDA-approved as a safety measure intended to identify bacterially contaminated platelet units within 24 h prior to transfusion, following primary testing with a bacterial culture [
21]. The PGD test may confer a 7-day shelf life provided that certain criteria are met, including the use of blood bags approved for extended storage, and testing and re-labeling conducted by an FDA-registered blood product manufacturer (blood center or hospital).
The evolving regulatory landscape, driven by the FDA draft guidance, has influenced hospitals to consider interventions such as PR and bacterial testing to mitigate bacterial contamination of platelets. As such, the budgetary impact of these technologies must be evaluated by healthcare purchasers and providers. The objective of this study was to develop a budget impact model allowing hospitals to assess the financial implications of these bacterial contamination mitigation options in the context of the total blood bank budget.
4 Discussion
We present an economic model to aid in hospital transfusion service decision making when evaluating new technologies for platelet preparation and/or new testing regimens. The recent introduction of new products such as pathogen-reduced platelets has provided the opportunity for hospital blood banks to assess the clinical and financial impact of such innovative advances. Our findings are particularly timely given the anticipated release of final FDA guidance on platelet contaminant mitigation.
The model demonstrates a small net annual cost increase (6.18%) for PR-PC compared with RT-PC. The primary factors driving this cost differential are the acquisition prices of the different PCs, their effective shelf lives, and related platelet wastage rates.
We assumed a greater acquisition price for PR-PC than RT-PC. The higher acquisition price may be justified by clinical benefits from inactivation of bacteria, viruses, protozoa, and T cells [
19]. Costs that may accrue due to complications of viral and/or protozoan TTIs and TA-GVHD are not included in this model. Nonetheless, such clinical implications and their potential cost impact should be considered in the context of overall blood safety when evaluating different technologies.
As examined in the model, shelf life is an important concept, both in terms of hospital supply management and cost impact. The PGD test is currently the only secondary rapid bacterial test approved as a safety measure by the FDA and may be used to extend platelet dating to 7 days for platelets suspended in 100% plasma. However, certain criteria must be met to extend shelf life, including the use of FDA-cleared 7-day platelet storage containers, potential modification of contractual agreements with outside suppliers to assure platelets are supplied with cleared storage containers, a new or updated FDA registration and blood product listing, new standard operating procedures to accommodate platelet testing, and relabeling every 24 h [
35]. This model did not include these overhead costs that a hospital may accrue when implementing 7-day platelets with secondary testing; however, it did estimate the extended shelf life and associated savings due to reduced wastage with 7-day RT-PC.
In contrast, pathogen-reduced platelets are approved for a 5-day shelf life, with no further testing or processing required by the hospital. Shelf life can be gained at the front end, allowing hospitals to receive younger platelets, depending on the turnaround time for the blood center supplier’s NAT; NAT is required despite implementation of PR, such as for HIV and HCV for which an FDA mandate exists. If NAT results are available within 12 h of collection, blood center suppliers can release units within the first or second day of platelet collection, preserving approximately 3–4 days of effective shelf life. This model assumes a conservative turnaround time estimate of 24 h for NAT results, with a 5-day shelf life for pathogen-reduced units.
In addition to acquisition and wastage costs, RT and sepsis-related costs were evaluated. RT costs include material and personnel costs of all routine secondary rapid bacterial tests, as well as those performed due to false positive results (per PGD package insert, two additional confirmatory tests are required for every positive result). In addition, PGD test results are valid for no more than 24 h prior to transfusion. In order to minimize costs but comply with this labeling, some hospital transfusion services may opt to quarantine platelets and not test until such time that a transfusion is required. However, other hospitals may prefer to avoid the risks involved in releasing an untested quarantined unit for transfusion, or encountering an emergency situation with no tested product available for immediate transfusion. For example, Level 1 trauma centers generally require immediate availability of platelets and would therefore likely need to have units with valid PGD test results readily available (tested ≤ 24 h prior to transfusion), which will likely increase the need for retesting [
36].
In another recent economic analysis [
37], the cost of implementing PGD is estimated to be approximately US$738 per unit, or US$3.69 million per year for 5000 units, which is comparable to the annual costs estimated by our model. In the same study, PR-PC cost estimates are much higher than ours, largely driven by the assumption that patients receiving pathogen-reduced platelets require more frequent transfusions. However, increased utilization of pathogen-reduced platelets is not observed in routine use. Amato et al. report no increase in platelet or red blood cell utilization when comparing conventional versus pathogen-reduced platelets after the implementation of PR [
38]. Multi-year hemovigilance programs with routine transfusions of over 400,000 pathogen-reduced PCs have also demonstrated no increase in platelet utilization [
31,
32,
39]. The same experience has been reported in the US by Mendez et al. [
40], demonstrating that utilization of the platelet and red cell components is comparable between C-PC and PR-PC.
Finally, sepsis cost assumptions in the model are quite conservative. The cost to treat non-lethal sepsis ranges widely in published reports, largely due to varying sepsis definitions and treatment protocols, and the fact that sepsis is often accompanied by comorbidities such as pneumonia. As such, there is no widely accepted approach to assessing sepsis costs [
41]. In this model, we queried the HCUP database for ICD-9 code 995.91 to obtain the mean cost per sepsis case of US$13,714 (per US$2014) [
30]. This cost is considerably lower than those reported for more severe stages of sepsis in which greater length of stay and treatment is required. For example, mean costs based on hospital reimbursement have been reported at US$39,736 and US$51,307 for severe sepsis and septic shock, respectively [
42]. Although difficult to quantify, there have been cases where deaths implicated with sepsis have led to legal disputes and settlements costing millions of dollars [
43]. Overall, while acquisition and wastage costs were lower for RT-PC than for PR-PC, RT- and sepsis-associated costs are avoided for PR-PC.
The landscape of transfusion safety and bacterial contamination mitigation continues to evolve. In November 2017, the FDA’s Blood Products Advisory Committee (BPAC) discussed additional safety options and recommended that these options be added to a future revised FDA draft guidance [
44]. In addition to PR-PC and RT-PC options already included in the FDA draft guidance, the BPAC recommended two options that entail the use of large-volume bacterial culture. Similar to RT, such methods would only mitigate risk due to bacteria (not viruses, protozoa, or T cells). As with RT-PC, the use of secondary or delayed culture may enable centers to extend shelf life to 7 days; however, due to extensive upfront product hold time requirements, the maximum effective shelf life may only be approximately 4 days.
In summary, our model anticipates a small increase in cost with the adoption of PR-PC when compared with RT-PC. This can be partially offset by outpatient reimbursement. Assuming an overall total annual hospital blood budget of US$130 million that includes platelet (5500 per year), plasma (15,000 per year), and red cell components (40,000 per year), and the associated costs of transfusion, the use of PR-PC represents a 0.13% increase in the overall annual blood products budget when compared with the use of RT-PC. The increase may be justified by the mitigation of TTIs due to viruses, protozoans (as well as bacteria), TA-GVHD, and the avoidance of implementing new tests that require process changes and staff training.
5 Limitations
Our findings are limited by the scenarios we chose to model. First, we assumed the hospital purchases all of its platelets for transfusion, and did not examine a ‘self-collector’ case in which the hospital collects and manufactures platelets on site. Costs will vary in the self-collection case as self-collectors tend to perform procedures such as irradiation in-house and therefore may not pay a premium for irradiated PC. Furthermore, only apheresis platelets, which comprise approximately 90% of platelet transfusions in the US [
45], are assumed in this model; whole blood-derived platelets are not considered.
Costs not considered for RT include costs of the durable equipment required to perform the test; only regular operating costs are considered. Other costs not included are potential FDA registration costs, as well as those attributed to the potential complexity in labeling and relabeling units to extend platelet dating to 7 days. Costs associated with recall, disposal of split units, and notification of the blood center for units that test positive via RT were also not considered. For pathogen-reduced components, all processing occurs at the supplier site; the hospital receives the finished transfusion-ready platelet product, thus incurring no capital equipment costs.
Lastly, costs that may accrue due to complications of viral and/or protozoan TTIs, TA-GVHD, and severe and/or lethal sepsis cases are not included in this model. Nonetheless, hospitals may wish to consider such clinical implications and potential cost impact in the context of overall blood safety when evaluating different technologies.