cost-effectiveness of blood donor screening for babesia microti in...

D O N O R - R E L A T E D I N F E C T I O N R I S K

Cost-effectiveness of blood donor screening for Babesia microtiin endemic regions of the United States

Matthew S. Simon,1,2 Jared A. Leff,1 Ankur Pandya,1 Melissa Cushing,3 Beth H. Shaz,4

David P. Calfee,1,2 Bruce R. Schackman,1,2 and Alvin I. Mushlin1,2

BACKGROUND: Babesia microti is the leadingreported cause of red blood cell (RBC) transfusion-transmitted infection in the United States. Donorscreening assays are in development.STUDY DESIGN AND METHODS: A decision analyticmodel estimated the cost-effectiveness of screeningstrategies for preventing transfusion-transmitted babe-siosis (TTB) in a hypothetical cohort of transfusionrecipients in Babesia-endemic areas of the UnitedStates. Strategies included: 1) no screening; 2) UniformDonor Health History Questionnaire (UDHQ), “statusquo”; 3) recipient risk targeting using donor antibodyand polymerase chain reaction (PCR) screening; 4) uni-versal endemic donor antibody screening; and 5) uni-versal endemic donor antibody and PCR screening.Outcome measures were TTB cases averted, costs,quality-adjusted life-years (QALYs), and incrementalcost-effectiveness ratios (ICERs; $/QALY). Weassumed a societal willingness to pay of $1 million/QALY based on screening for other transfusion-transmitted infections.RESULTS: Compared to no screening, the UDHQavoids 0.02 TTB cases per 100,000 RBC transfusionsat an ICER of $160,000/QALY whereas recipient risk–targeted strategy using antibody/PCR avoids 1.62 TTBcases per 100,000 RBC transfusions at an ICER of$713,000/QALY compared to the UDHQ. Universalendemic antibody screening avoids 3.39 cases at anICER of $760,000/QALY compared to the recipient risk–targeted strategy. Universal endemic antibody/PCRscreening avoids 3.60 cases and has an ICER of $8.8million/QALY compared to universal endemic antibodyscreening. Results are sensitive to blood donor Babesiaprevalence, TTB transmission probability, screening testcosts, risk and severity of TTB complications, andimpact of babesiosis diagnosis on donor quality of life.CONCLUSION: Antibody screening for Babesia inendemic regions is appropriate from an economic per-spective based on the societal willingness to pay forpreventing infectious threats to blood safety.

The intraerythrocytic protozoan Babesia microtiis currently the leading red blood cell (RBC)transfusion-transmitted pathogen reported tothe US Food and Drug Administration (FDA).1

Babesiosis most commonly occurs after an Ixodesscapularis tick bite and results in clinical manifestationsthat range from asymptomatic infection or influenza-likeillness to organ failure and death.2 Complications mayinclude acute respiratory distress syndrome (ARDS), dis-seminated intravascular coagulopathy, renal failure, orhemolytic anemia. In hospitalized or immunocompro-mised patients, mortality rates of 6% to 28% have beenreported.3-7

In the United States, the disease has a regional focusin seven Northeast and Upper Midwest states (Connecti-cut, Massachusetts, Minnesota, New Jersey, New York,Rhode Island, and Wisconsin) accounting for 97% of 1124babesiosis cases reported to the Centers for DiseaseControl and Prevention (CDC) in 2011.8 Over the

ABBREVIATIONS: ARDS = acute respiratory distress syndrome;

ICER(s) = incremental cost-effectiveness ratio(s); IDSA =

Infectious Diseases Society of America; QALY(s) = quality-

adjusted life-year(s); TTB = transfusion-transmitted babesiosis;

UDHQ = Uniform Donor Health History Questionnaire.

From the 1Department of Public Health, the 2Department of

Medicine, and the 3Department of Pathology, Weill Cornell

Medical College, New York, New York; and the 4New York Blood

Center, New York, New York.

Address reprint requests to: Matthew S. Simon, MD, MS,

Department of Public Health, Weill Cornell Medical College,

402 East 67th Street, New York, NY 10065; e-mail:

[email protected].

Preliminary findings were presented at the 34th Annual

Meeting of the Society for Medical Decision Making in Phoenix,

AZ, in October 2012.

Received for publication June 20, 2013; revision received

September 10, 2013, and accepted September 30, 2013.

doi: 10.1111/trf.12492

TRANSFUSION 2014;54:889-899.

Volume 54, March 2014 TRANSFUSION 889

past decade the geographic range of B. microti hasexpanded and more tick and transfusion-transmittedcases have been documented.4,9 In endemic states, donorseroprevalence10 can be as high as 2%, with incidenceranging from 1 in 604 to 1 in 100,000 cases per RBC unitstransfused.11,12

The current method of blood donor screening forasymptomatic B. microti infection relies on self-reportedhistory through the Uniform Donor Health History Ques-tionnaire (UDHQ) followed by indefinite deferral of donorsacknowledging a history of infection.13 In 2010, a FDABlood Products Advisory meeting concluded that alterna-tive strategies to mitigate the risk of transfusion-transmitted babesiosis (TTB) were needed.14 One strategyis blood product screening with antibody and/or poly-merase chain reaction (PCR) assays in regions with highBabesia prevalence. Another potential strategy is to test afraction of donors and maintain a separate inventory ofBabesia-negative RBC components for transfusion to high-risk recipients only. High-risk conditions include asplenia;organ transplantation; malignancy; human immunodefi-ciency virus (HIV); immunosuppressive medications;chronic heart, lung, and liver disease; advanced age; andpremature infants.2 In 2010, the Rhode Island Blood Centerinitiated the first laboratory-based blood donor screeningprogram for B. microti targeting thalas-semia, sickle cell disease, and neonatalpatients under an FDA investigationalnew drug protocol.15 The American RedCross, in collaboration with industry,is evaluating high-throughput immu-nofluorescence antibody and PCRB. microti blood screening assays andother assays are in development.16,17

Since the HIV epidemic, publicexpectations are zero tolerance forinfectious threats to blood safety.18 Asdiagnostic technology has improvedand new infections, such as West Nilevirus, have emerged, blood supplyscreening assays have been successfullyimplemented despite extremely highcost-effectiveness ratios.19 Experiencesuggests a societal willingness to adoptfor blood safety interventions at, orabove, 1 million dollars per quality-adjusted life-year ($/QALY), a 10- to20-fold higher threshold than for othermedical and pharmaceutical interven-tions.20,21 The unique geographic, sea-sonal, and microbiologic characteristicsof Babesia, combined with the difficultyof accurately identifying at-risk donorsand recipients, have posed exceptionalchallenges for transfusion medicine in

balancing the costs and benefits of potential screeninginterventions.22 We evaluated the cost-effectiveness of thestatus quo UDHQ and three laboratory-based blooddonor screening strategies compared to no screening forB. microti in endemic US regions.

MATERIALS AND METHODS

Model overviewWe developed a decision analytic model (Fig. 1) to simu-late the health and economic consequences of bloodsupply screening for B. microti in a hypothetical cohort oftransfusion recipients in endemic regions with a mean ageof 60 years.23 Transfusion recipients receive 1 unit of RBCsper donor. Recipients are assigned probabilities of receiv-ing correctly or incorrectly identified Babesia-infected oruninfected units of blood based on test sensitivity, speci-ficity, and blood donor Babesia prevalence. When aninfected RBC unit is transfused, transmission may or maynot occur. If B. microti is transmitted, recipients mayremain asymptomatic or develop symptomatic babesio-sis. Recipients with babesiosis can recover and return tobaseline health, experience long-term disability, or diefrom babesiosis or unrelated causes. Recipients who

M

M

M

M

M

M

M

Transfusion recipient

Donor negative/ RBC unit transfused

Donor positive/ RBC unit discarded

False negative

True negative

TTB

No TTB

Complicated TTB

Uncomplicated TTB

Transfusion recipient dies

Transfusion recipient survives

True positive/Blood discarded appropriately/Donor notified

False positive/Blood discarded inappropriately/Donor notified

Fig. 1. Decision tree structure for blood supply screening for B. microti. Closed

circles represent chance events and open circles represent Markov processes where

transfusion recipients transition between alive and dead health states to project life-

time outcomes. The model was run separately for high-risk and non–high-risk trans-

fusion recipients and results are a weighted average for all transfusion recipients.

SIMON ET AL.

890 TRANSFUSION Volume 54, March 2014

receive an uninfected unit can survive or die from unre-lated causes. Model inputs and sensitivity analysis rangesare reported in Table 1. The model was programmed incomputer software (TreeAge Pro 2012, TreeAge Software,Inc., Williamstown, MA).

The model projects the number of TTB cases averted,lifetime QALYs gained, and costs associated with transfu-sions and TTB. Costs and QALYs were projected foreach strategy and used to calculate incremental cost-effectiveness ratios (ICERs) that were compared to anICER threshold of $1 million/QALY, representing a societalwillingness to pay for blood safety.20 The analysis was con-ducted from the societal perspective over a lifetime timehorizon, with all costs in 2011 US dollars,47 and futurehealth costs and consequences were discounted at 3%annually.48

Screening strategiesFor the purposes of the analysis, Connecticut, Massachu-setts, Minnesota, New Jersey, New York, Rhode Island,and Wisconsin were considered endemic states and weassumed that screening would only occur in counties withbabesiosis incidence rates greater than 1.0 per 100,000persons based on CDC or local health department surveil-lance data. For example, in New York State screeningwould occur in Dutchess county (incidence of 17.8 per100,000), but not in Oswego county (incidence of 0 per100,000).49 We compared five screening strategies forB. microti in endemic regions: 1) no screening; 2) UDHQ,the status quo, a 48-item general medical history ques-tionnaire that includes one question asking donors if theyhave a history of babesiosis; 3) recipient risk–targetedscreening in endemic regions whereby only transfusionrecipients identified as high risk receive RBC unitsscreened with both antibody and PCR assays in parallel(simultaneous testing); 4) universal antibody screeningwhere all donated RBC units in an endemic region arescreened with an antibody assay; and 5) universalantibody/PCR screening where all donated RBC units inan endemic region are screened simultaneously with bothantibody and PCR assays allowing for the additionaldetection of donors in the window period before serologicresponse. In all laboratory screening strategies, RBC unitsthat screen positive are discarded and the correspondingdonor is notified and referred for medical evaluation.

DataWe used the proportion of hematology-oncology (15%),organ transplant (1%), neonates (2%), and intensive careunit (11%) transfusion recipients (total of 29%) from the2009 National Blood Collection and Utilization Surveyto estimate the transfusion population at high risk forbabesiosis complications.32 This estimate was similarto previously published reports (25%-27%) of immu-

nocompromised transfusion recipients used in cost-effectiveness analyses of West Nile virus blood supplyscreening.19,33 In the base case, we assumed no shortage ofblood products and that laboratory-screened RBC unitswould always be available for high-risk transfusion recipi-ents in the recipient risk–targeted strategy. Sensitivity andspecificity estimates for the UDHQ were based on NewYork24 and Rhode Island Blood Center15 data, and accuracyof antibody and PCR testing for babesiosis was based onpublished literature for diagnostic tests used in clinicalpractice.25-28 The base case prevalence of 0.9% was aweighted average of published serologic surveys of blooddonors in endemic states.10,15,29,30 We assumed that 4% ofall donors with Babesia would have a window periodinfection (PCR positive; antibody negative).31 The basecase, transmission probability (0.4%), was derived fromthe Rhode Island Blood Center’s incidence and prevalencedata and represents the likelihood of developing symp-tomatic babesiosis after transfusion of a potentially infec-tious unit.15 In the base case we assumed that all positiveunits (antibody positive only, PCR positive only, or bothantibody and PCR positive) were equally infectious. Insensitivity analysis, we examined the impact of increasingthe transmission probability of Babesia-infected RBCunits from a window period donors (antibody negativeand PCR positive). In the base case, high-risk transfusionrecipients were assumed to have a twofold greater risk ofdeveloping symptomatic babesiosis and a 1.8-fold greaterprobability of developing complications compared toother recipients.3 The probability of death after bloodtransfusion was based on results from a survival study of alarge cohort of US transfusion recipients.34 Survival esti-mates for the non–high-risk group were based on datafrom the 41- to 65-year-old cohort and survival of thehigh-risk group was modeled using the aged >65 yearscohort. We assumed a stable annual risk of death beyondYear 3 and merged US life table annual mortality prob-abilities when these values exceeded the cohort-basedestimates (at age 84 for non–high-risk recipients and age90 for high-risk recipients).50 A total of 99.9% of the cohortwas deceased by age 100.

The baseline quality of life of transfusion recipientswas derived from previously published cost-effectivenessanalyses of blood supply screening.19,35 There are no dataon quality of life for patients with babesiosis. Health stateutility weights were extrapolated from quality of lifestudies for influenza hospitalization,36 ARDS,37,51,52 andintensive care unit patients.38 Long-term disability associ-ated with complicated babesiosis was based on quality-of-life data from survivors of ARDS, the most frequentcomplication of severe babesiosis.5,7 In the base case, wedid not assign a quality-of-life change to blood donorswho screen positive assuming that they would remainasymptomatic, resolve the infection, and not requirefurther treatment per Infectious Diseases Society of

COST-EFFECTIVENESS OF TTB PREVENTION


TABLE 1. Model variablesInputs Base case Sensitivity range Reference(s)

Probability valuesScreening test characteristics*

QuestionnaireSensitivity 0.5% 0.1-5 15,24

Specificity 99.9% 90-100 15,24

AntibodySensitivity 94.0% 80-100 25,26

Specificity 97.7% 80-100 25,26

Antibody/PCR in parallelSensitivity 99.9% 90-100 27,28

Specificity 97.7% 80-100 27,28

Babesia microti prevalence*Seropositive 0.9% 0.1-2.0 10,15,29,30

Window period (antibody negative/PCR positive) 0.04% 0.01-0.09 31

Proportion of transfusion recipients at high risk for severe babesiosis* 29% 25-75 19,32,33

Transmission probability* 0.4% 0.1-2.2 15

Probability of complicated babesiosis†High risk 57% 20-80 7

Non–high risk 32% 10-50 3

Babesiosis case fatality rateHigh risk 21% 6-28 5-7

Non–high risk 6% 1-10 3,4

All-cause mortality after RBC transfusion‡Year 1

High risk 38% 27-49 34


Year 2High risk 19% 13-25 34


Year ≥3High risk 15% 10-20 34


Utility valuesBaseline transfusion recipient 0.90 0.60-0.90 19,35

Uncomplicated babesiosis§ 0.87 0.80-0.89 36

Complicated babesiosis¶ 0.67 0.40-0.80 37,38

Costs, 2011 US$Blood donation screening tests

Universal antibody $15 8-23 See textUniversal antibody/PCR $30 15-45 See textTargeted antibody/PCR $33 30-39 See text

Babesiosis hospitalization** (per day) $1,940 970-2,920 39

Outpatient costsSubacute rehabilitation care after complicated babesiosis†† $9,420 4,710-14,130 40

Medication costs (per week)‡‡Atovaquone $650 325-975 41

Azithromycin $22 11-33 41

Physician office visitInitial $152 76-228 42

Follow-up $61 31-92 42

Laboratory work-up of positive donor§§ $157 79-326 43,44

Blood center costsSpecimen collection¶¶ (per positive unit) $143 72-215 45

Screening and processing¶¶ (per positive unit) $67 34-101 45

Donor recruitment*** (per positive unit) $18 9-27 45

Unit destruction*** (per positive unit) $12 6-18 45

Investigation of TTB case††† $1,000 500-1,500 See textDonor time

Office visit $49 25-73 46

Blood donation $37 18-55 45

* See supplementary materials for additional information regarding model input calculations and sources.† High-risk conditions were presumed to confer a 1.8 increase in risk of complications based on the relative risk increase of babesiosis complications

associated with asplenia.3

‡ High-risk and non–high-risk transfusion recipient survival was modeled using outcomes for the 65-year-old cohort and the 45- to 65-year-old cohortfrom the referenced study.34

§ Utility value applied for 2 weeks in non–high-risk recipient and 4 weeks in high-risk recipient after which time the recipient returns to baseline healthstate.

¶ Assumes permanent disability.** Length of hospital stay is 5.3 days39 and 12.7 days5 for uncomplicated and complicated babesiosis, respectively.†† Mean 2009 Medicare payment to subacute nursing facility for diagnosis of severe sepsis.‡‡ Average wholesale price adjusted by average Medicaid discount and pharmacy dispensing fee. Azithromycin and atovaquone were assumed to be

prescribed for outpatient therapy whereas hospitalized patients could receive clindamycin and quinine depending on severity as per IDSA guide-lines.

§§ Laboratory work-up includes repeat B. microti serology, blood smear, NAT, Borrelia burgdorferi serology, complete blood count, liver function tests,and basic chemistry panel.

¶¶ Costs applied only for false positives representing opportunity cost of inappropriate deferral.*** Costs applied for both true and false positives.††† Includes costs of testing all potentially implicated RBC units and labor costs.

SIMON ET AL.


America (IDSA) recommendations.53 In sensitivity analy-sis, we considered a temporary utility decrement forpositive donors because the notification and medicalfollow-up process may result in emotional distress and lifedisruption.54

All TTB-related costs were assumed to occur dur-ing the first year after transfusion. The per-unit costs ofantibody screening and antibody/PCR screening wereestimated to be $15 and $30, respectively, since no FDA-approved test currently exists. The antibody/PCR cost wasincreased by 10% in the recipient risk–targeted strategy toaccount for additional costs to maintain a separate inven-tory of blood products and potentially higher per unitcosts. Babesiosis hospitalization costs were obtained from2009 Healthcare Cost and Utilization Project data39 andsubacute rehabilitation stay costs for complicated babe-siosis were extrapolated from Medicare data for sepsis.40

Medication costs for azithromycin and atovaquone werebased on average wholesale drug prices41 and durationswere per IDSA guidelines.53 The cost to blood centers toinvestigate reported TTB cases included confirmatorytesting of all potentially implicated RBC units and laborcosts (D.A. Kessler, personal communication, 2012). Thecosts of excluding donors who self-reported a historyof babesiosis included blood center screening andpredonation medical evaluation. Societal costs for dis-carding Babesia-positive RBC units included blood centercosts, such as increased recruitment and unit destruc-tion,45 as well as donor medical work-up and time.42-44,46

Additional costs for false positives represented the oppor-tunity costs for blood centers to collect, screen, andprocess donated RBCs that were inappropriately dis-carded. Additional details regarding the model inputs anddata sources are available in Appendix S1, available assupporting information in the online version of this paper.

Sensitivity analysesVariables were varied individually in one-way sensitivityanalysis to evaluate the sensitivity of results to plausiblevariations in model estimates. Overall model uncertainty

was evaluated in probabilistic sensitivity analysis bysimultaneously conducting 1000 random draws fromprobability distributions for each variable and recalculat-ing the cost-effectiveness of each strategy. All variableswere assumed to have triangular probability distributions,with the base case estimate as the mode and with uncer-tainty ranges in Table 1 representing the lower and upperlimits. To evaluate the stability of results to this assump-tion, probability distributions for key variables werechanged from triangular to uniform to represent greateruncertainty.

RESULTS

Base case cost-effectiveness results are displayed inTable 2. The predicted TTB incidence was similar with noscreening or the status quo UDHQ (approx. 3.6 cases per100,000 RBC transfusions). The projected number of TTBcases avoided per 100,000 RBC transfusions compared tono screening would be 1.6 for recipient risk–targeted strat-egy, 3.4 for universal endemic antibody screening, and 3.6for universal endemic antibody/PCR screening. The netcosts per RBC transfusion for the recipient risk–targeted,universal endemic antibody, and universal endemicantibody/PCR strategies would be $11.72, $20.42, and$35.57, respectively, increases of 5, 9, and 16% above themean price ($223) US hospitals paid per RBC unit in2009.32 The anticipated health benefit per 100,000 RBCstransfused would be 1.52 QALYs for recipient risk target-ing, an additional 1.14 QALYs for universal endemic anti-body, and an additional 0.17 QALYs for universal endemicantibody/PCR screening. Compared to no screening, thestatus quo UDHQ strategy had an ICER of $160,000/QALY.The ICER for recipient risk–targeted screening comparedto the status quo was $713,000/QALY and the ICERfor universal endemic antibody screening compared torisk-targeted screening was $760,000/QALY. Universalendemic antibody/PCR screening, the most effective andexpensive strategy, had an ICER of $8.8 million/QALYcompared to universal endemic antibody screening. If theonly policy option considered was screening all units

TABLE 2. Cost-effectiveness results of blood supply screening for B. microti in endemic regions

Screening strategy

TTB cases averted(/100,000 RBCs

transfused)Cost* (perRBC unit)

Incremental cost*(/100,000 RBCs

transfused)

QALYs (pertransfusionrecipient)

Incremental QALYs(/100,000 RBCs

transfused)ICER†

($/QALY)

No screening $0.83 5.9143787UDHQ (status quo) 0.02 $0.85 $2,000 5.9143798 0.01 160,000Recipient risk targeted

(antibody/PCR)1.62 $11.72 $1,086,000 5.9143942 1.52 713,000

Universal antibody‡ 3.39 $20.42 $871,000 5.9144056 1.14 760,000Universal antibody/PCR‡ 3.60 $35.57 $1,515,000 5.9144073 0.17 8,778,000

* 2011 US$.† In strict incremental analysis the ICERs represent the difference in costs and effects between a strategy and the next most effective alter-

native. The cost-effectiveness results for each strategy compared to no screening were: 1) recipient risk targeted (antibody/PCR) $708,000/QALY; 2) universal antibody $730,000; and 3) universal antibody/PCR $1,220,000/QALY.

‡ The term “universal” refers to a strategy of screening all donated blood units within an endemic region and not national screening.



in an endemic region with both antibody and PCR (vs. donothing), the cost-effectiveness ratio of this strategywould be $1.2 million/QALY.

In one-way sensitivity analyses, variables that exertedthe greatest influence on results were B. microti blooddonor prevalence, the transmission probability, screeningtest costs, the risk and severity of babesiosis complica-tions, and impact of babesiosis diagnosis on donor qualityof life (Table S1 in Appendix S1). Where babesiosis preva-lence exceeds 0.6% (compared to 0.9% in the base case),universal endemic antibody screening is the preferredstrategy at an ICER threshold of $1 million/QALY (Fig. 2).When the transmission probability was varied, universalendemic antibody screening is the preferred strategy atan ICER threshold of $1 million/QALY when incidenceexceeded 1 per 39,000 RBC units transfused, compared to1 per 28,000 RBC units transfused in the base case (Fig. S1in Appendix S1). The recipient risk–targeted strategy waspreferred if the transmission probability for a RBC unitfrom a window period donor was greater than four times

the transmission probability for a non–window perioddonor and universal endemic antibody/PCR was optimalif this value was 20 times greater.

Universal endemic antibody screening was no longerpreferred when antibody screening cost $18 or more perRBC unit or when antibody/PCR cost less than $22. Ifpooled testing of multiple blood units could reduce thecost of combination antibody/PCR by threefold to $10 perunit and sensitivity maintained at greater than 80%, uni-versal endemic antibody/PCR would be preferred at awillingness to pay of $1 million/QALY. If a recipient risk-targeted strategy employing antibody screening only (andnot parallel antibody/PCR) was a viable policy option, theICERs would be $426,000/QALY and $1.1 million/QALYfor risk-targeted and universal antibody screening,respectively.

Risk-targeted screening was preferable to universalendemic antibody screening when high-risk recipientshad an eightfold greater relative risk of symptomatictransmission (compared to twofold in base case) or a 2.4

0

1,000,000

2,000,000

3,000,000

4,000,000

5,000,000

6,000,000

7,000,000

8,000,000

0.1% 0.3% 0.5% 0.7% 0.9% 1.1% 1.3% 1.5% 1.7% 1.9%

$/QALY

Babesia microti prevalence

$1 million/QALY threshold

Base case

Fig. 2. Cost-effectiveness of each screening strategy as a function of B. microti prevalence in blood donors. At prevalence greater

than 0.6%, universal antibody screening is the most cost-effective strategy given a willingness to pay for blood safety of $1 million

per QALY. (– – –) Risk targeted (antibody/PCR); (—) universal antibody; (●) universal antibody/PCR.

SIMON ET AL.


times greater relative risk of developing complicatedbabesiosis (compared to 1.8 in the base case). Laboratorytesting was no longer preferred when donor quality of lifewas temporarily decreased by 0.02 (on a scale from 0 to 1)after the diagnosis of asymptomatic babesiosis.

In probabilistic sensitivity analysis (Fig. 3) at a cost-effectiveness threshold of $1 million/QALY, laboratoryscreening was preferred to the status quo in 84% ofsimulations: universal antibody (62%), recipient risk tar-geted (16%), and universal antibody/PCR (6%). If willing-ness to pay was $5 million/QALY (reflecting the currentpractice for nucleic acid testing [NAT] of donated bloodfor HIV, HBV, and HCV55,56), universal antibody/PCR waspreferred in 37% of simulations. At a cost-effectivenessthreshold frequently used outside of blood screening($100,000/QALY) laboratory screening strategies were pre-ferred in approximately 2% of simulations. Results werestable after probability distributions for key variables werereplaced with uniform distributions (SupplementaryFig. S2 in Appendix S1).

DISCUSSION

Medical community and public expectations for TTB pre-vention have intensified as a result of reported increasedincidence.57,58 We used a decision analytic model to evalu-ate the effectiveness and cost-effectiveness of laboratory-based blood supply screening for B. microti. We found thatuniversal antibody screening in endemic regions couldavoid approximately three cases of TTB per 100,000 RBCtransfusions with a cost-effectiveness ratio of less than $1million/QALY, which compares favorably to currentlyadopted practices for preventing other transfusion-transmitted infections (Table 3).59,60

Our analysis is the first to consider the cost-effectiveness of the current donor health history question-naire for preventing TTB. Using data from the RhodeIsland and New York Blood Centers we estimated theUDHQ has a sensitivity of 0.5% and a positive predic-tive value of 24% when compared to antibody testing.15,24

Laboratory screening strategies with better test

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000 2,000,000

Probability of being op�mal strategy

Willingness to pay ($/QALY)

$1 million/QALYthreshold

Fig. 3. Cost-effectiveness acceptability curve showing the probability that a screening strategy is optimal (provides the greatest

health benefit) at a specified willingness-to-pay value. (▲) No screening; (■) UDHQ (status quo); (—) universal antibody; (– – –) risk

targeted (antibody/PCR); (●) universal antibody/PCR.



characteristics prevented more cases of TTB and had cost-effectiveness ratios below $1 million/QALY. Althoughcombining antibody and PCR screening of all donatedblood would be the most effective strategy, the additionalhealth benefit compared to antibody screening is likely tobe small, and we found this strategy had an unfavorablecost-effectiveness ratio of more than $8 million/QALY.Importantly, this finding was sensitive to assumptionsregarding the infectivity of Babesia-infected RBC unitsthat came from a window period donor and estimates ofassay cost. In the base case, we assumed the transmissionprobability was the same for all test-positive units.However, when we assumed a window period donationwas approximately 20 times more likely to transmitBabesia, the preferred strategy changed, and testing of allRBC units in an endemic region with antibody and PCRwas the favored option.

In an effort to mitigate costs, policy makers have con-sidered selectively applying antibody/PCR screening toimmunocompromised transfusion recipients at risk forsevere babesiosis.61 In clinical practice, determining anappropriate high-risk population is challenging becauseof diverse and common risk factors for severe babesiosissuch as advanced age and heart disease. Our analysis cap-tured additional costs associated with a selective transfu-sion strategy, such as maintaining a separate inventory ofblood products, by assigning a 10% additional per unitcost for each unit tested under this strategy. We found thatuniversal endemic antibody screening would be preferredto risk-targeted antibody/PCR screening because it offersgreater overall health benefit (more TTB cases preventedand QALYs gained) with a comparable cost-effectivenessratio (approx. $700,000-800,000 per QALY). This result isexplained by the significant costs associated with Babesiaantibody/PCR screening of approximately 30% of theblood supply for transfusion recipients with easily identi-fiable high-risk conditions and the likelihood of severeTTB cases occurring in transfusion recipients with other

common comorbidities who would be difficult to targetthrough risk-based algorithms. Furthermore, prior workhas documented the logistic and ethical problems associ-ated with selective transfusion protocols designed toprevent transfusion-related complications.62,63 Our modelsuggests that, in addition to these issues, a risk-targetedtransfusion policy for TTB prevention in endemic regionsis unlikely to offer greater value compared to a universalantibody screening strategy.

If universal screening were to be adopted in endemicregions, the exclusion of many potential donors raisesadditional concerns related to cost, blood availability, anddonor follow-up. In our model, the costs of donor medicalevaluation and discarded blood amounted to approxi-mately $625 per donation testing positive. PCR-basedscreening offers the potential to reduce these costs due toimproved specificity. We did not consider PCR-basedscreening on its own as important determinants of theperformance of PCR assays in the donor population areunknown. These include optimal sample volume, primerselection, and the particular method employed (i.e., real-time PCR vs. nested PCR). In our analysis, we did notassume a shortage of blood products from increaseddonor exclusion because, on average, the US blood supplyoperates on approximately a 10% margin above demand.32

Excluding donors who were group O or phenotypematched for chronically transfused populations could beof greater concern. Future analyses examining the bloodcenter budget impact of Babesia screening and simulationmodeling of donor reentry protocols based on antibodyclearance are important areas for further investigation.Finally, to address additional unintended consequences oflaboratory screening, we considered potential adversequality-of-life effects on asymptomatic Babesia-positiveblood donors. Our results were sensitive to small changesin donor quality of life, which underscores the importanceof effective donor notification programs that addresspotential anxiety, confusion, and life disruption.54

TABLE 3. League table of blood safety interventions for transfusion-transmitted infection prevention

Source (first author, year) Intervention ComparatorYear of FDA

licensure ICER* ($/QALY)

Eisenstaedt, 198859 Anti-HIV No screen 1985 Cost savingBusch, 199560 Anti-HCV No screen 1990 Cost savingCuster, 200519 West Nile virus NAT† No screen 2006 701,000Current study Babesia microti antibody No screen Investigational 730,000Agapova, 201035 Chagas disease antibody‡ No screen 2006 863,000Jackson, 200355

Marshall, 200456HBV, HCV, and/or HIV minipool NAT§ HBsAg, anti-HBc

Anti-HCVAnti-HIV

1999-2005 5.4 million

* All costs updated to 2011 US$.† Strategy of minipool testing of RBC units and individual unit testing in a geographic region experiencing West Nile virus outbreak.‡ Strategy of universal one-time donor testing.§ Averaged ICER from the two referenced studies.HCV = hepatitis C virus; anti-HBc = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; ID = individualdonation.

SIMON ET AL.


Our analysis supports universal screening of donatedblood in regions with Babesia seroprevalence greaterthan 0.6%. Babesia prevalence among blood donorsin nonendemic regions has not been well quantified, but13% of 162 TTB cases reported to the CDC occurredoutside of endemic regions through donor travel orimported blood products.9 Recent data indicate 0.2%seroprevalence in areas of New Hampshire and Maine64

and 0.02% in Oklahoma and Arizona.65 Our results do notapply to areas in the Western United States where Babesiaduncani and other Babesia species are found since theywould not be identified with current screening assaysfor B. microti. However, other Babesia species have beenimplicated in only a small fraction (2%) of TTB casesreported to the CDC.9

Our analysis has important limitations pertaining tothe quality of data used to inform model inputs and otherassumptions. The point estimates for assay sensitivity andspecificity are based on diagnostic tests used in clinicalsettings (not blood donor screening) and test costs arebased on other blood donor screening tests. We used thebest available evidence describing babesiosis clinical out-comes, incorporating published studies of both tick- andtransfusion-associated disease. However, robust clinicaloutcome data are limited, with the existing evidence baseconsisting of small studies lacking long-term follow-up onthe frequency and severity of babesiosis morbidity. Clinicaloutcomes are better characterized for tick-associatedbabesiosis than transfusion-associated disease because ofthe small number of reported cases and likely under-recognition and underreporting. Evidence suggesting sig-nificantly worse outcomes for transfusion recipients withbabesiosis than the estimates in this study would onlyimprove the cost-effectiveness of screening. To account forthe uncertainty around our estimates, we incorporated abroad range of plausible values in sensitivity analysesrelated to these and other important model inputs.

Models by their nature are simplified representationsof complex real-world processes. We did not incorporatethe dynamic interplay of ecologic, host–parasite, andhuman behavioral factors that may impact on tick- andtransfusion-associated Babesia transmission. Our modelassumes that prevalence is uniformly distributed through-out an endemic region when, in reality, it is focal withoutclearly defined geographic borders. Further research isneeded to more precisely characterize B. microti’s geo-graphic range and the appropriate boundaries for donorscreening. We also did not consider a seasonally targetedTTB mitigation strategy. Tick-associated babesiosis has aseasonal peak from June through September, whereastransfusion-associated disease may occur year-round.The addition of PCR to antibody testing only duringmonths of high tick activity could hypothetically enhancethe cost-effectiveness of combination donor testing.However, seasonal variations in Babesia blood donor

epidemiology and the duration of the window period arenot well characterized.

In conclusion, we found that the cost-effectiveness ofB. microti antibody screening of donated blood comparesfavorably to adopted blood safety interventions. Selectiverecipient risk-targeted screening offers less value thanuniversal antibody screening using a cost-effectivenessthreshold for blood safety of $1 million/QALY. Based on thissocietal willingness to pay for preventing infectious threatsto blood safety, donor antibody screening for B. microti isappropriate in endemic areas of the United States.

ACKNOWLEDGMENTS

We acknowledge the input of Susan Stramer, PhD, American Red

Cross, and Debra Kessler, RN, MS, New York Blood Center, for

providing their expert opinion. Neither received compensation

for their contributions. MSS received educational support

through Grant UL1 TR000457 of the Clinical and Translational

Science Center at Weill Cornell Medical College. The funding

agency had no role in the design and conduct of the study; in the

collection, analysis, and interpretation of the data; or in the

preparation, review, or approval of the manuscript.

CONFLICT OF INTEREST

The authors report no conflicts of interest or funding sources.

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SUPPORTING INFORMATION

Additional Supporting Information may be found in theonline version of this article at the publisher’s web-site:

Appendix S1. Technical appendix.[Correction added after online publication 19-Nov-2013:The supporting information file has been updated.]

