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Research Article

# Cost-Effectiveness of Alternative Blood-Screening Strategies for West Nile Virus in the United States

• To whom correspondence should be addressed. E-mail: ck2187@columbia.edu

Affiliations: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, The Earth Institute, Columbia University, New York, New York, United States of America

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• Affiliation: The Harvard Center for Risk Analysis, Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts, United States of America

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• Affiliations: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America

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• Published: January 24, 2006
• DOI: 10.1371/journal.pmed.0030021

## Abstract

### Background

West Nile virus (WNV) is endemic in the US, varying seasonally and by geographic region. WNV can be transmitted by blood transfusion, and mandatory screening of blood for WNV was recently introduced throughout the US. Guidelines for selecting cost-effective strategies for screening blood for WNV do not exist.

### Methods and Findings

#### Sensitivity Analyses

Within areas of low infection /short duration of WNV, the questionnaire alone remained the least-costly strategy across a wide range of sensitivity analyses. When we assumed that assay sensitivity was as high as other nucleic acid tests, seasonally screening the entire donor pool by MP16-NAT was also on the efficiency curve; however, the ICER was US$1.2 million/QALY gained. Similarly, when we assumed an estimate from the high end of the plausible range for the probability of severe disease, ID-NAT added less than 1 min to the average quality-adjusted life expectancy at a cost of US$1 million/QALY. Further details are shown in Tables S1S6.

For areas with high infection/short duration, the rank order of strategies was sensitive to variations in test sensitivity and the risk of developing severe disease. When we assumed the high assay sensitivity, seasonally screening the entire donor pool by MP6-NAT was the least-costly strategy; seasonally screening the entire donor pool by ID-NAT was also on the efficiency curve but exceeded US$7 million/QALY. When we assumed a high risk of severe disease, unrestricted seasonal screening by ID-NAT was the only non-dominated strategy. We also evaluated the effect of shortened seasonal screening from mid-July to mid-October versus full seasonal screening from May to the end of October for this transmission area. Shortened seasonal screening offered the same clinical benefit at lower cost than full seasonal screening; targeted screening of blood designated for transfusion of immunocompromised patients was the least-costly strategy. The ICER for universal screening by ID-NAT versus targeted screening of blood designated for transfusion of immunocompromised patients remained too high for universal screening to be a cost-effective strategy, even with shortened seasonal screening. For the high-infection/long-duration scenario, our results were sensitive to both improved assay sensitivity and changes in assumptions about the risk of developing severe disease. When we assumed high assay sensitivity, seasonal screening by MP6-NAT was the only non-dominated strategy. When we assumed an estimate from the low end of the plausible range for risk of severe disease, the questionnaire strategy was least costly, although seasonal screening by ID-NAT of blood designated for transfusion of immunocompromised patients offered additional clinical benefit for an ICER of US$56,000/QALY gained.

### Discussion

The recent emergence of WNV in the US has led to a perceived need to safeguard the blood supply from viremic blood donations. Strategies for screening blood for emerging viral infections such as WNV are often put into place without systematic evaluation of their costs, benefits, and cost-effectiveness. In this study, we conducted a cost-effectiveness analysis of alternative strategies for blood screening and considered the efficacy of these strategies in areas with varying epidemic intensity, exploring the effect of variable assay characteristics, transfusion outcomes, and pricing that may affect current and future policy decisions.

Our analyses demonstrated that in areas with high infection rates, in the order of those seen in Mississippi and Nebraska in 2002, seasonal screening of blood designated for immunocompromised recipients prolongs quality-adjusted life expectancy compared with implementing a baseline questionnaire alone. Although other strategies, such as screening pooled samples designated for all donors, provided some benefit compared to a questionnaire alone, they were more costly and either less effective or only marginally more effective than restricted seasonal screening. In areas with low infection and seasonal transmission, none of the NAT strategies offered additional clinical benefit given current test-sensitivity estimates, although they were associated with substantial costs. These results suggest that the general screening of blood for WNV may not be as attractive a public health strategy as it first appeared to be, and that more restricted screening strategies may be preferable to currently mandated policies.

The finding that blood-screening strategies for WNV may be outside the usually accepted cost-effectiveness thresholds is consistent with previous cost-effectiveness analyses for blood screening for infectious agents [21,2932]. A recent analysis of NAT screening for hepatitis B and C and HIV compared to serological testing alone showed that the ICER exceeded US$1.5 million/QALY gained, well beyond the US$50,000–100,000 threshold commonly used as an indicator of willingness to pay for a health-care intervention [21]. AuBuchon et al. [29] have previously enumerated some of the reasons why cost-effectiveness estimates of blood-screening tests are so unattractive; risks are relatively low, transfusion recipients often have a reduced quality-adjusted life expectancy, and costs are incurred for all donations, few of which are infectious. Despite this, blood-screening tests are often implemented for reasons that are not captured in a cost-effectiveness analysis. There is a perception that blood recipients cannot be held responsible for avoiding risk, and therefore the system must protect them at any cost. Individuals are willing to pay more to avoid a catastrophic outcome, even when the risk is low compared to other outcomes. Furthermore, policy makers are more likely to apply an intervention to a small and defined group such as blood recipients rather than to a less-visible group [32]. Nonetheless, in an era of major cuts in public health expenditure and increasingly limited resources available for health care, it is worthwhile reconsidering the economic implications of this priority; resources spent preventing the rare case of transfusion-associated WNV might be better utilized in a host of other interventions against infectious disease, including those focused on reducing WNV transmission through mosquito vectors. If such an approach were successful, it might obviate the need for screening blood for the virus in many areas.

Our analysis has a number of limitations as the ecology of WNV in the US, and the clinical course and sequelae of transfusion-acquired WNV infection, have not been clearly defined. Transmission intensities have varied over the years within some geographic regions since the emergence of WNV. Choosing the most cost-effective approach to screening within a specific area will depend on the ability to predict transmission intensity for the current season. Recently, a risk equation based on mosquito abundance, infectivity, vector competence, and host feeding behavior was developed to predict short-term future human WNV infections in an area [33]. The utility of this index to predict human infections is under investigation. Methods to validate, and improve upon, current prediction tools for WNV infection would enhance our ability to select the most cost-effective screening strategies. Improved methods to both measure and efficiently monitor the mosquito population parameters that determine virus transmission to humans would allow us to shift policy in response to important temporal changes in transmission patterns.

Lacking other data, we estimated the risk of developing NI after an infected transfusion from a single study in which patients with cancer were deliberately inoculated with WNV [13]. These data may overestimate the true risk of disease, since the patients studied may have been more susceptible to severe disease than healthier blood recipients. Such a bias would exaggerate the benefits of screening in our analyses. Otherwise, if the potentially higher dose of virus from a transfusion-associated infection results in an even higher risk of developing NI than we estimated, the benefits of screening are underestimated in our analyses [10,11]. In addition, in the absence of large-cohort data, we assumed that data from small studies on the long-term clinical consequences of WNV-associated NI patients represent the expected sequelae of infection.

Among the least well-defined parameters used in this analysis were those reflecting the performance of the newly introduced nucleic acid–screening tests. These were FDA-approved prior to establishing their sensitivity and specificity, and these characteristics have yet to be published. Given the imprecision of these estimates together with our expectation that the assay will improve with further product development, we repeated our analyses assuming that NAT for WNV was highly sensitive and specific. However, this analysis assumed that an improved test bore no additional cost. While various measures to enhance detection of low levels of viremia have been proposed, these would add further steps to screening rather than replace existing approaches, possibly adding substantially to expense. New methods that achieve small boosts in sensitivity (such as IgM antibody testing as an adjunct method to detect positive samples that have escaped NAT detection) are unlikely to be cost-effective under the assumptions made in this analysis. Custer et al. [34] demonstrated that while continuous ID-NAT screening would overburden blood-testing laboratories, ID-NAT screening during select times of the transmission season is needed currently, since minipool assays fail to detect 23% of the viremic samples detected by ID-NAT.

In conclusion, we found that NAT screening of blood donations for WNV improved clinical outcomes only in those areas where the incidence of WNV is high, and that limiting screening to high-intensity transmission seasons and to blood donations designated for immunocompromised patients reduced costs without decreasing quality-adjusted life expectancy in most scenarios. We recommend that states adopt screening policies based on the intensity and duration of their WNV epidemics. Regional data, in conjunction with the results of this analysis and consideration of societal risk attitudes and preferences, may collectively point to a relaxation of the current federally mandated NAT screening of all donations in low-intensity areas. When high rates of natural infection indicate that NAT screening is appropriate, we recommend use of ID-NAT rather than minipool screening. States should consider the restricted screening of blood designated for immunocompromised patients alone. Finally, we suggest that blood-screening policies be carefully scrutinized for cost-effectiveness and that their relative contribution to safeguarding public health be considered in the making of policy decisions.

### Supporting Information

Table S1. Predicted QALYs, Costs, Clinical Outcomes, and ICERs Associated with NAT Blood Screening for WNV in a Cohort of 2,000,000

High-sensitivity estimates.

doi:10.1371/journal.pmed.0030021.st001

(82 KB DOC).

Table S2. Predicted QALYs, Costs, Clinical Outcomes, and ICERs Associated with NAT Blood Screening for WNV in a Cohort of 2,000,000

Low-severity estimates.

doi:10.1371/journal.pmed.0030021.st002

(76 KB DOC).

Table S3. Predicted QALYs, Costs, Clinical Outcomes, and ICERs Associated with NAT Blood Screening for WNV in a Cohort of 2,000,000

High-severity estimates.

doi:10.1371/journal.pmed.0030021.st003

(76 KB DOC).

Table S4. Predicted QALYs, Costs, Clinical Outcomes, and ICERs Associated with NAT Blood Screening for WNV in a Cohort of 2,000,000

Low-cost estimates.

doi:10.1371/journal.pmed.0030021.st004

(76 KB DOC).

Table S5. Predicted QALYs, Costs, Clinical Outcomes, and ICERs Associated with NAT Blood Screening for WNV in a Cohort of 2,000,000

High-cost estimates.

doi:10.1371/journal.pmed.0030021.st005

(76 KB DOC).

Table S6. Predicted QALYs, Costs, Clinical Outcomes, and ICERs Associated with NAT Blood Screening for WNV in a Cohort of 2,000,000

Shortened seasonal screening for high-infection/short-duration transmission area.

doi:10.1371/journal.pmed.0030021.st006

(43 KB DOC).

### Acknowledgments

Funding for CTK was provided by the National Institutes of Health grants T32 AI007535 and R01 AI052284–02 and by Harvard School of Public Health, Department of Epidemiology. We would like to acknowledge Dr. Anne Labowitz and Dr. Denis Nash, both formerly of the New York City Department of Health and Mental Hygiene, for sharing their data on long-term follow-up of patients with West Nile virus. We would also like to thank the editors and independent reviewers (Dr. Brad Biggerstaff and Dr. Bruce Lee) for helpful comments. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

### Author Contributions

CTK, SJG, and MBM designed the study and contributed to writing the paper. CTK and MBM analyzed the data. SJG provided oversight of the model-development process and model simulations.

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### Background

West Nile virus (WNV) was first isolated from a sick woman in the West Nile region of Uganda in 1937. The virus has subsequently been found to be widespread in Africa and Eurasia, and sporadic outbreaks have been reported throughout these regions. WNV was first detected in the US in 1999, in a sick woman in New York. The disease has since spread to most states in the continental US, making thousands of people ill and causing several hundred deaths. Wild birds are the principal host of WNV, and the virus is transmitted to humans mainly by mosquitoes that bite both birds and humans. Most of the people who get infected by a mosquito bite do not get sick at all, but about 20% develop a flu-like illness. In a small number of cases—especially among the elderly and people with a weakened immune system—the infection spreads to the nervous system and can cause death or long-term disability. Like other blood-borne diseases, WNV can be transferred by blood transfusion with contaminated blood. Such cases have occurred in the US and have killed few people.

WNV can be detected in blood samples by recently developed and approved tests. These tests detect most, but not all, cases of contamination with the virus. This means the WNV deaths resulting from transfusion of contaminated blood are potentially avoidable by screening donated blood. As a consequence, the US Food and Drug Administration (FDA) has mandated screening of donated blood samples. However, the FDA has not prescribed specific screening strategies, and the decision on how to best screen blood samples has been left to the individual states and the blood-collection agencies. The researchers who carried out this study wanted to determine which screening strategies would be cost-effective—that is, which strategies would prevent infections through contaminated blood for a reasonable price. In an ideal world, cost would not matter when it comes to protecting human life and health, but in reality there is limited money available for public health measures. Studies such as this one are therefore essential to help politicians decide how to spend the money.

### What Did the Researchers Do and Find?

They calculated the costs of screening and the number of prevented infections through blood transfusion for a number of different scenarios. They found that in states with low WNV infection rates, the risk of an infected person donating blood was so low that screening was unlikely to prevent cases of serious illness from WNV, despite substantial costs. In states where WNV is common, screening throughout the year is likely to prevent cases of serious illness, but at a substantial cost. In states where WNV is common, screening blood only from May to the end of October (the months when mosquitoes are around and people get infected from them), however, was as effective at identifying contaminated blood samples as screening throughout the year. One way to reduce costs substantially was to create a separate blood pool that is reserved for transfusions to people with a weakened immune system and to screen only those samples. Because those are the people most at risk for severe WNV illness, this strategy would still prevent most of those cases.

### What Do These Findings Mean?

It is not clear whether the current policy to screen all blood samples in all states makes sense from a health economy point of view. Restricting screening to states where WNV is common and to samples designated for people at higher risk for severe WNV illness would reduce costs significantly without putting the recipients of blood transfusions at a substantially higher risk of serious illness caused by WNV.

The following Web sites provide information on WNV.

Pages from the US Centers for Disease Control and Prevention:

Pages from the US National Biological Information Infrastructure:

MedlinePlus pages:

US Food and Drug Administration pages:

US Geological Survey pages:

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