1. Dengue Transfusion Risk Model Lyle R. Petersen, MD, MPH Brad Biggerstaff, PhD Division of Vector-Borne Diseases Centers for Disease Control and Prevention Blood Products Advisory Committee Meeting December 14, 2010

2. Agenda Arbovirus risk model Dengue transfusion transmission risk in non- endemic areas Dengue transfusion transmission risk in Puerto Rico, an endemic area of the United States Limitations Conclusions

3. General Arbovirus Transfusion Risk Model Risk of transmission = P d x T r x R s Where P d = Prevalence donors viremic T r = Transmission rate from viremic donors to susceptible recipients R S = Proportion of recipients susceptible to infection

4. Assumptions P d = Prevalence donors viremic – Symptomatic persons don’t donate – Donors are similar to the population-at-large with respect to mosquito exposure and infection risk T r = Transmission rate to susceptible recipients – 100% R S = Proportion of recipients susceptible to infection – For dengue, impossible to determine under most circumstances, so assume 100%

5. General Arbovirus Risk Model Risk derives from viremic persons who – remain asymptomatic and donate or – who donate before becoming symptomatic Transfusion transmission risk = Prevalence of viremic and asymptomatic persons in population-at-large Prevalence = incidence X duration of viremia

6. General Arbovirus Risk Model Risk = (I x P a ) x D a + (I x P s ) x D s Where I = Incidence of infection in population-at-large P a = Proportion infections that are asymptomatic D a = Duration of viremia for asymptomatic persons P S = Proportion of infections that are symptomatic D s = Duration of viremia before symptoms develop

7. Dengue Risk Model Variables Highly variable and uncertain – Incidence of infection Ranges from 30% per year in endemic areas – Proportion of infections that are symptomatic Varies by infecting strain and previous exposure to heterologous dengue viruses In adults in endemic areas, three studies range from 25- 50%

8. Dengue Risk Model Variables Less variable and more certain – Duration of viremia Approximately 5 days after onset of symptoms Very short before onset of symptoms, thought to be one day or less Unknown for asymptomatic persons, but presumably similar to that of symptomatic persons Duration viremia < duration NAT positivity

9. Predicted Dengue Transfusion Risk, Key West, FL First dengue outbreak in Florida since 1934* Population 23,262 First case onset July 19, 2009; – 27 infections identified through October 19 Household-based serosurvey in conducted Sept 23-27 – Old-Town area – 4.9% determined to have recent infection Transfusion risk model assumptions – 4.9% population infected in 70 days (July 19-Sept 27) Incidence = 7 per 10,000 per day – 33% infections symptomatic – 1-day viremia before symptoms develop – 6-day total period of viremia * MMWR 2010; 59: 577.

10. Predicted Dengue Transfusion Risk, Key West, FL – Estimated average transfusion risk from Key West donors during outbreak period = 18.7/10,000 – Risk may be overestimated 4.9% infection cumulative incidence in 70 days may not apply to all of Key West Outbreak duration may be longer than identified first case – Compares to estimated transfusion risk of 0.5/10,000 during a 2004 outbreak in Cairns, Australia* Estimated 0.19% cumulative infection incidence in 196 days * Transfusion 2009; 49:1482

11. Puerto Rico Dengue Transfusion Risk Modeling Method Statistical resampling approach*, which allows – Temporal estimates of risk Estimated viremia prevalences in population-at-large on any given day based on observed illnesses – Uncertainty of model parameters Random variation in model parameters within proscribed limits to quantify uncertainty 500 replicates 95% confidence intervals around risk estimates * Transfusion 2003; 43: 1007

12. Model Assumptions: Puerto Rico Proportion infections that are symptomatic 33% (range 25-50%) Duration of viremia for asymptomatic persons 6 days (range 5-7) Duration of viremia before symptoms develop 1 day (range 0.5-1.5) Underreporting of clinical cases – 15X (range 10-20)

13. Estimated Dengue Transfusion Risk per 10,000 donations, Puerto Rico, 1995-2010* Average risk 6.9 (4.6-9.2) Maximum risk51.1 (43.9-60.0)

14. Estimated Dengue Transfusion Risk; Puerto Rico, 1995-2010*

15. Actual NAT Yield versus Predicted Number of Viremic Donors; Puerto Rico, July –Dec, 2007 NAT yield American Red Cross, Puerto Rico – 29 TMA + of 15,325 donors (18.9 per 10,000) Predicted number viremic donors – 29 (13-50) of 15,325 donors

16. Limitations Inference of true infection incidence inferred from disease surveillance data – Underreporting estimates uncertain – Unapparent:apparent infection ratio uncertain and not constant over time Transfusion risk model only considered risk of viremic donations – True transmission rate less because of background immunity in recipients (immeasurable in most circumstances)

17. Conclusions Variation in dengue transfusion risk mostly depends on infection incidence and proportion infections symptomatic – Both difficult to measure and variable Transfusion risk model plausible – Predicted risk and observed NAT yield same in 2007 in Puerto Rico

18. Conclusions Estimated transfusion risk in Key West donors during 2009 outbreak – 18.7/10,000 – Model uncertainties regarding underlying incidence in population-at-large and duration of outbreak Estimated annual transfusion risk Puerto Rico, 1995-2010 – Average daily risk 6.9 (4.6-9.2)/10,000 – Highly seasonal and variable by year – Maximum daily risk 51.1 (43.9-60.0)/10,000 – Average predicted daily transfusion dengue risk over a 15-year period similar to predicted WNV risk in 6 high-incidence states during peak of 2002 epidemics (2.1-4.7/10,000)* * Transfusion 2003; 43:1007