Dengue Transfusion Risk Model

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 = Pd x Tr x Rs Where Pd = Prevalence donors viremic Tr= Transmission rate from viremic donors to susceptible recipients RS= Proportion of recipients susceptible to infection

4. Assumptions • Pd = Prevalence donors viremic • Symptomatic persons don’t donate • Donors are similar to the population-at-large with respect to mosquito exposure and infection risk • Tr = Transmission rate to susceptible recipients • 100% • RS = 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 ModelRisk = (I x Pa ) x Da + (I x Ps) x Ds Where I= Incidence of infection in population-at-large Pa = Proportion infections that are asymptomatic Da= Duration of viremia for asymptomatic persons PS= Proportion of infections that are symptomatic Ds= Duration of viremia before symptoms develop

7. Dengue Risk Model Variables • Highly variable and uncertain • Incidence of infection • Ranges from <1% to >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 risk 51.1 (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