How dangerous are Donor Travels? A Flaviviridae-based Risk Assessment Model M Caballero, C Niederhauser, N Andina, U Piazza, K Rotzetter, H Baumer, A Stadler, P Gowland, and S Fontana Blood Transfusion Service of the Swiss Red Cross, Berne

Flaviviridae and WNV: Definitions Primarily spread through arthropod vectors (mainly ticks and mosquitoes) The family gets its name from Yellow Fever virus, because of its propensity to cause jaundice in victims. Flaviviridae have linear, single-stranded RNA genomes. Virus particles are enveloped and spherical, about 40–60 nm in diameter. Flaviviridae challenging the safety of blood transfusion in the next years include for example: Dengue fever, West Nile encephalitis, Tick-borne encephalitis, Japanese encephalitis. West Nile Virus

Situation in Europa Increasing Flavivirus infection rates like WNV and Dengue in the general population has led to a potential increased risk of contaminated blood. Frequent blood donor travel activities and environmental changes have increased the risk of mosquito-transmitted human flaviviridae infections in Europe. Currently the most European countries rely on the ECDC definition of affected area for the implementation of safety measures, without taking into account their effect on blood supply and infection risk for patients. Definition of affected area: “At least one human case detected (i.e. probable or confirmed human case according to EU case definition).” (Commission Decision of 28/IV/2008)

The problem with the affected area The definition is independent from the dimension and the population of the area, although different areas may represent very different risks  no evaluation of the effective infectious risk The trigger for the implementation of precautionary measures (donor deferral, donor testing) is independent from the number of donors visiting the area  no evaluation of the risk on blood supply 2010 – 2013 several European countries reported single WNV cases (although >100 WNV affected persons per confirmed case are assumed)  the implemenation of precautionary measures may be arbitrary

Evolution of WNV reported cases in Europe

Evolution of WNV reported cases in Europe

Evolution of WNV reported cases in Europe

Evolution of WNV reported cases in Europe

Aims To build the fundament for a risk-effectiveness approach in taking precautionary decisions related to donor travel abroad. This by: developing a model to evaluate the effect of deferral policies on the infection risk of donors traveling to risk countries, collecting data on donors traveling abroad and putting them in the model, applying this model to West Nile Virus (WNV), a currently very relevant flavivirus infection in European blood transfusion medicine.

Methods Between 1 July – 30 November 2013 all blood donors were asked for travels abroad during the last month. A simple excel-based tool for risk calculation was developed. It incorporated disease specific variables, epidemiological data in the risk country, information about donors traveling abroad, and the number of blood donations performed in our region during the WNV season 2013 (1 July – 30 November). The effect of a one month deferral recommendation on the contamination risk of blood with WNV for affected countries publishing epidemiological data was calculated.

Model assumptions Mean asymptomatic infectivity 5.6 days Duration of epidemic: 150 days reported cases per country = number of confirmed cases reported by ECDC proportion of reported symptomatic cases = 30% the symptomatic cases length of stay 7 days (based on a control donor sample) N (blood donations) in our region during the epidemic period 39’293 traveling donors per country = effective numbers in 2013 Risk of infected donation applies to a donor donating within 30 days after returning from an endemic country The risk of an infected transfusion applies to a delivered component, considering the number of donors who donate within 30 days after travel and the total number of donations

Model assumptions Disease specific assumptions specific for one disease, the data are found in the current medical literature a: asymptomatic cases: 79% Proportion of asymptomatic cases of the disease under study (%/100) b: symptomatic cases: 21% Proportion of symptomatic cases of the disease under study (%/100) c: viraemia/bacteraemia among asymptomatic cases: 6.3 days Mean duration of viraemia/bacteraemia among asymptomatic cases of the disease under study (days) d: duration of asymptomatic viraemia/bacteraemia among symptomatic cases: 3.0 days Mean duration of asymptomatic viraemia / bacteraemia among symptomatic cases of the disease under study (days) Country specific variables specific for the country of interest e: duration of an epidemic: 150 days Duration of an epidemic of a disease in the country under study (days) g: cases detected during the epidemic period Number of cases detected during the epidemic period (n) h: population affected Population affected by the epidemic in the country or region (n inhabitants of the region)

Model calculations j: Mean duration of the asymptomatic infectivity in an infected case (blood donor) (days) j = [(a.c) + (b.d)]/100 k: Number of infected (asymptomatic and symptomatic) cases (n): k = [g+g(a/b)]/f f: corrector factor: which proportion of cases are documented in this country (%/100) m: attack rate in the country population under study m = k/h n: infection risk for blood donors visiting an affected country n = m(s/e) r: risk that an infected blood was donate during viremia period r= n(j/30) u: Number of blood donations during the considered time interval u t: risk that under all blood donations donated in a defined time interval – epidemics duration or month – one is infected t = (r.v)/u v = number of donors who traveled in an affected country in the given time interval v

Risk that the infected donor donates Risk of infected transfusion Results for WNV in coutries reporting to ECDC (number of confirmed cases known ) Country Confirmed cases (n) Traveling donors (n) Attack rate in country (x10-6) Risk that the infected donor donates Risk of infected transfusion (x10-9) Greece 58 140 86 0.75 2.66 Italy 69 1010 18 0.16 4.02 Serbia 200 7 436 3.81 0.68 Hungary 6 23 10 0.08 0.05 Romania 22 16 0.14 0.04 Bosnia Herz. 3 12 0.11 0.02 Israel 28 13 59 0.51 0.17 USA 2374 103 120 1.05 2.75 Canada 108 38 50 0.44 0.42 Low risk country, high donor numbers: low risk donor, high risk for patient  deferral useful but high impact on supply  threshold for WNV NAT? High risk country, low donor numbers: high risk donor, (rel.) high risk for patient  deferral useful and low impact on supply  deferral ok Low risk country and low donor numbers: low risk donor and patient  deferral less useful but low impact on supply  deferral or no measures?

Conclusions and future prospects The calculated risks of donors and patients acquiring a WNV infection are variable but are very low. This considering that the loss of virus infectivity during manufacturing and storage was not taken into account. This model allows comparing the effects of preventive measures on blood supply and on WNV infection risk, from both the perspective of blood banks and hospitals, who are involved in taking risk-adapted decisions. The model can be adapted to other transfusion-transmitted infections associated with travels abroad.

Conclusions and future prospects The monitoring of donors traveling abroad and of the deferrals will be repeated in 2014, in order to consolidate the data A long-range monitoring system will be introduced, in order to be able to evaluate the risks of every measure for both blood supply and transfusion transmidded infections Based on a risk analysis Switzerland already set the threshold for the introduction of WNV NAT in case of WNV outbreak in the country at 5 confirmed cases per month per affected area (base for comparison: cost-effectiveness on the HBV NAT) We suggest that in the future the evaluation of preventive measures for donors traveling in affected area will not onlyapply the definition of affected area, but will consider these risks.

Aknowledgements Merci viumau