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Chikungunya virus: new risk to transfusion safety in the A mericas

2014; Wiley; Volume: 54; Issue: 8 Linguagem: Inglês

10.1111/trf.12790

1537-2995

Lyle R. Petersen, Jay S. Epstein,

Viral Infections and Outbreaks Research

On December 5, 2013, the French National Reference Centre for Arboviruses confirmed autochthonous chikungunya virus (CHIKV) transmission on the Caribbean island of St Martin.1, 2 This mosquito-borne virus, so-named in the East African Makonde language for its ability to cause crippling arthralgia, has caused large outbreaks in multiple locations in Africa, Asia, and the Western Pacific in the past decade.3, 4 Before its arrival in St Martin, few doubted that CHIKV would eventually emerge and take hold in the Western Hemisphere given the widespread presence of competent mosquito vectors and opportunities for the virus to be introduced through travel and commerce.5-9 The virus' subsequent swift spread from St Martin throughout the Caribbean4 and onto South and Central America has created considerable concern regarding its eventual extent and intensity of transmission in the Western Hemisphere and hence its potential impact on transfusion safety. Although transfusion-associated CHIKV transmission has not been reported, possibly due to the difficulty in identifying and proving CHIKV transfusion-associated transmission in the context of large-scale community mosquito-borne outbreaks, the AABB Transfusion Transmitted Diseases Committee deemed CHIKV a priority area of concern10, 11 given its high-level viremia12-15 and high incidence during outbreaks.6, 16-18 As with other arboviruses, five factors will determine the impact of CHIKV on transfusion medicine in the Americas: 1) prevalence of viremia among blood donors, 2) proportion of components derived from viremic donations that transmit infection to recipients, 3) clinical impact on infected transfusion recipients, 4) availability of measures to reduce transfusion transmission when required, and 5) the cost and disruption incurred by those measures.19 The prevalence of viremia among blood donors relates to the incidence of infection in the population at large, and in regard to population incidence, the outlook for CHIKV in tropical America is concerning. CHIKV, like dengue, is transmitted efficiently in urban settings in a human–mosquito–human transmission cycle by Aedes aegypti mosquitoes, whose distribution extends from the southern United States to northern Argentina (Fig. 1). The Pan American Health Organization recorded more than 2.3 million dengue cases in 2013; the actual number of dengue infections likely vastly exceeded this number given disease underreporting and the high proportion of asymptomatic infections.20-22 One study estimated the true number of apparent and inapparent dengue infections in the Americas in 2010 was 13.3 and 40.5 million, respectively.23 Thus, CHIKV can be expected to spread throughout much of tropical America and cause explosive outbreaks involving tens or hundreds of thousands of persons as it has done in other dengue endemic areas of the Old World. Approximate distribution of A. aegypti and A. albopictus in the Western Hemisphere. The potential for large CHIKV outbreaks on the fringes of the A. aegypti distribution, such as the southern United States, is much less certain.24 Dengue outbreaks in Florida and Texas in recent years have been relatively focal and self-limited, likely due to sociologic conditions that limit contact with the indoor-biting A. aegypti mosquito, such as the frequent use of air conditioning.25-27 While CHIKV may follow a similar pattern, the transmission potential for CHIKV relative to dengue virus in these environments is unknown. In addition, Aedes albopictus, the outdoor-biting Asian tiger mosquito, is endemic in much of the southern and eastern United States (Fig. 1).28 Since this mosquito is also a competent vector for CHIKV,29 it could also help drive outbreaks, particularly in temperate areas where A. aegypti does not exist, as was demonstrated by an outbreak in northern Italy involving more than 300 persons. The Italian outbreak was caused by a southern/central/east African genotype CHIKV containing an envelope protein mutation (E1 A226V) that increases viral fitness in A. albopictus mosquitoes.30, 31 Although the Asian genotype CHIKV now circulating in the Americas does not possess this mutation,2, 32 a recent study indicated that A. albopictus mosquitoes collected throughout the Americas are generally competent to transmit the Asian genotype CHIKV strain.33 In this issue of TRANSFUSION, Appassakij and colleagues34 report on a study in which they adapted a modeling approach originally created to estimate West Nile virus transfusion transmission risk in the United States35, 36 to estimate the prevalence of viremic blood donors during a CHIKV outbreak in Thailand involving an estimated 71,000 ill persons (5.3%) in a population of 1,344,000. Assuming a 1.5-day viremia before symptoms and either a total 9.5-day or an 18.5-day viremia for asymptomatic persons, the model yielded a mean weekly prevalence of viremic donations of 38.2 and 52.3 per 100,000 donations, respectively, with a maximum weekly prevalence of 237.0 and 267.1 per 100,000 donations, respectively. The authors validated their model findings by comparing CHIKV nucleic acid amplification test (NAT) results (0.10% positive) of donations collected for a 5-week period during the waning period of the outbreak with their model results for the corresponding time frame (estimated prevalence 0.20%-0.33%). Of note, the authors predicted that 11 donations from CHIKV-infected donors would have been collected during the epidemic. Even if all blood components derived from these donations were transfused and resulted in transmitted infections, the infected recipients would have represented a tiny fraction of the estimated 71,000 cases in the population. Two similar previously published models have estimated the risk of CHIKV prevalence in donors during outbreaks. During a large outbreak on La Réunion Island involving approximately 244,000 persons, or 35% of the island's population, the model indicated a substantial prevalence (132 per 100,000 donations; maximum 1500 per 100,000 donations) of chikungunya viremic donors.16, 37 This model assumed a 1.5-day viremia before symptoms and a total 7.5-day viremia for those asymptomatic. As with the Thai study, the La Réunion Island model results (estimated prevalence 0.7%) compared favorably with the proportion of NAT-positive donations (0.4%) during a 4-month period during the outbreak, thus confirming the validity of the model results. Another study using the same modeling approach during the much smaller CHIKV outbreak in northern Italy involving 337 suspected cases (0.03%) in a population of 1,040,000, estimated a maximum weekly prevalence of viremic donations at 1.05 per 100,000 donations.38, 39 This model assumed a 2-day viremia before symptoms and a total 8-day viremia for those asymptomatic. All of these models estimated the proportion of donations that were viremic as measured by the duration of NAT positivity; however, this duration may not correlate with the actual duration of risk of transfusion transmission. Extensive experience with West Nile virus indicates that the measured duration of NAT positivity depends on the sensitivity of the assay, whether samples are pooled for testing, and the number of replicates tested.40 Furthermore, CHIKV specific IgM antibodies develop around 6 days after illness onset, a period shorter than the duration of NAT positivity.12, 15 If CHIKV is similar to West Nile virus in which NAT-positive donations containing West Nile virus specific IgM and particularly those containing IgG antibodies rarely transmit infection to recipients,41, 42 the duration of CHIKV transmission risk may be shorter than the duration of NAT positivity. In addition, not all recipients may be susceptible to infection, particularly if high population background immunity develops. While current background CHIKV immunity in populations in the Western Hemisphere is extremely low or nonexistent, this protection will evolve as the current epidemic continues. Despite these limitations, the model results from both La Réunion Island and Thailand indicate a significant short-term risk of transfusion-associated CHIKV transmission during the large outbreaks that will likely occur in tropical America, while the Italian model suggests a small, but quantifiable risk that may exceed accepted safety standards during smaller, focal outbreaks that may occur in temperate areas of the United States. This CHIKV transfusion transmission risk is likely to have clinical significance as upward of 80% of those infected via mosquito bite become symptomatic, often with considerable morbidity and occasional mortality among the elderly and those with existing conditions.17, 43-45 To mitigate this risk during the Thai outbreak, blood centers enhanced predonation screening questions about CHIKV-related symptoms and implemented an enhanced postdonation notification system.34 In addition, components from donors at high risk were quarantined for 7 days after donation, at which time donors were called to ascertain symptoms. It was not stated how the authors defined "high risk." Of the 299 donations initially deemed high risk, 11 developed symptoms suggestive of CHIKV infection. In the La Réunion Island CHIKV outbreak, routine blood collections were suspended except for platelets (PLTs), which were then photochemically inactivated.46 Two (0.4%) of 500 PLT donations were found to be NAT positive, thus documenting the possible benefit of this approach.37 During the northern Italian CHIKV outbreak, all collections were suspended in affected areas until the expected prevalence of viremic donors fell below one in 380,000 and visitors to affected areas were initially deferred from donation for 21 days.39 Blood products were imported from areas of continuing blood collections and efforts were made to reduce blood product usage. The economic costs associated with the Italian efforts exceeded €1.3 million. No data exist regarding the efficacy of deferring potential donors returning from areas experiencing outbreaks; however, one mathematical model suggested that deferring the approximately 4500 Dutch tourists visiting Thai CHIKV outbreak areas would have resulted in an expected reduction of 0.068 infected donors annually.47 Possible mitigation strategies to reduce CHIKV transfusion risk in the Western Hemisphere are indicated in Table 1. Curtailing donations during outbreaks, NAT, and photochemical inactivation of PLTs are likely to be highly effective, but expensive. Enhanced predonation screening for symptoms in potential donors, enhanced postdonation notification of symptoms by donors, or deferring potential donors with recent travel to outbreak areas will be less expensive, but could lack specificity and thus eliminate many low-risk donors. Three mitigation strategies have been employed on two Caribbean islands experiencing CHIKV outbreaks (Martinique and Guadeloupe): photochemical inactivation of PLTs, CHIKV NAT of donated red blood cells, and importation of plasma from France. In anticipation of the possible need for interventions in the United States and its territories, the U.S. Food and Drug Administration (FDA) is facilitating further development of CHIKV NAT assays for donor testing, in part, by providing candidate manufacturers reference panels to assure screening test kit sensitivity. Additionally, FDA plans a survey in cooperation with AABB to estimate donor losses if a policy of temporary deferral were implemented for travelers to outbreak regions. The inherent uncertainties regarding the timing and extent of transmission of CHIKV or other emergent arboviruses will continue to complicate decisions regarding implementation of mitigation strategies to reduce their transfusion transmission risk. Fortunately, as now demonstrated for the West Nile virus and CHIKV, the transfusion risk model based on estimations of rates of viremic donations from asymptomatic donors with assumptions of high rates of consequent transfusion transmission to recipients has proven a robust indicator of arboviral transfusion transmission risk from which to guide mitigation strategies once an outbreak begins. CHIKV is the latest, but certainly not the last, emerging pathogen to threaten blood safety. Until safe, effective, and practical pathogen inactivation techniques can be applied to all components of blood collections in a wide range of settings, we must rely on a menu of less satisfactory options to ensure blood safety. The authors have disclosed no conflicts of interest.