Arboviruses and TTID

Arboviruses are a heterogeneous group of viruses transmitted to humans by arthropods. The most significant insects acting as vectors for human diseases are the female individuals belonging to the Culicidae family, which feed on the blood of several vertebrate species including man. In this family two important genera of mosquitoes are found: Culex sp and Aedes sp. Two species of Aedes are of particular relevance to humans: A. aegypti and A. albopictus. Paleontological and phylogenetic evidence suggest the origin of A. aegypti in Africa [1] with recent introduction to the Americas by ships transporting slaves from Africa in the centuries XVI–XIX. Classical experiments carried by Walter Reed showed that the Yellow fever agent (YFV) was transmitted to humans by mosquito bites [2]. In fact, it was the first virus to be shown to be transmitted by a mosquito. These data fostered the research into effective measures to control and eradicate these arthropods, what has been achieved in many countries in the 1950s. Unfortunately, the well succeeded effort that eliminated this vector in the Americas was wasted by its re-introduction in the 1980s. From then on, A. aegypti presence has increased worldwide, being found, nowadays, in all continents. Arboviruses have adapted to a dual life cycle, being able to replicate on both vertebrate and invertebrate hosts, although with varying efficiencies. For example, the West Nile virus (WNV) reaches very high titers in birds while humans present lower levels, unable to sustain human-mosquito-human transmission cycles. In contrast, dengue virus replicates efficiently in human monocytes and the transmission from person to person mediated by a mosquito is a common mechanism [3]. The Flaviviridae family comprises the most medically significant arboviruses such as Dengue, YFV and WNV, focus of this article. Although taxonomically related, they present different vector preferences, replication capacity and clinical signs in infected subjects. Their life cycle in humans is usually very short, consisting of an incubation phase that lasts no more than 2 weeks, followed by a febrile phase of 1–7 days [4]. Almost all infected individuals develop a protective immune response upon defeverscence, being the presence of IgM and IgG markers at this stage useful for establishing diagnosis. The existence of a short incubation phase is the most important source of risk for transfusional transmission (TT) of these viruses, as infected donors cannot be identified by epidemiological questionnaires. Yellow fever is extremely harmful for humans, hence, unlikely to be transmitted by a healthy blood donor. However, Dengue and WNV infections may go asymptomatic in at least 50% of the cases, being these persons the source of risk for TT, if they decide to donate blood. As mentioned above, the attack rate of YFV is quite high, in fact, during outbreaks observed in the past, the mortality could reach 10% of the infected subjects [5]. Fortunately, an effective vaccine was developed by using attenuated YFV, and up to now this is still in use. From the blood bank perspective, vaccines developed from attenuated viruses represent some risk, since there is a small replication of the live vaccine virus in the vacinee body, which finally triggers the protective immune response [6, 7]. However, in immunodeficient patients, this replication can be harmful. For this reason, a common policy is to inquiry donors about YFV, and other vaccines, before donation. In the case of YFV vaccine, a 15–30 days deferral is observed. Recently a description of likely TT YFV was reported in the US [7]. Donors, 4 days after being immunized, were allowed to donate. Most units were interdicted, when the breach was detected. However, five patients received blood components, including platelets, irradiated platelets and red cells and fresh frozen plasma, obtained from the vaccinees. Four recipients were available for investigation post-transfusion, three of them presenting laboratorial evidence (high titer IgM) of YFV exposure. None displayed symptoms nor laboratorial abnormalities related to YFV infection. WNV has arrived in North America about 12 years ago [8]. Transmission by blood transfusion and organ transplantation was rapidly demonstrated [9]. As in the viremic phase there is no serological marker, detection of the virus itself, either by a nucleic acid test (NAT) or an antigenic fraction, were, in theory, the available options. The blood bank community in the US, took advantage of the platforms newly existing for NAT screening of blood for other agents (HCV and HIV) and introduced NAT for WNV, being able to block hundreds of infectious units [10]. In the WNV model, RNA is detected in plasma minipools during periods of low number of cases in patients and/or mosquitoes, shifting to NAT individual testing when evidence of an increasing incidence is verified [11]. As expected, during summer, when the vector population exponentially increases, is when high numbers of clinical cases and infected donors are observed. The fast development of the WNV NAT is one of the most successful cases of a positive and harmonic task carried by different society players, including manufacturers of NAT tests, regulators and the blood transfusion establishment. Nowadays NAT screening for WNV is routine in the US and Canada. In 2006, it has been described in an asymptomatic blood donor in Mexico [12]. Predictably, few years later, human and animal infections were reported in many Caribbean and Central America countries [13]. In South America, it is believed that WNV may soon become a transfusional threat. This idea derives from the well known migratory movement of birds, the natural host of WNV, between North and South America, and to the abundant population of vector species (Culex and Aedes) in the tropical portion of South America. Worrisome, animal cases were identified in Venezuela [14], Colombia [15], Brazil [16] and Argentina [17], but so far, not in humans. In Europe, many outbreaks of WNV occurred in the past, mainly on East Europe countries. Recent investigations on blood donors from the Netherlands [18] and Greece [19] failed to detect any positive subject. However, in 2004, two human cases of neuroinvasive disease in Portugal were etiologically linked to WNV. More recently, a similar report was made in Spain, and in Italy a significant number of human and animal cases were described in 2008 and 2009 [20]. Among all arboviruses, certainly dengue represents the greatest threat to human health. Millions of cases are recorded yearly, while more and more countries are reporting autochthonous outbreaks and, no prophylactic vaccine is available. In South America, due to the dimension of the epidemics, hitting virtually all countries in the region with the possible exception of continental Chile, one can say that this disease is the most important emerging threat to the blood supply. First because, during outbreaks, it reduces the number of available donors (infected symptomatic subjects); in addition, these patients demand a considerable attention by relatives or household, which also prevent them from donating. It must be highlighted however, that not a single case of TT dengue has been published in the region. Noticeably, there is an enormous disparity between the number of reported cases of Dengue worldwide and the paucity of reports of its TT, what prevented, so far, the large scale adoption of specific screening measures. Viremic donors have been detected in different countries [21, 22], so it is puzzling why TT dengue is not commonly verified. One possible explanation would be the high prevalence of seropositivity among recipients in endemic areas. We have observed IgG seroprevalence rates as high as 86% in blood donors from Fortaleza – Brazil [22]. In theory, antibodies could have prevented the transfused dengue virus to infect recipients. Intriguingly, heterotypic antibodies are thought to play a pivotal role on the development of severe dengue [23], what one would expect in population experiencing sequential outbreaks with distinct dengue serotypes. Certainly, more research is needed to prove or discard TT of dengue, and, whether shown not to be efficiently transmissible by blood, to learn the mechanisms that prevent this to happen, as we are obviously collecting and transfusing units from asymptomatic carriers during outbreaks in endemic countries. These forthcoming studies may contribute significantly to deepening the knowledge on the viral mechanism of pathogenesis. In fact there are, to my knowledge, only three published papers of TT dengue in [24-26]. Two of them, one in Singapore [24] and the other in Hong Kong [25], where revealed only when donor reported dengue compatible symptoms to the blood bank, days after donating or fortuitously discovered in a dengue surveillance program, which enrolled the implicated donor, carried months after the implicated donation. Lookback investigation on recipients depicted laboratorial evidence of dengue and clinical signs as well. More recently, a case of dengue haemorragic fever was observed in a bone marrow transplanted patient, receiving many units of blood in Porto Rico, an endemic area [26]. This led the American Red Cross to introduce universal testing of blood units from Porto Rico, by employing an antigenic assay that detects the presence of the NS1 antigen on serum/plasma. A caveat of using NS1 is that in secondary and tertiary dengue these tests have shown a much reduced sensitivity [27]. Although automated NAT for Dengue was developed and used for research, this was not further considered a priority, and consequently, these tests will not be available in the short-term. None.

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