The ongoing threat of new transfusion hazards requires vigilance to protect the safety of the blood supply. In Australia, the estimated transfusion transmission residual risks (RRs) for the major transfusion-relevant viruses — hepatitis B virus, human immunodeficiency virus, hepatitis C virus and human T-lymphotropic virus — have now been reduced to very small probabilities. The current RRs are less than one in 1 000 000 per unit transfused for each virus.1 These very low risk levels are due to a combination of a pre-donation questionnaire designed to identify donors at risk of infection, and universal donor screening for these viruses. However, over the past 20 years, there has been an increased awareness, both internationally and in Australia, of the potential threat to blood safety due to emerging infectious disease (EID) agents.2,3 A number of EID agents of relevance to blood safety in Australia are listed in Box 1. The public health implications of EID agents have received a renewed focus due to the 2015–16 outbreak of Zika virus (ZIKV) in the Americas, which has gained an extraordinary level of media coverage; has been the subject of numerous position statements, recommendations and risk assessments from public health organisations and government health departments; and has elicited considerable expert commentary.4 In addition, on 1 February 2016, the World Health Organization (WHO) Emergency Committee advised that the cluster of microcephaly cases and other neurological disorders associated with ZIKV infection reported in Brazil since 2015 constituted a Public Health Emergency of International Concern.5

In this review, we provide an overview of EID agents from a blood safety perspective and describe the strategies used to mitigate the potential risks posed by EID agents to blood safety in Australia. We also summarise how the potential risk from ZIKV to blood safety in Australia has been assessed and managed in light of the recent outbreak in the Americas. It is acknowledged that a number of EID agents may also be transmitted by organ and tissue transplantation, and many of the concerns highlighted here are therefore also applicable to a transplantation context.6,7 However, a detailed discussion is outside the scope of this review.

We searched PubMed for reviews and consensus conference reports relating to EIDs, focusing on prediction of future outbreaks, transfusion transmission, blood safety and donor management; reviews and studies on public perception of transfusion risk; and studies, reviews and commentaries on ZIKV epidemiology, disease association and impact on blood safety. We also accessed information on the websites of the WHO, the European Centre for Disease Prevention and Control, the United States Centers for Disease Control and Prevention, and the Australian Department of Health.

Emerging infectious diseases

A widely accepted definition of EIDs is “those [infectious diseases] whose incidence in humans has increased within the past 2 decades or threatens to increase in the near future”.8 EID agents can include agents that are newly arisen or previously present but undetected, as well as known agents for which a disease association has only recently been established.9,10 In contrast to the major transfusion-relevant viruses noted above, for most EID agents, suitable tests for blood donor screening have either not been developed or are not yet approved. In addition, EIDs are often not well characterised, giving rise to considerable uncertainty about their epidemiology, outbreak potential and public health risk.

Why emerging infectious disease outbreaks occur

International EID experts agree that we can continue to expect more EID outbreaks, primarily because of known zoonotic infections crossing over from animals to humans with the potential for subsequent enhancement of transmission due to pathogen mutation.2,8,9,11,12 Human activity may also enhance pathogen transmission from human to human (eg, international travel and large-scale human movements), as well as vector or reservoir to humans (eg, climate change; human population growth, with increasing encroachment onto animal habitats; intensive farming practices and the breakdown of public health measures). In addition, there is the possibility of completely new EIDs in humans, which are also expected to be primarily caused by zoonotic infections.8,13–15

Assessing the risk to blood safety from emerging infectious diseases

Given the uncertainties associated with many EIDs, it is essential that health authorities in general, and blood services in particular, carry out surveillance and monitoring and employ appropriate risk assessment methodologies to answer key questions:11

• When does an EID agent represent a potential risk to blood safety?

• What is the estimated level of any potential risk?

• What are the implications for public confidence in the safety of the blood supply?

The first threshold question may be dealt with by using the criteria outlined in Box 2. The second question may be managed by risk modelling that provides a quantitative estimate of risk level.16,17 The final question requires a more complex assessment against the mandate of blood services to provide a sufficient and safe blood supply. In Australia, this involves a number of stakeholders, including state and federal governments, the industry regulator (ie, the Therapeutic Goods Administration), clinicians and the general public.

Risk perception by the general public is complex, relying more on intuition rather than on probability-based assessments.18–20 It has been noted that non-experts tend to be swayed by events that are widely publicised, dramatised and image-laden, suggesting that extensive media coverage may influence risk perception, which in turn may affect the likelihood of patients being prepared to accept a transfusion and the willingness of donors to provide blood.18 Therefore, it is important that the public confidence in the safety of the national blood supply is maintained by ongoing surveillance of EIDs, robust risk assessments and effective communication with stakeholders and the general public.

Strategies to reduce the transfusion transmission risk of emerging infectious disease agents

There are a number of strategies to reduce the risk to blood safety from EIDs (Box 3). These are based on extensive surveillance, risk assessment (which may include risk modelling), donor deferrals related to recent travel (ie, temporarily restricting the use of donations) and targeted screening.3,21 It is worth noting that the Australian Red Cross Blood Service (Blood Service) donor travel deferrals are primarily based on recent travel to countries endemic for malaria (Plasmodium spp), dengue virus, West Nile virus or chikungunya virus. However, as a number of these countries are also endemic for other EIDs, these deferrals may also reduce the risk from additional EIDs. Variant Creutzfeldt–Jakob disease (vCJD) is an unusual infectious disease as the aetiological agent is a misfolded protein, not a microorganism.22 Most vCJD cases have been reported in the United Kingdom and have been associated with the consumption of beef contaminated with the bovine form of the disease (ie, bovine spongiform encephalopathy).23 In addition, four cases of transfusion-transmitted vCJD have been reported in the UK.24,25 To mitigate the potential risk to blood safety in Australia from vCJD, donors who spent a total cumulative period of ≥ 6 months in the UK between 1 January 1980 and 31 December 1996 — the period of the bovine spongiform encephalopathy epidemic in the UK — are permanently deferred from donating blood.

While universal or targeted donor screening would appear to be an effective approach to reducing the potential risk from EIDs, as shown by the implementation of the West Nile virus screening in the US,26 it may not always be feasible or appropriate. First, as previously noted, suitable and approved screening tests are not available for most EID agents. Second, even if a screening test is available, donor screening may not necessarily be a cost-effective approach if the cost of implementing a new screening test is high and the level of risk posed by the agent in question is low.

Assessing the risk of Zika virus to blood safety in Australia

The recent ZIKV outbreak in the Americas, the largest ever reported ZIKV outbreak, provided a very topical example for assessing the potential risk to blood safety in Australia from an EID agent. The outbreak, which was accompanied by extensive media coverage, was the latest reminder of the unpredictable nature of EIDs, how quickly they can become a public health problem and how rapidly information (reliable or otherwise)27 can be disseminated.

Epidemiology

ZIKV is a mosquito-borne flavivirus for which there has been a number of previous, albeit smaller, outbreaks.28 The recent outbreak in the Americas was due to what has been described as “a perfect storm” of temporal and geographical factors.29 After being imported to Brazil — possibly in 2013 or 2014 from French Polynesia28,30 — the presence of competent vectors, ZIKV-naive populations, a suitable climate and high urban population density and mobility resulted in an unexpected and explosive outbreak. At the same time, the extensive media coverage and focus from public health authorities were driven by a combination of factors. These included:

• the potential spread of the virus to the continental US;

• the unprecedented size of the outbreak, with over 554 479 suspected and 207 557 confirmed cases reported to 6 April 2017;31

• the reported disease association with microcephaly in newborns;32

• a previously recognised association with Guillain–Barré syndrome;33,34

• the reporting of several cases of probable sexual transmission of ZIKV, suggesting that sexual intercourse may be an important mode of non-vector transmission;35–37 and

• concerns in the lead-up to the 2016 Summer Olympic Games in Brazil.38

Moreover, as noted, on 1 February 2016 the WHO Emergency Committee advised that the ZIKV outbreak in Brazil constituted a Public Health Emergency of International Concern.5 Subsequently, on 18 November 2016, the Emergency Committee issued a statement noting that the association of ZIKV with microcephaly was established. Therefore, the committee felt that while ZIKV remained a significant and enduring public health challenge requiring intense action, it no longer represented a Public Health Emergency of International Concern as defined under the International Health Regulations.39

Transfusion transmission risk

Before the 2015–16 outbreak in the Americas, ZIKV had been regarded as a potential threat to blood safety40 as it met a number of criteria (Box 2):

• ZIKV is able to establish infection in humans and spread within local populations, giving rise to outbreaks;28

• infection includes a viraemic phase — albeit typically brief and with relatively low levels of virus — and most infections appear to be asymptomatic, while symptomatic infection includes a pre-symptomatic viraemic phase;41,42 and

• in addition to a previously noted association with Guillain–Barré syndrome, based on reports from the outbreak in the Americas, there is accumulating evidence and a general consensus that ZIKV infection is associated with microcephaly in newborns, although a causal relationship has not been conclusively proven.33–35,43

Moreover, the phylogenetically related flaviviruses, dengue virus44 and West Nile virus,45 have been shown to be transfusion transmissible. However, the first reported case of apparent transfusion-transmitted ZIKV was not notified until the recent outbreak in the Americas, when a case was reported in the Brazilian media in mid-December 2015.46 A peer-reviewed report of this case, which involved transfusion of a pooled platelet concentrate, was published in 2016.47 Transfusion transmission was considered the most likely cause of infection because ZIKV RNA was retrospectively detected in a stored sample from the implicated donor, which was taken at the time of donation; the ZIKV RNA was detected in the recipient 4 days after the transfusion; there was a high degree of sequence homology between the viral isolates from the implicated donor and the infected recipient; and there was no ZIKV outbreak in the local area. It is also of interest to note that the donor was asymptomatic at the time of donation. In addition, in early 2016, the media reported a possible second case of transfusion-transmitted ZIKV in Brazil.48 Later, two cases of transfusion-transmitted ZIKV infection associated with a pooled platelet concentrate from a single donor were reported.49 Given the size and extent of the 2015–16 outbreak and the potential transfusion transmissibility of ZIKV, it is not surprising that there have been renewed concerns about the impact of ZIKV on blood safety.50–55 Although current evidence suggests that ZIKV may not be efficiently transmitted by transfusion, some caution is required. The lack of reported cases may, in part, be related to underreporting owing to a high proportion of asymptomatic infections in recipients, a lack of surveillance and reporting systems in many endemic countries, and misdiagnosis due to co-infection or clinical similarities with cocirculating arboviruses, such as dengue virus.28 In response to concerns about the potential transfusion transmissibility of ZIKV, the US Food and Drug Administration approved two investigational tests to screen blood donations for ZIKV in areas with active mosquito-borne transmission of ZIKV.56,57 Moreover, it subsequently mandated universal ZIKV screening for all US blood centres.58

Is Zika virus a threat to blood safety in Australia?

Local transmission of ZIKV has not been reported in Australia, and only a relatively small number of imported cases have been notified, although there was a substantial increase in 2016. The annual number of imported confirmed or probable ZIKV cases reported in Australia for the period 2012–2015 was one, one, 13 and ten respectively.59 The number of reported cases increased in 2016, with 102 confirmed or probable. Of these 102 cases, 54 were acquired in the Pacific region and 47 in the Americas (the origin of one case was not specified).59 Consistent with the decrease in the number of reported cases in the Western Pacific region and the Americas during the latter part of 2016 and early 2017, only two imported cases of probable or confirmed ZIKV have been reported in Australia in 2017 — as at 25 March. This increase in imported cases, along with the presence of Aedes mosquito vectors (although primarily restricted to northern Queensland),60 indicates the potential for local transmission. However, a recent study of potential mosquito vectors in Australia has indicated that the risk of a local outbreak of ZIKV infection in Australia is relatively low.61 The study found that A. aegypti is the most likely, and possibly only, potential mosquito vector for ZIKV in Australia. While several other Aedes mosquitoes were permissible to ZIKV infection, they were unable to transmit the virus, and the Culex mosquitoes examined in the study were either refractory to ZIKV infection or did not develop systemic infection. Moreover, a high viral load of ZIKV in humans is required to infect a feeding A. aegypti mosquito (higher than the reported levels in the blood of symptomatic patients during recent outbreaks in the Western Pacific), and a high viral load in mosquitoes is required for virus transmission to humans. The low risk of a ZIKV outbreak in Australia is further indicated by the effective mosquito surveillance and control programs, the Department of Health recommendations to prevent the sexual transmission of ZIKV, advice for travellers to outbreak areas and ongoing monitoring of outbreaks.60,62

As at 7 April 2017, all countries that had reported autochthonous cases of ZIKV transmission in the recent outbreaks in the Western Pacific and the Americas63 were already subject to donor travel deferrals related to malaria, dengue virus or chikungunya virus. However, to further mitigate the already low risk of ZIKV to blood safety in Australia, the Blood Service has implemented a 4-month deferral from the date of recovery for donors with a current ZIKV infection, and a 6-month deferral from the date of last contact for donors who have had sexual contact with someone infected with ZIKV. With the geographical spread of ZIKV, it is possible that local transmission may be reported in countries without current donor travel deferrals. Therefore, the Blood Service has also implemented a 4-week deferral for donors who may have travelled to countries where ZIKV transmission has been reported but which do not have travel deferrals relating to other EIDs.

When assessing the ZIKV risk to blood safety in Australia, accurate risk modelling is difficult due to the unreliable reporting of ZIKV cases in many countries in the Americas — most reported cases are classified as suspected because they are not subject to laboratory confirmation — and there is uncertainty about a number of viral characteristics, including the ratio of symptomatic to asymptomatic infections and the duration of the pre-symptomatic incubation period.54 However, our risk assessment based on epidemiological data and known transmission modes (Box 4) indicates that, despite the extent of the 2015–16 outbreak in the Americas and growing public health concerns worldwide, ZIKV currently represents a low risk to blood safety in Australia.