Hepatitis E risks: pigs or blood-that is the question.

BACKGROUND: Infection with hepatitis E virus (HEV) Genotype 3 is recognized as a food-borne zoonosis in developed countries where it usually causes a mild self-limited acute hepatitis. It may cause a persistent infection in the immunosuppressed human that can progress to cirrhosis. To protect the patient from transfusion-acquired HEV infection, steps have been taken in the United Kingdom to provide for at-risk patients only components from donors screened for HEV viremia. This strategy does not protect from dietary exposure and calls into question estimation of relative risk between blood transfusion and diet. STUDY DESIGN AND METHODS: Using data on HEV viremia, component exposure, residual plasma volume, and resulting transmission, the dose of virus administered and subsequent transmission rates were determined and used to populate a model that can infer the relationship between blood and dietary exposure. RESULTS: The annual attack rate of a population, defined as seroconversion, provides an estimate of the risk of receiving a component containing HEV from a viremic donor. The lowest viral dose that resulted in infection was 2 × 104 IUs and 55% of components containing this dose transmitted infection. The transfusion risk of infection only exceeds the annual dietary risk when more than 13 individual donor components are transfused. CONCLUSION: For many solid organ transplant patients dietary exposure far exceeds the risk of transfusion from unscreened donors. It is only in the immunosuppressed patient requiring extensive blood component support that transfusion risk dominates. This understanding should inform policy decisions on HEV RNA screening of blood donations.

Virology, serology, and demography of hepatitis E viremic blood donors in South East England.

BACKGROUND: Hepatitis E virus (HEV) Genotype 3 (G3) in England comprises two principal phylogenetic groups (Group 1 and Group 2) and can be transmitted by transfusion. Unselected screening identified 79 viremic donors; 76 participated in a follow-up study. STUDY DESIGN AND METHODS: Viral RNA dynamics, phylogenetics, and seroconversion were characterized in the donors. Detailed demographic, travel, clinical, and lifestyle questionnaires were undertaken. RESULTS: The majority of viremic individuals (57/79) were seronegative at time of donation but all seroconverted. Viremia was short-lived, with a median of 6.5 weeks to confirmed viral clearance. All infections were acquired in the United Kingdom and were G3, with Group 2 viruses predominating (43/54; 80%). Infection was associated with some clinical symptoms both at and after donation (8/77; 10%). Viral loads and symptoms were more pronounced in Group 1 infections. There was no serologic evidence of reinfection. Donors were more commonly male (p = 0.002); both male and female donors were older than comparator donors. Animal contact was unlikely to be the source of infection. Consumption of chicken and pig meat was common to all infected donors; processed pig meat was most commonly purchased from one particular retail chain. CONCLUSION: Viremic donors represent primary infection in older members of the community and reflect a widespread zoonotic in the United Kingdom. The two phylogenetic groups of HEV G3 display different pathogenicity and the more common Group 2 appears less adapted to humans. There are no objective demographic criteria that can identify donors at enhanced HEV risk.

Hepatitis E virus in blood components: a prevalence and transmission study in southeast England.

BACKGROUND: The prevalence of hepatitis E virus (HEV) genotype 3 infections in the English population (including blood donors) is unknown, but is probably widespread, and the virus has been detected in pooled plasma products. HEV-infected donors have been retrospectively identified through investigation of reported cases of possible transfusion-transmitted hepatitis E. The frequency of HEV transmission by transfusion and its outcome remains unknown. We report the prevalence of HEV RNA in blood donations, the transmission of the virus through a range of blood components, and describe the resulting morbidity in the recipients. METHODS: From Oct 8, 2012, to Sept 30, 2013, 225,000 blood donations that were collected in southeast England were screened retrospectively for HEV RNA. Donations containing HEV were characterised by use of serology and genomic phylogeny. Recipients, who received any blood components from these donations, were identified and the outcome of exposure was ascertained. FINDINGS: 79 donors were viraemic with genotype 3 HEV, giving an RNA prevalence of one in 2848. Most viraemic donors were seronegative at the time of donation. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused before identification of the infected donation. Follow-up of 43 recipients showed 18 (42%) had evidence of infection. Absence of detectable antibody and high viral load in the donation rendered infection more likely. Recipient immunosuppression delayed or prevented seroconversion and extended the duration of viraemia. Three recipients cleared longstanding infection after intervention with ribavirin or alteration in immunosuppressive therapy. Ten recipients developed prolonged or persistent infection. Transaminitis was common, but short-term morbidity was rare; only one recipient developed apparent but clinically mild post-transfusion hepatitis. INTERPRETATION: Our findings suggest that HEV genotype 3 infections are widespread in the English population and in blood donors. Transfusion-transmitted infections rarely caused acute morbidity, but in some immunosuppressed patients became persistent. Although at present blood donations are not screened, an agreed policy is needed for the identification of patients with persistent HEV infection, irrespective of origin, so that they can be offered antiviral therapy. FUNDING: Public Health England and National Health Service Blood and Transplant.

Acute hepatitis B in blood donors over a 5-year period in England and North Wales: who is getting infected?

BACKGROUND: Hepatitis B virus (HBV) remains the infection most frequently recognized by donation testing in blood donors. It is usually a persistent infection and mostly reflects the country of origin of the donor or the donor's family. There are, however, a minority of acute infections and this study undertook their phylogenetic analysis to determine the likely source of infection. STUDY DESIGN AND METHODS: Plasma samples from 11 donors donating between July 2005 and June 2010, whose test results revealed recent infection with hepatitis B, were available for further analysis. Plasma DNA was extracted, amplified, sequenced, and analyzed phylogenetically. Donor and virus characteristics were compared with the overall demography of all hepatitis B-infected donors attending over the same period. RESULTS: Three of the 11 individuals were first-time donors. Nine were male, of whom eight were white British. All had serum markers of very recent infection. Only two indicated known HBV exclusion risk factors at postdonation discussion not declared previously. Genotype A was present in seven, Genotype B in two, and Genotype C in two, contrasting with the pattern in persistently infected persons in the United Kingdom. A single A2 strain was identified in six of the white British male donors, suggesting epidemiologic linkage. CONCLUSION: Phylogenetic analysis of HBV-infected donors performed in real time can potentially lead to identification of undeclared risk factors that donor health questionnaires may fail to identify.

The diversity of chronic hepatitis B virus infections within blood donors in England and North Wales 2005 through 2010.

BACKGROUND: In 2010 hepatitis B virus (HBV) was the most frequently detected infection in UK blood donation screening, typically found in first-time, male, chronically infected donors born abroad. To date there has been no comprehensive characterization of the virologic profile of these infections. STUDY DESIGN AND METHODS: Epidemiologic and serologic data were collected retrospectively for 344 chronically HBV-infected blood donors identified from July 2005 to June 2010. Additional laboratory testing was carried out to determine the HBV genotype, viral load, and prevalence of clinically significant mutations and to detect hepatitis delta virus (HDV) coinfection. RESULTS: Five HBV genotypes (A-E) were found, Genotypes D (45%), A (20%), and E (20%) were the most prevalent. A strong association was seen between genotype and donor ethnicity (p < 0.001) and between genotype and place of residence (p = 0.006). Clinically significant mutations were observed across hepatitis B surface antigen (17%), basal core promoter (25%) and precore (78%) regions. An antiviral resistance profile was identified in one donor. Evidence of HDV coinfection was found in 2% of donors. CONCLUSION: The data show the diversity of HBV in asymptomatic chronic infections detected in blood donors in England and North Wales and demonstrates the presence of mutations which may impact on disease. The global nature of these infections and the inability to identify chronically infected donors before donation highlights the importance of using screening assays capable of detecting a broad range of genotypes and mutations. Furthermore, the integration of the virologic and demographic data allows us to more accurately construct a profile of our chronically HBV-infected blood donors.

The early implementation of Trypanosoma cruzi antibody screening of donors and donations within England: preempting a problem.

BACKGROUND: Trypanosoma cruzi is a parasitic infection endemic in Central and Southern America, but is spreading into nonendemic countries with migration of infected individuals from endemic countries. The parasite is transmitted by transfusion or transplantation and donation screening is performed routinely in endemic countries to prevent transmission. In situations where migrants from endemic countries have settled in nonendemic countries and present as donors (blood or other cellular products), intervention is required to prevent transfusion or transplantation transmission. STUDY DESIGN AND METHODS: A screening program for T. cruzi was developed and has been used successfully for over 10 years that includes donor selection and donation screening. Donor selection criteria to identify specific risk of T. cruzi infection were developed together with laboratory screening of donations for T. cruzi antibodies and the subsequent confirmation of screen reactivity. RESULTS: Since the introduction of T. cruzi screening in England in 1998, a total of 38,585 donors and donations have been screened for T. cruzi antibodies, of which 223 were repeat reactive on screening and referred for confirmation: 206 confirmed negative, 14 inconclusive, and three positive. Since the move in 2005 from donor qualification to donation release testing, 15,536 donations were collected and screened, of which 15,499 (99.8%) were T. cruzi antibody negative and released to inventory. CONCLUSION: An effective program to minimize risk of the transmission of T. cruzi infection via donations has been developed and implemented. Not only does the program minimize risk of transmission, it also minimizes the cumulative, and needless, loss of donors and donations that would ensue if permanent donor deferral alone was adopted.

Comparison of Commercial ELISA Kits to Confirm the Absence of Transmission in Malaria Elimination Settings.

Background: Antimalarial antibody measurements are useful because they reflect historical and recent exposure to malaria. As such, they may provide additional information to assess ongoing transmission in low endemic or pre-elimination settings where cases are rare. In addition, the absence of antibody responses in certain individuals can indicate the cessation of transmission. Commercial malaria enzyme-linked immunosorbent assays (ELISA) detect antimalarial antibodies and are commonly used to screen blood donations for possible malaria infection. However, there is no standardized test to detect antimalarial antibodies for epidemiological use. Here we compared five commercially available ELISA kits (Trinity Biotech, newbio, DiaPro, Cellabs, and NovaTec) in search of a standardized tool for supporting claims of absence of malaria transmission. For comparison, a research-based (RB) ELISA protocol was performed alongside the commercial kits. Results: The commercial kits were first compared using serum samples from known malaria-unexposed individuals (n = 223) and Toxoplasma-infected individuals (n = 191) to assess specificity and cross-reactivity against non-malaria infections. In addition, 134 samples from ≥10-year-olds collected in a hyperendemic region in the Gambia in the early 1990s were used to assess sensitivity. Three out of five kits showed high sensitivity (90-92%), high specificity (98-99%), low cross-reactivity (0-3%) and were considered user-friendly (Trinity Biotech, newbio and NovaTec). Two of these kits (Trinity Biotech and NovaTec) were taken forward for epidemiological evaluation and results were compared to those using the RB-ELISA. Samples from two pre-elimination settings (Praia, Cape Verde; n = 1,396, and Bataan, the Philippines; n = 1,824) were tested. Serological results from both the Trinity Biotech kit and the RB-ELISA concurred with recent passively detected case counts in both settings. Results from the Trinity Biotech kit reflected a significant decrease in the number of reported cases in Bataan in the 1990s better than the RB-ELISA. Results from the NovaTec kit did not reflect transmission patterns in either setting. Conclusion: The Trinity Biotech commercial ELISA kit was considered reliable for epidemiological use and accurately described transmission patterns in two (previously) malaria endemic settings. The use of this simple and standardized serological tool may aid national control and elimination programs by confirming that regions are free from malaria.

Malaria blood safety policy in five non-endemic countries: a retrospective comparison through the lens of the ABO risk-based decision-making framework.

BACKGROUND: In non-endemic countries, malaria risk is addressed by selectively testing or deferring at-risk donors. These policy decisions were made using a variety of decision-making frameworks prior to the development of the Alliance of Blood Operators Risk Based Decision-Making Framework. It is unclear whether the range of items assessed in the decision-making process would be increased if the Framework were used. We compared assessments considered in France, England and Australia for decisions to implement selective testing, plus donor selection criteria (Canada and the USA included) with those recommended by the Framework. MATERIALS AND METHODS: Elements of the Framework were identified: the intervention, safety threat, availability threat, donor impact, financial implications, risk communication, stakeholder and regulatory aspects. Decisions about selective testing and donor selection criteria were analysed separately. Assessments were compared against elements of the Framework and the level of concern for considerations rated. RESULTS: Sufficiency of the blood supply (plus safety in France) were the drivers for selective testing; main trade-offs were high operational impact and cost. In three donor criteria examples, transfusion-transmitted malaria cases prompted the change. Social concerns were high in France and Australia, political/regulatory concerns influenced decisions in France, Australia and Canada, while sufficiency was a consideration in Canada and the USA. Decision trade-offs involved moderate operational impact. DISCUSSION: The assessments considered in each country were generally consistent with the assessments recommended by the Framework. When data supported quantified risk assessment, safety and operational feasibility had the greatest weight. When risk was not well defined, contextual factors such as social and political concern had greater weight.

The current status and potential role of laboratory testing to prevent transfusion-transmitted malaria.

Malaria remains a rare but serious complication of transfusion because of the asymptomatic persistence of parasites in some donors. In nonendemic countries, the predominant strategy of deferral or cellular component discard from "risk" donors is effective in minimizing the incidence but is wasteful. In endemic countries where recipients are commonly immune, transfusion strategies focus on chemoprophylaxis for the donor and recipient or ensure that blood collected in highly endemic regions is not transfused to patients from areas of low endemicity. Donors implicated in transfusion-transmitted malaria are predominantly "semi-immune" with very low parasite loads. Their detection by even the most sensitive antigen or polymerase chain reaction (PCR) assays cannot be guaranteed and, in a number of cases, is unlikely because the infectious dose is estimated to be 1 to 10 parasites in a unit of blood. Retrospective analysis of implicated donors has confirmed the presence of high titer antibodies in such individuals. In regions of low immunity, serological assays offer an efficient method to identify such infectious donors. The recent development of enzyme immunoassays (EIAs) with improved sensitivity to Plasmodium falciparum and Plasmodium vivax , the predominant transfusion threats, has heightened the appeal of serological testing. Although universal serological screening in nonendemic regions is not cost-effective, targeted screening of donors identified at risk by travel-based questioning can significantly reduce wastage through reinstatement. Importantly, transfusion safety does not appear to be compromised by this approach as evidenced by the lack of a documented transmission in France between 1983 and September 2002, where such a strategy has been used since 1976. The development of automated protein microarray-based technology has the potential to further enhance antibody/antigen sensitivity; however, its application to donor screening is likely to be some years off. There is also the potential that pathogen inactivation techniques currently under development to address the bacterial contamination of blood components may also be effective against malaria parasites to make malarial testing redundant or at least reduce its cost/benefit ratio. Nonetheless, there are still significant problems to be solved in respect of validating and licensing these systems. Assuming that they are successfully marketed, their high cost may also impact their cost-effectiveness in comparison with targeted malaria testing strategies already in place in some jurisdictions.

The Epidemiology of Imported Malaria and Transfusion Policy in 5 Nonendemic Countries.

Addressing risk of imported malaria is complicated by 5 human species of Plasmodium, semi-immunity in donors with long-term exposure, increasing travel and immigration, changing risk in endemic areas, and limitations of screening assays. To gain insight into policy formulation, we have compiled epidemiologic data from 5 countries with different policies involving either deferral (the United States and Canada) or selective testing (France, England, and Australia). The greatest risk is from semi-immune former residents of endemic areas, but the greatest impact on sufficiency (donor loss) is from low-risk short-term travel. France and the UK have the highest rates of travel to Africa where most malaria cases originate. The UK has substantial travel to the Indian subcontinent where Plasmodium vivax cases are more common, and Australia, to Southeast Asia and Papua New Guinea. In the United States and Canada, malaria risk travel is more often to lower risk areas such as Mexico and the Caribbean. Each country has imported cases, predominantly Plasmodium falciparum and P. vivax, although data are incomplete. Transfusion-transmitted malaria has been rare over the last 10 years, generally involving P. falciparum, but there were 2 US cases of Plasmodium malariae. Uncertainty due to limitations of epidemiologic data and reliance on donors' answers underpins much of the complexity of policy formulation. Variability in policies between countries reflects not only epidemiologic differences but also operational considerations, donor demographics, regulatory approaches, and public pressure to react to rare transfusion-transmitted malaria cases. Testing reduces the operational impact of addressing the very small risk from travelers and offers improvement over deferral by testing all former residents of endemic areas. Notwithstanding current international regulatory requirements, policies have "evolved" through a series of additions and revisions as concerns and issues arose, with resultant variability in donor selection criteria.

Hepatitis C virus window-phase infections: closing the window on hepatitis C virus.

BACKGROUND: The detection of hepatitis C virus (HCV) infection is of major importance for the prevention of transfusion-transmitted hepatitis. The testing of donations by nucleic acid testing (NAT) techniques may not be feasible or economic. Combined antigen and antibody assays are now available, and the performance of two combined assays on window-phase donations is evaluated. STUDY DESIGN AND METHODS: Three panels of antibody-negative plasma samples from HCV NAT-only-positive donors were characterized for HCV status by quantitative reverse transcription-polymerase chain reaction, a commercial third-generation HCV antibody assay (Ortho), and combined antigen and antibody assays (Bio-Rad MONOLISA and Murex). RESULTS: All 142 plasma samples were antibody negative by Ortho third-generation HCV. A total of 112 samples (79%) were found to contain HCV RNA; 32 were detected by the Bio-Rad assay (29%), whereas 56 (50%) were detected by the Murex assay. Of 45 samples with viral loads of greater than 10(6), 32 (71%) were positive in the Bio-Rad combination assay and 44 (98%) were positive in the Murex assay. Interestingly none of the 3a genotypes were detected by the Bio-Rad MONOLISA, including eight donations that were greater than 10(6) IU per mL. CONCLUSIONS: Combined antigen and antibody testing provides a useful improvement on the sole reliance on antibody testing for detection of HCV infection; however, it remains less sensitive than NAT for detecting viremic donors and may be genotype susceptible.