Perspectives on biovigilance and transmission of infection of donor origin in deceased organ donation-The evolving scenario in the United Kingdom.

BACKGROUND: A biovigilance program that has oversight of the entire organ and tissue donation and transplantation pathways underpins the quality and safety system in the United Kingdom. METHOD: A synopsis of the microbiological characterization of potential deceased organ donors and the processes for notification and investigation of possible donor-derived infections are described. A summary of the outcome of investigations performed over a 10-year period and a subset data frame of 5 years showing the proportion of infection incidents in relation to other incident types are also presented. CONCLUSION: A single, centralized system overseeing the entire donation and transplantation pathway has become an essential part of transplantation practice across the United Kingdom. Revision of processes and management options, awareness of clinical conditions, and review of guidance are some examples of benefits gained over time. Transmission figures provided reflect the UK setting; these should be interpreted in context, as donor and recipient epidemiology differs across regions and nations. Despite a well-established system in place, under reporting of cases continues to occur, with ongoing efforts to reassure professionals and patients of the true benefits of biovigilance in driving improvements in practice and patient outcomes.

Ultrasensitive PCR system for HBV DNA detection: Risk stratification for occult hepatitis B virus infection in English blood donors.

Occult hepatitis B (HBV) infection (OBI), characterized by low viral loads, accounts for much of the risk of HBV transfusion-transmitted infection. With anticore antibodies (anti-HBc) screening introduced in England, the imperative to identify OBI donors has increased. We aimed to develop an ultra-sensitive PCR system and investigate risk factors for HBV DNA presence in blood donations. Seven extraction methods and three PCR assays were compared. The optimal system was sought to determine HBV DNA presence in anti-HBc-positive donations. Predictors of DNA positivity were subsequently investigated. Extraction from 5 mL of plasma increased sample representation and resulted in HBV DNA detection in low viral load samples (~0.5 IU/mL). Screening of 487 763 donations in 2022 identified two OBI donors and 2042 anti-HBc-positive donors, 412 of the latter with anti-HBs < 100 mIU/mL. Testing of 134 anti-HBc-positive donations utilizing the 5 mL extraction method identified two further HBV DNA-positive donations. Higher anti-HBc titer and anti-HBs negativity were significant predictors of DNA detectability in anti-HBc-positive donations. An ultrasensitive PCR assay identified potentially infectious donations increasing HBV DNA detection in anti-HBc-positive donors from 0.5% to 1.9%. Anti-HBc titers may further complement the risk stratification for DNA positivity in anti-HBc screening and minimize unnecessary donor deferral.

Impact of Hepatitis E Virus Screening in the UK Deceased Organ Donor Population.

Universal Hepatitis E Virus (HEV) screening of deceased organ donors was implemented by the UK national organ procurement organisation in October 2017. Donor testing for HEV infection is done post-transplant; detection of HEV ribonucleic acid (RNA) in donor plasma is therefore not a contra-indication for organ donation, with the result being used to inform recipient management. Immediate post-transplant detection of donor HEV viraemia triggers notification to transplant centres. Follow up of liver and kidney recipients has shown that transmission through solid organs is very efficient, particularly through liver grafts, as expected; no other organ types were transplanted in this cohort. Although donors with higher plasma viral load (VL > 103 IU/mL) were invariably associated with recipient infection, transmission was also documented at lower VL levels. Knowledge of donor HEV status has led to identification of transmission of infection via solid organ grafts followed by close patient monitoring and informed clinical management decisions. The purpose of this strategy is to allow early detection of infection and recurrence and treatment to circumvent the risk of accelerated liver damage from chronic HEV infection due to undiagnosed, inadvertent donor-derived transmission of infection.

SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study.

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.

Antibody-based assay discriminates Zika virus infection from other flaviviruses.

Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged recently as a global health threat, causing a pandemic in the Americas. ZIKV infection mostly causes mild disease, but is linked to devastating congenital birth defects and Guillain-Barré syndrome in adults. The high level of cross-reactivity among flaviviruses and their cocirculation has complicated serological approaches to differentially detect ZIKV and dengue virus (DENV) infections, accentuating the urgent need for a specific and sensitive serological test. We previously generated a ZIKV nonstructural protein 1 (NS1)-specific human monoclonal antibody, which we used to develop an NS1-based competition ELISA. Well-characterized samples from RT-PCR-confirmed patients with Zika and individuals exposed to other flavivirus infections or vaccination were used in a comprehensive analysis to determine the sensitivity and specificity of the NS1 blockade-of-binding (BOB) assay, which was established in laboratories in five countries (Nicaragua, Brazil, Italy, United Kingdom, and Switzerland). Of 158 sera/plasma from RT-PCR-confirmed ZIKV infections, 145 (91.8%) yielded greater than 50% inhibition. Of 171 patients with primary or secondary DENV infections, 152 (88.9%) scored negative. When the control group was extended to patients infected by other flaviviruses, other viruses, or healthy donors (n = 540), the specificity was 95.9%. We also analyzed longitudinal samples from DENV-immune and DENV-naive ZIKV infections and found inhibition was achieved within 10 d postonset of illness and maintained over time. Thus, the Zika NS1 BOB assay is sensitive, specific, robust, simple, low-cost, and accessible, and can detect recent and past ZIKV infections for surveillance, seroprevalence studies, and intervention trials.

West Nile and Usutu Virus Infections and Challenges to Blood Safety in the European Union.

West Nile virus (WNV) and Usutu virus (USUV) circulate in several European Union (EU) countries. The risk of transfusion-transmitted West Nile virus (TT-WNV) has been recognized, and preventive blood safety measures have been implemented. We summarized the applied interventions in the EU countries and assessed the safety of the blood supply by compiling data on WNV positivity among blood donors and on reported TT-WNV cases. The paucity of reported TT-WNV infections and the screening results suggest that blood safety interventions are effective. However, limited circulation of WNV in the EU and presumed underrecognition or underreporting of TT-WNV cases contribute to the present situation. Because of cross-reactivity between genetically related flaviviruses in the automated nucleic acid test systems, USUV-positive blood donations are found during routine WNV screening. The clinical relevance of USUV infection in humans and the risk of USUV to blood safety are unknown.

Infections and associated behaviors among deceased organ donors: Informing the assessment of risk.

BACKGROUND: For infectious disease risk assessment among deceased organ donors, pre-donation clinical, microbiological, and behavioral information are reviewed; however, uncertainty may arise due to false negative screening results of recently acquired infections. METHOD: The burden of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), and residual risks (RR) of undetected virus was estimated, with the impact of more sensitive screening. RESULTS: For United Kingdom potential deceased organ donors between 2010 and 2014, prevalence of HBsAg was 0.1%, HIV 0.06% and HCV 0.9%, increasing to 25.7% in people who injected drugs (PWID). Incidence, derived from new blood donors, was multiplied by duration of screening assay window periods to give RR per 100 000 donors as 0.43 (95% confidence interval [CI] 0.03-3.99) for HBV, 0.08 (95% CI 0.02-0.21) for HIV, and 5.96 (95% CI 0.82-37.89) for HCV. For PWID, HCV RR was 163.3 (95% CI 22.8-1107.8) compared to 2.76 (95% CI 0.35-17.36) for non-PWID. RR decreased significantly with nucleic acid testing (NAT), and, for HCV, antigen testing had a similar impact. CONCLUSION: While the burden of HCV risk lies within PWID, these are in small numbers therefore few HCV antigen or NAT tests would be needed to more accurately assess risk.

Hepatitis E virus in blood donors in England, 2016 to 2017: from selective to universal screening.

IntroductionHepatitis E virus (HEV), the most common cause of acute hepatitis in many European countries, is transmitted through consumption of processed pork but also via blood transfusion and transplantation. HEV infection can become persistent in immunocompromised individuals.AimWe aimed to determine the incidence and epidemiology of HEV infection in English blood donors since the introduction of donation screening in 2016.MethodsBetween March 2016 and December 2017, 1,838,747 blood donations were screened for HEV RNA. Donations containing HEV RNA were further tested for serological markers, RNA quantification and viral phylogeny. Demographics, travel and diet history were analysed for all infected donors.ResultsWe identified 480 HEV RNA-positive blood donations during the 22-month period, most (319/480; 66%) donors were seronegative. Viral loads ranged from 1 to 3,230,000 IU/ml. All sequences belonged to genotype 3, except one which likely represents a new genotype. Most viraemic donors were over 45 years of age (279/480; 58%), donors aged between 17 and 24 years had a seven-times higher incidence of HEV infection than other donors between March and June 2016 (1:544 donations vs 1:3,830). HEV-infected blood donors were evenly distributed throughout England. Screening prevented 480 HEV RNA-positive blood donations from reaching clinical supply.ConclusionHEV screening of blood donations is a vital step in order to provide safer blood for all recipients, but especially for the immunosuppressed. The unusually high rates of HEV infection in young blood donors may provide some insight into specific risks associated with HEV infection in England.

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.

SAMBA HIV semiquantitative test, a new point-of-care viral-load-monitoring assay for resource-limited settings.

Routine viral-load (VL) testing of HIV-infected individuals on antiretroviral therapy (ART) is used to monitor treatment efficacy. However, due to logistical challenges, implementation of VL has been difficult in resource-limited settings. The aim of this study was to evaluate the performance of the SAMBA semi-Q (simple amplification-based assay semiquantitative test for HIV-1) in London, Malawi, and Uganda. The SAMBA semi-Q can distinguish between patients with VLs above and below 1,000 copies/ml. The SAMBA semi-Q was validated with diluted clinical samples and blinded plasma samples collected from HIV-1-positive individuals. SAMBA semi-Q results were compared with results from the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 test, v2.0. Testing of 96 2- to 10-fold dilutions of four samples containing HIV-1 subtype C as well as 488 samples from patients in the United Kingdom, Malawi, and Uganda yielded an overall accuracy for the SAMBA semi-Q of 99% (95% confidence interval [CI], 93.8 to 99.9%) and 96.9% (95% CI 94.9 to 98.3%), respectively, compared to to the Roche test. Analysis of VL data from patients in Malawi and Uganda showed that the SAMBA cutoff of 1,000 copies/ml appropriately distinguished treated from untreated individuals. Furthermore, analysis of the viral loads of 232 patients on ART in Malawi and Uganda revealed similar patterns for virological control, defined as either <1,000 copies/ml (SAMBA cutoff) or <5,000 copies/ml (WHO 2010 criterion; WHO, Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach, 2010). This study suggests that the SAMBA semi-Q has adequate concurrency with the gold standard measurements for viral load. This test can allow VL monitoring of patients on ART at the point of care in resource-limited settings.

Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B.

BACKGROUND & AIMS: Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance. METHODS: We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells. RESULTS: Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB. CONCLUSIONS: HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.

Vaccine Effectiveness Against the SARS-CoV-2 B.1.1.529 Omicron Variant in Solid Organ and Islet Transplant Recipients in England: A National Retrospective Cohort Study.

BACKGROUND: The effectiveness of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 Omicron variant in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear. METHODS: National registries in England were linked to identify SARS-CoV-2 positive tests, noninjury hospitalization within 14 d, and deaths within 28 d between December 7, 2020, and March 31, 2022 in adult SOT recipients. Incidence rate ratios (IRRs) for infection, and hospitalization or death, were adjusted for recipient demographics and calendar month for the Omicron-dominant period (December 20, 2021, to March 31, 2022). Mortality risk following SARS-CoV-2 infection was adjusted for recipient demographics and dominant variant using a Cox proportional-hazards model for the entire time period. RESULTS: During the Omicron-dominant period, infection IRRs (95% confidence intervals) were higher in those receiving 2, 3, and 4 vaccine doses than in unvaccinated patients (1.25 [1.08-1.45], 1.46 [1.28-1.67], and 1.79 [1.54-2.06], respectively). However, hospitalization or death IRRs during this period were lower in those receiving 3 or 4 vaccine doses than in unvaccinated patients (0.62 [0.45-0.86] and 0.39 [0.26-0.58], respectively). Risk-adjusted analyses for deaths after SARS-CoV-2 infection between December 7, 2020, and March 31, 2022, found hazard ratios (95% confidence intervals) of 0.67 (0.46-0.98), 0.46 (0.30-0.69), and 0.18 (0.09-0.35) for those with 2, 3, and 4 vaccine doses, respectively, when compared with the unvaccinated group. CONCLUSIONS: In immunosuppressed SOT recipients, vaccination is associated with incremental, dose-dependent protection against hospitalization or death after SARS-CoV-2 infection, including against the Omicron variant.

Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UK.

BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.