Effect of SARS-CoV-2 Incidence and Immunisation Rates on Sporadic Creutzfeldt-Jakob Disease Incidence.

BACKGROUND: Recent case studies and media outlets have hypothesised an effect of SARS-CoV-2 infection and immunisation on the development or progression of neurodegenerative diseases such as Alzheimer's disease or sporadic Creutzfeldt-Jakob disease (sCJD). OBJECTIVES: This study aims to identify potential associations of SARS-CoV-2 infections and SARS-CoV-2 immunisation with sCJD incidence, disease duration, and age of onset. METHOD: We used data from a prospective sCJD surveillance study in Germany (2016-2022) and publicly available datasets of SARS-CoV-2 cases and vaccination numbers in Germany for the years 2020-2022. Associations of SARS-CoV-2 incidence and immunisation rates with sCJD incidence were assessed by comparing quarterly and annual cumulative sCJD incidences in the periods before (2016-2019) and during the pandemic (2020-2022). RESULTS: We could not identify any time-related effect of SARS-CoV-2 incidence or immunisation rate on the sCJD incidence. Moreover, we did not find any sCJD incidence alterations before and during the SARS-CoV-2 pandemic on a federal or state level. The overall sCJD incidence was within expected ranges in the years 2020-2022. There were no changes in age of onset and clinical disease duration in these years. CONCLUSIONS: We found no evidence supporting a short-term effect of the pandemic on sCJD incidence. However, considering the extended pre-clinical phase of sCJD, continued surveillance is needed to identify potential future incidence alterations.

Importation of plasma and use of apheresis platelets as risk reduction measures for variant Creutzfeldt-Jakob disease: The SaBTO review.

Following recognition that blood, blood components, tissues and organs donated by infected donors could transmit infectious prions causing variant Creutzfeldt-Jakob Disease (vCJD), several risk reduction measures were introduced in the UK. The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) established a working group to review the measures in place. Factors considered included: ethical issues around the current provisions and potential changes; operational issues for blood establishments and hospitals; a review from the Advisory Committee on Dangerous Pathogens (ACDP) showing the downward trend in the estimated number of future cases of vCJD; and cost-effectiveness. The working group recommended that the current vCJD risk reduction measures for individuals born after 1995 or with thrombotic thrombocytopenic purpura (TTP) could be withdrawn. After consultation with stakeholders, SaBTO accepted these proposals which allow more equal provision of components, less operational complexity and risk, and more resources to be deployed elsewhere in the NHS. The potential saving on plasma will be £500 m and moving to using pooled platelets in additive solution for all recipients will bring potential savings of £280 m over the next 50 to 60 years. There could be small number of additional clinical cases of vCJD: 1-2 (<1-14; 95% CI) from plasma and 3-4 (<1 to 45; 95% CI) from platelets. Local and national guidelines will still be applied for managing individual conditions. UK Ministers for Health accepted SaBTO's recommendations on 9 Sept 2019 and implementation began immediately. This paper describes the review and rationale leading to these recommendations.

[Creutzfeldt-Jakob Disease and Lyodura:A Special Reference to Prion Disease Control in the Field of Neurosurgery].

In Japan, 156 cases of dura mater-transplanted Creutzfeldt-Jakob disease(dCJD)with a history of Lyodura transplantation have been confirmed until February 2022, with only a few new cases still being identified. The history of Lyodura transplantation is one involving a neurosurgical procedure. The cumulative global number of cases of bovine spongiform encephalopathy-related variant CJD(BSE-related vCJD), which has shaken societies around the world, is 232 as of 2019. Thus, the impact of dCJD on the society in Japan needs no explanation. Thanks to the world's concerted efforts in research and countermeasures, medically induced prion diseases are finally becoming a thing of the past. However, due to the extremely long incubation period of CJD and the difficulty of tracing the source of infection, immediate action in the event of an outbreak is not possible, and efforts must focus on preventing disease outbreaks. Independent of this, approximately 200 cases of solitary and hereditary prion diseases occur annually in Japan. If neurosurgery must be performed on such patients, secondary transmission of prion disease by neurosurgical instruments must be prevented. Therefore, sterilization methods for neurosurgical instruments are critical, and various measures including sterilization methods have been determined and published by a research group designated by the Japanese Ministry of Health, Labour and Welfare. The sterilization of neurosurgical instruments should comply with the latest guidelines that are published by this study group.

A naturally occurring variant of the human prion protein completely prevents prion disease.

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

Geographic exposure risk of variant Creutzfeldt-Jakob disease in US blood donors: a risk-ranking model to evaluate alternative donor-deferral policies.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) has been transmitted by blood transfusion (TTvCJD). The US Food and Drug Administration (FDA) recommends deferring blood donors who resided in or traveled to 30 European countries where they may have been exposed to bovine spongiform encephalopathy (BSE) through beef consumption. Those recommendations warrant re-evaluation, because new cases of BSE and vCJD have markedly abated. STUDY DESIGN AND METHODS: The FDA developed a risk-ranking model to calculate the geographic vCJD risk using country-specific case rates and person-years of exposure of US blood donors. We used the reported country vCJD case rates, when available, or imputed vCJD case rates from reported BSE and UK beef exports during the risk period. We estimated the risk reduction and donor loss should the deferral be restricted to a few high-risk countries. We also estimated additional risk reduction by leukocyte reduction (LR) of red blood cells (RBCs). RESULTS: The United Kingdom, Ireland, and France had the greatest vCJD risk, contributing approximately 95% of the total risk. The model estimated that deferring US donors who spent extended periods of time in these three countries, combined with currently voluntary LR (95% of RBC units), would reduce the vCJD risk by 89.3%, a reduction similar to that achieved under the current policy (89.8%). Limiting deferrals to exposure in these three countries would potentially allow donations from an additional 100,000 donors who are currently deferred. CONCLUSION: Our analysis suggests that a deferral option focusing on the three highest risk countries would achieve a level of blood safety similar to that achieved by the current policy.

Leukoreduction and blood-borne vCJD transmission risk.

PURPOSE OF REVIEW: Risk assessments for transmission of variant Creutzfeldt-Jakob disease predicted that leukocyte reduction would be inefficient at preventing transmission of the disease by blood transfusion. Nevertheless, approximately 14 years ago, a significant proportion of European countries decided to implement leukocyte reduction treatment within their human blood supplies in order to mitigate the risk of human prion disease transmission. RECENT FINDINGS: Current epidemiological studies seem to indicate that leukocyte reduction has had a positive impact on reducing the risk. In addition, over the last 5 years, various experimental studies carried out in animal models have confirmed that leukocyte reduction provides a high, but not absolute, protection against transmission of prion disease by blood transfusion. Observations that show the efficacy of blood-borne prion transmission is more dependent on the viability of leukocytes than the level of infectivity present in the blood product make a significant contribution to understanding the risk of prion infection by blood transfusion. SUMMARY: Considering the potential for significant numbers of subclinical variant Creutzfeldt-Jakob disease individuals in at least the United Kingdom, these findings strongly support the continuation of systematic leukoreduction for blood donations collected in individuals born before the effective prevention of human dietary exposure to bovine spongiform encephalopathy.

Development of a bifunctional filter for prion protein and leukoreduction of red blood cell components.

BACKGROUND: Leukofiltration of blood components is currently implemented worldwide as a precautionary measure against white blood cell-associated adverse effects and the potential transmission of variant Creutzfeldt-Jakob disease (vCJD). A newly developed bifunctional filter (Sepacell Prima, Asahi Kasei Medical) was assessed for prion removal, leukoreduction (LR), and whether the filter significantly affected red blood cells (RBCs). STUDY DESIGN AND METHODS: Sepacell Prima's postfiltration effects on RBCs, including hemolysis, complement activation, and RBC chemistry, were compared with those of a conventional LR filter (Sepacell Pure RC). Prion removal was measured by Western blot after spiking RBCs with microsomal fractions derived from scrapie-infected hamster brain homogenate. Serially diluted exogenous prion solutions (0.05 mL), with or without filtration, were injected intracerebrally into Golden Syrian hamsters. RESULTS: LR efficiency of 4.44 log with the Sepacell Prima was comparable to 4.11 log with the conventional LR filter. There were no significant differences between the two filters in hemoglobin loss, hemolysis, complement activation, and RBC biomarkers. In vitro reduction of exogenously spiked prions by the filter exceeded 3 log. The titer, 6.63 (log ID50 /mL), of prefiltration infectivity of healthy hamsters was reduced to 2.52 (log ID50 /mL) after filtration. The reduction factor was calculated as 4.20 (log ID50 ). CONCLUSION: With confirmed removal efficacy for exogenous prion protein, this new bifunctional prion and LR filter should reduce the residual risk of vCJD transmission through blood transfusion without adding complexity to component processing.

Evaluation of the protection of primates transfused with variant Creutzfeldt-Jakob disease-infected blood products filtered with prion removal devices: a 5-year update.

BACKGROUND: Analysis of archived appendix samples reveals that one in 2000 individuals in the United Kingdom may carry the infectious prion protein associated with variant Creutzfeldt-Jakob disease (vCJD), raising questions about the risk of transfusion transmission from apparently healthy carriers. Blood leukoreduction shows limited efficiency against prions. Therefore, in absence of antemortem diagnostic tests, prion removal filters, including the P-Capt filter were designed to improve blood transfusion safety. STUDY DESIGN AND METHODS: We evaluated the performances of two filters, the P-Capt and one prototype (PMC#005), with blood-borne infectivity in two independent experiments. Blood was drawn twice from prion-infected macaques. Corresponding RBCCs were prepared according to two different procedures: in Study A, the leukoreduction step was followed by the filtration through the P-Capt. In Study B, the leukoreduction and prion removal were performed simultaneously through the PMC#005. For each study, two groups of three animals were transfused twice with samples before or after filtration. RESULTS: Among the six macaques transfused with nonfiltered samples, five developed neurologic signs but only four exhibited peripheral detectable protease-resistant prion protein (PrPres) accumulation. In Study A, the three animals transfused with P-Capt-filtered samples remain asymptomatic and devoid of PrPres in lymph node biopsies 6 years after the transfusion. In Study B, one animal transfused with PMC#005-filtered samples developed vCJD. CONCLUSION: After 5 to 6 years of progress, this ongoing study provides encouraging results on the prion blood removal performances of the P-Capt filter in macaques, an utmost relevant model for human prion diseases.

Transmission of infection by flexible gastrointestinal endoscopy and bronchoscopy.

Flexible endoscopy is a widely used diagnostic and therapeutic procedure. Contaminated endoscopes are the medical devices frequently associated with outbreaks of health care-associated infections. Accurate reprocessing of flexible endoscopes involves cleaning and high-level disinfection followed by rinsing and drying before storage. Most contemporary flexible endoscopes cannot be heat sterilized and are designed with multiple channels, which are difficult to clean and disinfect. The ability of bacteria to form biofilms on the inner channel surfaces can contribute to failure of the decontamination process. Implementation of microbiological surveillance of endoscope reprocessing is appropriate to detect early colonization and biofilm formation in the endoscope and to prevent contamination and infection in patients after endoscopic procedures. This review presents an overview of the infections and cross-contaminations related to flexible gastrointestinal endoscopy and bronchoscopy and illustrates the impact of biofilm on endoscope reprocessing and postendoscopic infection.

Urgent revision required of NICE guidance relating to prevention of spread of vCJD through neurosurgical instruments.

In 2006, NICE brought out guidance relating to prevention of vCJD through contaminated surgical instruments. This was with the aim of protecting patients born after 1997 who did not have any risk of developing vCJD through eating beef contaminated with BSE through the food chain. Many adult neurosurgical units did not pay much attention to this until 2013 when they were suddenly faced with these children who were now 16 and being admitted to the adult neurosurgical service rather than pediatric. The NICE guidance requires that most patients born after 1997 be operated on using a separate set of neurosurgical instruments than those born before this. This is proving to be a huge financial, as well as logistical, challenge and also a clinical risk as attention is being diverted to searching for the right kit when it should be spent on saving lives. It is now clear in 2013 that the risks that NICE feared were perhaps overstated as there is nowhere near the number of deaths from vCJD that NICE had feared would happen. Worldwide there have been only five cases whereby CJD was transmitted through contaminated neurosurgical instruments and the last case was in 1976. There have been no cases of vCJD transmission attributed to use of contaminated neurosurgical instruments. NICE should revisit this guidance urgently in view of these circumstances.

Advancing surgical instrument safety: A screen of oxidative and alkaline prion decontaminants using real-time quaking-induced conversion with prion-coated steel beads as surgical instrument mimetic.

Iatrogenic transmission of prions, the infectious agents of fatal Creutzfeldt-Jakob disease, through inefficiently decontaminated medical instruments remains a critical issue. Harsh chemical treatments are effective, but not suited for routine reprocessing of reusable surgical instruments in medical cleaning and disinfection processes due to material incompatibilities. The identification of mild detergents with activity against prions is therefore of high interest but laborious due to the low throughput of traditional assays measuring prion infectivity. Here, we report the establishment of TESSA (sTainlESs steel-bead Seed Amplification assay), a modified real-time quaking induced cyclic amplification (RT-QuIC) assay that explores the propagation activity of prions with stainless steel beads. TESSA was applied for the screening of about 70 different commercially available and novel formulations and conditions for their prion inactivation efficacy. One hypochlorite-based formulation, two commercially available alkaline formulations and a manual alkaline pre-cleaner were found to be highly effective in inactivating prions under conditions simulating automated washer-disinfector cleaning processes. The efficacy of these formulations was confirmed in vivo in a murine prion infectivity bioassay, yielding a reduction of the prion titer for bead surface adsorbed prions below detectability. Our data suggest that TESSA represents an effective method for a rapid screening of prion-inactivating detergents, and that alkaline and oxidative formulations are promising in reducing the risk of potential iatrogenic prion transmission through insufficiently decontaminated instrument surfaces.

Prion removal capacity of plasma protein manufacturing processes: a data collection from PPTA member companies.

BACKGROUND: The variant Creutzfeldt-Jakob disease incidence peaked a decade ago and has since declined. Based on epidemiologic evidence, the causative agent, pathogenic prion, has not constituted a tangible contamination threat to large-scale manufacturing of human plasma-derived proteins. Nonetheless, manufacturers have studied the prion removal capabilities of various manufacturing steps to better understand product safety. Collectively analyzing the results could reveal experimental reproducibility and detect trends and mechanisms driving prion removal. STUDY DESIGN AND METHODS: Plasma Protein Therapeutics Association member companies collected more than 200 prion removal studies on plasma protein manufacturing steps, including precipitation, adsorption, chromatography, and filtration, as well as combined steps. The studies used a range of model spiking agents and bench-scale process replicas. The results were grouped based on key manufacturing variables to identify factors impacting removal. The log reduction values of a group are presented for comparison. RESULTS: Overall prion removal capacities evaluated by independent groups were in good agreement. The removal capacity evaluated using biochemical assays was consistent with prion infectivity removal measured by animal bioassays. Similar reduction values were observed for a given step using various spiking agents, except highly purified prion protein in some circumstances. Comparison between combined and single-step studies revealed complementary or overlapping removal mechanisms. Steps with high removal capacities represent the conditions where the physiochemical differences between prions and therapeutic proteins are most significant. CONCLUSION: The results support the intrinsic ability of certain plasma protein manufacturing steps to remove prions in case of an unlikely contamination, providing a safeguard to products.

Removal of TSE agent from plasma products manufactured in the United Kingdom.

BACKGROUND AND OBJECTIVES: The outbreak of vCJD in the UK leads to concern regarding the potential for human-to-human transmission of this agent. Plasma-derived products such as albumin, immunoglobulin and coagulation factors were manufactured by BPL from UK plasma up until 1999 when a switch to US plasma was made. In the current study, the capacity of various manufacturing processes that were in use both prior to and after this time to remove the TSE agent was tested. MATERIALS AND METHODS: Small-scale models of the various product manufacturing steps were developed. Intermediates were spiked with scrapie brain extract and then further processed. Samples were assayed for the abnormal form of prion protein (PrP(SC) ) by Western blotting, and the reduction in the amount of scrapie agent determined. RESULTS: Many of the manufacturing process steps produced significant reduction in the scrapie agent. Particularly effective were steps such as ethanol fractionation, depth filtration, ion-exchange and copper chelate affinity chromatography. Virus retentive filters, of nominal pore size 15 or 20 nm, removed >3 log. The total cumulative reduction capacity for individual products was estimated to range from 7 to 14 log. In the case of factor VIII (8Y), the total removal was limited to 3 log. CONCLUSION: All the processes showed a substantial capacity to remove the TSE agent. However, this was more limited for the intermediate purity factor VIII 8Y which included fewer manufacturing steps.

Surveillance for Creutzfeldt-Jakob disease in Australia: update to December 2012.

Nation-wide surveillance for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease (CJD) is undertaken by the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR), based at the University of Melbourne. Surveillance has been undertaken since 1993. During this period the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of CJD and other transmissible spongiform encephalopathies in the health care setting. In 2012, routine surveillance continued. This brief report provides an update on the surveillance data collected by the ANCJDR prospectively from 1993 to December 2012, and retrospectively to 1970. It also highlights the recent release of the revised Australian CJD Infection Control Guidelines.

Kinetics of the reduction of Creutzfeldt-Jakob disease prion seeding activity by steam sterilization support the use of validated 134°C programmes.

BACKGROUND: Prions are renowned for their distinct resistance to chemical or physical inactivation, including steam sterilization. Impaired efficacy of inactivation poses a risk to patients for iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) via contaminated surgical instruments. AIMS: Most established prion inactivation methods were validated against scrapie agents, although those were found to be generally less thermostable than human prions. Thus, knowledge gaps regarding steam-sterilization kinetics of CJD prions should be filled and current guidelines reviewed accordingly. METHODS: Prion inactivation through widely recommended steam sterilization at 134°C was assessed for several holding times by analysing the residual prion seeding activity using protein misfolding cyclic amplification (PMCA). FINDINGS: Scrapie 263K was found to be the least thermoresistant prion strain showing no seeding activity after 1.5 min at 134°C, while variant CJD was the most stable one demonstrating some seeding activity even after 18 min of steam sterilization. Sporadic CJD subtype VV2 exhibited residual seeding activity after 3 min, but no detectable activity after 5 min at 134°C. CONCLUSION: Validated steam sterilization for 5 min at 134°C as previously recommended for the routine reprocessing of surgical instruments in contact with high-risk tissues is able to substantially reduce the seeding activity of CJD agents, provided that no fixating chemical disinfection has been performed prior to sterilization and that thorough cleaning has reduced the protein load on the surface to less than 100 µg per instrument.

Iatrogenic Creutzfeldt-Jakob disease, final assessment.

The era of iatrogenic Creutzfeldt-Jakob disease (CJD) has nearly closed; only occasional cases with exceptionally long incubation periods are still appearing. The principal sources of these outbreaks are contaminated growth hormone (226 cases) and dura mater grafts (228 cases) derived from human cadavers with undiagnosed CJD infections; a small number of additional cases are caused by neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infection with variant CJD transmitted by transfusion of blood products. No new sources of disease have been identified, and current practices, which combine improved recognition of potentially infected persons with new disinfection methods for fragile surgical instruments and biological products, should continue to minimize the risk for iatrogenic disease until a blood screening test for the detection of preclinical infection is validated for human use.

Dealing with the uncertain risk of variant Creutzfeldt-Jakob disease transmission by coagulation replacement products.

The identification of variant Creutzfeldt-Jakob disease (vCJD) in the UK in 1996 led to significant concerns about the possibility of secondary transmission, however the prevalence of subclinical vCJD and risks of vCJD transmission by plasma are not known. In the UK, public health precautions have been implemented in all recipients of coagulation factor concentrates manufactured from UK plasma pools between 1980 and 2001. The recent demonstration of abnormal prion protein in a spleen sample at autopsy of a UK haemophilic patient who received coagulation factor concentrates to which a donor incubating vCJD had contributed most likely represents the first case of vCJD transmission by coagulation factor concentrates. We review the uncertainties that surround risk of vCJD transmission by coagulation factor concentrates, the challenges in dealing with undefined risks, the rationale behind current policies and the implementation of vCJD surveillance and risk management measures in bleeding disorder patients in the UK.

Cost-effectiveness of prion filtration of red blood cells to reduce the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease in the Republic of Ireland.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a rare, progressive fatal noninflammatory neurodegenerative disease. Ireland has the second highest rate of vCJD in the world with an ongoing risk of vCJD transmission through blood transfusion. Prion-removing filters have been developed to reduce the risk of vCJD transmission. This study aimed to evaluate the cost-effectiveness of implementing a policy of prion filtration of red blood cells (RBCs) in the Republic of Ireland. STUDY DESIGN AND METHODS: A cost-effectiveness model was developed to simulate the likelihood of RBC recipients developing clinical vCJD as a result of being transfused with infected RBCs. Model variables were collected from published literature and expert opinion. Costs were estimated based on the processing changes required to implement prion filtration. RESULTS: In the absence of prion filtration, it is estimated that two individuals will develop clinical vCJD arising from RBC transfusions over a 10-year time horizon. The discounted life-years lost will be 18.5 years. With prion filtration, there will be no deaths or life-years lost. The discounted cost of universal prion filtration is €68.2 million over 10 years with a corresponding incremental cost-effectiveness ratio of €3.7 million per life-year gained. In 25.3% of simulations there were no deaths from vCJD infection through infected blood transfusions, irrespective of prion filtration. CONCLUSION: Prion filtration is considered not cost-effective by traditional measures. Although numerous non-cost-effective blood safety strategies have been implemented in the past, consideration should be given to the most efficient use of finite resources in transfusion medicine.