Potential Exposure to Creutzfeldt-Jakob Disease VA Connecticut Healthcare System West Haven, Connecticut
VA OIG releases findings of potential CJD exposure
July 2, 2014
Healthcare Inspection – Potential Exposure to Creutzfeldt-Jakob Disease, VA Connecticut Healthcare System, West Haven, Connecticut
06/30/2014 08:00 PM EDT
OIG conducted an oversight review regarding potential exposure of two veteran patients to Creutzfeldt-Jakob Disease (CJD) at the VA Connecticut Healthcare System (facility), West Haven, CT. We reviewed the facility’s procedures for reprocessing of neurosurgical instruments, handling and tracking of loaner instrument trays, and responding to the potential exposures and the follow-up actions taken post-exposure.
In addition, we reviewed Veterans Health Administration (VHA) reprocessing requirements for neurosurgical instruments. We concluded that the facility took appropriate steps to address potential patient exposure to CJD. Managers were proactive in seeking counsel from subject matter experts within the VA and other Government agencies to ensure that proper patient follow-up and notification occurred in a timely manner. Facility providers notified and met with the involved patients and/or their family members to discuss the potential exposure to CJD, the risks of CJD transmission, and answer questions or concerns. Providers documented clinical disclosures in the patients’ electronic health records. Although the facility met the recommended manufacturer’s minimum requirement for sterilization of surgical instruments, the facility amended its process by increasing sterilization time from 4 to 18 minutes for neurosurgical instruments. Additionally, managers implemented a process for tracking all loaner instruments from receipt to return.
We concluded that VHA had appropriate policies and procedures for reprocessing neurosurgical instruments. We made no recommendations.
Department of Veterans Affairs Office of Inspector General Office of Healthcare Inspections
Report No. 13-04520-201
Healthcare Inspection
Potential Exposure to Creutzfeldt-Jakob Disease VA Connecticut Healthcare System West Haven, Connecticut
July 1, 2014
Washington, DC 20420
Executive Summary
The VA Office of Inspector General Office of Healthcare Inspections conducted an oversight review regarding potential exposure of two patients to Creutzfeldt-Jakob Disease (CJD) at the VA Connecticut Healthcare System (facility), West Haven, CT. We reviewed the facility’s procedures for reprocessing of neurosurgical instruments, handling and tracking of loaner instrument trays, and responding to the potential exposure and the follow-up actions taken post-exposure. In addition, we reviewed Veterans Health Administration (VHA) reprocessing requirements for neurosurgical instruments.
We concluded that the facility took appropriate steps to address potential patient exposure to CJD. Managers were proactive in seeking counsel from subject matter experts within the VA and other Government agencies to ensure that proper patient follow-up and notification occurred in a timely manner. Facility providers notified and met with the involved patients and/or their family members to discuss the potential exposure to CJD, the risks of CJD transmission, and answer questions or concerns. Providers documented clinical disclosures in the patients’ electronic health records.
Although the facility met the recommended manufacturer’s minimum requirement of 4 minutes for sterilization of surgical instruments, the facility amended its process by increasing sterilization time from 4 to 18 minutes for neurosurgical instruments. Additionally, managers implemented a process for tracking all loaner instruments from receipt to return. We concluded that VHA had appropriate policies and procedures for reprocessing neurosurgical instruments. We made no recommendations.
The Veterans Integrated Service Network and Facility Directors concurred with the report. (See Appendixes A and B, pages 9 – 1 0 , for the Directors’ comments.) No further action is required.
JOHN D. DAIGH, JR., M.D.
Assistant Inspector General for Healthcare Inspections
Purpose
The VA Office of Inspector General (OIG) Office of Healthcare Inspections conducted an evaluation of the VA Connecticut Healthcare System’s (facility) management of two veteran patients who had been potentially exposed to Creutzfeldt–Jakob disease (CJD). The specific objectives were to review the facility’s procedures for reprocessing neurosurgical instruments, handling and tracking loaner instrument trays, and responding to the potential exposure and the follow-up actions taken post-exposure. In addition, we reviewed Veterans Health Administration (VHA) reprocessing requirements for neurosurgical instruments.
Background
The facility, part of Veterans Integrated Service Network (VISN) 1, comprises two campuses located in West Haven and Newington, CT. The West Haven campus has 230 beds and provides patient care services that include internal medicine, surgery, psychiatry, physical medicine and rehabilitation, neurology, oncology, dentistry, and geriatrics and extended care. Newington is an ambulatory care center that provides primary and specialty care.
In August 2013, media reports described the potential exposure of patients to CJD. The source patient, who was located in New Hampshire, had died and during autopsy was diagnosed with suspected CJD. The instruments used on the source patient were also used on 15 other patients—8 in a New Hampshire community hospital, 5 in a Massachusetts community hospital, and 2 at the facility.
CJD Overview
CJD is a rare, degenerative, invariably fatal brain disorder, with about 200 cases per year in the United States. It usually appears later in life and runs a rapid course, with symptoms occurring at about age 60. There are three main categories of the disease:
Sporadic: Person has no known risk factors. This accounts for at least 85 percent of cases.
Hereditary: Person has a family history of the disease and/or tests positive for a genetic mutation associated with CJD. About 5–10 percent of CJD cases in the United States are hereditary.
Iatrogenic: Disease is transmitted by exposure to brain or nervous system tissue, usually through certain medical procedures.1
1 Rutala W, Weber D. SHEA Guideline for Disinfection and Sterilization of Prion-Contaminated Medical Instruments. Inf Control Hosp Epidemiol 2010;25:107–117.
Healthcare-associated2
CJD infections have occurred in less than 1 percent of all cases. All known cases of healthcare-associated or iatrogenic CJD resulted from exposure to infectious brain, pituitary, or eye tissue.3,4
CJD Exposure Overview at the Facility
Due to the complexities and costs of the instruments, hospitals often use loaner surgical instruments from a vendor or another hospital in order to provide necessary instruments to perform scheduled procedures without the financial burden of purchasing them.5 A neurosurgical loaner instrument tray was delivered to the facility in early May 2013 and was used during surgery involving two facility patients. The instruments were reprocessed following the manufacturer’s recommended decontamination and sterilization instructions before and after each case.
The first patient (Patient A), an 85-year-old male, had a brain biopsy to determine the reason for his brain lesions. The second patient (Patient B), a 67-year-old male, underwent a craniotomy6 for resection of a brain tumor. Table 1 below describes the dates and types of surgeries.
Table 1. Dates and Types of Surgeries
Patient Date of Surgery Diagnosis Surgical Procedure
Patient A May 30, 2013 Right homonymous hemianopsia (absence of vision toward one side of the visual world) Left parietooccipital stereotactic brain biopsy
Patient B June 11, 2013 Meningioma (brain tumor that develops from the meninges— the membrane that surrounds the brain and spinal cord) Craniotomy for resection meningioma
Source: OIG Review of Electronic Health Records
In late August, the neurosurgical instrument manufacturer (Medtronic, Inc.) notified the facility that the three instruments included in the loaner tray, a Vertek II Articulating Arm,
2 Healthcare-associated infections are ones patients acquire while receiving healthcare treatment for other conditions.
3 Brown P. Environmental causes of human spongiform encephalopathy. In: Baker H, Ridley RM, eds. Methods in
Molecular Medicine: Prion Diseases. Totowa, NJ: Humana Press; 1996:139–154.
4 Brown P, Gibbs CJ, Rodgers-Johnson P, et al. Human spongiform encephalopathy: the National Institutes of
Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994:35:513–529.
5 Seavy R. Reducing the Risks Associated with Loaner Instrumentation and Implants. AORN Journal, 2010:92:3:322.
6 Surgical removal of part of the skull to expose the brain. It is the most commonly performed surgery for brain tumor removal.
a Passive Planar Probe, and a Small Passive Cranial Reference Frame, had been used on the source patient in a non-VA facility in May. The source patient had died and was suspected of having CJD. The diagnosis of CJD was later confirmed by the Centers for Disease Control and Prevention (CDC). Exhibit 1 shows the instruments in the loaner tray.
Exhibit 1. Instruments Included in the Loaner Tray
Two of the three loaner instruments had no contact with the facility patients’ brain tissue. The Passive Planar Probe, used to locate the specific surgical area, was the only instrument inserted into the facility patients’ brain tissue.
Decontamination and Sterilization Parameters
In 1999, the World Health Organization (WHO) recommended the use of sodium hypochlorite (chlorine bleach) or sodium hydroxide (NaOH) to disinfect and/or sterilize instruments if instruments could not be destroyed or quarantined after use on a possible CJD patient.7 However, FDA investigators found that: (1) autoclaving (sterilizing) in a 1 Normal (N) solution of NaOH causes darkening of some instruments; (2) soaking in 1N NaOH at room temperature damages carbon steel but not stainless steel or titanium; and (3) soaking in chlorine bleach corrodes gold-plated instruments and will damage some stainless steel instruments.8 In addition, the CDC indicated that staff should avoid gaseous exposure to NaOH. Since the release of the WHO guidelines, studies have demonstrated the efficacy of using enzymatic detergents followed by steam sterilization in eliminating prions9 from steel surfaces.10,11 Table 2 describes the recommended procedures for the disinfection and sterilization of surgical instruments potentially contaminated with CJD from several organizations.
Table 2. Recommended Disinfection and Sterilization Procedures for Potentially Contaminated CJD Instruments 7 World Health Organization. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies, March 1999.
snip...
In this instance, the facility followed the manufacturer’s instructions for the loaner instruments and its own reprocessing procedures for surgical instruments that were consistent with industry standards cited in Table 2.
Scope and Methodology
We gathered information from key facility staff members. We interviewed a CJD subject matter expert from a VA facility and the prion epidemiologist from the CDC. We discussed the potential exposure in New Hampshire and Massachusetts with the respective State Health Departments. We also interviewed a VHA reusable medical equipment reprocessing subject matter expert.
We reviewed the patients’ electronic health records (EHRs), the facility’s reprocessing procedures, relevant facility policies and procedures, pertinent medical literature, and the manufacturer’s information on the involved instruments.
We conducted the inspection in accordance with Quality Standards for Inspection and Evaluation published by the Council of the Inspectors General on Integrity and Efficiency.
Inspection Results
Issue 1: Reprocessing of Neurosurgery Instruments
We found no evidence that sterilization procedures were compromised. The probe manufacturer recommended a sterilization time of 4–18 minutes, and the facility used a 4-minute sterilization time. After consultation with CDC, the Connecticut State Department of Health, and local infectious disease specialists, the facility determined that its sterilization processes were within established guidelines, including the minimum recommended sterilization time. Facility managers told us that experts determined that actual risk of CJD exposure to patients was minimal. We determined that the loaner neurosurgery instruments were decontaminated and sterilized according to the facility’s standard operating procedure (SOP) and manufacturer’s instructions.
The facility’s surgical instrument SOP includes pre-soaking the instruments in the operating room after every surgical procedure with an enzymatic product. Once the instruments are delivered to the Sterile Processing Service, staff manually clean them with enzymatic cleaners to flush instruments or equipment with lumens,14 items are again cleaned in an ultrasonic cleaner, and they are placed in a washer/sterilizer. The instruments are then dried and packaged for steam sterilization at 275 degrees (°) Fahrenheit (F) for 4 minutes. After the potential CJD exposure incidents, and to further minimize the risk of CJD transmission, the facility adopted a longer sterilization time of 18 minutes for neurosurgical instruments by incorporating industry standards15,16 and recommendations from SHEA.17
Issue 2: Handling and Tracking of Loaner Instruments
The facility utilized a standard process for handling loaner instruments and appropriately decontaminated and sterilized the loaner instruments upon receipt and after each patient use according to the manufacturer’s instructions.
However, at the time of the delivery of the loaner tray in May 2013, the facility did not have a process in place for tracking18 loaner instruments. The facility published a policy in May 2013, which was later revised in January 2014. The initial tracking tool used for signing in loaner instruments was initiated in early June 2013; however, the final tool did not come into use until mid-September. The facility did not have tracking records for the loaner instruments for the two patients.
14 An inner open space/cavity or the bore of a tube.
15 International Association of Healthcare Central Service Materiel Management Central Service Technical Manual,
7th edition, pp 324–325.
16 ANSI/AAMI St 79:2010&A1:2010&A2:2011, p. 163–167.
17 Rutala W, Weber D. SHEA Guideline for Disinfection and Sterilization of Prion-Contaminated Medical Instruments. Inf Control Hosp Epidemiol 2010;25:107–117.
18 Process for documenting loaner instrument information from the time of delivery or upon receipt until the final disposition when the instrument is returned to the manufacturer.
Issue 3: Facility Response and Follow-Up Actions
We found that the facility initiated multiple actions in response to the potential exposure. These included a multidisciplinary review of the internal events; ongoing communication by the facility’s epidemiologist with key staff at the New Hampshire, Connecticut, and Massachusetts Departments of Public Health, the prion epidemiologist at the CDC, and the manufacturer representative; revision of policies; and staff training. Additionally, the facility Chief Nurse and Epidemiologist provided information to staff and answered questions.
Facility clinicians notified both patients and/or their family members, and providers conducted clinical disclosures19 according to VHA policy.20 Once notified by the manufacturer on August 30 of the possible exposure, facility managers contacted the VA Central Office (VACO) Office of Public Health and VISN 1 Chief Medical Officer (CMO). The VISN then referred the issue to the VACO Clinical Event Response Team (CERT) for review and guidance. On September 5, the facility received approval to notify the patients. Both patients were notified by phone within 24 hours.
The hematology-oncology physician briefly discussed the potential exposure with Patient A’s wife by telephone on September 6. The decision was made to have additional discussions on September 10 during the patient’s clinic visit. During that clinic visit, the provider decided to admit the patient to the hospital for dehydration and falls. We did not find documentation of disclosure to the patient during that visit; however, an addendum progress note was written on October 1, documenting that the patient and his family were provided with an information sheet regarding his CJD-exposure during his September 10 clinic visit. Face-to-face clinical disclosure for Patient B was conducted on September 9. Exhibit 2 below shows the timeline of the patient notification process.
Exhibit 2. Patient Notification Timeline
snip...
Issue 4: VHA Requirements for Reprocessing of Neurosurgical Instruments
We queried a VHA subject matter expert to determine whether appropriate procedures are in place for disinfection and sterilization of neurosurgical instruments. We determined that VHA utilizes appropriate policies and procedures for reprocessing of neurosurgical instruments that are consistent with acceptable published guidelines from the following organizations:
International Association of Healthcare Central Service Materiel Management – Central Service Technical Manual, 7th edition
ANSI/AAMI St 79:2010&A1:2010&A2:2011
SHEA Guideline for Disinfection and Sterilization of Prion-Contaminated Medical Instruments
Conclusions
We concluded that the facility took appropriate steps to address potential patient exposure to CJD. Managers were proactive in seeking counsel from subject matter experts within the VA and other Government agencies to ensure that proper patient follow-up and notification occurred in a timely manner. Facility providers notified and met with the involved patients and/or their family members to discuss the potential exposure to CJD, the risks of CJD transmission, and answer questions or concerns. Providers documented clinical disclosures in the patients’ EHRs.
Although the facility met the recommended manufacturer’s minimum requirement for sterilization of surgical instruments, the facility amended its process by increasing sterilization time from 4 to 18 minutes for neurosurgical instruments. Additionally, managers implemented a process for tracking all loaner instruments from receipt to return. We concluded that VHA had appropriate policies and procedures for reprocessing neurosurgical instruments. We made no recommendations.
VISN Director Comments Department of Veterans Affairs Memorandum Date: June 11, 2014 From: Director, VA New England Healthcare System (10N1) Subject: Healthcare Inspection—Potential Exposure to Creutzfeldt-Jakob Disease, VA Connecticut Healthcare System, West Haven, CT To: Director, Region Office of Healthcare Inspections (54LA) Director, Management Review Service (VHA 10AR MRS OIG Hotline) I have reviewed and concur with the action plans regarding Potential Exposure to Creutzfeldt-Jakob Disease at VA Connecticut HCS, West Haven, CT. Sincerely, Michael F. Mayo-Smith, MD, MPH Network Director
VA Office of Inspector General 9
Potential Exposure to Creutzfeldt-Jakob Disease, VA Connecticut Healthcare System, West Haven, CT Appendix B Facility Director Comments Department of Veterans Affairs Memorandum Date: June10, 2014 From: VA Connecticut Healthcare System Director (689/00) Subject: Healthcare Inspection—Potential Exposure to Creutzfeldt-Jakob Disease, VA Connecticut Healthcare System, West Haven, CT To: Director, VA New England Healthcare System (10N1) I have reviewed and concur with the action plans regarding Potential Exposure to Creutzfeldt-Jakob Disease at VA Connecticut HCS, West Haven, CT. Sincerely, VA Office of Inspector General 10 Potential Exposure to Creutzfeldt-Jakob Disease, VA Connecticut Healthcare System, West Haven, CT Appendix C OIG Contact and Staff Acknowledgments Contact For more information about this report, please contact the OIG at (202) 461-4720. Contributors Kathleen Shimoda, BSN, Team Leader
Julie Kroviak, MD
Jovie Yabes, BSN Jackelinne Melendez, MPA
Appendix D Report Distribution VA Distribution Office of the Secretary Veterans Health Administration Assistant Secretaries General Counsel Director, VA New England Healthcare System (10N1) Director, VA Connecticut Healthcare System (689/00) Non-VA Distribution House Committee on Veterans’ Affairs House Appropriations Subcommittee on Military Construction, Veterans Affairs, and Related Agencies House Committee on Oversight and Government Reform Senate Committee on Veterans’ Affairs Senate Appropriations Subcommittee on Military Construction, Veterans Affairs, and Related Agencies Senate Committee on Homeland Security and Governmental Affairs National Veterans Service Organizations Government Accountability Office Office of Management and Budget U.S. Senate: Richard Blumenthal, Christopher Murphy U.S. House of Representatives: Joe Courtney, Rosa L. DeLauro, Elizabeth, Esty, Jim Hines, John B. Larson This report is available on our web site at www.va.gov/oig
follow up from the exposed ???
i don't think the VA has any idea of any potential iatrogenic CJD from any Veterans, unless it's by accident. i hope i am wrong...terry
Human Transmissible Spongiform Encephalopathies: A Critical scientific Investment
Final Report of the National Prion Research Program US Army Medical Research and Materiel Command Congressionally Directed Medical Research Programs
Fort Detrick, Maryland
2007
*** The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, and there may be asymptomatic individuals infected with the CWD equivalent. These circumstances represent a potential threat to blood, blood products, and plasma supplies.
FRIDAY, AUGUST 22, 2008
Creutzfeldt Jakob Disease and Veterans and how they are treated at death
least we forget...
*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery ***
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
Wednesday, July 28, 2021
France issues moratorium on prion research after fatal brain disease strikes two lab workers
France issues moratorium on prion research after fatal brain disease strikes two lab workers
By Barbara CasassusJul. 28, 2021 , 4:35 AM
PARIS—Five public research institutions in France have imposed a 3-month moratorium on the study of prions—a class of misfolding, infectious proteins that cause fatal brain diseases—after a retired lab worker who handled prions in the past was diagnosed with Creutzfeldt-Jakob disease (CJD), the most common prion disease in humans. An investigation is underway to find out whether the patient, who worked at a lab run by the National Research Institute for Agriculture, Food and Environment (INRAE), contracted the disease on the job.
If so, it would be the second such case in France in the past few years. In June 2019, an INRAE lab worker named Émilie Jaumain died at age 33, 10 years after pricking her thumb during an experiment with prion-infected mice. Her family is now suing INRAE for manslaughter and endangering life; her illness had already led to tightened safety measures at French prion labs.
The aim of the moratorium, which affects nine labs, is to “study the possibility of a link with the [new patient’s] former professional activity and if necessary to adapt the preventative measures in force in research laboratories,” according to a joint press release issued by the five institutions yesterday.
“This is the right way to go in the circumstances,” says Ronald Melki, a structural biologist at a prion lab jointly operated by the French national research agency CNRS and the French Alternative Energies and Atomic Energy Commission (CEA). “It is always wise to ask questions about the whole working process when something goes wrong.” "The occurrence of these harsh diseases in two of our scientific colleagues clearly affects the whole prion community, which is a small 'familial' community of less than 1000 people worldwide," Emmanuel Comoy, deputy director of CEA's Unit of Prion Disorders and Related Infectious Agents, writes in an email to Science. Although prion research already has strict safety protocols, "it necessarily reinforces the awareness of the risk linked to these infectious agents," he says.
In Jaumain’s case, there is little doubt she was infected on the job, according to a paper published in The New England Journal of Medicine (NEJM) in 2020. She had variant CJD (vCJD), a form typically caused by eating beef contaminated with bovine spongiform encephalopathy (BSE), or mad cow disease. But Europe’s BSE outbreak ended after 2000 and vCJD virtually disappeared; the chance that someone of Jaumain’s age in France would contract food-borne vCJD is “negligible or non-existent,” according to the paper.
A scientist with inside knowledge says the new patient, a woman who worked at INRAE’s Host-Pathogen Interactions and Immunity group in Toulouse, is still alive. French authorities were apparently alerted to her diagnosis late last week. The press release suggests it’s not yet clear whether the new case is vCJD or “classic” CJD, which is not known to be caused by prions from animals. Classic CJD strikes an estimated one person per million. Some 80% of cases are sporadic, meaning they have no known cause, but others are genetic or contracted from infected human tissues during transplantations. The two types of CJD can only be distinguished through a postmortem examination of brain tissue.
Lab infections are known to occur with many pathogens, but exposure to CJD-causing prions is unusually risky because there are no vaccines or treatments and the condition is universally fatal. And whereas most infections reveal themselves within days or weeks, CJD’s average incubation period is about 10 years.
For Jaumain, who worked at INRAE’s Molecular Virology and Immunology Unit in Jouy-en-Josas, outside Paris, that long period of uncertainty began on 31 May 2010, when she stabbed her left thumb with a curved forceps while cleaning a cryostat—a machine that can cut tissues at very low temperatures—that she used to slice brain sections from transgenic mice infected with a sheep-adapted form of BSE. She pierced two layers of latex gloves and drew blood. “Émilie started worrying about the accident as soon as it had happened, and mentioned it to every doctor she saw,” says her widower, Armel Houel.
In November 2017, Jaumain developed a burning pain in her right shoulder and neck that worsened and spread to the right half of her body over the following 6 months, according to the NEJM paper. In January 2019, she became depressed and anxious, suffering memory impairment and hallucinations. “It was a descent into hell,” Houel says. She was diagnosed with “probable vCJD” in mid-March of that year and died 3 months later. A postmortem confirmed the diagnosis.
“The occurrence of these harsh diseases in two of our scientific colleagues clearly affects the whole prion community.” Emmanuel Comoy, French Alternative Energies and Atomic Energy Commission
INRAE only recently admitted the likely link between Jaumain’s illness and the accident. “We recognize, without ambiguity, the hypothesis of a correlation between Emilie Jaumain-Houel’s accident … and her infection with vCJD,” INRAE chair and CEO Philippe Mauguin wrote in a 24 June letter to an association created by friends and colleagues to publicize Jaumain’s case and lobby for improvements in lab safety. (Science has obtained a copy of the letter, which has not been made public.)
Jaumain’s family has filed both criminal charges and an administrative suit against INRAE, alleging a range of problems at Jaumain’s lab. She had not been trained in handling dangerous prions or responding to accidents and did not wear both metal mesh and surgical gloves, as she was supposed to, says Julien Bensimhon, the family’s lawyer. The thumb should have been soaked in a bleach solution immediately, which did not happen, Bensimhon adds.
Independent reports by a company specializing in occupational safety and by government inspectors have found no safety violations at the lab; one of them said there was a “strong culture” of risk management. (Bensimhon calls the reports “biased.”)
The government inspectors’ report concluded that Jaumain’s accident was not unique, however. There had been at least 17 accidents among the 100 or so scientists and technicians in France working with prions in the previous decade, five of whom stabbed or cut themselves with contaminated syringes or blades. Another technician at the same lab had a fingerprick accident with prions in 2005, but has not developed vCJD symptoms so far, Bensimhon says. “It is shocking that no precautionary measures were taken then to ensure such an accident never happened again,” he says.
In Italy, too, the last person to die of vCJD, in 2016, was a lab worker with exposure to prion-infected brain tissue, according to last year’s NEJM paper, although an investigation did not find evidence of a lab accident. That patient and the lab they worked at have not been identified.
After Jaumain’s diagnosis, “We contacted all the research prion labs in France to suggest they check their safety procedures and remind staff about the importance of respecting them,” says Stéphane Haïk, a neuroscientist at the Paris Brain Institute at Pitié-Salpêtrière Hospital who helped diagnose Jaumain and is the corresponding author on the paper. Many labs tightened procedures, according to the government inspectors' report, for instance by introducing plastic scissors and scalpels, which are disposable and less sharp, and bite and cut-resistant gloves. A team of experts from the five research agencies is due to submit proposals for a guide to good practice in prion research to the French government at the end of this year.
The scientific community has long recognized that handling prions is dangerous and an occupational risk for neuropathologists, says neuropathologist Adriano Aguzzi of the University of Zurich. Aguzzi declined to comment on the French CJD cases, but told Science his lab never handles human or bovine prions for research purposes, only for diagnostics. “We conduct research only on mouse-adapted sheep prions, which have never been shown to be infectious to humans,” Aguzzi says. In a 2011 paper, his team reported that prions can spread through aerosols, at least in mice, which “may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories,” they wrote. Aguzzi says he was “totally shocked” by the finding and introduced safety measures to prevent aerosol spread at his own lab, but the paper drew little attention elsewhere.
The moratorium will "obviously" cause delays in research, but given the very long incubation periods in prion diseases, the impact of a 3-month hiatus will be limited, Comoy says. His research team at CEA also works on other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and will shift some of its efforts to those.
Although Jaumain’s diagnosis upset many in the field, it hasn't led to an exodus among researchers in France, Haïk says: “I know of only one person who resigned because they were so worried.”
With reporting by Martin Enserink.
Posted in: EuropeHealthScientific Community
doi:10.1126/science.abl6587
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 years earlier. The long incubation period was similar to that of the transfusion-transmitted form of the disease.
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
TO THE EDITOR:
We report a case of variant Creutzfeldt–Jakob disease (CJD) that was plausibly related to accidental occupational exposure in a technician who had handled murine samples contaminated with the agent that causes bovine spongiform encephalopathy (BSE) 7.5 years earlier.
In May 2010, when the patient was 24 years of age, she worked in a prion research laboratory, where she handled frozen sections of brain of transgenic mice that overexpressed the human prion protein with methionine at codon 129. The mice had been infected with a sheep-adapted form of BSE. During this process, she stabbed her thumb through a double pair of latex gloves with the sharp ends of a curved forceps used to handle the samples. Bleeding was noted at the puncture site.
In November 2017, she began having burning pain in the right shoulder and neck. The pain worsened and spread to the right half of her body during the following 6 months. In November 2018, an examination of a sample of cerebrospinal fluid (CSF) obtained from the patient was normal. Magnetic resonance imaging (MRI) of the brain showed a slight increase in the fluid-attenuated inversion recovery (FLAIR) signal in the caudates and thalami (Fig. S1A and S1B in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In January 2019, she became depressed and anxious and had memory impairment and visual hallucinations. There was hypertonia on the right side of her body. At that time, an analysis of CSF for 14-3-3 protein was negative. In March 2019, MRI showed an increased FLAIR signal in pulvinar and dorsomedial nuclei of thalami (Fig. S1C through S1E).
Figure 1.
Detection of Abnormal Prion Protein in Biologic Fluid Samples and Postmortem Findings.
The patient was found to be homozygous for methionine at codon 129 of the prion protein gene without mutation. An analysis of a sample of CSF on real-time quaking-induced conversion analysis was negative for a diagnosis of sporadic CJD. However, an analysis of plasma and CSF by means of protein misfolding cyclic amplification was positive for the diagnosis of variant CJD (Figure 1A and 1B). The patient died 19 months after the onset of symptoms. Neuropathological examination confirmed the diagnosis of variant CJD (Figure 1C and 1D). Western blot analysis showed the presence of type 2B protease-resistant prion protein in all sampled brain areas. The clinical characteristics of the patient and the postmortem neuropathological features were similar to those observed in 27 patients with variant CJD who had previously been reported in France.1 (Additional details are provided in the Supplementary Appendix.)
There are two potential explanations for this patient’s condition. Oral transmission from contaminated cattle products cannot be ruled out because the patient was born at the beginning of the French BSE outbreak in cattle. However, the last two patients who had confirmed variant CJD with methionine homozygosity at codon 129 in France and the United Kingdom died in 2014 and 2013, respectively, which makes oral transmission unlikely. In France, the risk of variant CJD in 2019 was negligible or nonexistent in the post-1969 birth cohort.2
Percutaneous exposure to prion-contaminated material is plausible in this patient, since the prion strain that she had handled was consistent with the development of variant CJD.3 The 7.5-year delay between the laboratory accident and her clinical symptoms is congruent with the incubation period in the transfusion-transmitted form of the disease. The ability of this strain to propagate through the peripheral route has been documented, and experimental studies with scrapie strains have shown that scarification and subcutaneous inoculation are effective routes.4,5 The last known Italian patient with variant CJD, who died in 2016, had had occupational contact with BSE-infected brain tissues, although subsequent investigation did not disclose a laboratory accident (Pocchiari M, Italian Registry of CJD: personal communication). Thus, the last two cases of variant CJD outside the United Kingdom have been associated with potential occupational exposure. Such cases highlight the need for improvements in the prevention of transmission of variant CJD and other prions that can affect humans in the laboratory and neurosurgery settings, as outlined in the Supplementary Appendix.
Jean-Philippe Brandel, M.D. Assistance Publique–Hôpitaux de Paris, Paris, France
M. Bustuchina Vlaicu, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Audrey Culeux, B.Sc. INSERM Unité 1127, Paris, France
Maxime Belondrade, M.Sc. Daisy Bougard, Ph.D. Etablissement Français du Sang, Montpellier, France
Katarina Grznarova, Ph.D. Angeline Denouel, M.Sc. INSERM Unité 1127, Paris, France
Isabelle Plu, M.D. Elodie Bouaziz-Amar, Pharm.D., Ph.D. Danielle Seilhean, M.D., Ph.D. Assistance Publique–Hôpitaux de Paris, Paris, France
Michèle Levasseur, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Stéphane Haïk, M.D., Ph.D. INSERM Unité 1127, Paris, France stephane.haik@upmc.fr
Supported by a grant (ANR-10-IAIHU-06) from Programme d’Investissements d’Avenir and Santé Publique France.
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
5 References
July 2, 2020
N Engl J Med 2020; 383:83-85
DOI: 10.1056/NEJMc2000687
Metrics
Wednesday, July 28, 2021
France issues moratorium on prion research after fatal brain disease strikes two lab workers
Volume 26, Number 8—August 2020
CME ACTIVITY - Research
Sporadic Creutzfeldt-Jakob Disease among Physicians, Germany, 1993–2018
Peter Hermann1Comments to Author , Johannes Treig1, Steffen Unkel, Stefan Goebel, Timothy Bunck, Martha Jünemann, Tim Friede, and Inga Zerr Author affiliations: University Medical Center Göttingen Department of Neurology, Göttingen, Germany (P. Hermann, J. Treig, S. Goebel, T. Bunck, M. Jünemann, I. Zerr); University Medical Center Göttingen Department of Medical Statistics, Göttingen (S. Unkel, T. Friede); German Center for Neurodegenerative Diseases, Göttingen (I. Zerr)
Abstract
We investigated sporadic Creutzfeldt-Jakob disease (sCJD) among physicians in Germany by analyzing occupational information of patients with sCJD recorded by the German CJD Surveillance Unit (1993–2005; 1,250 patients, of whom 4 [0.32%] were physicians) and the National Reference Center for Human Spongiform Encephalopathies (2006–2016; 1,491 patients, of whom 13 [0.87%] were physicians). Among the physicians, we did not identify any neurologists, neurosurgeons, psychiatrists, or pathologists. A cumulative sum test showed an increase in reported physicians over time. Data for 2017–2018 indicated an increased rate of physicians among all notified sCJD cases (5/239 [2.1%]) when we used the total population of Germany as control group. Our data suggest the possibility of an increased risk for sCJD among physicians in Germany. However, we can only speculate about the reasons, and larger multinational studies are needed to replicate the finding and to clarify whether this finding is a general or a country-specific phenomenon.
snip...
Creutzfeldt-Jakob disease (CJD) is a syndrome comprising dementia and various neurologic signs and symptoms (1) caused by the transmissible misfolded prion protein scrapie (2). Reported death rates and incidence rates differ from 1.67 (3) to >2 per million person-years (4,5). In contrast to animal prion diseases (6,7), transmitted human prion diseases are uncommon. Variant CJD (vCJD) caused by ingestion of beef is rare (231 cases worldwide) (8), and its incidence has decreased since 2000 (9). Most cases of human prion disease are sporadic CJD (sCJD; 84%–93%), followed by genetic CJD (5%–10%). Only <4% are considered to be iatrogenic (iCJD) (3,10–12). Clinical diagnostic criteria of iCJD imply the presence of an iatrogenic risk factor (13). Known cases were caused by cadaver-derived growth hormones, dura mater grafts, neurosurgical instrument contamination, and corneal grafts (12). On the other hand, iCJD might be overlooked when no classic risk factor is present. Neuropathologic characteristics can identify iCJD only in a subgroup of cases (14,15). Unrecorded cases related to surgery are likely because an increased risk for sCJD in persons with a history of surgery was reported (16); however, data on this issue remain ambiguous (17). vCJD transmitted by transfusion of blood products has been reported (8), but no confirmed case was recorded among recipients of blood from donors with sCJD (18–20).
An increased risk for iCJD among caregivers and healthcare professionals has been suggested, but its evaluation is complex (21–24). Previous studies neither unequivocally displayed nor ruled out relevant increases in risk for CJD among healthcare professionals (25,26). Furthermore, these investigations were mostly designed as case–control studies, which are prone to bias because of case selection. Therefore, we aimed to evaluate sCJD among physicians using historical epidemiologic data from 25 years of CJD surveillance in Germany and the whole population of that country as controls.
Methods
snip...
The high proportion of physicians among patients with sCJD and its increase over the last years were displayed in a statistical model based on data from the population of Germany. We showed that sCJD patients were significantly more likely than the general population to be physicians, suggesting that it might be an occupational risk factor. Previous epidemiologic studies have not clearly identified an elevated risk for sCJD among physicians (Table 4), but the most recent available data are from 2010. Our study yielded significant results only after 2005, and the CUSUM test identified an increased number of physicians with sCJD after 2008. No specialties involved specifically in treating patients with CJD have been reported. Nonetheless, we found that a high proportion of physicians with sCJD were surgeons, although we can only speculate about the reasons. A larger study comprising new data from other countries is needed to clarify whether this finding is a general or a country-specific phenomenon.
Dr. Hermann is is a study physician in the NRZ-TSE at the University Medical Center Göttingen. His research interests are diagnostic testing and epidemiology of prion diseases as well as biomarkers of atypical dementia. Acknowledgments
snip...see full text;
34 year old Doctor Orthopedic Surgeon dies from CJD
Dr. Adam Thomas Dialectos
1987 - 2021
BORN
BORN
April 29, 1987
DIED
June 21, 2021
FUNERAL HOME
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Reading, PA 19604
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Jun, 24 2021
9:00a.m. - 11:00a.m.
Saints Constantine & Helen Greek Orthodox Church
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On Monday June 21, 2021, Dr. Adam Thomas Dialectos, loving husband, father, son, brother, uncle, Nouno, friend at the age of 34. Adam was born on April 29, 1987 in Reading, PA to Athan and Gretchen Dialectos. Adam was a 2005 graduate of Governor Mifflin High School, before receiving his degree in Health Sciences from James Madison University in 2009. Adam attended Philadelphia College of Osteopathic Medicine for medical school and his subsequent residency in orthopedic surgery. Adam was completing his Spine Surgery Fellowship at New England Baptist Hospital in Boston, Massachusetts. On February 7, 2019 Adam married the love of his life and girlfriend of 12 years, Lindsey (Schuler) Dialectos. They brought a beautiful baby boy into this world on January 6, 2021, Athananosis Adam Dialectos. Adam’s passion in life was unceasingly seeking to help others, emphasized by his desire to be a surgeon— a decision he made in his early elementary years. Adam continued this love of medicine throughout his life, which led to his achieving of the Henrietta and Jack Avart Memorial Award in 2019, awarded to the Orthopedic surgery resident who exhibited unparalleled excellence in their field during the residency program. This passion to learn, teach and support was truly understood through the patients whose lives Adam touched. When it came to his patients and coworkers, there was never a job too small for Adam. Those who knew Adam saw his personality shine through in so many other aspects of his life. Adam loved traveling. Some of his most memorable trips were with his wife, and countless snowboard trips with his brother, family, and friends. Adam loved everyone he was around; he loved and was loved by so many. Adam was truly one in a million. Adam is survived by his loving wife, Lindsey, and their son, Athan Adam; His father and mother, Athan and Gretchen; His brother Jordan and sister-in-law Megan, and their daughter Livia, Adam’s Goddaughter. His sister, Rachel, and her significant other, Bo Wagner. Furthermore, Adam is survived by his Yiayia, Joanne Dialectos, wife of the late George Dialectos; his Pop Pop, Donald Harford, husband of the late Nancy Servent; his Aunt Angel and Uncle Scott Helm; his Aunt Kelly and Uncle Darrell Markley. Adam was preceded in death by his Aunt Maria and Uncle Bob Care. Funeral Service will be held at Saints Constantine & Helen Greek Orthodox Church, 1001 East Wyomissing Blvd. Reading on Thursday June 24th. Father Theodore Petrides and Father Thomas L. Pappalas will officiate. Interment will follow at Charles Evans Cemetery. The family will receive relatives and friends at Saints Constantine & Helen Greek Orthodox Church from 9:00am to 11:00am with services beginning at 11:00. In lieu of flowers, contributions may be made to the CJD Foundation at 3634 West Market Street Suite 110 Akron, Ohio 44333 or cjdfoundation.org in remembrance of Dr. Adam Dialectos. Donations may also be made to Saints Constantine & Helen Greek Orthodox Church. Bean Funeral Home, 1605 Rockland Street, Hampden Heights, is in charge of arrangements and online condolences may be made at www.beanfuneralhomes.com.
To plant trees in memory, please visit our Sympathy Store.
Published by Reading Eagle from Jun. 22 to Jun. 24, 2021.
Volume 26, Number 8—August 2020
Sporadic Creutzfeldt-Jakob Disease among Physicians, Germany, 1993–2018 high proportion of physicians with sCJD were surgeons
Saturday, January 23, 2021
Improved surveillance of surgical instruments reprocessing following the variant Creutzfeldt-Jakob disease crisis in England: findings from a 3-year survey
SUNDAY, JULY 19, 2020
Joseph J. Zubak Orthopaedic surgeon passed away Monday, July 6, 2020, Creutzfeldt-Jakob Disease (CJD)
Friday, January 29, 2021
Scientists identify locations of early prion protein deposition in retina, what if?
FRIDAY, SEPTEMBER 06, 2019
Disinfection of Multi-Use Ocular Equipment for Ophthalmological Procedures: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines
some history ;
Thursday, April 12, 2012
Health professions and risk of sporadic Creutzfeldt–Jakob disease, 1965 to 2010
Eurosurveillance, Volume 17, Issue 15, 12 April 2012
Research articles
Thursday, June 24, 2021
34 year old Doctor Orthopedic Surgeon dies from CJD, what about iatrogenic CJD?
Flexible Bronchoscopes and Updated Recommendations for Reprocessing: FDA Safety Communication
Date Issued: June 25, 2021
The U.S. Food and Drug Administration (FDA) is providing updated information about medical device adverse event reports and recommendations for health care providers on bronchoscopes.
The FDA is providing the following new recommendations:
Consider using a single-use bronchoscope in situations where there is increased risk of spreading infection (for example, multidrug resistant microorganisms, immunocompromised patients, or patients with prion disease) or when there is no support for immediate reprocessing of the bronchoscope.
When treating patients with Coronavirus Disease 2019 (COVID-19), refer to recent recommendationsExternal Link Disclaimer from the American Association for Bronchology & Interventional Pulmonology (AABIP).
i tried to tell GUT journal, and Bramble et al this way back, decades ago...terry
were not all CJDs, even nvCJD, just sporadic, until proven otherwise?
Terry S. Singeltary Sr., P.O. BOX, Bacliff, Texas 77518 USA
########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
Professor Michael Farthing wrote:
Louise Send this to Bramble (author) for a comment before we post. Michael
-----Original Message-----
From: Terry S. Singeltary Sr. [mailto:flounder@wt.net] ;
Sent: 03 June 2002 17:14
Subject: gutjnl_el;21 Terry S. Singeltary Sr. (3 Jun 2002) "CJDs (all human TSEs) and Endoscopy Equipment"
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Date submitted: 3 Jun 2002 eLetter ID: gutjnl_el;21
Gut eLetter for Bramble and Ironside 50 (6): 888
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Name: Terry S. Singeltary Sr. Email: flounder@wt.net Title/position: disabled {neck injury} Place of work: CJD WATCH IP address: 216.119.162.85 Hostname: 216-119-162-85.ipset44.wt.net Browser: Mozilla/5.0 (Windows; U; Win98; en-US; rv:0.9.4) Gecko/20011019 Netscape6/6.2
Parent ID: 50/6/888
Citation: Creutzfeldt-Jakob disease: implications for gastroenterology
M G Bramble and J W Ironside Gut 2002; 50: 888-890 (Occasional viewpoint)
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"CJDs (all human TSEs) and Endoscopy Equipment"
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regarding your article;
Creutzfeldt-Jakob disease: implications for gastroenterology
i belong to several support groups for victims and relatives of CJDs. several years ago i did a survey regarding endoscopy equipment and how many victims of CJDs have had any type of this procedure done. to my surprise, many victims had some kind of endoscopy work done on them. as this may not be a smoking gun, i think it should warrant a 'red flag' of sorts, especially since data now suggests a substantial TSE infectivity in the gut wall of species infected with TSEs. If such transmissions occur, the ramifications of spreading TSEs from endoscopy equipment to the general public would be horrible, and could potential amplify the transmission of TSEs through other surgical procedures in that persons life, due to long incubation and sub-clinical infection. Science to date, has well established transmission of sporadic CJDs with medical/surgical procedures.
Terry S. Singeltary Sr. CJD WATCH
Subject: Re: gutjnl_el;21 Terry S. Singeltary Sr. (3 Jun 2002) "CJDs (all human TSEs) and Endoscopy Equipment" Date: Thu, 20 Jun 2002 16:19:51 -0700 From: "Terry S. Singeltary Sr." To: Professor Michael Farthing CC: lcamp@BMJgroup.com References: <001501c21099$5c8bc620$7c58d182@mfacdean1.cent.gla.ac.uk>
Greetings again Professor Farthing and BMJ,
I was curious why my small rebuttal of the article described below was not listed in this month's journal of GUT? I had thought it was going to be published, but I do not have full text access. Will it be published in the future? Regardless, I thought would pass on a more lengthy rebuttal of mine on this topic, vCJD vs sCJDs and endoscopy equipment. I don't expect it to be published, but thought you might find it interesting, i hope you don't mind and hope to hear back from someone on the questions I posed...
Here is my short submission I speak of, lengthy one to follow below that:
Date submitted: 3 Jun 2002
snip...see full text;
Friday, September 27, 2019
Prion disease and recommended procedures for flexible endoscope reprocessing – a review of policies worldwide and proposal for a simplified approach Singeltary, GUT journal and Bramble et al
Saturday, January 16, 2010
*** Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al
Evidence For CJD/TSE Transmission Via Endoscopes
From Terry S. Singletary, Sr flounder@wt.net 1-24-3
Terry S. Singeltary Sr., P.O. , Bacliff, Texas 77518 USA
Professor Michael Farthing wrote:
*** Louise Send this to Bramble (author) for a comment before we post. Michael
iatrogenic creutzfeldt jakob disease
WEDNESDAY, OCTOBER 13, 2021
Continuing Enhanced National Surveillance for Prion Diseases in the U.S.
TUESDAY, SEPTEMBER 07, 2021
Atypical Bovine Spongiform Encephalopathy BSE OIE, FDA 589.2001 FEED REGULATIONS, and Ingestion Therefrom
ZOONOSIS OF SCRAPIE TSE PRION
O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases).
Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases.
We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases***
===============
***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
==============
***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.
***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
PRION 2016 TOKYO
Saturday, April 23, 2016
SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online
Taylor & Francis
Prion 2016 Animal Prion Disease Workshop Abstracts
WS-01: Prion diseases in animals and zoonotic potential
Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,
Natalia Fernandez-Borges a. and Alba Marin-Moreno a
"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France
Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion... Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.
To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.
These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.
Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.
Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
***> why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man.
***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough.
***> Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
Title: Transmission of scrapie prions to primate after an extended silent incubation period)
*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS.
*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated.
*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains.
***> Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility. <***
Transmission of scrapie prions to primate after an extended silent incubation period
Emmanuel E. Comoy, Jacqueline Mikol, Sophie Luccantoni-Freire, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Valérie Durand, Capucine Dehen, Olivier Andreoletti, Cristina Casalone, Juergen A. Richt, Justin J. Greenlee, Thierry Baron, Sylvie L. Benestad, Paul Brown & Jean-Philippe Deslys Scientific Reports volume 5, Article number: 11573 (2015) | Download Citation
Abstract
Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.
SNIP...
During the past decades, many protective measures have been successfully implemented to protect cattle from the spread of c-BSE, and some of these measures have been extended to sheep and goats to protect from scrapie according to the principle of precaution. Since cases of c-BSE have greatly reduced in number, those protective measures are currently being challenged and relaxed in the absence of other known zoonotic animal prion disease. We recommend that risk managers should be aware of the long term potential risk to human health of at least certain scrapie isolates, notably for lymphotropic strains like the classical scrapie strain used in the current study. Relatively high amounts of infectivity in peripheral lymphoid organs in animals infected with these strains could lead to contamination of food products produced for human consumption. Efforts should also be maintained to further assess the zoonotic potential of other animal prion strains in long-term studies, notably lymphotropic strains with high prevalence like CWD, which is spreading across North America, and atypical/Nor98 scrapie (Nor98)50 that was first detected in the past two decades and now represents approximately half of all reported cases of prion diseases in small ruminants worldwide, including territories previously considered as scrapie free... Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.
3.2.1.2 Non‐cervid domestic species
The remarkably high rate of natural CWD transmission in the ongoing NA epidemics raises the question of the risk to livestock grazing on CWD‐contaminated shared rangeland and subsequently developing a novel CWD‐related prion disease. This issue has been investigated by transmitting CWD via experimental challenge to cattle, sheep and pigs and to tg mouse lines expressing the relevant species PrP.
For cattle challenged with CWD, PrPSc was detected in approximately 40% of intracerebrally inoculated animals (Hamir et al., 2005, 2006a, 2007). Tg mice expressing bovine PrP have also been challenged with CWD and while published studies have negative outcomes (Tamguney et al., 2009b), unpublished data provided for the purposes of this Opinion indicate that some transmission of individual isolates to bovinised mice is possible (Table 1).
In small ruminant recipients, a low rate of transmission was reported between 35 and 72 months post‐infection (mpi) in ARQ/ARQ and ARQ/VRQ sheep intracerebrally challenged with mule deer CWD (Hamir et al., 2006b), while two out of two ARQ/ARQ sheep intracerebrally inoculated with elk CWD developed clinical disease after 28 mpi (Madsen‐Bouterse et al., 2016). However, tg mice expressing ARQ sheep PrP were resistant (Tamguney et al., 2006) and tg mice expressing the VRQ PrP allele were poorly susceptible to clinical disease (Beringue et al., 2012; Madsen‐Bouterse et al., 2016). In contrast, tg mice expressing VRQ sheep PrP challenged with CWD have resulted in highly efficient, life‐long asymptomatic replication of these prions in the spleen tissue (Beringue et al., 2012).
A recent study investigated the potential for swine to serve as hosts of the CWD agent(s) by intracerebral or oral challenge of crossbred piglets (Moore et al., 2016b, 2017). Pigs sacrificed at 6 mpi, approximately the age at which pigs reach market weight, were clinically healthy and negative by diagnostic tests, although low‐level CWD agent replication could be detected in the CNS by bioassay in tg cervinised mice. Among pigs that were incubated for up to 73 mpi, some gave diagnostic evidence of CWD replication in the brain between 42 and 72 mpi. Importantly, this was observed also in one orally challenged pig at 64 mpi and the presence of low‐level CWD replication was confirmed by mouse bioassay. The authors of this study argued that pigs can support low‐level amplification of CWD prions, although the species barrier to CWD infection is relatively high and that the detection of infectivity in orally inoculated pigs with a mouse bioassay raises the possibility that naturally exposed pigs could act as a reservoir of CWD infectivity.
Chronic wasting disease: a cervid prion infection looming to spillover
Alicia Otero 1 2 3, Camilo Duque Velásquez 1 2, Judd Aiken 2 4, Debbie McKenzie 5 6
Affiliations expand
PMID: 34488900 DOI: 10.1186/s13567-021-00986-y
***> CHRONIC WASTING DISEASE TSE PRP HUMANS ZOONOSIS ZOONOTIC <***
Published: 26 September 2021
Generation of human chronic wasting disease in transgenic mice
Zerui Wang, Kefeng Qin, Manuel V. Camacho, Ignazio Cali, Jue Yuan, Pingping Shen, Justin Greenlee, Qingzhong Kong, James A. Mastrianni & Wen-Quan Zou
Acta Neuropathologica Communications volume 9, Article number: 158 (2021)
Abstract
Chronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.e. mad cow disease) is the only animal prion disease known to be zoonotic, the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrPSc by elk CWD PrPSc-seeded conversion of PrPC in normal human brain homogenates using in vitro protein misfolding cyclic amplification (PMCA). Western blotting with human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human PrPC substrate. Two lines of humanized transgenic mice expressing human PrP with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc can cross the species barrier to convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice.
Snip...
It is worth noting that the annual number of sporadic CJD (sCJD) cases in the USA has increased, with the total number of suspected and confirmed sCJD cases rising from 284 in 2003 to 511 in 2017 (https://www.cdc.gov/prions/cjd/occurrence-transmission.html). The greatly enhanced CJD surveillance and an aging population in the USA certainly contributed to the observed increase in annual sCJD case numbers in recent years, but the possibility cannot be excluded that some of the increased sCJD prevalence is linked to CWD exposure.
In the present study, using serial protein misfolding cyclic amplification (sPMCA) assay we generate PrPSc by seeding CWD prions in normal human brain homogenates. Importantly, we reveal that two lines of humanized Tg mice expressing human PrP-129VV and 129MM develop prion diseases upon intracerebral inoculation of the abnormal PrP generated by sPMCA. We believe that our study provides the first opportunity to dissect the clinical, pathological and biochemical features of the CWD-derived human prion disease in two lines of humanized Tg mice expressing two major human PrP genotypes, respectively.
i thought i might share some news about cwd zoonosis that i got, that i cannot share or post to the public yet, i promised for various reasons, one that it will cause a shit storm for sure, but it was something i really already knew from previous studies, but, i was told that ;
==================
''As you can imagine, 2 and 5 (especially 5) may raise alarms. The evidence we have for 4 are not as strong or tight as I would like to have. At this point, please do not post any of the points publicly yet, but you can refer to points 1-3 in private discussions and all 5 points when discussing with relevant public officials to highlight the long-term risks of CWD zoonosis.''
====================
so, i figure your as about as official as it gets, and i think this science is extremely important for you to know and to converse about with your officials. it's about to burn a whole in my pocket. this is about as close as it will ever get for cwd zoonosis to be proven in my time, this and what Canada Czub et al found with the Macaques, plus an old study from cjd surveillance unit back that showed cjd and a 9% increase in risk from folks that eat venison, i will post all this below for your files Sir. i remember back in the BSE nvCJD days, from when the first BSE case in bovine was confirmed around 1984 maybe 83, i forget the good vets named that screwed it up first, Carol something, but from 83ish to 95 96 when nvCJD was linked to humans from BSE in cattle, so that took 10 to 15 years. hell, at that rate, especially with Texas and cwd zoonsis, hell, i'll be dead before it's official, if ever, so here ya go Sir. there was a grant study on cwd zoonosis that had been going on for some time, i followed it over the years, then the grant date for said study had expired, so, i thought i would write the good Professor about said study i.e. Professor Kong, CWRU et al. i will post the grant study abstract first, and then after that, what reply i got back, about said study that i was told not to post/publish...
CWD ZOONOSIS GRANT FIRST;
===============
Cervid to human prion transmission
Kong, Qingzhong
Case Western Reserve University, Cleveland, OH, United States
Abstract Prion disease is transmissible and invariably fatal. Chronic wasting disease (CWD) is the prion disease affecting deer, elk and moose, and it is a widespread and expanding epidemic affecting 22 US States and 2 Canadian provinces so far. CWD poses the most serious zoonotic prion transmission risks in North America because of huge venison consumption (>6 million deer/elk hunted and consumed annually in the USA alone), significant prion infectivity in muscles and other tissues/fluids from CWD-affected cervids, and usually high levels of individual exposure to CWD resulting from consumption of the affected animal among often just family and friends. However, we still do not know whether CWD prions can infect humans in the brain or peripheral tissues or whether clinical/asymptomatic CWD zoonosis has already occurred, and we have no essays to reliably detect CWD infection in humans. We hypothesize that: (1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues; (2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence; (3) Reliable essays can be established to detect CWD infection in humans; and (4) CWD transmission to humans has already occurred. We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.
Aim 1 will prove that the classical CWD strain may infect humans in brain or peripheral lymphoid tissues at low levels by conducting systemic bioassays in a set of humanized Tg mouse lines expressing common human PrP variants using a number of CWD isolates at varying doses and routes. Experimental human CWD samples will also be generated for Aim 3.
Aim 2 will test the hypothesis that the cervid-to-human prion transmission barrier is dependent on prion strain and influenced by the host (human) PrP sequence by examining and comparing the transmission efficiency and phenotypes of several atypical/unusual CWD isolates/strains as well as a few prion strains from other species that have adapted to cervid PrP sequence, utilizing the same panel of humanized Tg mouse lines as in Aim 1.
Aim 3 will establish reliable essays for detection and surveillance of CWD infection in humans by examining in details the clinical, pathological, biochemical and in vitro seeding properties of existing and future experimental human CWD samples generated from Aims 1-2 and compare them with those of common sporadic human Creutzfeldt-Jakob disease (sCJD) prions.
Aim 4 will attempt to detect clinical CWD-affected human cases by examining a significant number of brain samples from prion-affected human subjects in the USA and Canada who have consumed venison from CWD-endemic areas utilizing the criteria and essays established in Aim 3. The findings from this proposal will greatly advance our understandings on the potential and characteristics of cervid prion transmission in humans, establish reliable essays for CWD zoonosis and potentially discover the first case(s) of CWD infection in humans.
Public Health Relevance There are significant and increasing human exposure to cervid prions because chronic wasting disease (CWD, a widespread and highly infectious prion disease among deer and elk in North America) continues spreading and consumption of venison remains popular, but our understanding on cervid-to-human prion transmission is still very limited, raising public health concerns. This proposal aims to define the zoonotic risks of cervid prions and set up and apply essays to detect CWD zoonosis using mouse models and in vitro methods. The findings will greatly expand our knowledge on the potentials and characteristics of cervid prion transmission in humans, establish reliable essays for such infections and may discover the first case(s) of CWD infection in humans.
Funding Agency Agency National Institute of Health (NIH) Institute National Institute of Neurological Disorders and Stroke (NINDS) Type Research Project (R01) Project # 1R01NS088604-01A1 Application # 9037884 Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND) Program Officer Wong, May Project Start 2015-09-30 Project End 2019-07-31 Budget Start 2015-09-30 Budget End 2016-07-31 Support Year 1 Fiscal Year 2015 Total Cost $337,507 Indirect Cost $118,756
snip...
Professor Kongs reply to me just this month about above grant study that has NOT been published in peer reveiw yet...
=================================
Here is a brief summary of our findings:
snip...can't post, made a promise...tss
On Sat, Apr 3, 2021 at 12:19 PM Terry Singeltary <flounder9@verizon.net> wrote:
snip...
end...tss
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CWD ZOONOSIS THE FULL MONTY TO DATE
International Conference on Emerging Diseases, Outbreaks & Case Studies & 16th Annual Meeting on Influenza March 28-29, 2018 | Orlando, USA
Qingzhong Kong
Case Western Reserve University School of Medicine, USA
Zoonotic potential of chronic wasting disease prions from cervids
Chronic wasting disease (CWD) is the prion disease in cervids (mule deer, white-tailed deer, American elk, moose, and reindeer). It has become an epidemic in North America, and it has been detected in the Europe (Norway) since 2016. The widespread CWD and popular hunting and consumption of cervid meat and other products raise serious public health concerns, but questions remain on human susceptibility to CWD prions, especially on the potential difference in zoonotic potential among the various CWD prion strains. We have been working to address this critical question for well over a decade. We used CWD samples from various cervid species to inoculate transgenic mice expressing human or elk prion protein (PrP). We found infectious prions in the spleen or brain in a small fraction of CWD-inoculated transgenic mice expressing human PrP, indicating that humans are not completely resistant to CWD prions; this finding has significant ramifications on the public health impact of CWD prions. The influence of cervid PrP polymorphisms, the prion strain dependence of CWD-to-human transmission barrier, and the characterization of experimental human CWD prions will be discussed.
Speaker Biography Qingzhong Kong has completed his PhD from the University of Massachusetts at Amherst and Post-doctoral studies at Yale University. He is currently an Associate Professor of Pathology, Neurology and Regenerative Medicine. He has published over 50 original research papers in reputable journals (including Science Translational Medicine, JCI, PNAS and Cell Reports) and has been serving as an Editorial Board Member on seven scientific journals. He has multiple research interests, including public health risks of animal prions (CWD of cervids and atypical BSE of cattle), animal modeling of human prion diseases, mechanisms of prion replication and pathogenesis, etiology of sporadic Creutzfeldt-Jacob disease (CJD) in humans, normal cellular PrP in the biology and pathology of multiple brain and peripheral diseases, proteins responsible for the α-cleavage of cellular PrP, as well as gene therapy and DNA vaccination.
SUNDAY, JULY 25, 2021
North American and Norwegian Chronic Wasting Disease prions exhibit different potential for interspecies transmission and zoonotic risk
''Our data suggest that reindeer and red deer from Norway could be the most transmissible CWD prions to other mammals, whereas North American CWD prions were more prone to generate human prions in vitro.''
MONDAY, JULY 19, 2021
***> U Calgary researchers at work on a vaccine against a fatal infectious disease affecting deer and potentially people
Prion Conference 2018 Abstracts
BSE aka MAD COW DISEASE, was first discovered in 1984, and it took until 1995 to finally admit that BSE was causing nvCJD, the rest there is history, but that science is still evolving i.e. science now shows that indeed atypical L-type BSE, atypical Nor-98 Scrapie, and typical Scrapie are all zoonosis, zoonotic for humans, there from.
HOW long are we going to wait for Chronic Wasting Disease, CWD TSE Prion of Cervid, and zoonosis, zoonotic tranmission to humans there from?
Studies have shown since 1994 that humans are susceptible to CWD TSE Prion, so, what's the hold up with making CWD a zoonotic zoonosis disease, the iatrogenic transmissions there from is not waiting for someone to make a decision.
Prion Conference 2018 Abstracts
P190 Human prion disease mortality rates by occurrence of chronic wasting disease in freeranging cervids, United States
Abrams JY (1), Maddox RA (1), Schonberger LB (1), Person MK (1), Appleby BS (2), Belay ED (1)
(1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA.
Background
Chronic wasting disease (CWD) is a prion disease of deer and elk that has been identified in freeranging cervids in 23 US states. While there is currently no epidemiological evidence for zoonotic transmission through the consumption of contaminated venison, studies suggest the CWD agent can cross the species barrier in experimental models designed to closely mimic humans. We compared rates of human prion disease in states with and without CWD to examine the possibility of undetermined zoonotic transmission.
Methods
Death records from the National Center for Health Statistics, case records from the National Prion Disease Pathology Surveillance Center, and additional state case reports were combined to create a database of human prion disease cases from 2003-2015. Identification of CWD in each state was determined through reports of positive CWD tests by state wildlife agencies. Age- and race-adjusted mortality rates for human prion disease, excluding cases with known etiology, were determined for four categories of states based on CWD occurrence: highly endemic (>16 counties with CWD identified in free-ranging cervids); moderately endemic (3-10 counties with CWD); low endemic (1-2 counties with CWD); and no CWD states. States were counted as having no CWD until the year CWD was first identified. Analyses stratified by age, sex, and time period were also conducted to focus on subgroups for which zoonotic transmission would be more likely to be detected: cases <55 years old, male sex, and the latter half of the study (2010-2015).
Results
Highly endemic states had a higher rate of prion disease mortality compared to non-CWD states (rate ratio [RR]: 1.12, 95% confidence interval [CI] = 1.01 - 1.23), as did low endemic states (RR: 1.15, 95% CI = 1.04 - 1.27). Moderately endemic states did not have an elevated mortality rate (RR: 1.05, 95% CI = 0.93 - 1.17). In age-stratified analyses, prion disease mortality rates among the <55 year old population were elevated for moderately endemic states (RR: 1.57, 95% CI = 1.10 – 2.24) while mortality rates were elevated among those ≥55 for highly endemic states (RR: 1.13, 95% CI = 1.02 - 1.26) and low endemic states (RR: 1.16, 95% CI = 1.04 - 1.29). In other stratified analyses, prion disease mortality rates for males were only elevated for low endemic states (RR: 1.27, 95% CI = 1.10 - 1.48), and none of the categories of CWD-endemic states had elevated mortality rates for the latter time period (2010-2015).
Conclusions
While higher prion disease mortality rates in certain categories of states with CWD in free-ranging cervids were noted, additional stratified analyses did not reveal markedly elevated rates for potentially sensitive subgroups that would be suggestive of zoonotic transmission. Unknown confounding factors or other biases may explain state-by-state differences in prion disease mortality.
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P172 Peripheral Neuropathy in Patients with Prion Disease
Wang H(1), Cohen M(1), Appleby BS(1,2)
(1) University Hospitals Cleveland Medical Center, Cleveland, Ohio (2) National Prion Disease Pathology Surveillance Center, Cleveland, Ohio.
Prion disease is a fatal progressive neurodegenerative disease due to deposition of an abnormal protease-resistant isoform of prion protein. Typical symptoms include rapidly progressive dementia, myoclonus, visual disturbance and hallucinations. Interestingly, in patients with prion disease, the abnormal protein canould also be found in the peripheral nervous system. Case reports of prion deposition in peripheral nerves have been reported. Peripheral nerve involvement is thought to be uncommon; however, little is known about the exact prevalence and features of peripheral neuropathy in patients with prion disease.
We reviewed autopsy-proven prion cases from the National Prion Disease Pathology Surveillance Center that were diagnosed between September 2016 to March 2017. We collected information regarding prion protein diagnosis, demographics, comorbidities, clinical symptoms, physical exam, neuropathology, molecular subtype, genetics lab, brain MRI, image and EMG reports. Our study included 104 patients. Thirteen (12.5%) patients had either subjective symptoms or objective signs of peripheral neuropathy. Among these 13 patients, 3 had other known potential etiologies of peripheral neuropathy such as vitamin B12 deficiency or prior chemotherapy. Among 10 patients that had no other clear etiology, 3 (30%) had familial CJD. The most common sCJD subtype was MV1-2 (30%), followed by MM1-2 (20%). The Majority of cases wasere male (60%). Half of them had exposure to wild game. The most common subjective symptoms were tingling and/or numbness of distal extremities. The most common objective finding was diminished vibratory sensation in the feet. Half of them had an EMG with the findings ranging from fasciculations to axonal polyneuropathy or demyelinating polyneuropathy.
Our study provides an overview of the pattern of peripheral neuropathy in patients with prion disease. Among patients with peripheral neuropathy symptoms or signs, majority has polyneuropathy. It is important to document the baseline frequency of peripheral neuropathy in prion diseases as these symptoms may become important when conducting surveillance for potential novel zoonotic prion diseases.
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P177 PrP plaques in methionine homozygous Creutzfeldt-Jakob disease patients as a potential marker of iatrogenic transmission
Abrams JY (1), Schonberger LB (1), Cali I (2), Cohen Y (2), Blevins JE (2), Maddox RA (1), Belay ED (1), Appleby BS (2), Cohen ML (2)
(1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA.
Background
Sporadic Creutzfeldt-Jakob disease (CJD) is widely believed to originate from de novo spontaneous conversion of normal prion protein (PrP) to its pathogenic form, but concern remains that some reported sporadic CJD cases may actually be caused by disease transmission via iatrogenic processes. For cases with methionine homozygosity (CJD-MM) at codon 129 of the PRNP gene, recent research has pointed to plaque-like PrP deposition as a potential marker of iatrogenic transmission for a subset of cases. This phenotype is theorized to originate from specific iatrogenic source CJD types that comprise roughly a quarter of known CJD cases.
Methods
We reviewed scientific literature for studies which described PrP plaques among CJD patients with known epidemiological links to iatrogenic transmission (receipt of cadaveric human grown hormone or dura mater), as well as in cases of reported sporadic CJD. The presence and description of plaques, along with CJD classification type and other contextual factors, were used to summarize the current evidence regarding plaques as a potential marker of iatrogenic transmission. In addition, 523 cases of reported sporadic CJD cases in the US from January 2013 through September 2017 were assessed for presence of PrP plaques.
Results
We identified four studies describing 52 total cases of CJD-MM among either dura mater recipients or growth hormone recipients, of which 30 were identified as having PrP plaques. While sporadic cases were not generally described as having plaques, we did identify case reports which described plaques among sporadic MM2 cases as well as case reports of plaques exclusively in white matter among sporadic MM1 cases. Among the 523 reported sporadic CJD cases, 0 of 366 MM1 cases had plaques, 2 of 48 MM2 cases had kuru plaques, and 4 of 109 MM1+2 cases had either kuru plaques or both kuru and florid plaques. Medical chart review of the six reported sporadic CJD cases with plaques did not reveal clinical histories suggestive of potential iatrogenic transmission.
Conclusions
PrP plaques occur much more frequently for iatrogenic CJD-MM cases compared to sporadic CJDMM cases. Plaques may indicate iatrogenic transmission for CJD-MM cases without a type 2 Western blot fragment. The study results suggest the absence of significant misclassifications of iatrogenic CJD as sporadic. To our knowledge, this study is the first to describe grey matter kuru plaques in apparently sporadic CJD-MM patients with a type 2 Western blot fragment.
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P180 Clinico-pathological analysis of human prion diseases in a brain bank series
Ximelis T (1), Aldecoa I (1,2), Molina-Porcel L (1,3), Grau-Rivera O (4), Ferrer I (5), Nos C (6), Gelpi E (1,7), Sánchez-Valle R (1,4)
(1) Neurological Tissue Bank of the Biobanc-Hospital ClÃnic-IDIBAPS, Barcelona, Spain (2) Pathological Service of Hospital ClÃnic de Barcelona, Barcelona, Spain (3) EAIA Trastorns Cognitius, Centre Emili Mira, Parc de Salut Mar, Barcelona, Spain (4) Department of Neurology of Hospital ClÃnic de Barcelona, Barcelona, Spain (5) Institute of Neuropathology, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona (6) General subdirectorate of Surveillance and Response to Emergencies in Public Health, Department of Public Health in Catalonia, Barcelona, Spain (7) Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Background and objective:
The Neurological Tissue Bank (NTB) of the Hospital Clínic-Institut d‘Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain is the reference center in Catalonia for the neuropathological study of prion diseases in the region since 2001. The aim of this study is to analyse the characteristics of the confirmed prion diseases registered at the NTB during the last 15 years.
Methods:
We reviewed retrospectively all neuropathologically confirmed cases registered during the period January 2001 to December 2016.
Results:
176 cases (54,3% female, mean age: 67,5 years and age range: 25-86 years) of neuropathological confirmed prion diseases have been studied at the NTB. 152 cases corresponded to sporadic Creutzfeldt-Jakob disease (sCJD), 10 to genetic CJD, 10 to Fatal Familial Insomnia, 2 to GerstmannSträussler-Scheinker disease, and 2 cases to variably protease-sensitive prionopathy (VPSPr). Within sCJD subtypes the MM1 subtype was the most frequent, followed by the VV2 histotype.
Clinical and neuropathological diagnoses agreed in 166 cases (94%). The clinical diagnosis was not accurate in 10 patients with definite prion disease: 1 had a clinical diagnosis of Fronto-temporal dementia (FTD), 1 Niemann-Pick‘s disease, 1 Lewy Body‘s Disease, 2 Alzheimer‘s disease, 1 Cortico-basal syndrome and 2 undetermined dementia. Among patients with VPSPr, 1 had a clinical diagnosis of Amyotrophic lateral sclerosis (ALS) and the other one with FTD.
Concomitant pathologies are frequent in older age groups, mainly AD neuropathological changes were observed in these subjects.
Discussion:
A wide spectrum of human prion diseases have been identified in the NTB being the relative frequencies and main characteristics like other published series. There is a high rate of agreement between clinical and neuropathological diagnoses with prion diseases. These findings show the importance that public health has given to prion diseases during the past 15 years. Continuous surveillance of human prion disease allows identification of new emerging phenotypes. Brain tissue samples from these donors are available to the scientific community. For more information please visit:
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P192 Prion amplification techniques for the rapid evaluation of surface decontamination procedures
Bruyere-Ostells L (1), Mayran C (1), Belondrade M (1), Boublik Y (2), Haïk S (3), Fournier-Wirth C (1), Nicot S (1), Bougard D (1)
(1) Pathogenesis and control of chronic infections, Etablissement Français du Sang, Inserm, Université de Montpellier, Montpellier, France. (2) Centre de Recherche en Biologie cellulaire de Montpellier, CNRS, Université de Montpellier, Montpellier, France. (3) Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
Aims:
Transmissible Spongiform Encephalopathies (TSE) or prion diseases are a group of incurable and always fatal neurodegenerative disorders including Creutzfeldt-Jakob diseases (CJD) in humans. These pathologies include sporadic (sCJD), genetic and acquired (variant CJD) forms. By the past, sCJD and vCJD were transmitted by different prion contaminated biological materials to patients resulting in more than 400 iatrogenic cases (iCJD). The atypical nature and the biochemical properties of the infectious agent, formed by abnormal prion protein or PrPTSE, make it particularly resistant to conventional decontamination procedures. In addition, PrPTSE is widely distributed throughout the organism before clinical onset in vCJD and can also be detected in some peripheral tissues in sporadic CJD. Risk of iatrogenic transmission of CJD by contaminated medical device remains thus a concern for healthcare facilities. Bioassay is the gold standard method to evaluate the efficacy of prion decontamination procedures but is time-consuming and expensive. Here, we propose to compare in vitro prion amplification techniques: Protein Misfolding Cyclic Amplification (PMCA) and Real-Time Quaking Induced Conversion (RT-QuIC) for the detection of residual prions on surface after decontamination.
Methods:
Stainless steel wires, by mimicking the surface of surgical instruments, were proposed as a carrier model of prions for inactivation studies. To determine the sensitivity of the two amplification techniques on wires (Surf-PMCA and Surf-QuIC), steel wires were therefore contaminated with serial dilutions of brain homogenates (BH) from a 263k infected hamster and from a patient with sCJD (MM1 subtype). We then compared the different standard decontamination procedures including partially and fully efficient treatments by detecting the residual seeding activity on 263K and sCJD contaminated wires. We completed our study by the evaluation of marketed reagents endorsed for prion decontamination.
Results:
The two amplification techniques can detect minute quantities of PrPTSE adsorbed onto a single wire. 8/8 wires contaminated with a 10-6 dilution of 263k BH and 1/6 with the 10-8 dilution are positive with Surf-PMCA. Similar performances were obtained with Surf-QuIC on 263K: 10/16 wires contaminated with 10-6 dilution and 1/8 wires contaminated with 10-8 dilution are positive. Regarding the human sCJD-MM1 prion, Surf-QuIC allows us to detect 16/16 wires contaminated with 10-6 dilutions and 14/16 with 10-7 . Results obtained after decontamination treatments are very similar between 263K and sCJD prions. Efficiency of marketed treatments to remove prions is lower than expected.
Conclusions:
Surf-PMCA and Surf-QuIC are very sensitive methods for the detection of prions on wires and could be applied to prion decontamination studies for rapid evaluation of new treatments. Sodium hypochlorite is the only product to efficiently remove seeding activity of both 263K and sCJD prions.
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WA2 Oral transmission of CWD into Cynomolgus macaques: signs of atypical disease, prion conversion and infectivity in macaques and bio-assayed transgenic mice
Schatzl HM (1, 2), Hannaoui S (1, 2), Cheng Y-C (1, 2), Gilch S (1, 2), Beekes M (3), SchulzSchaeffer W (4), Stahl-Hennig C (5) and Czub S (2, 6)
(1) University of Calgary, Calgary Prion Research Unit, Calgary, Canada (2) University of Calgary, Faculty of Veterinary Medicine, Calgary, Canada, (3) Robert Koch Institute, Berlin, Germany, (4) University of Homburg/Saar, Homburg, Germany, (5) German Primate Center, Goettingen, Germany, (6) Canadian Food Inspection Agency (CFIA), Lethbridge, Canada.
To date, BSE is the only example of interspecies transmission of an animal prion disease into humans. The potential zoonotic transmission of CWD is an alarming issue and was addressed by many groups using a variety of in vitro and in vivo experimental systems. Evidence from these studies indicated a substantial, if not absolute, species barrier, aligning with the absence of epidemiological evidence suggesting transmission into humans. Studies in non-human primates were not conclusive so far, with oral transmission into new-world monkeys and no transmission into old-world monkeys. Our consortium has challenged 18 Cynomolgus macaques with characterized CWD material, focusing on oral transmission with muscle tissue. Some macaques have orally received a total of 5 kg of muscle material over a period of 2 years. After 5-7 years of incubation time some animals showed clinical symptoms indicative of prion disease, and prion neuropathology and PrPSc deposition were found in spinal cord and brain of euthanized animals. PrPSc in immunoblot was weakly detected in some spinal cord materials and various tissues tested positive in RT-QuIC, including lymph node and spleen homogenates. To prove prion infectivity in the macaque tissues, we have intracerebrally inoculated 2 lines of transgenic mice, expressing either elk or human PrP. At least 3 TgElk mice, receiving tissues from 2 different macaques, showed clinical signs of a progressive prion disease and brains were positive in immunoblot and RT-QuIC. Tissues (brain, spinal cord and spleen) from these and preclinical mice are currently tested using various read-outs and by second passage in mice. Transgenic mice expressing human PrP were so far negative for clear clinical prion disease (some mice >300 days p.i.). In parallel, the same macaque materials are inoculated into bank voles. Taken together, there is strong evidence of transmissibility of CWD orally into macaques and from macaque tissues into transgenic mouse models, although with an incomplete attack rate. The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology. Our ongoing studies will show whether the transmission of CWD into macaques and passage in transgenic mice represents a form of non-adaptive prion amplification, and whether macaque-adapted prions have the potential to infect mice expressing human PrP. The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD.
See also poster P103
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD.
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WA16 Monitoring Potential CWD Transmission to Humans
Belay ED
Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA.
The spread of chronic wasting disease (CWD) in animals has raised concerns about increasing human exposure to the CWD agent via hunting and venison consumption, potentially facilitating CWD transmission to humans. Several studies have explored this possibility, including limited epidemiologic studies, in vitro experiments, and laboratory studies using various types of animal models. Most human exposures to the CWD agent in the United States would be expected to occur in association with deer and elk hunting in CWD-endemic areas. The Centers for Disease Control and Prevention (CDC) collaborated with state health departments in Colorado, Wisconsin, and Wyoming to identify persons at risk of CWD exposure and to monitor their vital status over time. Databases were established of persons who hunted in Colorado and Wyoming and those who reported consumption of venison from deer that later tested positive in Wisconsin. Information from the databases is periodically cross-checked with mortality data to determine the vital status and causes of death for deceased persons. Long-term follow-up of these hunters is needed to assess their risk of development of a prion disease linked to CWD exposure.
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P166 Characterization of CJD strain profiles in venison consumers and non-consumers from Alberta and Saskatchewan
Stephanie Booth (1,2), Lise Lamoureux (1), Debra Sorensen (1), Jennifer L. Myskiw (1,2), Megan Klassen (1,2), Michael Coulthart (3), Valerie Sim (4)
(1) Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg (2) Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg (3) Canadian CJD Surveillance System, Public Health Agency of Canada, Ottawa (4) Division of Neurology, Department of Medicine Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton.
Chronic wasting disease (CWD) is spreading rapidly through wild cervid populations in the Canadian provinces of Alberta and Saskatchewan. While this has implications for tourism and hunting, there is also concern over possible zoonotic transmission to humans who eat venison from infected deer. Whilst there is no evidence of any human cases of CWD to date, the Canadian CJD Surveillance System (CJDSS) in Canada is staying vigilant. When variant CJD occurred following exposure to BSE, the unique biochemical fingerprint of the pathologic PrP enabled a causal link to be confirmed. However, we cannot be sure what phenotype human CWD prions would present with, or indeed, whether this would be distinct from that see in sporadic CJD. Therefore we are undertaking a systematic analysis of the molecular diversity of CJD cases of individuals who resided in Alberta and Saskatchewan at their time of death comparing venison consumers and non-consumers, using a variety of clinical, imaging, pathological and biochemical markers. Our initial objective is to develop novel biochemical methodologies that will extend the baseline glycoform and genetic polymorphism typing that is already completed by the CJDSS. Firstly, we are reviewing MRI, EEG and pathology information from over 40 cases of CJD to select clinically affected areas for further investigation. Biochemical analysis will include assessment of the levels of protease sensitive and resistant prion protein, glycoform typing using 2D gel electrophoresis, testing seeding capabilities and kinetics of aggregation by quaking-induced conversion, and determining prion oligomer size distributions with asymmetric flow field fractionation with in-line light scattering. Progress and preliminary data will be presented. Ultimately, we intend to further define the relationship between PrP structure and disease phenotype and establish a baseline for the identification of future atypical CJD cases that may arise as a result of exposure to CWD.
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Source Prion Conference 2018 Abstracts
Volume 24, Number 8—August 2018 Research Susceptibility of Human Prion Protein to Conversion by Chronic Wasting Disease Prions
Marcelo A. BarriaComments to Author , Adriana Libori, Gordon Mitchell, and Mark W. Head Author affiliations: National CJD Research and Surveillance Unit, University of Edinburgh, Edinburgh, Scotland, UK (M.A. Barria, A. Libori, M.W. Head); National and OIE Reference Laboratory for Scrapie and CWD, Canadian Food Inspection Agency, Ottawa, Ontario, Canada (G. Mitchell)
Abstract Chronic wasting disease (CWD) is a contagious and fatal neurodegenerative disease and a serious animal health issue for deer and elk in North America. The identification of the first cases of CWD among free-ranging reindeer and moose in Europe brings back into focus the unresolved issue of whether CWD can be zoonotic like bovine spongiform encephalopathy. We used a cell-free seeded protein misfolding assay to determine whether CWD prions from elk, white-tailed deer, and reindeer in North America can convert the human prion protein to the disease-associated form. We found that prions can convert, but the efficiency of conversion is affected by polymorphic variation in the cervid and human prion protein genes. In view of the similarity of reindeer, elk, and white-tailed deer in North America to reindeer, red deer, and roe deer, respectively, in Europe, a more comprehensive and thorough assessment of the zoonotic potential of CWD might be warranted.
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Discussion Characterization of the transmission properties of CWD and evaluation of their zoonotic potential are important for public health purposes. Given that CWD affects several members of the family Cervidae, it seems reasonable to consider whether the zoonotic potential of CWD prions could be affected by factors such as CWD strain, cervid species, geographic location, and Prnp–PRNP polymorphic variation. We have previously used an in vitro conversion assay (PMCA) to investigate the susceptibility of the human PrP to conversion to its disease-associated form by several animal prion diseases, including CWD (15,16,22). The sensitivity of our molecular model for the detection of zoonotic conversion depends on the combination of 1) the action of proteinase K to degrade the abundant human PrPC that constitutes the substrate while only N terminally truncating any human PrPres produced and 2) the presence of the 3F4 epitope on human but not cervid PrP. In effect, this degree of sensitivity means that any human PrPres formed during the PMCA reaction can be detected down to the limit of Western blot sensitivity. In contrast, if other antibodies that detect both cervid and human PrP are used, such as 6H4, then newly formed human PrPres must be detected as a measurable increase in PrPres over the amount remaining in the reaction product from the cervid seed. Although best known for the efficient amplification of prions in research and diagnostic contexts, the variation of the PMCA method employed in our study is optimized for the definitive detection of zoonotic reaction products of inherently inefficient conversion reactions conducted across species barriers. By using this system, we previously made and reported the novel observation that elk CWD prions could convert human PrPC from human brain and could also convert recombinant human PrPC expressed in transgenic mice and eukaryotic cell cultures (15).
A previous publication suggested that mule deer PrPSc was unable to convert humanized transgenic substrate in PMCA assays (23) and required a further step of in vitro conditioning in deer substrate PMCA before it was able to cross the deer–human molecular barrier (24). However, prions from other species, such as elk (15) and reindeer affected by CWD, appear to be compatible with the human protein in a single round of amplification (as shown in our study). These observations suggest that different deer species affected by CWD could present differing degrees of the olecular compatibility with the normal form of human PrP.
The contribution of the polymorphism at codon 129 of the human PrP gene has been extensively studied and is recognized as a risk factor for Creutzfeldt-Jakob disease (4). In cervids, the equivalent codon corresponds to the position 132 encoding methionine or leucine. This polymorphism in the elk gene has been shown to play an important role in CWD susceptibility (25,26). We have investigated the effect of this cervid Prnp polymorphism on the conversion of the humanized transgenic substrate according to the variation in the equivalent PRNP codon 129 polymorphism. Interestingly, only the homologs methionine homozygous seed–substrate reactions could readily convert the human PrP, whereas the heterozygous elk PrPSc was unable to do so, even though comparable amounts of PrPres were used to seed the reaction. In addition, we observed only low levels of human PrPres formation in the reactions seeded with the homozygous methionine (132 MM) and the heterozygous (132 ML) seeds incubated with the other 2 human polymorphic substrates (129 MV and 129 VV). The presence of the amino acid leucine at position 132 of the elk Prnp gene has been attributed to a lower degree of prion conversion compared with methionine on the basis of experiments in mice made transgenic for these polymorphic variants (26). Considering the differences observed for the amplification of the homozygous human methionine substrate by the 2 polymorphic elk seeds (MM and ML), reappraisal of the susceptibility of human PrPC by the full range of cervid polymorphic variants affected by CWD would be warranted.
In light of the recent identification of the first cases of CWD in Europe in a free-ranging reindeer (R. tarandus) in Norway (2), we also decided to evaluate the in vitro conversion potential of CWD in 2 experimentally infected reindeer (18). Formation of human PrPres was readily detectable after a single round of PMCA, and in all 3 humanized polymorphic substrates (MM, MV, and VV). This finding suggests that CWD prions from reindeer could be more compatible with human PrPC generally and might therefore present a greater risk for zoonosis than, for example, CWD prions from white-tailed deer. A more comprehensive comparison of CWD in the affected species, coupled with the polymorphic variations in the human and deer PRNP–Prnp genes, in vivo and in vitro, will be required before firm conclusions can be drawn. Analysis of the Prnp sequence of the CWD reindeer in Norway was reported to be identical to the specimens used in our study (2). This finding raises the possibility of a direct comparison of zoonotic potential between CWD acquired in the wild and that produced in a controlled laboratory setting. (Table).
The prion hypothesis proposes that direct molecular interaction between PrPSc and PrPC is necessary for conversion and prion replication. Accordingly, polymorphic variants of the PrP of host and agent might play a role in determining compatibility and potential zoonotic risk. In this study, we have examined the capacity of the human PrPC to support in vitro conversion by elk, white-tailed deer, and reindeer CWD PrPSc. Our data confirm that elk CWD prions can convert the human PrPC, at least in vitro, and show that the homologous PRNP polymorphisms at codon 129 and 132 in humans and cervids affect conversion efficiency. Other species affected by CWD, particularly caribou or reindeer, also seem able to convert the human PrP. It will be important to determine whether other polymorphic variants found in other CWD-affected Cervidae or perhaps other factors (17) exert similar effects on the ability to convert human PrP and thus affect their zoonotic potential.
Dr. Barria is a research scientist working at the National CJD Research and Surveillance Unit, University of Edinburgh. His research has focused on understanding the molecular basis of a group of fatal neurologic disorders called prion diseases.
Acknowledgments We thank Aru Balachandran for originally providing cervid brain tissues, Abigail Diack and Jean Manson for providing mouse brain tissue, and James Ironside for his critical reading of the manuscript at an early stage.
This report is independent research commissioned and funded by the United Kingdom’s Department of Health Policy Research Programme and the Government of Scotland. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health or the Government of Scotland.
Author contributions: The study was conceived and designed by M.A.B. and M.W.H. The experiments were conducted by M.A.B. and A.L. Chronic wasting disease brain specimens were provided by G.M. The manuscript was written by M.A.B. and M.W.H. All authors contributed to the editing and revision of the manuscript.
Prion 2017 Conference Abstracts
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress Stefanie Czub1, Walter Schulz-Schaeffer2, Christiane Stahl-Hennig3, Michael Beekes4, Hermann Schaetzl5 and Dirk Motzkus6 1
University of Calgary Faculty of Veterinary Medicine/Canadian Food Inspection Agency; 2Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes; 3 Deutsches Primaten Zentrum/Goettingen; 4 Robert-Koch-Institut Berlin; 5 University of Calgary Faculty of Veterinary Medicine; 6 presently: Boehringer Ingelheim Veterinary Research Center; previously: Deutsches Primaten Zentrum/Goettingen
This is a progress report of a project which started in 2009.
21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer (WTD) or elk by intracerebral (ic), oral, and skin exposure routes. Additional blood transfusion experiments are supposed to assess the CWD contamination risk of human blood product. Challenge materials originated from symptomatic cervids for ic, skin scarification and partially per oral routes (WTD brain). Challenge material for feeding of muscle derived from preclinical WTD and from preclinical macaques for blood transfusion experiments. We have confirmed that the CWD challenge material contained at least two different CWD agents (brain material) as well as CWD prions in muscle-associated nerves.
Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice.
At present, a total of 10 animals are sacrificed and read-outs are ongoing. Preclinical incubation of the remaining macaques covers a range from 6.4 to 7.10 years. Based on the species barrier and an incubation time of > 5 years for BSE in macaques and about 10 years for scrapie in macaques, we expected an onset of clinical disease beyond 6 years post inoculation.
PRION 2017 DECIPHERING NEURODEGENERATIVE DISORDERS ABSTRACTS REFERENCE
8. Even though human TSE‐exposure risk through consumption of game from European cervids can be assumed to be minor, if at all existing, no final conclusion can be drawn due to the overall lack of scientific data. In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids. It might be prudent considering appropriate measures to reduce such a risk, e.g. excluding tissues such as CNS and lymphoid tissues from the human food chain, which would greatly reduce any potential risk for consumers. However, it is stressed that currently, no data regarding a risk of TSE infections from cervid products are available.
SATURDAY, FEBRUARY 23, 2019
Chronic Wasting Disease CWD TSE Prion and THE FEAST 2003 CDC an updated review of the science 2019
TUESDAY, NOVEMBER 04, 2014
Six-year follow-up of a point-source exposure to CWD contaminated venison in an Upstate New York community: risk behaviours and health outcomes 2005–2011
Authors, though, acknowledged the study was limited in geography and sample size and so it couldn't draw a conclusion about the risk to humans. They recommended more study. Dr. Ermias Belay was the report's principal author but he said New York and Oneida County officials are following the proper course by not launching a study. "There's really nothing to monitor presently. No one's sick," Belay said, noting the disease's incubation period in deer and elk is measured in years. "
Transmission Studies
Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}....TSS
resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest incubation period in the ferret.
snip....
Prion Infectivity in Fat of Deer with Chronic Wasting Disease▿
Brent Race#, Kimberly Meade-White#, Richard Race and Bruce Chesebro* + Author Affiliations
In mice, prion infectivity was recently detected in fat. Since ruminant fat is consumed by humans and fed to animals, we determined infectivity titers in fat from two CWD-infected deer. Deer fat devoid of muscle contained low levels of CWD infectivity and might be a risk factor for prion infection of other species.
Prions in Skeletal Muscles of Deer with Chronic Wasting Disease
Here bioassays in transgenic mice expressing cervid prion protein revealed the presence of infectious prions in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk to prion exposure.
*** now, let’s see what the authors said about this casual link, personal communications years ago, and then the latest on the zoonotic potential from CWD to humans from the TOKYO PRION 2016 CONFERENCE.
see where it is stated NO STRONG evidence. so, does this mean there IS casual evidence ???? “Our conclusion stating that we found no strong evidence of CWD transmission to humans”
From: TSS
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To: Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam,
In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD.. That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091). Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.
Ermias Belay, M.D. Centers for Disease Control and Prevention
-----Original Message-----
From: Sent: Sunday, September 29, 2002 10:15 AM
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Sunday, November 10, 2002 6:26 PM .......snip........end..............TSS
Thursday, April 03, 2008
A prion disease of cervids: Chronic wasting disease 2008 1: Vet Res. 2008 Apr 3;39(4):41 A prion disease of cervids: Chronic wasting disease Sigurdson CJ.
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*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,
snip... full text ;
> However, to date, no CWD infections have been reported in people.
sporadic, spontaneous CJD, 85%+ of all human TSE, did not just happen. never in scientific literature has this been proven.
if one looks up the word sporadic or spontaneous at pubmed, you will get a laundry list of disease that are classified in such a way;
sporadic = 54,983 hits https://www.ncbi.nlm.nih.gov/pubmed/?term=sporadic
spontaneous = 325,650 hits https://www.ncbi.nlm.nih.gov/pubmed/?term=spontaneous
key word here is 'reported'. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can't, and it's as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it's being misdiagnosed as sporadic CJD. ...terry
*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***
> However, to date, no CWD infections have been reported in people.
key word here is ‘reported’. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can’t, and it’s as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it’s being misdiagnosed as sporadic CJD. …terry
*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***
*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***
CWD TSE PRION AND ZOONOTIC, ZOONOSIS, POTENTIAL
Subject: Re: DEER SPONGIFORM ENCEPHALOPATHY SURVEY & HOUND STUDY
Date: Fri, 18 Oct 2002 23:12:22 +0100
From: Steve Dealler
Reply-To: Bovine Spongiform Encephalopathy Organization: Netscape Online member
To: BSE-L@ References: <3daf5023 .4080804="" wt.net="">
Dear Terry,
An excellent piece of review as this literature is desparately difficult to get back from Government sites.
What happened with the deer was that an association between deer meat eating and sporadic CJD was found in about 1993. The evidence was not great but did not disappear after several years of asking CJD cases what they had eaten. I think that the work into deer disease largely stopped because it was not helpful to the UK industry...and no specific cases were reported. Well, if you dont look adequately like they are in USA currenly then you wont find any!
Steve Dealler ===============
''The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).''
CREUTZFELDT JAKOB DISEASE SURVEILLANCE IN THE UNITED KINGDOM THIRD ANNUAL REPORT AUGUST 1994
Consumption of venison and veal was much less widespread among both cases and controls. For both of these meats there was evidence of a trend with increasing frequency of consumption being associated with increasing risk of CJD. (not nvCJD, but sporadic CJD...tss) These associations were largely unchanged when attention was restricted to pairs with data obtained from relatives. ...
Table 9 presents the results of an analysis of these data.
There is STRONG evidence of an association between ‘’regular’’ veal eating and risk of CJD (p = .0.01).
Individuals reported to eat veal on average at least once a year appear to be at 13 TIMES THE RISK of individuals who have never eaten veal.
There is, however, a very wide confidence interval around this estimate. There is no strong evidence that eating veal less than once per year is associated with increased risk of CJD (p = 0.51).
The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).
There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY OF LAMB EATING (p = 0.02).
The evidence for such an association between beef eating and CJD is weaker (p = 0.14). When only controls for whom a relative was interviewed are included, this evidence becomes a little STRONGER (p = 0.08).
snip...
It was found that when veal was included in the model with another exposure, the association between veal and CJD remained statistically significant (p = < 0.05 for all exposures), while the other exposures ceased to be statistically significant (p = > 0.05).
snip...
In conclusion, an analysis of dietary histories revealed statistical associations between various meats/animal products and INCREASED RISK OF CJD. When some account was taken of possible confounding, the association between VEAL EATING AND RISK OF CJD EMERGED AS THE STRONGEST OF THESE ASSOCIATIONS STATISTICALLY. ...
snip...
In the study in the USA, a range of foodstuffs were associated with an increased risk of CJD, including liver consumption which was associated with an apparent SIX-FOLD INCREASE IN THE RISK OF CJD. By comparing the data from 3 studies in relation to this particular dietary factor, the risk of liver consumption became non-significant with an odds ratio of 1.2 (PERSONAL COMMUNICATION, PROFESSOR A. HOFMAN. ERASMUS UNIVERSITY, ROTTERDAM). (???...TSS)
snip...see full report ;
http://web.archive.org/web/20090506050043/http://www.bseinquiry.gov.uk/files/yb/1994/08/00004001.pdf
http://web.archive.org/web/20090506050244/http://www.bseinquiry.gov.uk/files/yb/1994/07/00001001.pdf
BSE Inquiry Steve Dealler
Management In Confidence
BSE: Private Submission of Bovine Brain Dealler
snip...see full text;
MONDAY, FEBRUARY 25, 2019
***> MAD DOGS AND ENGLISHMEN BSE, SCRAPIE, CWD, CJD, TSE PRION A REVIEW 2019
***> ''The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).''
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
North American and Norwegian Chronic Wasting Disease prions exhibit different potential for interspecies transmission and zoonotic risk
Sandra Pritzkow1,*, Damian Gorski1,*, Frank Ramirez1 , Glenn C. Telling2 , Sylvie L. Benestad3 and Claudio Soto1,#
1 Mitchell Center for Alzheimer's disease and related Brain disorders, Department of Neurology, University of Texas McGovern Medical School at Houston, Texas, USA 2 Prion Research Center, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA 3 Norwegian Veterinary Institute, OIE Reference Laboratory for CWD, Oslo, Norway.
Summary: We investigated the in vitro spillover and zoonotic potential of CWD from various cervid species. Our results suggest that Norway CWD prions have a higher potential to infect other animals, but NorthAmerican CWD appear more prone to generate human prions.
The current evidence for CWD transmission to humans is controversial; indeed, while transgenic mice expressing human PrP did not develop disease when challenged with CWD prions in various laboratories [6-8, 41], experimental inoculation of CWD into squirrel monkeys produced disease [9, 10]. Studies in macaques, which are phylogenetically closer to humans than squirrel monkeys [45] have shown mixed results. A study from Czub and colleagues found that CWD prions can induce disease and pathologic abnormalities typical of prion disease in macaques exposed to CWD prions, even by oral inoculation of muscle tissue from cervids affected by CWD [46]. However, a different study found no evidence for prion disease in macaques inoculated with CWD [47]. To assess the cervid/human species barrier, we previously used PMCA to determine prion replication in vitro. We found that, after stabilization by successive passages in deer PrPC, PrPSc from CWD infected deer can convert human PrPC into a novel form of PrPSc [13]. Our current study to evaluate in vitro zoonotic potential of various CWD prions showed that although the cervid/human barrier is large, we were able to observe generation of human PrPSc with some specific CWD strains in a second round of PMCA (Fig. 5). The three North American CWD isolates were capable to sustain generation of human PrPSc, with white-tailed deer showing the highest efficiency. Conversely, none of the three Norway CWD isolates generated any detectable PrPSc signal up to the second round of PMCA. This data suggest that North American CWD prions might be of a greater risk to humans than the infected animals in Northern Europe. We speculate that these differences might be due to Norwegian CWD being less stable prion strains as compared to North American CWD, which have had longer time to replicate in cervids and become stabilized through many rounds of natural infection. Our findings may provide important information to understand the diversity of natural CWD prion strains in different animals across distinct geographical areas and their consequences for the spillover into other animal species, including humans.
MONDAY, JULY 19, 2021
U Calgary researchers at work on a vaccine against a fatal infectious disease affecting deer and potentially people
TUESDAY, JULY 13, 2021
Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors Current Knowledge Risks and Policy Options
''The science is progressing on the possibility of transmission of CWD to humans through oral transmission, but the complete assessment of this possibility remains to be done.''
MONDAY, DECEMBER 16, 2019
Chronic Wasting Disease CWD TSE Prion aka mad cow type disease in cervid Zoonosis Update
***> ''In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
What if?
TUESDAY, MAY 11, 2021
A Unique Presentation of Creutzfeldt-Jakob Disease in a Patient Consuming Deer Antler Velvet
Conclusion
We believe that our patient’s case of CJD is highly suspicious for cervid etiology given the circumstances of the case as well as the strong evidence of plausibility reported in published literature. This is the first known case of CJD in a patient who had consumed deer antler velvet. Despite the confirmed diagnosis of CJD, a causal relationship between the patient’s disease and his consumption of deer antler velvet cannot be definitively concluded.
Supplemental data including molecular tissue sample analysis and autopsy findings could yield further supporting evidence. Given this patient’s clinical resemblance to CBD and the known histological similarities of CBD with CJD, clinicians should consider both diseases in the differential diagnosis of patients with a similarly esoteric presentation. Regardless of the origin of this patient’s disease, it is clear that the potential for prion transmission from cervids to humans should be further investigated by the academic community with considerable urgency.
''We believe that our patient’s case of CJD is highly suspicious for cervid etiology given the circumstances of the case as well as the strong evidence of plausibility reported in published literature. This is the first known case of CJD in a patient who had consumed deer antler velvet. Despite the confirmed diagnosis of CJD, a causal relationship between the patient’s disease and his consumption of deer antler velvet cannot be definitively concluded.''
Thursday, July 29, 2021
TSE PRION OCCUPATIONAL EXPOSURE VIA ANIMAL OR HUMAN, iatrogenic transmission, nvCJD or sCJD, what if?
TUESDAY, AUGUST 03, 2021
USA Tables of Cases Examined National Prion Disease Pathology Surveillance Center Cases Examined July 9th, 2021
now think iatrogenic from all the above exposure?
Terry S. Singeltary Sr.
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