December 10, 2018: Olympus Medical Systems Corporation, Former Senior Executive Plead Guilty to Distributing Endoscopes After Failing to File FDA-Required Adverse Event Reports of Serious Infections
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Food and Drug Administration
Office of Criminal Investigations |
U.S. Department of Justice Press Release
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For Immediate Release
December 10, 2018 |
United States Department of Justice
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Olympus Medical Systems Corporation (Olympus) and a former senior executive in Japan pleaded guilty today in Newark, New Jersey, to failing to file required adverse event reports involving infections connected to duodenoscopes, and to continuing to sell the duodenoscopes in the United States despite those failures, the Justice Department announced today.
Olympus’s and Yabe’s Failure to File Required Adverse Event Reports
To enable FDA and others to identify and monitor adverse events, the FDCA requires medical device manufacturers to file adverse event reports – known as Medical Device Reports (MDRs) – when the manufacturer becomes aware of information that reasonably suggests that the manufacturer’s device may have caused or contributed to a death or serious injury. The FDCA also requires manufacturers to file supplemental MDRs if they subsequently obtain information about the event that was not known or available when the initial MDR was filed.
Olympus today admitted that it failed to make the required initial MDR filing regarding the Kremlin Bicetre infections, and failed to file required supplemental MDRs relating to the Erasmus Medical Center and Clinique de Bercy infections, for which Olympus had filed initial MDRs. Under the FDCA, devices for which required MDRs and supplemental MDRs have not been filed are deemed misbranded, and it is a crime to ship such devices in interstate commerce. Between August 2012 and October 2014, Olympus shipped hundreds of misbranded duodenoscopes in the United States, generating approximately $40 million in revenue and approximately $33 million in total gross profit. Olympus’s payment of $85 million is more than 2½ times Olympus’s total profit from sales of the misbranded duodenoscopes.
As part of its plea agreement with the Justice Department, Olympus has agreed to: retain an independent MDR expert to inspect and review Olympus’s policies and procedures to determine their compliance with the MDR requirements of the FDCA and its implementing regulations; periodic review by the MDR expert of Olympus’s continued compliance with the MDR requirements of the FDCA and its implementing regulations; and conduct a review and audit of the device classification and market pathway for all endoscope device types manufactured by Olympus that are intended for use in the sterile body cavity and that are currently sold in the United States. The MDR expert will report back to FDA and the Justice Department periodically for three years. In addition, the President of Olympus and Olympus’s Board of Directors will periodically conduct a review of Olympus’s MDR compliance measures and classification/marketing pathway review and provide certifications to FDA and the Justice Department relating to those reviews. Olympus also is obligated to inform health care providers in the United States who received Q180Vs between August 2012 and October 2014 of Olympus’s plea today, and to provide information to those health care providers regarding Olympus’s failure to file the required MDRs.
The guilty pleas are the culmination of an investigation conducted by special agents from FDA’s Office of Criminal Investigations, under the direction of Special Agent in Charge Jeffrey J. Ebersole of the New York Field Office, along with special agents from the U.S. Department of Health and Human Services, Office of Inspector General, under the direction of Special Agent in Charge Scott J. Lampert, and special agents of the FBI, under the direction of Special Agent in Charge Gregory W. Ehrie.
The government is represented in the criminal case by Assistant U.S. Attorneys Jacob T. Elberg and R. David Walk, Jr. of the U.S. Attorney’s Office’s Health Care and Government Fraud Unit, and Senior Litigation Counsel Patrick Jasperse of the Justice Department’s Consumer Protection Branch, with the assistance of Senior Counsel Shannon M. Singleton of the FDA’s Office of Chief Counsel.
Topic(s):
Consumer Protection
Component(s):
Press Release Number:
18-1623
Greetings CJD TSE Prion world,
i started in on Olympus et al on their endoscopy equipment and risk factors there from way way back, around 1999 or so, maybe 1998, and the risk factors that were/are from the cjd tse prion disease. submitted my concern to many officials, and to the JOURNAL GUT, that was going to print my concerns, until Bramble et al pulled it. so sad, no phd i have. but i was correct all along. here is the history there from. crazy though, that was 2 decades ago. wonder how many humans were exposed and or then died from CJD TSE Prion, and or how many are waiting? so damn sad, the science has been there all along...terry
> Subj: [CJDVoice] [Fwd: re-CJD endoscope document URL???] re-Marie???
> Date: 10/15/99 9:58:57 AM Eastern Daylight Time
> From: flounder@w... (Terry S. Singeltary Sr.)
> Reply-to: cjdvoice@onelist.com
> To: cjdvoice@onelist.com
>
> Also, I spoke with this Doctor over the phone, to confirm the Co.s
> position. He did confirm, the company is concerned of the effectiveness
> of the cleaning procedures, and CJD. That is why they put forth the
> warning, to all medical institutions, and the CDC.
> Terry
>
> Hi Terry: I have been attempting to get a copy of that doc myself.
> In fact, I rec an e-mail from an Olympus person sayin he would send me
> a copy to my fax machine. But have not rec it. Here is a copy of the
> mesg I rec. from him. You may wish to contact him yourself
> Please let me know what he tells you. And if you get a copy, please
> copy it to me.
> Thanks
>
> Subject: CJD Inquiry
> Date: Tue, 28 Sep 1999 20:11:42 -0400
> From: "Steve Goldstine"
> To: spyridon@p...
> Olympus does have a position statement regarding flexible endoscopes
> and CJD. We as also distribute CDC's draft statement about CJD along
> with the letter. Please send your mailing address or fax number and we
> will send a copy.
>
> Dr. Steve Goldstine
> Manager, Microbiology
> Olympus America, Inc
> 6601 Tennyson St, N.E. #10105
> Albuquerque NM 87111
>
> EMail: goldss@o...
> Phone: 505.323.1222
> Fax: 505.323.1221
> Voice Mail: 800.645.8100 mailbox #5461
> ======================================
Subject: Creutzfeldt-Jakob disease: implications for gastroenterology & CJD 38 years after _diagnostic_ use of hGH (Iatrogenic CJDs & sporadic CJDs)
Date: Mon, 17 Jun 2002 16:46:46 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######## Bovine Spongiform Encephalopathy #########
OCCASIONAL VIEWPOINTS
Creutzfeldt-Jakob disease' implications for gastroenterology
M G Bramble, J W Ironside
Gut 2002;50:888-890
The current clinical views regarding variant Creutzfeldt-Jakob disease, and in particular transmission via endoscopy, of those representing both gastroenterology and the Spongiform Encephalopathy Advisory Committee are presented in an attempt to guide clinicians as to "best practice" given the current state of our knowledge.
See end of article for authors' affiliations
Correspondence to: Professor MG Bramble, Endoscopy Centre, James Cook University Hospital, Marton Rd, Middlesbrough TS4 3BN, UK;
Most gastroenterologists working in the UK have been aware for some time that endoscopy may be a vector for the transmission of prions from a patient incubating, but not clinically manifesting, variant Creutzfeldt-Jakob disease (vCJD) to the next individuals undergoing the same procedure on the same list. To date there are no recorded cases of iatrogenic transmission of vCJD via endoscopy but it remains a risk which will be present for many years to come. Advice to health authorities on individual cases is through the CJD Incidents Panel. However, we are aware that advice to health professionals performing endoscopy needs to be as comprehensive as current evidence will allow, without making it impossible to perform endoscopic procedures on patients who will clearly derive long term health benefits from an accurate endoscopic diagnosis and/or treatment. This article represents the current clinical views of those representing both gastroenterology and the Spongiform Encephalopathy Advisory Committee (SEAC). Both authors sit on the CJD Incidents Panel and have been advising the Department of Health on individual cases during the last year. It is important to note that the advice given in this article may be superseded if additional information or evidence becomes available.
CJD is a member of a group of neurological disorders known as the transmissible spongilorm encephalopathies or prion diseases, which affect both animals (such as scrapie in sheep or bovine spongiform encephalopathy (BSE) in cows) and humans. The precise nature of the transmissible agents responsible for these disorders is unknown but there is increasing evidence to support the prion hypothesis, which states that the agent is composed of an abnormally folded form of a host encoded protein, prion protein. The normal prion protein (PrPc) is expressed in many tissues but occurs at the highest levels in neurones in the central nervous system (CNS) where it may act as a copper binding protein, although its precise physiological role is unknown. The abnormal form of the protein (PrPSc) accumulates in the CNS in prion diseases; the infectious agent is remarkably resistant to most forms of degradation. The association between PrPSc and the gut has been eloquently described in a previous leading article1 and gastroenterologists need to understand where we are in terms of our present day knowledge of this entity.
In humans, prion diseases occur in three major categories: sporadic, acquired, and familial. All are currently untreatable and universally fatal although recent studies have indicated that a combination of drugs may be effective in experimental prion diseases2: this approach is under consideration as a clinical trial. The sporadic form of CJD affects approximately one person per million per annum in the population on a worldwide basis. CJD has also occurred as an acquired iatrogenic disorder, transmitted to other humans through direct (inadvertent) inoculation of the brain via contaminated neurosurgical instruments, via corneal and dura mater grafts, or through administration of human pituitary extracts used to treat growth hormone or gonadotrophin deficiency. Variant CJD (vCJD) is a new acquired form of CJD which was first reported in 1996 affecting mainly young adults and with a unique neuropathological phenotype.3 It is now widely accepted that bovine prions passed into the human population through consumption of BSE infected bovine tissues; the transmissible agent responsible for vCJD is identical to the BSE agent (but different from the agent in sporadic CJD). The incubation period for vCJD is likely to be lengthy and may have a mean value of 10-30 years. During this time the affected person has the potential to transmit the disease to others via surgical procedures which might result in the transfer of infected tissue into the next person operated on with the same surgical instruments.
The distribution of PrPSc in the body is different in sporadic and variant CJD, reflecting the different pathogenesis of the two forms. In the case ot sporadic CJD, prion infectivity is largely limited to the CNS (including the retina) and only operations involving the brain and eye have resulted in iatrogenic transmission of the disease. Gastrointestinal endoscopy is unlikely to be a vector for the transmission of sporadic CJD as infected tissue is not encountered during the procedure. No special precautions are necessary during or after the procedure and the endoscope should be cleaned and disinfected in the normal thorough way.4
"Endoscopy on patients who are incubating vCJD may result in exposure of the instrument (and particularly the biopsy forceps) to PrPsc''
In contrast, in vCJD the lymphoreticular system throughout the body contains PrPSc at the time of death, and experimental evidence suggests that the lymphoreticular system may contain significant levels of infectivity for most of the incubation period.5 To support this, in vCJD abnormal prion protein was found in the germinal centres in the wall of an appendix from a vCJD patient that was removed eight months before the onset of neurological disease.6 As lymphoid follicles and germinal centres are widely distributed in the gastrointestinal tract (and are often biopsied), it is possible that endoscopy on patients who are incubating vCJD may result in exposure of the instrument (and particularly the biopsy forceps) to PrPsc. Consequently, the question now arises, how great is the risk of secondary (person to person) transmission in endoscoping a patient incubating vCJD? There are three scenarios which gastroenterologists are likely to encounter and this editorial will attempt to guide clinicians as to "best practice" given the current state of our knowledge.
UPPER GASTROINTESTINAL ENDOSCOPY
Scenario No 1
Occasionally gastroenterologists may be requested to endoscope a patient with known or probable sporadic CJD (usually to site a PEG feeding tube). This can be carried out in the routine way provided vCJD is not suspected. If inadvertently a patient with suspected vCJD is endoscoped, the instrument used should be quarantined until the postmortem diagnosis is known. If sporadic CJD is diagnosed, the endoscope can be returned to use following thorough cleaning and decontamination, as is normal practice. If vCJD is diagnosed the endoscope cannot be used again and should be quarantined or sent to the National CJD Surveillance Unit in Edinburgh for research purposes. The previous advice to destroy such instruments represents a lost opportunity to study the risks involved in more detail. It would also be good practice to inform colleagues locally that a quarantined instrument was available for use in other endoscopy units if they too had a patient with suspected vCJD requiring endoscopy.
Scenario No 2
For patients with known or probable vCJD,7 endoscopy should only be a last resort. Ultrasound guided insertion of a gastrostomy feeding tube would be preferable to a PEG feeding tube if local expertise is available. If not, endoscopy should be performed using an instrument already set aside for such patients. If no such instrument is available locally, one can be loaned to any hospital by the National CJD Surveillance Unit in Edinburgh (contact telephone number 0131 537 1980). If scenario No 2 becomes more common, endoscopes may need to be held regionally for this purpose.
Scenario No 3
This scenario covers patients who have been endoscoped by an instrument previously used on a patient who was not known to be incubating vCJD at the time of endoscopy but who subsequently went on to develop the disease. This could become the commonest scenario and it must be assumed that the patient who went on to develop vCJD was incubating the disease at the time of the original endoscopy. This also means that infectious material may not have been removed completely by current methods of decontaminating endoscopes, and that subsequent patients have been exposed to the prion agent. The instrument used should therefore be quarantined until advice has been sought from the CJD Incidents Panel (Department of Health, Skipton House, London; contact telephone 0207 972 1761) as to the management of the situation. Local infection control teams will need to be involved with contact tracing and information handling.
LOWER GASTROINTESTINAL ENDOSCOPY
It is unlikely that colonoscopy would be clinically justifiable in a patient known or strongly suspected as suffering from vCJD. However, it is quite possible that an asymptomatic patient incubating vCJD may undergo colonoscopy prior to diagnosis and this situation is essentially the same as in scenario 3. The risks of transmitting prion protein to the next patient are much greater however, due to a number of factors which relate to the amount of lymphatic tissue encountered during endoscopy and the number, site, and size of mucosal biopsies obtained by this method.
In general the risks of transmitting vCJD from one patient to another are dependent on the infectivity of the tissues involved, the amount of tissue contaminating the instrument, the effectiveness of the decontamination processes, and the susceptibility of subsequently exposed patients. Experimental studies suggest that levels of infectivity in prion diseases are highest in the CNS and retina, which are approximately two logs higher than in the tonsils and other lymphoreticular tissue. A recent study has also detected the abnormal form of the prion protein in rectal tissue from a patient with vCJD by western blot examination of autopsy tissues.8 The risk of transmitting vCJD through the endoscopy procedure itself is likely to be small, but contamination of the endoscope and forceps as a result of biopsy of lymphoid tissues may represent a larger (but currently unquantifiable) risk, even though only small amounts of tissue are involved.
"The risks of transmitting vCJD from one patient to another are dependent on the infectivity of the tissues involved, the amount of tissue contaminating the instrument, the effectiveness of the decontamination processes, and the susceptibility of subsequently exposed patients"
The greatest risk is undoubtedly that which ensues from biopsy of the terminal ileum where Peyer's patches may contain significant levels of prion protein for a patient incubating vCJD. The biopsy forceps and the colonoscope become potential vectors for disease transmission under these circumstances. Meticulous manual cleaning of the colonoscope is probably the best defence against person to person transmission. The same is true of the biopsy forceps, but as disposable forceps are now available there is a strong argument for moving towards the universal use of disposable biopsy forceps for mucosal samples taken at colonoscopy. Endoscopy units should now work towards a policy of using disposable biopsy forceps as the only practical way of minimising the risk which results from ileal biopsy. In addition, "random" biopsies should be kept to a minimum as lymphoid tissue is distributed widely throughout the gastrointestinal tract. Although thorough cleaning of flexible endoscopes ensures patient safety for "normal" pathogens, the same process may not be adequate for the PrPsc. The main benefit of the decontamination process under these circumstances is undoubtedly effective manual cleaning, as glutaraldehyde may stabilise PrPSc on the metal surface of the endoscope, with potentially adverse consequences. It follows that brushes used to clean the channels of the endoscope are used only once to ensure maximum efficiency and biopsy forceps should also be functioning optimally and discarded as soon as they appear to be under performing (tearing tissue rather than cutting it). The rubber valve protecting the biopsy channel is another item which is potentially disposable and serious consideration should be given to single use valves. Again, more research is required to determine "best practice". For rigid endoscopes, autoclaving at the recommended conditions for CJD9 is the best way of attempting decontamination.
What should endoscopists do in the short term? The answer to this question must be to ensure as far as possible that manual cleaning of endoscopes and reuseable accessories is of the highest standard. Endoscopy has a major role in patient care, and this should not be compromised unless it is absolutely unavoidable in the public interest. It is also essential that endoscopes should be individually identifiable and their use traceable in any given patient population. Random biopsies should be kept to an absolute minimum (particularly of the ileum in colonoscopy) and endoscopy itself should be as atraumatic as possible, especially gastroscopy where the instrument is in contact with the mucosa covering the tonsils. Biopsy forceps should be treated as "high risk" and undergo thorough ultrasonic cleaning followed by autoclaving. As research in the UK progresses, it is likely that other procedures will be developed to inactivate prion infectivity and to remove proteins from instrument surfaces. The development of such techniques (along with more sensitive tests for prion detection) may well have an impact on future advice concerning endoscopy and CJD.
Depending on the final numbers of people infected with vCJD, we must assume that a significant number may undergo endoscopy before neurological symptoms appear10. It is therefore up to every endoscopist to be aware of the dangers and follow the advice set out here. Further advice on specific cases and possible exposure incidents can be obtained from the CJD Incidents Panel (Department of Health, Skipton House, London; contact telephone 0207 972 1761).
Authors' affiliations M G Bramble, Endoscopy Centre, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK J W Ironside, CJD Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
mike.bramble@stees.nhs.uk
Accepted for publication 19 November 2001
REFERENCES
1 Shmakov AN, Ghosh S. Prion proteins and the gut: une liaison dangereuse? Gut 2001;48:443-7.
2 Korth C, May BCH, Cohen FE, et al. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Nail Acad Sci USA 2001;98:9836-41.
3 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:921-5.
4 Report of a Working Party of the British Society of Gastroenterology Endoscopy Committee. Cleaning and disinfection of equipment for gastrointestinal endoscopy. Gut 1998;42:585-93.
5 Hill AF, Butterworth R J, Joiner S, et al. Investigation of variant Creutzfeldt-Jacob disease and other human prion diseases with tonsil biopsy samples. Lancet 1999;353:183-9.
6 Hilton DA, Fathers E, Edwards P, et al. Prion immunoreactivity in the appendix before the clinical onset of new variant Creutzfeldt-Jacob disease. Lancet 1998;352:703-4.
7 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neuro12000;47:575-82.
8 Wadsworth JD, Joiner S, Hill AF, et al. Tissue distribution of protease resistant prion protein in variant Creutxfleldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 2001 ;358:171-80.
9 Dangerous Pathogens Spongiform Encephalopathy Advisory Committee. Transmissible spongiform encephalopathy agents: safe working and the prevention of infection. London: The Stationary Office, 1998.
10 Ironside JW, Hilton DA, Ghani A, et al. Retrospective study of prion protein accumulation in tonsil and appendix tissue. Lancet 2000;355:1693-94.
http://www.gutjnl.com/cgi/content/abstract/50/6/888 ========================================================
Greetings List Members,
this is _very_ disturbing to me;
snip...
>The distribution of PrPSc in the body is different in sporadic and variant CJD, reflecting the different pathogenesis of the two forms. In the case ot sporadic CJD, prion infectivity is largely limited to the CNS (including the retina) and only operations involving the brain and eye have resulted in iatrogenic transmission of the disease. Gastrointestinal endoscopy is unlikely to be a vector for the transmission of sporadic CJD as infected tissue is not encountered during the procedure. No special precautions are necessary during or after the procedure and the endoscope should be cleaned and disinfected in the normal thorough way.4
snip...
i personally believe it is irresponsible for anyone to state in this day and time, that sporadic CJDs (now at 6 variants) will not transmit the disease by this route. considering infective dose cannot be quantified, only speculated, such a statement is thus, irresponsible. to hypothosize that sporadic CJD just happens spontaneously (with no scientific proof), that the PrPSc distribution in tissues of all sporadic CJDs is entirely different than that of vCJD, without being able to quantify the titre of infection, or even confirm all the different variants yet, again is _not_ based on all scientific data, then it's only a hypothosis. who is to say that some of these variants of sporadic CJD were not obtained _orally_?
also stated;
snip...
> Although thorough cleaning of flexible endoscopes ensures patient safety for ''normal'' pathogens, the same process may not be adequate for the PrPSc.
snip...
> The sporadic form of CJD affects approximately one person per million per annum in the population on a worldwide basis.
who is to say how much infectivity are in some of these variants of sporadic CJDs, without confirming this? if we look at the 6 different variants of sporadic CJDs, has the infective dose for all 6 _documented_ variants been quantified, and documented as being 'measurable'?
will there be more variants of sporadic CJDs, and what of the ramifications from them?
what of other strains/variants of TSE in cattle, BSE in sheep, CWD in cattle, or any of the 20+ strains of Scrapies in deer/elk? i get dizzy thinking of the different scenerio's. what would the human TSEs from these species look like and how can anyone quantify any tissue infectivity from these potential TSE transmissions to humans, and the risk scenerio described here from this potential route? could not some of these sporadic CJDs have derived directly or indirectly from one of these species, and if so, pose a risk by the route described here?
something else to consider, in the recent finding of the incubation period of 38 years from a _small_ dose of human growth hormone;
snip...
> We describe the second patient with hGH related CJD in the Netherlands. The patient developed the disease 38 years after hGH injections. To our knowledge, this is the longest incubation period described for any form of iatrogentic CJD. Furthermore, our patient was _not_ treated with hGH, but only received a _low_ dose as part of a diagnostic procedure. (see full text below).
snip...
so my quesion is, how low is 'low' in quantifing the infectious dose in vCJD, comparing to _all_ sporadic CJDs, from the different potential routes, sources, and infectivity dose?
will the titre of infectivity in every tissue and organ of all sporadic CJDs stay exact or constant, no matter what the infective dose, route and species may be? this is considering you don't buy the fact that sporadic CJDs 85%+ of _all_ CJDs, are a happen stance of bad luck, happen spontaneously without cause, and are one-in-a-million world wide, with no substantial surveillance to confirm this.
Diagnosis and Reporting of Creutzfeldt-Jakob Disease T. S. Singeltary, Sr; D. E. Kraemer; R. V. Gibbons, R. C. Holman, E. D. Belay, L. B. Schonberger
http://jama.ama-assn.org/issues/v285n6/ffull/jlt0214-2.html
and what of Dr. Prusiner et al recent work about tissue infectivity;
Prions in skeletal muscle
snip...
Our data demonstrate that factors in addition to the amount of PrP expressed determine the tropism of prions for certain tissues. That some muscles are intrinsically capable of accumulating substantial titers of prions is of particular concern. Because significant dietary exposure to prions might occur through the consumption of meat, even if it is largely free of neural and lymphatic tissue, a comprehensive effort to map the distribution of prions in the muscle of infected livestock is needed. Furthermore, muscle may provide a readily biopsied tissue from which to diagnose prion disease in asymptomatic animals and even humans.
snip...
http://www.pnas.org/cgi/content/abstract/99/6/3812?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=prusiner&author2=prusiner&titleabstract=prions+meat+tissue+mice&fulltext=prions+meat+tissue+mice&searchid=1024346978866_6016&stored_search=&FIRSTINDEX=0&fdate=1/1/2002
can the science/diagnostic measures used to date, measure this, and at the same time guarantee that no titre of infectivity exists from sporadic CJDs (all of the variants), from this potential mode and route of transmission?
i don't think so, this is just my opinion. this is why i get paid nothing, and these scientists get the big bucks. i just hope i am wrong and the big bucks are correct in their _hypothisis_ of this potential mode/route of transmission with endoscopy equipment, from _all_ human TSEs.
i understand we have to weigh the risks of what we know to what we don't know, to the disease we _may_ catch to what we are having the procedure for, but to categorically state at this present time of scientific knowledge;
snip...
"Gastrointestinal endoscopy is unlikely to be a vector for the transmission of sporadic CJD as infected tissue is not encountered during the procedure. No special precautions are necessary during or after the procedure and the endoscope should be cleaned and disinfected in the normal thorough way.4"
snip...
but, to categorically state this, in my opinion, is not only wrong, but potentially very dangerous to the future of human health...TSS
SHORT REPORT
Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth hormone
E A Croes, G Roks, G H Jansen, P C G Nijssen, C M van Duijn ...............................................................
J Neurol Neurosurg Psychiatry 2002;72:792-793
A 47 year old man is described who developed pathology proven Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human derived growth hormone (hGH) as part of a diagnostic procedure. The patient presented with a cerebellar syndrome, which is compatible with iatrogenic CJD. This is the longest incubation period described so far for iatrogenic CJD. Furthermore, this is the first report of CJD after diagnostic use of hGH. Since the patient was one of the first in the world to receive hGH, other cases of iatrogenic CJD can be expected in the coming years.
Prion diseases are potentially transmissible. Human to human transmission was first reported in 1974, when a 55 year old woman was described who developed symptoms of Creutzfeldt-Jakob disease (CJD) 18 months after a corneal transplant.1 Since then, transmission has been reported after stereotactic electroencephalographic (EEG) depth recording, human growth hormone (hGH) and gonadotrophin treatment, and dura mater transplantation.2-5 More than 267 patients with iatrogenic CJD are known today and their number is growing.6 The most important iatrogenic cause of CJD is still contaminated cadaveric hGH. Exposure to contaminated hGH occurred before 1985, when recombinant growth hormone became available. In a recent study, incubation periods in 139 patients with hGH associated CJD were found to range from 5-30 years, with a median of 12 years.6 One of the factors influencing incubation time is genotype on polymorphic codon 129 of the prion protein gene.7 The incubation time is significantly shorter in people who are homozygous for either methionine or valine on this polymorphism.7
We describe the second patient with hGH related CJD in the Netherlands. The patient developed the disease 38 years after hGH injections. To our knowledge, this is the longest incubation period described for any form of iatrogenic CJD. Further-more, our patient was not treated with hGH but only received a low dose as part of a diagnostic procedure.
CASE REPORT
This patient presented at the age of 47 years with paraesthesia in both arms for six months, difficulty with walking for four weeks, and involuntary movements of mainly the upper extremities of two weeks' duration. He did not notice any change in cognitive function, although his twin sister had noticed minor memory disturbances. There was no family history of neurological disease. During childhood the patient had experienced a growth delay compared with his twin sister and with the average in the Netherlands. When he was 9 years old, a nitrogen retention test with 6 IU hGH over five days was performed to exclude growth hormone deficiency. Since the result was not decisive, a quantitative amino acid test was performed, which measures 30 amino acids during fasting and one, two, and three hours after growth hormone injection. No abnormal amino acid concentrations were found making the diagnosis of primordial dwarfism most likely. Therefore, no treatment with hGH was given.
On neurological examination we found a slight dysarthria without aphasia. Cranial nerve function was normal. Walking was unstable and wide based. During movements of the upper extremities myoclonic jerks were present. Sensation, muscle tone, and strength were normal. Co-ordination was impaired in all four limbs with a disturbed balance. Tendon reflexes were brisk at the arms and increased at the legs with a clonus in the ankle reflex. Plantar responses were both normal. On the mini mental state examination, the patient scored 30/30. Routine laboratory investigation, thyroid function, vitamin concentrations (B-1, B-6, B-12, and E), and copper metabolism were normal. Admission EEG examination showed generalised arrhythmic slow activity with diffuse spikes and spike waves. EEG examination two months later showed a further slowing of the rhythm with bilateral diphasic sharp waves but was not typical for CJD. Cerebral magnetic resonance imaging was normal. Cerebrospinal fluid examination showed 1 cell/3 µl, normal glucose and protein concentrations, and a strongly positive 14-3-3 protein test. The patient was homozygous for methionine on the PRNP codon 129 polymorphism. On clinical grounds, CJD was diagnosed. Within one month the patient's condition deteriorated rapidly and because of severe disturbances in coordination and progressive myoclonus he became bedridden. An eye movement disorder developed with slow saccadic and dysmetric eye movements. Temperature became unstable with peaks of 39°C without an infectious focus, for which a disorder of autoregulation was presumed. Until a very advanced stage, cognitive function was intact. The patient died five months after admission. The diagnosis of CJD was confirmed at necropsy. The brain weighed 990 g and showed clear cortical and cerebellar atrophy. Spongiosis, neuronal loss, and gliosis were found predominantly in the putamen, caudate nucleus, and basotemporal and cerebellar cortex; the cerebellum was the most severely affected of these. Vacuoles ranged from 2-12 µm. No amyloid or Kuru plaques were found. Immunohistochemical staining (3F4 antibody 1:1000, Senetek, USA) was clearly positive for prion protein accumulation in a "synaptic" distribution. Most deposition was found in the stratum moleculare of the cerebellum.
DISCUSSION
We describe a 47 year old patient who developed pathology proven CJD 38 years after hGH injections. The patient was never treated with hGH but received a small dose as part of a diagnostic procedure. The onset of CJD was signalled by prodromal symptoms of paraesthesia followed by a rapidly progressive ataxia. The disease presentation and course with predominantly cerebellar and eye movement disorders are compatible with iatrogenic CJD caused by hGH treatment.6 8
Growth hormone treatment was first described in 1958 but hGH was not produced on a larger scale from human pituitary glands until the beginning of the 1960s. In the Netherlands growth hormone extraction started in 1963 and was soon centrally coordinated. Until 1979 growth hormone was extracted non-commercially from pituitaries by a pharmaceutical company. In 1971 commercial products also became available. Our patient was one of the first to receive hGH in the Netherlands but the origin of this product was not recorded. A causal relation can therefore not be established with full certainty, but coincidentally receiving growth hormone and developing this very rare disease is unlikely. Since the clinical course in this relatively young patient is in accordance with an iatrogenic cause, we think the probability is high that the hGH injections explain the development of CJD in this patient.
The first Dutch patient with hGH related CJD died in 1990. 9 During several periods from 1963 to 1969 she received intramuscular injections of hGH. During an unknown period the hGH was derived from South America. At age 39, 27 years after starting the treatment, she developed an ataxic gait, slurred speech, sensory disorders, and myoclonus, but her cognitive function remained normal. Postmortem examination of the brain confirmed the diagnosis of CJD.9 Following the identification of this patient, a retrospective study was started to trace all 564 registered hGH recipients who were treated before May 1985. Until January 1995, none of these was suspected of having CJD.10 Since 1993 prospective surveillance for all forms of human prion disease has been carried out in the Netherlands and, apart from the patient described above, a further two patients with iatrogenic CJD have been identified, who developed the disease after dura mater transplantation.11
An incubation period as long as 38 years had never been reported for iatrogenic CJD. Huillard d'Aignaux et al7 studied the incubation period in 55 patients with hGH related CJD in a cohort of 1361 French hGH recipients. The median incubation period was between 9 and 10 years. Under the most pessimistic model, the upper limit of the 95% confidence interval varied between 17 and 20 years. Although the infecting dose cannot be quantified, it can be speculated that the long incubation period in our patient is partly explained by the administration of a limited amount of hGH. This hypothesis is supported by experimental models, in which higher infecting doses usually produce shorter incubation periods.6 Since our patient was one of the first in the world to receive hGH, this case indicates that still more patients with iatrogenic CJD can be expected in the coming years. Another implication of our study is that CJD can develop even after a low dose of hGH. This case once more testifies that worldwide close monitoring of any form of iatrogenic CJD is mandatory.
ACKNOWLEDGEMENTS
We are grateful to M Jansen PhD MD for his search for the origin of the growth hormone and P P Taminiau MD. CJD surveillance in the Netherlands is carried out as part of the EU Concerted Action on the Epidemiology of CJD and the the EU Concerted Action on Neuropathology of CJD, both funded through the BIOMED II programme, and is supported by the Dutch Ministry of Health. This surveillance would not have been possible without the cooperation of all Dutch neurologists and geriatricians. ........................................
Authors' affiliations
E A Croes, G Roks*, C M van Duijn, Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands
P C G Nijssen, Department of Neurology, St Elisabeth Hospital, PO Box 90151, 5000 LC Tilburg, Netherlands
G H Jansen, Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
*Also the Department of Neurology, St Elisabeth Hospital
Correspondence to: Professor C M van Duijn, Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands; vanduijn@epib.fgg.eur.nl
Received 27 December 2001 In revised form 1 March 2002 Accepted 12 March 2002
Competing interests: none declared
REFERENCES
1 Duffy P, Wolf J, Collins G, et al. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974;290:692-3.
2 Bernoulli C, Siegfried J, Baumgartner G, et al. Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by surgery. Lancet 1977;i:478-9.
3 Koch TK, Berg BO, De Armond SJ, et al. Creutzfeldt-Jakob disease in a young adult with idiopathic hypopituitarism: possible relation to the administration of cadaveric human growth hormone. N Engl J Med 1985;313:731-3.
4 Cochius JI, Burns RJ, Blumbergs PC, et al. Creutzfeldt-Jakob disease in a recipient of human pituitary-derived gonadotrophin. Aust NZ J Med 1990;20:592-3.
5 Thadani V, Penar PL, Partington J, et al. Creutzfeldt-Jakob disease probably acquired from a cadaveric dura mater graft: case report. J Neurosurg 1988;69:766-9.
6 Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000;55:1075-81.
7 Huillard d'Aignaux J, Costagliola D, Maccario J, et al. Incubation period of Creutzfeldt-Jakob disease in human growth hormone recipients in France. Neurology 1999;53:1197-201.
8 Billette de Villemeur T, Deslys JP, Pradel A, et al. Creutzfeldt-Jakob disease from contaminated growth hormone extracts in France. Neurology 1996;47:690-5.
9 Roos RA, Wintzen AR, Will RG, et al. Een patiėnt met de ziekte van Creutzfeldt-Jakob na behandeling met humaan groeihormoon. Ned Tijdschr Geneeskd 1996;140:1190-3.
10 Wientjens DP, Rikken B, Wit JM, et al. A nationwide cohort study on Creutzfeldt-Jakob disease among human growth hormone recipients. Neuroepidemiology 2000;19:201-5.
11 Croes EA, Jansen GH, Lemstra AF, et al. The first two patients with dura mater associated Creutzfeldt-Jakob disease in the Netherlands. J Neurol 2001;248:877-81.
re-CJD after diagnostic use of human growth hormone
from a donor sourcing aspect, seems the record keeping here has a lot to be desired for, let us hope it has improved for recipients sake.
also, they speak of 'low dose fitting long incubation'. what about KURU still existing after some 40 years exposure had ceased. i don't believe in most instances the dose with kuru is low. just something else to ponder?
TSS
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12023427&dopt=Abstract
1: Ann Neurol 1999 Aug;46(2):224-33
Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.
Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
snip...
The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.
snip...
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10443888&dopt=Abstract
were not all CJDs, even nvCJD, just sporadic, until proven otherwise?
Terry S. Singeltary Sr., P.O. BOX 42, 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 To: lcamp@bmjgroup.com Subject: gutjnl_el;21 Terry S. Singeltary Sr. (3 Jun 2002) "CJDs (all human TSEs) and Endoscopy Equipment"
----------------------------------------------------------------- Date submitted: 3 Jun 2002 eLetter ID: gutjnl_el;21
Gut eLetter for Bramble and Ironside 50 (6): 888 ----------------------------------------------------------------- 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) http://www.gutjnl.com/cgi/content/abstract/50/6/888 http://www.gutjnl.com/cgi/content/full/50/6/888 ----------------------------------------------------------------- "CJDs (all human TSEs) and Endoscopy Equipment" -----------------------------------------------------------------
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
=====2018 and 2019=====
JUST OUT CDC;
Tuesday, November 20, 2018
Eyes of CJD patients show evidence of prions Finding could help early diagnosis, raise concern for eye exams and transplants.
Singeltary 1999
***> THE EYES HAVE IT, CJD, AND THEY COULD BE STEALING THEM FROM YOUR LOVED ONE!...year 1999
i said that 20 years ago about this very thing. but did anyone listen...no!
prepare for the storm...terry
year 1999 to 2000
Subject: RE-The Eyes Have It (cjd) and they could be stealing them from your loved one... "pay back time"
Date: Sat, 16 Sep 2000 10:04:26 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
Greetings List Members,
I hate to keep kicking a madcow, but this still is very disturbing to me. Not only for the recipient of the cornea's, but as well, for the people whom would be operated on, using the same tools that were used to put those stolen cornea's in the recipient with. No history of this donor or his family (re-ffi), or anything would be known, using stolen organs and or tissue's. I just think this is not only wrong, but very dangerous to a great many other people, as this is one of the most infectious tissues of TSE's. It seems that this practice of stealing organ/tissue happens more than we think. Anyway, the family of the victim which had their cornea's stolen, are now suing. In the example I used with my Mother, if 3 months before, she would have been in a catastrophic accident (car wreck, whatever), no autopsy (for whatever reason), no family (for whatever reason), she lay in the morgue, and after 4 hours, they come steal the cornea's, lot of people could have been infected, just because of lack of medical history of donor/family. It may be hypothetical, but very real. We need to stop the spread of this disease.
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
===========================================
Previous story--
Cadaver corneal transplants -- without family permission...
Cadaver corneal transplants -- without family permission Houston, Texas channel 11 news 28 Nov 99
Reported by Terry S. Singeltary Sr.son of CJD victim
"It was a story about how the Lions eye bank were harvesting corneas from victims in the Morgue, without their consent. Under Texas law, this appears to be legal (remember Texas has the Veggie liable law). Even if Family says no, this appears to happen, from what the news story said.
They said the only way to prevent this, is to fill out a form, stating not to have this done. So if you don't fill out the form, they can do this. How many people don't know about the form?
This is not only disgusting and appalling, it could be highly infectious. Without proper background checking of the donors, on their physical history, checking on past dementia, and/or family history, some of these unfortunate victims, could be passing a human TSE.
Response Jill Spitler Clevelland Eye Bank:
"No, we are not stealing.........Yes, you do have such a law in the state of Texas, but not all your state Eye Banks utilize the law. The Eye Bank that you're speaking of is only one of 43 certified Eye Bank throughout the USA.
And there are measure taken per the Medical Standards of the Eye Bank Association of America, the certifying body for eye banks and per FDA regulations to address those concerns that you speak of.
I would suggest that those interested/concern with transplant contact their local agencies. The Eye Bank Association of America has a web. site . Further if anyone has problems contacting or finding out about their local organization(s), call me or e-mail me I would be glad to help. My e-mail address is jill@clevelandeyebank.org"
Terry Singeltary responds:
"Explain this to the family in Houston who went to their loved ones funeral, only to find out that the loved one that was in the casket, had their corneas removed without their permission, without the consent of the victim or it's family. They would not have known it, only for the funny look the victim had. So, they questioned, only to find out, the corneas, had in fact, been removed without consent.
I call that stealing, regardless what the law states. This type of legal grave robbing is not a logical thing to do without knowing any type of background of the victims medical past, which really will not prove anything due to the incubation period. Eye tissue being potentially a highly infective source, there are risks here.
Should they not at least know of the potential ramifications of TSE's (the person receiving the corneas)?
Should there not be some sort of screening?
Should there be some sort of moral issue here?
If this is the case, and in fact, they can come take your corneas, without your consent, then what will they start taking next, without your consent?
Lets look at a hypothetical situation:
What would happen if my Mom (DOD 12-14-97 hvCJD) would have gotten into a car wreck and died, before the symptoms of CJD appeared. Not much money, so there was no autopsy. What would have happened to that recipient of those infecting corneas?"
Comment (webmaster): Actual transmission of CJD by means of corneal transplant may or may not be rare. The incidence of infectivity in older people could be fairly high; this is not to be confused with the lower incidence of symptomatic (clinical) CJD. It is very unlikely that familial CJD would have been diagnosed in earlier generations; however, without interviewing the family even known kindreds would not be excluded.
In blood donation, a much stricter policy is followed, even though corneal transplant may be far more dangerous (being a direct link to the brain and not going through purification steps).
Since highly sensitive tests for pre-clinical CJD are now available, it would make sense to screen corneas for CJD, just as they are screened for AIDS, hepatitus, and a host of other conditions.
Eye procedure raises CJD concerns
BySTEVE MITCHELL, Medical Correspondent
WASHINGTON, Nov. 18 (UPI) -- A New York man who died from a rare brain disorder similar to mad cow disease in May underwent an eye procedure prior to his death that raises concerns about the possibility of transmitting the fatal disease to others, United Press International has learned.
The development comes on the heels of the announcement Thursday by U.S. Department of Agriculture officials of a possible second case of mad cow disease in U.S. herds.
Richard Da Silva, 58, of Orange County, N.Y., died from Creutzfeldt Jakob disease, an incurable brain-wasting illness that strikes about one person per million.
Richard's wife Ann Marie Da Silva told UPI he underwent a check for the eye disease glaucoma in 2003, approximately a year before his death. The procedure involves the use of a tonometer, which contacts the cornea -- an eye tissue that can contain prions, the infectious agent thought to cause CJD.
Ann Marie's concern is that others who had the tonometer used on them could have gotten infected.
A 2003 study by British researchers suggests her concerns may be justified. A team led by J.W. Ironside from the National Creutzfeldt-Jakob Disease Surveillance Unit at the University of Edinburgh examined tonometer heads and found they can retain cornea tissue that could infect other people -- even after cleaning and decontaminating the instrument.
"Retained corneal epithelial cells, following the standard decontamination routine of tonometer prisms, may represent potential prion infectivity," the researchers wrote in the British Journal of Ophthalmology last year. "Once the infectious agent is on the cornea, it could theoretically infect the brain."
Prions, misfolded proteins thought to be the cause of mad cow, CJD and similar diseases, are notoriously difficult to destroy and are capable of withstanding most sterilization procedures.
Laura Manuelidis, an expert on these diseases and section chief of surgery in the neuropathology department at Yale University, agreed with the British researchers that tonometers represent a potential risk of passing CJD to other people.
Manuelidis told UPI she has been voicing her concern about the risks of corneas since 1977 when her own study, published in the New England Journal of Medicine, showed the eye tissue, if infected, could transmit CJD.
At the time the procedure was done on Richard Da Silva, about a year before he died, she said it was "absolutely" possible he was infectious.
The CJD Incidents Panel, a body of experts set up by the U.K. Department of Health, noted in a 2001 report that procedures involving the cornea are considered medium risk for transmitting CJD. The first two patients who have a contaminated eye instrument used on them have the highest risk of contracting the disease, the panel said.
In 1999, the U.K. Department of Health banned opticians from reusing equipment that came in contact with patients' eyes out of concern it could result in the transmission of variant CJD, the form of the disease humans can contract from consuming infected beef products.
Richard Da Silva was associated with a cluster of five other cases of CJD in southern New York that raised concerns about vCJD.
None of the cases have been determined to stem from mad cow disease, but concerns about the cattle illness in the United States could increase in light of the USDA announcement Thursday that a cow tested positive on initial tests for the disease. If confirmed, this would be the second U.S. case of the illness; the first was detected in a Washington cow last December. The USDA said the suspect animal disclosed Thursday did not enter the food chain. The USDA did not release further details about the cow, but said results from further lab tests to confirm the initial tests were expected within seven days.
Ann Marie Da Silva said she informed the New York Health Department and later the eye doctor who performed the procedure about her husband's illness and her concerns about the risk of transmitting CJD via the tonometer.
The optometrist -- whom she declined to name because she did not want to jeopardize his career -- "didn't even know what this disease was," she said.
"He said the health department never called him and I called them (the health department) back and they didn't seem concerned about it," she added. "I just kept getting angrier and angrier when I felt I was being dismissed."
She said the state health department "seems to have an attitude of don't ask, don't tell" about CJD.
"There's a stigma attached to it," she said. "Is it because they're so afraid the public will panic? I don't know, but I don't think that the answer is to push things under the rug."
New York State Department of Health spokeswoman Claire Pospisil told UPI she would look into whether the agency was concerned about the possibility of transmitting CJD via tonometers, but she had not called back prior to story publication.
Disposable tonometers are readily available and could avoid the risk of transmitting the disease, Ironside and colleagues noted in their study. Ann Marie Da Silva said she asked the optometrist whether he used disposable tonometers and "he said 'No, it's a reusable one.'"
Ironside's team also noted other ophthalmic instruments come into contact with the cornea and could represent a source of infection as they are either difficult to decontaminate or cannot withstand the harsh procedures necessary to inactivate prions. These include corneal burrs, diagnostic and therapeutic contact lenses and other coated lenses.
Terry Singletary, whose mother died from a type of CJD called Heidenhain Variant, told UPI health officials were not doing enough to prevent people from being infected by contaminated medical equipment.
"They've got to start taking this disease seriously and they simply aren't doing it," said Singletary, who is a member of CJD Watch and CJD Voice -- advocacy groups for CJD patients and their families.
U.S. Centers for Disease Control and Prevention spokeswoman Christine Pearson did not return a phone call from UPI seeking comment. The agency's Web site states the eye is one of three tissues, along with the brain and spinal cord, that are considered to have "high infectivity."
The Web site said more than 250 people worldwide have contracted CJD through contaminated surgical instruments and tissue transplants. This includes as many as four who were infected by corneal grafts. The agency noted no such cases have been reported since 1976, when sterilization procedures were instituted in healthcare facilities.
Ironside and colleagues noted in their study, however, many disinfection procedures used on optical instruments, such as tonometers, fail. They wrote their finding of cornea tissue on tonometers indicates that "no current cleaning and disinfection strategy is fully effective."
Singletary said CDC's assertion that no CJD cases from infected equipment or tissues have been detected since 1976 is misleading.
"They have absolutely no idea" whether any cases have occurred in this manner, he said, because CJD cases often aren't investigated and the agency has not required physicians nationwide report all cases of CJD.
"There's no national surveillance unit for CJD in the United States; people are dying who aren't autopsied, the CDC has no way of knowing" whether people have been infected via infected equipment or tissues, he said.
Ann Marie Da Silva said she has contacted several members of her state's congressional delegation about her concerns, including Rep. Sue Kelly, R-N.Y., and Sen. Charles Schumer, D-N.Y.
"Basically, what I want is to be a positive force in this, but I also want more of a dialogue going on with the public and the health department," she said.
Friday, December 04, 2009
New guidance on decontamination of trial contact lenses and other contact devices has been revealed for CJD AND vCJD
SUNDAY, JANUARY 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
TUESDAY, NOVEMBER 20, 2018
CDC Eyes of CJD patients show evidence of prions concerns for iatrogenic transmission
https://creutzfeldt-jakob-disease.blogspot.com/2018/11/cdc-eyes-of-cjd-patients-show-evidence.html
Wednesday, January 16, 2019
***> Early preclinical detection of prions in the skin of prion-infected animals
snip...see much more here:
FRIDAY, MARCH 30, 2018
Detection of Creutzfeldt-Jakob disease prions in skin: implications for healthcare
WEDNESDAY, NOVEMBER 22, 2017
NIH scientists and collaborators find infectious prion protein in skin of CJD patients
WEDNESDAY, NOVEMBER 22, 2017
Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease
TUESDAY, JUNE 20, 2017
Prion 2017 Conference
Transmissible prions in the skin of Creutzfeldt-Jakob disease patients
Prion 2017 Conference Transmissible prions in the skin of Creutzfeldt-Jakob disease patients
Dr. Wenguan Zou1, Dr. Christina Orru2, Jue Yuan1, Brian Appleby1, Baiya Li1, Dane Winner1, Yian Zhan1,3, Mark Rodgers1, Jason Rarick1, Robert Wyza1, Tripti Joshi1, Gongxian Wang3, Mark Cohen1, Shulin Zhang1, Bradley Groveman2, Robert Petersen1, James Ironside4, Miguel Quinones-Mateu1, Jiri Safar1, Qingzhong Kong1, Byron Caughey2
1Case Western Reserve University, Cleveland, United States, 2Rocky Mountain Laboratories, National Institutes of Health, Hamilton, United States, 3Nanchang University, Nanchang, China, 4Universitv of Edinburgh, Edinburgh, United Kingdom
Aims: Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible by neuroinvasive iatrogenic routes due to abundant prion infectivity in the central nervous system (CNS). The disease-associated prion protein (PrPSc) and its infectivity have never been detected in skin from sCJD patients; however, some epidemiological studies have associated sCJD risk with skin-involved non-CNS surgeries. The aims of our study were to explore potential prion seeding activity and infectivity of skin and the feasibility of skin-based CJD diagnosis.
Methods: Skin samples were collected at autopsy or biopsy from twenty-one sCJD, two variant CJD, and fifteen non-CJD patients and analysed by Western blotting and real-time quaking-induced conversion (RT- QulC) for PrPSc. Infectivity of skin from two sCJD patients was determined by bioassay using two lines of humanized transgenic (Tg) mice.
Results: Western blotting demonstrated PrPSc in the skin of one of five deceased sCJD patients examined. However, the more sensitive RT-QuIC assay detected prion-seeding activity in skin from all 23 CJD decedents but not in non-CJD controls, indicating preliminary ClD diagnostic sensitivities and specificities of 100% (95% confidence intervals of 85-100%, and 78-100%, respectively). Although sCJD skins contained ~102-105-fold lower RT-QuIC seeding activity than sCJD brains, ten out of twelve mice from two Tg mouse lines inoculated with skin homogenates of two patients with two different subtypes of sCJD succumbed to prion disease within 450 days after inoculation.
Conclusions: sCJD patients' skin may contain both detectable prion seeding activity and transmissible prions. Our findings not only suggest a new basis for diagnostic sCJD testing, but also raise concerns about the potential for iatrogenic sCJD transmission via skin. (Funded by the CJD Foundation, the National Institute of Neurological Disorders and Stroke, the Centers for Disease Control and Prevention, as well as others)
DISORDERS PRION 2017 DECIPHERING NEURODEGENERATIVE
MONDAY, NOVEMBER 19, 2018
Benefit cuts hit mad cow disease sufferer A girl born severely disabled from vCJD may lose her home under universal credit
2006-2007
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory
TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption.
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.
With all the science to date refuting it, to continue to validate this myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, surgical, blood, medical, cosmetics etc.
I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down.
Accumulation and Transmission are key to the threshold from subclinical to clinical disease, and of that, I even believe that physical and or blunt trauma may play a role of onset of clinical symptoms in some cases, but key to all this, is to stop the amplification and transmission of this agent, the spreading of, no matter what strain.
BUT, to continue with this myth that the U.K. strain of BSE one strain in cows, and the nv/v CJD, one strain in humans, and that all the rest of human TSE is one single strain i.e. sporadic CJD (when to date there are 6 different phenotypes of sCJD), and that no other animal TSE transmits to humans, to continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come.
ONE was enough for me, My Mom, hvCJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human.
WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE?
Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE.
There must be a proper classification that will differentiate between all these human TSE in order to do this.
With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously.
My name is Terry S. Singeltary Sr. and I am no scientist, no doctor and have no PhDs, but have been independently researching human and animal TSEs since the death of my Mother to the Heidenhain Variant of Creutzfeldt Jakob Disease on December 14, 1997 'confirmed'.
...END
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor:
In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
BRITISH MEDICAL JOURNAL
BMJ
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well....
02 January 2000
Terry S Singeltary
retired
US scientists develop a possible test for BSE
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7220.1312b (Published 13 November 1999) Cite this as: BMJ 1999;319:1312
Rapid responses Response
Re: vCJD in the USA * BSE in U.S.
15 November 1999
Terry S Singeltary
NA
medically retired
January 28, 2003; 60 (2) VIEWS & REVIEWS
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Ermias D. Belay, Ryan A. Maddox, Pierluigi Gambetti, Lawrence B. Schonberger
First published January 28, 2003, DOI: https://doi.org/10.1212/01.WNL.0000036913.87823.D6
Abstract
Transmissible spongiform encephalopathies (TSEs) attracted increased attention in the mid-1980s because of the emergence among UK cattle of bovine spongiform encephalopathy (BSE), which has been shown to be transmitted to humans, causing a variant form of Creutzfeldt-Jakob disease (vCJD). The BSE outbreak has been reported in 19 European countries, Israel, and Japan, and human cases have so far been identified in four European countries, and more recently in a Canadian resident and a US resident who each lived in Britain during the BSE outbreak. To monitor the occurrence of emerging forms of CJD, such as vCJD, in the United States, the Centers for Disease Control and Prevention has been conducting surveillance for human TSEs through several mechanisms, including the establishment of the National Prion Disease Pathology Surveillance Center. Physicians are encouraged to maintain a high index of suspicion for vCJD and use the free services of the pathology center to assess the neuropathology of clinically diagnosed and suspected cases of CJD or other TSEs.
Received May 7, 2002. Accepted August 28, 2002.
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
Published March 26, 2003
26 March 2003
Terry S. Singeltary, retired (medically) CJD WATCH
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
Reply to Singletary Ryan A. Maddox, MPH Other Contributors: Published March 26, 2003
Mr. Singletary raises several issues related to current Creutzfeldt- Jakob disease (CJD) surveillance activities. Although CJD is not a notifiable disease in most states, its unique characteristics, particularly its invariably fatal outcome within usually a year of onset, make routine mortality surveillance a useful surrogate for ongoing CJD surveillance.[1] In addition, because CJD is least accurately diagnosed early in the course of illness, notifiable-disease surveillance could be less accurate than, if not duplicative of, current mortality surveillance.[1] However, in states where making CJD officially notifiable would meaningfully facilitate the collection of data to monitor for variant CJD (vCJD) or other emerging prion diseases, CDC encourages the designation of CJD as a notifiable disease.[1] Moreover, CDC encourages physicians to report any diagnosed or suspected CJD cases that may be of special public health importance (e.g., vCJD, iatrogenic CJD, unusual CJD clusters).
As noted in our article, strong evidence is lacking for a causal link between chronic wasting disease (CWD) of deer and elk and human disease,[2] but only limited data seeking such evidence exist. Overall, the previously published case-control studies that have evaluated environmental sources of infection for sporadic CJD have not consistently identified strong evidence for a common risk factor.[3] However, the power of a case-control study to detect a rare cause of CJD is limited, particularly given the relatively small number of subjects generally involved and its long incubation period, which may last for decades. Because only a very small proportion of the US population has been exposed to CWD, a targeted surveillance and investigation of unusual cases or case clusters of prion diseases among persons at increased risk of exposure to CWD is a more efficient approach to detecting the possible transmission of CWD to humans. In collaboration with appropriate local and state health departments and the National Prion Disease Pathology Surveillance Center, CDC is facilitating or conducting such surveillance and case- investigations, including related laboratory studies to characterize CJD and CWD prions.
Mr. Singletary also expresses concern over a recent publication by Asante and colleagues indicating the possibility that some sporadic CJD cases may be attributable to bovine spongiform encephalopathy (BSE).[4] The authors reported that transgenic mice expressing human prion protein homozygous for methionine at codon 129, when inoculated with BSE prions, developed a molecular phenotype consistent with a subtype of sporadic CJD. Although the authors implied that BSE might cause a sporadic CJD-like illness among persons homozygous for methionine, the results of their research with mice do not necessarily directly apply to the transmission of BSE to humans. If BSE causes a sporadic CJD-like illness in humans, an increase in sporadic CJD cases would be expected to first occur in the United Kingdom, where the vast majority of vCJD cases have been reported. In the United Kingdom during 1997 through 2002, however, the overall average annual mortality rate for sporadic CJD was not elevated; it was about 1 case per million population per year. In addition, during this most recent 6-year period following the first published description of vCJD in 1996, there was no increasing trend in the reported annual number of UK sporadic CJD deaths.[3, 5] Furthermore, surveillance in the UK has shown no increase in the proportion of sporadic CJD cases that are homozygous for methionine (Will RG, National CJD Surveillance Unit, United Kingdom, 2003; personal communication).
References
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Diagnosis and reporting of Creutzfeldt-Jakob disease. JAMA 2001;285:733-734.
2. Belay ED, Maddox RA, Gambetti P, Schonberger LB. Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States. Neurology 2003;60:176-181.
3. Belay ED. Transmissible spongiform encephalopathies in humans. Annu Rev Microbiol 1999;53:283-314.
4. Asante EA, Linehan JM, Desbruslais M, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 2002;21:6358-6366.
5. The UK Creutzfeldt-Jakob Disease Surveillance Unit. CJD statistics. Available at: http://www.cjd.ed.ac.uk/figures.htm. Accessed February 18, 2003.
Competing Interests: None declared.
doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem..” ............................
MONDAY, JANUARY 21, 2019
Bovine Spongiform Encephalopathy BSE TSE Prion Surveillance FDA USDA APHIS FSIS UPDATE 2019
Texas Chronic Wasting Disease CWD TSE Prion Symposium 2018 posted January 2019 VIDEO SET 18 CLIPS
See Wisconsin update...terrible news, right after Texas updated map around 5 minute mark...
update on Wisconsin from Tammy Ryan...
SATURDAY, JANUARY 19, 2019
Texas Chronic Wasting Disease CWD TSE Prion Symposium 2018 posted January 2019 VIDEO SET 18 CLIPS
think of the iatrogenic risk factors there from, of all of the above over the next 50 years?
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***
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***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...
Discussion We describe the transmission of spongiform encephalopathy in a non-human primate inoculated 10 years earlier with a strain of sheep c-scrapie. Because of this extended incubation period in a facility in which other prion diseases are under study, we are obliged to consider two alternative possibilities that might explain its occurrence. We first considered the possibility of a sporadic origin (like CJD in humans). Such an event is extremely improbable because the inoculated animal was 14 years old when the clinical signs appeared, i.e. about 40% through the expected natural lifetime of this species, compared to a peak age incidence of 60–65 years in human sporadic CJD, or about 80% through their expected lifetimes. 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.
The second possibility is a laboratory cross-contamination. Three facts make this possibility equally unlikely. First, handling of specimens in our laboratory is performed with fastidious attention to the avoidance of any such cross-contamination. Second, no laboratory cross-contamination has ever been documented in other primate laboratories, including the NIH, even between infected and uninfected animals housed in the same or adjacent cages with daily intimate contact (P. Brown, personal communication). Third, the cerebral lesion profile is different from all the other prion diseases we have studied in this model19, with a correlation between cerebellar lesions (massive spongiform change of Purkinje cells, intense PrPres staining and reactive gliosis26) and ataxia. The iron deposits present in the globus pallidus are a non specific finding that have been reported previously in neurodegenerative diseases and aging27. Conversely, the thalamic lesion was reminiscent of a metabolic disease due to thiamine deficiency28 but blood thiamine levels were within normal limits (data not shown). The preferential distribution of spongiform change in cortex associated with a limited distribution in the brainstem is reminiscent of the lesion profile in MM2c and VV1 sCJD patients29, but interspecies comparison of lesion profiles should be interpreted with caution. It is of note that the same classical scrapie isolate induced TSE in C57Bl/6 mice with similar incubation periods and lesional profiles as a sample derived from a MM1 sCJD patient30.
We are therefore confident that the illness in this cynomolgus macaque represents a true transmission of a sheep c-scrapie isolate directly to an old-world monkey, which taxonomically resides in the primate subdivision (parvorder of catarrhini) that includes humans. With an homology of its PrP protein with humans of 96.4%31, cynomolgus macaque constitutes a highly relevant model for assessing zoonotic risk of prion diseases. Since our initial aim was to show the absence of transmission of scrapie to macaques in the worst-case scenario, we obtained materials from a flock of naturally-infected sheep, affecting animals with different genotypes32. This c-scrapie isolate exhibited complete transmission in ARQ/ARQ sheep (332 ± 56 days) and Tg338 transgenic mice expressing ovine VRQ/VRQ prion protein (220 ± 5 days) (O. Andreoletti, personal communication). From the standpoint of zoonotic risk, it is important to note that sheep with c-scrapie (including the isolate used in our study) have demonstrable infectivity throughout their lymphoreticular system early in the incubation period of the disease (3 months-old for all the lymphoid organs, and as early as 2 months-old in gut-associated lymph nodes)33. In addition, scrapie infectivity has been identified in blood34, milk35 and skeletal muscle36 from asymptomatic but scrapie infected small ruminants which implies a potential dietary exposure for consumers.
Two earlier studies have reported the occurrence of clinical TSE in cynomolgus macaques after exposures to scrapie isolates. In the first study, the “Compton” scrapie isolate (derived from an English sheep) and serially propagated for 9 passages in goats did not transmit TSE in cynomolgus macaque, rhesus macaque or chimpanzee within 7 years following intracerebral challenge1; conversely, after 8 supplementary passages in conventional mice, this “Compton” isolate induced TSE in a cynomolgus macaque 5 years after intracerebral challenge, but rhesus macaques and chimpanzee remained asymptomatic 8.5 years post-exposure8. However, multiple successive passages that are classically used to select laboratory-adapted prion strains can significantly modify the initial properties of a scrapie isolate, thus questioning the relevance of zoonotic potential for the initial sheep-derived isolate. The same isolate had also induced disease into squirrel monkeys (new-world monkey)9. A second historical observation reported that a cynomolgus macaque developed TSE 6 years post-inoculation with brain homogenate from a scrapie-infected Suffolk ewe (derived from USA), whereas a rhesus macaque and a chimpanzee exposed to the same inoculum remained healthy 9 years post-exposure1. This inoculum also induced TSE in squirrel monkeys after 4 passages in mice. Other scrapie transmission attempts in macaque failed but had more shorter periods of observation in comparison to the current study. Further, it is possible that there are differences in the zoonotic potential of different scrapie strains.
The most striking observation in our study is the extended incubation period of scrapie in the macaque model, which has several implications. Firstly, our observations constitute experimental evidence in favor of the zoonotic potential of c-scrapie, at least for this isolate that has been extensively studied32,33,34,35,36. The cross-species zoonotic ability of this isolate should be confirmed by performing duplicate intracerebral exposures and assessing the transmissibility by the oral route (a successful transmission of prion strains through the intracerebral route may not necessarily indicate the potential for oral transmission37). However, such confirmatory experiments may require more than one decade, which is hardly compatible with current general management and support of scientific projects; thus this study should be rather considered as a case report.
Secondly, transmission of c-BSE to primates occurred within 8 years post exposure for the lowest doses able to transmit the disease (the survival period after inoculation is inversely proportional to the initial amount of infectious inoculum). The occurrence of scrapie 10 years after exposure to a high dose (25 mg) of scrapie-infected sheep brain suggests that the macaque has a higher species barrier for sheep c-scrapie than c-BSE, although it is notable that previous studies based on in vitro conversion of PrP suggested that BSE and scrapie prions would have a similar conversion potential for human PrP38.
Thirdly, prion diseases typically have longer incubation periods after oral exposure than after intracerebral inoculations: since humans can develop Kuru 47 years after oral exposure39, an incubation time of several decades after oral exposure to scrapie would therefore be expected, leading the disease to occur in older adults, i.e. the peak age for cases considered to be sporadic disease, and making a distinction between scrapie-associated and truly sporadic disease extremely difficult to appreciate.
Fourthly, epidemiologic evidence is necessary to confirm the zoonotic potential of an animal disease suggested by experimental studies. A relatively short incubation period and a peculiar epidemiological situation (e.g., all the first vCJD cases occurring in the country with the most important ongoing c-BSE epizootic) led to a high degree of suspicion that c-BSE was the cause of vCJD. Sporadic CJD are considered spontaneous diseases with an almost stable and constant worldwide prevalence (0.5–2 cases per million inhabitants per year), and previous epidemiological studies were unable to draw a link between sCJD and classical scrapie6,7,40,41, even though external causes were hypothesized to explain the occurrence of some sCJD clusters42,43,44. However, extended incubation periods exceeding several decades would impair the predictive values of epidemiological surveillance for prion diseases, already weakened by a limited prevalence of prion diseases and the multiplicity of isolates gathered under the phenotypes of “scrapie” and “sporadic CJD”.
Fifthly, considering this 10 year-long incubation period, together with both laboratory and epidemiological evidence of decade or longer intervals between infection and clinical onset of disease, no premature conclusions should be drawn from negative transmission studies in cynomolgus macaques with less than a decade of observation, as in the aforementioned historical transmission studies of scrapie to primates1,8,9. Our observations and those of others45,46 to date are unable to provide definitive evidence regarding the zoonotic potential of CWD, atypical/Nor98 scrapie or H-type BSE. The extended incubation period of the scrapie-affected macaque in the current study also underscores the limitations of rodent models expressing human PrP for assessing the zoonotic potential of some prion diseases since their lifespan remains limited to approximately two years21,47,48. This point is illustrated by the fact that the recently reported transmission of scrapie to humanized mice was not associated with clinical signs for up to 750 days and occurred in an extreme minority of mice with only a marginal increase in attack rate upon second passage13. The low attack rate in these studies is certainly linked to the limited lifespan of mice compared to the very long periods of observation necessary to demonstrate the development of scrapie. Alternatively, one could estimate that a successful second passage is the result of strain adaptation to the species barrier, thus poorly relevant of the real zoonotic potential of the original scrapie isolate of sheep origin49. The development of scrapie in this primate after an incubation period compatible with its lifespan complements the study conducted in transgenic (humanized) mice; taken together these studies suggest that some isolates of sheep scrapie can promote misfolding of the human prion protein and that scrapie can develop within the lifespan of some primate species.
In addition to previous studies on scrapie transmission to primate1,8,9 and the recently published study on transgenic humanized mice13, our results constitute new evidence for recommending that the potential risk of scrapie for human health should not be dismissed. Indeed, human PrP transgenic mice and primates are the most relevant models for investigating the human transmission barrier. To what extent such models are informative for measuring the zoonotic potential of an animal TSE under field exposure conditions is unknown. 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.
THURSDAY, OCTOBER 04, 2018
Cervid to human prion transmission 5R01NS088604-04 Update
Saturday, December 15, 2018
***> ADRD Summit RFI Singeltary COMMENT SUBMISSION BSE, SCRAPIE, CWD, AND HUMAN TSE PRION DISEASE December 14, 2018
Terry S. Singeltary Sr., Bacliff, Texas USA 77518, Galveston Bay...on the bottom...flounder9@verizon.net