Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation
Nadège Bourvis1,2, Pierre-Yves Boelle1,2,3, Jean-Yves Cesbron4,5,6, Alain-Jacques Valleron1,2,3*
1 Université Pierre et Marie Curie-Paris6, Unité de Recherche Epidémiologie-Systèmes d'information-Modélisation, UMR S 707, Paris, France, 2 INSERM, U707, Paris, France, 3 Assistance Publique-Hôpitaux de Paris (AP-HP), Unité de Santé Publique, Hôpital St Antoine, Paris, France, 4 Laboratoire Adaptation et de Pathogénie des Micro-organismes, Université Joseph Fourier, UMR 5163, Grenoble, France, 5 Centre National de la Recherche Scientifique (CNRS), UMR 5163, Grenoble, France, 6 Centre hospitalier universitaire (CHU) de Grenoble, Laboratoire d'Immunologie, Grenoble, France
Experimental results evidenced the infectious potential of the dental pulp of animals infected with transmissible spongiform encephalopathies (TSE). This route of iatrogenic transmission of sporadic Creutzfeldt-Jakob disease (sCJD) may exist in humans via reused endodontic instruments if inadequate prion decontamination procedures are used.
To assess this risk, 10 critical parameters in the transmission process were identified, starting with contamination of an endodontic file during treatment of an infectious sCJD patient and ending with possible infection of a subsequent susceptible patient. It was assumed that a dose-risk response existed, with no-risk below threshold values. Plausible ranges of those parameters were obtained through literature search and expert opinions, and a sensitivity analysis was conducted. Without effective prion-deactivation procedures, the risk of being infected during endodontic treatment ranged between 3.4 and 13 per million procedures. The probability that more than one case was infected secondary to endodontic treatment of an infected sCJD patient ranged from 47% to 77% depending on the assumed quantity of infective material necessary for disease transmission. If current official recommendations on endodontic instrument decontamination were strictly followed, the risk of secondary infection would become quasi-null.
The risk of sCJD transmission through endodontic procedure compares with other health care risks of current concern such as death after liver biopsy or during general anaesthesia. These results show that single instrument use or adequate prion-decontamination procedures like those recently implemented in dental practice must be rigorously enforced.
The results of this modelling approach show that the risk of sCJD transmission due to the reuse of instruments during ET may not be ignored in absence of effective prion-decontamination procedures.
How should our conclusions be used in a public health assessment? First note that this risk is already of concern to national health agencies as well as to health professionals –. Our work makes it possible to go beyond a qualitative assessment, towards more quantitative predictions where all hypotheses are clearly stated. The conclusions of this approach may easily be updated as new data accrue.
The details of ET were obtained from the latest official reports in France and UK or from experts. We conducted a literature search to collect the best estimates available of the possible quantities of infectious material left on the instruments, and subsequently partially removed by the classical disinfection procedures used until the last years of the 20th century. We obtained similarly estimates of the values of brain infectivity and of the ratio of brain infectivity to pulp infectivity. These parameters were obtained from animal experiments as they are clearly unknown in humans.
A comparable approach can be found in the HPA report on vCJD transmission in dentistry with two notable differences . First, the route of instrument contamination and subsequent transmission considered in the HPA report was a very rare accidental process: the abrasion of tonsillar tissue during dental care. On the contrary, we considered the process of accessing the dental pulp during ET as certain, which obviously leads to a higher risk. Second, the HPA report considered infectivity of tonsils to be 106–107 i/c ID50 per gram, while we used dental pulp with a slightly lower range of infectivity from 104-106i/c ID50 per gram ( = BI* BPR).
The hypotheses we used concerning the relationship between the estimated inoculums and the probability of infection are obviously critical. In our assessment, we postulated that too small an inoculum (below 10-1 and 10-2 ID50 were considered with functions ?1 and ?2) would not lead to infection, and that there was a linear dose–response relationship above this threshold. This effectively complies with the “zero risk below a threshold” hypothesis rather than with the “single infectious particle” hypothesis. There is indeed experimental evidence that even very small quantities of infectious material may trigger infection in mice , , and this hypothesis was previously used in assessing decontamination procedures. However, we adopted a more conservative risk estimate.
The duration of the infectious period of CJD is unknown but could be very long. We used as a reference the incubation period estimated from hGH iatrogenic cases . To make comparison easier, and for want of better or more recent evidence, the duration of the infectious period relative to incubation was the same as in the HPA report, i.e. 40% of the incubation period .
Our risk assessment should have used the prevalence of infectious sCJD in those undergoing ET instead of that in the general population. Presumably, the former is the largest and the risk was therefore minimized. Indeed, children, who do not develop sCJD are taken into account in the general population estimate, when that in ET patients concerns only adults.
The ranges of values of risk assessment generated with our model were broad. They mirror the current lack of knowledge and the uncertainties concerning data and hypotheses. However, our model makes it clear that the ET of the 20th century were not risk-free in terms of CJD. Therefore, our model suggests that patients may well have been contaminated at the end of 20th century, and still be in the latency period and at risk of transmitting the disease.
The estimated individual risk of sCJD transmission during ET was low in our assessment. However, these values compared with the mortality rates in general anaesthesia , transcutaneous liver biopsy  or voluntary abortion  which are of concern in the modern health care.
We also studied the possible impact of ET at a population level and showed that there was a high probability that the reproduction rate R exceeded 1 in the absence of effective prion decontamination of the instruments: one of the conditions for the initiation of an epidemic process is fulfilled. To date, epidemiological surveillance data did not evidence such an epidemic process. However, would our hypothesis be true, the increase in incidence could remain modest and hard to identify for dozens of years because the incidence of sCJD is low, the incubation period long and in competition with all mortality causes present. CJD surveillance systems is too recent to show such trends.
Vacuum autoclaving and porous-load autoclaving for 18 min at 134°C are currently recognised as appropriate methods for prion decontamination, leading to a reduction of the infectivity load by of 3–5 log10 or more. According to our model, this decontamination would prevent CJD transmission in dental practice, even considering that the residual infectivity is not strictly reduced to zero. These methods are recommended in official reports in various countries. However, in a US study conducted in 1996 , only 53% of dentists used autoclaves to decontaminate root-canal files. In a survey conducted in France in 2004, only 79% of dentists used an autoclave . The problem of correct use of the autoclaves and regular checking of their efficacy has also been raised by many authors in several countries . A recent survey on dental practice also showed that other elementary precautionary measures against CJD transmission were not widely respected. For example, the vast majority of dentists did not actively seek out patients at-risk for any form of CJD (sporadic, iatrogenic or familial) . Therefore, in the current situation and despite recommended decontamination procedures, the risk of sCJD transmission during dental care might still not be zero. In any case, our findings constitute a strong argument for the strict respect of the official recommendations on decontamination procedures in dentistry, and even suggest that the cost-benefit of single-use endodontic instruments should be re-evaluated.
The risk analysis approach we have used relies on a “problem dissection” in which all components to a risk are identified and linked to the available scientific data, knowledge, and expert opinion. It may be of help in other emerging diseases, when data on the natural history of the disease and transmission are still scarce and clinical events cannot be observed directly. In all these cases, the output of the work will always be questionable, because of the lack of data, but the strength of the method is that its results and final statements are refutable as data accrues.
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Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
BSE (Mad Cow) Update:
Do Reports of sCJD Clusters Matter?
snip... see full text ;
10 January 1990
NOT FOR PUBLICATION
COMMITTEE ON SAFETY OF MEDICINES
WORKING PARTY ON BOVINE SPONGIFORM ENCEPHALOPATHY
SURGICAL CATGUT SUTURES
2.1 At the first meeting of the Working Party on Bovine Spongiform Encephalopathy on 6 September 1989, detailed consideration was given to XXXXX Surgical Catgut. This arose from the Company's response to the Letter to License Holders, indicating that the bovine small intestine source material was derived from UK cattle, unlike 8 other licensed catgut sutures. In contrast XXXXX Surgical Catgut was stated to hold over 90% share of the market for catgut sutures, and to constitute approximately 83% of all sutures used in U.K.
IMPORTS OF SUTURES FROM THE KNOWN BSE COUNTRY;
snip... see full text ;
SEAC 99th meeting on Friday 14th December 2007
AS one of them _lay_ folks, one must only ponder ;
"WITH the Nor-98 now documented in five different states so far in the USA in 2007, and with the TWO atypical BSE H-BASE cases in Texas and Alabama, with both scrapie and CWD running rampant in the USA, IS there any concern from SEAC with the rise of sporadic CJD in the USA from ''UNKNOWN PHENOTYPE'', and what concerns if any, in relations to blood donations, surgery, optical, and dental, do you have with these unknown atypical phenotypes in both humans and animals in the USA ???"
"Does it concern SEAC, or is it of no concern to SEAC?"
"Should it concern USA animal and human health officials?"
----- Original Message -----
Sent: Thursday, November 22, 2007 5:39 AM
Subject: QUESTION FOR SEAC
Mr Terry S Singeltary Sr., Bacliff, Texas 77518 USA.
Dear Mr Singeltary,
"Thank you for your e-mail of yesterday with the question for SEAC. I can confirm that this will be asked at the meeting on your behalf and the question and answer will appear in the minutes of the meeting which will be published on the SEAC Internet site."
snip...see full text ;
NOR-98 ATYPICAL SCRAPIE CASES USA
In FY 2007, 331 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), including 59* Regulatory Scrapie Slaughter Surveillance (RSSS) cases (Figure 5 and Slide 16). In FY 2007, two field cases, one validation case, and two RSSS cases were consistent with Nor-98 scrapie. The Nor98-like cases originated from flocks in California, Minnesota, Colorado, Wyoming and Indiana respectively. Nineteen cases of scrapie in goats have been reported since 1990 (Figure 6). The last goat case was reported in September 2007.
see full report here ;
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E11National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway
Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was firstdescribed in Norway in 1998. Several features of Nor98 were shown to be differentfrom classical scrapie including the distribution of disease associated prion protein(PrPd) accumulation in the brain. The cerebellum is generally the most affected brainarea in Nor98. The study here presented aimed at adding information on theneuropathology in the cerebellum of Nor98 naturally affected sheep of variousgenotypes in Sweden and Norway. A panel of histochemical and immunohistochemical(IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein,amyloid, and cell markers for phagocytic cells were conducted. The type of histologicallesions and tissue reactions were evaluated. The types of PrPd deposition werecharacterized. The cerebellar cortex was regularly affected, even though there was avariation in the severity of the lesions from case to case. Neuropil vacuolation wasmore marked in the molecular layer, but affected also the granular cell layer. There wasa loss of granule cells. Punctate deposition of PrPd was characteristic. It wasmorphologically and in distribution identical with that of synaptophysin, suggestingthat PrPd accumulates in the synaptic structures. PrPd was also observed in thegranule cell layer and in the white matter. The pathology features of Nor98 in thecerebellum of the affected sheep showed similarities with those of sporadicCreutzfeldt-Jakob disease in humans.
It will be critical to see whether the atypical BSE isolates behave similarly to typical BSE isolates in terms of transmissibility and disease pathogenesis. If transmission occurs, tissue distribution comparisons will be made between cattle infected with the atypical BSE isolate and the U.S. BSE isolate. Differences in tissue distribution could require new regulations regarding specific risk material (SRM) removal.
Terry S. Singeltary Sr. [firstname.lastname@example.org]
Monday, January 08, 200l 3:03 PM
freas@CBS5055530.CBER.FDA.GOV CJDIBSE (aka madcow) Human/Animal TSE’s--U.S.--Submission To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)
Greetings again Dr. Freas and Committee Members,
with same feeding and rendering practices as that of U.K. for years and years, same scrapie infected sheep used in feed, for years and years, 950 scrapie infect FLOCKS in the U.S. and over 20 different strains of scrapie known to date. (hmmm, i am thinking why there is not a variant scrapie, that is totally different than all the rest)? just being sarcastic. ...
snip...end... see full text Monday, January 08, 200l 3:03 PM ;
Archive Number 20071105.3602 Published Date 05-NOV-2007 Subject PRO/AH/EDR> Prion disease update 2007 (07)
PRION DISEASE UPDATE 2007 (07) ****************************** A ProMED-mail post
 USA: National Prion Disease Pathology Surveillance Center Date: June 2007 Source: National Prion Disease Pathology Surveillance Center (USA) [edited]
CJD Cases examined ---------------------- Year / Referrals / Prion disease / Sporadic / Familial / Iatrogenic / vCJD
1996 / 42 / 32 / 26 / 4 / 0 / 0 1997 / 115 / 68 / 57 / 9 / 0 / 0 1998 / 93 / 53 / 45 / 7 / 1 / 0 1999 / 114 / 69 / 61 / 8 / 0 / 0 2000 / 151 / 103 / 89 / 14 / 0 / 0 2001 / 208 / 116 / 106 / 9 / 0 / 0 2002 / 255 / 143 / 118 / 23 / 2 / 0 2003 / 272 / 174 / 132 / 41 / 0 / 0 2004 / 334 / 183 / 157 / 21 / 0 / 1* 2005 / 352 / 195 / 152 / 37 / 1 / 0 2006 / 372 / 186 / 143 / 30 / 0 / 1** 2007 / 120 / 68 / 35 / 7 / 0 / 0 TOTAL / 2428*** / 1390**** / 1121 / 210 / 4 / 2
*Acquired in UK ** Acquired in Saudi Arabia *** Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007. **** Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, 26 from 2007).
-- Cases are listed based on the year of death when available. If the year of death is not available, the year of sample receipt is used.
-- Referrals: Cases with possible or probable prion disease from which brain tissue or blood in the case of familial disease were submitted.
-- Inconclusive: Cases in which the samples were not sufficient to make a diagnosis.
-- Non-vCJD type unknown are cases in which the tissue submitted was adequate to establish the presence but not the type; in all cases, vCJD could be excluded.
-- Communicated by: Terry S. Singeltary Sr.
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
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  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?
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9
BY Philip Yam
CHAPTER 14 LAYING ODDS
Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk
Tracking spongiform encephalopathies in North America
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." ...
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
JAMA.2001; 285: 733-734.Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.
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, SrBacliff, Tex1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakobdisease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
Like lambs to the slaughter
31 March 2001 Debora MacKenzie Magazine issue 2284
FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris.
Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb. ...
DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen) USA: Loch in der Mauer Die BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der Aufsichtsbehörden sind lax. Link auf diesen Artikel im Archiv: http://service.spiegel.de/digas/find?DID=18578755
"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA regulations. ...
Thu Dec 6, 2007 11:38
FDA IN CRISIS MODE, AMERICAN LIVES AT RISK
FDA SCIENCE AND MISSION AT RISK
2 January 2000
British Medical Journal
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well
15 November 1999
British Medical Journal
vCJD in the USA * BSE in U.S.