NR AQGL
AU Smith,P.; Bassett,J.; Brown,D.; Browne,C.; Bulfield,G.; Carrell,R.; Chambers,J.; Hooper,N.; Jinman,P.; Lasmezas,C.I.; McConnell,I.; Manson,J.; Medley,G.; Rudge,P.
AK Spongiform Encephalopathy Advisory Committee (SEAC)
TI Minutes of the 81st meeting held on 25th February 2004
QU Internet
IA http://www.seac.gov.uk/minutes/final81.pdf
PT Stellungnahme
VT
SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE
Minutes of the 81st meeting held on 25th February 2004
At Dti Conference Centre, Victoria St, London
Members: Professor P. Smith (Chairman)
Mr J. Bassett
Dr D. Brown
Mr C. Browne
Professor G. Bulfield
Professor R. Carrell
Dr J. Chambers
Professor N. Hooper
Mr P. Jinman
Dr C. Lasmezas
Professor I. McConnell
Dr J. Manson
Dr G. Medley
Dr P. Rudge
Technical Advisors: Dr P. Barrowman (Defra)
Dr S. Dixon (FSA)
Mr P. Soul (Defra)
Dr J. Stephenson (DH)
Dr D. Matthews (VLA)
Assessors: Dr M. Bailey (Defra)
Mr A. Harvey (FSA)
Dr R. Jecock (DH)
SEAC Secretary: Dr C. Boyle
Secretariat: Mr M. Pemberton
Dr P. Keep
Dr B. Jeffery
Dr C. Ravirajan
Ms T. Dale
ITEM 1 - CHAIR'S INTRODUCTION
1. The Chair welcomed members of the public to the sixth open meeting, and provided a reminder of SEAC's remit. (The remit of SEAC is 'to provide scientifically based advice to the Department for Environment, Food and Rural Affairs, the Department of Health, devolved administrations, and the Food Standards Agency on matters relating to spongiform encephalopathies, taking account of the remits of other bodies with related responsibilities'.) The Chair noted apologies for absence from Professor James Ironside, Professor Chris Bostock and Ms Diane McCrea.
2. The Chair welcomed eight new members of the committee and reminded members of the importance of declaring potential or real conflicts of interest at the start of each agenda item.
3. The Chair welcomed Dr Patricia Hewitt (National Blood Service), Dr Hester Ward (NCJDSU) and Dr Mandy Bailey (Defra) who were presenting to the committee. The Chair also welcomed four Italian researchers, Dr Cristina Casalone and Dr Pierluigi Acutis from the National Reference Centre for Animal Encephalopathies and Dr Sergio Ferrari & Dr Gianluigi Zanusso from the Department of Neurological and Visual Science, who had kindly agreed to present and discuss their recently published research.
ITEM 2 - APPROVAL OF DRAFT MINUTES FROM 26TH NOVEMBER 2003
(SEAC 80)
4. The minutes of the 26th November meeting were agreed subject to the following amendments:
- change paragraph 7 line 3 from "However, the strain typing of the sCJD..." to read "However, the strain typing in mice of the sCJD...",
- change paragraph 10 line 1 from "...due to the possibility that bovine bone marrow might be infective." to read "...due to the possibility that, in addition to DRG being infective, bovine bone marrow might be infective.",
- change paragraph 23 line 3 from "...that epidemiological investigations should continue and if any of the unclassified samples originated from farms with previous cases of BSE or scrapie they should be investigated further." to read "... that epidemiological investigations should continue to determine if the unclassified samples originated more commonly from farms with an unusual incidence of BSE or scrapie.",
- change paragraph 26 line 3 from "...by active surveillance compared to almost 70% up until October 2003." to read "...by active surveillance compared to almost 70% in 2003, up until October 2003.", and
- change paragraph 54 line 1 from "The FSA informed the member of the public that the decision on changing the OTMR..." to read "The FSA informed the member of the public that the recommendation on changing the OTMR...".
Matters arising
5. At the meeting on 26th November 2003, SEAC endorsed previous recommendations made on the importance of sequencing the PrP gene of the BARB cases. Dr Yvonne Boyd (Defra) updated the committee on the progress with the genotyping of BARB cases. The research proposal was undergoing peer review and, if successful, work would commence at the beginning of April 2004, with the results from the first phase of the work expected in the autumn of 2004.
6. At the meeting on 26th November 2003, the committee recommended that an ad-hoc SEAC epidemiological sub-group be set up to assist with the design of a case-control study to investigate potential differences between the BARB cases and suitable controls. A meeting of this group was scheduled for the end of March 2004.
7. Mr Jim Clapp submitted a question for the public Q & A at the 26th November 2003 meeting about sewage sludge. As Mr Clapp was not present at the meeting, it was agreed that his query would be dealt with by correspondence. Members were provided with the response to Mr Clapp's question (SEAC/INF/81/8).
ITEM 3 - UPDATE ON 'TRANSFUSION' vCJD CASE
8. Dr Patricia Hewitt from the National Blood Service informed SEAC about the Transfusion Medicine Epidemiology Review (TMER) study. The study, funded by the Department of Health and set up by the UK Blood Services (UKBS) and National CJD Surveillance Unit examines possible links between sporadic and variant CJD and blood transfusion.
9. As part of this study, the UKBS performs a search of blood donor records of all cases of vCJD. If a vCJD case is found to have donated or received blood then the fate and origin of all donations are traced. As at 15 December 2003, one hundred and thirty five vCJD cases had been notified to the UKBS. Fifteen of these cases were identified as having previously donated blood, and from these donations, 55 blood components had been issued for hospital use of which 48 had been transfused to identified recipients. Of these recipients who had died within 2 years of receiving the transfusion were from causes unrelated to vCJD. Fifteen of the 48 recipients were still alive.
10. SEAC was informed that two blood donations from March 1996 and December 1996 respectively had been traced through the TMER study to a donor who was, at the time of donation, free of clinical signs of vCJD, but who subsequently developed vCJD in 1999. The recipient of the December 1996 donation had been identified, and had died of unrelated causes 5 months after transfusion. However, the recipient of the March 1996 donation developed vCJD and died in the autumn of 2003. Members noted that the recipient received blood before the protective measures of leucodepletion, advised by SEAC, were adopted in the UK in 1998.
11. Members were informed that autopsy samples were not available from the peripheral tissues, to investigate the pathogenesis of vCJD, in this case potentially due to blood transfusion, as permission for a limited brain-only post mortem had been granted. Dr Hester Ward, of the NCJDSU, informed members that the glycotype profile of the case was typical of vCJD.
12. Members noted the ongoing studies at the Institute of Animal Health on the transfusion of leucodepleted blood from sheep infected with BSE and uninfected sheep. These studies which originally showed that transmission of BSE infection can occur via whole blood transfusion in sheep, would provide an indication if leucodepletion protected against BSE transmission. SEAC was informed that among the 15 living recipients of blood from donors who subsequently developed vCJD, some individuals transfused more recently had received leucodepleted blood, and that some had been transfused much closer to the onset of vCJD in the donor.
13. The committee noted that the cases of currently healthy individuals transfused with blood from individuals who went on to develop vCJD have been referred to the CJD Incidents Panel and these recipients had been informed of their potential risk of developing vCJD.
14. The committee concurred that the risk of cases arising via blood transfusion from vCJD-infected individuals was difficult to quantify as the prevalence of infection in the blood donor population was unknown. The Chair noted that studies in sheep indicated that it was possible to transmit BSE through transfusion from at least halfway through the incubation period of the disease.
15. One member asked whether, given that some plasma products were sourced from other countries, tracing systems similar to those in the UK were in place. SEAC was informed that other European and North American countries have mechanisms in place to trace donations from individuals diagnosed with any transmissible infection. Dr Hewitt informed members that the UK sources plasma products from the USA and that an audit trail was in place to identify the fate of products from any donor who subsequently developed CJD.
16. SEAC was informed that, in the light of this case, a range of possible risk management options, such as exclusion of transfused individuals from blood donation, are under discussion with the advisory committee on the Microbiological Safety of Blood and Tissues for Transplantation. The committee agreed that previous risk assessments had indicated the possibility of transmission through blood transfusion. Statistical analysis suggests that a case of vCJD infection in a recipient of blood from a vCJD-infected donor was unlikely to have occurred by chance, suggesting that the disease was transmitted by transfusion in the reported case. Members noted this was a single case, however, and that the recipient had received blood before the protective measures of leucodepletion were adopted in the UK.
17. In closing, the Chair noted the continuing importance of the TMER study.
ITEM 4 - vCJD UPDATE
18. Members were updated on cases of vCJD in the UK and worldwide. The total number of definite and probable vCJD cases in the UK, as at January 2004, was 146, of which 7 cases are still alive. No significant sex difference has been observed in vCJD cases with 82 and 64 male and female cases respectively. The mean age at death was 29 years (range 14-74) and the mean age at onset was 28 years (range 12-74). The median duration of illness remained at 14 months (range 6-40). All cases tested (n=124) are homozygous for methionine at codon 129 in the PrP gene.
19. To date, six vCJD cases have been reported in France, and a single case in each of Ireland, Italy, Canada and the USA. The vCJD cases reported in France and Italy did not have a history of residence in the UK. No new cases of vCJD have been reported in France for over a year. The cases reported in Ireland, Canada and the USA had a history of UK residence during the late 1980's.
20. The number of onsets and deaths per annum peaked in the UK in 1999 and 2000 respectively. Statistically, the incidence of vCJD shows a significant departure from an exponential trend to a trend that better fits a quadratic model, which suggests a slowing of the incidence increase and a possible peak in the onset of cases. The quadratic model estimates the current incidence to be 2.5 onsets and 3.5 deaths per quarter and predicts 11 deaths in the next 12 months. SEAC was informed that a plateau model could also be applied to the observed quarterly incidence of deaths, estimating 4.9 deaths per quarter and 19 deaths in the next 12 months. The higher level of deaths compared with onsets is expected for an epidemic in decline. The committee agreed the trend of the surveillance data was encouraging but that it remains premature to conclude there is definitive evidence that the epidemic has peaked and that the possibility of future peaks cannot be discounted.
21. The duration of illness for sporadic CJD (sCJD) continues between 1-4 months and between 10-19 months for vCJD. The number of deaths from sCJD per annum has increased from approximately ten per year at the beginning of the 1970s, to about fifty per year in the 1990's. This may be attributed to improved case ascertainment.
ITEM 5 - UPDATE ON AMERICAN BSE CASE
22. Professor Ian McConnell declared a potential conflict of interest for this item. He had been approached by his son, David McConnell, who was researching a possible documentary on the United States (US) BSE case for Granada television. Professor McConnell stated that he had upheld a clear demarcation between his role as a SEAC member and that of an expert on TSEs, and had offered his expert advice on the case and on TSEs in general. The Chair noted the declaration and thanked Professor McConnell for the information.
23. Members had asked for a summary of the US BSE case. The Chair welcomed Dr Mandy Bailey (Defra) who updated the committee on the issue. Dr Bailey clarified the position of casualty animals in the UK. There are three categories of animals 1. that undergo emergency slaughter on farm, 2. that undergo emergency slaughter at the abattoir and 3. that show any signs of illness at ante-mortem inspection. In all cases, veterinary inspection of the animal is required before it can be confirmed fit for human consumption. Casualty animals over the age of 24 months are tested for BSE, and those over 30 months are not permitted to enter the food chain under the Over Thirty Month Rule (OTMR). The carcases of casualty animals between 24 and 30 months tested for BSE are detained pending results and only those that test negative enter the food chain.
24. Dr Danny Matthews (VLA) was invited to update the committee on this issue given his involvement on the international TSE expert panel, established by the US authorities to review the US surveillance and control measures. The committee was informed that of the 35 million cattle slaughtered in the US per annum, 200,000 were downers and a further 400,000 were dead, dying, emaciated or injured, providing a total of 600,000 'at-risk' animals. Current surveillance was focussed on the 'at risk' animals and approximately 40,000 were to be tested for BSE in 2004. The US agriculture department has proposed the introduction of an animal identification system, although this would take time to establish. The Canadian authorities were considering additional funding for surveillance, which would include testing of 8,000 cattle (approximately 1% of the total number of animals slaughtered).
25. Members were informed that historically, the case definition for BSE, had been broad to maximise the reporting of suspect cattle. In the UK approximately 40-50% of downer cows that were reported as BSE suspect were confirmed as having BSE. Dr Matthews explained that differing case definitions for casualty animals made it difficult to make comparisons between countries. The US authorities have, however, focused on the surveillance methodology used in the UK.
26. The Chair asked how the UK category of 'downer' cattle related to the UK casualty animals, and what proportion of casualties in the UK were considered as downers. Professor Wilesmith (Defra) explained that a survey was currently underway to obtain accurate estimates but at present it is estimated that around 2% of casualty animals were downers. One member suggested that the definition of a downer animal provided in (SEAC 81/3 Annex 1) was too narrow and that it should be amended to include a broader range of conditions.
27. The USDA had tested almost 20,000 animals in the 2002 fiscal year (ending October 2003), with one positive result. The small number of animals tested suggested a number of cases could be missed. Dr Matthews explained that 40,000 US cattle were due to be tested for BSE, although this is a small proportion of the total size of the US cattle population. However, raising the numbers of cattle tested to give meaningful results would create logistical problems for sample testing, particularly in abattoirs where carcasses would have to be stored and provision made for the disposal of specified risk material. In addition, it was questionable whether this testing programme was proportionate to the risk of BSE from US cattle.
28. The US authorities had fulfilled the Office des International Epizooties (OIE) criteria for BSE surveillance but also recognised the need to increase the numbers of animals tested. One approach being considered was to sub divide the US into testing regions, with each region required to meet OIE testing targets. Dr Matthews informed the committee that BSE testing in the US would not provide an accurate estimate of the prevalence of indigenous disease, as substantial cattle movements took place across the US, Canadian and Mexican borders.
29. Dr Matthews informed the committee that the US experience of BSE would probably resemble mainland Europe; that is partial controls have suppressed, but not eliminated an epidemic.
30. In response to a question on the recycling of ruminant protein in the US, Dr Matthews explained that a ban had been put in place in 1997 on the recycling of ruminant protein into ruminant feed, but it could still be fed to pigs and poultry. The US authorities were currently considering a ban on this latter exception, on the basis that effects associated with low dose exposure to BSE could not be discounted. Another control measure in the US involves the recall of food or meat thought to be a risk to public health. In the BSE case, all high-risk tissues from the case had gone into the rendering system, with the meat going into the food chain and a large amount of this had been recalled.
31. The committee asked about the position of UK consumers with respect to imported beef products from the US. Dr Bailey confirmed that EU wide rules already existed for material imported into the EU, which required the same level of controls for third countries as for other EU countries. All imported meat and meat products enter the UK or EU via an approved border inspection post where they are subject to documentary checks and inspection by an official veterinary surgeon. Members were informed that the EU (including the UK) imports a relatively small amount of beef and beef related products from the US due to the use of prohibited growth hormone and therefore the risk to UK consumers was small.
32. The Chair stated that SEAC would continue to monitor surveillance results in the US.
ITEM 6 - DISCUSSION OF ATYPICAL BSE CASES
33. The committee considered a recent research paper published in the Proceeding of the National Academy of Science (Casalone et al (2004)). The work was carried out by research groups in Italy and the researchers involved with this work attended to discuss their work with SEAC.
34. The researchers presented their data to the committee explaining that a total of 103 BSE positive animals had been detected out of 1.6 million animals during active surveillance in Italy. Eight of these cases (age range 5-15 years) were selected for further investigation and the molecular and neuropathological features of different regions of whole brain examined. The analysis showed that two animals had atypical molecular and biochemical characteristics when compared to the "classical" BSE pattern. These two animals had a normal prn-p genotype. Analysis by immunohistochemistry (IHC) and biochemical analysis showed that the animals (11 and 15 years of age) showed PrPsc positive amyloid plaques in the supratentorial region of the brain with weak staining of the brainstem. Western blot (WB) analysis showed a predominance of the unglycosylated glycoform and a protease-resistant fragment of faster electrophoretic mobility. The PrPsc molecular signature was different from typical BSE cases and similar to that of a subtype of sporadic CJD (sCJD). The researchers suggested that they had identified a second form of TSE in cattle, which they termed "bovine amyloidotic spongiform encephalopathy".
35. The committee agreed that implementation of large-scale surveillance coupled with the use of new and more sensitive test methods may explain why atypical cases are now being detected. Members noted that the bulk of the BSE epidemic in the UK predated the availability of the rapid tests used in this investigation. In view of this, they agreed, that the possibility that atypical cases may have always existed in the UK cattle population could not be excluded. They noted that the Italian research involved a more extensive examination of the BSE cases than was conducted in the UK. This was practically feasible given the small number of BSE cases reported in Italy. Members were informed that a similar extensive investigation had not been performed, historically at least, in the UK due to the methodology available at the time but also because of the very large number of BSE cases. Since January 1996, WB analysis of BSE cases in the UK had not shown any atypical profiles. However, Members acknowledged that the routine screening tests used to detect BSE would not necessarily be sensitive enough to detect small differences in molecular weight of the unglycosylated band.
36. Members agreed that the detection of a different phenotype of BSE in cattle was an interesting and significant development. They noted that experimental work at VLA has already showed that cattle inoculated (ic) with pooled material from scrapie infected sheep gives rise to different molecular phenotypes in cattle. However this was the first demonstration with respect to "natural" BSE. The distribution profile of PrPsc in the Italian atypical BSE cases showed only limited involvement of the brainstem. Members noted that it was not possible to compare the atypical BSE cases with historical UK BSE cases as IHC examination had only been carried out on the brainstem region.
37. Members noted that the atypical BSE cases reported by French and Japanese researchers were different to the cases reported by the Italians as abnormal PrPsc glycoforms were detected in the brainstem region of the brain. Members agreed that the atypical BSE cases reported thus far are based solely on phenotypical differences and that further verification and research was required. Members discussed the scientific uncertainties associated with these observations, namely that it's not known if the atypical pattern represents a disease-related isoform, also as these animals were "old" - it's not clear if any of the pathology could be attributable to age or breed related differences in these animals. Members were informed that research from the VLA did not demonstrate an association between either the breed or age of animal and the resulting brain lesion profile. However it was acknowledged that this conclusion was based on analysis of tissue from the brainstem region of the brain.
38. In view of the limited data and scientific uncertainty, Members were cautious about the extent to which these results could be interpreted. The committee agreed that atypical phenotypic differences alone did not constitute sufficient evidence to demonstrate the identification of a new strain of BSE. Further research such as mouse strain-typing experiments were critical to this work before any interpretation or claims could be verified. The Italian researchers agreed with this conclusion. The committee noted that unlike the WHO classification of CJD subtypes, no guidelines on classification of BSE exist. Members noted the need for an OIE-approved definition of BSE diagnosis, on the basis of molecular phenotype, clinical signs, pathology and epidemiology.
39. The Italian researchers had speculated in their paper that the differing distribution of PrPsc may arise from non-alimentary routes of exposure. Members agreed this was an interesting observation but that current evidence suggests that the lesion profile is primarily defined not by the route of infection but by the strain of agent. Members agreed that transmission studies in syngeneic mice could help resolve both these issues.
40. The committee noted that the European Commission has put forward proposals to retain the whole brain during routine BSE surveillance until the screening test is confirmed. This would have the benefit of providing sufficient material for scientific research. These proposals have not yet been accepted by all member states because of resource implications. Dr Matthews indicated that there were several hundred historical samples of whole brains collected during the period of the UK BSE epidemic. These tissues had been analysed by histology, but may still be suitable, (providing sufficient material was available) for IHC and advanced WB. A potential difficulty is that most of the archived frozen BSE tissue had been released to other researchers for study.
41. Members agreed it was important to gather information on these atypical cases and while efforts were being made to obtain whole brain, in the first instance it would be useful if additional effort were aimed at identifying further cases. It was suggested that a retrospective examination of the WB from positive BSE animals may provide additional information. Dr Matthews informed members that this may be possible for the cases analysed by the Prionics-Check system within the first year of active surveillance, however it was very dependent on the quality of WB. Additionally, during 2001, the constraints of the Foot & Mouth epidemic meant that delays between death and collection may mean that autolysis may have compromised the integrity of the samples.
42. Members suggested that positive cases identified by the rapid test should be examined further via confirmatory tests using a sensitive WB technique and IHC. Dr Matthews commented that in the UK, there was no prospect of doing this prospectively other than on clinical BSE cases, as they were the only animals from which whole brains were available. In terms of retrospective analysis it would be possible for animals testing positive under the passive surveillance system but limited for the active surveillance system as at present this only permitted the collection of brainstem.
43. It was suggested that the atypical results could represent sporadic BSE as it would be easier to detect a low frequency of sporadic cases in a situation where cases due to food are very low. In the UK, if sporadic BSE was present in the UK cattle population, it may have been masked at the height of the BSE epidemic. It may now be possible to detect these cases given that the overall number of BSE cases has fallen.
44. The Italian researchers proposed that some of the biochemical features of the two Italian atypical cases showed molecular similarities with human sporadic CJD (sCJD). The committee have always recognised that there may be other manifestations of infection with BSE agent in human, other than vCJD. The committee referred to a discussion of research from Professor Collinge?s group (Feb 2003) showing that sub-passage of BSE infection could produce a disease phenotype similar to sCJD in transgenic mice expressing human prion proteins. At that time, the committee agreed that the work was interesting and significant but the analogy with human situation was theoretical. Members agreed that the Italian results were scientifically interesting, but again any potential association with sCJD remained theoretical.
IN
Blut-Transfusionen und das Risiko der CJK-Übertragung
Im Herbst 2003 starb an der "neuen", höchstwahrscheinlich auf BSE-Infektionen zurück gehenden CJK-Variante ein Emfänger einer Blutspende, die im März 1996 von einem Menschen gespendet wurde, der seinerseits 1999 an der nvCJK erkrankte. Proben von peripheren Geweben des mutmaßlich durch Blut eines BSE-infizierten Menschen sekundär mit BSE infizierten Patienten durften nicht entnommen werden. Die Mengenverhältnisse der unterschiedlich glykosilierten Formen des proteaseresistenten Prionproteins im Gehirn dieses Patienten entsprachen aber dem für die nvCJK typischen Muster.
Die Leukozytendepletion, von der sich das SEAC eine Schutzwirkung verspricht und die seit 1998 in Großbritannien zur Anwendung kommt, kam bei der anscheinend infektiösen Blutspende noch nicht zum Einsatz. Am britischen Institute of Animal Health läuft eine Studie, in der an BSE-infizierten Schafen untersucht wird, ob die Leukozytendepletion tatsächlich eine Schutzwirkung hat.
Vermutlich wegen der offensichtlichen Mitverantwortung von Politik und Behörden, aber sicher auch wegen des Risikos der weiteren Verbreitung von BSE-Infektionen beim Menschen durch sekundäre Übertragung von Mensch zu Mensch werden in Großbritannien die Empfänger von Blutspenden bekannter nvCJK-Opfer aufwändig ermittelt und informiert. Das SEAC verweist in diesem Zusammenhang auf die beunruhigende Tatsache, dass das Blut eines mit BSE infizierten Schafes bereits nach der Hälfte der Inkubationszeit für ein weiteres Schaf tödlich infektiös war. Den deshalb zu betreibenden Aufwand zur Vermeidung von Mensch-zu-Mensch-Übertragungen muß man also auch berücksichtigen, wenn man über die Kosten der BSE-Bekämpfung und der Verhinderung von BSE-Infektionen beim Menschen nachdenkt. Die britische Beratungskommission "Microbiological Safety of Blood and Tissues for Transplantation" überlegt auch, ob die Empfänger des Blutes von nvCJK-Patienten weiterhin ihrerseits Blut spenden dürfen. Zu prüfen wäre aber natürlich auch, bei welchen Organtransplantationen und Operationen ein besonderes Risiko von direkt oder möglicherweise indirekt mit BSE infizierten Personen ausgehen kann. Insgesamt wird da ein erhebliches ethisches und wirtschaftliches Problem sichtbar, auf welches ich allerdings schon 1995 aufmerksam gemacht hatte [ANDB].
Epidemiologie der neuen CJK-Variante
Außerhalb Großbritanniens gab es bis zu dieser Stellungnahme des SEAC 6 nvCJK-Fälle in Frankreich sowie je einen Fall in Irland, Italien, Kanada und den USA. Aber nur die französischen und italienischen Fälle lebten nicht in den späten 80er Jahren im Vereinigten Königreich. Dem SEAC wurde von 146 britischen nvCJK-Fällen bis zum Januar 2004 berichtet, von denen 7 noch lebten. Einen signifikanten Unterschied zwischen Frauen (64) und Männern (82) konnte das SEAC nicht erkennen. Das Durchschnittsalter betrug zum Zeitpunkt der Erkrankung 28 Jahre (12-74) und zum Zeitpunkt des Todes 29 Jahre (14-74). Die mittlere (mediane) Krankheitsdauer betrug 14 Monate (6-40). Alle 124 daraufhin untersuchten Fälle waren Methionin-homozygot hinsichtlich der Aminosäure 129 des Prionproteins.
Zur Entwicklung der Fallzahlen stellt das SEAC fest, dass eine zuverlässige Vorhersage nicht möglich ist und das weitere Peaks für die Zukunft nicht ausgeschlossen werden können, obwohl die Entwicklung momentan ermutigend aussieht.
Unterschiede in den Systemen zur BSE-Überwachung
Im Vereinigten Köngreich werden laut Aussage von Dr. Mandy Baily (DEfRA) mindestens 2 Jahre alte Rinder auf BSE getestet, wenn sie auf der Farm oder im Schlachthof krank oder notgeschlachtet werden müssen. Sind die Tiere über 30 Monate alt, dann kommt ihr Fleisch nicht in den Handel. Der Text macht aber nicht ganz klar, ob diese Tiere dennoch getestet werden.
Dr. Danny Matthews vom Central Veterinary Laboratory in Addlestone (Surrey, United Kingdom) machte darauf aufmerksam, dass die Definitionen der BSE-Risikogruppen länderübergreifend kaum vergleichbar unterschiedlich seien, dass sich aber die USA an dem seiner Ansicht nach auf eine Maximierung der Verdachtsmeldungen angelegten britischen System orientieren. Professor Wilesmith meinte allerdings, dass nur etwa 2% der in England als Risikorinder betrachteten Tiere in den USA als Downers gelten würden. Er findet diese Definition in den USA zu eng. Dank teilweise wirksamer Schutzmaßnahmen vermutet Dr. Matthews in den USA ein mit Kontinentaleuropa vergleichbares BSE-Risiko.
Dr. Matthews berichtete dem SEAC, dass in den USA jährlich 35 Millionen Rinder geschlachtet werden und das man dort mit jährlich 600.000 verendeten, kranken oder verletzten Rindern mit potentiell erhöhtem BSE-Risiko rechnen müsse. Im Fiskaljahr 2002 (10/2002-20/2003) wurden in den USA nicht einmal 20.000 Rinder getestet. Die sehr niedrigen Anforderungen des Office des International Epizooties (OIE) wurden damit erfüllt, aber den Verantwortlichen in den USA ist selbst klar, dass diese Testzahl deutlich zu niedrig war. Trotz einer starken Zunahme der Tests werden selbst im Jahr 2004 nur 40.000 Risiko-Rinder getestet. Einer Steigerung auf eine angemessene Testzahl stehen nach Ansicht von Dr. Matthews logistische Probleme entgegen. Seltsam, dass Japan und die meisten europäischen Staaten relativ problemlos zu Testquoten in der Lage waren, welche die Supermacht USA überfordern sollen.
Ein US-System zur individuellen Rinder-Identifizierung soll in den USA eingeführt werden. In Kanada überlegen die Behörden, ob sie mehr Geld in die BSE-Überwachung investieren und (vermutlich jährlich) 8.000 Rinder (rund 1% der Schlachtrinder) auf BSE testen sollen.
BSE-Schutzmaßnahmen in den USA
Wiederkäuerprotein darf in den USA seit 1997 nicht mehr an Wiederkäuer, aber immer noch an Schweine und Geflügel verfüttert werden. Als weitere US-amerikanische Schutzmaßnahme wertet Dr. Matthews Rückrufaktionen, mit denen die Behörden als riskant eingestufte Rinderprodukte aus dem Verkehr zu ziehen versuchen. Im Falle des ersten in den USA geschlachteten BSE-Falles gelang dies aber nicht vollständig, weil das Testverfahren viel zu lange dauerte und man das Testergebnis nicht vor dem Verkauf abwartete. Das für EU-Bürger von US-amerikanischem Fleisch ausgehende Risiko wird aber schon deshalb als gering eingestuft, weil wegen des Gebrauchs von in der EU unzulässigen Hormonen kaum amerikanisches Fleisch nach Europa importiert wird.
Hinweise auf eine neue BSE-Variante in Italien
Dr. Cristina Casalone, Dr. Pierluigi Acutis, Dr. Sergio Ferrari und Dr. Gianluigi Zanusso berichteten dem SEAC, dass in Italien im Rahmen einer aktiven Überwachung mit 1,6 Millionen Schnelltests 103 BSE-Fälle gefunden wurden. Von diesen wurden nur acht 5-15 Jahre alte Tiere einer genaueren Untersuchung unterzogen. Zwei der 8 untersuchten Rinder erwiesen sich trotz normalen Prionprotein-Genotyps als atypisch. Mit Antikörpern gegen das Prionprotein fand man amyloide Plaques oberhalb des Kleinhirndaches, aber nur eine schwache Markierung im Stammhirn. Im Western blot dominierte die unglykosilierte Form des Prionproteins und die Protease K erzeugte ein ungewöhnlich kleines Prionprotein-Fragment. Damit ähnelten diese beiden Fälle molekularbiologisch eher einer klassischen als der neuen CJK-Variante. Anscheinend zur Unterstreichung der Bedeutung ihrer Entdeckung halten es die Autoren für angemessen, gleich einen ganz neuen Namen für die von ihnen gefundene BSE-Variante einzuführen. Sie nennen diese bovine amyloidotic spongiform encephalopathy (BASE).
Seit Januar 1996 werden auch im Vereinigten Königreich Western blots zur BSE-Diagnose eingesetzt, aber man hat dort noch keine BSE-Varianten gefunden. Allerdings muß man auch genau hinsehen, denn sehr auffallend sind die Unterschiede nicht. Das SEAC hat dies ebenso erkannt, wie die Tatsache, dass bei den allermeisten britischen BSE-Fällen nie solche sensitiven Methoden angewendet wurden.
Die Mitglieder des SEAC stimmen in der Einschätzung überein, dass die Entdeckung eines alternativen BSE-Phänotyps eine interessante und wichtige Entwicklung ist und wissen, dass auch experimentell im Central Veterinary Laboratory in Addlestone mit Scrapie infizierte Rinder von normalem BSE abweichende molekulare Phänotypen zeigten. Das SEAC erwähnt speziell die beunruhigende Tatsache, dass bei der italienischen Variante ausgerechnet im für die Probennahme verwendeten Hirnstamm relativ wenig PrPsc zu finden war. Deshalb ist es auch problematisch, dass man bei den früheren britischen BSE-Fällen nur die Stammhirne und diese auch nur immunhistochemisch untersuchte, sodaß man diese nun nicht mit den neuen Varianten vergleichen kann. Natürlich besteht das selbe Poblem auch in anderen EU-Ländern und insbesondere auch in Deutschland.
Auch in Japan und Frankreich gibt es Hinweise auf neue BSE-Varianten
Die japanischen und französischen Fälle molekular abweichender Glykosylierungsmuster sollen sich laut SEAC von den italienischen unterscheiden. Das SEAC sieht aber Forschungsbedarf, weil die bekannten Unterschiede im Glykosylierungsmuster und in der Verteilung des PrPsc im Gehirn bestehen und sonst praktisch nichts über die Varianten bekannt ist. Das SEAC schließt offenbar die Möglichkeit nicht aus, dass es sich bei den neuen BSE-Varianten um spontan entstandene Fälle handelt. Man fragt sich sogar, ob nicht die Varianten einfach geschlechts- oder alterbedingt sein könnten. Forschung im VLA zeigte keinen Einfluß von Rasse und Alter auf das Schädigungsmuster, aber dabei wurde anscheinend nur das Stammhirn untersucht.
Was ist zu tun?
Das SEAC hält es vor einer Stammtypisierung in Mäusen für verfrüht, allein aufgrund phänotypischer Unterschiede in einigen Rindern von einem neuen BSE-Stamm zu sprechen. Überhaupt beklagen seine Mitglieder das Fehlen von Richtlinien für eine BSE-Klassifizierung nach dem Vorbild der CJK-Klassifizierung. Sie wünschen sich von der OIE eine Definition der BSE-Diagnose aufgrund des molekularen Phänotyps, klinischer Symptome, der Pathologie und der Epidemiologie.
Offenbar hatte die EU-Kommission vorgeschlagen, ganze Gehirne bis zum Abschluß der BSE-Schnelltests zu verwahren, um dann im Falle eines positiven Testergebnisses Untersuchungsmaterial für die Suche nach und die genauere Untersuchung von neuen BSE-Varianten zu haben. Leider stieß dieser Vorschlag nicht auf die Zustimmung aller Länder. Einige Hundert in England gesammelte BSE-Gehirne könnten allerdings möglicherweise noch untersucht werden. Das SEAC betonte die Wichtigkeit der Identifizierung und Untersuchung weiterer BSE-Fälle mit ungewöhnlichen Eigenschaften. Es schlägt vor, ältere Western blots noch einmal gründlich im Hinblick auf Lauflängen und Glykosilierungsmuster zu untersuchen. Seltsamerweise sieht es diese Möglichkeit aber nur bei den Prionics-Schnelltests, obwohl doch auch die mittels BioRad-ELISA entdeckten BSE-Verdachtsfälle zumindest in Deutschland anschließend mit einem OIE-Western blot nach untersucht werden. Das SEAC schlägt vor, dass genau dies getan werden solle und das die Hirnproben außerdem immunhistochemisch untersucht werden sollten. Letzteres bringt natürlich nur dann große Vorteile, wenn das ganze Gehirn vorhanden ist. Zumindest in England ist dies nach Auskunft von Dr. Matthews nur bei bereits klinisch auffällig gewordenen Tieren der Fall. Aber auch in Deutschland werden ja zumindest bei Schlachttieren nur die Hirnstämme gesammelt.
Die Beduetung neuer BSE-Varianten für den Menschen wird vom SEAC nur gestreift
Die italienischen Gäste erwähnten auch die Ähnlichkeit ihrer neuen BSE-Variante mit sporadischen CJK-Fällen, so wie umgekehrt die Collinge-Gruppe gezeigt hatte, dass man beim Passagieren des normalen BSE-Stammes in Mäusen auch Änderungen der Stammeigenschaften in Richtung sporadischer CJK beobachten kann [AAUB]. Das SEAC findet beides interessant und wichtig, weist aber darauf hin, dass sich Maus-Experimente nicht einfach auf den Menschen übertragen lassen.
SP englisch
PO England
ZF kritische Zusammenfassung von Roland Heynkes