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From: TSS ()
Subject: Public consultation SCENIHR Opinion on the Safety of Human-derived Products with regard to Variant Creutzfeldt- Jakob Disease
Date: December 22, 2005 at 1:17 pm PST

Public consultation SCENIHR Opinion on
the Safety of Human-derived Products with regard to Variant Creutzfeldt- Jakob Disease
Variant Creuzfeldt-Jakob Disease (vCJD) is a human version of the mad cow disease. Typical for this incurable neurodegerative disorder is a very long incubation period of several years. During this period asymptomatic vCJD infected individuals in the population may cause secondary transmission of the disease.


The European Parliament and Council directives on Blood Safety (2002/98/EC), Tissues and cells (2004/23/EC) and on Medical Devices (93/42/EEC) ensure that the necessary control systems for disease prevention are in place and well implemented. In 2004, two vCJD cases were reported indicating the possible secondary transmission of vCJD by blood transfusion. In response to the request from the Commission, the independent experts of the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) have assessed the situation and have adopted an opinion on “the Safety of Human-derived Products with regard to Variant Creutzfeldt-Jakob Disease ”.


The Commission, in consultation with the Committee, invites interested stakeholders to submit their views on the opinion by Friday, 10 February 2006 via this website.


Following the consultation, the SCENIHR and Commission services will carefully examine the comments and assess the need for further refinement of approaches to safety assessment of the human–derived products with regard to variant Creutzfeldt-Jakob disease. The outcome of the consultation will be published on this page.

http://europa.eu.int/comm/health/ph_risk/committees/04_scenihr/scenihr_cons_02_en.htm

SCIENTIFIC COMMITTEE ON EMERGING AND NEWLY

IDENTIFIED HEALTH RISKS

(SCENIHR)

Opinion on

The Safety of Human-derived Products with regard to Variant

Creutzfeldt-Jakob Disease

Adopted by the SCENIHR

during the 7th plenary meeting of 28-29 September 2005

EUROPEAN COMMISSION

HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL

Directorate C - Public Health and Risk Assessment

C7 - Risk assessment

snip...

EXECUTIVE SUMMARY

In 2004 two cases were reported indicating the possible transmission of variant

Creutzfeldt-Jakob disease (vCJD) by blood transfusion. This prompted a review of the

current state of knowledge and practice of vCJD infection in relation to the safety of

blood and blood components, including the evaluation of previous scientific Opinions of

Scientific Committee for Medicinal Products and Medical Devices (SCMPMD). The

general conclusions and recommendations of the previous Opinions on the safety of

human derived products including blood and blood components are still valid. However,

two aspects do need our attention: 1) the possibility of transmission of vCJD by blood

and blood components, and 2), the presence of asymptomatic vCJD infected individuals

in the population who may be responsible for secondary transmission of the disease by

blood/blood components or surgery.

While neither of the two transfusion-related cases reported is definitively proven to be

caused by the preceding blood transfusion this is the most likely explanation. These two

cases raise serious concern over the possibility of infection by blood transfusion (or

through surgery) from asymptomatic preclinically or subclinically infected donors.

Therefore, it is assumed that vCJD infectivity is likely to be present in human peripheral

blood which is in accord with the results of recent work in experimental animals on

transmission by transfusion. The present risk assessment of exposure to vCJD infectivity

in whole blood and in blood components allows a rationale to define precautionary

measures to reduce vCJD transmission within the human species by the intravenous or

other routes.

While all the clinical cases of vCJD so far have been homozygous for methionine, (MM)

at codon 129 of the prion protein (PRNP) gene, one of the two reported transfusionrelated

cases was heterozygous (MV). In addition, the results of the UK study evaluating

anonymised appendix surgical specimens, showed that vCJD infection might be more

common than is suggested by the numbers of actual cases of vCJD to date. It is therefore

possible that following exposure to BSE, vCJD infectivity is present in a considerable

number of individuals in the UK in an asymptomatic phase of the disease, including

individuals with MV genotypes. This poses an additional threat to the use of blood and

other products of human origin as a potential source of secondary transmission. The

potential transmission by blood raises concern, especially in view of the fact that routine

screening with respect to vCJD is not (yet) possible. A possible iatrogenic transmission

through surgical instruments used in invasive procedures also has important

implications.

Considerable advances in test methodologies for prion diseases have been made in recent

years. However, no diagnostic system has yet emerged with the level of sensitivity and

specificity required for routine screening of blood or urine. It is essential that

confirmatory assays are available for any assay proposed for large scale screening of

donated blood. In addition, prior to introduction into routine practice, such assays should

be independently assessed and validated for their analytical performance. Validation of

any new methodology should be mandatory prior to introduction, and it is recommended

that the EU adopts a procedure similar to that used for the BSE testing. For validation,

carefully controlled vCJD reference materials should be used. The issue of false positives

needs especially careful consideration. Even minute percentages of false positives may

SCENIHR/003/05

The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease

_______________________________________________________________________

5

actually involve a large number of individuals if the tests are performed on a large scale

in the EU population, with a varying "prevalence" of asymptomatic carriers. The ethical

implications of testing and informing an individual of a positive test result, without

providing any certainty as to the likelihood of progression to clinical disease, should not

be considered lightly.

Based on conservative assumptions made for the purposes of this risk assessment, there

is a considerable risk that an asymptomatic donor infected with vCJD could cause

infective material to be passed on to one or more recipients of blood or blood

components. In the worst case scenario each therapeutic unit of blood from an

asymptomatic infected donor could contain as much as 4500iv ID50. This amount of

infectivity is deemed sufficient to cause transmission of the infection, with or without

development of the disease. Because the donor population is much younger than the

recipient population, with only a small overlap in age, modelling studies strongly

indicate that blood transfusion alone will not be sufficient to maintain vCJD in the

human population at large.

Taking into account the eligible blood donor population, and using the data of the UK

appendix study, the number of donations and the percentage of the population actually

donating blood, up to 1250 infected donations may occur per year. As donations are

typically split between 3 recipients, 3750 new infections would occur each year in the

UK as a result of these infected donations in the worst case scenario. Transfusion

statistics show that in general only about 50 % of blood recipients survive more than 3

years. Accordingly half of the blood recipients will not live long enough after

transfusion to develop vCJD. If all the surviving recipients do develop disease, 1875

new individuals per year could develop vCJD in the UK population

The current decline in the onset of clinical vCJD in the UK and the general low number

of cases in the older age groups who comprise the majority of blood recipients, strongly

indicate that this worst case scenario considerably overestimates transfusion-related

vCJD disease development.

There are several possible explanations for this. It is possible that most infections have a

very long incubation period so that the individual dies before disease develops, or that

infections in some groups such as the MV heterozygotes are not associated with blood

infectivity, or that different genotypes do not transmit efficiently to each other even if

the unit is infectious. There are analogies in animal models for these scenarios, and they

reflect the difficulty in making realistic estimates of the number of cases expected from

blood transfusion. Taking the lower limit of the confidence interval of the prevalence

from the UK appendix study and assuming that only ten percent of infectious donations

actually transmit the infectious agent, the number of infections resulting would be 9 per

year in contrast to the 1250 predicted by the worst case scenario. Independent of the

method of calculation transmission by blood transfusion may occur. Based on current

data, the frequency cannot be reliably estimated, but even in the UK it is probably low.

The frequency is largely dependent on the number of asymptomatic vCJD infected

individuals in the general population which is likely to differ from one Member State to

another. Epidemiological studies, similar to the UK appendix study, are needed to

collect data on the presence of infection (PrPRes) in the general population before

estimations can be made on the possible frequency of contaminated blood donations in

countries other than the UK.

SCENIHR/003/05

The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease

_______________________________________________________________________

6

There is no evidence that individuals working in hospital settings have developed vCJD

by virtue of their profession. Transmission of TSEs during surgical procedures remains

a concern, but to date there is no evidence that it has actually occurred in relation to

vCJD. To minimize the risk of transmission of vCJD by surgical instruments procedures

are recommended based on the probability of the patient under investigation/treatment

being infected with vCJD (or any other TSE).

There are no proven instances of vertical transmission of any human prion disease. The

available animal data are inadequate to allow firm conclusions concerning vertical

transmission to be drawn. It is recommended that there is a follow-up for children that

are born to mothers who had or developed clinical vCJD. There are no data indicating

that breast milk transmits human prion disease.

In the absence of evidence on vertical transmission in man, the risk posed by the use of

cord blood can be considered to be negligible.

In conclusion, as long as there is a risk that infectious prion protein is present in blood

and blood components, there will be a risk of transmission of vCJD disease by

transfusion. Blood transfusion appears the most likely route for inter-human

transmission of vCJD. The Committee does not consider that specific measures are

needed to reduce the risk from vCJD infectivity in blood. However, it recognises that

there are good practices to reduce any risk for transmission of infectious diseases such as

optimal use of the transfusion to reduce the number of patients exposed, and optimal

blood donation techniques and blood transfusion practices which minimize the number

of blood donors to which an individual patient is exposed. The Committee recognises

that it is important that Member States maintain the principle of regional blood supply

structures, national surveillance systems and international information exchange at the

EU level.

snip...full text 78 pages...TSS

http://europa.eu.int/comm/health/ph_risk/committees/04_scenihr/docs/scenihr_o_004.pdf

1: Transfusion. 2003 Dec;43(12):1687-94. Related Articles, Links


Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy.

Cervenakova L, Yakovleva O, McKenzie C, Kolchinsky S, McShane L, Drohan WN, Brown P.

Jerome H Holland Laboratory for the Biomedical Sciences, Red Cross, Rockville, MD 20855, USA. cervenakl@usa.redcross.org

BACKGROUND: The possible transmission of variant CJD (vCJD) through blood transfusion or use of plasma-derived products prompted this study comparing infectivity in murine models of vCJD and Gerstmann-Straussler-Scheinker (GSS) disease, a non-vCJD form of transmissible spongiform encephalopathy (TSE). STUDY DESIGN AND METHODS: RIII/Fa/Dk (RIII) or Swiss-Webster (Swiss) mice were inoculated intracerebrally (IC) with mouse-adapted strains of vCJD or GSS (Fukuoka-1) of similar infectivity. Groups of RIII mice were euthanized 17 weeks after inoculation (during the incubation period), and another 23 weeks after inoculation (when symptomatic). Blood was collected, separated into components, and inoculated into groups of healthy mice; brains and spleens from all mice were harvested and tested for the presence of PrPres by Western blot using 6H4 MoAb. RESULTS: Levels of 20-30 infectious doses per mL were present in buffy coat and plasma during both the incubation and symptomatic stages of disease; PLT pellet infectivity was lower (10 ID/mL) and RBCs were not infectious. The disease was transmitted more efficiently by IV than IC inoculation of plasma, but there was no difference observed with inoculation of buffy coat. The incubation period was shorter after IC inoculation of GSS- than vCJD-brain inocula. The amount of PrPres in spleens was similar for both TSE agents, but was slightly lower in brains of vCJD than GSS mice. CONCLUSION: Infectivity was detected in blood components of mice infected with a human-derived strain of vCJD during both the preclinical and clinical phases of disease in a similarly low range of concentrations as in mice infected with a human-derived nonvariant strain (GSS, Fukuoka-1). Other measures of virulence, including brain infectivity titers, incubation periods, and the accumulation of PrPres in spleens and brains, were also comparable in both experimental models.

PMID: 14641865 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14641865&dopt=Abstract

1: Brain. 1990 Dec;113 ( Pt 6):1891-909. Related Articles, Links


Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Straussler-Scheinker diseases.

Baker HF, Duchen LW, Jacobs JM, Ridley RM.

Division of Psychiatry, MRC Clinical Research Centre, Harrow, Middlesex, UK.

A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Straussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.

Publication Types:
Case Reports

PMID: 2276050 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2276050&dopt=Abstract

Infectivity in the blood of mice with a BSE-derived agent

D. M. Taylor, K. Fernie, H. E. Reichl, R. A. Somerville


Sir,

The occurrence of variant Creutzfeldt-Jakob disease (vCJD) was first reported in 1996, and there is now convincing evidence that is caused by the bovine spongiform encephalopathy (BSE) agent. So far, 61 cases have been detected in the UK but it is unknown how many more will occur. PrPres, a disease-specific form of normal PrP protein, has been consistently detected in lymphoid tissues from cases of vCJD but not classical sporadic CJD.1 The healthcare industry has therefore been obliged to consider the possibility that the vCJD agent may be present in the blood of apparently healthy individuals incubating the disease. To minimize the risk of iatrogenic transmission, blood for transfusion in the UK is now leuco-depleted, and plasma-derived products are only manufactured from imported plasma.

Although there have been several reports of infectivity being detected in the blood of individuals with sporadic CJD, none of these stand up to rigorous scrutiny2. We can now report that the plasma of mice challenged with the 301V strain of mouse-passaged strain of BSE agent contains low levels of infectivity during the clinical stages of disease. The blood from 55 VM mice infected with the 301V mouse-passaged strain of BSE agent was collected aseptically by heart-puncture when they developed clinical neurological disease. The individual samples where pooled after their collection into citrate dextrose anticoagulant (10% v/v), and the plasma was drawn off after sedimentation. The plasma was injected intracerebrally into 48 VM mice (20µL per mouse) that were observed for up to 300 days for the development of clinical neurological disease. When such symptoms appeared, the affected mice were killed and their brains where examined histopathologically to confirm the presence of the spongiform encephalopathy that is pathognomonic for 301V in VM mice. Of the 48 mice injected, four became infected with 301V. The average incubation period was 208 days (SE+16.60) which is at the end of the dose-response curve for 301V in VM mice, and means that the plasma contained around five intracerebral ID50/mL.

In two studies where small amounts of scrapie infectivity were detected in mouse blood by bioassay, it was suggested that this might have originated from heart-muscle during the collection of blood by heart-puncture. This was speculative, however, and seems unlikely in view of the failure to detect scrapie infectivity in mouse blood by bioassay in the most extensive study of this type that has been carried out. Also, infectivity has not been detectable in heart-muscle of the nine sheep with natural scrapie3, or the four humans with sporadic CJD4 that have been investigated to date.

The data presented here relating to 301V should not be interpreted as a definitive representation of the situation in humans with vCJD. They do, however, add to the increasing evidence that low levels of infectivity can be detected in the blood of individuals with CJD-like diseases if the sensitivity of the assay systems is adequate. Somewhat similar levels of infectivity have been detected in the plasma of mice showing clinical signs after challenge with a mouse-passaged strain of Gerstmann-Straussler-Scheinker syndrome agent, although it was much more difficult to detect infectivity during the pre-clinical stage of disease.5 It is unknown at present whether infectivity can be recovered from the blood of 301V-infected mice during the pre-clinical phase of disease, and this may be an important question if (as seems likely) the pathogenesis 301V in mice and that of vCJD in humans are similar.


D. M. Taylor, Neuropathogenesis Unit
K. Fernie, Institute for Animal Health
H. E. Reichl, West Mains Road
R. A. Somerville, Edinburgh EH9 3JF, UK
And Haemosan GmbH
Kahngasse 20, A - 8045 Graz, Austria


References

Hill AF, Butterworth RJ, Joiner S et al. Investigation of variant Creutzfeldt-Jakob disease and other human Prion disease with tonsil biopsy samples. Lancet 1999; 353: 183-189
Brown P. Can Creutzfeldt-Jakob disease be transmitted by transfusion? Curr Opin Haematol 1995; 2: 472-477
Hadlow WJ, Kennedy RC, Race RE. Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 1982; 146 : 657-664.
Asher DM, Gibbs CJ, Gajdusek DC. Subacute spongiform encephalopathies: slow infections of the nervous system. Microbiol Newsletter 1985, 7: 129-133.
Brown P, Cervenakova L, McShane LM et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39: 1169-1178.

http://tse-ip.org/article-infectivity-blood-mice.html


Transmission of prion diseases by blood transfusion

http://www.google.com/url?sa=t&ct=res&cd=26&url=http%3A//www.socgenmicrobiol.org.uk/JGVDirect/18580/18580ft.pdf&ei=rEEDQ7LdNc6I4AGpvpE-

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 2005. 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 Tranmissible 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'. ...TSS


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518




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