Saturday, December 08, 2007

Transfusion Transmission of Human Prion Diseases

Volume 22, Issue 1, Pages A1-A8, 1-96 (January 2008)

Transfusion Transmission of Human Prion Diseases

Shimian Zou, Chyang T. Fang, and Lawrence B. Schonberger

No transmission through transfusion has been reportedfor classic Creutzfeldt-Jakob disease (CJD). Moreover, a series of epidemiological surveillance, case-control, and look-back studies have provided no evidence of sucht ransmission of CJD. Hence, the risk of such transfusion transmission of classic CJD remains theoretical. In contrast, based on data from the United Kingdom, the likelihood of transmission of the agent of the variant formof CJD (vCJD) through blood transfusion by donors who develop the disease within several years of donation is about 14% for recipients who survive longer than 5 years post transfusion. Leukodepletion may reduce the likelihoodof vCJD transmissions, although this procedure by itself removes less than half of the prion infectivity of blood. The potentially longer incubation periods of vCJD with infections in donors who are not methionine/methionine homozygous at codon 129 of the prion proteingene, the unknown number of such donors, and the unknown infectivity of their blood during the incubation period suggests caution in assuming that only known cases of vCJD represent a risk for the transfusion transmission of vCJD. Results from ongoing look-back investigations and other studies will enable continued monitoring and more precise estimations of the risks ofthe transfusion transmission of CJD and vCJD.

Published by Elsevier Inc.


Consistent with the results of the case-controlstudies, the mortality rates of CJD in the United States have remained relatively stable despite a major increase in the number of blood transfusions. Age-adjusted mortality rates for CJD inthe United States—beginning in 1979, when a separate code for CJD was established—have been roughly 1 case per million persons per year.9


The potentially long incubation periods for prion diseases; the possible future occurrence of vCJD among persons with a Val at codon 129 of PRNP; and the lack of any practical, FDA approved, sensitive screening methods for detecting the prion agents in human blood contribute to uncertainties and aggravate concerns about the transfusion transmission risks for classic CJD andvCJD. These uncertainties will hopefully be lessened as new sensitive assays for screening blood are developed and as data from longer-term follow-up studies of transfusion recipients, as well as other studies, provide more precise estimates of the transfusion transmission risks. For the United States, similar to many other countries, the present data are sufficient to underscore the prudence of increasing efforts to minimize and monitor potential exposures of people to BSE-infected cattle products to ensure the safety of the national blood supply.

Until recently, in the United States, the BSE monitoring and control efforts have not been justified or assessed based on preserving blood safety but rather on maintaining the safety of food and protecting trade. ...

ProMED-mail <>

[2] USA: National Prion Disease Pathology Surveillance CenterDate: June 2007Source: National Prion Disease Pathology Surveillance Center (USA) [edited]<>

CJD Cases examined----------------------
Year / Referrals / Prion disease / Sporadic / Familial / Iatrogenic / vCJD1996 / 42 / 32 / 26 / 4 / 0 / 01997 / 115 / 68 / 57 / 9 / 0 / 01998 / 93 / 53 / 45 / 7 / 1 / 01999 / 114 / 69 / 61 / 8 / 0 / 02000 / 151 / 103 / 89 / 14 / 0 / 02001 / 208 / 116 / 106 / 9 / 0 / 02002 / 255 / 143 / 118 / 23 / 2 / 02003 / 272 / 174 / 132 / 41 / 0 / 02004 / 334 / 183 / 157 / 21 / 0 / 1*2005 / 352 / 195 / 152 / 37 / 1 / 02006 / 372 / 186 / 143 / 30 / 0 / 1**2007 / 120 / 68 / 35 / 7 / 0 / 0TOTAL / 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, 1from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36type pending (2 from 2005, 8 from 2006, 26 from 2007).

Notes:-- 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 tothe 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]


Enhanced Surveillance of Persons Identified as at Increased Risk of CJD Due to Blood Transfusion or Healthcare Procedures

Brookes, D1; Chow, Y1; Ward, HJT2; Will, RG2; Hewitt, P3; Gill, ON1 1HPA,CJD, UK; 2National CJD Surveillance Unit, UK; 3Colindale, NHS Blood andTissue, UK


Reports of four iatrogenic transmissions of variant-CJD (vCJD) infection inthe UK (all due to transfusion of blood from donors who later developed vCJD), evidence from iatrogenic transmissions of sporadic CJD and experimental work on CJD infectivity in tissues and on health care instruments have given rise to concern about the risks of iatrogenic transmission of CJD. This risk warrants a) certain public health precautions, and b) follow-up of individuals with identified risks in order to gain evidence about their risks and ensure appropriate management of these risks. Evidence of transmission via iatrogenic routes is important to inform public health measures and so prevent ongoing transmission of CJD.


The Health Protection Agency and Health Protection Scotland holds details of persons identified as ‘at-risk’ of vCJD due to blood transfusion and of persons identified as ‘at-risk’ of CJD (of any type) from other healthcare procedures. The GPs/clinicians of all persons identified as ‘at-risk’ forpublic health purposes are provided with: information; risk assessment updates; advice on public health precautions and advice on referral to specialist care. Procedures are being established to obtain enhanced surveillance data on these individuals, including: clinical status updates,date and cause of death, surplus tissue and blood specimens, and postmortem investigations.


Persons ‘at-risk’ of CJD have experienced a range of exposures. Estimated risks are uncertain and overlapping. Some individuals - recipients of vCJD implicated blood components - are considered to be at a clearly higher risk of infection: active follow-up is currently conducted for these individuals. In time, the enhanced surveillance of persons at increased risk of CJD will provide estimates of transmission risks and of the impact of iatrogenic exposures on mortality.


Knowledge about iatrogenic transmission of CJD is being gained by the follow-up of individuals who have been identified as ‘at-risk’ of CJD in the UK. This enhanced surveillance may need to be sustained for many years.

Prions in Plasma of Patients with Sporadic Creutzfeldt-Jakob Disease

Safar,J.G1,3, Geschwindm M.D2,3, Letessier, F1, Kuo, A1, Pomeroy, K1, Deering, C1,Serban, A1, Groth, D1, Miller, B.L2,3, DeArmond, S.J1,4, Prusiner, S.B1,3,51
Institute for Neurodegenerative Diseases, 2Memory and Aging Center,Departments of 3Neurology, 4Pathology, and 5Biochemistry and Biophysics,University of California, San Francisco, California 94143


vCJD case study highlights blood transfusion risk

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States


IN response to the following ;


MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob diseasein the United States

Email Terry S.

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 inthe 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?

I URGE you to consider my response once again. I think I have been provencorrect now.



Hardcover, 304 pages plus photos and illustrations.ISBN 0-387-95508-9

June 2003

BY Philip Yam


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.

IN REALITY, sporadic CJD is 1 in 9,000 in 50 years of age and above, and that's with a inadequate or what I call passive surveillance system. see below ;

Dr. William Shulaw, a veterinarian with The Ohio State University extension service, is involved in a nationwide program to eradicate scrapie, the form of BSE found in sheep. Shulaw said the chances of a person getting sporadic Creutzfeldt- Jakobdisease is about one in a million. But that's the total population, infants,children, adults and the elderly. Chances increase to one in 9,000 when the group is restricted to those age 50 and older.

FURTHER into my journal of neurology article, some years later, again, sadly, I was proven correct ;


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.

and today we indeed find ;

PLEASE NOTE IN USA CJD UPDATE AS AT JUNE 2007, please note steady increasein ''TYPE UNKNOWN'' CJD IN THE USA ;

1 Acquired in the United Kingdom; 2 Acquired in Saudi Arabia; 3 Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007); 4 Includes 17non-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)

HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory

snip... see full text ;


Diagnostic Utility of CSF Biomarkers and General CSF Findings in a U.S Sporadic CJD Cohort

Geschwind, MD; Haman, A; Torres-Chae, C; Raudabaugh, BJ; Devereux, G;Miller, BL University of California, San Francisco, USA


The diagnostic utility of CSF biomarkers, including 14-3-3 protein, neuron-specific enolase (NSE), AB42, total Tau (T-Tau), and phosphorylated Tau (PTau)/ T-Tau ratio are often are used for sporadic CJD (sCJD) diagnosisis controversial. We have previously reported the CSF 14-3-3 protein to have poor sensitivity for CJD diagnosis. In this study, now report the sensitivity and specificity of several CSF biomarkers and general characteristics in a U.S. cohort of sCJDand non-prion rapidly progressive dementia (RPD) controls (Non-CJD cohort)subjects.


Clinical diagnoses are made through review of medical records, clinical evaluation, and in many cases pathology. Data is stored in a secure clinical relational database,which was queried for various CSF findings, including cell count, protein, IgG index, oligoclonal bands (OCBs), 14-3-3, NSE, T-Tau in patients with probable or definite sporadic CJD and non-prion rapidly progressive dementias (RPD), most of whom were referred to our center with a potential diagnosis of CJD. For probable sCJD diagnosis, we used UCSF criteria that are modified from WHO to substitute MRI for 14-3-3. T-Tau and NSE were considered positive if > 1300pg/ml and > 35 ng/ml, respectively. For this analysis, ambiguous 14-3-3 results were considered as negative.


14-3-3 protein (n=149) sensitivity was only 48% (47% for definite; 50% for probable sCJD). NSE (n=49) sensitivity was 63% (66% for definite; 59% for probable sCJD). T-Tau (n=28) was the most sensitive at 68% (69% for definite; 67% for probable sCJD). The specificity of these biomarkers among our CJD and RPD controls(n=72) was 66% for 14-3-3 (n=47), 81% for NSE (n=21), and 100% for T-Tau(n=7). The 14-3-3 had the lowest sensitivity and specificity. Mildly elevated CSFprotein (<100>20, is uncommon in sCJD.


In a cohort from a major U.S. CJD referral center, the 14-3-3 is neither sensitive nor specific for sCJD. NSE and T-Tau also show poor sensitivity for sCJD. T-Tau may be more specific than 14-3-3 and NSE, but our “n” is small. WHO sCJD criteria should be revised; by eliminating 14-3-3 and including brain MRI into the criteria. We are currently analyzing the effects of disease duration and codon 129 polymorphism on these CSF biomarker results.


I am beginning to think that the endless attempt to trackdown and ban, potential victims from known BSE Countries from giving blood will be futile. You would have to ban everyone on the Globe eventually? AS well, I think we MUST ACT SWIFTLY to find blood test for TSE's, whether it be blood test, urine test, eyelid test, anything at whatever cost, we need a test FAST. DO NOT let the incubation time period of these TSEs fool you. To think of Scrapie as the prime agent to compare CJD, but yet overlook the Louping-ill vaccine event in 1930's of which 1000's of sheep where infected by scrapie from a vaccine made of scrapie infected sheep brains, would be foolish. I acquired this full text version of the event which was recorded in the Annual Congress of 1946 National Vet. Med. Ass. of Great Britain and Ireland. From the BVA and the URL is posted in my (long version). U.S.A. should make all human/animal TSE's notifiable at all ages,with requirements for a thorough surveillance and post-mortem examinations free of charge, if you are serious about eradicating this horrible disease in man and animal.






BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPScC-terminal Truncated Fragments

Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini,M3; Lescoutra, N4; Ruchoux,MM4; Casalone, C5; Caramelli, M5; Ferrari, S3;Lasmezas, C6; Deslys, J-P4; Monaco, S31University of Verona, of Neurologicaland Visual Sciences, Italy; 2CEA, IMETI/SEPIA,France; 3University of Verona,Neurological and Visual Sciences, Italy; 4IMETI/SEPIA,France; 5IZSPLVA,Italy; 6The Scripps Research Insitute, USA

The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, remains still unknown. The marked disease phenotype heterogeneity observed in sCJD is thought to be influenced by the type of proteinase K-resistant prion protein, or PrPSc (type 1 or type 2 according tothe electrophoretic mobility ofthe unglycosylated backbone), and by the hostpolymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type, distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD subtypes. Based on the combination of CTFs and PrPSc type, we distinguished three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of allgenotypes, ;(ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V-2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJD subtype M/V-2 shared molecular and pathological features with an atypical form of BSE, named BASE, thus suggesting a potential link between the two conditions. This connection was further confirmed after 2D-PAGE analysis, which showed an identical PrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, we obtained brain homogenates from Cynomolgus macaques intracerebrally inoculatedwith brain homogenates from BASE. Samples were separated by using a two dimensional electrophoresis (2D-PAGE) followed by immunoblotting. We here show that the PrPSc pattern obtained in infected primates is identical to BASE and sCJDMV-2 subtype. These data strongly support the link, or at least a common ancestry, between a sCJD subtype and BASE. This work was supported by Neuroprion (FOOD-CT-2004-506579)

see full text mad cow BASE USA ;

Transmissible Mink Encephalopathy TME




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