Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic surveyBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b1442 (Published 21 May 2009) Cite this as: BMJ 2009;338:b1442
- Jonathan P Clewley, clinical scientist1,
- Carole M Kelly, research epidemiologist1,
- Nick Andrews, statistician1,
- Kelly Vogliqi, research technician1,
- Gary Mallinson, clinical scientist2,
- Maria Kaisar, research scientist2,
- David A Hilton, consultant neuropathologist3,
- James W Ironside, professor of clinical neuropathology4,
- Philip Edwards, biomedical scientist3,
- Linda M McCardle, biomedical scientist4,
- Diane L Ritchie, research assistant4,
- Reza Dabaghian, research scientist1,
- Helen E Ambrose, research scientist1,
- O Noel Gill, consultant epidemiologist1
- 1Centre for Infections, Health Protection Agency, London NW9 5EQ
- 2Bristol Institute for Transfusion Sciences, National Blood Service, Bristol BS10 5ND
- 3Department of Histopathology, Derriford Hospital, Plymouth PL6 8DH
- 4National CJD Surveillance Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU
- Correspondence to: JP Clewley
- Accepted 15 December 2008
Objective To establish with improved accuracy the prevalence of disease related prion protein (PrPCJD) in the population of Britain and thereby guide a proportionate public health response to limit the threat of healthcare associated transmission of variant Creutzfeldt-Jakob disease (vCJD).
Design Cross sectional opportunistic survey.
Study samples Anonymised tonsil pairs removed at elective tonsillectomy throughout England and Scotland.
Setting National anonymous tissue archive for England and Scotland.
Main outcome measure Presence of PrPCJD determined by using two enzyme immunoassays based on different analytical principles, with further investigation by immunohistochemistry or immunoblotting of any samples reactive in either assay.
Results Testing of 63 007 samples was completed by the end of September 2008. Of these, 12 753 were from the birth cohort in which most vCJD cases have arisen (1961-85) and 19 908 were from the 1986-95 cohort that would have been also exposed to bovine spongiform encephalopathy through infected meat or meat products. None of the samples tested was unequivocally reactive in both enzyme immunoassays. Only two samples were reactive in one or other enzyme immunoassay and equivocal in the other, and nine samples were equivocally reactive in both enzyme immunoassays. Two hundred and seventy six samples were initially reactive in one or other enzyme immunoassay; the repeat reactivity rate was 15% or less, depending on the enzyme immunoassay and cut-off definition. None of the samples (including all the 276 initially reactive in enzyme immunoassay) that were investigated by immunohistochemistry or immunoblotting was positive for the presence of PrPCJD.
Conclusions The observed prevalence of PrPCJD in tonsils from the 1961-95 combined birth cohort was 0/32 661 with a 95% confidence interval of 0 to 113 per million. In the 1961-85 cohort, the prevalence of zero with a 95% confidence interval of 0 to 289 per million was lower than, but still consistent with, a previous survey of appendix tissue that showed a prevalence of 292 per million with a 95% confidence interval of 60 to 853 per million. Continuing to archive and test tonsil specimens, especially in older birth cohorts, and other complementary large scale anonymous tissue surveys, particularly of post-mortem tissues, will further refine the calculated prevalence of PrPCJD.
We thank Chris Kelly, Sally Hayes, Jahnavi Joshi, Tom Turner, and Lisa Walker for laboratory testing; Caroline Lawson for administrative help; Philip P Mortimer and David W G Brown for advice; Colin Southwell for help with the tender process; Philip Minor and Jillian Cooper of the National Institute for Biological Standards and Control for collaboration on the initial validation studies; Alan Hill for help with Excel programs; Peter Horby, Frankie Lever, and Anna Molesworth for initial work establishing the national anonymous tissue archive; Rosemary Baugh for assistance with the immunohistochemistry in Plymouth; Suzanne Lowrie and Margaret LeGrice for assistance with the immunohistochemistry in Edinburgh; all the ENT consultants, pre-assessment nurses, theatre staff, and pathologist collaborators at 134 hospitals; Michelle Clarke, Johanna Reilly, and Joan Sneddon at Health Protection Scotland; Hester Ward and Mark Head at the National CJD Surveillance Unit; Neil Raven and Joanne George for the provision of a brain from a hamster infected with scrapie; Danny Matthews and Sue Bellworthy of the Veterinary Laboratories Agency’s TSE Archive for provision of tonsil tissue from sheep with scrapie and from uninfected sheep; Jonathan D F Wadsworth and John Collinge at the MRC Prion Unit for providing control negative tonsils and 3000 untested tonsils, and vCJD tonsil and brain samples.
This study was originally proposed by a Medical Research Council and Department of Health committee. It was overseen by an Expert Advisory Group on the Laboratory Testing Strategy for Large Scale Abnormal Prion Prevalence Studies with a membership of N Andrews, D W G Brown, J P Clewley, J Cooper, R Eglin, E Gadd, O N Gill, M Head, D A Hilton, J W Ironside, G Jackson, C M Kelly, G Mallinson, D Matthews, P Minor (chair), P P Mortimer, N Raven, J R Stephenson, and J D F Wadsworth.
Data from this anonymous tonsil survey were discussed in public at meetings of the Spongiform Encephalopathy Advisory Committee (www.seac.gov.uk) in December 2007 and April 2008; and see a statement issued in August 2008 (www.seac.gov.uk/statements/state-cjd-infections.pdf).
Contributors: JPC designed and analysed the laboratory studies and wrote the paper with ONG, who initiated the study and did clinical and epidemiological analyses. CMK recruited hospitals to the study and did epidemiological analyses. NA did statistical and epidemiological analyses. KV organised the National Anonymous Tissue Archive laboratory, tonsil processing, and enzyme immunoassay testing. GM, MK, and RD did the immunoblotting. DAH, PE, JWI, LMcC, and DLR did the immunohistochemistry. JWI provided some of the vCJD clinical tissue used in the work. HEA did the codon 129 genotyping. JPC and ONG are the guarantors.
Funding: The study was funded by the Department of Health; the work was carried out independently of the funder.
Competing interests: None declared.
Ethical approval: The study received ethical approval from the Trent Multi-centre Research Ethics Committee (MREC/03/4/073). None of the participants in the study was subsequently identifiable.
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