Published 21 May 2009, doi:10.1136/bmj.b435
Cite this as: BMJ 2009;338:b435

Editorials

Prevalence of variant CJD in the UK

The limited number of cases and diagnostic problems make accurate measurement difficult

The number of cases of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom has decreased since 2000,¹ but controversy remains about how many people carry the infectious agent and will eventually develop disease. In the linked study (doi:10.1136/bmj.b1442), Clewley and colleagues add to the debate by assessing 63 007 pairs of tonsils for the only available marker of prion disease—the pathological, partially protease resistant, prion protein.² Although more than half of the samples came from people born between 1961 and 1995, when the risk of exposure to bovine spongiform encephalopathy (BSE) infection was high, no convincingly positive tonsil specimens were detected. The study estimates that the prevalence of vCJD in the British population is zero, but with a large confidence interval of 0 to 113 per million.

This result agrees with one UK survey of 2000 tonsil specimens,³ but it differs from another survey of 1427 tonsils and 11 247appendices, which found that more than 10 000 people were incubating the disease.⁴ However, despite the discrepancy, the 95% confidence intervals of the two studies overlap, indicating that the results do not differ significantly and that many people in the UK may be carriers. Is that reasonable?

The chance that no one in the UK is incubating the disease, as suggested by the lower confidence limit of Clewley and colleagues’ study,² is unlikely because backup calculations predict up to 100 new cases of vCJD in the next 50 years.⁵ This prediction seems reasonable unless most cases of vCJD were missed by surveillance in the past years. Is that possible?

Until December 2008, all 210 people reported to have vCJD (164 in the UK, 46 in other countries) were homozygous for methionine at the polymorphic codon 129 of the prion protein gene (PRNP), suggesting that genetic factors strongly influence the development of disease. Whether people who are heterozygous for methionine and valine or homozygous for valine at this codon (about 60% of the population) will develop vCJD in the future is still unknown. However, data from gene targeted transgenic mice indicate that these people are also susceptible to BSE and vCJD, although incubation periods are longer than in those who are homozygous for methionine.⁶

This notion is supported by information from three sources. Firstly, the identification of preclinical vCJD in a heterozygous patient who died of a non-neurological disorder five years after receiving an infected blood transfusion.⁷ Secondly, the identification of prion protein in the appendices of two people who were homozygous for valine at the polymorphic codon 129 of PRNP after a retrospective tonsil and appendix survey.⁸ Finally, the recently announced suspected case of vCJD in a heterozygous patient in the UK.⁹ Also, brain lesions in transgenic mice that are heterozygous for methionine and valine or homozygous for valine on codon 129 of the PrP gene are reportedly different from those seen in mice that are homozygous for methionine.⁶ This suggests that clinical signs, neuropathological lesions, and possibly magnetic resonance imaging scans of the brain might be different in patients who are not homozygous for methionine, which would make the available diagnostic criteria for vCJD inappropriate and mean that these patients are misdiagnosed as having sporadic CJD. However, data collected for more than 15 years in the UK and elsewhere in Europe by national surveillance centres found no evidence of cases of sporadic CJD in the UK that are clinically or pathologically different from those reported in other countries, suggesting that this scenario is highly unlikely.¹⁰

It is still possible that in people who are heterozygous for methionine and valine or homozygous for valine, the BSE agent is prevented from moving from the lymphatic tissues to the central nervous system, so that most of them do not develop clinical signs of disease. These subclinical carriers could be sources of infection for people who are homozygous for methionine at codon 129 of the PRNP gene through blood transfusion and surgical procedures, including major dental or ocular surgery.

Predicting the number of vCJD carriers in the UK is difficult for several reasons. Firstly, the best peripheral tissue for detecting the prion protein is not known. The best choice at the moment is lymphoreticular tissue, but both appendix and tonsil are occasionally negative in patients with vCJD^{11 12} and in blood donors who are infected with vCJD but do not develop disease.⁷ Secondly, it is not clear how soon after infection peripheral tissues become positive for the prion protein. Thirdly, most specimens will now be taken from people who are not exposed to BSE. Finally, any positive or negative results should be interpreted with caution because of the lack of a confirmatory test on infectivity. Repeating surveys of prion protein in tissue specimens may not yield further information unless a more sensitive and specific test is developed. Therefore, the precautionary measures already in force must be maintained to avoid transmission of vCJD between humans and surveillance of disease in the UK and in the rest of Europe should remain active.

Finally, Clewley and colleagues’ negative results indicate that public health authorities in other countries should not carry out such studies; an enormous number of samples would be needed to yield useful information because exposure to the BSE agent in the rest of the world is probably much lower than in the UK.

Cite this as: BMJ 2009;338:b435

¹ Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy

Research, doi:10.1136/bmj.b1442

---

Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. National Creutzfeldt-Jakob Disease Surveillance Unit (NCJDSU). CJD statistics. 2009. www.cjd.ed.ac.uk/figures.htm.
2. Clewley JP, Kelly CM, Andrews N, Vogliqi K, Mallinson G, Kaisar M, et al. Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey. BMJ 2009;338:b1442.[Abstract/Free Full Text]
3. Frosh A, Smith LC, Jackson CJ, Linehan JM, Brandner S, Wadsworth JD, et al. Analysis of 2000 consecutive UK tonsillectomy specimens for disease-related prion protein. Lancet 2004;364:1260-2.[CrossRef][Web of Science][Medline]
4. Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Ritchie D, et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 2004;203:733-9.[CrossRef][Web of Science][Medline]
5. Clarke P, Ghani AC. Projections of the future course of the primary vCJD epidemic in the UK: inclusion of subclinical infection and the possibility of wider genetic susceptibility. J R Soc Interface 2005;2:19-31.[Abstract/Free Full Text]
6. Bishop MT, Hart P, Aitchison L, Baybutt HN, Plinston C, Thomson V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol 2006;5:393-8.[CrossRef][Web of Science][Medline]
7. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004;364:527-9.[CrossRef][Web of Science][Medline]
8. Ironside JW, Bishop MT, Connolly K, Hegazy D, Lowrie S, Le Grice M, et al. Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study. BMJ 2006;332:1186-8.[Abstract/Free Full Text]
9. Watts S. Fears raised over new vCJD wave. BBC Online 17 Dec 2008. http://news.bbc.co.uk/1/hi/health/7788627.stm.
10. Ladogana A, Puopolo M, Croes EA, Budka H, Jarius C, Collins S, et al. Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada. Neurology 2005;64:1586-91.[Abstract/Free Full Text]
11. Wadsworth JD, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, et al. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 2001;358:171-80.[CrossRef][Web of Science][Medline]
12. Brandel JP, Heath CA, Head MW, Levavasseur E, Knight R, Laplanche JL, et al. Variant Creutzfeldt-Jakob disease in France and the United-Kingdom: evidence for the involvement of same agent strain. Ann Neurol (in press).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Ignorance and certainty

Jane Smith
BMJ 2009 338: b2156. [Extract] [Full Text]

Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey

Jonathan P Clewley, Carole M Kelly, Nick Andrews, Kelly Vogliqi, Gary Mallinson, Maria Kaisar, David A Hilton, James W Ironside, Philip Edwards, Linda M McCardle, Diane L Ritchie, Reza Dabaghian, Helen E Ambrose, and O Noel Gill
BMJ 2009 338: b1442. [Abstract] [Full Text] [PDF]

Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study

James W Ironside, Matthew T Bishop, Kelly Connolly, Doha Hegazy, Suzanne Lowrie, Margaret Le Grice, Diane L Ritchie, Linda M McCardle, and David A Hilton
BMJ 2006 332: 1186-1188. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

• (2009). Prevalence of Variant CJD-Related Prion Protein in the U.K.. JWatch Infect. Diseases 2009: 5-5 [Full text]  

Rapid Responses:

Read all Rapid Responses

when I say a word...

Philip A Smith
bmj.com, 29 May 2009 [Full text]

prions and blood transfusion

Frank E Boulton
bmj.com, 2 Jun 2009 [Full text]

Online poll

Find out more on doc2doc >>