BMJ  2006;332:1164-1165 (20 May), doi:10.1136/bmj.332.7551.1164

Editorial

A new human genotype prone to variant Creutzfeldt-Jakob disease

New evidence may rekindle fears of a larger epidemic and greater risk of iatrogenic spread

From the initial discovery of variant Creutzfeldt-Jacob disease (vCJD) in the United Kingdom a decade ago, there has been concern about the ultimate extent and magnitude of the epidemic.¹ Early estimates varied widely, with one model predicting up to 136 000 cases.² Fortunately, the magnitude of the epidemic at present seems to match the lower limit of the early estimates, with 161 definite or probable cases in the United Kingdom. However, the article by Ironside and colleagues on p 1186 may rekindle fears that a larger epidemic is an ongoing threat.³

The study reports a genotype analysis that identified the presence of the homozygous valine (VV) genotype in two samples of appendix tissue that harboured prion proteins. The implication of this finding of most concern is that it raises the possibility that ongoing iatrogenic transmission of vCJD may sustain the epidemic.

Why are the findings from this study worrisome? The current estimates of the prevalence of vCJD have primarily been restricted to populations with one specific genotype (MM), and all clinical cases have occurred in these individuals. This study is the first report of infection in individuals with the VV genotype. One case of infection, but not clinical disease, had been identified in one person with a heterozygous genotype (MV).⁴ The fear is that the 60% of people with non-MM genotypes may be at risk of developing the condition, possibly with longer incubation periods.⁵ Alternatively, these people may be asymptomatic carriers who might transmit the condition to other susceptible individuals.

It is important to be cautious in interpreting the results of this study. The study shows the existence of the prion protein in two tissue samples, not clinical evidence of vCJD in two patients. The study also provides no evidence to suggest that tissue from these two people could transmit vCJD to others.

Policy implications

Nevertheless, there are compelling reasons why health officials should take notice. It is conceivable that, having jumped the species barrier, transmission of the prion within the species becomes easier. This is supported by case reports, which suggest that vCJD, unlike classic CJD, can be transmitted through blood transfusion.^{4 6 7} Given that long incubation periods (up to 30 years) have been described in cases of iatrogenic transmission of classic CJD,⁸ it is reasonable to consider that there are people in an extended preclinical stage of vCJD during which their tissue, in particular their blood, may pose an infectious risk to others.

On the basis of this evidence, should health officials take precautionary actions to protect against this risk? Several countries have instituted measures to protect against transmission of vCJD through transfusion and these measures seem to have at least been partly validated as new evidence has emerged.⁹

However, there are real problems with continuing and, in particular, extending this approach. Apart from the financial costs, measures to prevent transmission of vCJD reduce the pool of blood donors. And strategies such as rejecting donors on the basis of their country of residence are blunt instruments that, while protecting against a proportion of the risk, also eliminate many other donors who pose no risk. At some point the sustainability of continuing such precautionary actions will come into question. This will be particularly true as new infectious threats emerge that further reduce the donor pool, a pool that may not be able to withstand further reduction.

Health officials will have to consider other strategies to reduce the threat of iatrogenic infection. Efforts are currently under way to develop techniques to reduce prion contamination of medical and surgical instruments.¹⁰ Similarly, techniques that reduce prion infectivity of transfusions, such as specialised forms of leukoreduction, could also be pursued.¹¹ These technologies are not developed to an extent that they offer a viable solution to the dilemma, however.

The ideal solution would be to develop a test that would identify people with presymptomatic vCJD. A blood test, or test of easily accessed tissue, would allow preventive precautions to be selectively applied to those with positive results, thereby limiting the negative impact of wider measures. However, developing an accurate test poses a substantial practical challenge. It will also pose difficult ethical questions, such as whether positive individuals should be informed that they have a condition which may or may not develop and for which there is no treatment.¹²

Studies such as the one by Ironside and colleagues³ are essential to the continuing effort to control the extent of the epidemic and highlight the urgent need for ongoing surveillance for vCJD. They also pose challenges to health officials who have to formulate policies comprising difficult trade-offs based on uncertain evidence. Such decision making dilemmas will probably become more common as as society becomes increasingly risk averse.

Department of Medicine, Toronto General Hospital, University Health Network, Toronto, ON, Canada M5G 2C4
(kumanan.wilson{at}uhn.on.ca)

Office of Public Health Practice, Public Health Agency of Canada, Ottawa, ON

---

Research p 1186

Competing interests: None declared.

References

1. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347: 921-5.[CrossRef][ISI][Medline]
2. Ghani AC, Ferguson NM, Donnelly CA, Anderson RM. Predicted vCJD mortality in Great Britain. Nature 2000;406: 583-4.[CrossRef][Medline]
3. Ironside JW, Bishop MT, Connolly K, Hegazy D, Lowrie S, Grice ML, 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]
4. 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][ISI][Medline]
5. Bishop M, Hart P, Aitchison L, Baybutt H, Plinston C, Thomson V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurology 2006;5: 393-398.[Medline]
6. Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;363: 417-21.[CrossRef][ISI][Medline]
7. Wilson K, Code C, Ricketts MN. Risk of acquiring Creutzfeldt-Jakob disease from blood transfusions: systematic review of case-control studies. BMJ 2000;321: 17-9.[Abstract/Free Full Text]
8. Brown P, Preece M, Brandel JP, Sato T, McShane L, Zerr I, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000;55: 1075-81.[Abstract/Free Full Text]
9. Wilson K, Ricketts MN. The success of precaution? Managing the risk of transfusion transmission of variant Creutzfeldt-Jakob disease. Transfusion 2004;44: 1475-8.[Medline]
10. Fichet G, Comoy E, Duval C, Antloga K, Dehen C, Charbonnier A, et al. Novel methods for disinfection of prion-contaminated medical devices. Lancet 2004;364: 521-6.[CrossRef][Medline]
11. Sowemimo-Coker S, Kascsak R, Kim A, Andrade F, Pesci S, Kascsak R, et al. Removal of exogenous (spiked) and endogenous prion infectivity from red cells with a new prototype of leukoreduction filter. Transfusion 2005;45: 1839-44.[Medline]
12. McCullough J, Anderson D, Brookie D, Bouchard JP, Fergusson D, Joly J, et al. Consensus conference on vCJD screening of blood donors: report of the panel. Transfusion 2004;44: 675-83.[CrossRef][Medline]

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