Behind The Medical Headlines

Variant Creutzfeldt-Jakob disease and the risks from blood transfusion

• Dr AC Ghani, Ph.D., Reader in Infectious Disease Modelling, Infectious Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.
• Dr P Clarke, Ph.D., Lecturer in Statistics, Infectious Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.

Summary

196 people have died from vCJD in the UK since it was first detected in 1996. While the primary route of transmission has been through eating infected meat, concern has recently focussed on onward human to human transmission. In this article Dr Azra Ghani reviews vCJD and the risks from blood transfusion.

Declaration of interests: This work was supported by the Department of Health. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.

Whilst the incidence of clinical cases of variant Creutzfeldt-Jakob disease (vCJD) has declined in recent years, concern has increased over the possibility of an epidemic arising through blood transmission. Here we review important aspects of the disease and its epidemiology and consider their implications for the risks from blood transfusion.

vCJD

vCJD is one of a family of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies (TSEs). The oldest known disease of this type is scrapie, which affects sheep and has been endemic in most parts of the world for over 200 years. Bovine Spongiform Encephalopathy (BSE) or ‘mad cow disease’ also belongs to this family of diseases. Human forms of the disease include CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia and kuru. The latter was first discovered in the 1950s among the Fore population in Papua New Guinea, with the epidemic resulting in approximately 2,500 deaths from 1957 onwards. The disease was transmitted through cannabilistic consumption of, or contact with, human tissues during funeral rites. Sporadic cases of CJD occur worldwide with an annual incidence of approximately one case per million of the population, whilst inherited forms of the disease are even rarer (approximately 10% of all cases of CJD). Transmissible Spongiform Encephalopathies are characterised by spongiform changes in the brain, neuronal loss and amyloid plaque formation, which occur with the accumulation of an abnormal protease-resistant prion in the brain. A particular characteristic shared by these diseases is a long and variable incubation period, typically of many years, during which there is little or no detectable immune response to the pathogen.

Epidemiology

vCJD was first identified in the UK in 1996 and was distinguished from classical CJD by its different clinical presentation and neuropathology.¹ Through March 2006 there have been 154 deaths from vCJD in the UK with a further six probable cases remaining alive. Elsewhere cases have been reported in Ireland, France, Italy, United States, Canada, Saudi Arabia, Portugal and Japan.

The incidence of deaths in the UK peaked in 2000 with 28 deaths and has declined thereafter with only 5 deaths in 2005. The median age at death has remained stable at approximately 28 years, with a significant excess of cases in those aged 10 to 40 years. This excess is most likely to be due to increased susceptibility in the young, but could also be due to greater exposure. Host genetics also influence susceptibility, with all clinical cases to date having a genetic characteristic shared by approximately 40% of the population (methionine homozygous at codon 129 of the prion protein gene). Recent findings have shown that other genetic groups are also susceptible to infection² but to date no clinical cases have been observed.

Transmission

The primary route of transmission of vCJD from cattle to humans is believed to occur through consumption of BSE-infected beef and beef products. Over the course of the BSE epidemic in Great Britain it is estimated that up to two million infected animals were slaughtered for human consumption. Whilst the majority of the population was therefore likely to have been exposed to the infectious agent, it is still uncertain to what extent the population is infected. Studies in mice and hamsters have demonstrated a substantial species barrier for these types of disease and hence it is likely that transmission from cattle-to-cattle is much more effective than from cattle-to human.

Recently, concern has arisen over the possibility of onward human-to-human transmission. High levels of the infectious prion agent are believed to aggregate in regions of the body including the brain, the central nervous system and lymphoreticular tissues. One theoretically possible source of transmission is via surgical instruments used on multiple patients which permit transmission because prions are able to withstand high temperatures and sterilisation methods. A second potential transmission route is via blood transfusion, which was demonstrated to be feasible in sheep studies.³ More recently, three vCJD infections have been identified in UK patients who received red blood cell transfusions using blood donated from individuals who later went on to develop vCJD.^2,4,9 The first transmission occurred through blood donated from the index patient 3·5 years before onset of disease and resulted in the onset of clinical vCJD in the recipient 6·5 years after receiving the blood transfusion.⁴ The second transmission occurred through blood donated by the index patient 18 months before onset of disease.² In this case, the recipient died from unrelated causes five years after receiving the blood transfusion, but at autopsy was found to have signs of vCJD infection in her spleen.

Risks from blood transfusion

The risk of acquiring any infection from a blood transfusion will depend on the prevalence of that infection in the population (and hence in the blood supply). The prevalence of vCJD infection in the UK population remains highly uncertain. To date, our best estimate comes from a large-scale retrospective survey of tonsil and appendix tissues removed during routine operations between 1995 and 2000.⁵ This survey, designed to focus on the 10–30 age group, found three appendix tissues that were positive for infection in a sample of 12,674 tissues, giving a prevalence estimate of 237 per million (95% confidence interval 49–692 per million) if the test is assumed to detect all infections. Translated into numbers of people, this suggests approximately 3,800 infected individuals among those aged 10–30 years. In contrast, a smaller prospective study of tonsil tissues did not detect any positives.⁶ These results are consistent with the retrospective study: the sample size was smaller, and around half of this sample were tissues removed from those aged under nine, who were less likely to have been exposed to BSE infection. There are, however, a number of uncertainties to consider when interpreting these results. On the one hand, it is likely that the ability of the tests to detect infection will increase over the course of the incubation period but will never be perfect, meaning there are more people infected than suggested by these results. On the other hand, it is possible that one or more of the three positives may be ‘false-positives’ which would suggest that the true prevalence is lower. In addition, it is not possible to say whether those infected in this way are themselves infectious to others, or even whether they will go on to develop clinical disease within their normal lifespan.

The risk of acquiring infection will also depend on the risk of receiving infected blood via transfusion. In a study in North-East England, the mean age of those receiving a transfusion was 63 years. As those in the 10–50 age-group are most likely to have acquired vCJD infection through infected beef, they will have donated infected blood and thus led to the first generation of blood-related infections. However, the eventual size of the epidemic will be limited by the age characteristics of the second, and subsequent, generations of infections, who tend to be transfusion recipients (mean age 60-plus) and who donate relatively small amounts of blood.⁷ Conversely, blood donors are normally aged 18 to 65 with most in the 40–50 age-group. As it is the 10–50 age-group who were most affected by vCJD, this suggests that the first generation transmission could be effective, but that susequent generations from these transfusion recipients (aged 60-plus) may be less effective since this group donate relatively little blood. Modelling work is required to assess whether a self-sustaining epidemic (i.e. several generations of transmission) is possible before measures to eliminate onward transmission are introduced (see below).

A study co-ordinated by the National CJD Surveillance Unit in Edinburgh has traced and followed up all individuals known to have received blood components donated by vCJD patients.⁴ As of 30 January 2006, 18 of the vCJD cases were known blood donors and could be traced to donation centres. Sixty-six components of blood were transfused from these patients to 66 named recipients, 26 of whom are currently alive.

Measures to reduce the risks from blood transfusion

Several measures have been put in place in the UK to reduce the risks from blood transfusion. From 1997 onwards, all probable vCJD cases have been reported to the National Blood Service and any remaining blood donated by the cases is destroyed. Between July 1998 and October 1999, leucodepletion was phased in; recent research has suggested that approximately 40% of infectivity is removed through this process,⁸ but the effect of lower infectivity on the risk of infection is unclear. From April 2004, recipients of blood transfusions received since 1980 in the UK have been excluded from donating blood. In August 2004, this was extended to exclude apheresis donors who were unsure about whether they have had a blood transfusion.

Other blood products

Blood, or its derivatives, are used in a number of other products including clotting factors for haemophilia patients. Whilst transmission via these other products has not yet been observed, the potential risks of acquiring infection similarly depend on the prevalence of infection in the population. One particular concern is that such products are derived from large ‘pooled’ donations and, as such, the potential for receiving infected blood could be much greater. To reduce these risks, between November 1998 and December 1999, UK-sourced plasma was phased out in the manufacture of blood products.

Summary

The incidence of vCJD has continued to decline from its peak in 2000. However, there remains substantial uncertainty about the number of people harbouring infection, with recent survey results suggesting approximately 3,800 infected individuals in the 10–30 age-group. The risks of transmission via blood transfusion depend on this underlying prevalence of infection and on the age-dependent patterns of blood donation and transfusion. Measures are currently in place to reduce this risk including leucodepletion and a ban on donating blood for those who have previously received a blood transfusion.

References

1. Will RG et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996. 347:921–925.
2. Peden A et al. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364:527–528.
3. Houston F et al. Transmission of BSE by blood transfusion in sheep. Lancet 2000. 356:999–1000.
4. Llewelyn CA et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363:417–421.
5. Hilton DA et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 2004; 203:733–739.
6. Frosh A et al. Analysis of 2000 consecutive UK tonsillectomy specimens for disease-related prion protein. Lancet 2004; 364(9441):1260–2.
7. Wells AW et al. Where does blood go? Prospective observational study of red cell transfusion in North England. BMJ 2002; 325:803.
8. Gregori L et al. Effectiveness of leucoreduction for removal of infectivity of transmissible spongiform encephalopathies from blood. Lancet 2004; 364(9433):529–31.
9. HPA, New case of transfusion-associated variant-CJD. CDR Weekly, 2006: 16 (published online, http://www.hpa.org.uk/cdr/archives/archive06/news06_1.htm). London: Health Protection Agency.