NR AQAX
AU Gore,S.M.
TI More than happenstance - Creutzfeldt-Jakob-disease in farmers and young-adults
QU British Medical Journal 1995 Nov 25; 311(7017): 1416-8
IA http://bmj.bmjjournals.com/cgi/content/full/311/7017/1416/a
PT Article
VT
In 1986, four years after a change in the processing of offals - including those from sheep infected with scrapie - into cattle meal, the first British case of bovine spongiform encephalopathy was confirmed.
Median incubation period in cattle is around four to five years[i] By 14 April 1995, bovine spongiform encephalopathy had been confirmed in 53.3% of dairy herds, 14.7% of beef suckler herds, and 33.8% of all herds with adult breeding cattle; people who work on farms without confirmed cases of bovine spongiform encephalopathy may, however, have worked on farms with infected, but not affected, cattle. The aim of ongoing studies in cattle is to find evidence of direct transmission of bovine spongiform encephalopathy by the two suggested means of transmission of scrapie in sheep: from mother to offspring or between unrelated animals around parturition.
The incubation period of human spongiform encephalopathies - Kuru and Creutzfeldt-Jakob disease - is poorly estimated from data[ii] but is apparently in the range 15-40 years, possibly shorter in people who were young at exposure. The potential for the agent responsible for bovine spongiform encephalopathy to cross species barriers after occupational or dietary exposure including exposure to cattle meal by ingestion or inhalation - has been a major concern for human health. Whether the agent is pathogenic to humans cannot be known by direct experimentation. Thus, surveillance of cases of sporadic Creutzfeldt-Jakob disease - in terms of occupational distribution, temporal changes in incidence, and dietary correlations - is the only way to get early warning of pathogenesis of bovine spongiform encephalopathy in humans. British surveillance of Creutzfeldt-Jakob disease was therefore reactivated in May 1990,[iii] and a grant from the European Community in 1993 enabled surveillance projects elsewhere in Europe to share common diagnostic criteria, methodologies, and case control questionnaires. Two observations from the other participating countries set the British data (see below) in wider context: the incidence of Creutzfeldt-Jakob disease was similar in France, Germany, Italy, the Netherlands, and Britain in 1993-4 (about 0 72 cases per million person years); and, across countries, the reported incidence in dairy farmers was consistently higher than in all farmers (pooled estimates: 6.31 v 0.74 cases per million person years).[iii]
Creutzfeldt-Jakob disease in British farmers
Based on the 1991 population and deaths from sporadic Creutzfeldt-Jakob disease in the United Kingdom from 1 May 1990 to 2 March 1995, the age specific incidence of the disease (per million person years) was estimated to be 0.05 (ages 40-44, 1 case), 0.42 (ages 45-49, 7 cases), 0.62 (ages 50-54, 9 cases), 1.80 (ages 55-59, 25 cases), 2.62 (ages 60-64, 36 cases), and 2.06 (ages 65 and over, 89 cases), with no cases for the age group 15-39 (R G Will, personal communication). These age specific incidences (irrespective of sex) were used in conjunction with the age distribution of farmers in England and Wales - available from the 1990 European Community structure survey (C Jennings, personal communication) - to derive the expected age appropriate incidence of sporadic Creutzfeldt-Jakob disease in farmers: 0.77 per million person years (male or female, full or part time employment, and including spouses and other family members). The structure survey gives the number of people employed in farming in England and Wales as 442,300, 136,440 of them in dairy farming. Corresponding numbers for the United Kingdom - including Scotland and Northern Ireland - have been arrived at on a population pro rata basis: that is, multiplying by 1.13 and rounding up to nearest thousand, to give 500,000 and 155,000 respectively. The number of people employed on farms with adult cattle is not easily available but is unlikely to exceed twice the number in dairy farming. An upper limit of 310,000 has been assumed (see table). An estimated 105,000 of these 310,000 (33.8%: rounded up to nearest thousand) work on farms with cattle affected with bovine spongiform encephalopathy.
Probability of occurrence of Creutzfeldt-Jakob disease in British farm workers and their families
Farms with adult cattle
Affected by Not affected by
All Dairy bovine bovine
farms farms All spongiform spongiform
encephalopathy encephalopathy
Population
size* 500,000 155,000 310,000** 105,000 205,000
Expected No
of cases in 2.31 0.7161 1.4322 0.4851 0.9471
six years
Probability
of cases:
At least 1 0.90 0.51 0.76 0.38 0.61***
At least 2 0.67 0.16 0.42 0.09 0.24
At least 3 0.41 0.036 0.17 0.013 0.07
At least 4 0.20 0.006*** 0.06 0.0016*** 0.016
At least 5 0.085*** 0.00087 0.016*** 0.00015 0.0029
At least 6 0.031 0.00010 0.0036 0.000012 0.00045
At least 7 0.010 0.00001 0.0007 0.000001 0.00006
*Rounded up to nearest thousand. **Upper limit ***Confirmed cases.
EXPECTED INCIDENCE OF CREUTZFELDT-JAKOB DISEASE
The expected number of cases of sporadic Creutzfeldt-Jakob disease during the six years from 1 May 1990 to 30 April 1996 in people who work on British farms at time of diagnosis is thus: 0.77 (expected age appropriate incidence per million person years)x0.5 million x6 years=2.31. Based on this Poisson expectation,[iv] the table shows the probability of observing n or more actual cases for n= 1, 2, . . . 7. The probability of five or more cases in farm workers is 0.085.
If we restrict attention to people who work on British dairy farms the expected number of cases of sporadic Creutzfeldt-Jakob disease during six years is 0.72, and the probability of observing four of more confirmed cases is 0.006.
For people who work on British farms with adult cattle, the expected number of cases in six years is 1.43, and the probability of observing five or more confirmed cases is 0.016. Subdivision of farms with adult cattle according to whether cattle are affected with bovine spongiform encephalopathy suggests that the probability of observing four or more cases from affected farms and one or more from unaffected farms is 0 0016x0.61, or 1 in 1,000.
All four confirmed cases of Creutzfeldt-Jakob disease in people who worked on farms affected by bovine spongiform encephalopathy were male, lifelong, full time farm workers. The 1990 European Community structure survey reports that 44% of all farm labour is performed by men working full time. I estimate that 46,000 men work full time on British farms with cattle affected by bovine spongiform encephalopathy: on the basis of 0.2134 cases of sporadic Creutzfeldt-Jakob disease expected in six years, the probability of observing four or more confirmed cases in such men is less than 1 in 10,000.
FURTHER STUDIES
Possible occupational exposure to the agent responsible for bovine spongiform encephalopathy (or other spongiform encephalopathy) agent must be rigorously researched therefore. If the bovine spongiform encephalopathy agent is implicated it is likely that any such exposure first occurred in the early 1980s when cattle were also first exposed. Have there been changes in farm practices, including changes in farm workers' diet, that have limited possible occupational exposures since the first cases of bovine spongiform encephalopathy were confirmed? Do historical or current farm practices differ between lifelong farm workers and others, between full time and part time farm workers, between dairy and other cattle farmers, or between farming families in which Creutzfeldt-Jakob disease has occurred and other farming families? The European data warn that aspects of dairy farming other than working with herds affected by bovine spongiform encephalopathy could be implicated in higher incidences of Creutzfeldt-Jakob disease in dairy farmers.[iii]
The potential for bias in case-control comparison of recalled diet when the item of interest is public knowledge[v,vi] has been underlined elsewhere.[iii] Transmission experiments in mice have begun with brain tissue from farmers who have died from Creutzfeldt-Jakob disease and whose herds were affected by bovine spongiform encephalopathy, but these will require two to three years for completion.
Creutzfeldt-Jakob disease in young adults
Three cases of sporadic Creutzfeldt-Jakob disease in people aged under 40 have been reported in the United Kingdom since May 1990,[vii-ix] two of them in people aged under 20. About 21 million persons in the United Kingdom are aged 15-39, and the incidence of Creutzfeldt-Jakob disease increases with age (see above). The Poisson probability of observing n or more cases of sporadic Creutzfeldt-Jakob disease during six years in the age group 15-39 - if the sporadic incidence is taken as 0 01 or as 0 001 per million person years (a fifth or a fiftieth of that for the age group 40-44) - can easily be computed based on 1.26 or 0.126 expected cases. If the higher of the two postulated incidences is the more reasonable, three or more cases in people aged under 40 in six years are not untoward (P=0.13) but four or more begins to be (P=0.04). Even three or more cases are highly improbable if the alternative postulate applies (P=0.0003).
A clear epidemiological priority is to pool data from comparable European surveillance studies of Creutzfeldt-Jakob disease to derive a best estimate of incidence for people aged 15-39. A new environmental or dietary exposure to a spongiform encephalopathy pathogenic to humans is likely to be first evident in young adults because background sporadic cases are rare and the incubation period may be shorter in young people. Transmission experiments with brain tissue from young adults who have died from Creutzfeldt-Jakob disease will be needed.
Taken together, cases of Creutzfeldt-Jakob disease in farmers and young adults are more than happenstance.[x] They signal an epidemiological alert to investigate intensively possible exposures - farm related and dairy - and to devise means of doing so that are minimally compromised by pre-existing publicity.
i. Spongiform encephalopathy Advisory Committee. Transmissible spongiform encephalopathies: a summary of present knowledge and research. London: HMSO, 1994.
ii. Woolridge M. A study of the incubation periods or age at onset of the transmissible spongiform encephalopathies/prion diseases [PhD thesis] London: University of London, 1995.
iii. National CJD Surveillance Unit and Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine. Creutzfeldt-Jakob disease surveillance in the United Kingdom. Edinburgh: National CJD Surveillance Unit, 1995
iv. Gore SM, Altman DG. Statistics in practice. London: BMA, 1982:95.
v. Watkins A Mad cow disease: now fifth farmer is suspect. Today 1995 October 25:1-2
vi. Sinclair K Scot sues over death from CJD. Herald 1995 October 25:11.
vii. Watkins A. Now CJD kills dad aged 30. Today 1995 November 10:8.
viii. Britton TC, Al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK.Lancet 1995;346:1155.
ix. Bateman D, Hilton D, Loce S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in an 18-year-old in the UK. Lancet 1995;346: 1155-6.
x. Bibby J. Quotes, damned quotes, and... Milton Keynes: Open University, 1983:45.
ZR 9
AD
MRC Biostatistics Unit Institute of Public Health Cambridge CB2 2SR Sheila M Gore senior statistician
Department of Epidemiology and Biostatistics Erasmus University Medical School PO Box 1738 3000 DR Rotterdam Netherlands
SP englisch
OR Prion-Krankheiten G