Reopening the debate on the origins of vCJD

LONDON — It's a fair bet that the letters pages of the British Medical Journal will not be short of correspondence in the coming weeks. A paper in 13 October edition suggesting there may be no link between bovine spongiform encephalopathy (BSE) — or 'mad cow disease' — and variant Creutzfeldt-Jacob disease (vCJD), its human equivalent, is certain to spark a heated debate.And that, according to George Venters, the public health specialist at Lanarkshire Health Board who wrote the paper, is exactly what he intended. Venters, an epidemiologist with long experience of infectious diseases, is deeply troubled by what he calls 'speculation that has evolved into orthodoxy' on the causal link between the consumption of BSE-infected meat and variant CJD.Such is the sensitivity of his argument that it seems inconceivable it will not have the desired effect. Already, senior officials at the UK's Creutzfeldt-Jacob disease surveillance unit, based in Edinburgh, are penning a response to Venter's article (BMJ 2001, 323:858-861).The contents of the letter have not been revealed but it's almost inevitable that they will attempt to deconstruct his case and substantiate the available evidence that eating infected meat is the most probable cause of the disease in humans.At the core of Venter's argument is the accusation that the available medical evidence has been used to support a causal association between the two diseases, rather than challenge it. In short, he believes, variant CJD is not caused by the BSE prion and is not a new disease — it's simply that increased awareness has led to better diagnosis.To examine the evidence supporting the hypothesis, he applied a range of criteria. These included biological plausibility, strength of association, consistency of findings between different populations at different times and temporality of association — whether exposure to the cause precedes the development of disease.He also accounted for specificity — whether the cause triggers only the disease in question and the disease results only from that cause, as well as reversibility — is the disease prevented once the cause is removed?In terms of biological plausibility, Venters concluded that while the BSE prion can trigger encephalopathies in other species, there is no direct evidence that it"s infectious to humans. Furthermore, he argued, ingestion is an inefficient route of transmission of prions "other than by cannibalism". "To be infectious, the prion would have to survive cooking, digestion and the human immune system. Infection of humans from eating the BSE prion is therefore unlikely."On temporality, he argued that there was little parallel between the incidence of vCJD and population exposure to infection. He insisted that the pattern of distribution in any food borne epidemic displayed a characteristic curve when plotted on a graph, with initial small numbers giving way to a rapidly accelerating increase and, ultimately, a peak.And this should hold true whether the incubation is a matter of days, as with Escherichia coli 0157, or years, as with prions. "As these cattle entered the food chain they became a potential source of infections. Consequently, the rate at which humans were likely to have been exposed to infection should have paralleled that curve. Cases have been appearing since 1994 (but) their rate of increase then falls far short of what would be expected if this was a food borne infection."Confirmed cases of vCJD in the UK have fluctuated. In 1995 there were just three, rising to ten in years 1996 and 1997 and 18 in 1998. The following year they dipped to just 15, before jumping again to 28 in 200. But by the end of September this year, there were just 16 cases.On the question of specificity, Venters claimed that proponents of the link base their theory on the grounds that BSE prions and vCJD prions display similar physicochemical properties and strain typing. At best, he insists, this means specificity of the link "can only be inferred".There are other anomalies too, Venters argued. He claims the experts who made the link between infected meat and CJD never raised the possibility that it might be kuru - the prion encephalopathy found in the Fore people in Papua New Guinea and spread by cannibalism. There's no obvious source, he admitted, but the possibility should still be investigated.And it's entirely possible, he also claimed, that the appearance of this 'new disease' may simply have been a result of setting up the CJD surveillance unit back in 1990. As evidence, he points to the original letter from the unit published in the Lancet in 1996 (Lancet 1996, 347:921-925) that said the 10 index cases of variant CJD "would not ordinarily have been referred to the unit".But if the disease is not new and it's not transmitted through infected meat, how does Venters explain the deaths of five young people in the Leicestershire village of Queniborough from vCJD — something an official Government report blamed on traditional butchery practices? "It may be a cluster. You get clusters in cancer and all sorts of diseases. The presumption was that BSE was infectious to humans but the hypothesis testing process has not been done as rigorously as it should have been."The official line is that one of main characteristics in support of vCJD being a new disease is that it strikes people at a younger age than 'sporadic' CJD. But Venters pointed out that the original case described by H.G. Creutzfeldt in 1920 was a young girl of 23, "with clinical features and gross neuropathology entirely consistent with vCJD". "All I am doing is developing an argument," said Venters. "I'm looking for a robust argument (in return) and I have not received one."But Richard Knight, a senior figure at the CJD Surveillance Unit, believes Venter"s argument is not only "eccentric" but also emotionally damaging to those who have lost relatives or friends to vCJD. "I read Dr Venter's hypothesis and his rather ill-informed opinion, which expressed views that are decidedly eccentric. "He says there is no evidence of a relationship between BSE and vCJD — but that's not new. There have been a number of papers explaining how the relationship is by no means proven. "But the question is whether or not the agent which causes both is identical and that's been proven beyond any reasonable doubt. We have very hard evidence — and I say that bearing in mind that a scientific fact is simply true until the next experiment proves it to be false. "There's considerable evidence that BSE and vCJD agents have the same biological properties."Knight said that the peak period of exposure to infected meat would have been 1989 but some was still in the food chain as late as December 1995 — when mechanically recovered meat was banned.That means the minimum incubation period is about five years but it could potentially be much longer, he said. "There's a longer incubation period for Kuru — up to 45 years. If that's true of vCJD then it has amazing implications for the number of cases."Knight insisted taht ingestion is a viable means of transmission and claimed it only takes half a gramme of infected tissue to transmit the disease to a human. And while it's possible vCJD could have been mistaken for something else in the past, it's unlikely. "This disease, which affects and kills young people, is unusual," said Knight. "I am a clinical neurologist and I have spent 25 years seeing people and I do not often see a 16 year old with the symptoms these people have and dying over a period of six to 18 months."A study in 2000 for the UK Office for National Statistics looked at whether it could have gone undiagnosed in the past, he said, and found nothing to support its existence (BMJ 2000, 320:145-147).But Venters remains determined to press for incontrovertible proof of the link between BSE and vCJD. Perhaps the best outcome would be that he doesn't find it.

Reopening the debate on the origins of vCJD

A new epidemiological study suggests that variant Creutzfeldt-Jacob disease may have developed independently of animal spongiform encephalopathies.

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