Canadian Medical Association Journal 1996; 155: 565-568
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© 1996 Peter Vaughan
Yet around the world, confidence in the blood supply has been shaken. In the 1980s blood and blood products contaminated with HIV and hepatitis C infected thousands of people, and although no blood product can be guaranteed 100% safe, health officials and policymakers have struggled to learn from the past and prevent the spread of new diseases in blood and blood products.
The latest concerns are prion diseases, and in particular Creutzfeldt-Jakob disease (CJD). A June conference in Toronto, sponsored by Health Canada in collaboration with the McGill Centre for Medicine, Ethics and Law, brought together 86 participants from Canada, the US and the United Kingdom to examine the ethical, legal and policy issues surrounding this rare degenerative neurologic disorder. There was wide interest in the conference because a new variant form of CJD had turned up in Britain and France, where it became known as "mad cow disease," and because of Europe's widely publicized ban on beef imports from the UK, where cows were being fed ruminant waste.
Estimates of the incidence of CJD range from 0.5 to 1 case per million people per year, and the infectious agent is thought to be a prion protein. Classic disease manifestations include memory loss, involuntary muscle movement and deterioration of motor function. CJD has a long incubation period of from 1 to 30 years, and diagnosis is based on clinical features, a characteristic "periodic EEG pattern" and confirmation by examination of brain tissue. Typical brain histology shows a Swiss-cheese or spongiform pattern with amyloid plaques.
Because there is a dramatic deterioration in the clinical condition, most people with the disease require hospitalization. Death occurs within 1 year, commonly in 4 to 7 months. Disease frequency is the same around the world. There is no prophylaxis and no treatment; CJD is always fatal and there are no screening tests that can detect disease in the general population.
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Another tainted-blood scandal?
Fear of another tainted-blood scandal has scientists and policymakers scrambling to understand how the disease is spread. And the thorny issue of notifying those who have received blood or blood products from persons with CJD haunted the Toronto conference.
There are three types of CJD. Familial CJD, which has an autosomal dominant pattern of inheritance, is responsible for 5% to 10% of cases. Iatrogenic CJD accounts for less than 1% of cases; the cause is thought to be direct transmission between people as a result of contaminated instruments, tissue transfer (cornea, dura mater grafts) and tissue-extract transfer (human growth hormone). However, 90% of cases are considered sporadic CJD, the cause of which is unknown.
Dr. Paul Brown of the National Institutes of Health in Bethesda, Maryland, said no human cases of CJD have been linked definitively to blood transfusion, but such a connection is theoretically possible. "Infectivity is potentially in the blood, probably in white cells," he said.
The infectious prion-protein agent is highly stable, resisting heat at normal cooking temperatures and higher temperatures such as those used for pasteurization and sterilization, as well as freezing and drying. "This thing could be immortal," Brown commented.
Although periodic activity is shown in the electroencephalogram (EEG) as the disease progresses, Brown said EEGs cannot be used for screening because they don't show changes early enough. Spinal fluid could be used to test for a Wassermann reaction but that would require a healthy person to submit to a lumbar puncture.
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The mystery of prion disease
Dr. David Westaway, a molecular biologist studying prion diseases at the University of Toronto, said the molecular basis of prion strains remains "obscure." However, research into a similar condition in sheep called scrapie raised eyebrows in the 1960s, when experiments implied that prions might not have a nucleic acid. Today, the debate over whether prion strains are devoid of nucleic acid continues. The formation of scrapie prion protein from cellular prion protein is a post-translational process involving the conversion of alpha-helices into beta-sheets. This change in prion protein (PrP) appears to be the determining event in prion propagation and the development of prion diseases. The unique structure of the infectious agent and the dissemination of prion diseases set prions apart from all other infectious pathogens.
The genetic origin of this infectious protein appears to play a pivotal role. It could be encoded by a hypothetical scrapie virus -- that is, encoded by foreign genes or a host-encoded protein. Nucleic-acid probes derived from peptide-sequence research have pulled out a messenger RNA (mRNA) that encodes the prion protein.
"The gene in an infected animal is no different [from that in] an uninfected animal," Westaway said. "All mammals have a prion-protein gene, but we don't know why we have this gene."
This has baffled researchers for years because we all have prion protein and we all make mRNA. "The prevailing wisdom," Westaway said, "is that this is a disease of protein folding. Cellular PrP folds into a stable configuration and then is partially unfolded, and then can be converted into the pathogenic form of the protein."
CJD is one of a spectrum of prion diseases known as human transmissible spongiform encephalopathies (TSEs). They are a group of rapidly progressive disorders with a variety of clinical abnormalities that include cognitive impairment, ataxia and myoclonus. They share a spongiform degeneration and variable amyloid plaque formation. Examples of TSEs are CJD, kuru (an infectious disease caused by a slow virus) and the rare familial disorders Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia (FFI). With the exception of FFI, all these disorders have been experimentally transmitted to nonhuman primates and laboratory rodents.
"An infectious protein lies at the heart of these diseases," Westaway said. He believes that by taking this protein apart, atom by atom, the mystery of prion disease will eventually become clear.
Despite numerous epidemiologic and laboratory studies, however, the etiologic agent and mode of transmission remain unclear. Clinical diagnosis is challenging and is based on symptoms. No specific treatment is available and medical management is limited to supportive care.
To heighten the mystery and the urgency, a newly recognized variant form of CJD (V-CJD) has been identified in 10 patients in the United Kingdom and one in France. In sharp contrast to the typical sporadic CJD, this disease strikes young people (ages 18-41, mean age 27.6, with a duration of 13 months).
The characteristic neuropathological findings in V-CJD include widespread kuru-type amyloid plaques with severe cerebellar lesions. The major presenting features are psychiatric: anxiety, depression, withdrawal and behavioural changes, followed by ataxia, memory loss, dementia and myoclonus.
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Why was the blood withdrawn?
No link has been proven between V-CJD and bovine spongiform encephalopathy (BSE), widely referred to as "mad cow disease," although this is the most likely hypothesis, said Dr. Robert Will of the United Kingdom's CJD Surveillance Unit in Edinburgh. The unit could not find any increased risk from blood transfusion in relation to control groups, Will said.
Why, then, was blood from patients with CJD pulled from blood-bank shelves last year? Dr. Maung (Bert) Aye, national director of blood services with the Canadian Red Cross, defended the recall, saying that while there is no evidence of a direct spread of CJD through the blood supply, it is still a "theoretical risk." In light of what other countries were doing at the time, it was considered prudent to remove from the market blood products identified as coming from persons at risk of CJD -- including people treated with pituitary-derived growth hormone, blood donors who had received corneal or dura mater grafts, and blood relatives of anyone with familial CJD. (Corneal grafts from donors who have been screened for neurologic disease are not considered a CJD-related risk.)
[The decision to withdraw blood and inform patients they have received blood traced to donors later diagnosed as having CJD has proved controversial. In July, a patient told the Winnipeg Free Press that the form letter he received from a hospital "just about knocked me on my butt." -- Ed.]
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The ruminant-waste controversy
Feeding cows ruminant waste was a disaster waiting to happen, according to many speakers at the Toronto conference. The overriding motivating factor was an economic imperative: more beef to market, faster, without concern for public health. In the case of BSE in Britain, market forces and public health had a head-on collision.
Author and social historian John Ralston Saul said "the citizens of Britain and Europe woke up one morning and discovered that after 2500 years of eating herbivores, government policy had turned herbivores into carnivores without telling people. And this has had a profoundly upsetting effect on the population."
He said "the real point is we don't know what it will cause. It appears on the surface to be driven by money. The reality is it is driven by an interest-based corporate system where no one is asking the question about the impact on the public's health.
"For me," he added, "it's not that CJD represents a different problem from, for example, the HIV crisis. The point is, we don't seem to have any ongoing inclusive [which includes the public] mechanisms for dealing with crises. The result is we are inevitably acting in a reactive manner."
He also believes a shroud of unnecessary secrecy has encouraged the media to do a poor job. "There have to be structures in place which mean the media are simply part of a conversation which involves those who know and the general public."
Although the specific scientific question is whether or not this disease is transmissible, he said broader questions must be answered. Should risks of this sort, such as feeding ruminant waste to cattle, be taken? Have relevant parties been asked in advance whether they want to take such risks? Is it naïve to believe progress equals uncontrolled technology? "We are smart enough to invent things but not smart enough to give them direction."
Dr. Paul Gully, chief of the Division of the Division of Blood Borne Pathogens at the Laboratory Centre for Disease Control in Ottawa, said the conference reached consensus on a number of points, including the public's right to be informed. "The major difficulty is, how do you get that information to people? How do we assist them in using it? How do we find out what they want to know?"
Organized medicine and the media have a role to play in disseminating information about new diseases and public risk. Physicians are experts, said Gully, who also can act "as the voice of their patients and their clients."
Physicians should ask themselves why a patient is asking for information, he added. "What is their frame of reference? Is it because they really feel they are at risk, or do they want the physician to say to them, 'Well, the risk is one in a million, let's work this through.' "
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The legal implications
Ken Arenson, a Toronto litigation lawyer, offered participants a legal perspective. "I have satisfied myself that CJD is transmissible by white cells, that we could do better in separating white cells in our component production [and] make a better effort to ensure that red cells are not contaminated with white cells. That is a simple measure we could take."
He represents clients who have been infected with HIV and hepatitis C through contaminated blood and blood products, and he spoke passionately in favour of full public disclosure. "We should obviously continue to deter at-risk CJD donors, and we should adopt a policy of full disclosure of the whole unvarnished story. The only remaining question is: What do we know today? We should make an effort to decide what we know and disclose it fully, and we should commit ourselves to updating that regularly."
Arenson also was critical of the conference, arguing that there should have been more dissidents and consumer representatives. He said physicians should learn from previous handling of HIV and hepatitis C disclosures.
John Ralston Saul agreed that there is a need to rethink the way issues like this are handled. "It isn't enough to keep responding to these crises in a good, medium or a bad way. The good doctors and scientists have always been able to talk to the public. But they've been told they can't, or shouldn't, or the structure discourages them from doing it. So we've built up over the past half-century this wall of specialization. That's why I always say the modern elites are both villains and victims, because if you want to do something that is intelligent and wisely based you actually will be punished for doing it. I guess that's why they invite people like me [here], because I can say what they'd like to say, but they might lose their jobs if they said it."
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What's next?
When the next unknown disease comes along are we going to react in the same way? Are we doomed to repeat the mistakes of the past? These are some of the questions the CJD conference raised but couldn't answer.
The only certainty, it seems, is that important decisions will still have to be made with incomplete or uncertain knowledge.
| The clinical basics of Creutzfeldt-Jakob disease |
Creutzfeldt-Jakob disease is extremely rare (one case per million people).
|