The Lingering Shadow of Mad Cow Disease

Optimists are proclaiming that variant Creutzfeldt-Jakob disease (CJD), the human form – always fatal – of bovine spongiform encephalopathy (BSE), or “Mad Cow Disease,” is on the wane. Obviously, given the degree of suffering and public anxiety that variant CJD has caused, the possibility that it is receding is welcome news. But is it true?

CJD belongs to the family of what are called prion diseases, a unique group of neurodegenerative diseases that can be transmitted. Although the precise nature of the disease’s transmission remains uncertain, a key event in these disorders is the conversion of the prion protein’s normal cells to an abnormal form that appears to be the major (if not the sole) component of the infection.

Variant CJD was first described in 1996, following intensive surveillance activities undertaken by the UK National CJD Surveillance Unit (NCJDSU) in Edinburgh. This new form of prion disease had distinctive clinical and pathological features, and occurred in young patients within a single genetic subgroup.

My colleagues and I in NCJDSU argued that this new form of human prion disease was likely to be linked to exposure to the BSE agent, probably by eating BSE-infected meat products. Later investigations have shown that the transmitting agent in variant CJD shares identical biological properties with BSE’s agent, supporting a causal relationship.

BSE occurred as an epidemic in the UK after its identification in 1986, and several million BSE-infected cattle are likely to have entered the human food chain between 1980 and 1996. It is estimated that most of the UK population was exposed to BSE through diet at this time. Subsequent epidemiological studies in the NCJDSU indicate that individuals with variant CJD are likely to have consumed more meat products than control patients, further supporting a link between these disorders.

Moreover, epidemiological studies indicated that BSE was likely to have been transmitted to cattle (and other species) by meat-and-bone-meal animal feed produced by UK rendering plants and exported to many countries. This pattern of trade has now been mirrored in the increasing geographical spread of BSE from the UK to other countries in Europe, and more recently to Japan and the United States. This unfortunately has been accompanied by increasing number of variant CJD cases in Canada, France, Ireland, Italy, Japan, Netherlands, Portugal, Saudi Arabia and the USA.

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In the UK, however, the epidemic of variant CJD seems to have peaked in 2000 and is now in decline, with 156 cases being identified so far. However, a retrospective study of abnormal prion protein accumulation in appendix and tonsil samples from over 12,600 people in the UK has yielded three more cases, which suggests that the level of BSE infection in the UK population is much higher than the actual number of confirmed variant CJD cases indicates.

Given the extensive exposure of the UK population to BSE in the late 1980’s and early 1990’s, what explains the low number of confirmed cases? One clue lies in the results of studies of the transmission of BSE and variant CJD in mice, which in many cases does not result in death from clinical disease, but instead can produce an asymptomatic “carrier state,” in which the disease has not yet manifested itself.

These findings have been reinforced by an extensive control study to identify risk factors for variant CJD, which recently identified two cases of human-to-human transmission of variant CJD infection through transfusions of particular types of red blood cells. These cases are particularly interesting, because the first case resulted in the clinical onset of variant CJD (with typical symptoms and pathology) 6.5 years after the transfusion from a donor who, although asymptomatic at the time of donation, subsequently developed and died from CJD. 

The second case involved a known recipient of such cells transfused from another asymptomatic donor who subsequently died from variant CJD, whereas the recipient showed no evidence of neurological disease and died of unrelated causes. However, abnormal prion protein was detected in the recipient’s lymphoid tissues, indicating transmission of infection from an asymptomatic individual.

These cases have major implications for blood safety everywhere, implying additional restrictions on eligibility for blood donation and on the processing and handling of blood and blood products. Individuals infected with BSE who remain in an asymptomatic state during their lives could represent a risk to others of potential secondary transmission of variant CJD through blood transfusion or surgery.

Further uncertainty regarding the future of variant CJD arises from the observation that the average age of the patients in the UK has not increased significantly over the past 10 years. If the epidemic were in decline, it might be anticipated that the average age of the patients would increase in the final stages (as occurred with cattle in the UK that were infected with BSE). But variant CJD affects patients who are much younger than sporadic CJD patients, which might be due to either age-related exposure to BSE or age-related susceptibility.

Until we know the answers to these questions, it seems premature to decide that we are witnessing the beginning of the end of variant CJD. On the contrary, the cases identified so far may be only the tip of the iceberg, with a much larger number of asymptomatic infections posing a risk to public health through secondary transmission.

Indeed, secondary transmission by blood transfusion or surgical instruments might even result in variant CJD becoming endemic in the UK population. This would prove impossible to eradicate in the absence of improved means of cleaning and decontaminating surgical instruments and a specific test – preferably based on a blood assay – to screen asymptomatic carriers.