Prions and dentistry
The prion diseases (or transmissible spongiform encephalopathies) belong to a group of diseases known as the protein misfolding diseases. This group also includes diseases such as Alzheimer’s and Parkinson’s disease. In these diseases, a normal host protein does not assume its normal functional structure but is described as misfolding and as such accumulates in large deposits in the brain.
In prion diseases, the protein which misfolds is known as the prion protein (PrPC) and the misfolded form PrPSc. These diseases typically have a very long asymptomatic phase during which the protein accumulates in the brain and there is a gradual loss of neurones and neuronal function. This results, finally, in a relatively short clinical phase with a variety of clinical symptoms depending on which region of the brain is affected.
The folding and misfolding pathways of a protein are very complex and result in many different forms of the protein. Which of these forms is involved in the death of neurones is not known. It is, however, known that the host protein is central to the disease as removal of the PrPC in animal models leads to a total resistance to prion disease1, 2.
Prion diseases are set apart from the other protein misfolding diseases, as they are known to be infectious. This was first demonstrated as early as 1936, when the prion disease in sheep known as sheep scrapie was shown to be experimentally transmitted between sheep3. Infection has since been demonstrated for a variety of prion diseases of both animals and humans by transmission to animal models4, 5.
Importantly, although diseases in animals had been recorded for more than 200 years, there was never any evidence prior to 1996 of prion disease in animals transmitting to humans6, 7. Moreover, while many prion diseases have been shown to be infectious, it is not certain that all prion diseases are infectious8.
The nature of the infectious agent has been proposed to be the misfolded form of the prion protein known as PrPSc9. There is, however, no certainty over which form of the misfolded protein is infectious or whether indeed other components are required to render the protein infectious.
Prion diseases can pass from individual to individual within a species and on occasions have been shown to pass from one species to another. However, there is a major barrier for transmission between species10, which is in part, but not solely, dependent on the differences in prion protein from species to species11.
This ’species barrier’ is likely to explain the relatively low numbers of variant Creutzfeld-Jakob disease (vCJD) in the human population when compared with the very large number of cases of bovine spongiform encephalopathy (BSE) and the widespread exposure of the human population to BSE-infected meat products. However, the implementation of regulations preventing the highly infected tissues from entering the food chain12 were also likely to have been important in containing the epidemic. The current position of the vCJD epidemic is described below.
vCJD– the current position
Variant CJD was identified in 19966 and the hypothesis that this novel human disease was caused by BSE has been supported by a range of epidemiological and laboratory evidence. Notably, transmission studies in animal models have demonstrated that the prion strain in vCJD is the same as that causing BSE and different from the prion strains in other human prion disease such as sporadic CJD7.
Risk factors for vCJD include residence in the UK, dietary exposure to foodstuffs containing high levels of BSE infectivity and a specific genetic background, homozygosity at codon 129 of the human prion protein gene. There is no evidence, as yet, that other potential risk factors such as occupation and exposure to surgical or dental instruments increase the risk for vCJD.
The UK population was extensively exposed to the BSE agent in the human food chain, mainly in the 1980s, and there were fears of a large epidemic of vCJD. However, deaths in the outbreak peaked in 2000 and has subsequently declined with only small numbers of new cases in recent years (Table 1). There have been limited outbreaks of BSE in cattle populations in other countries, mainly in Europe, and potentially infected cattle and cattle products were exported from the UK. As a result, small numbers of vCJD cases have been identified in other countries (Table 2) and this includes cases that were likely exposed to BSE while living in the UK.
Just as with the British outbreak, there has been a decline in the number of new cases of vCJD in countries outside the UK in recent years. It is possible that the primary outbreak of vCJD may be nearly over, but there is the possibility of further cases in individuals with alternative genetic backgrounds and extended incubation periods.
vCJD differs from other human prion disease as the infectious agent is found not only in the central nervous system, but also extensively in lymphoreticular tissue such as the spleen and lymph nodes. This has resulted in concern about transmission of infection through blood transfusion or surgical instruments that contact these infected peripheral tissues.
There is evidence of transmission of vCJD from person to person through blood transfusion, including three individuals who developed vCJD six to eight years after receiving blood donated by individuals who themselves developed vCJD13. Concern about secondary transmission of vCJD has been heightened by evidence from prevalence studies of routine appendicetomy specimens, which suggest that there may be thousands of individuals in the UK who are cryptically infected14.
These individuals may never develop clinical disease, but may have asymptomatic infection in lymphoreticular tissues, which might be present for many years. While secondary transmission of vCJD has been identified via blood transfusion, there is no indication of transmission by other routes.
However, the incubation periods in human prion disease can extend to decades and the period of observation is currently too short to exclude the possibility that further routes of transmission of vCJD will be identified. This suggests that measures to minimise human exposure to infection continue to be important. One area of concern for transmission of vCJD is through dental procedures as discussed below.
Prions and dentistry
The Department of Health has published two risk assessments assessing the potential for vCJD transmission risks via dentistry. The first was published in 2003 and the second in 2007. Both attempted to clarify the level of risk to public health and the relative impact of risk reductions methods.
This was dealt with on a number of levels: the possible scale of risk, infectivity in relevant tissues, efficacy of decontamination and the epidemiology of vCJD. Each of these inputs is compounded by multiple uncertainties and the very large number of dental procedures undertaken annually means that even small transmission risks per procedure could create an appreciable risk to public health.
The report further describes that the impact of dentistry on vCJD transmission dynamics could range from no detectable effect to several hundred transmissions per annum, dependent on a number of variables including infectivity in oral tissues and efficacy of instrument decontamination.
The Scottish approach to limiting the risk of iatrogenic CJD via operative dental procedures followed on from work undertaken first by the ’Old’ group, reported in 2001, which included an observational survey of Sterile Service Departments, general medical practices and five general dental practices in Scotland15. This was the first reported study in over 40 years investigating instrument decontamination in the NHS and in common with earlier work demonstrated deficiencies in a number of key areas across all sectors.
A risk-based approach was taken to reduce the likelihood of iatrogenic CJD from contaminated medical devices. Surgical instruments were classified into high, medium or low risk for vCJD, dependant on the tissues they were likely to encounter during surgical procedures (Table 3). A programme of work to improve decontamination processes then followed which initially focused on interventions involving tissues containing high levels of infectivity (CNS and posterior orbit of eye) and subsequently medium risk tissues (lymphoreticular tissue), which involved major upgrades to central decontamination units.
To inform the development of an evidence-based approach to limit risks associated with dental surgery (low risk), a number of pieces of work were undertaken. The first of these was a large observational investigation into the current practice of instrument decontamination against a benchmark of the BDA A12 advice sheet and good practice recommendations for the decontamination of surgical instruments16.
The findings in dental practice were in principle no different from those undertaken in sterile service departments and endoscope reprocessing units in demonstrating several shortcomings. This led to the publication of the Health Protection Scotland (HPS) Local Decontamination Unit (LDU) guidance17 and a series of Scottish Executive Health Department letters outlining recommendations for the upgrading of instrument reprocessing in dental practice (and dental hospitals).
Additional elements of evidence have been published on inadequate cleaning of first, matrix bands18 and then endodontic files19. These pieces of work perhaps sum up many of the challenges in adapting to calls to improve decontamination in dental practice in that, although this work demonstrated residual blood and tissue residues on reprocessed devices, it was not linked directly to adverse events in patients.
Nevertheless, these instruments are now single-use devices. Further risk is reduced by good decontamination practice and the methods to achieve good decontamination practice are outlined in the HPS LDU guidelines17.
Although the BSE epidemic is substantially over, there are still considerable uncertainties over the number of cases of vCJD that may appear in the future. Moreover, there are a number of prion diseases still present in animals. Chronic Wasting disease has been found in both farmed and wild deer populations in the USA and increased surveillance in Europe has detected a number of newly identified diseases in cattle, sheep and goats.
The ability of these diseases to transmit to humans is not known. It therefore remains important to retain both animal and human surveillance for prion diseases. Additionally, it is important to ensure safe practices are maintained to prevent such disease entering the animal or human food chain to ensure another prion disease does not impact on human health.
- Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. (1993) Mice devoid of PrP are resistant to scrapie. Cell 73(3): 1339-47.
- Manson J, Clarke A, McBride P, Aitchison L, McConnell I, Hope J (1994) PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3(4): 331-40.
- Cuille J, Chelle P-L. (1936) Pathologie animale: la maladie dite tremblante du mouton est-elle inoculable? C R Acad Sci 203: 1552-4.
- Beck E, Daniel P, Alpers M, Gajdusek D, Gibbs C Jr (1966) Experimental ’kuru’ in chimpanzees. A pathological report. Lancet 2 (7472): 1056-9.
- Gibbs CJ Jr, Gajdusek DC, Asher DM, Alpers MP, Beck E, Daniel PM, Matthews WB. (1968) Creutzfeldt-Jakob disease: transmission to the chimpanzee. Science 161(3839): 388-9.
- Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG. (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347: 921-5.
- Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ. Transmissions to mice indicate that ’new variant’ CJD is caused by the BSE agent. (1997) Nature 1997 389: 498-501.
- Piccardo P, Manson J, King D, Ghetti B, Barron R (2007) Accumulation of prion protein in the brain that is not associated with transmissible disease. PNAS 104(11): 4712-7.
- Prusiner SB (1982) Novem proteinaceous infectious particles cause scrapie. Science 216(4542): 136-44.
- Pattison I.H. 1966 The relative susceptibility of sheep, goats and mice to two types of goat scrapie Res.Vet.Sci. 7, 207-212
- Barron RM, ThomsonV, Jamieson E, Melton DW, Ironside J,Will R, Manson JC (2001) Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J 20: 5070-8.
- The Specified Bovine Offal (Amendment) Order 1995. Available at: http://www.legislation.gov.uk/uksi/1995/3246/made?view=plain
- Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. (2006) Vox Sang 91: 221-30.
- Health Protection Agency (2012). Summary results on the second national survey of abnormal prion prevalence in archived appendix specimens. Vol 6, No. 29, 20 July 2012.
- Scottish Executive Health Department (2001) The decontamination of surgical instruments and other medical devices. NHS HDL. 20 August. http://www.sehd.scot.nhs.uk/publications/dsmid/dsimd-00.htm.
- Scottish Executive Health Department (2004) NHS Scotland: Sterile Services Provision Review Group: survey of decontamination in general dental practice. 26 November. http://www.scotland.gov.uk/Publi cations/2004/11/20093/45220.
- Health Protection Scotland (HPS) (2007) Local Decontamination Units: Guidance on the requirements for equipment, facilities and management. http://www.documents.hps.scot.nhs.uk/hai/decontamination/publications/ldu-001-02-v1-2.pdf
- Lowe AH, Bagg J, Burke FJT, MacKenzie D, McHugh S. (2001) A study of blood contamination of Siqveland matrix bands. British Dental Journal 192: 43-5.
- Letters S, Smith AJ, McHugh S, Bagg J. (2005) A study of visual and blood contamination on reprocessed endodontic files from general dental practice. British Dental Journal 199: 522-5.