Creutzfeldt-Jakob disease (CJD) is one of a group of diseases called Transmissible Spongiform Encephalopathies (TSE) or prion diseases. These diseases in general, have long incubation periods and are characterized by severe and irreversible damage to the central nervous system resulting in death. The diseases are caused by prions, which differ from conventional microorganisms such as bacteria and viruses. So far there are no clinically effective treatments for any TSE including CJD.
Sporadic CJD (sCJD), which was first described in the early 1920s, occurs worldwide and affects around one to two persons per million per year with a median age of onset of 65 years. Patients experience a rapidly progressive dementia with death typically occurring within six months of their first symptoms. Other forms of human prion disease have since been described, including kuru which was endemic in the Fore people of Papua New Guinea in the 1950s and transmitted through cannibalistic funeral rites. There are also rare familial forms of human prion disease due to inherited genetic abnormalities. In addition, transmission of sCJD has occurred during medical care through neurosurgical instruments, corneal and dura mater grafts and cadaveric pituitary derived human growth hormone and gonadotrophins. A series of epidemiological case control, look back and surveillance studies over the last twenty years have not revealed any confirmed cases of transmission of sCJD by blood components, plasma products, or peripheral tissues (such as bone, skin and heart valves). However, as a precautionary measure, UK Blood Services apply agreed UK and European exclusion criteria (in line with WHO recommendations) to exclude anyone who could have an increased risk of iatrogenic or familial CJD from donating blood, tissues or stem cells.
A different form of Creutzfeldt-Jakob disease - vCJD - was first identified in 1996. Unlike sCJD, the new disease affects younger people (a median age at death of 28, range 14-75 years old). Clinical presentation is also different. Variant CJD patients show signs of behavioural disorder, depression and anxiety followed by problems with sensation and co-ordination leading to progressive dementia and death over a period of on average six months to two years. The clinical, epidemiological, neuropathological and experimental data all point to vCJD being caused by the same strain of prion as Bovine Spongiform Encephalopathy (BSE). This is a different strain of prion from those seen in sCJD.
To date there have been 176 definite and probable cases of vCJD in the UK, 27 cases in France, 5 cases in Spain, 4 in the Irish Republic, 3 in the USA and The Netherlands, 2 in Portugal, Italy and Canada and one case each in Saudi Arabia, Taiwan and Japan. Two of the Irish and USA cases, one of the French and Canadian cases and the Taiwan case are thought to have acquired the disease in the UK. The third USA case is believed to have been infected when a child in Saudi Arabia. The other patients are thought to have been infected in their country of origin. Details on the number of UK cases of vCJD can be found on the The National Creutzfeldt-Jakob Disease Research and Surveillance Unit (NCJDRSU) website (www.cjd.ed.ac.uk). The eventual number of individuals within the UK population likely to develop vCJD remains uncertain and it is similarly uncertain how many current or past blood or tissue donors could be incubating the disease. All cases of clinical vCJD, except three from the UK, are believed to be primary cases resulting from eating BSE contaminated meat products. In December 2003, the first presumed transmission of vCJD by blood transfusion was described. The transfusion occurred in 1996, the blood donor at the time was well but went on to develop symptoms of vCJD in 1999. The recipient was diagnosed with vCJD in 2003. A probable transmission of vCJD prions, not leading to clinical disease, was reported in July 2004. On this occasion the patient received blood in 1999 from a donor who went on to develop symptoms of vCJD 18 months later. The recipient died of unrelated causes 5 years after the transfusion with no evidence of neurological disease but at post-mortem was found to have evidence of abnormal prion accumulation in the spleen and a lymph node. The second presumed blood associated transmission leading to clinical disease was reported in February 2006. The patient developed symptoms about 8 years after receiving a blood transfusion from a donor who developed symptoms of vCJD about 20 months after donating blood. A third presumed blood associated transmission leading to clinical disease was reported in January 2007 in a patient who developed symptoms just over 8 years after receiving a blood transfusion from a donor whose symptoms of vCJD appeared about 17 months after donating this blood. This donor was also associated with one of the earlier transmissions.
A further presumed transmission of abnormal prions was described in February 2009. The patient suffered from haemophilia and had received batches of factor VIII to which a donor who subsequently developed vCJD had contributed plasma. The patient died of other causes but was found at post-mortem to have evidence of prion accumulation in his spleen. Further details are published in Peden et al. (Haemophilia 2010; 16: 296-304).
The UK blood services have taken a number of measures to try to reduce the risk of transmission of vCJD by blood, plasma and tissue products:
- How many people are currently incubating vCJD in the UK?
Estimates of the number of people likely to develop vCJD (and therefore currently incubating the disease) continue to vary. It is also possible that some people could be "infected" with this agent but never progress to clinical disease. Data collected by the National CJD Research and Surveillance Unit suggest that vCJD mortality in the UK peaked in 2000 and has since fallen. The observation is encouraging, however some caution should be exercised. There is currently a discrepancy between the likely incidence of cases projected from the current clinical evidence of vCJD and the number of infected people projected from retrospective studies of tonsil and appendix samples which suggests that around 1/2,000 (range 1/1,250 to 1/3,500) healthy people in the general population could be sub-clinically infected (http://transparency.dh.gov.uk/2012/08/13/tse-risk-assessment-july-2012/).
To date all probable and definite cases of clinical vCJD have been in people who are methionine homozygous at codon 129 of the prion protein gene. A single UK case of possible vCJD in a patient who was heterozygous at this genetic locus has been described. In addition, the second of the transfusion recipients and the patient with haemophilia referred to above, both of whom had evidence of abnormal prion protein, were heterozygous at this locus and two of the patients positive for abnormal prion accumulation in the retrospective study of tonsils and appendices were homozygous for valine. These observations suggest that other genotypes may also be susceptible to infection with vCJD prions, possibly with a lower frequency of disease and/or longer incubation periods (as has been seen in some cases of kuru and peripherally transmitted iatrogenic CJD). In addition, further cases may arise due to secondary human to human transmission via medical or surgical instruments or blood, plasma, cell or tissue products, though no known such cases have been seen.
- How many patients have been exposed to blood components or plasma products from donors who went on to develop vCJD and have they be informed?
Eighteen people who later developed vCJD have been traced as blood donors and gave blood donations that were transfused to recipients. Sixty-seven recipients of blood components from these donors have been identified of whom 17 are still alive, all of whom have survived for at least 5 years since the blood transfusion. Their doctors have been informed of their exposure to these products (http://www.cjd.ed.ac.uk/TMER/TMER.htm).
Eleven blood donors have contributed to 25 plasma pools from which 191 plasma product batches have been manufactured. The CJD Incidents Panel has developed a model to allow an assessment of the level of risk of exposure of recipients to vCJD through the implicated plasma products. They have calculated a dose of each product beyond which it is likely that an infection-control threshold will be surpassed. Patients recognized to fall into this category have, where possible, been informed of their exposure to these products and precautionary steps taken to minimize the risk of any further transmission through blood, tissue or organ donation, or by medical or surgical instrumentation. Further information can be obtained from the Health Protection Agency website.
- How many patients are exposed to blood components each year and have not developed vCJD?
Estimates of numbers of transfusion recipients in hospitals supplied by NHSBT were made from data collected from representative hospitals in 2001/2002 and published in 2009. The figures for the 12 month period were: red cells: 433,000 recipients, FFP: 57,500, and platelet components 41,500. Since NHSBT accounts for the majority of issued blood components in the UK, the approximate figures for total number of UK recipients can be estimated by uplifting these figures by 20%. The median age of the recipients was 69 years, 64 years, and 59 years respectively. The EASTR study is following the survival of these recipients for 10 years post-transfusion to determine the long-term survival of the cohort, but previous studies have suggested that approximately 50% of blood components are transfused into recipients who die within 10 years of transfusion. A proportion of recipients in any one year may be transfused in following years, so it is not possible to give an accurate figure for the total number of people who have been transfused in the UK since the appearance of vCJD (1996) but the total will be many millions of people. Just seven of these many millions have developed clinical vCJD, including the three (referred to above) who have been linked to a donor who also later developed vCJD. In the remaining four cases, no infected donor has been identified.
- Are additional donor selection criteria being applied?
Countries outwith the UK including the USA, Canada, New Zealand, Australia, Hong Kong and several European countries including Germany, Switzerland, Austria and Eire have taken the precautionary step of excluding blood donors who have spent more than a defined period in the UK between 1980 and 1996. From 5th April 2004, whole blood donors who know that they have received blood component transfusions in the UK since 1 January 1980 have been excluded from blood donation. This measure generally resulted in the deferral of 3-5% of potential blood donors. From August 2004 this deferral criterion was extended to blood donors unsure whether they have received a transfusion and to platelet apheresis donors. From July 2005 live bone donors were also included in this deferral criterion. The potential impact, on the supply of tissues, of extending this deferral criterion to deceased tissue donors is currently being assessed. Anyone who has received UK derived coagulation factors, intravenous normal immunoglobulin or underwent plasma exchange between 1980 and 2001 is also deferred from blood donation.
- Will the UK blood services continue to use non- transfused UK donors?
At present, the majority of blood components (i.e. red cells, platelet and clinical plasma) and peripheral tissue (bone, skin, tendon, heart valves and cells) are derived from UK donors. It is unlikely that large quantities of blood or tissues could be sourced from non-remunerated donors outwith the UK. Even if this were possible, it could increase the risk of exposure to other infectious agents, would be very difficult to implement for components with short shelf lives and could precipitate critical shortages. The issue is therefore one of a balance of risks. The UK Blood Services import FFP, which is then methylene blue treated in the UK, from non-UK volunteer donors for neonates and children born after 1st January 1996. The rationale for this cut off date is that children born since 1996 are considered to have received minimal exposure to the BSE agent because of the effectiveness of the animal feed ban which was fully implemented from 1996 and the exclusion of animals above 30 months entering the food chain. The importation of FFP was extended to the treatment of all patients under 16 years of age and this was further extended to all born on or after 1 January 1996 as they began to turn 17 on 1 January 2012. Consideration was given to extending this to all patients, but in March 2012 SaBTO recommended against this.
The option of importation of some tissues for children born after January 1996 has also commenced.
- Is there a blood test available for vCJD?
Not at present. The types of tests that are used to screen blood and tissue donations for viruses cannot be applied to vCJD because of the different type of infectious agent (abnormal prion protein rather than bacteria or virus). Several international groups of research workers are working to develop a blood test and recently two groups have published data on prototypic tests which appear to be sensitive enough to detect abnormal prion in the blood of some patients with clinical vCJD. However, considerable work is required to bring a test from the research laboratory through to the clinic and it remains unclear when, if ever, a suitable for blood donor screening test will become available.
- Can donors contract vCJD from giving blood or tissues?
No. Blood donations are taken through sterile, non-reusable, disposable needles and equipment so it is not possible for anyone to contract vCJD by blood donation. The UK Blood Services have a duty to supply hospitals with the blood components needed for patient care. This can only be achieved with the help of blood donors and their continued support is vital.
In the context of cadaveric tissue donations this risk is not applicable. For live tissue donation, no excess risk is involved in the operation, that would not otherwise be incurred as part of the operation itself, to treat the patient’s underlying condition.
- Does universal leucodepletion reduce the risk of transmission of vCJD?
Universal leucodepletion was introduced in the UK in 1999. In patients with sCJD and in animal models where infectivity has been found in the peripheral blood, a large proportion has been associated with the white blood cells. Recently published animal data show that leucodepletion removes a proportion (about 50%) of prion infectivity, but is unlikely, by itself, to remove all infectivity.
- Are there any other components processing steps which could reduce the risk of transmission of vCJD by blood or tissues?
The UK Blood Services are engaged in a programme to increase the sourcing of all platelet components from individual donors using a process known as apheresis, in order to reduce the number of donors to whom an individual patient is exposed. Currently 80% of platelet donation are sourced through apheresis.
A number of commercial companies are working on the development of filters designed to selectively remove abnormal prions from blood components and the UK Blood Services and other organizations are evaluating the clinical safety and the efficacy of these technologies.
An extensive validation has been carried out by the Blood Services to remove as much marrow (containing a large proportion of white blood cells) from bone as possible. Investigations are now taking place on refining the process, to make it operationally possible.
- Are plasma derivatives likely to be infectious?
As of October 1999, all plasma products including Factor VIII and Factor IX, immunogloblins and albumin have been derived from non-UK donors. The majority of clotting factors now used in the UK are recombinant products which pose no risk of vCJD infection. Therefore, there should be minimal risk to patients now receiving plasma products provided donors are from countries with a known low risk for BSE. The risk to patients who received plasma products before October 1999 is uncertain, but it does now appear that a case of transmission of infection to a patient with haemophilia has occurred, though the patient himself did not develop clinical disease. The UK Blood Services have engaged in research on the ability of the plasma fractionation processes to remove prions. These experimental spiking studies have shown that there are steps during each manufacturing process which remove prions, though it remains unclear how closely these reflect the way in which the natural infective agent behaves. Similar studies have been performed by other organisations with similar results. The starting level of infection in plasma from UK donors also remains unknown. The risk from most UK derived plasma products is likely therefore to have been low, but it cannot be assumed that the risk was zero.
- Are cell or tissue products likely to be infectious?
The Standing Advisory Committee on Tissues and Cellular Therapy Products has undertaken a formal review together with the Health Protection Analytical Team to consider the risks of transmission of vCJD by cells and tissues including new safety issues raised through in vitro propagation of cells.
Some specific initiatives have also been considered and / or implemented for improvement in the safety of tissues within the UK Blood Services to try to reduce the risk of transmission of vCJD by bone and tissue transplantation. These include:
- Improved washing and blood removal techniques for processed sterilized bone grafts.
- The use of disposable instruments for some types of tissue retrieval and processing.
- Improvement in decontamination procedures prior to sterilization of instruments.
- Batching of retrieval and processing of instruments to allow for the tracking of their use.
- Dura mater grafts are not provided
Further processing measures are under evaluation
- Should UK patients continue to accept blood and tissue products?
Blood, plasma, cell and tissue products should only be given when they are essential to the quality of life, health or survival of the patient, and where there is patient consent. In these circumstances the benefits are carefully weighed against other transmission risks including vCJD. In some circumstances alternatives are available which could reduce the exposure to blood or tissue products. UK Blood Services’ clinicians continue to work with colleagues throughout the National Health Service in establishing and implementing guidelines for the appropriate use of blood and tissues. It is a priority for the UK Chief Medical Officers and the medical community in the UK to ensure that patients are treated with blood or tissue products only when there is real clinical need.
- What is being done to ensure that blood and tissues are used only when there is a good clinical indication?
On the advice of the UK Chief Medical Officers, national programmes for good transfusion practice have been established, supporting the work of local Hospital Transfusion Committees. Transfusion practitioners have been or are being appointed to many hospitals. Their roles include training staff in safe blood administration (including detailed documentation), assisting with clinical audit, the development and implementation of evidence based clinical guidelines for the use of blood, and assisting with the investigation and reporting of adverse events to the Serious Hazards of Transfusion reporting scheme (SHOT). There is increasing use in the NHS of techniques that can, for some patients, reduce the need for transfusion of donor blood or avoid it all together. Among these are: the use of regional and hypotensive anaesthetic techniques, good temperature control in the perioperative period, salvage and reinfusion of red blood cells lost during surgery and the use of antifibrinolytic agents. However, transfusion may be unavoidable and life saving for patients who suffer massive blood loss and, for those undergoing chemotherapy for leukaemia or being treated for cancer, there may be no alternative to the use of donor blood components during periods when the bone marrow is not functioning normally.
Tissue usage is much more restricted than that of blood and in many instances tissues are used when there is no better alternative. Notwithstanding, there are initiatives on auditing usage of particular tissues in specific circumstances to encourage and facilitate best practice.
- Is any treatment available for CJD?
There is no treatment currently available for CJD.