Written evidence submitted by the National CJD Research & Surveillance Unit (BTO0008)
Executive Summary
The responding organisation and individuals
The National CJD Research & Surveillance Unit (NCJDRSU)-originally the National CJD Surveillance Unit- was established in the University of Edinburgh in 1990 (following recommendations of the Southwood Committee). The core surveillance function of the Unit is to identify and study all potential cases of CJD in the UK and to monitor any changes in the number of cases or the nature of the disease from previous years. It is funded by the Department of Health and Scottish Government Health Department. The Unit is involved in a variety of research projects (in-house, and with national and international collaboration). The NCJDRSU is a WHO Collaborative Centre for reference and research on the surveillance and epidemiology of human TSE, the Coordinating Centre for EUROCJD (an international collaborative organisation) and the vCJD Reporting Hub for ECDC.
This response has been produced by the following NCJDRSU staff:
Professor Richard Knight. Current Director of NCJDRSU. Clinical Neurologist.
Dr Mark Head. Current Deputy Director NCJDRSU. Molecular & Cell Biologist
Professor James Ironside. Neuropathologist. Past Director of NCJDRSU.
Professor Bob Will. Neurologist. Past Director of NCJDRSU and Founder of the Unit
Dr Anna Molesworth. Epidemiologist.
Notes concerning response
Our response is based mainly on those areas relating to our own surveillance and research activities with an emphasis on the evidence thereby underpinning public health actions and policy decisions.
Professor James Ironside provided written and oral evidence on variant CJD to the Committee in December 2013.
Various members of the Unit staff are members of committees relevant to the Inquiry, as listed below:
ACDP (Advisory Committee on Dangerous Pathogens): Richard Knight, James Ironside.
ACDP Transmissible Spongiform Encephalopathies Subgroup: Richard Knight, James Ironside
SaBTO (Advisory Committee on Safety of Blood , Tissues & Organs): Richard Knight.
CJD Resource Centre Oversight Committee: Bob Will, Richard Knight.
CJD Support Network Management Committee: Richard Knight (Chair).
UK Blood Services Prion Working Group: Mark Head
Independent Archive Advisory Group: Mark Head (Chair)
CJD Incidents Panel (disbanded March 2013): James Ironside, Bob Will, Anna Molesworth
National CJD Working Group (Scotland): Anna Molesworth
RESPONSE
A: EVIDENCE BASE FOR ACTIONS & DECISIONS CONCERNING UK BLOOD, BLOOD PRODUCTS, OTHER TISSUES & ORGANS
A1: INTRODUCTORY COMMENTS
With the effective control of cattle BSE, the protective measures concerning human dietary exposure and the clear decline in numbers of primary (diet-related) human vCJD cases, concern has centred on the risk of human-to-human secondary transmission. Observations on the fact that likely large population exposure to BSE has so far led to only a relatively small number of human vCJD cases (even taking into account potentially long incubation periods and the known effects of the genetic PRNP-129 polymorphism), combined with experimental animal study results, suggested that (fortunately) there was a significant inter-species barrier to transmission from cattle to humans via the dietary route. However, these data suggested also that prolonged, or even life-long, subclinical infection isa probable outcome of dietary exposure to BSE, with these ‘silently’ affected individuals being a potential source of infection. This concern was heightened by the fact that secondary transmission would be intra-species with no inter-species barrier and, indeed, probable species-adaptation. If secondary transmission were to occur, it could be via: neurosurgery or ophthalmic surgery, other surgery (including dentistry), blood and or products, and organ or tissue transplants. Experience with prion human diseases strongly suggests that other, more ordinary, contact would pose no risk and that neurosurgery or ophthalmic surgery would carry the largest risk. Other transmission routes had not been definitively implicated (apart from human cadaveric derived hormone treatments). Indeed, in relation to blood, past studies had failed to identify a risk associated with sporadic CJD and early animal experimental studies with vCJD showed no disease transmission. Despite this potentially reassuring background, it was recognised that vCJD was a novel prion disease and the previous studies had limitations. Therefore, at an early stage in the UK vCJD epidemic, various measures were put in place, including a study to identify any instances of human-human transmission by blood [see TMER below]. It should be noted that the UK CJD Surveillance system was obtaining data about blood donation and transfusion exposure for all referred cases from 1990 onwards (and, indeed, had done so in a past study in England and Wales).
A2: EPIDEMIOLOGICAL EVIDENCE FOR INFECTIVITY IN BLOOD AND BLOOD PRODUCTS, TISSUES AND ORGANS.
A theoretical risk of human vCJD transmission by blood, organs or tissues, whether or not supported by animal experimentation, is not as powerful an argument for concern as the demonstration of its actual occurrence. A variety of inter-related surveillance and epidemiological approaches were adopted to attempt to detect such occurrences: the identification of links between cases (the Transfusion Medicine Epidemiological Review, enhanced surveillance of people exposed to TSE risks, other look-back studies, cluster analysis and other incidental investigations of, for example, surgical or occupational exposures) as well as risk factor analysis (case-control studies).
Underpinning all of these approaches is effective clinico-pathological surveillance for cases and obtaining good data on potential risk factors for disease (see www.cjd.ed.ac.uk), The NCJDRSU is integral to these processes.
In 2003, the surveillance system identified a case of CJD with a blood transfusion history and the TMER study confirmed linkage to a CJD-affected donor, with other cases identified subsequently (details below).
A separate study of potentially exposed haemophilia patients (examining their tissues for evidence of disease-related prion protein) has identified one instance of vCJD infection being most likely transmitted by a blood product (factor VIII).
To date, no other instance of actual human-to-human transmission has been identified.
RELEVANT STUDIES:
TRANSFUSION MEDICINE EPIDEMIOLOGICAL REVIEW (TMER)
In the UK, all vCJD cases over 17 years of age are notified by NCJDRSU to the UK blood services on diagnosis and a look-back is undertaken to identify the fate of all blood donations made by these cases. For vCJD cases with a known transfusion history, the hospital records are searched to identify blood donors. The details of identified recipients and donors are regularly cross-checked against the NCJDRSU surveillance register to identify links between cases [Ref 1].
It was in this way that three cases of transfusion associated vCJD have been detected, two of which were associated with a common blood donor [Refs 2,3,4]. A further instance of transfusion associated infection was also detected post-mortem in a blood recipient with no clinical symptoms of vCJD [Ref 5]. All four patients were recipients of non-leucodepleted red blood cells donated by asymptomatic individuals who subsequently went on to develop vCJD. There have been no new cases of transfusion-associated vCJD detected since 2006 (ie after the introduction of universal leucodepletion), but we remain vigilant to this possibility. The TMER is funded presently until 2015 but continued study is clearly of great importance and an extension of the study is planned but and further funding is necessary for this. The TMER addresses the critical issue of the extent of transfusion transmission of variant CJD and also provides data from look-back studies of blood transfusion in sporadic CJD and hereditary prion diseases. It also provides a mechanism for the notification of cases to the national blood authorities to enable subsequent public health actions to be taken in terms of withdrawal of implicated blood products, and contact identification and notification.
ORGANS AND TISSUE LOOKBACK
With regard to organs and tissues, in vCJD the abnormal prion protein is widely dispersed throughout the body {Refs 6,7,8,9]]. Risk assessments on bone, organ and tissues indicate a potentially high risk to transplant recipients if the donor were infected with vCJD, depending on the relative infectivity of the tissue, the mass of the tissue and the site of transplant [Ref 10].
A medical look-back study has recently been undertaken by the NCJDRSU with the UK blood and transplant services to investigate whether UK cases could have contracted vCJD by receiving an organ or tissue transplant, or could have transmitted vCJD to others by this route. We have identified one situation to date, where an organ (liver) recipient had subsequently developed vCJD, the donor having died from causes unrelated to CJD. No links were detected between any of the other cases. A manuscript detailing the findings has been submitted for publication.
As part of national surveillance activities the NCJDRSU will continue to give a high profile to asking about blood, organ and tissue donation and receipt, along with other surgical procedures into the future, and will continue to look for links between cases as part of our surveillance of risk factors for CJD. In addition, staff at NCJDRSU support local clinicians in their prompt referral of new and suspect CJD cases to local health protection teams for further public health investigations and follow-up of surgical procedures. This enables public health action to be taken, including for organ and tissue donation/ transplantation, in line with UK guidance (Ref 11). Any vCJD cases with a known history of organ or tissue donation, or transplantation, are also referred by NCJDRSU to the relevant UK organ and tissue authorities.
PUBLIC HEALTH MONITORING OF AT-RISK INDIVIDUALS
In order to minimise the risk of onward vCJD transmissions, vCJD-implicated blood recipients and certain donors to vCJD cases and other recipients from these donors, are notified of their possible exposure and asked to take public health precautions. vCJD-implicated organ and tissue recipients and certain donors of organs and tissues to vCJD cases, and other recipients from these donors are managed in the same way. Other categories of individuals have also been placed at-risk of vCJD as a result of their medical care, including certain surgical contacts of vCJD cases, highly transfused patients and recipients of UK-sourced plasma products.
The potential for secondary transmission of vCJD has led to NCJDRSU entering collaborative studies with Public Health England (PHE) and Health Protection Scotland (HPS) or, for bleeding disorder patients, with the UK Haemophilia Centre Doctors Organisation. This “ enhanced surveillance” is aimed at identifying whether there is evidence of clinical or sub-clinical infection in those judged to be at increased risk of vCJD, identified by review of clinical records and medical histories, and examination following after death.
A review of autopsy and biopsy samples in 2010 showed evidence of vCJD-infection in the spleen of one individual, a patient with no history of neurological disease, who had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor – to which the most likely route of infection was attributed [Ref 12]. To date there have been no further reports of vCJD in individuals “at-risk” of vCJD. The ESS remains an essential component to the surveillance of secondary transmission for vCJD.
OCCUPATIONAL EXPOSURE TO PRION DISEASESIN HEALTHCARE AND LABORATORY WORKERS
A joint project between the NCJDRSU and PHE was initiated in 2010 to allow the prospective long term follow up of any possible occupational exposures to prion disease that have been reported in the healthcare setting.
To date, no exposures to vCJD patients have been registered. An exercise to retrospectively identify links between healthcare workers and patients with, or who subsequently went on to develop CJD is ongoing.
(http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/CreutzfeldtJakobDisease/RegistryForCJDAndTSEOccupationalExposures/).
OTHER REVIEWS OF LINKS BETWEEN CASES AND CLUSTER INVESTIGATIONS
In addition to the more formal mechanisms described above, the systematic investigation, by NCJDRSU, of spatio-temporal links between cases may help identify mechanisms of case-to-case transmission or common aetiological factors. This is addressed through two main approaches, detailed below:
1. The NCJDRSU undertakes a retrospective review of potential surgical contacts between any vCJD cases as a new case is reported. Although data may be incomplete and as a result links between patients may be missed, reviews of surgical histories of vCJD cases to date show no compelling evidence of geographic and temporal links (medical or dental, including organ and/or tissue transplants) between cases that might indicate transmission by these routes.
2. Investigations by NCJDRSU in collaboration with local and national public, veterinary, and environmental health teams into geographically associated cases of vCJD have found no convincing evidence of any factors, including medical or dental factors, which may have augmented local risks for vCJD. To date there has only been one statistically significant cluster of five cases in Leicestershire, ascribed to local butchery practice of splitting of bovine heads and removal of brains prior to butchering the remaining carcass [Ref 13] resulting in the contamination of low risk material with high risk material. We continue to explore apparent clustering of vCJD cases as these have both scientific interest (in relation to the cause of disease) and public health implications.
CASE CONTROL STUDY
As part of routine surveillance activities undertaken by NCJDRSU, relatives of patients with suspected CJD are approached and interviewed about the patient, using a standard questionnaire, relating to possible risk factors for CJD, including residential, occupational, dietary and medical histories. A general population control group was recruited in 2002-2003 to investigate potential risk factors for vCJD and sporadic CJD.
Results from a case-control study of relative reported risk factors for vCJD are consistent with dietary exposure to contaminated beef products being the main route of infection of vCJD. There was no compelling indication of increased risk through medical exposures, but recall bias cannot be excluded as an explanation [Ref 14].
A further case-control study investigating dental treatment as a risk factor for vCJD, based on dental practice records provided no evidence of a causal link between vCJD and dental treatment, however because a large volume of dental treatment information was missing, we cannot exclude this possibility [Ref 15]. A similar analysis investigating potential medical and surgical risk factors for sporadic CJD in the UK based on GP medical history, rather than simply the recall of relatives is ongoing.
B: ACTIONS TAKEN
It is notable that precautionary measures, in relation to blood and blood products, were adopted very early in the vCJD epidemic (see below: Measures introduced in 1997 & 1998), well before any actual instance of human-human transmission was actually identified Although the existing evidence suggested that blood was not a likely infection risk, it was recognised from the outset that BSE/vCJD as due to a novel agent and that early lympho-reticular involvement in vCJD had potential implications for blood. These have been continually reviewed and altered in the light of developments and research.
In his submission to the Committee, Professor Ironside listed the measures currently in place to reduce the risk of vCJD transmission via blood (www.gov.uk/government/news/measures-currently-in-place-in-the-uk-to-reduce-the-potential-risk-of-vCJD-transmission-via-blood) (April 2013):
1997: Blood components, plasma products or tissues from any individual who later develops clinical vCJD are withdrawn/recalled to prevent their use.
1998. Recombinant clotting factors for the treatment of haemophilia provided to patients under the age of 16, and since 2005 this was extended to all patients for whom it is suitable.
1999: Leucodepletion used in all blood for transfusion.
1999: Plasma for the manufacture of fractionated plasma products is obtained from non-UK sources.
2004: Individuals who received a transfusion of blood components since January 1980 are excluded from donating blood.
2004: Exclusion criteria for blood donation were extended to previously transfused platelet donors and donors who are unsure if they have ever received a blood transfusion.
2004-5: Fresh frozen plasma for treating babies and children born on or after 1st January 1996 is obtained from the USA.
2005: Individuals who donated blood to recipients who later developed clinical vCJD and excluded from blood donation and the donation of tissues and organs for transplantation.
In addition, efforts have been successful in promoting the appropriate use of blood in the NHS, especially in reducing the use of blood in surgery.
There are established Public health actions to be taken following a report of a new case of CJD or a person at increased risk of CJD [Public Health England & Health Protection Scotland. Colindale, London]. The measures standing at 2013 are available at: http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1225960588712
C: RECENT OBSERVATIONS & RESEARCH
In relation to blood risk, there are four relatively recent observations stemming from surveillance, research and analysis. In some respects, these observations are potentially difficult to reconcile.
C1
The accumulating data from sheep transfusion experiments has confirmed three things: Blood transfusion is a potentially efficient route of infection transmission, infectivity is present throughout a substantial part of the pre-clinical period and all components of blood are potentially relevant. This is, of course, a sheep model, but it has studied the BSE agent, used intravenous transfusion of clinically relevant blood volumes and prepared transfusion components according to protocols used in human blood transfusion services. Outlines of these research data with references can be found in the reports listed in C3 below.
C2:
The important risk in blood arises from subclinical (asymptomatic) infection in the donor population. This was studied by lymphoreticular tissue surveys. There have been two major such studies reported in the UK, both of which were given research ethics approval requiring the use of anonymised samples from patients of known birth cohorts [Refs 16,17]. These were detailed in the submission to the committee from Professor Ironside. As he stated there, it is not unreasonable to conclude that the prevalence of subclinical vCJD infection in the UK may be around 1 in 2,000 of the population and that all genetic subgroups are susceptible. He noted two caveats:
(a) The positive results reported might be false positives, either due to non-specific staining, or positivity due to other human prion diseases e.g. sCJD. [The question of non-specific staining is being addressed in an on-going DH-funded study of appendixes removed from the 1970s and earlier – before BSE is thought to have entered the human food chain. Immunohistochemistry has not detected accumulation of disease-associated prion protein in sections of appendixes, tonsils and spleens from individuals who have died from sCJD, although one report exists of very low levels of disease-associated prion protein detected in unfixed samples of the spleen in a subgroup of sCJD patients by Western blot assay, a method considered to have a greater sensitivity.
(b) The positive results reported, if true positives, might give an underestimate of the prevalence of vCJD infection in the UK population, since immunohistochemistry is perhaps not as sensitive as other assays, e.g. Western blot, for the detection of disease-associated prion protein in tissues. However, Western blot assays require unfixed tissues, and all the samples in UK Histopathology Department archives are formalin-fixed paraffin-embedded tissues.
I n current risk assessments, the figure of ~1:2000 is taken as the best current estimate.
C3:
The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments. The assumptions have been critically reviewed in the light of accumulating data. These data and assumptions will not be presented here as they are available in detailed reports (two principal reports being: ‘Blood-borne transmission of vCJD. Re-Examination of scenarios’. DH. 09.11.11 and “vCJD and transfusion of blood components; an updated risk assessment. DH 14.02.13. Both by Peter Bennet and Marea Daraktchiev). These reports have been discussed in detail by appropriate advisory bodies (such as ACDP and SaBTO as can be viewed in their committee minutes).
C4:
One notable point of discussion in the reports mentioned in C3 is the potential difficulty in reconciling the apparent risk of blood transmission (on the basis of the assumptions made in modelling) and the very few actual transmission cases observed (as well as their distribution over time, with no recently identified cases). Clearly, it is vital to continue human surveillance and studies such as the TMER so as any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered.
D: CURRENT & POSSIBLE FURTHER ACTIONS
D1
THE DEVELOPMENT OF A BLOOD TEST FOR vCJD
It is important to note that a blood test for vCJD in humans has four potential roles:
Firstly, the diagnosis of clinically apparent illness
Secondly, the detection of preclinical infection in an individual
Thirdly, the use of such a test to determine levels of subclinical infection in the general population.
Fourthly, to ‘screen’ for infection in clinical material eg blood donations.
It is also important to note that a test satisfactory for one of these roles will not necessarily be entirely satisfactory in all of these roles.
It is also important to understand that the proposed tests have, in essence, been tests to detect abnormal prion protein and, while this is an entirely reasonable marker for infectivity, it is not necessarily synonymous with it.
There are significant technical difficulties with such tests using blood with various attempts at development that have, in the final analysis, failed.
One problem with the assessment of a proposed test is the availability of suitable samples to use in its evaluation.
A great deal of discussion of these difficulties has taken place and a committee set up (under the auspices of NIBSC). This committee will be submitting evidence separately.
It is also the case that standard screening tests would usually be subject to a confirmatory test. Therefore, in considering the question of screening clinical materials such as blood donations, we would really require two tests not just one.
Quite aside from the technical aspects of such a blood test, there are other important considerations (that have been discussed in detail in various committees):
D2
The further examination of the meaning of the appendix study results has been discussed above.
D3
It is vital that all of the theoretical considerations are supported by facts. Continued human disease surveillance, with gathering of risk factor data and the special studies such as the TMER are an essential basis for future analysis and decisions. The current funding for the National CJD Research and Surveillance Unit ends in March 2015 and the present TMER funding also finishes in 2015.
January 2014
REFERENCES
The two Reports referred to in C3:
‘Blood-borne transmission of vCJD. Re-Examination of scenarios’. DH. 09.11.11
‘vCJD and transfusion of blood components; an updated risk assessment.’ DH 14.02.13.
Both by Peter Bennet and Marea Daraktchiev)