Variant Creutzfeldt-Jakob Disease (vCJD) was first recognised in 1996. The disease is thought to be caused by the same agent that causes Bovine Spongiform Encephalopathy (BSE) in cattle, but the route(s) by which transmission to humans occurs remains to be established.

Cases of vCJD have been identified that appear to be associated with one another geographically. This may be by virtue of geographical proximity of residence or another link with the same area e.g. attending the same school or work place. The geographical association may be current or historic. Individuals with vCJD who appear to be associated in these ways are referred to here as geographically associated cases.

The association between these cases may reflect a common experience that is related to their having become infected with the BSE agent. Investigating cases that are associated geographically may therefore help to identify risk factors for transmission of infection.

An understanding of how the infectious agent is transmitted is important for a number of reasons:

• It allows the design of appropriate control strategies.

• It will permit more accurate estimates of how many people are likely to have been exposed to the agent causing vCJD.

• It will improve predictions of how the epidemic will develop and thereby facilitate appropriate planning.

In addition to the reasons outlined above, when geographically associated cases of vCJD are identified, the Director of Public Health (DPH) of the Health Authority or Health Board involved will to want to determine if there is a continuing risk to public health. The DPH of a Health Authority or Board has a statutory duty to ensure that effective arrangements are in place to control communicable diseases.

However, it is important to recognise that cases of vCJD that are geographically associated may have acquired their infection through a different route to cases that are not geographically associated. Hence any hypotheses generated for geographically associated cases will also need to be tested in cases that have no apparent geographical association with other cases.

All suspected cases of vCJD should be referred to the National Creutzfeldt-Jakob Disease Surveillance Unit (NCJDSU) for confirmation of diagnosis. As soon as possible after referral the NCJDSU will carry out a medical examination of the individual and interview a close family member. The interview seeks detailed information on diet, medical procedures, occupation, and educational and residential histories. Since individuals from the NCJDSU are amongst the first to become aware of new cases of vCJD and have early contact with the families of cases, the NCJDSU is most likely to identify an association between cases.

All suspected cases of vCJD referred to the NCJDSU will be reported to the Public Health Department of the Health Authority or Board where the case is resident (see guidance on local reporting of CJD). Local public health teams may therefore identify geographical associations between cases.

The detailed investigation of geographically associated cases of vCJD requires a co-ordinated and consistent approach that incorporates local and national expertise, knowledge and information.

A National Steering Group will provide guidance on the appropriate response to geographically associated cases of vCJD (Appendix 1). This National Steering Group will be composed of representatives from the NCJDSU, the Scottish Centre for Infection and Environmental health (SCIEH), the Department of Health, the London School of Hygiene and Tropical Medicine (LSHTM), the Public Health Laboratory Service, Communicable Disease Surveillance Centre (CDSC) and the Public Health Medicine Environmental Group (PHMEG).

When a decision is required on whether to undertake a detailed investigation of geographically associated cases of vCJD, a Working Group of the National Steering Group will be convened. This Working Group will comprise the relevant Consultant(s) in Communicable Disease Control (C(s)CDC) from the Health Authority or Board where the cases currently reside, the relevant Regional Epidemiologist (RE), a representative from the NCJDSU, a representative from LSHTM and a representative from CDSC. To avoid delays, this group may convene by teleconference. An individual known as the Investigation Co-ordinator will act as the Secretary to the Working Group.

If the Working Group recommends detailed investigation of an apparent association, the Investigation Co-ordinator will be appointed to act on behalf of the National Steering Group and provide support to local agencies.

The agency that should lead the local investigation of geographically associated cases of vCJD is the Public Health Department of the Health Authority or Board in which the cases live. The relevant CCDC will lead the local Investigation Team on behalf of the DPH.

This protocol will be updated as information from these investigations accumulates.

To identify, through a series of co-ordinated and standardised investigations of geographically associated cases of vCJD, routes of transmission of the BSE agent to humans.

1. To combine and co-ordinate local and national expertise and information.
2. To investigate geographically associated cases of vCJD in a standardised way.
3. To identify if geographically associated cases of vCJD share any common factors which may represent a plausible route of transmission of the BSE agent to humans.
4. To determine whether there is any continuing risk of transmission of infection.
5. To document the circumstances, methods and findings of these investigations in a standardised way.
6. To inform the relevant local and national agencies of the findings of investigations in a timely and consistent way.

Because knowledge of vCJD is currently rudimentary, a useful definition of geographically associated cases will necessarily be loose.

There are a number of mechanisms by which geographically associated cases may be identified:

1. When the NCJDSU is first notified of a suspected case of vCJD staff will be aware of earlier cases from the same area and therefore may identify a close geographical association.
2. An association may be picked up during the interview of family members of a case. The interviewer may identify a link with a previous case or the family may be aware of a link with a previous case.
3. Information on lifetime residential addresses of each case is collected by NCJDSU. The LSHTM in collaboration with the NCJDSU performs a monthly systematic check of the residential database to identify all pairs of cases who have lived within 5 km of each other at any time since 1980.
4. The NCJDSU regularly reviews data held at NCJDSU in order to identify other possible associations between cases e.g. school, occupational addresses.
5. As all cases of vCJD will be reported to local public health departments, local agencies may be the first to identify an association between cases.
6. On occasions the press may be the first to uncover a link between cases.

• The agreed national procedure will apply for reporting of all cases of vCJD.
• If the NCJDSU becomes aware of a geographical association between probable or definite vCJD cases they will as a first step inform the CCDC of the Health Authority or Board where the cases live and also the relevant RE. If the associated cases live in different Health Authorities or Boards then each CCDC will be informed. The CCDC will be responsible for informing other relevant individuals in the locality such as the DPH.
• The decision to undertake further investigation of an association should be jointly taken by a Working Group made up of; the relevant C(s)CDC, RE, and representatives from the NCJDSU, LSHTM and CDSC (See section 6).

• The agreed national procedure will apply for reporting of all cases of vCJD.
• The agency that should lead the local investigation of geographically associated cases of vCJD is the Public Health Department of the Health Authority or Board in which the cases live. If any other person or agency becomes aware of an association between cases of vCJD they should as a first step contact the CCDC of the Health Authority or Board where the cases live. If the associated cases live in different Health Authorities or Boards then each relevant CCDC should be informed.
• If the NCJDSU have not already informed the Health Authority or Board of the cases or the apparent association, then the C(s)CDC should as first step contact the NCJDSU (Tel: 0131 537 2128).
• The NCJDSU will confirm if the individuals are probable or definite cases of vCJD. If the individuals are not probable or definite cases then further investigation is not warranted at this time.
• If the individuals are probable or definite cases of vCJD the CCDC should inform the RE. A decision then needs to be taken on whether further investigation is required. The decision should be jointly taken by a Working Group made up of the C(s)CDC, RE and representatives from the NCJDSU, LSHTM and CDSC (See section 6).

A Working Group of the National Steering Group should be convened by telephone to review available evidence including that already gathered by the NCJDSU. The membership of this working group should include:

1. The relevant C(s)CDC
2. Regional Epidemiologist
3. NCJDSU representative
4. LSHTM representative
5. CDSC representative [SCIEH representative in Scotland]

In deciding whether further investigation is necessary, the Working Group will consider the following information:

1. The total number of cases, the certainty of diagnosis and the dates of onset of illness.
2. The proximity, duration and nature of the geographical association between the cases.
3. The reliability of information on the geographical association. There may be a need to corroborate the information through other sources before embarking on a detailed investigation.
4. The influence of population density and chance on apparent geographical clustering of cases. However, statistical confirmation that a geographical association is unlikely to be due to chance is not a pre-condition for investigation.
5. Whether further information, in addition to that already collected, is required.
6. The local context and how it may influence the feasibility of particular courses of action.

If the decision is taken not to initiate further investigations this should be documented along with the rationale for this decision. All decisions will have to be re-visited if further associated cases are identified.

Once the decision to initiate further investigations has been taken, the Working Group will inform the relevant Department(s) of Health. The Department of Health will consider cascading the information to other national agencies if necessary e.g. Food Standards Agency, Ministry of Agriculture Fisheries and Food.

As Secretary to the Steering and Working groups, the Investigation Co-ordinator will be responsible for ensuring that the Department of Health is kept informed of decisions made by these two groups.

The Working Group will meet every six months to review all geographically associated cases. At this meeting the group will review:

1. Findings of completed investigations.
2. Progress of ongoing investigations.
3. Changes to the investigation protocol.
4. Recently identified geographically associated cases.

The six monthly review meetings will be timetabled to take place approximately one month before the six monthly meeting of the Spongiform Encephalopathy Advisory Committee (SEAC) Epidemiology sub-group. This will allow the Working Group to prepare a summary report for the SEAC Epidemiology sub-group.

The full National Steering Group will meet annually, alternately in London and Edinburgh.

The investigation will be undertaken by a Local Investigation Team. The chair and lead investigator should normally be the CCDC of the Health Authority or Board in which the majority of the cases reside. Suggested membership of the Local Investigation Team includes:

1. C(s)CDC (Chair)
2. Senior Environmental Health Officer
3. Regional Epidemiologist
4. Director of Public Health
5. Representative of local MAFF Veterinary Investigation Centre
6. Investigation Co-ordinator supported by:

1. NCJDSU representative
2. CDSC (national) representative

The Local Investigation Team should deal with the following issues as a priority at their first meeting:

• Terms of reference of the Local Investigation Team
• Remit of the investigation
• Roles and responsibilities of members of the Team
• Likely duration of investigation and resources required
• Communications strategy
• Liaison with the families and possibility of press injunction

The investigation can be divided into a number of phases.

• Review all the available information
• Establish working definitions

• Consider hypotheses

This phase is likely to be important whilst hypotheses for transmission are being developed. This phase may involve the use of more qualitative techniques to gather information to guide the investigation. Whilst novel hypotheses may be explored, it is envisaged that a ‘minimum information set’ will be generated which provides essential details relating to the most likely hypotheses (Appendix 3). Steps in the descriptive phase may include:

• Interviews with relatives of the cases to develop hypotheses further. The NCJDSU will have already undertaken interviews and careful consideration will be needed as to how valuable additional information will be.
• Interviews with key local informants – farmers, butchers, vets etc. (See environmental investigation below)
• Review of medical and dental records to gather information on certain hypotheses e.g. immunisation or surgery. Primary care notes are likely to be the most accessible and comprehensive records. Note that for any individual case of vCJD a review of medical and dental records may be necessary to assess the risk of iatrogenic transmission of vCJD.

• Environmental investigation

Once all the relevant descriptive information has been gathered it should be reviewed. Certain hypotheses may be discarded at this stage. Others may appear more plausible or new hypotheses may present themselves. At this stage the Investigation Team need to decide whether a formal epidemiological study is required to test specific hypotheses.

This phase may become more important as information from investigations accumulates and hypotheses need to be tested.

As is normal practice, the Chair of the Local Incident Control Team will be responsible for producing a full report of the investigation. Due to the lengthy delays that can occur in writing and agreeing final reports, the Investigation Co-ordinator will compile a standardised interim report for each investigation. This will be agreed by the local team and reviewed by the Working Group. The National Steering Group will present a summary of all investigations to the SEAC Epidemiology Sub-group biennially.

1. To establish and develop an informative and acceptable process for the detailed investigation of geographically associated cases of vCJD.
2. To provide members for the Working Group deciding whether to undertake detailed investigation of geographically associated cases of vCJD.
3. To review and interpret the results of the investigations.
4. To present a biennial summary of the investigations to the SEAC Epidemiology Sub-group.

1. To decide if further investigation of geographically associated cases of vCJD is necessary.
2. To document the circumstances, methods and findings of these investigations in a standardised way.
3. To provide operational guidance to the Local Investigation Team on the investigation of geographically associated cases of vCJD.
4. To support the Investigation Co-ordinator.
5. To review and interpret the results of the investigations.
6. To report to the National Steering Group

1. To undertake investigation of geographically associated cases of vCJD when agreed by the Working Group.
2. To adhere to standard ‘good practice’ in local outbreak investigation.
3. To address community concerns and to keep relatives and the local community informed of the progress of the investigation.
4. To control any ongoing risk after taking national advice.
5. To write an incident report.

1. To inform the NCJDSU and RE of geographically associated cases of vCJD of whom the CCDC becomes aware.
2. To serve as a member of the Working Group deciding whether to undertake further investigation of geographically associated cases of vCJD.
3. To chair the Local Investigation Team.
4. To co-ordinate the local investigation of geographically associated cases of vCJD.

1. To provide direct support to the Local Investigation Team in the field investigation.
2. To ensure a standardised approach to the investigation of geographically associated cases of vCJD.
3. To write an interim investigation report agreed by the Local Investigation Team for review by the Working Group.
4. To liaise between the Local Investigation Team and members of the Working Group.
5. To act as Secretary for the National Steering Group and the Working Group.

1. To provide a representative for the National Steering Group and Working Group.
2. To attempt to ascertain if cases of vCJD referred to NCJDSU are geographically associated, working in collaboration with statistical & epidemiological support from the LSHTM.
3. To inform local CCDC, RE, & CDSC of any geographically associated cases of vCJD that are identified by NCJDSU.
4. To provide epidemiological advice and more general advice on all aspects of vCJD to the local investigation team.

1. To provide a representative for the National Steering Group and Working Group.
2. To perform statistical analysis, in collaboration with the NCJDSU, which will help to inform the decision as to whether geographically associated cases merit detailed investigation.
3. To perform monthly checks of the vCJD residential database to identify pairs of cases who have lived within 5 km of each other.
4. To inform local CCDC, RE, & CDSC of geographically associated cases on behalf of NCJDSU if necessary.
5. To provide epidemiological and statistical guidance to the Local Investigation Team.

1. To provide a representative for the National Steering Group and Working Group.
2. To inform the NCJDSU of geographically associated cases of vCJD that CDSC becomes aware of.
3. To provide epidemiological guidance and assistance to the Local Investigation Team.

1. To provide a representative for the National Steering Group.
2. To provide policy guidance to the Local Investigation Team.
3. To cascade information to other relevant Government Departments.
4. To provide generic press support to the Local Investigation Team.

If you have any questions or comments on this protocol please contact Dr Hester Ward at the NCJDSU (h.ward@ed.ac.uk) or Dr Noel Gill at CDSC (ngill@phls.org.uk).

Dr N Connor – Department of Health, Communicable Diseases Branch

Mr A Harvey – Department of Health, Communicable Diseases Branch

Dr N Gill – PHLS Communicable Disease Surveillance Centre (convenor)

Dr R Salmon - PHLS Communicable Disease Surveillance Centre

Dr H Ward – National CJD Surveillance Unit

Mr S Cousens - London School of Hygiene and Tropical Medicine

Dr D Walker – Durham HA / Public Health Medicine Environmental Group

Dr P Horby – PHLS Communicable Disease Surveillance Centre (secretary)

Rationale: Large numbers of BSE infected cattle were slaughtered for human consumption.

Specific hypothesis of interest: local butchering practices, particularly butchering of the head on the same premises as the butchering of the rest of the carcass, may have led to consumption of material with a high infectious titre.

Rationale: a large number of medical products were produced using bovine materials including a wide range of medicines, some vaccines and catgut sutures. Surgical procedures also carry the theoretical risk of secondary transmission from an infected individual to another individual.

Specific hypotheses of interest:

1. Individuals may have been infected by exposure to a common batch of medical products contaminated with BSE infected bovine products.
2. Infection may have been transmitted from one infected individual to other, previously uninfected individuals, through medical procedures.

Did cases share the same dentist at any time between 1980 and 1996? If so, did they undergo any dental procedures (other than cleaning/dental hygiene) at around the same time?

Did the cases use contact lenses in the period 1980 to 1996, including those worn for social reasons (e.g. to change eye colour)? Did they undergo tonometry in the same location at around the same time during this period?

Rationale: it has been suggested that waste material from abattoirs or rendering plants, spread onto fields could lead to infectious material reaching the water course and hence the water supply.

Specific hypothesis: individuals were infected through contamination of a shared water supply.

Rationale: individuals may have been exposed to a common source of infection through social or leisure activities.

Specific hypothesis: individuals may have been infected through a common exposure linked to social or leisure activities.

Rationale: individuals may have been exposed to a common source of infection at work.

Specific hypothesis: individuals may have been infected through a common exposure to infected materials linked to work.

Rationale: individuals may have been exposed to a common source of infection at school.

Specific hypothesis:

Rationale: it is known that cats get FSE. It has been suggested that transmission of BSE to humans could have occurred indirectly through transmission to other animals, such as cats.

Specific hypothesis: individuals were infected through being bitten or scratched by animals such as cats.

Rationale: individuals may have been infected through cross- contamination of re- used needles for non- medical or recreational purposes.

Specific hypothesis: individuals were infected through ear piercing, body- piercing, acupuncture, intravenous drug use.

The National CJD Surveillance Unit (NCJDSU) undertakes a detailed interview of every suspected case of vCJD referred to them. The interview seeks detailed information on diet, medical procedures, occupation, and educational and residential histories. However, since associations between cases will often only become apparent some time after the initial interview, the initial interview cannot probe for particular associations between cases.

When geographically associated cases of vCJD are identified the information in the following tables should be checked or collected. Given that exposure of the UK population to the BSE agent is likely to have been greatest between 1980 and 1996, it is reasonable to limit the investigation to exposures or events occurring from 1980 onwards.

Where an association is identified, further investigation may be necessary. For instance, it may be discovered that a number of cases purchased meat from the same source. Information that might then be required includes the original source of the meat, the BSE history of the particular farms that supplied the meat, where the animals were butchered and the butchering practices in the establishment that supplied the meat.

A detailed review of medical and dental records may not always be a necessary part of the investigation of associations between cases of vCJD e.g. if the cases were never registered with the same dental practice. However, such a review may be necessary for individual cases to establish if there is any risk of iatrogenic transmission of vCJD. The CJD Incident Panel at the Department of Health (Tel: 020 7972 5324) has been established to provide advice on the management of the possible risk of transmission resulting from medical or dental procedures in people subsequently diagnosed with CJD.