1. Variant CJD and Plasma Products Risk assessment methods, assumptions and public health actions in the UK Kate Soldan & Anna Molesworth February 2005 Communicable Disease Surveillance Centre Health Protection Agency Centre for Infections London, UK

2. In UK: THE CONTEXT OF ‘PERSON TO PERSON’ CJD RISK REDUCTION PUBLIC HEALTH RESPONSE TO RISK ASSESSMENTS RISK ASSSESSMENT FOR PLASMA-PRODUCTS PATIENT NOTIFICATION EXERCISE ONGOING SURVEILLANCE OF PLASMA-PRODUCT RECIPIENTS OVERVIEW

3. THE CONTEXT OF ‘PERSON TO PERSON’ CJD RISK REDUCTION IN UK PRIMARY VS SECONDARY EPIDEMIC Primary epidemic: Secondary transmission: Under certain assumptions, iatrogenic transmission could lead to a second epidemic, and/or self-sustaining level of infection

4. BACKGROUND potential but unknown risk of transmission of variant CJD through healthcare interventions including –neurosurgery, eye surgery (all CJD including vCJD) –surgery involving lymphoreticular tissues (vCJD) –blood transfusions & blood products (vCJD) uncertainty regarding number of people infected and ‘incubating’ variant CJD young age of cases of variant CJD (blood donors, future surgery) prions accumulate in tissues for very long time before onset of symptoms of disease possibility of sustaining vCJD in absence of BSE CJD may be diagnosed some time after surgery

5. THE CONTEXT OF ‘PERSON TO PERSON’ CJD RISK REDUCTION IN UK THE CJD INCIDENTS PANEL UK-wide expert committee Set-up by Department of Health at end of 2000 To advise healthcare professionals on action to take in incidents involving potential transmission of CJD between patients through clinical interventions – surgical instruments, tissue, organs & blood Reports to Advisory Committee on Dangerous Pathogens (ACDP) Working Group on TSEs

6. RATIONALE FOR CJD INCIDENTS PANEL Need to apply precautionary principal Can only eliminate risk by –single use instruments too expensive / not available / less safe –decontamination process that removes all prions process not identified yet –test everyone for CJD/vCJD before surgery test not invented yet Public health action can reduce risk of onward transmission Not possible to write guideline to cover all possible types of incidents Need to consider each incident on a case-by case basis

7. MAJOR PRINCIPAL & AIM OF CJDIP RISK REDUCTION (not Risk Elimination)

8. CATEGORIES OF PATIENTS FOR CJDIP ADVICE Symptomatic diagnosed with possible, probable or definite CJD of any type with neurological symptoms & differential diagnosis including CJD or vCJD Asymptomatic, ‘at-risk’ ‘at-risk’ of familial CJD –> 2 relatives with CJD –relative with genetic mutation known to be familial –genetic testing suggests increased risk ‘at-risk’ of iatrogenic CJD –human growth hormone recipients (sCJD) –dura mater graft recipients (sCJD) –‘at-risk’ patients as advised by CJD Incidents Panel (sCJD and vCJD) –corneal graft recipients - risk assessment awaited

9. DETERMINING PATIENTS TO BE CONSIDERED ‘AT-RISK’ BY CJDIP Source: Department of Health. Risk Assessment for Transmission of vCJD via Surgical Instruments. EOR (2001) The CJD Incidents Panel. Management of Possible Exposure to CJD through Medical Procedures. Framework Document (2004)

10. DETERMINING PATIENTS TO BE CONSIDERED ‘AT-RISK’ BY CJDIP Infectivity is expressed as an ID 50.. This is the dose that is expected to cause disease in 50% of recipients. Infectivity is present in CJD patients and transmission via surgical instruments can occur. Each time surgical instruments are used the risk of transmitting infection decreases. Based on a modelling approach the CJDIP considered a risk of infection via surgical instruments equating to a potential exposure to about 0.02 ID 50. The same threshold has been applied to the risk of infection via plasma products. Exposure to 0.02 ID 50 is equivalent to a 1% risk of infection.

11. CJDIP ADVICE TO ‘AT-RISK’ PATIENTS In order to reduce the risk of further transmission of infection and should NOT be seen as a way of advising individuals about their potential additional risk of developing vCJD/CJD. ‘At-risk’ patients: Do not donate blood. Do not donate organs or tissues. Tell whoever is treating you before you undergo medical, surgical or dental treatment, so they can then arrange any special procedures for the instruments used in your care. It would be best if you tell your family about this in case you might need emergency surgery in the future.

12. CJDIP ADVICE TO ‘AT-RISK’ PATIENTS Clinicians caring for ‘at-risk’ patients: know that their patient is being informed about their ‘at-risk’ status; record the patient’s ‘at-risk’ status and the special precautions required in their primary care records (The CJD Incidents Panel advises that this should only be done once the patient is aware); include this information in any referral letters should the patient require invasive medical or dental procedures, for example a surgical operation (guidance for infection control http://www.advisorybodies.doh.gov.uk/acdp/tseguidance/Index.htm) http://www.advisorybodies.doh.gov.uk/acdp/tseguidance/Index.htm check if the patient has given any donations (blood or other tissues) since the time of the exposure that has put them ‘at-risk’, or undergone any recent surgery at other hospitals and, if they have, liaise with their local Health Protection Team and the CJDIP in order to ascertain whether any further action needs to be taken.

13. PRECAUTIONS FOR SURGICAL INSTRUMENTS Tissue infectivity Status of patient Definite/ probable PossibleAt risk GeneticIatrogenic High:  Brain  Spinal cord  Posterior eye Destroy*QuarantineDestroy* Medium:  Anterior eye  Olfactory epithelium & for vCJD only:  Lymphoid tissue Destroy*QuarantineDestroy* Low/none detectable No special precautions * Can be used for patient-isolation, or sent for research Full advice (and for specialised equipment): www.advisorybodies.doh.gov.uk/acdp/tseguidance

14. BACKGROUND TO PLASMA-PRODUCT RISK ASSESSMENT In 1997 the Department of Health commissioned Det Norske Veritas (DNV) to undertake a Risk Assessment of Exposure to vCJD infectivity in blood and blood products. In 2003 an update of the DNV Risk Assessment was completed that - included the latest research, and - provided a tool that could be used to estimate risks to recipients of implicated products In 2004 two reports of probable transmission of vCJD infection by blood transfusion - Symptomatic case, confirmed on post-mortem, onset 6.5 yrs after implicated transfusion. Llewelyn CA et al, 2004 Lancet 363;417-421 - Asymptomatic recipient died 4 yrs after implicated transfusion, PrP sc found in spleen and lymph node. Peden AH et al, 2004 Lancet 364;527-529

15. DNV RISK ASSESSMENT 1. Reviewed all the experimental research available on the infectivity of blood and its components, and produced a value for infectivity in one unit of blood. Brown et al, 1998

16. DNV RISK ASSESSMENT 2. Assessed how infectivity might be distributed within the different blood components and plasma fractions Brown et al, 1998 & 1999

17. DNV RISK ASSESSMENT 3. Derived values for the infectivity in each component and fraction per unit of blood. Whole blood: 900 ID 50 /unit Plasma: 480 ID 50 Cryoprecipitate: 60 ID 50 Fraction I+III: 34.4 ID 50 Fraction II: 1.6 ID 50 Fraction IV: 11.5 ID 50 Fraction V: 3.4 ID 50 Cryosupernate: 50.6 ID 50 RBC: 219 ID 50 Buffy coat: 201 ID 50

18. DNV CONCLUSIONS  Level of risk from any vCJD infectivity in blood of people incubating disease is unclear  Evidence for vCJD infectivity in blood is based mostly on animal models  vCJD infectivity may be present in plasma and other components  If level of infectivity is as suggested by animal models this infectivity may be sufficient to cause infection  Certain plasma products could carry a risk of infection

19. IDENTIFYING ‘AT-RISK’ STATUS 1.BATCH RISK CALCULATION Infectivity per unit (I u ) = n x I f x (p1/p2) Unit where n= number of implicated donations in plasma start pool I f = fraction-specific infectivity 1 p1= amount of implicated fraction used to make batch 2 p2= amount of implicated fraction made from pool 2 1 Source: DNV vCJD Blood Risk Assessment Table II.3.14 2 Source: Plasma fractionators 2.INDIVIDUAL EXPOSURE ASSESSMENT Infectivity received = Σ(I u x dose received) batch1-n Potential exposure to 0.02 ID 50 is equivalent to a 1% risk of infection.

20. KEY ASSUMPTIONS & UNCERTAINTIES RISK ASSESSMENT is built on a number of major assumptions, with considerably uncertainty. These relate to:  the infectivity of blood,  processing, and  the susceptibility of recipients to infection. Where there was uncertainty the most precautionary option was used in line with the approach traditionally taken by the UK national blood services

21. INFECTIVITY OF HUMAN BLOOD 1.Blood from someone incubating vCJD is infectious. 10 ic ID 50 /ml human blood 2 iv ID 50 /ml human blood (0.2-60) 2.Infectivity is constant throughout the incubation period, and assumed present at the time of donation and as far back as 1980. 3.Infectivity in blood components and plasma fractions varies from the value for whole blood according to ratios determined from endogenous low dose experiments using blood from mice inoculated with a mouse adapted human TSE (Brown 1998, 1999). 4.Leucodepletion does not reduce infectivity of plasma.

22. EFFECTS OF PROCESSING 5.There are only the specified number of implicated donations in the plasma start pool. 6.There is no cross-contamination during manufacture 7.Every fraction manufactured could contain the potential levels of infectivity found per unit fraction of blood. (This is distributed in final products in proportion to the volume of intermediate used for the batch). 8.There is no reduction in infectivity through processing beyond fractionation, or through storage.

23. SUSCEPTIBILITY OF RECIPIENTS 9.The dose response for infectivity is linear 1ID 50 = 50% risk of infection 2ID 50 = 100% risk of infection 0.02ID 50 = 1% risk of infection 10.Risk to patients is additive over their lifetime of exposure (the cumulative effect of regular doses is the same as a single administration of a cumulative dose) 11.All recipients are equally vulnerable 12.Animal models are applicable to humans

24. PATIENT NOTIFICATION The CJD Incidents Panel has advised that patients who are exposed to a 1% or greater potential risk of infection, via: - surgical exposure - exposure to plasma-products in addition to the background risk from potential dietary exposure, should be considered ‘at-risk’ of vCJD for public health purposes and advised of the special precautions they need to take.

25. TRACING IMPLICATED DONATIONS Identify blood donors who subsequently developed vCJD (n=9 donors) Identify plasma sent for fractionation (n=23 donations) Identify batches of plasma product/intermediate made from implicated plasma, estimate dose equivalent to 0.02ID 50 (n=187 batches)

26. BATCH RISK STRATIFICATION based on batch specific infectivity and how product was used in clinical practice

27. PANEL RECOMMENDATIONS The CJDIP recommends the following action in relation to each implicated batch of plasma product, according to the likelihood that recipients will have surpassed the ‘at-risk’ threshold for public health purposes: HIGH: These batches should be traced and the individual recipients considered ‘at-risk’ of vCJD for public health purposes. MEDIUM: Efforts should be made to trace these batches and to assess individual recipients to determine if special precautions should be taken for public health purposes. LOW: These batches do NOT need to be traced and the individual recipients do not need to be informed.

28. NOTIFICATION STRATEGY Patient group management strategies were developed through negotiation with professional and patient group representatives, the UK national blood services, and other expert opinion. Arrangements were made for each patient group on the basis of: a) their likelihood of surpassing the ‘at-risk’ threshold, b) estimated numbers of patients possibly affected c) the feasibility of tracing products/ doses to patients, and d) the possible impact of public health measures

29. POPULATION APPROACH PATIENTS WITH BLEEDING DISORDERS All patients with bleeding disorders and congenital antithrombin III deficiency who have been treated with UK-sourced pooled factor concentrates or antithrombin between 1980 and 2001 should be considered ‘at-risk’ of vCJD for public health purposes. The decision to take a population approach was on the basis that: a single dose of implicated product in a small child or a fraction in an adult would be sufficient to place a recipient ‘at- risk’, future batches may be implicated as more cases arise, a large proportion of patients with bleeding disorders exposed to UK-sourced products were likely to be affected, and risk associated with too great uncertainty to favor an individual approach in the context of appropriate care for this patient group

30. INDIVIDUAL APPROACH ALL OTHER PATIENTS Patients with other conditions who have been assessed as having been exposed to a 1% or greater potential additional risk of infection should be considered ‘at-risk’ of vCJD for public health purposes. The decision to take an individual approach was on the basis that: for most of these patients the products used to treat their conditions were such that substantial quantities of the material in question would be required to place a recipient ‘at-risk’, and therefore few patients were likely to be affected this approach was consistent with that used for surgically exposed patients

31. WHO MAY BE AFFECTED?

32. ONGOING SURVEILLANCE OF ‘AT-RISK’ INDIVIDUALS Study of patients with haemophilia (UKHCDO) National Surveillance of CJD cases (NCJDSU ) Follow-up of other ‘at-risk’ individuals identified by CJD Incidents Panel (HPA/CJDIP) Astute clinicians

33. ACKNOWLEDGEMENTS We thank the following organisations and their staff for their contribution to the plasma-product risk assessment and patient notification  Bio-Products Laboratory, Elstree  Department of Health (England)  Department of Health, Social Services and Public Safety (N.Ireland)  Det Norske Veritas Consulting  Haemophilia Nurses Organisation (UK)  Haemophilia Society (UK)  HPA Centre for Infections,  HPA Local & Regional Services  Health Protection Scotland  National Blood Service  National Public Health Service for Wales  NHS Direct  Primary Immunodeficiency Association  Protein Fractionation Centre, Scotland  Scottish National Blood Transfusion Service  UK Haemophilia Centre Doctors Organisation,  UK Primary Immunodeficiency Network of Clinicians,  UK CJD Incidents Panel