Variant CJD and Plasma ProductsRisk assessment methods,

assumptions and public health actions

in the UK

Kate Soldan & Anna MolesworthFebruary 2005

Communicable Disease Surveillance CentreHealth Protection Agency Centre for Infections

London, UK

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

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

Figure2: Quadratic and plateau models for vCJD deaths incidence trend

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Observed data

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

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

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

MAJOR PRINCIPAL & AIM OF CJDIP

RISK REDUCTION(not Risk Elimination)

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

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)

DETERMINING PATIENTS TO BE CONSIDERED ‘AT-RISK’ BY CJDIP

• Infectivity is expressed as an ID50.. 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 ID50.

• The same threshold has been applied to the risk of infection via plasma products. Exposure to 0.02 ID50 is equivalent to a 1% risk of infection.

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.

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)

• 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.

PRECAUTIONS FOR SURGICAL INSTRUMENTS

Tissue infectivityStatus of patient

Definite/probable

Possible At risk

Genetic Iatrogenic

High: BrainSpinal cordPosterior eye

Destroy* Quarantine

Destroy* Destroy*

Medium:Anterior eyeOlfactory epithelium& for vCJD only:Lymphoid tissue

Destroy* Quarantine

Destroy* Destroy*

Low/none detectable

No special precaution

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No special precaution

s

No special precaution

s

No special precaution

s* Can be used for patient-isolation, or sent for research

Full advice (and for specialised equipment): www.advisorybodies.doh.gov.uk/acdp/tseguidance

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, PrPsc found in spleen and lymph node. Peden AH et al , 2004 Lancet 364;527-529

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

DNV RISK ASSESSMENT

2. Assessed how infectivity might be distributed within the different blood components and plasma fractions

Brown et al, 1998 & 1999

DNV RISK ASSESSMENT

3. Derived values for the infectivity in each component and fraction per unit of blood.

Whole blood: 900 ID50/unit

Plasma: 480

ID50Cryoprecipitate: 60 ID50

Fraction I+III: 34.4 ID50

Fraction II: 1.6 ID50

Fraction IV: 11.5 ID50

Fraction V: 3.4 ID50

Cryosupernate: 50.6 ID50

RBC: 219 ID50

Buffy coat: 201 ID50

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

IDENTIFYING ‘AT-RISK’ STATUS

1. BATCH RISK CALCULATION

Infectivity per unit (Iu) = n x If x (p1/p2)Unit

wheren = number of implicated donations in plasma start poolIf = fraction-specific infectivity1 p1 = amount of implicated fraction used to make batch2

p2 = amount of implicated fraction made from pool2

1 Source: DNV vCJD Blood Risk Assessment Table II.3.142 Source: Plasma fractionators

2. INDIVIDUAL EXPOSURE ASSESSMENT

Infectivity received = Σ(Iu x dose received)batch1-n

Potential exposure to 0.02 ID50 is equivalent to a 1% risk of infection.

KEY ASSUMPTIONS & UNCERTAINTIES

RISK ASSESSMENT is built on a number of majorassumptions, 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 optionwas used in line with the approach traditionally taken by the UK national blood services

INFECTIVITY OF HUMAN BLOOD

1. Blood from someone incubating vCJD is infectious.10 ic ID50/ml human blood 2 iv ID50/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.

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.

SUSCEPTIBILITY OF RECIPIENTS

9. The dose response for infectivity is linear1ID50 = 50% risk of infection2ID50 = 100% risk of infection0.02ID50 = 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

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.

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 0.02ID50 (n=187 batches)

BATCH RISK STRATIFICATION

based on batch specific infectivity and how product was used in clinical practice

(Likelihood of surpassing 1% threshold) Product

Total batches

Estimated Units required

(High) Factor VIII (intermediate) 16 20 -1003 iu Factor IX 8 144 – 885 iu Anti-thrombin 1 346 iu (Medium) Intravenous immunoglobulin 11 150 – 1779 grams Albumin 4.5% 28 3.9 – 311.0 litres (Low) Albumin 20% 21 Intramuscular human normal immunoglobulin 10 Anti-D 2 Factor VIII (excipient) 77 Total implicated product batches 174

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.

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

POPULATION APPROACHPATIENTS 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

INDIVIDUAL APPROACHALL 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

WHO MAY BE AFFECTED?

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

ACKNOWLEDGEMENTSWe 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