Variant CJD and Plasma Products Risk assessment methods, assumptions and public health actions in the UK Kate Soldan

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Variant CJD and Plasma ProductsRisk assessment
methods, assumptions and public health actionsin
the UKKate Soldan Anna MolesworthFebruary
2005Communicable Disease Surveillance
CentreHealth Protection Agency Centre for
InfectionsLondon, UK
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OVERVIEW

• 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

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THE CONTEXT OF PERSON TO PERSON CJD RISK
REDUCTION IN UKPRIMARY 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

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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

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THE CONTEXT OF PERSON TO PERSON CJD RISK
REDUCTION IN UKTHE 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

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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

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MAJOR PRINCIPAL AIM OF CJDIP

• RISK REDUCTION
• (not Risk Elimination)

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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
• gt 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

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

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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.

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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 patients 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/tseguida
  nce/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.

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PRECAUTIONS FOR SURGICAL INSTRUMENTS
Tissue infectivity Status of patient Status of patient Status of patient Status of patient
Tissue infectivity Definite/ probable Possible At risk At risk
Tissue infectivity Definite/ probable Possible Genetic Iatrogenic
High Brain Spinal cord Posterior eye Destroy Quarantine Destroy Destroy
Medium Anterior eye Olfactory epithelium for vCJD only Lymphoid tissue Destroy Quarantine Destroy Destroy
Low/none detectable No special precautions No special precautions No special precautions 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/tse
guidance
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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 363417-421 - Asymptomatic
recipient died 4 yrs after implicated
transfusion, PrPsc found in spleen and lymph
node. Peden AH et al , 2004 Lancet 364527-529
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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
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DNV RISK ASSESSMENT 2. Assessed how infectivity
might be distributed within the different blood
components and plasma fractions
Brown et al, 1998 1999
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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 ID50
Buffy coat 201 ID50
RBC 219 ID50
Cryoprecipitate 60 ID50 Fraction IIII 34.4
ID50 Fraction II 1.6 ID50 Fraction IV 11.5
ID50 Fraction V 3.4 ID50 Cryosupernate 50.6
ID50
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• 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

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• IDENTIFYING AT-RISK STATUS
• BATCH RISK CALCULATION
• Infectivity per unit (Iu) n x If x (p1/p2)
• Unit
• where
• n number of implicated donations in plasma
  start pool
• If 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.3.14
• 2 Source Plasma fractionators
• INDIVIDUAL EXPOSURE ASSESSMENT
• Infectivity received S(Iu x dose
  received)batch1-n

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• 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

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• INFECTIVITY OF HUMAN BLOOD
• Blood from someone incubating vCJD is infectious.
• 10 ic ID50/ml human blood
• 2 iv ID50/ml human blood (0.2-60)
• Infectivity is constant throughout the incubation
  period, and assumed present at the time of
  donation and as far back as 1980.
• 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).
• Leucodepletion does not reduce infectivity of
  plasma.

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• EFFECTS OF PROCESSING
• There are only the specified number of implicated
  donations in the plasma start pool.
• There is no cross-contamination during
  manufacture
• 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).
• There is no reduction in infectivity through
  processing beyond fractionation, or through
  storage.

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• SUSCEPTIBILITY OF RECIPIENTS
• 9. The dose response for infectivity is linear
• 1ID50 50 risk of infection
• 2ID50 100 risk of infection
• 0.02ID50 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

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• 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.

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TRACING IMPLICATED DONATIONS
Identify blood donors who subsequently developed
vCJD (n9 donors)
Identify plasma sent for fractionation (n23
donations)
Identify batches of plasma product/intermediate
made from implicated plasma, estimate dose
equivalent to 0.02ID50 (n187 batches)
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• BATCH RISK STRATIFICATION
• based on batch specific infectivity and how
  product was used in clinical practice

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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.

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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
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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

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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

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WHO MAY BE AFFECTED?
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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

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• 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

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