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How is Causality

Assessment done?

WHO

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ObjectivesBy the end of this session you should be able to:

Explain what information is required prior to commencing AEFI causality assessment

Understand the basic components of a formal AEFI causality assessment process

Describe the roles, functions and characteristics of a national expert committee for causality assessment

List the criteria for selecting AEFI cases for formal causality assessment.

Apply the principles of causality assessment to specific cases and clusters of cases.

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Challenges in Causality Assessment: Data Input Issues

AEFI:– not recognized– not reported– misreported (case does not meet definitions)– delayed reporting– Inadequate case report information for

causality assessment: quality/quantity All may lead to delay or lack of recognition

of program or vaccine problem and/or inappropriate conclusion on causality

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Challenges: Assessment Issues• No systematic process: review, code, triage, collate,

analyze and store• Backlog of cases for review• Screening process not systematic, not of quality• No criteria for AEFI referral for formal CA process• Formal CA process not systematic, not of quality• Expertise inadequate for CA and/or focus on drugs• Conflicts of interest – lack of independence, political

pressure• No analysis done on cumulative data

May undermine program credibility, quality & timeliness

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Challenges: Regional/National Level: Follow Up Issues

• Failure to have outcome pathway for dealing with the AEFI causality assessments

• Failure to feedback results to field

• Failure to recognize importance of information for media

• Failure to compile a regular report nationally

• Failure to report on to international level

May undermine program stability, credibility and quality

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Model and Practical Steps for Case Review and Causality

AssessmentCritical to develop a local, regional and national case review and causality assessment process that is: • sustainable• trustworthy• consistent• systematic• flexible• timely • evidence based

WHO

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Systematic Review Checklist1. Verify Reason for reporting

verify case meets definition, code diagnosis

and severity

2. Routine review for minor and well known AEFI-

done by trained immunization program staff at

regional/national level in systemic manner.

3. Collate and analyze data to detect any decrease or

increase in frequency and/or severity of events

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Systematic Review Checklist

4. Determine if AEFI meets preset criteria for referral to independent committee for formal causality assessment process (ie triage)

5. Gather additional data for cases for formal assessment

6. Prepare cases for formal causality assessment including anonymizing (block out patient name, state, clinic or hospital name etc) information

7. Store data on all AEFIs

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Elements of Formal Causality Assessment

National level• National Expert Committee for Causality Assessment

• Criteria (including case definitions) for formal

assessment

• Method of causality assessment

• System for classifying causality

– (e.g. definite, possible, probable, unlikely etc.)

• System for communicating on causality assessment

• Program intervention: taking action when needed

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Expert committee should: • Be Independent

– free of real or perceived government, industry conflicts of interest

• Have terms of reference• Have broad range of expertise

– infectious diseases, epidemiology, microbiology, pathology, immunology, neurology, vaccine program expertise, other…

• Liaise with national immunization program– investigative team

– ensuring high quality case data for review

– administrative support

Expert Committee for Causality Assessment National level

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Criteria for selecting cases for formal causality assessment (1)

• Serious AEFIs (as per definition)

• Clusters and events above expected rate

• Signals

• Other AEFIs (WHO recommendation)– AEFIs that may have been caused by programme error (e.g.

bacterial abscess, severe local reaction, high fever or sepsis, BCG lymphadenitis, toxic shock syndrome, clusters of AEFIs)

– Significant events of unexplained cause occurring within 30 days after a vaccination (and not listed in product label)

– events causing significant parental or community concern

DeathHospitalization

Significant disabilityLife threatening

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Assessment of Routine and Serious AEFIs

Previous knowledge

Clinical characteristicsLab findings

Data quality

Likelihood/exclusion of other causes

CAUSALITY

Association (time, place)

Biological Plausibility

Temporal Relation

Consistency ReproducibilityReliability

Specificity and Strength of AssociationRx, risk factors, susceptibility, program error

Concomitant or Preceding ConditionsConfident diagnosis of lesion lab results favour causation

Previously Known Reaction

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Sample format for causality assessment case review

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Case Example of Systematic Causality Assessment

10 am: 6 ½ month old baby received routine DPT + OPV at a clinic session

1:30 pm: baby brought to University Medical Centre with dyspnoea, pharyngeal edema, and mottling

– Diagnosed as anaphylactic shock

– given fluids, oxygen, antihistamine, steroids

– admitted

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• 4 pm: cyanosis, respiratory distress, change in state, cool skin with mottling, prolonged capillary refill time, fever– Chest exam: rales and rhonchi but no evidence of

upper airway obstruction– normal pharyngeal examination– given fluids, oxygen; antibiotics started – 10 pm: generalized convulsion, given phenobarb,

followed by apnea, resuscitated with intubation– pronounced dead at 0050 hours

• Clinical diagnosis at death: septic shock, apnea due to bronchiolitis and anaphylactic shock

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Anaphylaxis

Definition

• Severe, whole body allergic reaction following exposure to allergen person is sensitized to

• Changes develop over several minutes

• Involve 2 or more systems: skin, resp, circulatory

Cardinal Signs

• Itchy, urticarial rash>90%

• Painful swelling face/mouth (angioedema)

• Resp symptoms - sneeze, cough, wheeze, upper airway swelling

• Hypotension - develops later and may progress to collapse and shock

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Additional Information from Investigation

• Mother stated baby had cough and respiratory distress BEFORE the vaccination and a convulsion 3 hours after immunization.

• Unknown if baby had rapid rise in temp before seizure.

• Chest x-ray 3 hrs after admission showed signs of bronchiolitis.

• Clinically no evidence of anaphylaxis – no skin changes-such as hives– no documented evidence of facial, tongue swelling -

statement of pharyngeal edema but no clinical findings to support + timing > 3 hours after vaccination.

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Frequency of Occurrence of AE

very common > 10%

common > 1to < 10%

uncommon > 0.1% to < 1%

rare > 0.01% to < 0.1%

very rare < 0.01%

NPR: not previously reported

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WHO Causality Assessment Criteria

Very likely / Certain Clinical event with a plausible time relationship to

vaccine administration and which cannot be explained by concurrent disease or other drugs or chemicals

Probable Clinical event with a reasonable time relationship to

vaccine administration and is unlikely to be attributed to concurrent disease or other drugs or chemicals

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WHO Causality Assessment Criteria

Possible Clinical event with a reasonable time relationship to vaccine administration but which could

also be explained by concurrent disease or other drugs or chemicals

Unlikely Clinical event whose time relationship to vaccine

administration makes causal connection improbable but which could plausibly be explained by underlying disease or other drugs or chemicals

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WHO Causality Assessment Criteria

Unrelated

Clinical event with an incompatible time relationship to vaccine administration and which could be explained by underlying disease or other drugs or chemicals

Unclassifiable

Clinical event with insufficient information to permit assessment and identification of the cause.

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Conclusion

• A 6 ½ month old who died from respiratory failure and shock like picture most likely due to bronchiolitis 13 hours after immunization.

• Areas of concern– education needed on the presenting signs and symptoms

(including timing of onset) and correct treatment of anaphylaxis.

– major delay in the recognition and treatment of severe bronchiolitis

– post mortem would have been helpful as would have been test for RSV.

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Categories of Causality using WHO Causality Assessment Criteria

Very likely Probable Possible

Vaccine reactionInjection ReactionProgrammatic error

Coincidental events

UnclassifiableInsufficient evidence

to classify

UnlikelyUnrelated

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Causality of Passive AEFI Serious Reports (ACCA review, Canada, 1994-1999)

Number Proportion

of Total

Proportion

Of Evaluated

Very likely 31 8.7% 11.7%

Probable 31 8.7% 11.7%

Possible 58 16.3% 22.0%

Unlikely 56 15.7% 21.2%

Unrelated 88 24.7% 33.3%

Unclassifiable 92 25.8%

When data quality and/or quantity are poor or limited; causality assessment NOT possible

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Review Of Case Series or Cluster: Practical Approach

1. Develop case definition for cluster selected for review

1. Determine if each AEFI case meets definition for inclusion in the review

2. Same systematic causality assessment process for each case

3. Collate cases, analyze data

4. Determine if frequency of event is as expected, increased, decreased or a newly recognized event

5. Follow remaining steps for individual case assessment (ie. Summary, education, communication, intervention)

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EPIDEMIOLOGICAL STUDIES

Adverse event

Yes No Total

Vaccine Yes a b a+bNo c d c+d

Auriche M, Loupi E. Drug Safety 1993; 9 (3): 30-35

Risk ratio= Risk in vaccinated: A/A+BRisk in unvaccinated: C/C+D

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Summary questions

What information do you need before starting causality assessment procedures?

What are the basic components of a formal AEFI causality assessment process?

What are the is needed for a national expert committee for causality assessment to succeed?

Which types of AEFI should be selected for formal causality assessment?