Aefippt
- 1. Causality Assessment Of An Adverse Event Following Immunization (AEFI) Moderator : Dr. Shamila Hamid (Assistant Professor) Presenter : Dr. Basina Gulzar (PG)
- 2. LEARNING OBJECTIVES To Understand the basic components of a formal AEFI causality assessment process To understand the roles, functions and characteristics of a national expert committee for causality assessment To know the criteria for selecting AEFI cases for formal causality assessment. To Apply the principles of causality assessment to specific cases and clusters of cases.
- 3. …Any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of vaccine The adverse event may be any unfavorable or unintended sign, abnormal laboratory finding, symptom or disease. symptom sign Lab finding disease AEFI DEFINITION
- 4. Types Of AEFI For Reporting For purpose of reporting, AEFIs can be minor, severe and serious. Minor AEFI Severe AEFI Serious AEFI • Common, self limiting reactions Examples: pain, swelling at injection site, fever, irritability, malaise etc. • Can be disabling and rarely life threatening • Do not lead to long-term problems Examples: include non- hospitalized cases of anaphylaxis that has recovered, high fever (>102-degree F), etc. • Death • Inpatient hospitalization • Persistent or significant disability • Cluster • Significant parental/community concern
- 5. CIOMS/ WHO cause specific classification of AEFIs 1 Vaccine product-related reaction 2 Vaccine quality defect-related reaction 3 Immunization error-related reaction 4 Immunization anxiety-related reaction 5 Coincidental event EXAMPLE Thrombocyt openia after Measles vaccine EXAMPLE Failure by the manufacturer. to completely inactivate a lot of inactivated polio vaccine leads to cases of paralytic EXAMPLE Transmission of infection by contaminated multi dose vial. EXAMPLE Vasovagal syncope in an adolescent following vaccination. EXAMPLE A fever after vaccination temporal association) and malarial parasite Isolated from blood
- 6. AEFI Surveillance An effective immunization safety surveillance system must be able to detect and differentiate the types of AEFI in order to prevent their occurrence and reduce their impact. It was started in India 1986
- 7. The Central Drug Standard Control Organization (CDSCO) and the universal immunization programme (UIP) coordinate the implementation of the AEFI surveillance system. The National, State and District AEFI committee, central drug laboratory ( Kasauli and Kolkata). National and sub-national drug authorities and state forensic laboratories plays a pivotal role.
- 8. Goals of AEFI surveillance Minimize the negative impact of AEFI on public health. Monitor the quality of vaccine used for immunization. Ensure and monitor the quality of immunization services. Reduce morbidity and mortality due to AEFIs.
- 9. Potential objectives for immunization safety surveillance system Detect, correct, and prevent programme errors. Identify problems with vaccine lots or brands. Prevent false blame from coincidental events. Maintain confidence by properly responding to parent/community concerns while increasing awareness (public and professional) about vaccine risks.
- 10. Generate new hypotheses about vaccine reactions that are specific to the population Estimate rates of occurrence on AEFI in the local population, compared with trial and international data (particularly for new vaccines being introduced)
- 11. Elements Of AEFI Surveillance Timely investigation and completeness of reporting are the critical indicators of a functioning AEFI system in the district/corporation Zero or no reporting of any non serious AEFI cases in the district or a block or a ward indicates poor sensitivity towards vaccine safety issues
- 12. Causality & causality assessment Levels of causality assessment Case selection Criteria Steps Multiple AEFI and Clusters Challenges Conclusion
- 13. Immunization is among the most successful and cost-effective public health interventions. It has led to the global eradication of smallpox as well as the elimination of poliomyelitis in regions of the world. Allegations that vaccines/vaccination cause adverse events must be dealt with rapidly and effectively. Failure to do so can undermine confidence in a vaccine and ultimately have dramatic consequences for immunization coverage and disease incidence long after proof is generated that the adverse event was not caused by vaccine (e.g. autism and MMR, encephalopathy and pertussis).
- 14. • Causality assessment of adverse event following immunization (AEFI) is thus a vital component of AEFI risk assessment, decision-making and the initiation of action.
- 15. CAUSALITY AND CAUSALITY ASSESSMENT Causality • Is the relationship between two events (the cause and the effect), where the second event is a consequence of the first Causality Assessment: ● Determining if such a relationship exists and if so to what extent *A direct cause is a factor in absence of which the effect would not occur (necessary cause ) *Sometimes there are multiple factors that can precipitate o function as co factors for the effect (event) to occur
- 16. Compare results Why causality assessment for AEFI? To avoid automatically concluding that "the event happened after vaccination, therefore it happened because of vaccination“... Best evidence is randomized trial comparing AEFI in vaccinated and non vaccinated groups. Random assignment But...never large enough to detect rare events Persons Unvaccinated group Vaccinated group Follow up Follow up
- 17. Causality assessment is the systematic review of data about an AEFI case. It determines the likelihood of a causal association between the event and the vaccine(s) received. Causality assessment helps determine: If an AEFI is attributable to the vaccine or the vaccination programme, What steps — if any — need to be taken to address the event.
- 18. Causality assessment outcomes help raise awareness of vaccine associated risks among healthcare workers. This combined with knowledge of benefits of immunization, forms the basis of vaccine information for parents and/or vaccinees.
- 19. The quality of a causality assessment depends on the: quality of AEFI case report, effectiveness of AEFI reporting system, quality of the causality review process.
- 20. Levels of causality assessment Causality assessment of AEFI should be performed at several different levels: The population level, where it is necessary to test if there is a causal association between the use of a vaccine and a particular AEFI in the population. The individual level AEFI case report, one should review previous evidence and make a logical deduction to determine if an AEFI in a specific individual is causally related to the use of the vaccine. The third level of assessment is in the context of the investigation of signals.
- 21. Population-based evidence for causality – — A definitive “Yes” at the population level is consistent with causality at the individual level. — A strong “No” at the population level is inconsistent with causality at the individual level.
- 22. If there is no clear answer to the question at the population level, this will often lead to an indeterminate conclusion at the individual level. If there are significant numbers of individual cases, however, this clearly points to the need to try to answer the question at the population level
- 23. The objective of signal evaluation is to draw conclusions on the presence or absence of a suspected causal association between an adverse event and a vaccine, and to identify the need for additional data collection or for risk minimization measures. This may also prompt the regulatory authorities to request the marketing authorization holder (MAH) for an additional analysis of its available data on a particular event under investigation.
- 24. Case selection for causality assessment Clusters & events above expected rate/severity Serious AEFI EVALUATION OF SUSPECTED SIGNALS Other AEFI Death , hospitalization, significant disability, life threatening, or congenital anomaly As decided by reviewing committee/team If immunization error is suspected Significant events of unexplained cause within 30 days of vaccination Events causing significant parental or community concern (HHE, febrile seizures
- 25. Pre-requisites for assessing causality for an AEFI case The AEFI case investigation should have been completed All details of the case should be available at the time of assessment There must be a "valid diagnosis“ The valid diagnosis refers to the extent to which the unfavourable or unintended sign, abnormal laboratory finding, symptom or disease is defined.
- 26. Expert committee should: • Be Independent – free of real or perceived government, industry conflicts of interest • Have written 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 Who Should Do Causality Assessment
- 27. 27 Assessment of Routine and Serious AEFIs Previous knowledge Clinical characteristics Lab findings Data quality Likelihood/exclusion of other causes CAUSALITY Association (time, place) Biological Plausibility Temporal Relation Consistency Reproducibility Reliability Specificity and Strength of Association Rx, risk factors, susceptibility, program error Concomitant or Preceding Conditions Confident diagnosis of lesion lab results favour causation Previously Known Reaction
- 28. Model and Practical Steps for Case Review and Causality Assessment Critical to develop a local, regional and national case review and causality assessment process that is: sustainable trustworthy consistent systematic flexible timely evidence based
- 29. Why 4 steps? Step 1: Eligibility To determine that the AEFI case satisfies minimum criteria for causality assessment Step 2: Check list To systematically review available information Step 3: Algorithm To obtain a trend on causality with the check list information Step 4. Classification To categorize the association of the AEFI to vaccine/ vaccination
- 30. Step 1: Eligibility AEFI Case Retain case details in a retrievable database Ensure AEFI investigation is completed and all details of the case is available Identify(vaccine) Identify one vaccine (implicated) administered before this event Select the unfavourable or unintended sign, abnormal laboratory finding, symptom or disease you want to check causality. Brighton Collaboration definition, Standard literature definition National definition or other approved definition Valid Diagnosis Case definition
- 31. Creating a Causality Question Has the vaccine A caused hepatomegaly?" (An example of an unfavourable or unintended sign) "Has the vaccine B caused thrombocytopenia?"" (An example of a laboratory finding) "Has the patient complained that the vaccine C caused itching and redness?" (An example of a symptom) "Has the vaccine D crossed meningitis?" (An example of a disease) Has the …………… vaccine/ vaccination caused………………………… Vaccine Name Valid diagnosis Example of causality questions Should address the unfavourable or unintended sign or laboratory ending or symptom or disease.
- 32. Step 2: Check list I. Is there strong evidence for other causes? II. Is there a known causal association with the Vaccine /Vaccination Relationship with vaccine ingredients Immunization error Relationship with vaccine administration II. (Time). Was the event within the time window of increased risk? III. Is there a strong evidence against a causal association? IV. Other Qualifying Factors Y N UK NA
- 33. Step 3: Algorithm (Summary) Inconsistent causal association to Immunization I.Is there strong evidence for other causes? Inconsistent causal association to Immunization II. Is there a known causal association with the vaccine/ vaccination III Is there a strong evidence against a causal association? 4. Review other qualifying factors (Time). Was the event within the time window of increased risk? Consistent causal association to Immunization Is the event classifiable? Unclassifiable? Consistent causal association to Immunization Intermediate Inconsistent causal association to Immunization Yes Yes No Yes Yes Yes
- 34. Step 4. Classification A1. Vaccine product- related (as per published literature) A2. Vaccine quality defect related reaction A3. immunization error- related reaction A4. immunization anxiety- related reaction Adequate information available A. Consistent causal association to Immunization B. Intermediate B1. Temporal relationship is consistent but there is insufficient definitive evidence for vaccine causing event (may be new vaccine- linked event) B2. Qualifying factors result in conflicting trends of consistency and inconsistency with casual association to immunization C. Inconsistent causal association to immunization c. Coincidental Underlying or ending condition(s), or condition(s) caused by exposure to something other than vaccine Adequate information Unavailable Unclassifiable Specify the additional information required for classification B1. Potential signal and maybe considered or investigation
- 35. Classification examples A1 Thrombocytopenia after MMR Vaccination A2. Paralytic polio caused by failure of manufacturer to inactivate IPV completely. A3. Transmission of infection by contaminated multidose vial. A4. Vasovagal syncope in an adolescent following vaccination. A. Consistent causal association to Immunization B. Intermediate B1. Irritable bowel syndrome after TT vaccine (hypothetical and unproved so far) B2. Thrombocytopenia after MMR Vaccine in a dengue endemic area C. Inconsistent causal association to immunization C. Coincidental Child dies after DPT vaccine and autopsy shows congenital heart disease OR Fever occurs after vaccination (temporal association) and malarial parasite isolated from blood
- 37. Case Examples of Systematic Causality Assessment
- 38. Example : 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
- 39. • 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
- 40. 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.
- 41. 42
- 42. Multiple Vaccines, Multiple AEFI and Clusters Multiple Vaccines in the same patient Multiple AEFI in the same patient AEFI cluster Each vaccine should be assessed separately. Each event should be listed separately and specific eligibility question (step 1) asked and independently evaluated. Each patient in the cluster should be separately evaluated.
- 44. Summarize the classification logic in the order of priority: With available evidence, we could conclude that the most likely classification is __________ because: 1. ______________________ 2. ______________________ With available evidence, we could NOT classify the case because
- 45. Initiating action after causality assessment of AEFI The lessons learned from the assessment should provide insights and guidance for the technical, immunization programme and administrative managers on the causes and the logical next steps – including training, research, modifying systems, refining tools and so on – to avoid and/or minimize recurrences.
- 46. Lack of communication of findings, not addressing all target audiences, or lack of diplomacy and/or cultural sensitivity Challenges to causality assessment Causality assessment not done, not systematic, not done by trained personnel and/or not done timely Information in AEFI report is so limited that causality assessment can not be done Lack of expertise and/or independence of the review committee responsible for formal causality assessment undermines credibility Non analysis of AEFI data may delay recognition of clusters and programme errors
- 47. CONCLUSION In assessing causality of an AEFI, the human elements of experience, proficiency, resources and teamwork clearly play an important role. Tools like the one described above empower investigators to think about the rationale of an assessment, collect relevant data and help to improve consistency in assessments.
- 49. References: Causality assessment of an adverse event following immunization (AEFI)Updated user manual for the revised WHO classification (Second edition 2019) http://www.who.int/immunization_safety/en/