causality assessment aefi

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Causality assessment of adverse

events following immunization

Report of an intercountry workshop

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© World Health Organization 2014

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The World Health Organization (WHO) Regional Office for South-East Asia organized an intercountry workshop on causality of adverse events following immunization (AEFI) from 18 to 20 February 2014 in Bangkok, Thailand, as part of the regional strategy to support countries to strengthen national vaccine safety surveillance and AEFI monitoring systems. Since 2008, WHO has provided training support to national regulatory authorities (NRAs) and national immunization programmes (NIPs) in the South-East Asia Region to strengthen capacity to detect, report and investigate AEFI. WHO training material is utilized in all countries to conduct training programmes. These programmes are adapted to local needs by national immunization programmes and national regulatory authorities and National AEFI committees for peripheral level immunization service delivery and may be translated into local languages in some countries. WHO provided follow-up support to some countries to establish national AEFI committees and their secretariats, update national guidelines, implement pilot projects to test and validate notification forms and investigation templates, and to standardize data analysis and reporting. The countries of the South-East Asia Region have thus experienced enhanced reporting of AEFI cases for which the causes were not always understood. This resulted in unnecessary concerns and disrupted routine immunization programme for some vaccines in some countries.

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The workshop provided a platform for experts in each country to share their experiences and report on their performances in an open forum with presentations using standardized templates. The new definitions for AEFI and vaccine pharmacovigilance were presented and discussed in plenary sessions. The WHO revised causality assessment methodology was

further tested in the process of reviewing selected cases and participants’

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The Expanded Programme on Immunization (EPI) was established in 1974

at a time when only 5% of the world’s children were protected by

vaccination against six diseases, that is, polio, diphtheria, tuberculosis, pertussis, measles and tetanus. Today, that figure is 83%, with some low-income countries (LICs) reaching 99% immunization coverage. Consequently, some vaccine preventable diseases (VPDs) are today on the verge of eradication. The challenge for immunization programmes throughout the world has become to maintain high immunization coverage with VPDs disappearing from the collective memory. Vaccines are the safest medicines with very rare serious adverse events following immunization (AEFI). Although, serious AEFI are in the range of 1 per million doses, public tolerance is much lower than for medicines because vaccines are given mostly to infants who are healthy at the time the vaccine is administered. In addition, vaccines are provided to children less than one year of age, a vulnerable age in many LICs. A country with an infant mortality of 50 per 1000 live births may expect 14 deaths of children below one year every day. As vaccination is routinely provided, those deaths could be attributed to the vaccine when in fact they are coincidental and are due to underlining diseases which were not diagnosed at the time of the vaccination. Thus, it is essential to sustain public confidence in immunization to establish surveillance systems that detect and report AEFI in the national immunization programme (NIP), experts committees able to conduct scientific AEFI causality assessments and ministry of health capacity to address vaccine safety concerns.

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Meanwhile, NRAs have initiated capacity-strengthening activities to meet international/WHO standards for vaccine safety, quality and efficacy. In the South-East Asia Region countries, national expertise increased and new requirements emerged to further expand the basic AEFI course in order to meet training requirements with new more complex vaccines and additional experts added to the national AEFI committees. The WHO course content of the basic AEFI training package was revised to cater to the needs of national AEFI committees as they were being established by NRAs/national control laboratories (NCLs) and NIPs with pharmacists, experts in allergies, forensic specialists, professors in immunology, etc. who were not always knowledgeable about their national vaccine safety surveillance system.

To further support AEFI causality assessment, the revised AEFI training material was tested in 2012 in Myanmar and Nepal with participants from national AEFI committee members, NRA representatives and EPI managers. In Myanmar1_{, the training methodology was adapted to maximize time for}

participants to breakup in small groups to conduct formal causality assessment of selected AEFI cases. Analyses of cases were reviewed in small working group sessions using the WHO 2012 revised causality assessment methodology for causality association and the findings were debated in plenary sessions to reach consensus on the conclusions of the committee about the causal association of the vaccine with the symptoms.

Since 2008, the Regional Office for South-East Asia has conducted 11 training workshops on AEFI monitoring in eight countries of the South-East

Asia Region, that is, Bangladesh, Bhutan, Democratic People’s Republic of

Korea, India, Indonesia, Nepal, Myanmar and Sri Lanka. The Regional Office for South-East Asia support toward training on AEFI2_{is a}

two-pronged approach to address needs in the NRA capacity strengthening programme

(1) for vaccine pharmacovigilance and the building of national AEFI committee with national AEFI experts to periodically review cases

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1_{Report on the Training Workshop on Adverse Events Following Immunizaton 26}_–_{30 April 2012, Nay Pyi Taw,} Myanmar. Report available within Regional Office for South-East Asia/FHR/IVD library.

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of AEFI and to respond scientifically to serious AEFI cases and concerns of vaccine safety and;

(2) to improve the detection and reporting of AEFI, including to update monitoring guidelines and implement pilot projects with enhanced AEFI surveillance systems to validate notification forms and reporting mechanisms.

Consequently, AEFI cases which were neither detected nor reported before AEFI strengthening activities have started to be increasingly detected and reported to national AEFI committees. Several countries have established surveillance systems that not only detect serious AEFI cases which result in hospitalization but also detect minor AEFI cases.

In the South-East Asia Region, the countries are introducing or have plans to introduce new vaccines in their NIPs; therefore, programme managers along with regulators and the members of national AEFI committees, and other national vaccine safety stakeholders in South- East Asia, identified the need to strengthen procedures to investigate and analyse AEFI cases in a systematic and scientific manner in order to provide timely and accurate responses to address errors to help immunization providers and the public at large. Strengthened procedures will also address vaccine safety concerns.

Countries in the WHO Western Pacific Region identified similar training needs following recent allegations concerning vaccine safety that resulted in temporary suspension of specific immunization programmes until further findings could reject a causal association with the vaccine in question. The South- East Asia and Western Pacific Regions share the same suppliers for most of the vaccines for their NIPs, making vaccine safety a cross regional issue requiring mechanisms to share information and analyse cases for causality assessments. In this connection, both regions have been cooperating to undertake joint efforts and to initiate joint activities on vaccine safety surveillance and AEFI monitoring when possible. Regional and intercountry workshops agendas are designed to address training needs in the two regions.

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This intercountry workshop on causality of AEFI conducted in Bangkok, Thailand, from 18 to 20 February 2014 was primarily aimed at countries with an established surveillance system (to detect and report AEFI) supported by a national AEFI committee that meets regularly to conduct AEFI causality assessments. The session plan of the standard WHO five day advanced course on AEFI monitoring, investigation and causality assessment was adapted to a three-day agenda focusing predominately on causality assessment. The training methodology emphasized working group sessions to stimulate discussions and exchange of experience and also to create a work environment similar to a meeting of an AEFI causality assessment committee which would meet to review and to determine causes of selected cases of AEFI. The 29 participants were from Bangladesh, Bhutan, India, Indonesia, Maldives, Nepal, Sri Lanka, Thailand and Timor- Leste in the South-East Asia Region and Viet Nam in the West Pacific Region. They included representatives of national AEFI committees, NRAs and NCLs, EPI managers, hospital paediatricians and professors from university and medical institutes and two WHO country office representatives from India and Nepal. (See Annex A for List of participants.) The intercountry workshop was facilitated by Professor Noni MacDonald, Professor of Paediatrics, Dalhousie University, Halifax, Canada; Dr Ananda Amarasinghe, Consultant epidemiologist, Epidemiology Unit, Ministry of Health, Sri Lanka; Dr Madhava Ram Balakrishnan, Medical Officer, Quality, Safety and Standards, WHO Geneva and Mr Stephane Guichard, Regional Adviser, Vaccine Supply and Quality, WHO Regional Office for South-East Asia.

2. Methodology and objectives

2.1 Objective

The main objective of the workshop was to build regional capacity to assess AEFI with the following specific objectives:

 to review selected AEFI cases from 2011–2013 in the WHO South-East Asia and Western Pacific regions using WHO revised the methodology for causality assessment;

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non-serious AEFI) to standardize terminology and case definitions to enable comparison and also signal detection by aggregating data from several countries;

 to streamline AEFI data collection procedures by introducing core variables and data analysis methods;

 to apply the new WHO causality assessment tool in different country settings, in order to strengthen its wider application; and

 to set the prerequisites for sustainable regional collaboration to share vaccine safety data of regional and global importance.

The agenda was spread over three days with the first day centred on sessions for country presentations by national counterparts to inform the participants about the status of vaccine pharmacovigilance system in their countries and activities to strengthen detection, reporting and analysis of AEFI cases (The agenda of the intercountry workshop is shown in Annex B)

2.2 Methodology

Prior to the workshop, the countries were contacted by the WHO Regional Office and country offices to provide a standard presentation template to report on the current status of vaccine safety surveillance systems, activities of the national AEFI committee and current constraints and opportunities. Initially, countries presented their situation analysis, enabling participants to gain understanding of the various country scenarios. Then the audience was updated on the recent Council for International Organizations of Medical Sciences (CIOMS) definitions and the concepts of vaccine pharmacovigilance in order to facilitate harmonization of procedures and data-sharing and data mining. Definitions and classifications of AEFI were updated by the CIOMS/WHO working group established in November 2005 3 _{to develop general definitions strictly focused on vaccine}

pharmacovigilance and to contribute to the development review evaluation and approval of definitions on AEFI as developed by the Brighton Collaboration process and to their dissemination.

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The second day was devoted to the review of selected cases for AEFI causality assessment. Participants were divided into three groups. Each group was given three AEFI cases which had occurred in the South-East Asia Region between 2011 and 2013. Several weeks before the meeting, chairmen of the national AEFI committees in the South-East Asia and Western Pacific Regions were contacted by WHO country offices to provide a minimum of five AEFI investigation reports. A total of 23 AEFI investigation reports were provided by six of the 10 countries represented at this workshop. Each AEFI investigation report was then anonymised by removing names of the case and other identifiers including name of institutions and addresses. Once the cases had been anonymised, nine were selected by the facilitators. Selection criteria included cases with well-documented reports and cases with AEFI known to be linked to vaccines. The cases were then numbered from 1 to 9 and each working group received three of these case reports to review and to present the outcomes of their analysis in plenary. Two groups managed to review all their assigned cases with one group reviewing only two cases. The participants therefore, analysed eight cases and presented their findings in the plenary sessions.

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3. Proceedings

3.1 Vaccine pharmacovigilance systems

Nine countries from the South-East Asia and one from Western Pacific regions presented their AEFI surveillance and causality assessment systems. Annex 3 summarizes country profile, status and performance of the vaccine pharmacovigilance systems in each country.

Of the 10 countries, only Maldives and Timor-Leste do not have yet an established AEFI surveillance system with a national AEFI committee. Of four vaccine-producing countries, Thailand reported more than 1000 AEFI cases. Indonesia in the last three years has significantly improved its capacity to detect AEFI with more than 18 000 reports in 2013. The two other vaccine-producing countries, that is, India and Viet Nam respectively reported 536 cases and 31 cases in 2013, highlighting significant under-reporting occurring under these systems. During the plenary discussions, India explained that the figures included only severe AEFI; the nonserious AEFI are monitored through the health management information system (HMIS) and were not included in the India presentation.

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than 6400 cases per year. In the other countries that procure vaccine through UNICEF, that is, Bangladesh, Bhutan and Timor-Leste, the capacity of the surveillance systems to detect and report AEFI varies widely. Bangladesh, which has plans to produce vaccines itself, has shown significant progress with more than 2200 cases reported per year. The other three countries report only serious cases, that is, hospitalizations and deaths. In 2013, Bhutan reported 16 cases, Maldives no cases and Timor-Leste one case. These countries have relatively small populations and may not have a serious AEFI at all for several years. Thus, it may not be sustainable for them to maintain a full-fledged system with national AEFI committee to detect very rare events and then carry out causality assessment on serious AEFI, and a rapid response system might be more suitable. However, these countries as well as all the others were encouraged to monitor nonserious AEFI which could help to detect programmatic errors and/or signals.

Progress is most significant in the capacity of the countries to analyse AEFI data. The cornerstone of vaccine pharmacovigilance is the national AEFI committee that collects, consolidates, reviews and analyses AEFI data to conduct causality assessment. All participating countries except Maldives and Timor-Leste have established a national AEFI committee. India is the only country that has a secretariat for the national AEFI committee, officially established in 2012. All the national AEFI committees were reorganized in the last three years to address the increasing number of AEFI to be reviewed because of improvement in AEFI surveillance systems. The national AEFI committees, however, do not meet regularly in all countries, which results in a substantial number of serious cases not being reviewed in a timely fashion. In 2013, India managed to review 30% of serious cases while Bangladesh reviewed only 27%. On the other hand, the national AEFI committees of Indonesia, Nepal, Thailand and Viet Nam managed to review all the serious AEFI cases reported in 2013.

Out of 10 countries, four listed poor quality of data as a major constraint and three mentioned high staff turnover. Finally, six countries reported difficulties in sending the investigation team to the field within 24 hours and their lack of training in AEFI field investigation.

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definition of AEFI. The latter raised concerns among the participants, especially

with the term “unfavourable”.

AEFI is defined as any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with usage of a vaccine. The adverse event maybe an unfavourable or unintended sign, abnormal laboratory finding, symptom or disease.

Several participants noted that the term “unfavourable” was not easily translated, is a negative of a positive term and is not clear in its meaning.

Several participants raised the question of what is an “unfavourable or unintended sign” compared to a sign. An abnormal laboratory finding,

symptom or disease was understood. Why was a sign dealt with differently?

Some participants proposed “an abnormal laboratory finding, symptom, sign or disease”. One participant noted that the revised definition was more difficult to

explain at the working level compared to the previous definition. Participants also argued that the term AEFI is too negative for the NIP and that they would

prefer a more neutral terminology, such as “vaccine safety surveillance”. Dr

Madhava Ram Balakrishnan said he would raise the concern about

“unfavourable” with the CIOMS.

Professor Noni MacDonald then discussed causality assessment: AEFI case definitions and case scenarios (formerly Module G in the advance course) followed by a new lecture on common fallacies and pitfalls (Module C) with emphasis on anaphylaxis and sudden infant death syndrome (SIDS). The latter was well received with many comments on pitfalls; more topics might be included, such as misinterpretation of data, confusion with academic jargon, etc. This was followed by Dr Ananda Amarasinghe’s presentation on the systematic review of the vaccine safety database. This piqued the interest of several participants and engendered good discussions.

3.2 Case studies

The participants worked on a case study (see Annex 4) through the WHO revised causality assessment methodology. The approach to causality assessment process for the case raised a number of issues, both clinical and

methodological. For example, the term “valid diagnosis” was found

confusing by some. Which diagnosis to choose – death, thrombocytopenia,

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form or several forms? Is the purpose of conducting AEFI causality assessment solely to determine if the vaccine was associated with the symptoms? Several noted that anxiety rose if only that is done as many then ask why the child died. There may be a need to review what the parent

/media/politician is concerned about even if that is not a “medically

relevant diagnosis” upon review of the case. Queries were also raised about

some of the terminology on the WHO form as well as the process.

This was followed by a review of eight cases from the countries that had been anonymized both to patient as well as to country and institutions (nine AEFI cases were prepared for review, but due to time constraint, eight were reviewed). Three working groups were carefully formed in order to contain clinical expertise as well as a wide country mix. Out of the eight selected AEFI reports reviewed in working group session, one case had onset in 2006, one in 2011, three in 2012, one in 2013 and two cases in 2014. The ages ranged from one day to 18 months. The eight AEFI reports involved seven serious AEFI cases with hospitalization; two cases recovered.

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3.3 Format of the revised causality assessment methodology

More issues were raised about the format of the revised causality assessment methodology and the applicability of some of the Brighton definitions. The eight AEFI case histories and the salient features of discussions are summarized in Annex 5. In several instances, participants from other countries noted they had seen cases similar to the one discussed. Many participants commented on how very helpful this session was for not only increasing their knowledge about AEFI causality assessment, but also on account of the breadth of the discussions and different views of the cases in the groups. All saw this as a very valuable exchange of experiences.

Given the comments about the WHO form and process for causality assessment, a questionnaire was developed for the participants to specifically comment on the usefulness of each section of the revised causality assessment methodology and process (Annex 6). Out of 20 questionnaires distributed, 17 were returned by participants. Among the respondents, 82% felt that the eligibility step was useful. However, 35% felt that some wording not always easy to understand. Likewise, 82%, 71% and 82% indicated that the causality question, event checklist and algorithm respectively were helpful. Only 18% indicated that there were some situations where the event checklist did not work, and 61% and 71% respectively expressed satisfaction at the approaches used for the classification and summarizing the logic of classification.

Suggestions for making the methodology more user-friendly were made by 35% of respondents. They included:

 provision of more details on the indeterminate steps B1 and B2 particularly the differences;

 addition of sections on feedback, recommendations and corrective actions;

 recommendations from the committee to prevent the event from occurring in future; and

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Suggestions for improving causality assessment in the countries included:

 training for expert committee members, paediatricians or other members;

 training on critical cases of causality assessment through the WHO collaborating centres, Brighton collaboration etc;

 training on communication issues, especially in rumoured cases;

 guidance on special considerations before immunization;

 standardized verbal autopsy; and

 special studies.

3.4 Vaccine safety and pharmacovigilance assessment tools

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provided an example of good practices for postmarketing surveillance of vaccines.

3.5 Global vaccine pharmacovigilance initiatives

The different tools and resources available for vaccine pharmacovigilance were demonstrated and the methods for accessing them were discussed by Dr Madhav Ram Balakrishnan.

3.6 Vaccine adverse event information management System

Dr Ajit Pal Singh gave a brief overview of International Vaccine Institute in Seoul, Korea and then reviewed the rationale for and how to use the VAEIMS (Vaccine Adverse Event Information Management System). The screen shot examples came from Sri Lanka which is piloting the programme in the Region. This covered learning from the workshop, gaps, concerns and potential solutions. The participants discussed the benefit of inviting representatives of the vaccine industry in the intercountry workshop on causality of AEFI, and felt that inviting industry might be helpful to enhance understanding of AEFI issues. In Annex 7 an overview of the discussions are provided. A key and strong recommendation was that such intercountry workshops on causality assessment of AEFI take place in the Region every 12 to 28 months. The next discussion covered the potential for publication of an article about this process (rationale, methods) with summary of the eight cases and summary of recommendations from the meeting, that is, more than just a meeting report. Permission to use the anonymized cases will be sought and a title for the group volunteering to be on the writing committee.

Recommendations and follow-up

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(2) Countries are encouraged to advocate to the respective ministries of health for additional resources to support the ongoing functioning of the post-marketing vaccine safety surveillance and to establish AEFI secretariat, particularly in vaccine-producing countries.

(3) Guidelines to assist NIPs to plan for serious AEFI field investigations and promptly respond to AEFI should be developed

(4) The WHO revised causality assessment methodology and CIOMS AEFI definition should be reviewed based upon suggestions from the homework questionnaire and concerns raised by end users at the meeting. The questionnaire might be revised based on responses for use in assessing causality using the WHO revised causality assessment methodology in other settings.

(5) An informal technical working group should be set up to initiate development of regional guidelines to plan serious AEFI field investigation and to adapt WHO verbal autopsy to fit AEFI case clinical needs.

(6) Several small-scale studies were identified to improve and document signal detection; for example(1) to approach pediatric societies in the Region to see if they could develop a practical set of questions and observations for detection of infants with clinically significant congenital heart disease for referral but not to let this impede immunization; (2) to develop a small survey to identify to what extent the NRA is involved in AEFI monitoring in each of the participating countries in this forum and which strategies countries have used to increase involvement; (3) to explore development of a practical tool AEFI definition, time interval, rates AEFI with different vaccines used in the Region and (4) how immunization and AEFI can be better incorporated into teaching at medical and nursing schools in the Region.

(7) A formal review of Brighton definitions should be undertaken to develop definitions at levels that will work in settings where there is no equipment and limited health worker training (for example, outside a clinical trial in an LIC context)

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Annex 1

List of participants

Bangladesh

Dr Shafiqur Rahman

Deputy Director and Programme Manager EPI and Surveillance

Department of Epidemiology

National Institute of Preventive and Social Medicine (NIPSOM)

Mohakhali

Mr A A Salim Barami Director (cc)

Directorate General of Drug Administration and Deputy Chief, NCL

Dhaka

Bhutan

Mr Tshewang Dorji Tamang Senior Programme Officer Department of Public Health Ministry of Health

Thimphu

India

Dr Ajay Khera

Deputy Commissioner (CH & I) Ministry of Health & Family Welfare New Delhi

Indonesia

Dr Hingky Hindra Irawan Satari Head of National Committee of AEFI National Committee of AEFI, Indonesia Departemen IKA FKUI-RSCM

Jakarta Pusat

Dr Rahma Dewi Handari

Staff of Sub Directorate of Surveillance and Risk Analyses of Therapeutic Products Sub Directorate of Surveillance and Risk Analysis of Therapeutic Product (PV unit) National Agency of Drug and Food Control Jakarta

Dr Sherli Karolina

Staff of Immunization Sub Directorate Ministry of Health

Jakarta

Maldives

Ms Aishath Thimna Latheef Public Health Programme Manager Health Protection Agency

Ministry of Health Malé

Nepal

Dr Neelam Adhikari

Chairperson, AEFI Committee Nepal Consultant Pediatrician

B & B Hospital, Gwarku Patan, Kathmandu

Dr Shyam Raj Upreti EPI Chief,

Child Health Division, Teku, Kathmandu

Sri Lanka

Dr Pathiraja Dissanayakelage Sriyani Dissanayake

Deputy Director

Medical Technology & Supplies (Cosmetic Devices & Drug Regulatory Authority)

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Dr Duminda Samarasinghe Consultant Paediatric Cardiologist Lady Ridgeway Hospital for Children Colombo

Thailand

Clinical Professor Dr. Suchitra Nimmanitya Consultant

Department of Disease Control Ministry of Public Health Nonthaburi

Dr Pornsak Yoocharoen

Medical Officer, Senior Professional Level

Bureau of General Communicable Diseases Department of Disease Control

Ministry of Public Health Nonthaburi

Miss Kanoktip Thiparat

Public Health Technical Officer – Professional Level

Bureau of Epidemiology Department of Disease Control Ministry of Public Health Nonthaburi

Miss Pattreya Pokhagul Pharmacist – Professional Level

Health Product Pharmacovigilance Center Technical and Policy Administration Division Food and Drug Administration

Ministry of Public Health Nonthaburi

Timor-Leste

Mrs Liliana dos Santos Varela Official VPD Surveillance

Department of Epidemiological Surveillance Ministry of Health

Dili

Viet Nam

Dr. Nguyen Lien Huong EPI Staff

National Expanded Programme on Immunization (EPI)

National Institute of Hygiene and Epidemiology

Hanoi

Dr Nguyen Thi My Hanh Officer

Division of Vaccine, Biological and Biosafety General Department of Preventive Medicine Ministry of Health

Hanoi

WHO Headquarters, Geneva

Dr Madhav Balakrishnan

Medical Officer, Safety and Vigilance (SAV) Regulation of Medicines and other Health Technologies (RHT)

Department of Essential Medicines and Health Products (EMP)

Health Systems and Innovation (HIS)

WHO South-East Asia Regional Office, New Delhi, India

Mr Stephane Guichard Regional Adviser

Vaccine Supply and Quality

Ms Aunyawan Thavinkaew WHO Country Office, Thailand Ministry of Public Health Nonthaburi

WHO country offices

Dr Sujeet Kumar Jain

AEFI and VPD Surveillance Focal person WHO Country Office for India – NPSP New Delhi, India

Dr Santosh Gurung New Vaccines Officer

Programme for Immunization Preventable Diseases

WHO Country Office for Nepal Kathmandu

Facilitators

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Professor Nora Noni Elisabeth Macdonald Professor of Paediatrics

Dalhousie University IWK Health Centre Halifax, Nova Scotia Canada

Observers

Mrs Teeranart Jivapaisarnpong

Director, Institute of Biological Products Department of Medical Sciences Ministry of Public Health Nonthaburi, Thailand

Mrs Prapassorn Thanaphollert Acting Director

Bureau of Drug Control Food and Drug Administration Ministry of Public Health Nonthaburi, Thailand

Mrs Porpit Varinsathien Public Health Technical Officer

Bureau of General Communicable Disease Department of Disease Control

Ministry of Public Health Nonthaburi, Thailand

Dr Suchada JiamSiri Medical Officer EPI Programme

Bureau of General Communicable Diseases Ministry of Public Health

Nonthaburi, Thailand

Mr Pramote Akarapanon Senior Pharmacist

Biological Products Section Bureau of Drug Control Food and Drug Administration Ministry of Public Health Nonthaburi, Thailand

Ms Werayarmarst Jaroenkunathum Chief of Vaccine Section

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Annex 2

Agenda

Sessions

1 Objectives

2 Country presentations: AEFI monitoring systems, past experience in investigation and causality assessment

 Bangladesh

 Bhutan

 India

 Indonesia

 Maldives

 Nepal

 Sri Lanka

 Thailand

 Timor-Leste

 Viet Nam

3 Revised WHO Causality Assessment Methodology

4 Causality assessment: AEFI case definitions and case scenarios 5 Common fallacies and pitfalls

6 Systematic review of the vaccine safety database

7 Review of selected AEFI cases and categorization on a specially designed WHO causality assessment form

8 Assessment tools to assess vaccine safety post marketing surveillance system 9 Global vaccine pharmacovigilance initiatives

10 International Vaccine Institute Vaccine Adverse Event Information Management System

11 Building sustainable country and regional vaccine pharmacovigilance and identification of needs and next steps

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C

Summary country profile, status of AEFI and performances of vaccine pharmacovigilance systems

Bangladesh Bhutan India Indonesia Maldives Nepal Sri Lanka Thailand Timor-Leste Viet Nam

Country profile

NA Pentavallent in

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rt and list updated on 13 March 2011

15 July 2009 List updated on 15 June 2012

25 January 2008 list updated July 2013,

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C NRA, professors of virology, pathology, 2013 to March 2014

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rt

Bangladesh Bhutan India Indonesia Maldives Nepal Sri Lanka Thailand

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Annex 4

Case Study

AEFI investigation report

TM, the daughter of XX and YY, residing at 66 C K Colony, Green Park, Salem City 1203, was born on 1 October 2010. She was born by lower segment Caesarean section at the Salem general hospital at a gestational age of 38 weeks+2 days. Her birth weight was 3200g. Apgar score at birth was 10. There were no significant findings detected during neonatal examination.

She received measles vaccine at 11:30 on 4 September 2011 along with Vitamin A (100 000 IU batch no. SA 298 expiry date March 2012) at the Pushpa clinic in C.K colony. There was no postimmunization observation for AEFI. The measles vaccine (Khasravac) batch number was 605434. The expiry date was 12 December 2014. The diluent (batch no A3D4345 expiry date Jan 2015) recommended by the manufacturer was used. The vaccine (0.5 ml) was given by the subcutaneous route in the left upper arm. The needle length and gauge was 25 mm, 23G. Thirty children were immunized at the same clinic on the same day and nine children were immunized with the same vaccine vial at the same clinic on the same day. There were no similar events with other children.

There was no breakdown in the cold chain since the receipt of incriminated stocks of vaccine at the provincial office was correct according to the daily temperature record. There was no breakdown in the cold chain since the receipt of incriminated stocks of vaccine at the distribution point was correct according to the temperature data logger and the status of the VVM on the stocks of incriminated vaccines was normal (stage 1). The clinic was recording vaccine reconstitution time on the vial labels.

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(12.5 mg). On admission, the white blood cell (WBC) count was 3800 mm−3_{and platelet count, 152 000 mm}−3_.

On the morning of 13 September, she had high fever and right hypochondrial tenderness. Liver was 1 cm, tender. She was haemodynamically stable. The WBC count was 1300 mm−3_{and the platelet}

count, 112 000 mm−3_{(05:00). She was provisionally diagnosed with a}

probable dengue infection. That afternoon, she developed watery diarrhoea and convulsions and was treated for acute gastroenteritis with intravenous (IV) antibiotics and fluids. The evening platelet count was 77 000 mm−3_{(17:00) and 54 000 mm}−3_(20:00).

During the 21:00 evaluation on 13 September, she was considered to have entered into critical phase with haemodynamic instability (heart rate >200, systolic blood pressure 60 mmHg). Patient on intravenous fluids over six hours exceeding the fluid quota (1330 ml given – 90.5%). She was transferred to the intensive care unit (ICU). The HR remained high – haemodynamically unstable. Pupils wide, tachypnoea, peripheral cyanosis

– fluid overload. She died at 09:00 on 14 September.

TM’s father is working as an agricultural labourer in Salem. According

to the field staff, there are some conflicts between mother and father. There are no siblings. Prior to immunization, TM's feeding was normal and she had normal activity. Her growth and milestones were normal. She did not have any obvious allergies to any particular food. There is no evidence of abuse/ harm/ neglect/ accidental injury/previous need for child protection. There was history of febrile illness a week prior to vaccination, but at the time of immunization, she was fine. She did not receive any medication within 24 hours prior to immunization. She had received BCG, pentavalent vaccine (three doses) and oral polio vaccine (OPV) earlier. The documents are unavailable.

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Annex 5

Eight AEFI case reports with findings of working group

and summary of plenary discussions

Group 1 – Case 1

Sex: Male

Date of birth: 2 March 2012 Address: Rural

A. Information about the case

Variables Investigation findings

1 Age at the day of vaccination

6 weeks and 6 days

2 Birth date 2 March 2012

3 Date/time that received vaccine

19 April 2012 at 11:00

4 Type of vaccine DPT-HepB-Hib first dose and OPV first dose 5 Place of vaccination Routine immunization session

6 Date/time of onset of AEFI 19 April 2012 at 13:30 7 Date/time of death 20 April at 20:00

8 Health history Four days prior to vaccination, the child attended clinic in a health post and received treatment with cefixime oral suspension and cetamol for cough, cold, nose block and fever.

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9 Symptoms and treatment Field investigation was conducted by local health authorities.

On 19 April 2012 at 11:00, a 48 days old baby

weighing 4.5 kg received DPT-HepB-Hib first dose and OPV first dose. About 15 minutes later, on his way back home, the child became blue and developed

convulsions.

Baby was brought to hospital and was treated with: O2 inhalation (O2 saturation increased from 44% to

76%), IV fluids, injection phenobarbitone, IV cefotaxim and cloxacillin.

However, O2 saturation broke down, and the child was

referred to another hospital three hours away, but on arrival, the equipment was not available and the child was brought to a third hospital admitted in ICU at around midnight on 19 April.

In the hospital, the child was ventilated and given antibiotics, fluids and other related investigations. On 20 April 2012 the child died at around 20:00. 10 Condition of other children

vaccinated in the same health facility

It was not possible to visit the health facility because in the rural area vaccination sessions take place once a month. However, stock records in the district vaccine cold room showed 6625 doses of the same lot of pentavalent vaccine had been distributed and no other case of AEFI was reported.

11 Vaccine management The cold chain was maintained in good order at the vaccination centre and districts. Small quantities of vaccine are distributed to health centres because power supply was not reliable at the primary health care level. 12 Details of implicated

vaccine/ diluent administered

DPT-HepB-Hib Lot Number 1422120 manufactured by Berna Biotech Korea.

13 Laboratory/autopsy Brain – congested; both lungs – congested and

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14 Investigation team’s conclusion

Septicaemia with multiple-organ failure. Coincidental AEFI as the baby had pre-existing on-going pneumonia leading to septicaemia.

B. Working Group 1 – Case 1: findings and conclusions

In Step 1 of the revised causality assessment methodology for causal association, the valid diagnostic identified by the group is anaphylaxis. Then the case definition as per Brighton definition is summarized in the box. The

question for causality is “Has the pentavalent DPT-HepB-Hib vaccine

caused the anaphylaxis?”

To question I, “Is there strong evidence for other causes?” the group responded “Yes” because the autopsy findings showed septicaemia with multi-organ failure.

To question II, “Is there a known causal association with the vaccine or vaccination?”, the group responded “Yes” because evidence in the literature that the vaccine may cause anaphylaxis in about 20 individuals per million doses administered. Rapid progression within 20 min but the group did not know if there is a specific test to demonstrate the causal role of the vaccine. All the other questions responses were negative.

To question III “Is there a strong evidence against a causal association?”, the group responded “Yes”.

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The conclusion of the group that the available evidence could conclude that the classification is coincidental association with the vaccination because the child had pre-existing illness prior to the vaccination and autopsy findings showed septicaemia and multiorgan failure.

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Group 1 – Case 2

Sex: no data

Date of birth: 19 November 2013 Address: Rural

A. Information about the case:

One year and six weeks

2 Birth date 19 November 2013

31 December 2013, no time provided 4 Type of vaccine DPT-HepB-Hib (right thigh)

OPV (oral) 5 Place of vaccination Rural

6 Date/time of onset of AEFI 3 January 2014 11:30 (notification time) 7 Date/time of death Recovered

8 Health history The child had a history of cough two days prior to vaccination.

The child had received BCG, Hep B and OPV as per immunization schedule.

9 Symptoms and treatment The child was diagnosed with bronchiolitis/anaemia. He received injections of ampicillin and gentamicin and dexamethasone.

10 Condition of other children vaccinated in the same health facility

No data

11 Vaccine management No data 12 Investigation of vaccine No data

13 Autopsy Not performed

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The valid diagnostic used by the group was “Has the pentavalent caused bronchiolitis?” To question I, “Is there strong evidence for other causes?”, the group responded “Yes” as anaemia was suggested in the history of the patient. All the questions in parts 2 and 3 were responded to by negatives.

In part IV “Other qualifying factors for classification”, the group responded “Yes” to the question “Could the event occur independently of vaccination…?” because bronchiolitis is common in this age group in many low and middle-income countries (LMICs). The factor that informed the group about potential exposure to toxin or risks of disease prior to vaccination is that the child was reported to cough for two days before the vaccination.

The group concluded that the causal association with the vaccine is indeterminate due to lack of information regarding laboratory investigations, clinical history and detailed course of events.

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Group 1 – Case 3

Sex: Male

Date of birth: 20 March 2005 Address: Rural

A. Information about the case:

1 year and 6 months

2 Birth date 20 March 2005

21 September 2006. Time of vaccination not recorded 4 Type of vaccine DTP4 (left hip) Lot No 000444 Expiry October 2006

JE (upper arm) Lot No JJ4806-3 Expiry February 2007 OPV4 (oral) Lot No Z5316 Expiry October 2006 5 Place of vaccination District hospital

6 Date/time of onset of AEFI 22 September 2006, fever and difficulty in walking 26 September 2006, could not walk, ptotic right eye lid, drowsy, cannot drink milk. He was then referred to another hospital.

7 Date/ time of death Recovered

8 Health history 20 March 2005, born in hospital 3 September 2005, dyspepsia

4 February 2006, acute upper respiratory infection, unspecified

9 June 2006, acute upper respiratory infection, unspecified

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The child developed fever and could not walk. Brought to the community hospital, he was diagnosed with myalgia and asked to come back in a week to follow up. On 26 September 2006, the child came before the appointment because his legs were very weak and couldn’t walk, ptotic right eye lid, drowsy, cannot drink milk. The doctor transferred him to the district hospital. At first the child couldn’t breathe by himself; he had to be put on a machine to help him breathe.

The medical record is as below:

The patient was very weak, no strength, refused to sit down, didn’t walk, started to have drooping eye lids so the mother took him to community hospital and found that V/s: BT 36.8c BR 120, PR 36, ptosis RE, pupil 3 mm RTL BE, Motor upper gr V. lower gr O-I, DTR 1 + all, BBK absent, Clonus neg Imp. Paraplegia so the patient was sent to the main hospital.

PE: BW 9.1 kg

V/S: BT 37.3, PR 184, RR36, BP 90/60 HEENT: not pale, no jaundice, no cervical lymphadenopathy

Heart: normal S1, S2, no murmur Lung: clear

Abd: soft, not tender, liver and spleen cannot be palpated

Ext: no petechiae, no oedema N/S: MSE: good consciousness CN: pupil 3 mm RTL BE, ptosis RE – 50% EOM by observed – 30-40% all direction, No facial palsy; gag reflex: positive Sensory can’t be evaluated

Motor flaccid tone, Power: UE gr III, LE gr 0 DTR: upper1+, lower 0

BBK absent, Clonus: neg, Stiffness of neck: neg Investigation:

CT brain: 26 September 2006: Normal study 4 October 2006: Mild cerebral atrophy causing dilate ventricular system Otherwise normal

Electrodiagnostic findings (NCV):

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peroneal nerves

 No CMAP response of RT tibial nerve

 No SNAP response of Rt sural nerve

 Normal repetitive nerve stimulation

Axonal loss, motor greater than sensory polyneuropathy DD: acute inflammatory demyelinating

polyradiculoneuropathy acute axonal form (acute axonal Guillain–Barré syndrome (GBS))

LP (26 September 2006) – colourless, no cell, CSF protein 51 CSF sugar 72 BS

CSF IgM (12 October 2006): Herpes Simplex Virus IgM – Negative

Dengue IgG Positive JE IgM to follow Enterovirus to follow

Other: CBC (2 September 2006) : Hb 12.2, Hct 3, WBC 6880 (N50, L43, M6, Eo1) Plt 664 000 BUN 13, Cr 0.1 Electrolyte: Na 140, K 4.4, Cl 98, CO 220

Progress note:

28 September 2006: Weaker, drowsier PE: MSE: drowsiness

CN: ptosis BE, total ophthalmoplegia, drooling, facial BE, gag reflex: neg

Motor gr 0 all DTR O all

Rx: Intubation and ventilator support

 Start IVIG but need to wait for medicine from Bangkok

 IVIG 400 mg/kg per day × 5 days 4 October 2006: High fever V/S: unstable IMP: Sepsis with septic shock and pneumonia Rx:- Start antibiotic: Tienam + inotropic drug Septic work up: H/C: pneumonia

5 October 2006: clinical starts to be stable N/S: eye opening, eye blinks. Eye EOM 10-20% Motor: gr 0 all DTR 0

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consciousness

CN: intact motor: UE gr IV, LE gr III DTR:0 10 Condition of other children

The other 18 children who got vaccine at the health station on the same day, as the patients have no unusual symptoms.

Children who received the same type and lot number of vaccine include: DTP 1174 people, OPV 1462 people, JE 387 people. All has no unusual symptoms.

11 Vaccine management Vaccine DTP lot number 000444 expiry October 2006, manufacturer P.T. Bio FARMA

Vaccine OPV lot number Z5316 expiry February 2007, manufacturer Aventis Pasteur in France

Vaccine JE lot number JJ4806-3 expiry 6 October 2006, GPO

By reviewing details and quality control policies from summary protocol and quality control for vaccines, it was found that all vaccines were produced and quality controlled according to the factories’ standards. So it could be confirmed that the vaccines passed the safety standard.

12 Investigation of vaccine Vaccine DTP lot number 000444 expiry October 2006, manufacturer P.T. Bio FARMA

Vaccine OPV lot number Z5316 expiry February 2007, manufacturer Aventis Pasteur in France

Vaccine JE lot number JJ4806-3 expiry 6 October 2006, GPO

By reviewing details and quality control policies from summary protocol and quality control for vaccines, it was found that all vaccines were produced and quality controlled according to the factories’ standards. So it could be confirmed that the vaccines passed the safety standard.

Investigation of vaccine DTP lot number 000444 expiry October 2006, produce company P.T. BIO FARMA Appearance – Pass

sterility test – Pass

Abnormal toxicity test – Pass

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Pass

Specific toxicity for whole cell pertussis – Pass Conclusion: Vaccine is at the standard as agreed by manufacturer and not below the standards set by WHO Investigation of vaccine OPV lot number Z5316 expiry February 2007 from Aventis Pasteur, France

Appearance – Pass Sterility test – Pass

Abnormal toxicity test – Pass Hydrogen ion – Pass Protein content – Pass Identity test – Pass

Bacteria endotoxin test – Pass (this is an additional test, not used in standard of vaccine investigation; if

compared to other type of vaccine ex Hep B, amount of endotoxin is at the normal standard level)

Conclusion: Vaccine meets the required standard Investigation of vaccine JE lot number JJ4806-3 expiry 6 October 2006 produced by GPO

Appearance – Pass Sterility test – Pass`

Abnormal toxicity test – Pass Protein content – Pass Inactivation – Pass Pyrogen – Pass

Bacterial endotoxin test – Pass (this is an additional test, not used in standard of vaccine investigation; if

compared to other type of vaccine ex Hep B, amount of endotoxin is at the normal standard level)

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Variables Investigation findings 14 Investigation team’s

conclusion

Elementary diagnosis paraplegia r/o GBS from vaccine was given from the hospital on 24 October 2006 Last diagnosis encephalopathy neuropathy r/o (GBS) post vaccination

B. Working group 1 – Case 3: Findings and conclusions

The valid diagnostic used by the group was “has the DTP4 caused GBS”. The group then compared GBS case definition levels 1 to 6 (Brighton definitions) with the clinical examination and laboratory investigations available in the investigation report. In the absence of other clinical examination and laboratory tests that could confirm other cause and with the documented evidence of risks of GBS following DTP vaccination, the group concluded there is consistent causal association of this event with immunization because GBS is known to be associated with DTP.

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Group 2 – Case 1

Sex: Male

Date of birth: 24 November 2011 Address: Rural

1 Age at the day of vaccination One week and six days

2 Birth date 24 November 2013

6 January 2014. Time not specified 4 Type of vaccine DTP-HepB-Hib

OPV

5 Place of vaccination Not specified 6 Date/time of onset of AEFI 6 January 20:00 7 Date/time of death 7 January 2014 at 11:00

8 Health history Child reported well before the vaccination. He attended three postnatal clinics.

9 Symptom and treatment January 6 2014, the baby was immunized and returned home.

January 6 at 18:00 the baby had mild fever and mother gives syrup paracetamol.

At 20:00 baby was crying excessively and not feeding. At 21:30 the baby had three episodes of loose stools but no vomiting.

January 7 at 00:00 (midnight), the baby was found lethargic and taken to the emergency unit of the national referral hospital.

January 7, the child was admitted in the hospital in shock and had cyanosis, hypotension, hypothermia, anaemia and severe respiratory distress with grunting. He received IV fluids, O2 inhalation, Inj. ceftriaxone, Inj. gentamicin,

ranitidine. The baby’s condition deteriorated and he developed UGI bleed including bleeding from the endotracheal tube.

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No data

11 Vaccine management No data 12 Investigation of vaccine No data

13 Laboratory/autopsy Blood culture test results not available.

Complete blood count (WBC, 21.8 × 10³; neutrophils, 64%; lymphocytes, 29%; Hb, 7.3g/dl; ESR 7; CRP, 4.1), LFT-ALP, 460; total bilirubin, 2.2; direct bilirubin, 0.9; sodium, 129; potassium, 5.9; chloride, 101.

Anaphylaxis/sepsis

The valid diagnostic used by the group who reviewed this case was septic shock but the group noted the absence of a Brighton case definition for

this. The causality question is “Does the DTP-HepB-Hib and OPV caused

sepsis?”

To question I “Is there strong evidence for other causes?”, the group

responded “Yes” because clinical exam show multiorgan dysfunction and

the laboratory tests reveal leukocytosis.

To question II “Is there a known causal association with the vaccine?”,

the group responded “Yes” because anaphylaxis may be caused by vaccine. All the other questions were answered “unknown” because of lack of information in the investigation report. However, the outcome of the group discussion was that this event was not caused by excessive anxiety and the elapsed time too long for sepsis or anaphylaxis. It was also agreed that OPV could be taken out of consideration, because although it could cause sepsis, the question would be in what way.

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Group 2 – Case 2

Sex: Male

Date of birth: 11 February 2013 Address: Rural

52 days

2 Birth date 11 February 2013

03 April 2013 at 12.00

4 Type of vaccine DTP-HepB-Hib dose 1, batch 124P2011B OPV dose 1, Batch 2010312

5 Place of vaccination Health post

6 Date/time of onset of AEFI 3 April 2013 at 13:00 7 Date/time of death 4 April 2013 at 15:30

8 Health history History of vomiting after feeding since birth. Other than that the child was asymptomatic and was playful and feeding well until the vaccination. The birth history was uneventful, with a normal vaginal delivery in zonal hospital. BCG was given at birth.

09 Symptom and treatment According to the mother, the child was well prior to receiving the vaccine. The Penta /OPV 1 was

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child was attended at 19:45 at the GYT Medical College with C/C;

Sudden onset of abdominal distension about six hrs Rapid breathing with difficulty with chest in drawing and marked shortness of breath about six hrs

On examination severe respiratory distress; crepilations and rhonci bilaterally.

The treatment the child received included: NG decompression; Inj. ceftriaxone 150 mg IV BD, Inj. amikacin 35 mg IV BD, Inj. Isolytep 175 ml IV 12 hourly Inj. Lasix 3.5 mg IV OP.

Call was attended at ICU at 11.15 on 4 April 2013 with nil respiratory effort and cyanosis, CPR done and Inj. adrenaline 1ml IV and Inj. aminophylline was also given and endotracheal intubation was done, shifted to NICU under ventilator support. Initially was in SIMV mode in ventilator was switched at CPAP Mode as the saturation was varying from 70-75% and fighting. Hypotension was also stated in the h/o. On 4 April 2013, at 15.15, call attended with no signs of life observed and was declared dead at 15:30. 10 Condition of other children

Six other children were vaccinated at the outreach clinic on 3 April 2013. The vaccinator had vaccinated the first three children with the remaining vial from the previous day (MDVP – multi dose vial policy and ten dose DPT vial available). Three other children were vaccinated with the newly opened vial; the AEFI notified child was the last child to be vaccinated with the newly opened vial.

The other children were also investigated to see if any concurrent cases. Another child was observed with symptoms of upper respiratory tract infection was referred to the hospital for observation, was discharged the following day

11 Vaccine management Maintenance of the cold chain was satisfactory 12 Investigation of vaccine No investigation on the vaccine. VVM status not

recorded 13 Laboratory investigation Findings:

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RR: 88/min with marked intercostal and sub costal indrawing.

Temp: 98 Fahrenheit. SPO2: 89% without O2

Chest: coarse basal b/l creps + and expiratory grunting Investigations:

Hb, 10.2; TC, 28 500; N, 84%; L 82%; E, 3%; N, 1% 14 Investigation team’s

conclusion

Pneumonia with severe illness with septicaemia

B. Working group 2 – Case 2: findings and conclusions

The group identified “pneumonia” as the valid diagnosis and thus created

the causality question “Has the Penta1 and OPV1 vaccines/vaccination

caused pneumonia?” To question 1, is there strong evidence for other causes, the group responded “Yes” because symptoms of acute respiratory distress, abdominal distension, cyanosis, hypoxia and increased TLC had been reported upon examination of the patient. Going through the algorithm, the experts responded “No” to questions II and III except the

answer to the question “Is there strong evidence against causal association?”

is positive because of acute onset of symptoms and clinical as well as laboratory findings confirming pneumonia.

The group of AEFI causality experts, therefore, could conclude that the classification is coincidental (pneumonia) most likely due to aspiration. Increased TLC and long duration of illness exclude anaphylaxis. Toxic shock syndrome is also excluded as this was an isolated case and no other child developed any symptoms after vaccination with the same vial.

During the plenary, although Professor Noni MacDonald agreed with the conclusions of the experts group, she recommended verifying the hypothesis of anaphylaxis using the same revised causality assessment

methodology with the causality question “Has the pentavalent

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Group 3 – Case 1

Sex: Female

Date of birth: 9 June 2012 Address: Rural

3 days

2 Birth date 9 June 2012

In two sessions: 10 June and 12 June 2012

4 Type of vaccine _ _{10 June 2012 vaccine HepB lot no.0390929} expiry 9 April 2012

 12 June 2012 vaccine BCG lot no.01310 exp. 2 September 2012 (in the afternoon, no exact time recorded)

5 Place of vaccination District hospital

6 Date/time of onset of AEFI 12 June 2012 between 20:00 and 21:30 7 Date/time of death 12 June 2012 around 22:00

8 Health history The second child of a 29-year-old woman who is a bank employee, attended for antenatal care at clinic, regular delivery at provincial hospital, APGAR 9, 10, 10; weight at birth 3090 g. No unusual signs at birth, left the hospital with mother

9 Symptom and treatment 12 June 2012

 Went home with her mother, no fever, but the mother reported that the child drinks milk very little

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 Around 22:00, mother noticed that the child wasn’t moving, so she checked on her and found out that the child’s face, legs, arms were green and the child was not breathing. The child was brought to the hospital. Nurses gave oxygen by mask and did chest compressions, and then the doctor inserted an ET tube and then milk came out in the child’s mouth so the doctor did suction by using ET tube. They got around 5cc of milk. The child died.

 Doctor diagnosed the child with respiratory arrest (respiratory failure of newborn)

The seven children who received the same BCG vaccine and the other child who receive the same HepB vaccine did not experience unusual reactions. 11 Vaccine management No data

12 Investigation of vaccine Vaccine wasn’t sent for investigation

13 Autopsy No autopsy

14 Investigation’s team conclusions

From AEFI committee at regional level:

 Unlikely because the death of the child matches the death from hypoxiand milk found in the mouth and ET tube, the death is likely to happen because of choking. However, there are some doubts:

- Milk stain may come from chest compressions before insertion of ET tube.

- Vaccination may make a child drowsy and then cause choking.

Suggestion:

 Doctor should have sent for CXR after the death if suspected aspiration including asking death scene history and checking the milk stain on the child’s body.

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The valid diagnostic used by the group is “respiratory failure”. They noted

that there is no Brighton case definition for respiratory failure but found it in the paediatric advanced life support, where the case definition is “failure to maintain oxygenation with simple measures – positioning and oxygen by

mask”. The participants then wrote down the causality question as “Has the

BCG vaccine/vaccination cause acute respiratory failure?”

In the revised causality assessment methodology questionnaire to

question I “Does clinical examination confirm another cause?” they

responded “Yes” because symptoms occurred after feeding and there is milk present in the ET tube. Responses to all parts of question II were negative. To question III “Is there strong evidence against a causal association?” the group responded “Yes” because of the child’s history of choking and presence of milk in the tube. In question IV “Other qualifying factors for classification”, the group responded “yes” to both “Could the event occur independently of vaccination?” because aspiration is not uncommon among babies and the second question “Could the event be a manifestation of another health condition?” because symptoms of aspiration were present. Responses to all other parts of question IV were negative.

The group conclusion was that this case is coincidental because there is history as well as clinical evidence of milk aspiration leading to respiratory failure. It is not anaphylaxis as BCG is not known to cause anaphylaxis. It does not fit toxic shock syndrome as there are no clinical findings and no other cases were reported. However, Hepatitis B expiry date had passed and its efficacy might be lower than expected.

causality assessment aefi

Causality assessment of adverse

events following immunization

Report of an intercountry workshop

Contents

2.

Methodology and objectives

2.1

Objective

2.2

Methodology

3.

Proceedings

3.1

Vaccine pharmacovigilance systems

3.2

Case studies

3.3

Format of the revised causality assessment methodology

3.4

Vaccine safety and pharmacovigilance assessment tools

3.5

Global vaccine pharmacovigilance initiatives

3.6

Vaccine adverse event information management System

Recommendations and follow-up

Annex 1

List of participants

Annex 2

Agenda

Annex 4

Case Study

AEFI investigation report

Annex 5

Eight AEFI case reports with findings of working group

and summary of plenary discussions

Group 1 – Case 1

Group 1 – Case 2

Group 1 – Case 3

Group 2 – Case 1

Group 2 – Case 2

Group 3 – Case 1