Causality assessment of adverse events following...
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SEA-Immun-88
Distribution: General
Causality assessment of adverse
events following immunization
Report of an intercountry workshop
18–20 February 2014, Bangkok, Thailand
ii
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Contents
Page
Acronyms .............................................................................................................. v
Executive summary ............................................................................................... vi
1. Background ................................................................................................... 1
2. Methodology and objectives .......................................................................... 4
3. Proceedings ................................................................................................... 7
Annexes
1. List of participants ....................................................................................... 15
2. Agenda ........................................................................................................ 18
3. Summary country profile, status of AEFI and performances of vaccine
pharmacovigilance systems .......................................................................... 19
4. Case Study AEFI investigation report ............................................................ 24
5. Eight AEFI case reports with findings of working group and summary of
plenary discussions ...................................................................................... 26
6. Questionnaire to assess usefulness of causality algorithm tools to
participants ................................................................................................. 52
7. Plenary discussions ...................................................................................... 58
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Acronyms
AEFI - Adverse Events Following Immunization
NIP - National Immunization Programmes
NRA - National Regulatory Authorities
EPI - Expanded Programme on Immunization
LIC - Low-Income Countries
VPD - Vaccine Preventable Diseases
NCL – National Control Laboratory
CIOMS - International Organizations of Medical
HMIS - Health Management Information System
SIDS - Sudden Infant Death Syndrome
LMIC - Low and Middle-Income Countries
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Executive summary
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.
As part of the strategy to address this risk of loss of public confidence
in the immunization programmes, the countries in the South-East Asia
Region strengthened their national AEFI committees with new members
with expertise in neurology, forensic specialists, paediatricians,
epidemiologists and professors in teaching hospitals. WHO proposed to
organize this intercountry workshop involving 29 vaccine experts from ten
countries in the South-East Asia and Western Pacific Regions to review,
discuss and analyse selected cases of AEFI for the period 2011–2013. WHO
country offices were instrumental in mobilizing national AEFI committee
members to identify specific AEFI case reports for discussion. Six out the ten
participating countries provided a total of 23 AEFI case reports. Not all
cases submitted could be reviewed because of time constraints and so nine
cases were short-listed and anonymized for the purpose of this workshop.
In addition to South-East Asia Region countries, Viet Nam in the WHO
Western Pacific Region participated in the workshop.
vii
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’
opinions on the usefulness of the tool were collected through a
questionnaire developed during the workshop. Participants appreciated the
opportunities to discuss with experts from different fields and learned a
great deal by working on AEFI case reports in the Region. All countries
acknowledge the need for further collaborative initiatives like this workshop
in the field of vaccine pharmacovigilance and developed a set of
recommendations to foster increased cooperation among countries in the
Region and beyond.
1
1. Background
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.
The World Health Organization (WHO) has a long history of technical
support to build the national capacity of Member States in the South-East
Asia Region to monitor AEFI. In 2003, the WHO Regional Office for South-
East Asia established the Global Training Network (GTN) centre in
Colombo, Sri Lanka to provide training on AEFI monitoring to South-East
Asia Region Member States and to other WHO regions. The GTN centre in
Sri Lanka was instrumental in providing training on AEFI monitoring to
national regulatory authority (NRA) and EPI representatives of the countries
of the South-East Asia Region.
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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
________________________ 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.
2 Adverse Events Following immunization in the South East Region 2008–2010; Report on WHO support to
training programme.
Causality assessment of adverse events following immunization
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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.
As of 2009, all countries in the Regional Office for South-East Asia,
except Maldives and Timor-Leste, had established a national AEFI committee
to review and analyse AEFI cases on a periodic basis. Thus the time was ripe
for an intercountry workshop on causality assessment to share learning and
discuss experiences with the currently recommended tools and processes.
Report of an intercountry workshop
4
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;
to identify critical AEFI cases of common interest for countries of
the South-East Asia and Western Pacific regions (serious and
Causality assessment of adverse events following immunization
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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
20053
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.
________________________
3 http://vaccinepvtoolkit.org/vaccine-wp/wp-content/uploads/2013/12/report_working_group_on_vaccine_LR-
CIOMS-WHO-WG.pdf
Report of an intercountry workshop
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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.
On the third day, following presentations on vaccine pharmacovigilance
global initiatives, the workshop provided a platform for participants to discuss
and provide comments on the different tools recently developed by WHO to
conduct causality assessment, including the revised causality assessment
methodology, the AEFI core variables, sample reporting forms and supporting
materials available on the web. It was an opportunity to have representatives
from national AEFI committees, NCLs and NRAs meet together to discuss
important questions, such as the need to (1) establish a regional/biregional
group of experts to respond to serious AEFI cases which could have public
health impacts that occur in countries with limited capacity; (2) analyse
regional data with particular interest in signal detection; (3) explore how to
sustain national vaccine pharmacovigilance systems and to increase
involvement of academicians and medical colleges and institutes involved in
postmarketing vaccine safety surveillance; and (4) discuss what countries saw
as the regional needs for monitoring AEFI and maintaining public confidence in
immunization programmes.
Causality assessment of adverse events following immunization
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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.
Nepal and Sri Lanka are among countries that procure vaccine directly
except for pentavalent DPT-HepB-Hib vaccine which is procured through
UNICEF. Nepal, with its nascent system, reports fewer than 30 AEFI cases a
year, whereas Sri Lanka has a well-established AEFI system and reports more
Report of an intercountry workshop
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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.
The country presentations were followed by a series of lectures to review
causality assessment. Dr Madhava Ram Balakrishnan presented the revised
WHO causality assessment methodology including the revised CIOMS
Causality assessment of adverse events following immunization
9
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,
etc.? How should the different “diagnoses” be worked through – all on one
Report of an intercountry workshop
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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.
All groups worked enthusiastically with lively discussions and full
participation. The findings of the assessment were presented by the
representative of each working group. During the plenary discussions,
comments and insights made for lively audience participation.
Causality assessment of adverse events following immunization
11
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
inclusion of an instruction page on how to fill the form, ensuring
that it covers the key definitions and terms used.
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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
Dr Ananda Amarasinghe described vaccine safety and pharmacovigilance
assessment tools to review vaccine safety postmarketing surveillance
performance at the subnational levels. Many countries acknowledged a lack
of proper use of vaccine safety data for evidence-based practice and the
need to focus on improving critical reviews of database and vaccine safety
data analysis at different administrative levels. This session not only
generated much interest but also led to a number of questions. The
experience of using field data for analysis and interpretation in Sri Lanka
Causality assessment of adverse events following immunization
13
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
(1) The major constraints of the national vaccine pharmacovigilance
are lack of planning for regular reviews of AEFI cases through a
committee of experts and the poor quality of investigation,
affecting data quality and causality assessments.
Report of an intercountry workshop
14
(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)
(8) An article about the methods, findings, and recommendations
from the workshop should be prepared for publication.
Causality assessment of adverse events following immunization
15
Annex 1
List of participants
Bangladesh
Dr Shafiqur Rahman
Deputy Director and Programme Manager EPI
and Surveillance
EPI Headquarter
DGHS, Mohakhali,
Dhaka
Dr Md. Shafiqul Islam
Associate Professor
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)
Colombo
Report of an intercountry workshop
16
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
Dr Ananda Amarasinghe
Consultant Epidemiologist
Epidemiology unit
Ministry of Health
Colombo, Sri Lanka
Causality assessment of adverse events following immunization
17
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
Institute of Biological Products
Department of Medical Sciences
Ministry of Public Health
Nonthaburi, Thailand
Report of an intercountry workshop
18
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
12 Closing remarks
Causality assessment of adverse events following immunization
19
An
nex 3
Su
mm
ary co
un
try p
ro
file, statu
s o
f A
EFI an
d p
erform
an
ces o
f vaccin
e p
harm
aco
vigilan
ce system
s
B
an
gla
desh
B
hu
tan
In
dia
In
do
nesia
M
ald
ives
Nep
al
Sri Lan
ka
Th
ail
an
d
Tim
or-Leste
Vie
t N
am
Co
un
try p
ro
file
To
tal
po
p.
15
3
90
4
23
8
74
5
15
7
1
20
0
00
0
24
4
00
0
00
0
32
0
00
0
28
6
00
0
00
2
1
00
0
00
0
64
1
81
0
01
1
1
54
6
25
9
0
00
0
00
0
Ch
ild
. <
1
3
47
8
23
6
14
6
79
2
6
00
0
00
0
4
60
0
00
0
55
00
7
00
0
00
3
50
0
00
7
96
3
17
4
2
11
4
1
70
0
00
0
Vaccin
e i
n t
he
imm
un
izatio
n
sch
ed
ule
BC
G,
DP
T-
Hep
B-H
ib,
OP
V,
MR
,
measle
s,
TT
BC
G,
Hep
B
(bir
th
do
se),
DP
T-H
ep
B-
Hib
MR
DP
T (
2 y
rs)
Td
HP
V (
12
yrs)
BC
G,
Hep
B,
DP
T-H
ep
B-
Hib
, O
PV
,
DT
P,
measle
s,
JE (
LA
V),
TT
Hep
B (
bir
th
do
se),
BC
G,
OP
V,
DP
T-
Hep
B-H
ib,
measle
s,
DT
,
Td
, T
T
BC
G,
OP
V,
DP
T-H
ep
B-
Hib
, m
easle
s,
MM
R,
TT
, D
T
BC
G,
DP
T-
Hep
B-H
ib,
OP
V,
MR
, JE
BC
G,
DP
T,
DP
T-H
ep
B-
Hib
, O
PV
MM
R,
JE,
Ru
bella,
DT
,
TT
BC
G,
Hep
B,
OP
V,
MM
R,
JE,
DT
P,
Td
,
DT
P-H
ep
B,
Influ
en
za (
po
p
at r
isk H
CW
)
BC
G,
OP
V,
DP
T-H
ep
B-
Hib
, m
easle
s,
TT
.
BC
G,
DP
T-
Hep
B-H
ib,
DP
T,
OP
V,
measle
s,
TT
,
ch
ole
ra (
2–5
yrs),
typ
ho
id
(3–5
yrs),
JE
(1–5
yrs)
Date n
ew
vaccin
e
intro
du
ced
-H
ep
B f
ro
m
20
03
to
20
05
-P
en
ta 2
00
9
-M
R 2
01
2
(Sep
t)
-m
easle
s 2
nd
do
se 2
01
2
Sep
t
Pen
ta 2
00
9
(Sep
t)
HP
V 2
01
0
(May)
Pen
ta (
started
20
11
in
2
states w
ith
grad
ual
exp
an
sio
n)
Td
(2
01
1)
Pen
ta (
20
13
)
in 4
/33
pro
vin
ces
20
14
all
pro
vin
ces
Pen
ta (
20
12
)
Pen
ta (
20
09
)
Pen
ta (
Jan
20
08
)
MM
R O
ct
20
12
JE L
AV
(Oct2
01
2)
NA
P
en
tavallen
t in
20
12
.
Pen
ta (
20
10
)
measle
s2
(20
11
)
DP
T b
oo
ster
(20
11
)
Co
verage f
or
each
an
tig
en
20
13
BC
G: 9
9%
OP
V3
: 9
2%
Pen
ta3
: 9
2%
measle
s: 8
6%
Fu
lly im
mu
ne:
81
%
20
12
BC
G: 9
4%
OP
V3
: 9
7%
DP
T-H
ep
B-
Hib
: 9
7%
MR
1: 9
5%
MR
2: 8
9%
20
13
BC
G: 9
2%
DP
T3
: 7
6%
Hep
B3
:6
7%
Hib
3: N
A
MC
V1
: 8
8%
MC
V2
: 4
2%
20
13
Hep
B0
:8
3.4
%
BC
G: 9
4%
DP
T-
Hep
B3
:9
5.6
%
OP
V4
: 9
5.3
%
MEA
: 9
3.5
%
20
13
BC
G: 9
9.7
%
DP
T3
: 9
9.4
%
Hep
B3
: 9
9.2
%
Hib
3: 9
9.5
%
MC
V1
: 9
9.4
%
MC
V2
: 9
8.6
%
20
13
BC
G: 9
7%
DP
T3
: 9
2%
Hep
B3
: 9
2%
Hib
3: 9
2%
OP
V3
: 9
2%
MC
V1
: 8
8%
20
12
Pen
ta3
: 9
9%
MM
R2
: 9
6%
JE: (
99
%)
20
13
BC
G: 1
00
%
DP
T3
: 9
9.4
%
OP
V3
:9
9.4
%
Hep
B3
:9
9.4
%
Measle
s:
98
.7%
JE3
: 8
9.3
%
20
13
BC
G: 8
1.6
%
Pen
ta3
: 7
6.3
%
OP
V3
: 7
6%
MEA
: 6
9%
Report of an intercountry workshop
20
B
an
gla
desh
B
hu
tan
In
dia
In
do
nesia
M
ald
ives
Nep
al
Sri Lan
ka
Th
ail
an
d
Tim
or-L
este
V
iet
Nam
Dates a
nd
no
.
vaccin
ated
SIA
an
d N
ID
s
in 2
01
2–2
01
3
if a
ny
20
th
NID
Jan
–Feb
20
12
: 4
4 0
93
25
5
21
st
NID
Dec 2
01
3:
20
6
30
0
62
No
v 2
01
2 R
ou
nd
1
(DT
P 2
–3
6 m
ths):
98
.3%
(DT
3–7
yrs):
10
0%
(Td
7–1
5 y
rs):
10
0%
Jun
20
13
Ro
un
d 2
(DP
T 2
–3
6m
s):
96
.6%
(D
T 3
–7
yrs):
97
.2
(Td
7–1
5 y
rs):
96
.3%
No
v 2
01
3 R
ou
nd
3
(DP
T 2
–3
6
mth
s):
97
.3%
(DT
3–7
yrs):
97
.6%
(Td
7–1
5 y
rs):
98
%
Vaccin
e
su
pp
ly
so
urces
Pro
cu
rem
en
t
servic
es a
greem
en
t
with
UN
ICEF,
Go
vern
men
t
fun
ded
. Lo
cal
ph
arm
aceu
tic
al
ind
ustr
y w
ith
cap
acity t
o
man
ufa
ctu
re
vaccin
es
Pro
cu
rem
en
t
servic
e
agreem
en
t
with
UN
ICEF.
Go
vern
men
t
fun
ded
Go
vern
men
t o
f In
dia
fro
m lo
cal p
ro
du
cers
mo
stly W
HO
PQ
All v
accin
e a
re
su
pp
lied
fro
m o
ne
do
mestic p
ro
du
cer
an
d a
re W
HO
PQ
UN
ICEF
Go
vern
men
t
of
Nep
al
excep
t P
VV
thro
ugh
UN
ICEF.
Vaccin
es a
re
all f
ro
m W
HO
PQ
so
urces.
Go
vern
men
t o
f
Sri-
Lan
ka f
ro
m
WH
O P
Q
so
urces.
On
ly
PV
V s
up
plied
by U
NIC
EF
with
GA
VI
fun
ds
Go
vern
men
t o
f
Th
ailan
d f
ro
m 3
local
man
ufa
ctu
rers
an
d im
po
rte
d
fro
m I
nd
ia,
Ind
on
esia
,
Ko
rea a
nd
Eu
ro
pe.
UN
ICEF
Go
vern
men
t
of
VT
N f
ro
m
local
su
pp
liers:
BC
G,
OP
V,
DP
T,
Hep
B,
JE,
oral
ch
ole
ra,
typ
ho
id,
measle
s a
nd
imp
orted
thro
ugh
UN
ICEF
Pen
tavale
nt
Statu
s A
EFI
Date A
EFI
co
mm
ittee
estab
lish
ed
10
Jan
uary 2
00
4
an
d lis
t u
pd
ate
d o
n
13
March
20
11
15
Ju
ly 2
00
9
Lis
t u
pd
ate
d
on
15
Ju
ne
20
12
25
Jan
uary 2
00
8 lis
t
up
dated
Ju
ly 2
01
3,
Secreta
ria
t o
f N
at’
l
AEFI
co
mm
itte
e
esta
blish
ed
in
20
12
.
30
Sep
tem
ber 1
99
7
an
d r
eo
rgan
ized
in
20
12
.
No
co
mm
itte
e
20
04
reo
rgan
ized
in
20
08
.
20
08
2
00
4 a
nd
up
dated
in
20
10
No
co
mm
itte
e
Causality assessment of adverse events following immunization
21
B
an
gla
desh
B
hu
tan
In
dia
In
do
nesia
M
ald
ives
Nep
al
Sri Lan
ka
Th
ail
an
d
Tim
or-
Leste
Vie
t N
am
List o
f A
EFI
co
mm
ittee
mem
bers
In
clu
des 1
3
mem
bers
rep
resen
tin
g, EP
I,
NR
A, p
ro
fesso
rs o
f
vir
olo
gy, p
ath
olo
gy,
paed
iatric
ian
s an
d
pro
fesso
rs o
f
med
ical co
lleges
Paed
iatric
ian
,
med
ical
sp
ecia
list,
mic
ro
bio
logis
t,
dis
tric
t h
ealth
offic
er, clin
ical
Lab
N
RA
an
d
ph
arm
acis
t
Ep
idem
iolo
gis
ts/p
ub
lic
health
sp
ecia
list,
paed
iatric
ian
, N
RA
,
mic
ro
bio
logis
t,
neu
ro
logis
t,
path
olo
gis
t, fo
ren
sic
scie
ntis
t, m
em
ber o
f
infectio
us d
iseases
su
rveilla
nce, p
ro
fesso
r
in teach
ing
ho
sp
ital/m
ed
ical
co
lleges
Rep
resen
tativ
e o
f
In
fectio
logis
t
In
do
nesia
P
aed
iatric
So
cie
ty (ID
AI),
In
do
nesia
n So
cie
ty o
f
Ob
stetric
s/G
yn
eco
logy
an
d H
ealth
Law
Asso
cia
tio
n
(P
ER
HU
KI);
paed
iatric
ian
s fro
m
th
e N
atio
nal P
ub
lic
Ho
sp
ital;
Fo
ren
sic
sp
ecia
list, EP
I
man
agers, N
RA
tech
nic
ian
s,
ph
arm
acis
ts,
rep
resen
tativ
e o
f th
e
legal b
ureau
M
OH
an
d p
ro
fesso
rs fro
m
med
ical in
stitu
tes.
NA
C
hair
ed
b
y
ind
ep
en
den
t
sen
ior
paed
iatric
ian
with
rep
resen
tativ
es
fro
m C
hild
Health
Div
isio
n,
Lo
gis
tic
s &
Man
agem
en
t
Div
isio
n,
Dep
artm
en
t o
f
Dru
g
Ad
min
istratio
n,
WH
O,
UN
IC
EF an
d
ped
iatric
ian
s
Pro
fesso
rs o
f
paed
iatric
s an
d
mic
ro
bio
logy
Facu
lty o
f
med
icin
es;
vir
olo
gis
ts,
path
olo
gis
ts,
imm
un
olo
gis
ts
Med
ical,
Research
In
stitu
tes, EP
I
man
agers, N
RA
rep
resen
tativ
es,
card
iolo
gis
t
Ch
ild
ren
Ho
sp
ital,
Neu
ro
logis
t
an
d p
ro
fesso
rs
of
ph
arm
aco
logy
an
d d
irecto
r o
f
Matern
al &
Ch
ild
H
ealth
div
isio
n
Ep
idem
iolo
gis
t,
paed
iatric
ian
fo
r
infectio
us
dis
eases,
paed
iatric
ian
fo
r
neu
ro
logy,
neo
nato
logy,
rep
resen
tativ
e
of th
e N
CL,
asso
cia
te
pro
fesso
r
fo
ren
sic
med
icin
e,
neu
ro
path
olo
gy,
ep
idem
iolo
gis
t
an
d
rep
resen
tativ
e
of th
e N
IP
NA
No
. o
f
co
mm
ittee
meetin
g
20
12
–2
01
3
Irregu
lar
20
12
: 2
20
13
: 3
Estab
lish
ed
fix
ed
cale
nd
ar, m
et fo
ur
tim
es b
tw
A
ugu
st
20
13
to
M
arch
2
01
4
Co
re m
eetin
g tw
ice a
year +
u
po
n req
uest.
AEFI co
mm
ittee m
et
10
tim
es in
2
01
2 an
d
4 tim
es in
2
01
3 to
co
nd
uct cau
sality
assessm
en
ts
NA
20
12
: 3
20
13
: 1
20
12
: 4
20
13
:3
NA
AEFI
gu
id
elin
e
dates an
d
up
date
Gu
idelin
es (2
00
5)
revis
ed
in
2
01
0 an
d
SO
P d
evelo
ped
in
20
11
.
Gu
idelin
e (2
00
5),
AEFI tech
nic
al
gu
idelin
e (2
01
2); A
EFI
MO
H regu
latio
n
(2
01
3)
Natio
nal
gu
idelin
es
un
der
develo
pm
en
t
Gu
idelin
es
20
03
in
Nep
ale
se
lan
gu
age in
20
08
Gu
idelin
es
20
07
u
pd
ated
in 2
01
2
20
03
an
d
up
dated
in
20
08
NA
2
00
3 an
d
up
dated
in
20
13
an
d
20
14
Report of an intercountry workshop
22
B
an
gla
desh
B
hu
tan
In
dia
In
do
nesia
M
ald
ives
Nep
al
Sri Lan
ka
Th
ail
an
d
Tim
or-
Leste
Vie
t N
am
Defin
itio
n
to
id
en
tify
serio
us
AEFI, i.e.
wh
at is
rep
orted
as
serio
us A
EFI
Death
,
ho
sp
italizatio
n,
clu
ster o
f rep
ortab
le
AEFI,
paren
tal/co
mm
un
ity
co
ncern
s
In
clu
des d
eath
,
ho
sp
italizatio
n,
clu
ster, p
ersis
ten
t o
r
sig
nific
an
t d
isab
ility
/in
cap
acity o
r life-
th
reaten
ing co
nd
itio
n
Severe lo
cal
reactio
n,
inje
ctio
n site
ab
scess
BC
G
lym
ph
ad
en
itis
Hig
h fever
(m
ore th
an
1
01
F) w
ith
in 4
8
hrs
Rash
Seiz
ures w
ith
in
14
d
ays
En
cep
halitis
/
Men
ingitis
with
in 2
8 d
ays
En
cep
halo
path
y
with
in 3
d
ays
Lo
ss o
f
co
nscio
usn
ess /
sh
ock w
ith
in 4
8
ho
urs
An
ap
hyla
xis
To
xic
sh
ock
syn
dro
me
VA
PP
Ho
sp
italizatio
n
Death
Pu
blic co
ncern
s
Death
s an
d
ho
sp
italizatio
n
Death
s,
ho
sp
italizatio
n,
an
y even
t
believed
to
b
e
asso
cia
ted
to
vaccin
e an
d/o
r
an
y p
eo
ple
co
ncern
s
Death
,
ho
sp
italizatio
n
an
d cases
su
sp
ected
to
b
e
asso
cia
ted
to
vaccin
e, p
eo
ple
co
ncern
s
NA
A
nap
hyla
ctic
sh
ock,
into
xic
atio
n
sh
ock
syn
dro
me,
su
sp
ected
pro
gram
me
erro
r an
d
death
Causality assessment of adverse events following immunization
23
B
an
gla
desh
B
hu
tan
In
dia
In
do
nesia
M
ald
ives
Nep
al
Sri Lan
ka
Th
ail
an
d
Tim
or-
Leste
Vie
t N
am
Vaccin
e P
V p
erfo
rm
an
ce
No
. o
f
rep
orted
AEFI cases
20
12
–2
01
3
22
98
(2
01
2)
22
88
(2
01
3)
3 (2
01
2)
16
(2
01
3)
38
6 (2
01
2)
53
6 (2
01
3)
On
ly serio
us cases are
rep
orted
to
co
mm
ittee. N
on
-
serio
us cases rep
orted
th
ro
H
MIS, b
ut d
ata
no
t availab
le at
natio
nal le
vel yet.
10
4
69
(2
01
2)
18
6
21
(2
01
3)
1
9 (2
01
2)
22
(2
01
3)
64
55
(2
01
2)
13
59
(2
01
2)
76
9 (2
01
3)
0 (2
01
2)
1 (2
01
3)
30
(2
01
2)
31
(2
01
3)
No
. o
f
serio
us A
EFI
rep
orted
20
12
–2
01
3
54
(2
01
2)
73
(2
01
3)
1 (2
01
2)
3 (2
01
3)
38
6 (2
01
2)
53
6 (2
01
3)
12
3 (2
01
2)
12
0 (2
01
3)
1
9 (2
01
2)
22
(2
01
3)
24
14
(2
01
2)
89
4 (2
01
3)
15
4 (2
01
2)
83
(2
01
3)
0 (2
01
2)
1 (2
01
3)
30
(2
01
2)
31
(2
01
3)
No
. o
f cases
in
vestigated
54
(2
01
2)
62
(2
01
3)
1 (2
01
2)
3 (2
01
3)
32
% o
f cases h
ad
tim
ely
in
vestig
atio
n
with
Fir
st In
vestig
atio
n
Rep
ort availab
le
(2
01
2)
30
% (2
01
3)
16
3 (2
01
2)
15
6 (2
01
3)
No
A
EFI
investig
ated
19
(2
01
2)
22
(2
01
3)
24
14
(2
01
2)
89
4 (2
01
3)
11
07
(2
01
2)
46
9 (2
01
3)
0 (2
01
2)
0 (2
01
3)
30
(2
01
2)
31
(2
01
3)
No
. o
f cases
review
ed
b
y
co
mm
ittee
15
(2
01
2)
17
(2
01
3)
1 (2
01
2)
3 (2
01
3)
86
(2
01
2) in
clu
des
backlo
g p
revio
us
years
89
(2
01
3)
16
3 (2
01
2)
15
6 (2
01
3)
1
9 (2
01
2)
22
(2
01
3)
8 (2
01
2)
2 (2
01
3)
11
07
(2
01
2)
46
9 (2
01
3)
NA
A
ll
Report of an intercountry workshop
24
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.
On the evening of the day of immunization the mother noticed that
TM had mild fever. On 7 September the mother noticed that she had high
fever, cough, vomiting and flushed face. On 12 September, she was
admitted to the General Hospital, Salem with a tentative diagnosis of lower
respiratory tract infection. She was treated with panadol, piriton,
cefaloxine, salbutamol, theophylline and diclofenac sodium suppository
Causality assessment of adverse events following immunization
25
(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.
An autopsy was conducted and the official report is awaited. The
forensic pathologist indicated that the appearance is compatible with a viral
infection. There was, however, no macroscopic evidence of bleeding or
fluid leakage. The relevant specimens were collected and sent for
laboratory analysis.
Report of an intercountry workshop
26
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.
Born in rural hospital 30 km away from residence. The
pregnancy and delivery was uneventful. The parents are
both 20 years old and have been married for the past
three years and this was their first child. Weight of the
baby at birth was 3.5 Kg. The baby was exclusively
breastfed and doing well.
Causality assessment of adverse events following immunization
27
Variables Investigation findings
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 (O
2 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
oedematous with fluid in pleural cavity; heart – normal;
abdominal cavity contains fluid; liver – elongated and
congested; spleen –elongated; intestine – congested;
spleen full of fluid; both kidneys – normal. Cause of
death autopsy: septicaemia.
Report of an intercountry workshop
28
Variables Investigation findings
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”.
To question IV, “Other qualifying factors”, the group responded “Yes”
to the two questions “Could the event occur independently of
vaccination?” and “Could the event be a manifestation of another health
condition?” because for the first question, anaphylaxis can occur due to
many other causes and for the second question because of the pre-existing
illness of the child at the time of the vaccination. In responding to the
questions, the group identified exposure to potential risk factors or toxin
because the child had fever-four days prior that could reveal an acute
illness prior to the event. The group also acknowledged that the patient was
under antibiotics and antipyretics prior to the vaccination. The group
identified a biological plausibility that the vaccine could cause the event.
Causality assessment of adverse events following immunization
29
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.
During plenary discussions, Professor Noni Macdonald suggested that
we could also conclude that there is no evidence of toxic shock as well as
no evidence of hypotonic hypo-responsive episode (HHE) because HHE
does not cause death. The audience also mentioned that there are
programmatic issues to be addressed including proper examination before
vaccination, for example, taking the pulse. Case management in the
hospital also should be reviewed. Overall, the audience enjoyed the value
of the exercise. It is anonymous, allowing to make recommendations away
from conflict of interest issues. There are communication challenges to
communicate such an event to the family and the public at large.
Report of an intercountry workshop
30
Group 1 – Case 2
Sex: no data
Date of birth: 19 November 2013
Address: Rural
A. Information about the case:
Variables Investigation findings
1 Age at the day of
vaccination
One year and six weeks
2 Birth date 19 November 2013
3 Date/time that received
vaccine
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
14 Investigation team’s
conclusion
Inconsistent causal association to immunization because
the child was sick prior to the immunization.
Causality assessment of adverse events following immunization
31
B. Working Group 1 – Case 2: findings and conclusions
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.
During the plenary discussion, participants asked the difference
between indeterminate and unclassified. Professor Noni MacDonald
explained that indeterminate refers to an association that is possible, but
one element does not match the case definition, for example, timing is not
correct. Unclassified means that we do not have enough information.
Report of an intercountry workshop
32
Group 1 – Case 3
Sex: Male
Date of birth: 20 March 2005
Address: Rural
A. Information about the case:
Variables Investigation findings
1 Age at the day of
vaccination
1 year and 6 months
2 Birth date 20 March 2005
3 Date/time that received
vaccine
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
9 Symptoms and treatment 22 September 2006, hardness on the left hip was
treated by the mother with lemon and massage of the
area which turned to a bruise. Mother noticed that the
child started limping in the morning, and in the evening
didn’t want to walk, arms still can move, no fever,
regular urine. The mother took the child to community
hospital and was prescribed with prednisolone (5mg/ta)
1x1 @pc
Causality assessment of adverse events following immunization
33
Variables Investigation findings
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):
Small CMAP amplitude, normal motor distal
latency and motor NCV of Rt: median, ulnar and
Report of an intercountry workshop
34
Variables Investigation findings
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
22 October 2006 Before D/C N/S: MSE: good
Causality assessment of adverse events following immunization
35
Variables Investigation findings
consciousness
CN: intact motor: UE gr IV, LE gr III DTR:0
10 Condition of other children
vaccinated in the same
health facility
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
Specific toxicity for diphtheria and tetanus component –
Report of an intercountry workshop
36
Variables Investigation findings
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)
13 Laboratory/autopsy Specimen Date Laboratory
location
Results
CSF for
Virus
24 October
2006
Department
of Medical
Sciences,
MOPH
Herpes simplex
virus IgM –
negative
Dengue IgG –
positive
JE IgM – waiting
for a result
Enterovirus –
negative
Causality assessment of adverse events following immunization
37
Variables Investigation findings
CSF 12 October
2006
Regional
hospital
Protein 114,
glucose 68
Stool for
polio
12 October
2006
Department
of Medical
Sciences,
MOPH
Negative
Blood
culture
4 October
2006
Regional
hospital
Microbial
susceptibility =
Acinetobacter
sp., K.
pneumoniae +
ve
CT brain 4 October
2006
Regional
hospital
Mild cerebral
atrophy causing
dilated
ventricular
system
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.
Professor Noni MacDonald agreed with the group, although she
mentioned that GBS is not well documented in very young children in
relation to vaccines but is known to occur following campylobacter
infection (not tested for). GBS is a very rare event and sometimes has no
known cause It is likely that it would have been helpful to discuss the
possibility of vaccine-associated paralytic poliomyelitis.
Report of an intercountry workshop
38
Group 2 – Case 1
Sex: Male
Date of birth: 24 November 2011
Address: Rural
A. Information about the case
Variables Investigation findings
1 Age at the day of vaccination One week and six days
2 Birth date 24 November 2013
3 Date/time that received
vaccine
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.
At 10:40 the baby suffered a cardiac arrest.
January 7, at 11:00 the baby was declared dead.
Causality assessment of adverse events following immunization
39
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 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.
14 Investigation team’s
conclusion
Anaphylaxis/sepsis
B. Working Group 2 – Case 1: findings and conclusions
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.
The participants recognized that the event could happen
independently of vaccination, given the underlining illness of the baby. The
consensus was the case is coincidental because the baby showed signs of
sepsis and developed shock 12 hours after immunization. There was
evidence of bacterial infection in the form of leukocytosis and diarrhoea
episodes and liver dysfunction.
Report of an intercountry workshop
40
Professor Noni Macdonald mentioned that there are in fact two
questions to answer with the first question being did the vaccine cause the
event and the second being did the vaccine contribute to the event which
is more difficult to answer in the absence of in-depth clinical and post-
mortem investigations. In this connection, the group acknowledged the
difficulties in proceeding with post-mortem autopsy and a verbal autopsy
adapted to AEFI and countries with limited resources could improve
investigation and thus data quality.
Causality assessment of adverse events following immunization
41
Group 2 – Case 2
Sex: Male
Date of birth: 11 February 2013
Address: Rural
A. Information about the case
Variables Investigation findings
1 Age at the day of
vaccination
52 days
2 Birth date 11 February 2013
3 Date/time that received
vaccine
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
administered on 3 April 2013 at 12:00 (most probably).
They left for home 5–10 minutes later and reached
home in about 25 minutes. The baby slept for about 15
minutes. The child woke up and had a vacant look,
crying and had difficulty in breathing (around 13:00) -
bluish coloration was also present. The mother tried to
breastfed but the baby did not respond well. The child
was rushed to the private clinic, where no treatment/
intervention done. After the child’s condition
deteriorated, he was taken to the health facility and
with any further treatment was referred to the GYT
Medical College and was admitted at about 19:30. The
Report of an intercountry workshop
42
Variables Investigation findings
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
vaccinated in the same
health facility
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:
GC: ill looking having marked intercostal respiratory
system indrawing and abdominal distension.
Causality assessment of adverse events following immunization
43
Variables Investigation findings
RR: 88/min with marked intercostal and sub costal
indrawing.
Temp: 98 Fahrenheit.
SPO2: 89% without O
2
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
vaccine/vaccination caused anaphylaxis?” There are no reports in the
literature of anaphylaxis with oral vaccines like OPV. It is also necessary to
consider whether a reaction to the vaccine contributed to the aspiration.
Report of an intercountry workshop
44
Group 3 – Case 1
Sex: Female
Date of birth: 9 June 2012
Address: Rural
A. Information about the case
Variables Investigation findings
1 Age at the day of
vaccination
3 days
2 Birth date 9 June 2012
3 Date/time that received
vaccine
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
20:00, when taking milk, the child choked, her
mother held her over the shoulder and put her to
bed and let her sleep with turned face alone
Causality assessment of adverse events following immunization
45
Variables Investigation findings
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)
10 Condition of other children
vaccinated in the same
health facility
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.
For newborns, when receiving vaccine, the child
should go home immediately, and the parent
should be advised to monitor their child.
Report of an intercountry workshop
46
B. Working Group 3 – Case 1: findings and conclusions
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.
Professor MacDonald noted that drowsiness is not common after BCG
or HBV hence would not have contributed to aspiration.
Causality assessment of adverse events following immunization
47
Group 3 – Case 2
Sex: Male
Date of birth: 16 March 2012
Address: Rural
A. Information about the case
Variables Investigation findings
1 Age at the day of
vaccination
2 months and 3 days
2 Birth date 16 March 2012
3 Date/time that received
vaccine
24 May 2012 at 10:00
4 Type of vaccine DTP-HepB-Hib 1 (Batch No 1452046) and OPV 1
(Batch No H5006)
5 Place of vaccination Health station, routine immunization
6 Date/time of onset of AEFI 24 May, 18:30 excessive crying
7 Date/time of death 24 May at 22.45 –13 hours after the vaccination
8 Health history No antenatal complications reported
Born in district hospital, born at term + 3 days, mode
of delivery normal, birth weight 2240 g. The child was
breastfed and was not hospitalized before the event.
The child received BCG, but there was no record on
the health card.
The child had two sisters four and eight years old with
no neonatal major illness reported by the father and
the mother. There is no history of infant death in the
family.
9 Symptom and treatment 24 May 18:30, child crying excessively, father sought
advice from the estate medical assistant (EMA) without
taking the child with him. EMA advised admission to
the hospital; baby was brought to the hospital and
admitted at 22.45 most probably due to delay in taking
a decision to seek medical care from hospital. (District
Hospital X is situated about 18 km away from
residence of parent and roads are in good condition.
EMA arranged transport facilities but father refused
Report of an intercountry workshop
48
Variables Investigation findings
saying that they are going by their own transport).
On the way to hospital, child’s crying reduced and the
child became unresponsive 15 minutes before reaching
hospital. At the time of the hospital admission at 22.45,
the child was pronounced dead.
10 Condition of other children
vaccinated in the same
health facility
No similar events were reported with other children
vaccinated (3) either with the same vaccine vial or
vaccine batch.
11 Vaccine management VVM was at stage 1 and no cold chain break down was
reported during the transportation of the vaccine.
12 Investigation of vaccine
13 Autopsy No written report available, awaiting the pathological
report
Personal communication with forensic medical
officer:
No macroscopic abnormality was found.
Histopathological examination: Cerebral oedema
and features of acute respiratory distress syndrome
Most probably death was not associated with the
immunization: may be atypical pneumonia.
14 Investigation team’s
conclusions
Coincidental. History and pathological observations
support the diagnosis of underlying acute infection.
B. Working Group 3 – Case 2: findings and conclusions
The group identified “excessive crying” as the valid diagnostic and thus
established the causality question “Has the pentavalent vaccine/vaccination
caused excessive crying?” However, experts groups debated on the strong
evidence for other causes because autopsy findings revealed acute
respiratory distress and cerebral oedema.
Concerning question II “Is there a known causal association with the
vaccine?”, the participants of this group responded “Yes” because of
evidence in the literature that vaccine/vaccination may cause excessive
crying but it does not cause death. By going through questions III “Is there
strong evidence against causal association?” and IV “Other qualifying factors
Causality assessment of adverse events following immunization
49
for classification”, the group of experts concluded that with available
evidence the classification is coincidental, because the child had cough and
cold which evolved into acute respiratory distress. Respiratory distress
eventually causes cerebral oedema. These features were found at the
autopsy.
Professor Noni MacDonald pointed out that excessive crying can lead
to the parent shaking the baby in frustration – leading to shaken baby
syndrome with cerebral oedema. The medical team did not consider it
child abuse although the father’s actions were noteworthy.
Report of an intercountry workshop
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Group 3 – Case 3
Sex: Female
Date of birth: 9 November 2010
Address: unknown
A. Information about the case:
Variables Investigation findings
1 Age at the day of
vaccination
6 months 14 days
2 Birth date 9 November 2010
3 Date/time that received
vaccine
28 May 2011 at 11:00
4 Type of vaccine Pentavalent DTP-HepB-Hib (2nd
dose) Lot No 0451421
expiry August 2013.
OPV no batch or expiry records
5 Place of vaccination NOT AVAILABLE
6 Date/time of onset of AEFI 29 May at 02:00
7 Date/time of death 29 May at 03:30
8 Health history Normal vaginal delivery. Birth weight 1800 kg. The
baby was exclusively breastfed for four months. No
hospitalization, no allergy, no congenital abnormality.
Received previous immunization with BCG pentavalent
and OPV with no report of AEFI.
9 Symptoms and treatment 29 May 2011 at 02:00 child cried, breathed loudly and
abdominal distension noted. Mother tried to breast
feed but child refused. She tried to give paracetamol
syrup ½ teaspoon but child refused to take.
At 03:35, the child was admitted to the district hospital
paediatric ward. Pulse 90/m, RR 56/m, irregular,
cyanosis, cold extremes, abdomen distended. CPR
initiated immediately IV saline, adrenaline 0.3 n=ml
(1:10 000), repeated after 10 minutes. Child improved
but cardiac arrest at 5:00, CPR done.
At 5:30, the child was dead.
Causality assessment of adverse events following immunization
51
Variables Investigation findings
10 Condition of other children
vaccinated in the same
health facility
61 children were vaccinated in the same clinic the
same day, out of which 35 were vaccinated with the
same vaccine. No similar events were reported.
11 Vaccine management No cold chain breakdowns were reported and the VVM
on the incriminated vaccines was stage 1.
12 Investigation of vaccine Not available
13 Laboratory/Autopsy In the district hospital, autopsy was conducted by the
forensic medical officer. No features of any
allergic/anaphylactic reaction were noted. Congenital
heart disease comprising: truncus arteriosus, absent
pulmonary artery, VSD, RV hypertrophy, dilated RA.
14 Investigation team’s
conclusion
Cause of death: Congestive cardiac failure following
congenital heart disease
B. Working Group 3 – Case 3: findings and conclusions
The valid diagnostic used by the group is shock. There is no Brighton case
definition for shock. The participants then stated their question as “Has the
pentavalent and/or OPV vaccine caused shock?”
The answer to question I “Is there strong evidence for other causes?”
is positive because the autopsy showed truncus arteriosus, absent
pulmonary artery, VSD, RV hypertrophy and dilated RA. The responses to
all parts of question II were negative and for question III “Is there strong
evidence against a causal association?” participants responded “yes”
because autopsy showed complicated congenital heart disease. To question
IV “Could the event occur independently of vaccination?” and “Could the
event be a manifestation of another health condition?” the participants
responded “Yes” because many conditions can cause shock and because of
the complicated congenital heart disease the child had at the time of the
vaccination. All the other answers in questions IV were negatives.
Therefore, in light of the information collected during the
investigation, this group conclusion is coincidental because of underlining
complicated heart disease.
Professor MacDonald concurred. Also noted that the baby had low
birth weight.
Report of an intercountry workshop
52
Annex 6
Questionnaire to assess usefulness of causality
algorithm tools to participants
Worksheet for AEFI causality assessment
Step 1 (Eligibility)
Do you think the above step is helpful? Yes No No opinion
If “No” – Please suggest modifications by writing on the figure above and/
or providing suggestions below.
1.
2.
3.
Name of the
Patient
Name of one or
more vaccines
administered
before this event
What is the valid
diagnosis?
Does the diagnosis
meet a case
definition?
Create your question on causality here
Has the ___________ vaccine / vaccination caused ______________? (The event for
review in step 2)
Causality assessment of adverse events following immunization
53
Is the above causality question helpful? Yes No No opinion
If “No” – Please suggest modifications by writing on the figure above and/
or providing suggestions below.
1.
2.
3.
Step 2 (Event checklist) (check) all boxes that apply
I. Is there strong evidence for other causes? Y N UK NA Remarks
Does a clinical examination, or laboratory tests on the patient,
confirm another cause?
II. Is there a known causal association with the vaccine or vaccination?
Vaccine product(s)
Is there evidence in the literature that this vaccine(s) may cause the
reported event even if administered correctly?
Did a specific test demonstrate the causal role of the vaccine or any
of the ingredients?
Immunization error
Was there an error in prescribing or non-adherence to
recommendations for use of the vaccine (e.g. use beyond the expiry
date, wrong recipient etc.)?
Was the vaccine (or any of its ingredients) administered unsterile?
Was the vaccine's physical condition (e.g. colour, turbidity, presence
of foreign substances etc.) abnormal at the time of administration?
Was there an error in vaccine constitution/preparation by the
vaccinator (e.g. wrong product, wrong diluent, improper mixing,
improper syringe filling etc.)?
Was there an error in vaccine handling (e.g. a break in the cold chain
during transport, storage and/or immunization session etc.)?
Was the vaccine administered incorrectly (e.g. wrong dose, site or
route of administration; wrong needle size etc.)?
Immunization anxiety
Could the event have been caused by anxiety about the
immunization (e.g. vasovagal, hyperventilation or stress-related
disorder)?
Report of an intercountry workshop
54
II (time). If “yes” to any question in II, was the event within the time window of increased risk?
Did the event occur within an appropriate time window after vaccine
administration?
III. Is there strong evidence against a causal association?
Is there strong evidence against a causal association?
IV. Other qualifying factors for classification
Could the event occur independently of vaccination (background
rate)?
Could the event be a manifestation of another health condition?
Did a comparable event occur after a previous dose of a similar
vaccine?
Was there exposure to a potential risk factor or toxin prior to the
event?
Was there acute illness prior to the event?
Did the event occur in the past independently of vaccination?
Was the patient taking any medication prior to vaccination?
Is there a biological plausibility that the vaccine could cause the
event?
Y: Yes N: No UK: Unknown NA: Not applicable
Are these questions useful? Yes No No opinion
If “No” – Please suggest modifications by writing on the checklist above
and/ or providing suggestions below.
1.
2.
3.
Are there situations where the checklist does not work? Yes No No
opinion How could they be fixed?
If “Yes” – Please suggest modifications by writing on the figure above and/
or providing suggestions below.
1.
2.
3.
Causality assessment of adverse events following immunization
55
Step 3 (Algorithm) review all steps and all the appropriate boxes
Is step 3 algorithm helpful in this the causality assessment process?
Yes No No opinion
If “No” – Please suggest modifications by writing on the figure above and/
or providing suggestions below.
1.
2.
3.
Notes for Step 3:
Report of an intercountry workshop
56
Step 4 (Classification) all boxes that apply
Is the step 4 classification useful? Yes No No opinion
If “No” – Please suggest modifications by writing on the figure above and/
or providing suggestions below
1.
2.
3.
Summarize the classification logic: With available evidence, we could conclude that the classification is
___________________________________because:
Causality assessment of adverse events following immunization
57
Do you find the above summary step useful? Yes No No opinion
If “No” – Please suggest modifications by writing on the figure above and/
or providing suggestions below
1.
2.
3.
If you have any suggestion for another format or a modification, e.g .a new
section on recommendations etc., please suggest and provide brief details.
Do you have any other general suggestions to improve causality assessment
process in your country? E.g. special studies, select communication issues,
training issues, verbal autopsy etc.
You are with the EPI / NRA / Clinician / Other – specify
_______________________
Number of years of experience with AEFI
_____________________________
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Annex 7
Plenary discussions
Day 3: Summary comments
(1) What are we going to do with what have we learned at the
workshop?
To adapt and to use the material for causality committee
updates and to develop teaching material for training
workshops on causality assessment. Guidelines on AEFI
monitoring need to be updated in several countries to
include new definitions.
(2) What have we learned in this process?
The value of learning together and the opportunity to
exchange experience among countries in the South-East Asia
and Western Pacific regions.
Importance of laboratory investigation and collection of
quality data, although there are significant constraints in
many countries on post-mortem autopsy.
Need to strengthen procedures with standing operating
procedures/guidelines in countries where post-mortem
autopsy is performed. From the eight AEFI cases reviewed
during working group sessions, those with post-mortem
autopsy, the findings contributed significantly to establish
causal association with the vaccine administered, for
example, the GBS case.
Need to define criteria for SIDS case autopsy in this
low/middle income setting.
Need to use verbal autopsy – caretaker, parents,
practitioners and streamline field investigation procedures.
AEFI investigation teams should include clinicians, especially
paediatricians from outside of the NIP. This is a confidence
issue for parents and local health- care workers.
Causality assessment of adverse events following immunization
59
(3) What are the suggestions for research studies?
Need background rates for VPD, for example, pertussis.
Need background rates for AEFI with Penta, for example,
excessive crying and seizures
Need background rates for SIDS. India has prospective study
ongoing of 40 000 children that may provide some regional
data on SIDS.
Need to learn about the immunization of children with
congenital heart disease. For congenital heart disease, the
paediatric associations might work to develop a strategy to
increase early detection of clinically significant cases. This is
a challenge in many countries as the immunizer has very
limited health-training background. A set of simple questions
to be asked by the vaccinator could help to identify such
children. Recommendation: Approach paediatric societies in
the Region to see if they could develop a practical set of
questions and observations for detection of coronary heart
disease for referral (still immunize).
(4) Combined measles rubella vaccine was given to > 53 million in
Bangladesh- an opportunity to see AEFI on big population vs.
background rates of events. (Bangladesh provided to WHO AEFI
data during the measles and rubella vaccination campaigns to
help to prepare a summary presentation of findings).
(5) How can the NRA become more involved?
Thailand has NRA representative at the National AEFI
committee.
(6) Participants noted that in countries procuring vaccines through
UNICEF, the NRA has very limited capacity to review vaccine
dossiers for a full licensing. WHO has developed for those
countries a guideline – Procedure for expedited review of
imported prequalified vaccines for use in national immunization
programmes – which describes the procedure for the market
authorization of vaccines supplied through UN procurement
agencies, that is, WHO pre-qualified vaccines. It includes a
simplified lot release procedure for the NRA in the receiving
country to perform a visual check of the product and to review
Report of an intercountry workshop
60
documents in the packing list to verify compliance with
specifications in the national tender. This expedited procedure
aims to enhance NRA product knowledge and to encourage
NRAs/NCLs to maintain small dossiers of essential information on
each lot to be consulted in case of serious AEFI.
Recommendation: a small survey to identify to what extent the
NRA is involved in AEFI in each of the participating countries.
(7) To the question “Do you find the Brighton definitions useful?”,
the participants responded positively; however, definitions need
to be adapted to LMIC immunization settings, for example,
diagnosis of fever needs a thermometer, yet no thermometer is
available in many LMIC sites where vaccine is administered. The
participants also identify the need to expand definitions to cover
pneumonia and septic shock, taking into account basic
equipment for diagnosis available in LMICs. Recommendation:
Request a formal review of Brighton definition to develop
definitions levels that will work in settings where no equipment
and limited health-worker training (for example, outside of a trial
in the real LIC world).
(8) Time interval for when to expect AEFI with different vaccines is
very helpful for AEFI causality assessment. Some Brighton
definitions have this – some do not. Recommendations: To
explore development of a practical tool – definition, time interval,
rates AEFI with different vaccines.
(9) To the question “Do you find the WHO vaccine position papers
useful?”, most participants responded it was helpful to have short
abstract or tables containing essential information. There is a
need to make contraindications of use with other vaccines easier
to find. A WHO position paper on subsequent immunization
would be helpful.
(10) Vaccine compensation programmes are starting to appear in the
Region, for example, in Indonesia; other countries are interested
but raised concerns as well. Recommendation: It would be
helpful to have the 10 countries get together to review
compensations schemes – pros, cons, strategies and assess what
might work in the Region – not just extrapolate from high income
country experiences.
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(11) Analysis and causality assessment are priority areas, especially as
more AEFI are detected and being reported. There is a need to
ensure these analyses are translated into helpful, not harmful,
messages for public and politicians.
(12) The value and importance of AEFI detection and quality causality
assessments needs to be taught in medical and nursing schools.
The National Medical Council may be the entry point – need to
identify procedure to update curriculum. Recommendation:
Explore how immunization and AEFI can be better incorporated
into medical school curriculum (and nursing school).
(13) Need for advocacy for AEFI and causality assessment – especially
for policy-makers.
(14) India is changing the name of its AEFI committee to Vaccine
Safety Committee; NB “Vaccine pharmacovigilance “ is jargon
and not understood easily by public or politicians
(15) What next? All the participants appreciated the use of AEFI cases
from the Region; they found the country presentations to be very
informative. The size of the meeting was suitable but if the
number of participants increases, we will need to increase the
number of working groups and thus the number of facilitators.
Participants proposed to conduct this meeting in the Region once
every year or every two years.