Vaccine 22 (2004) 547550

Editorial

Standardized case definitions of adverse events

following immunization (AEFI)
The development of sustainable immunization programs
delivering safe and effective vaccines to all human populations is an ongoing and dynamic global challenge [1]. As immunization programs in each country mature and incidence
rates of the targeted diseases are substantially decreased by
high vaccine coverages, and as personal experience with the
eliminated vaccine-preventable disease diminishes, real or
perceived adverse effects of immunization in turn receive
relatively more attention [2,3]. To maintain public confidence in immunizations for the continued protection from
vaccine-preventable diseases in this new era, delivery of the
safest possible vaccines is needed. Consequently, immunization safety research needs to be placed on the most rigorous
scientific basis possible.
The Brighton Collaboration was launched in 2000 as a
voluntary international organization to facilitate the development, evaluation, and dissemination of high quality information about the safety of human vaccines [4]. As its first
task, the Collaboration chose to focus on the harmonization
and standardization of case definitions of adverse events following immunizations (AEFI). This decision was made because unlike efficacy, safety can not be measured directly.
The safety of a vaccine can only be inferred indirectly
by the relative presence or absence of multiple AEFI. Furthermore, the safety profile of any specific vaccine represents a unique combination of various AEFI, only some of
which (e.g. fever, local reaction) are shared across vaccines.
Therefore, standardized case definitions of AEFI are a key
element for scientific assessment of immunization safety as
they provide a common vocabulary and understanding of
AEFI and thus allow for comparability of data from clinical
trials and surveillance.
The Collaboration aims ultimately to develop 50100
standardized case definitions of AEFI including guidelines
for the standardized collection, analysis, and presentation/publication of vaccine safety data. The structure and
process for the Brighton Collaboration have been described
earlier [4,5]. In this issue of Vaccine, we are pleased to
present the first six case definitions of AEFI together with
their guidelines developed by the respective Brighton Col Readers are invited to contact secretariat@brightoncollaboration.org
for comments and inquiries.

0264-410X/$ see front matter. Published by Elsevier Ltd.

doi:10.1016/S0264-410X(03)00511-5

laboration working groups: fever, generalized convulsive

seizure, hypotonic-hyporesponsive episodes (HHE), intussusception, nodule at injection site, and persistent crying.
These documents represent thousands of person hours of
work by hundreds of experts from tens of countries around
the world. They have also been reviewed by relevant reference groups worldwide. Aside from the coordinators, all
of this work has been achieved on a voluntary basis. This
is an impressive vote of confidence on the importance of
this work given the credentials of the volunteers. The members of each working group are listed with their respective
case definitions and guidelines. We owe them our collective
gratitude for a job well done.
Beyond these initial six AEFI, the Collaboration has
already or will soon be forming new working groups on
allergic reactions, chronic fatigue syndrome, idiopathic
thrombocytopenia, myalgia, paresthesia, rash, smallpox
vaccine-associated AEFI, and methodological problems
across working groups. Information about the structure,
process and progress of the working groups are available at
http://www.brightoncollaboration.org. Volunteers such as
yourself are invited to contact us at secretariat@brightoncollaboration.org. Further AEFI are selected based on frequency, severity, public interest and emerging needs. We
also plan to evaluate and improve developed case definitions
as needed in the future.
We will next describe in greater detail: (1) the intended
use of these case definitions and guidelines; (2) differences
between AEFI and drug adverse events; (3) the format of
Brighton Collaboration case definitions and guidelines; and
(4) their implementation, evaluation, and revision process.
Intended use of case definitions and guidelines
As required for all risk factor analyses, both exposure
AND outcome need to be clearly defined before we can
analyze how an outcome (i.e. AEFI) relates to an exposure
(i.e. immunization).
Post hoc ergo propter hocafter this, therefore because
of this is a well-known fallacy in human logic: not every
Y that follows X is caused by X; it could be just coincidental [6]. The term AEFI, when used appropriately, carries exactly this concept (i.e. the pathophysiological onset
of the event was after a given immunization). This concept

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states that the occurrence of such an event after an exposure

(immunization) does not imply by itself that the event was
caused by the exposure. A temporal relation of an outcome
to a given exposure is a necessary but insufficient condition
for the inference of a causal relation.
For scientific case assessment we can differentiate two
scenarios. First, a given clinical event may be the result
of a previously known etiology and pathogenesis. In this
case we can establish causality by proving the presence of
a known etiology. This is the perspective of the clinician
confirming a diagnosis of a known disease. Alternatively, a
clinical condition may be of as yet unknown etiology and
pathogenesis. In this case, the causal link between the event
and a hypothetical etiology will have to be established first.
This is the perspective of an investigator aiming to identify
different potential etiologies and pathogeneses for a given
clinical event.
In vaccine safety, the vast majority of AEFI are methodologically similar to the second situation described above
of a clinical event without known etiology and pathogenesis. A common first line approach of causality assessment
in this case is to collect information on the outcome (AEFI)
for exposed (immunized) and unexposed (non-immunized)
study cohorts. It is then possible to determine if those exposed are more likely to be cases. To avoid bias in this kind
of investigation, the outcome (AEFI) has to be clearly defined first and without any implication on a causal relation
to a particular exposure (immunization).
Such case definitions of AEFI serve the need of determining the diagnostic certainty of a reported AEFI and thus
enable meaningful further evaluation based on well-defined
data. If such case definitions and guidelines are globally standardized, they will enable data comparability across vaccine
safety studies and thus allow for evaluation of AEFI based
on large data sets. This is particularly relevant for rare and
sometimes serious events.
AEFI versus drug adverse events
An adverse drug reaction is a harmful and unintended
event which occurs following administration of a drug used
for prophylaxis, diagnosis, or therapy of diseases, or for
the alteration of a physiological process. A drug adverse
event could be a true adverse drug reaction or a coincidental event following drug administration. A drug adverse
event could therefore theoretically include immunizations.
However, there are substantial differences between the assessment of most drug adverse events and AEFI since immunization is a very different biologic process from most
therapeutic drugs.
First, there are different types of AEFI. Those that are
perceived as adverse events but can be visible signs of effective immunization (e.g. sometimes fever, some forms of
local reactions); those reflecting the clinical picture of the
disease immunized for (measles rash following MMR); and
those that are unintended and a causal relation remains to
be elucidated or disproved. Second, the populations of vac-

cine recipients are usually much larger and more heterogeneous than the ones of drug recipients. Third, the immune
response to a vaccination may depend more on individual
host factors than the pharmacological effects of drugs (e.g.
the distribution, absorption and elimination of the antigen,
pre-existing antibodies or memory cells, individual immune
competence). Further, de-challenge and often re-exposure
testing in the presence of an AEFI are so far not possible and
not only the intended reactive ingredientthe antigen, but
additives and excipients for production, inactivation, preservation, and stabilization of vaccines also play an important
role in evaluating the causal relation of an AEFI with a given
immunization. Finally, less evidence is generally available
about the pathophsiological link between immunization and
adverse events compared to drug adverse reactions.
These differences have to be considered in the development of standardized case definitions and guidelines for
AEFI. Case definitions and guidelines developed for the assessment of adverse drug reactions may therefore be of only
limited usefulness when transferred to the field of vaccine
safety.
The Brighton Collaboration format of case definitions
Case definition documents follow this format: (1) a preamble, which describes some of the essential or most controversial decisions that were madeoften topics for which
arbitrary decisions had to be made due to a lack of published scientific evidence; (2) the case definition itself; and
(3) guidelines for the standardized collection, analysis and
presentation of AEFI data.
The main methodological challenges identified during
case definition development by the Brighton Collaboration were presented in detail previously [5]. In summary,
the format of Brighton Collaboration case definitions
had to:
(1) be globally useful in as many research settings as possible by being adaptive to the level of resources available, including clinical trials, epidemiologic studies, and
post-marketing surveillance systems for AEFI in both
developed and less developed countries. In general, in
clinical trials and developed countries more information on AEFI may be expected to be collected and thus
allowing for greater diagnostic certainty. On the other
hand, information from passive surveillance systems as
well as from studies in developing countries are likely
to yield less diagnostic certainty. The case definitions
therefore had to anticipate and accommodate a wide
range of informational adequacy within individual reports. This is achieved by a case definition format allowing for varying levels of diagnostic certainty, where the
level of specificity is relaxed for the level of sensitivity;
(2) be adjustable to the wide range of AEFI (e.g. clinical signs, symptoms or diseases, syndromes, categorical
and continuous AEFI), yet represent a format uniform
enough to be recognizable across the different AEFI;

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(3) be a learning tool to gain additional knowledge about

AEFI. The lack of knowledge on a given event sometimes requires arbitrary decisions to be made on a case
definition criterion. Formal evaluations and research will
hopefully result in future revisions if needed;
(4) be primarily a tool for data analysis rather than for AEFI
reporting. Investigators using the definitions need the
option of being a splitter by applying various levels
of a case definition appropriate to the specific situation, rather than being constrained to be a lumper in
the first place. Thus, the case definition allows investigators with different interests in the safety profile to
merge data sets from different well-defined categories
of diagnostic certainty rather than being limited to combine cases in a single category without the option to
differentiate;
(5) require as little medical interpretation of the definition as
possible. Subjective terms in the definition are avoided
and clear-cut clinical criteria are combined by Boolean
operators to arrive at a definition. This is in contrast
to the descriptive teaching style definitions used in
textbooks;
(6) be clinically most useful to improve the quality of data
on the background rate of a given AEFI;
(7) be free of any implications on the causal relationship
between the event and immunization unless the event
was specific to a given vaccine.
Therefore, the Brighton Collaboration case definitions consist of Level 1 or 2 or 3 of diagnostic certainty for the
AEFI. The terms definite, probable, or possible frequently used with other case definitions was intentionally
avoided by the Brighton Collaboration. This is because in
the realm of vaccine safety, these terms may also be used to
describe degrees of certainty of causal relationship of the
AEFI to the immunization. Level 1 is defined by a combination of criteria, which outline the best achievable diagnostic
certainty for a given AEFI. Level 2 is defined by a combination of criteria, which select for cases with less specific
evidence for the diagnosis. Level 3 is the least specific and
is defined by a combination of criteria, which represent the
minimum requirement for an event to be called a case of
[AEFI]. Reported events, which do not meet these criteria,
may still be true cases, but need additional follow-up to be
confirmed.
Case definitions alone are not sufficient to achieve data
comparability. Hence, the Brighton Collaboration has also
developed guidelines including essential recommendations
for collection, analysis, and presentation for data on each
AEFI to achieve a common, comparable understanding and
assessment of these data.
A key element of these guidelines is the event classification in five categories for data analysis. They include the
three levels of diagnostic certainty as defined in the respective case definition plus two categories for (1) those reports
that have insufficient evidence to meet the case definition, or

549

(2) have to be rejected (e.g. because exclusion criteria have

been met).
The classification of events according to the different categories for analysis might not elicit a different response (e.g.
follow up and/or prospective trials) to (a cluster of) reported
events. However, it is useful to differentiate reported events
which fulfill at least a set of minimal requirements from
those with insufficient evidence. Differentiation might even
improve the quality of passive surveillance data, which often
provide insufficient detail for classification of an event as a
case. The heterogeneity of data in surveillance systems may
be analyzed more systematically and render parts of the data
collected comparable with data from other study designs.
Passive reporting behavior is not influenced by such a tool
for data analysis, but passive reports can be classified into
a given category and could be communicated accordingly.
In addition, data collection guidelines can also be used to
collect follow-up information in a systematic fashion for a
given AEFI.
Implementation, evaluation, and revision
Now that the case definition and guidelines documents for
the first six specific AEFI have been developed, it is our hope
that the vaccinology community will adopt them as their
own and fully integrate them into vaccine safety research
and surveillance irrespective of the setting: pre-licensure or
post-licensure, in developed and developing settings. Whenever possible, we have structured them to facilitate translation into various study protocols (e.g. approximation of
checklist format for the guidelines). It is also our hope
that, while using the case definitions and the guidelines,
they are formally evaluated (e.g. for applicability, usefulness, reliability, sensitivity, specificity, positive and negative
predictive values), whenever the opportunity arises. Guidance documents for such evaluations are currently under
development.
We anticipate to actively follow-up with registered users
to solicit feedback on experience gained during implementation. We will then review and, when indicated, revise the
definitions and guidelines on a regular (i.e. every 35 years)
or as needed basis. Registered users of the definitions
and guidelines will also automatically be informed about
updated versions available at the Brighton Collaboration
website (http://brightoncollaboration.org/en/index/aefi.html).
We therefore strongly encourage users to support this effort
by registering as a user at this website.

Acknowledgements
We are sincerely thankful to our two new Steering Committee members Miles Braun, MD, MPH and S Michael
Marcy, MD, who joined the Steering Committee in May
2003. We are grateful to our project manager Bakary Drammeh, DrPH for his invaluable support in the Secretariat.

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References
[1] Melgard B. Immunization in the 21st centurythe way forward. Acta
Trop 2001;80(Oct 22):11924.
[2] Chen RT. Vaccine risks: real, perceived, and unknown. Vaccine
1999;17:S416.
[3] Chen RT, Rastogi SC, Mullen JR, Hayes SW, Cochi SL, Donlon JA,
et al. The vaccine adverse event reporting system (VAERS). Vaccine
1994;12:54250.
[4] Bonhoeffer J, Kohl KS, Chen RT, et al. The Brighton Collaboration:
addressing the need for standardized case definitions of adverse events
following immunization (AEFI). Vaccine 2002;21:298302.
[5] Kohl KS, Bonhoeffer J, Chen RT, et al. The Brighton Collaboration:
enhancing comparability of vaccine safety data. ISPE Commentary.
Pharmacoepidemiol Drug Saf 2003;12:16.
[6] Rothman KJ, Greenland S. Causation and causal inference. In:
Rothman KJ, Greenland S, editors. Modern Epidemiology. 2nd ed.
Philadelphia: Lippincott-Raven; 1998. Chapter 2, p. 728.

Jan Bonhoeffer
Ulrich Heininger
University Childrens Hospital Basel
Basel, Switzerland
Corresponding author
E-mail address: secretariat@brightoncollaboration.org
(J. Bonhoeffer)

Katrin Kohl 1
Robert T. Chen
Centers for Disease Control and Prevention, USA
1 Co-corresponding author
Philippe Duclos
World Health Organization, Switzerland
Harald Heijbel
Swedish Institute for Infectious Disease Control, Sweden
Tom Jefferson
Cochrane Vaccines Field and Health Reviews Ltd
Rome, Italy
Elisabeth Loupi
Aventis Pasteur, S.A., France
The Brighton Collaboration
Sources of support: The Brighton Collaboration is
presently supported by the Centers for Disease Control
and Prevention (CDC), the European Research
Program for Improved Vaccine Safety Surveillance
(EUSAFEVAC, European Commission
Contract No. QLG4-2000-00612 and the
World Health Organization (WHO)