report on terminology mapping and aefi/ade definitions
TRANSCRIPT
This project has received funding from the European Union’s Seventh Framework Programme for research, technological development
and demonstration under grant agreement n. 261060
Deliverable number D2.5
Report on terminology mapping and AEFI/ADE definitions
GRiP
Global Research in Paediatrics
Network of Excellence
HEALTH-F5-2010-261060
Lead Beneficiary: NICHD-NIH
Authors:
Osemeke Osokogu, Florentia Kaguelidou, Daniel Weibel, Katia Verhamme, Yolanda Brauchli Pernus, Steven
Hirschfeld, Jan Bonhoeffer, Miriam Sturkenboom
Revision date 21-7-2104
Disseminat ion Level
Publ ic PU
Start date 01/01/2011
Duration 5 years
Project Coordinator Dr. Carlo GIAQUINTO
Azienda Ospedaliera di Padova (AOPD)
Refe rence W P WP2 – In tegra ted in frastructure for epidemiologica l and
post market ing studies
Refe rence Ac t iv i t y Task 2 .05 – Map terminologies and
harmonize data
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D2.5 - Report on terminology mapping and AEFI/ADE definitions 2
Index 1 List of Authors .............................................................................................................................................. 4
2 Abstract ......................................................................................................................................................... 5
3 Abbreviations used in this document ........................................................................................................ 6
4 Introduction ................................................................................................................................................... 8
4.1 General embedding .............................................................................................................................. 8
4.2 Drug & vaccines safety assessment and the need for identification of events ........................... 8
5 Objectives ................................................................................................................................................... 13
6 Methodology ............................................................................................................................................... 14
6.1 Coding systems .................................................................................................................................. 14
6.2 Harmonization process for event data extraction .......................................................................... 14
6.2.1 Events for mapping ..................................................................................................................... 14
6.2.2 Definition of events ..................................................................................................................... 15
6.2.3 Mapping of terminologies........................................................................................................... 16
7 Results ......................................................................................................................................................... 19
8 Discussion/Limitations .............................................................................................................................. 24
8.1 Discussion ............................................................................................................................................ 24
8.2 Limitations ............................................................................................................................................ 25
9 Conclusion/Next steps .............................................................................................................................. 27
10 References ............................................................................................................................................... 28
11 Appendix 1: Selection criteria for concepts related to the events of interest .................................. 30
11.1 Inclusion criteria ................................................................................................................................ 30
11.2 Exclusion criteria ............................................................................................................................... 30
12 Appendix 2: Clinical definitions for events of interest in the drug and vaccine reference set ..... 31
12.1 acute kidney injury (AKI) .................................................................................................................. 31
12.2 Agranulocytosis ................................................................................................................................. 32
12.3 aplastic anemia ................................................................................................................................. 32
12.4 bullous eruptions ............................................................................................................................... 33
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12.5 drug-induced liver injury (DILI) ....................................................................................................... 35
12.6 Psychosis ........................................................................................................................................... 37
12.7 QT prolongation ................................................................................................................................ 38
12.8 Seizure ............................................................................................................................................... 39
12.9 Sepsis ................................................................................................................................................. 40
12.10 Sudden death .................................................................................................................................. 41
12.11 Sudden infant death ....................................................................................................................... 42
12.12 Suicide .............................................................................................................................................. 42
12.13 Thrombocytopenia .......................................................................................................................... 43
12.14 Venous thromboembolism............................................................................................................. 44
12.15 ventricular arrhythmia .................................................................................................................... 46
12.16 Anaphylaxis as AEFI ...................................................................................................................... 48
12.17 Thrombocytopenia .......................................................................................................................... 49
12.18 (Febrile) seizures ............................................................................................................................ 49
12.19 Disseminated BCGitis .................................................................................................................... 50
12.20 Hypotonic hyporesponsive episode ............................................................................................. 51
12.21 Encephalitis ..................................................................................................................................... 51
12.22 Intussusception ............................................................................................................................... 51
12.23 Vaccine-associated paralytic poliomyelitis (VAPP) ................................................................... 52
12.24 Disseminated Oka VZV ................................................................................................................. 53
12.25 Arthritis ............................................................................................................................................. 55
12.26 Guillain Barré Syndrome ............................................................................................................... 56
12.27 Wheezing ......................................................................................................................................... 57
12.28 IDDM ................................................................................................................................................. 58
12.29 Bell’s palsy ....................................................................................................................................... 59
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1 List of Authors
Name Institution
Osemeke Osokogu EMC
Daniel Weibel EMC
Florentia Kaguelidou EMC
Katia Verhamme EMC
Yolanda Brauchli Pernus Brighton Collaboration Foundation
Steven Hirschfield NICHD-NIH
Jan Bonhoeffer Brighton Collaboration Foundation
Miriam Sturkenboom EMC
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2 Abstract
Within the context of the Global Research in Paediatrics (GRiP) - Network of excellence
(http://www.grip-network.org), task 2.05 of work package 2 (WP2) is aimed at mapping
pediatric events that were selected in task 2.6 to be relevant for safety signal detection
across spontaneous reporting system (SRS) and electronic health record (EHR)
databases.
In task 2.6 (D2.07) Sixteen ADEs and 14 AEFIs were identified for reference sets which
will be the basis for the methods development and testing in signal detection on SRS and
EHR databases. Since SRS and EHR databases use different terminologies for events
(e.g. Medical Dictionary for Regulatory Activities (MedDRA); International Statistical
Classification of Diseases and related health problems - 9th revision, clinical modification
(ICD9-CM); International Statistical Classification of Diseases and related health
problems - 10th revision (ICD10); READ coding system; and International Classification of
Primary Care (ICPC)). In order to make the work in task 2.6 possible we adapted a
workflow for mapping as previously published in the EU-ADR project. This workflow
comprised of the following steps: 1) cinical definition of the events; 2) automated
searching of unique concept identifiers (CUI) in the Unified Medical Language System; 3)
manual review of all unique concepts by two experts, to verify inclusions and exclusions;
4) automated mapping of retained CUIs to underlying terminologies (ICD-9, ICD-10,
ICPC, READ, MEDDRA); 5) verification of selected codes with existing and published
identification strategies for some 6) verification of completeness of ICD-10 codes using a
SNOMED based pathway.
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3 Abbreviations used in this document
EMC Erasmus medical Center
BCF Brighton Collaboration Foundation
NICHD-NIH Eunice Kennedy Shriver National Institute of Child Health and Human
Development – National Institutes of Health
SRS Spontaneous Reporting System
EHR Electronic Health Record
EU-ADR European Adverse Drug Reaction
OMOP Observational Medical Outcomes Partnership
ADR Adverse Drug Reaction
ICD9-CM International Statistical Classification of Diseases and related health
problems - 9th revision, clinical modification
ADR Adverse Drug Reaction
IPCI Integrated Primary Care Information
ICPC International Classification of Primary Care
THIN The Health Improvement Network
BSI Bloodstream infection
UMLS Universal Medical Language System
CUI Concept Unique Identifier
SAFEGUARD Safety Evaluation of Adverse Reaction in Diabetes
GP General Practice
RL Record linkage
AMI Acute Myocardial Infarction
ARF Acute renal failure
ICD10 International Statistical Classification of Diseases and related health
problems - 10th revision
PROTECT Pharmacoepidemiological Research on Outcomes of Therapeutics
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SOS Non-steroidal anti-inflammatory drug related gastrointestinal and
cardiovascular risks
ARITMO Arrhythmogenic risk of drugs
WHO World Health Organization
AKI Acute kidney injury
DILI Drug-induced liver Injury
FDE Fixed drug eruption
SJS Stevens-Johnson syndrome
TEN Toxic Epidermal Necrolysis
IOM Institute of Medicine
HHE Hypotonic hyporesponsive episode
VAPP Vaccine-associated paralytic poliomyelitis
GBS Guillain Barré Syndrome
IDDM Insulin-dependent diabetes mellitus
BC Brighton Collaboration
CIOMS Council for International Organizations of Medical Sciences
UNESCO United Nations Educational, Scientific and Cultural Organization
RCD READ code
SNOMED Systematized Nomenclature of Medicine
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4 Introduction
4.1 General embedding
In the paediatric population, for which experimental data are scarce, there is a need to
build pharmaco-epidemiological research capacity to better exploit the evidence that is
being compiled in real life and is often captured in electronic health record (EHR)
databases (administrative or medical records).
Workpackage 2 is aimed at improving paediatric drug development by creating a research
infrastructure that will allow for estimating disease burden, drug and vaccine utilization,
safety of drug and vaccine use in paediatrics as well as effectiveness of drugs. To allow
the combination of large scale research databases from various countries in Asia, Africa,
the European Union and America, they will have to be converted to a simple common data
model and diagnosis and drug terminologies need to be mapped.
GRiP intends to create thesauri for disease coding systems used throughout the
world as well as the definition of procedures for data mining and data pooling. Signal
detection methods as well as common methodologies for assessing drug utilisation,
disease incidence and prevalence studies as well as drug safety assessment and
effectiveness methodologies will be developed.
The methodology that will be developed for large scale distributed assessments of
drug utilization, signal generation, comparative effectiveness and short and long-term
safety evaluation will be tested for selected topics (e.g. vaccines, oral antidiabetics,
antidepressants, psychoanaleptic drugs, antibiotics, oral contraceptives) with a variety of
healthcare databases from the EU and US that will be included in these analyses.
4.2 Drug & vaccines safety assessment and the need for identification
of events
This deliverable is related to the work of safety signal detection methods and how to
extract data from spontaneous reporting system (SRS) and EHR databases.
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Analysis of SRS is currently the most common approach to monitoring vaccine and
drug safety in the postmarketing period. While it may quickly signal emerging safety issues
thereby prompting quick regulatory action, the usefulness of results is limited by biases like
underreporting[2], lack of denominator data, and the differential reporting of vaccines
within pediatric spontaneous reports[3]. Recording and ascertainment biases may also
occur[4].
Analysis of EHR may yield more valid results [5-9]. The added benefit of EHR data
has been investigated within the Sentinel, European Adverse Drug Reaction (EU-ADR),
and Observational Medical Outcomes Partnership (OMOP) projects[10-12], and methods
for analyzing such data were tested. However, pediatric data was not evaluated
specifically, and many EHR databases do not include adequate number of pediatric data.
Yet children deserve special focus because they have unique characteristics that
predispose them to unexpected adverse drug reactions (ADRs) [13-19]. Sufficient pediatric
data may be obtained by pooling data from multiple databases. However, different
databases are set up for unique primary purposes [5, 20], thus influencing the way
information is recorded within such databases. This could impact on the validity and
comparability of results obtained by analyzing pooled data. Harmonization of data
extraction from databases with different coding systems is hence important for research
purposes in order to assure comparability of results or to allow for pooling of data across
various databases.
Administrative claims (reimbursement) data are obtained primarily for billing and
record-keeping purposes[20, 21], while medical records are collected for hospital services
and the patient care process[22]. Utilizing such data for research requires identification of
patient cohorts with specific experiences that represent clinical realities i.e. diagnosis,
laboratory test procedures, drug prescriptions and dispensing[20]. For example: ‘287.5’
(within the International Statistical Classification of Diseases and related health problems -
9th revision, clinical modification [ICD9-CM] coding system) should identify patients that
were treated for thrombocytopenia. Unfortunately, database coding systems may not
accurately reflect these clinical realities. Pressures to maximize financial benefits may
influence outcome codes in administrative databases, while semantic precision and quality
of medical records may affect the validity of codes utilized in medical record databases
[20]. Other sources of heterogeneity across databases include: the use of different coding
systems, and the recording of information in different languages[4]. For example: the
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Integrated Primary Care Information (IPCI) database (Netherlands) utilizes International
Classification of Primary Care (ICPC) coding system to code clinical events, unlike The
Health Improvement Network (THIN) database (United Kingdom) which utilizes READ
codes for the same purpose. Moreover, free text is recorded in the Dutch language within
IPCI, while similar information is recorded in English within THIN.
Data sources may also vary with regard to the medical definition of clinical events
in different healthcare settings. For example, neonatal bloodstream infection (BSI) was
found to have various definitions across healthcare settings in the United Kingdom [23].
Yet for efficient pooling of event data across different databases and countries, it is
important to start with a common case definition that can be projected to multiple
databases. In previous studies, this was achieved via the Universal Medical Language
System (UMLS) [4, 24, 25]. The UMLS allows the identification of all concepts that
describe the event defined in the case definition. Subsequently, these concepts can be
mapped to the coding systems of interest.
The UMLS (Figure 1) is a freely accessible compendium of many controlled
vocabularies that are utilized in biomedical sciences
(http://www.nlm.nih.gov/research/umls/)[25]. It comprises of >100 source vocabularies and
a set of software tools that link these sources. Broadly, there are 3 main knowledge
sources: 1) the multilingual metathesaurus which has ~1 million unique concepts (each
having its own ‘concept unique identifier’ – CUI), and ~5 million concept names, for
example the same concept ‘Constitutional aplastic anemia’ (C0702159) is described as
‘Congenital aplastic anaemia’, ‘Constitutional aplastic anaemia’, and ‘Hypoplastic
anaemia – familial’ depending on the knowledge source; 2) the semantic network which
describes the relationship between different concepts, and consists of ~134 semantic
types organized into 54 relationships; 3) the specialist lexicon which is intended to be a
general English dictionary that includes many biomedical terms. It is designed to describe
the meaning of natural language words/terms that have high variability; for example ‘treat’
which has 3 variants – ‘treats’, ‘treating’, and ‘treated’ depending on how it is used in a
sentence.
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Within the context of the OMOP and Sentinel projects, case definitions were
developed and validated for 10 and 25 selected safety outcomes, respectively [26, 27].
However these definitions may not generally apply or be of interest to children. Also, these
projects are USA based and mapped events to ICD9-CM codes only as this is the
predominants terminology used to code diseases in the USA. Mapping of events to
multiple coding systems has been demonstrated within other (mostly EU based) projects.
The EU-ADR project mapped 11 events [4]. The databases were General Practice (GP) or
record linkage (RL) systems, and utilized ICD9-CM, ICD10, ICPC and READ to code
events. [30, 31].The Safety Evaluation of Adverse Reaction in Diabetes (SAFEGUARD)
project extracted cases of heart failure, ischemic stroke, and hemorrhagic stroke from 8
European (and 1 North American) EHR database(s)[28, 29]. The databases included GP
records, administrative claims, or other RL systems and consisted of data recorded using
ICD9-CM, ICD10, READ, or ICPC codes, in addition to free text. Similar projects that
combined multiple EHR databases (and therefore required harmonization of event
extraction) are the ‘Pharmacoepidemiological Research on Outcomes of Therapeutics’
(PROTECT, http://www.imi-protect.eu/), the ‘non-steroidal anti-inflammatory drug related
gastrointestinal and cardiovascular risks’ (SOS, http://www.sos-nsaids-project.org/), the
‘arrhythmogenic risk of drugs’ (ARITMO, http://www.aritmo-project.org), and Post-
Licensure Rapid Immunization Safety Monitoring (PRISM) projects[32]. However, all the
previous projects aimed to extract cases within general population cohorts or drug
inceptions cohorts and did not include children specifically.
Figure 1: Basic organization of the UMLS (http://www.nlm.nih.gov/research/umls/user_education/presentations.html)
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The GRiP deliverable D2.05: ‘Report on terminology mapping and event identification
describes the harmonization process for the identification of pediatric medical events in
SRS and EHR databases. The medical events included so far are those defined in the
reference set that was created for T2.6: events that can occur following drug use (adverse
drug event [ADE] [1]) as well as vaccine use (adverse events following immunization
[AEFI]).
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5 Objectives
The main objective was to harmonize the process of extracting data regarding 16 events
from the drug reference set and 14 events from the vaccine reference set for methods
development and testing in safety signal detction. Specific objectives were:
1. The development of case definitions for the selected events.
2. Based on the case definitions, the extraction of codes in different coding systems
i.e. MedDRA, ICD9-CM, ICD10, READ and ICPC.
3. The development of case identification algorithms, applicable to SRS and EHR
databases.
For this report, we focus on points 1 and 2. In the remainder of this document, the process adopted to achieve these objectives is described as ‘mapping’.
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6 Methodology
6.1 Coding systems
There are several available terminologies that are utilized to code diagnoses/conditions in
SRS and EHR databases. From the GRiP survey of databases (D2.3) we know that the
most frequently used terminologies are: 1) Medical Dictionary for Regulatory Activities
(MedDRA); 2) International Statistical Classification of Diseases and related health
problems - 9th revision, clinical modification (ICD9-CM); 3) International Statistical
Classification of Diseases and related health problems - 10th revision (ICD10); 4) READ
coding system; and 5) International Classification of Primary Care (ICPC). MedDRA is
utilized in most SRS databases, unlike the others which are utilized in EHR databases.
These coding systems were selected because they are utilized in many EHR databases.
6.2 Harmonization process for event data extraction
6.2.1 Events for mapping
Sixteen potential ADEs and 14 potential AEFIs were selected for signal detection method
development based on criteria that are described in D2.07:
Drug reference set: Acute kidney injury (AKI), drug-induced liver Injury (DILI),
agranulocytosis, thrombocytopenia, aplastic anemia, anaphylaxis, bullous eruptions (fixed
drug eruption [FDE], erythema multiforme, Stevens-Johnson syndrome [SJS], and toxic
epidermal necrolysis [35]), QT prolongation, ventricular arrhythmia, sudden death, sudden
infant death syndrome (SIDS), psychosis, suicide, seizure, sepsis, and venous
thromboembolism.
Vaccine reference set: Anaphylaxis, thrombocytopenia, (febrile) seizures, disseminated
BCG-itis, hypotonic hyporesponsive episode (HHE), encephalitis, intussusception,
vaccine-associated paralytic poliomyelitis (VAPP), disseminated Varizella zoster infection
due to Oka vaccine strain (disseminated Oka VZV), arthritis, Guillain Barré Syndrome
(GBS), wheezing, insulin-dependent diabetes mellitus (IDDM), and Bell’s palsy.
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6.2.2 Definition of events
It was necessary to clearly define the selected events in order to avoid misclassification
when mapping these events to unique concept identifers and for code review. For the
events in the drug reference set, this was achieved by utilizing information from 3
resources: 1) UptoDate.com which is publicly accessible [36]; 2) definitions developed by
two scientific non-profit organizations:the Brighton Collaboration (BC) and the Council for
International Organizations of Medical Sciences (CIOMS) [37, 38]; 3) standard medical
textbooks such as ‘CURRENT Diagnosis & Treatment in Family Medicine’[39],which was
consulted for the definition of aplastic anemia. Similar resources were considered
including publications in the literature for the events from the vaccine reference set that
had not been defined by a Brighton Collaboration working group. Otherwise, the already
existing Brighton Collaboration case definitions were used (finalized or in draft, i.e. GBS,
anaphylaxis, encephalitis, intussusception, seizure, HHE, thrombocytopenia, Bell’s palsy)
UptoDate.com is an evidence-based knowledge system which is authored by
clinicians and is designed as a medical decision-making tool. All its content is written and
edited by a global community of over 5000 physicians who are all world-renowned experts
in their fields of specialization, they are supported by about 46 in-house physician editors.
The authors follow a thorough editorial process ensuring that the content is of the highest
quality and based on the latest evidence. Among the contents of this resource are
definitions of clinical events with appropriate references.
The Brighton Collaboration (BC) (https://brightoncollaboration.org/public/who-we-
are.html) is the world’s largest network of vaccine safety professionals. It is a scientifically
independent partnership, comprising of professional volunteers and organizational
partners around the globe. It is unique in its capacity to leverage highly specific expertise
and large data sources on the investigation of vaccine safety concerns. Among other
activities, BC links healthcare databases from different countries, and develops case
definitions for AEFIs, such as thrombocytopenia.
CIOMS (http://www.cioms.ch/) is an international, non-governmental, non-profit
organization established jointly by WHO and UNESCO in 1949. Through its membership,
CIOMS is representative of a substantial proportion of the biomedical scientific community.
In 2013, its membership included about 46 international, national and associate member
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organizations, representing many of the biomedical disciplines, national academies of
sciences and medical research councils. Among other activities, CIOMS develops clear
definitions of specific clinical events following drug use. An example is Drug-Induced Liver
Injury (DILI)[40].The case definitions for events in the drug reference set were developed
by OO, and reviewed by GWJ. OO is a junior researcher (with medical training) at the
Erasmus Medical Center (EMC), Rotterdam (Netherlands) while GWJ is a senior
researcher/pediatrician at the University of Mannitoba, Canada. The case definitions for
events from the vaccine reference set for which no Brighton Collaboration case definitions
exist were developed by YB and reviewed by JB.
6.2.3 Mapping of terminologies
The complete work-flow for mapping of terminologies across different databases is shown
in figure 2. The process is sequential.
Figure 2: Workflow for event code mapping
In order to establish a semantic baseline for event definition, we ensured that the
case definition of each event was projected to the 5 coding systems of interest i.e.
MedDRA, ICD9-CM, ICD10, READ, and ICPC. This was achieved via the Unified Medical
Language System (UMLS v 2013AA). Based on the case definitions created and/or the
definition
•Selection of events (D2.07)
•Definition of events (EMC/BCF)
UMLS concept identification
•Searching for events/symptoms/synonyms as concepts in UMLS
•Manual review of CUIs by independent experts (EMC/BCF)
Mapping
•Retrieval of codes in different terminologies (ICD-9, ICD-10, ICPC, READ, MEDDRA) by linking to CUIs by NIHCD
Benchmark
•Verification of codes by comparing with published event identification algorithms (EMC/BCF)
•Extending of searches through ICD-10-SNOMED route (NIHCD)
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specific event term, we selected appropriate CUI codes in the UMLS Metathesaurus
Browser (Release 2013AA, Search type: Word, Source: RCD (=Read), SNOMEDCT (=
SNOMED), WHO (WHOArt), MDR (MedDRA), ICPC (IPCI), ICD10 (=ICD10), ICD9CM
(=ICD9)). For drug-induced liver injury, some of its clinical signs were also applied as
search terms i.e. ‘necrosis’, ‘cirrhosis’, drug-induced’, ‘hepatocellular’, and ‘cholestatic’.
This was done to increase the number of relevant concepts that were retrieved. For the
events in the vaccine reference set, we selected terms describing the event, but also
describing signs and symptoms based on the case definitions. The CUIs for the events
from the vaccine reference set were already marked as specific or sensitive (low, high) at
this stage (needed for step 2 in figure 3)
Figure 3: Further steps for mapping, initial CUIs will be extended and divided in sensitive and specific definitions, which will allow us to look at the impact of different choices on the signal detection methods in task 2.7
Of the retrieved unique concepts with corresponding ‘concept unique identifiers’
(CUIs), those concepts that were deemed relevant to the event definition were selected,
whether they had implied drug-related/vaccine-related aetiology or not. Appendix 1 shows
the criteria that were applied to select the relevant concepts for the events. Two
researchers (OO and FK) independently selected relevant concepts for the events from
the drug reference set. Then both researchers together with a third (KV) discussed
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differences in selection until a consensus was reached. OO is a junior researcher (with
medical training) at the Erasmus Medical Center (EMC) Rotterdam (Netherlands) while FK
(a pediatrician) and KV (a medical doctor, epidemiologist) are both senior researchers at
EMC. With regards to the evets of the vaccine reference set, one researcher extracted and
selected relevant codes from the UMLS (YB), followed by another senior researcher who
reviewed the codes (JB).
Since the 5 different terminologies of interest (MedDRA, ICD9-CM, ICD10, READ
and ICPC) are part of the UMLS, the selected concepts were then mapped to the codes
for these systems; this was done by the NICHD in collaboration with the National Cancer
Institute’s Enterprise Vocabulary Services and the Food and Drug Administration.
Verification/benchmarking
In order to extract more ICD10 codes and to verify completeness of ICD-10 codes, CUI
codes were mapped (via SNOMED and additional routes) to the ICD10 coding system by
NICHD. An initial review of these additional codes was done.
Two researchers (YB & OO) benchmarked the retrieved codes against event identification
codes as described by PRISM, OMOP and Sentinel and Standardized Medical Queries
(SMQ) to check for completeness.
Codes for AEFI were verified against PRISM, OMOP and Mini Sentinel codes for the
following AEFI that could be compared:
PRISM: Type 1 diabetes, febrile seizures, seizures unspecified (febrile seizures and
seizures unspecified fall under our outcome seizure), Guillain-Barré syndrome, Bell's
palsy, Transverse myelitis, acute disseminated encephalomyelitis (Transverse myelitis and
acute disseminated encephalomyelitis fall under our outcome encephalitis), bronchospasm
(falls under our outcome wheezing), intussusception, rheumatoid arthritis, juvenile
rheumatoid arthritis ( rheumatoid arthritis and juvenile rheumatoid arthritis fall under our
outcome arthritis), anaphalyctic shock or acute systemic allergic reaction (fall under our
outcome anaphylaxis)
Mini-Sentinel: seizure/convulsion/epilepsy, anaphylaxis, arthritis
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OMOP: angioedema (as part of anaphylaxis), anaphylaxis, thrombocytopenia, seizure
The following events were verified against available SMQs: seizure, anaphylaxis,
encephalitis, acute renal failure, psychosis
7 Results
Step 1: Appendix 2 describes the clinical definitions for the drug & vaccine reference set
that were selected.
Step 2: A large number of concepts (CUIs) were selected based on the 30 case definitions
developed for the events of interest. The CUIs are included in the excel sheet that
accompanies this deliverable Step 3: ICD-9, 10, MedDRA, READ and ICPC codes were
retrieved for each of the CUIs (see attached excel document, EVS mappings)
Step 4: NICHD verified completeness of ICD-10 codes by taking a route through the
SNOMED and additional routes (see attached excel document, additional ICD10
mappings, and list below for the various mapping strategies)
List: Multiple mapping strategies for identification of additional ICD10 mappings
Group 1: An ICD10 code exists within the CUI.
Group 2: There is an ICD10 code that matches to the SNOMED code within the CUI. (Similar to Group 1).
Group 3: The CUI has a SNOMED code that IHTSDO has mapped to ICD10.
Group 4: The CUI has a SNOMED code; follow the IHTSDO mappings from
ICD10CM code and check for an ICD10 code in that CUI.
Group 5: The CUI has a SNOMED code; follow the IHTSDO mappings from
ICD10CM code; walk up one level in ICD10CM hierarchy and check for an ICD10 code in that CUI.
Group 6: The CUI has a SNOMED code; follow the IHTSDO mappings from
ICD10CM code; walk up two levels in ICD10CM hierarchy and check for an ICD10 code in that CUI.
Group 7: The CUI has a SNOMED code; follow the IHTSDO mappings from
ICD10CM code; walk up three levels in ICD10CM hierarchy and check for an ICD10 code in that CUI.
Group 8: The CUI has an ICD10CM code, which is the same as an ICD10 code in another concept.
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Group 9: Search for an ICD9CM code in the CUI; walk up one level to the ICD9CM code's parent; check for an ICD10 code in that CUI.
Group 10: Search for ICD10CM code in the CUI; walk up one level to the ICD10CM code's parent; check for an ICD10 code in that CUI.
mapping. Walk up to the parent of the ICD10CM code; check for an ICD10 code in that CUI.
ICD10CM mapping. Walk up to the grandparent of the ICD10CM code; check for an ICD10 code in that CUI.
An initial review of these additional codes was done by classifying the codes according to their
relevance (see attached excel document, additional ICD10 mappings, column F and KEY of
classification at the end of that sheet). For the AEFI not many additional or relevant codes
could be gained through this approach.
The verification against PRISM, OMOP, and Mini-Sentinel showed that most codes were
retrieved and provided re-assurance in completeness. Furthermore, through our approach
we identified also additional codes.
Out of 21 preferred (narrow) terms comprising the standardized MedDRA query
(SMQ) for seizure, 13 were extracted within the current project. Moreover, all 13 terms
(including ‘Atonic seizures[10003628’], ‘Clonic convulsion[10053398]’,and ‘Convulsion in
childhood [10052391]’) were considered relevant to the case definition of seizure.
Similarly, 6 of the 10 preferred (narrow) terms (components of the SMQ) for anaphylaxis
were retrieved within the current project, out of which 5 were considered relevant.
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Example
Table 1 shows an example for the definition of disseminated BCG-itis; Table 2 shows the
extracted CUIs and table 3 the mapped codes
Table 1: case definition for disseminated BCG-itis
Disseminated BCG-itis
It is a recognized but rare consequence of BCG vaccination traditionally
seen in individuals with severe cellular immune deficiencies.
The case definition was created with information from the resources listed
under references.
Level 1
1. BCG cultured and identified by biochemical methods at least.
2. Dissemination evidenced by either A or B.
A. A positive blood or bone marrow culture.
B. Evidence of infection at two or more anatomic sites beyond the
region of vaccination. Evidence of infection includes a positive culture
or histopathologic demonstration of acid-fast bacilli. Examples of
acceptable sites include the following: lymph node nodes beyond the
ipsilateral axillary lymph nodes; one or more cutaneous abscesses
beyond the region of vaccination; osteomyelitis at one or more sites;
brain or CSF; lung biopsy specimen, sputum, pleura and/or pleural
fluid, or gastric aspirate; liver; spleen; intestine and/or stool; and kidney
and/or urine. Multiple isolates from the same organ system are
counted only once. For example, infection of multiple distant lymph
nodes constitutes one site. Isolation of BCG from both sputum and
pleural fluid constitutes one site.
3. A systemic syndrome compatible with mycobacterial disease. Typical
cases include fever, weight loss, anemia, and death.
Level 2
Clinical signs of infection at two or more anatomic sites (see above) beyond the region of vaccination OR
systemic syndrome compatible with mycobacterial disease following BCG vaccination
Remark: For case identification in databases (algorithm): Further
classification into
- reported disseminated BCGitis with insufficient evidence to meet the case
definition +/- respective treatment (potentially referrals to specialists?).
Adapted from:
Talbot EA, et al.
Disseminated
bacille Calmette-
Guérin disease after
vaccination: case
report and review.
Clin Infect Dis.
1997;24(6):1139-
46.
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Table 2: Selected UMLS concepts (CUIs) for disseminated BCG-itis
C0860040 BCG infection
C2721713 Disseminated BCG
C0857596 BCG related lymphadenitis
C0393461 Post BCG vaccination encephalitis
C1274385 BCG-induced scrofuloderma
C0851328 BCG vaccine causing adverse effects in therapeutic use
C0413539 Adverse reaction to BCG vaccine
C0473539 Cutaneous complication of BCG immunization
C0261932 Adverse effects in the therapeutic use of BCG vaccine
C1274386 BCG-induced tuberculide
C0406149 BCG granuloma
C0406150 BCG ulcer
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Table 3: Mapping of selected UMLS concepts (CUIs) to 5 coding systems for
disseminated BCG-itis
CUI UMLS Preferred Name
Meddra ICD9CM ICD10 RCD ICPC
C0860040
BCG infection BCG infection - (LT/10004188)
C2721713
Disseminated BCG Disseminated BCG - (LT/10069636)
C0857596
BCG related lymphadenitis
BCG related lymphadenitis - (LT/10004189)
C0393461
Post BCG vaccination encephalitis
Post BCG vaccination encephalitis - (PT/F0340)|Encephalitis-post BCG vaccine - (AB/F0340)
C1274385
BCG-induced scrofuloderma
C0851328
BCG vaccine causing adverse effects in therapeutic use
Bcg vaccine causing adverse effects in therapeutic use - (PT/E948.0)|Adv eff bcg vaccine - (AB/E948.0)
BCG vaccine - (PS/Y58.0)
[X]BCG vacc caus advers eff - (AB/U60J0)|[X]BCG vaccine causing adverse effects in therapeutic use - (PT/U60J0)
C0413539
Adverse reaction to BCG vaccine
Adverse reaction to BCG vaccine - (OP/TJJ0.)|AR - BCG vaccine - (OA/TJJ0.)
C0473539
Cutaneous complication of BCG immunization
Cutaneous complication of BCG immunisation - (PT/X502H)|Complic of BCG immunisation - (AB/X502H)
C0261932
Adverse effects in the therapeutic use of BCG vaccine
Adverse effects in the therapeutic use of BCG vaccine - (PX/Y58.0)
C1274386
BCG-induced tuberculide
C0406149
BCG granuloma BCG granuloma - (PT/X502I)
C0406150
BCG ulcer BCG ulcer - (PT/X502J)
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8 Discussion/Limitations
8.1 Discussion
The aim of this task was to harmonize future identification of a selection of 30 events of
interest in SRS and EHR databases. Although this process has been conducted for
several drug safety studies in the EU e.g. EU-ADR, SOS, ARITMO, SAFEGUARD, none
of these projects focused on paediatrics. In order to accomplish the mapping of events to
codes for different commonly used coding systems, we followed a systematic approach
based on the process that was developed in EU-ADR. First, we developed case
definitions for our events of interest or used existing ones. Based on these definitions, we
selected appropriate UMLS concepts which were then mapped to the 5 coding systems –
MedDRA, ICD9-CM, ICD10, READ, ICPC – that are often utilized in databases.
A clear case definition is required for extracting valid cases of an event from EHR
[42]. Relevant disease, diagnostic procedure, and laboratory test/result codes can be
retrieved, which are then utilized (possibly with free text) to build appropriate case
identification algorithms [1]. We developed (or selected available) definitions of our events
of interest, even for those events that are usually difficult to diagnose because they do not
have specific distinguishing features, such as psychosis. Event definitions were tailored to
pediatric manifestations, in order to account for age and/or organ maturation related
differences in children. For example, a serum creatinine level > 0.4 mg/dL (35 micromol/L)
may suggest acute kidney injury in an infant, unlike a value > 1.0 mg/dL (88 micromol/L)
for adolescents[43].
We utilized standard resources, assuming that this would improve the acceptability of
the definitions. Uptodate.com has been shown to enhance the healthcare process by
improving patient outcomes[44]. This is possibly due to a faster diagnosis of diseases
(and earlier commencement of appropriate treatment) arising from easy access to clear,
current definitions. In Canada, application of the Brighton Collaboration case definition for
generalized seizure improved reporting of such cases that occurred following vaccine
administration [45].
In mapping the case definitions to MedDRA, ICD9-CM, ICD10, READ and ICPC via
the Unified Medical Language System(UMLS), 2 appropriately qualified researchers
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independently conducted manual review of all the concepts retrieved upon querying the
UMLS, to determine their relevance for the case definitions. Differences were discussed
with a third (senior) researcher. For the events from the vaccine reference sets, concepts
retrieved based on the application of clinical symptoms and signs as search terms were
further classified based on their specificity/sensitivity for the event. Although this was not
objectively assessed, we assume that this manual review enhanced the quality of the
mapping process by ensuring that only relevant concepts were subsequently mapped to
the various coding systems, thus yielding valid codes. The UMLS is well suited for this,
given that it comprises of >100 source vocabularies (including the aforementioned ones)
in multiple languages, and ~1 million unique concepts with ~5 million concept names. It
has been utilized in similar projects, with satisfactory results [4].
For drug-induced liver injury (DILI), we applied additional terms/clinical signs (i.e.
‘necrosis’, ‘cirrhosis’, drug-induced’, ‘hepatocellular’, and ‘cholestatic’) as search terms in
UMLS. This was done to increase the possibility of retrieving more relevant disease
codes. Otherwise, applying only ‘drug-induced liver injury’ (which is too specific) would
have meant that we missed relevant concepts like ‘C0333501 [acute necrosis]’ which was
rather retrieved by applying ‘necrosis’. On the other hand, applying only ‘liver injury’
yielded several irrelevant UMLS concepts such as ‘C0160399 (Injury of liver with open
wound into abdominal cavity) which better describes liver injury following physical trauma
rather than following drug use.
8.2 Limitations
We cannot exclude the possibility that we missed UMLS concepts for some of the
events as we may not have applied all relevant search terms. Hence, the final mapping will
be presented to database holders who are familiar with the respective coding systems for
their feedback on completeness of the codes for each event. Furthermore, there may be
UMLS concept codes included at this stage which will be omitted after further review of the
table and upon compiling the case identification algorithms.
Despite our efforts to ensure that only relevant disease codes were extracted, some
irrelevant ones were also retrieved. For example, ‘cardiac arrhythmia, unspecified (I49.9)’
was extracted as a concept corresponding to the event: ‘ventricular arrhytthmia’ even
though cardiac arrhythmia is not specific and includes ‘atrial arrhythmia’. This might have
been due to the complementary approach adopted to yield more ICD10 codes. This
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approach may also account for the extraction of irrelevant codes for ‘suicide’ i.e. ‘Neurotic
disorder, unspecified (F48.9)’, or ‘Mental disorder, not otherwise specified (F99)’.
Nevertheless, we have enough relevant codes for both events, upon which to build valid
case identification algorithms.
There were many UMLS concepts for which READ yielded several codes unlike the
other coding systems, although this is not surprising. The high granularity of the READ
code is well recognized [46]. Still, many UMLS concepts could not be mapped to any
coding system including READ, for example ‘Anemia: [aplastic and other] or [aplastic] or
[hypoblastic]’(C1534248). This concept may have been too specific. However it may have
been captured by one of the other concepts retrieved for thrombocytopenia, such as
‘Aplastic Anemia’ (C0002874); this concept was mapped to MeDDRA, ICD9-CM, ICD10
and ICPC.
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9 Conclusion/Next steps
We have described the mapping of selected events to five coding systems. In the
next steps, we will build identification algorithms to extract relevant cases from various
spontaneous reporting and electronic health record databases.
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23. Kim, T.Y., N. Hardiker, and A. Coenen, Inter-terminology mapping of nursing problems. Journal of Biomedical Informatics, 2014((Kim T.Y., [email protected]) Betty Irene Moore School Nursing, University of California Davis, 4610 X Street, Sacramento, CA 95817, USA).
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11 Appendix 1: Selection criteria for concepts related to the
events of interest
11.1 Inclusion criteria
(1) Immune-mediated events.
(2) Events where the clinical course is described regardless of the exact description i.e.
acute, chronic etc. However, there are some exceptions such as acute kidney
injury; for this event, chronic kidney disease will not be considered.
(3) Cases where severity/scaling of the event is implied i.e. 'high risk'.
(4) Events for which the cause is ‘unknown’ i.e. primary, idiopathic, etc.
(5) For seizure, all cases of epilepsy.
11.2 Exclusion criteria
(1) Events that occur following use of drugs/vaccines that are not in the reference set
i.e. fixed drug eruption (FDE) due to phenolphthalein.
(2) Events that occur following blood transfusion.
(3) Events that are clearly not related to drugs/vaccines i.e. anaphylaxis due to bee
sting.
(4) All events that are related to pregnancy.
(5) Events that are congenital i.e. congenital dysmegakaryopoietic thrombocytopenia.
(6) Events that are a result of non-pharmacological interventions i.e. surgery,
radiotherapy.
(7) Events that are a result of non-drug related primary health, e.g., psychosis following
abortion
(8) Events that occur following non-drug induced pathophysiologic specific mechanism,
i.e. thrombocytopenia due to sequestration.
(9) All 'previous history’ or 'family history' of the event.
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12 Appendix 2: Clinical definitions for events of interest in the drug and vaccine reference
set
12.1 acute kidney injury (AKI)
S/N Event Medical (case) definition References
1 acute kidney injury (AKI)
“acute kidney injury (AKI) is defined as a decrease in
glomerular filtration rate (GFR), which traditionally is manifested by an elevated or a rise in serum creatinine. However, serum creatinine is often a delayed and imprecise test as it reflects GFR in individuals at steady state with stable kidney function, and does not accurately estimate the GFR in a patient whose renal function is changing”. “The term AKI has largely replaced acute renal failure (ARF) as it more clearly defines renal dysfunction as a continuum rather than a discrete finding of failed kidney function” “pediatric AKI presents as a wide range of clinical manifestations from a minimal elevation in serum creatinine to anuric renal failure, arises from multiple causes, and occurs in a variety of clinical settings”. Below are the normal range of values of serum creatinine for different pediatric age groups:
Newborn – 0.3 to 1.0 mg/dL (27 to 88
micromol/L)
Infant – 0.2 to 0.4 mg/dL (18 to 35
micromol/L)
Child – 0.3 to 0.7 mg/dL (27 to 62
micromol/L)
Adolescent – 0.5 to 1.0 mg/dL (44 to 88
micromol/L)
(1) Nephrology TA. The American Society of Nephrology Renal Research Report. J Am Soc Nephrol. 2005;16:1886–1903
(2) Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 2006; 17: 1503–1520
(3) Devarajan P. Emerging urinary biomarkers in the diagnosis of acute kidney injury. Expert Opin Med Diagn. 2008;2:387–398
(4) Zappitelli M. Epidemiology and diagnosis of acute kidney injury. Semin Nephrol 28: 436–446, 2008
(5) Andreoli SP: Acute kidney injury in children. Pediatr Nephrol 2009; 24:253–263 (6) Askenazi D. Evaluation and Management of Critically Ill Children with Acute Kidney Injury.
Curr Opin Pediatr. 2011 April ; 23(2): 201–207. doi:10.1097/MOP.0b013e328342ff37. (7) Devarajan P (2011) Biomarkers for the early detection of acute kidney injury. Curr Opin
Pediatr 23: 194–200. 10.1097/MOP.0b013e328343f4dd [doi] (8) The Harriet Lane Handbook, 19th ed, Tschudy KM, Arcara KM (Eds), Mosby, St. Louis 2012.
p.642.
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12.2 Agranulocytosis
S/N Event Medical (case) definition References
2 Agranulocytosis agranulocytosis means the absence of
granulocytes (i.e. Absolute Neutrophil count [34] of
zero).
However, “agranulocytosis or acute neutropenia
currently refers to a profound decrease or an
absolute lack of circulating granulocytes, classically
resulting in a neutrophil count of <0.5 × 10^9/l”
In the majority of patients, the neutrophil count is <
0.1 × 10^9/l
(1) Andres E., Zimmer J., Mecili M., Weitten T., Alt M., Maloisel F. Clinical presentation and
management of drug-induced agranulocytosis. Expert Rev. Hematol. 2011; 4 (2): 143- 151
(2) Frank Andersohn, Christine Konzen, Edeltraut Garbe; Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs. Annals of Internal Medicine. 2007 May;146(9):657-665
12.3 aplastic anemia
S/N Event Medical (case) definition References
4 aplastic anemia
Aplastic anemia is characterized by the
suppression of all bone marrow lines – erythroid,
granulocytic and megakaryocytic ultimately leading
to pancytopenia
Characteristics
(1) Pancytopenia
(2) Hypocellular bone marrow
(3) Normal hematopoetic cells
(1) Primack BA, Mahaniah KJ. Chapter 31. Anemia. In: South-Paul JE, Matheny SC, Lewis EL, eds. CURRENT Diagnosis & Treatment in Family Medicine. 3rd ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=8153552. Accessed October 2, 2012
(2) Neal S. Young; Acquired Aplastic Anemia. Annals of Internal Medicine. 2002 Apr;136(7):534-546
(3) Guinan EC. Diagnosis and management of aplastic anemia. Hematology Am Soc Hematol Educ Program. 2011;2011:76–81
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12.4 bullous eruptions
S/N Event Medical (case) definition References
5 bullous eruptions
fixed drug eruption
These are reactions characterized by:
(1) One or more sharply demarcated, erythematous lesions, sometimes leading to a blister.
(2) Hyperpigmentation which often results after resolution of the acute inflammation.
(3) With rechallenge, the lesion recurs in the same (i.e., fixed) location. (4) Lesions often involve the lips, hands, legs, face, genitalia, and oral mucosa
and cause a burning sensation. (5) Most patients have multiple lesions.
(1) Shinkai K, Roujeau J, Stern RS, Wintroub BU. Chapter 55.
Cutaneous Drug Reactions. In: Longo DL, Fauci AS, Kasper
DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's
Principles of Internal Medicine. 18th ed. New York: McGraw-
Hill; 2012.
http://www.accessmedicine.com/content.aspx?aID=9098524
. Accessed October 1, 2012
(2) Stern RS, Shear NH. Cutaneous reactions to drugs and
biological modifiers. In: Cutaneous Medicine and Surgery,
Arndt KA, LeBoit PE, Robinson JK, Wintroub BU (Eds), WB
Saunders, Philadelphia 1996. Vol 1, p.412.
(3) Yawalkar N. Drug-induced exanthems. Toxicology.
2005;209:131–134. doi: 10.1016/j.tox.2004.12.023
erythema multiforme
Characteristics include: (1) Acute self-limited, usually mild and often relapsing muco-cutaneous
syndrome. (2) Usually benign but with frequent recurrences (3) The skin lesions are usually target-shaped plaques with or without central
blisters, predominant on the face and extremities. sub-types
(1) Erythema multiforme minor: Skin lesions without involvement of mucous
membranes
(2) Erythema multiforme major: Skin lesions with involvement of mucous
membranes
(3) Mucosal erythema multiforme (Fuchs syndrome, ectodermosis
pluriorificialis): Mucous membrane lesions without cutaneous involvement
(1) Roujeau J. Chapter 39. Erythema Multiforme. In: Goldsmith
LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Dallas NA,
eds. Fitzpatrick's Dermatology in General Medicine. 8th ed.
New York: McGraw-Hill; 2012.
http://www.accessmedicine.com/content.aspx?aID=5603294
4. Accessed October 2, 2012.
epidermal necrolysis (Stevens-Johnson’s Syndrome and toxic epidermal
necrolysis)
Characteristics include:
(1) They are “rare and life-threatening, mainly drug induced”.
(2) There is “widespread apoptosis of keratinocytes provoked by the activation
of a cell-mediated cytotoxic reaction and amplified by cytokines, mainly
granulysin”
(3) “Confluent purpuric and erythematous macules evolving to flaccid blisters
and epidermal detachment predominating on the trunk and upper limbs and
associated with mucous membrane involvement”.
(1) Valeyrie-Allanore L, Roujeau J. Chapter 40. Epidermal
Necrolysis (Stevens–Johnson Syndrome and Toxic
Epidermal Necrolysis). In: Goldsmith LA, Katz SI,
Gilchrest BA, Paller AS, Leffell DJ, Dallas NA, eds.
Fitzpatrick's Dermatology in General Medicine. 8th ed.
New York: McGraw-Hill; 2012.
http://www.accessmedicine.com/content.aspx?aID=56033
128. Accessed October 2, 2012.
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S/N Event Medical (case) definition References
(4) Pathologic analysis shows full-thickness necrosis of epidermis associated
with mild mononuclear cell infiltrate
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12.5 drug-induced liver injury (DILI)
S/N
Event Medical (case) definition References
6 drug-induced liver injury (DILI)
In defining DILI, an important requirement will be the availability or otherwise of histological data. The
following manifestations will be considered:
- Hepatic necrosis
- Liver cirrhosis
Liver injury (any case of DILI in which there is no histological data available)
(A) On the basis of availability of histological data:
(1) hepatic necrosis: characterized by
- Death of hepatic parenchyma: single cell (necrobiosis), or multicell in piecemeal, focal,
periacinar, midzonal, periportal or paracentral locations.
- Massive necrosis: refers to events in individual acini in which all hepatocytes are dead.
(2) liver cirrhosis: Features include
- Necrosis of liver cells, slowly progressive over a long period and ultimately causing chronic
liver failure and death
- Fibrosis, involving both central veins and portal areas
- Regenerative nodules, the result of hyperplasia of surviving liver cells
- Distortion of normal hepatic lobular architecture
- Diffuse involvement of the whole liver
N.B: A regenerative nodule is an abnormal mass of liver cells without a normal cord pattern or central
venule and surrounded completely by fibrosis
(B) In the absence of histological data, only liver tests (NOT liver function tests) can be used in
diagnosis as follows:
(1) liver injury:
- Increase of over 2N (2 times N; where N is the upper limit of normal range) in Alanine
Aminotransferase (ALT) or Conjugated Bilirubin (CB)
OR
- A combined increase in Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP) and
Total Bilirubin (TB), provided one of them is above 2N
Various forms of drug-induced “liver injury”
(1) Bénichou C. 1990 Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 11:272–276
(2) UpToDate. Drug-induced liver injury. 2014 [cited 2014 19th June]; Available from: http://www.uptodate.com/contents/drug-induced-liver-injury?source=search_result&search=drugs+and+the+liver+patterns+of+druinduced+liver+injury&selectedTitle=6~150.
(3) Chandrasoma P., Taylor C.R. (1998). Chapter 43. The Liver: II. Toxic & Metabolic Diseases; Neoplasms. In P. Chandrasoma, C.R. Taylor (Eds), Concise Pathology, 3e. Retrieved September 18, 2012 from http://www.accessmedicine.com/content.aspx?aID=189816.
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S/N
Event Medical (case) definition References
- hepatocellular: increase of over 2N in ALT alone, or R≥5 [where R (ratio) is the serum activity of
ALT/serum activity of AP. Each activity is measured as a multiple of N. Both should have been
measured together at the time of recognition of liver injury].
- cholestatic: Liver injury is designated cholestatic when there is increase of over 2N in AP alone,
or R≤2
- mixed: occurs when there is a combination of the following: increase in ALT (over 2N) and AP as
well as 2<R<5. R ismost useful in patients with jaundice and may vary during the course of liver
injury.
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12.6 Psychosis
S/N Event Medical (case) definition References
7 psychosis “psychosis is a disturbance in the perception of reality,
evidenced by hallucinations, delusions, or thought
disorganization. Psychotic states are periods of high risk for
agitation, aggression, impulsivity, and other forms of behavioral
dysfunction”
“hallucinations are false sensory perceptions occurring in any
of the five sensory modalities. Auditory hallucinations are the
most common, followed by visual, tactile, olfactory, and
gustatory”
“delusions are false beliefs that are firmly held despite
obvious evidence to the contrary, and not typical of the
patient's culture, faith, or family. Persecutory, grandiose,
religious, somatic, and other delusions are all common and cut
across diagnostic boundaries”
“thought disorganization - disruption of the logical process of
thought may be represented by loose associations,
nonsensical speech, or bizarre behavior. These symptoms are
typically accompanied by a high level of functional impairment
and high risk for agitated and aggressive behavior”
(1) Shelton RC. Chapter 17. Other Psychotic Disorders. In: Ebert MH, Loosen PT,
Nurcombe B, Leckman JF, eds. CURRENT Diagnosis & Treatment: Psychiatry. 2nd
ed. New York: McGraw-Hill; 2008.
http://www.accessmedicine.com/content.aspx?aID=3284695. Accessed October 2,
2012.
(2) UpToDate. Overview of psychosis. 2013 [cited 2014 19th June]; Available from:
http://www.uptodate.com/contents/overview-of-
psychosis?source=search_result&search=overview+of+psychosis&selectedTitle=1
~150.
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12.7 QT prolongation
S/N
Event Medical (case) definition References
8 QT prolongation.
“Torsades de pointes (TdP)” will be included in this definition
QT prolongation
It refers to prolongation of heart rate-corrected QT (QTc) interval from a 12-
lead electrocardiogram (ECG).
For children aged 1 – 15 years, prolonged QTc is defined as:
> 460 milliseconds
Bazett formula (QTc=QT/RR0.5
) is most often used for heart rate correction
Long QT syndrome (LQTS)
This is characterized by prolonged QT with clinical manifestations/sequelae
like palpitations, syncope, seizures, and sudden cardiac death (SCD).
Torsades de pointes (TdP)
Torsades de pointes (TdP) is a form of polymorphic ventricular tachycardia
(VT) that occurs in the setting of acquired or congenital QT interval
prolongation. It is usually found on ECG.
Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per
min with frequent variations of the QRS axis, morphology, or both. In the
specific case of TdP, these variations take the form of a progressive,
sinusoidal, cyclic alteration of the QRS axis. The peaks of the QRS
complexes appear to "twist" around the isoelectric line of the
recording; hence the name torsades de pointes or "twisting of the
points."
(1) ICH Topic E 14 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non Antiarrhythmic Drugs; CPMP/986/96. The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. London: Committee for proprietary medicinal products. 1997
(2) UpToDate. Definition of normal, borderline, and prolonged corrected QT interval (QTc) in seconds according to age and gender. [cited 2012 18th October]; Available from: http://www.uptodate.com/contents/image?imageKey=CARD/78934&topicKey=CARD%2F1053&source=preview&rank=undefined.
(3) El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol
2003;18(1):6–13
(4) Passman R, Kadish A. Polymorphic ventricular tachycardia, long
Q-T syndrome, and torsades de pointes. Med Clin North Am.
2001;85: 321–341.
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12.8 Seizure
S/N Event Medical (case) definition References
9 seizure Only Generalized convulsive seizure will be considered
This is defined in 3 levels with respect to diagnostic certainty. All levels are
acceptable.
Level 1 of diagnostic certainty
(1) witnessed sudden loss of consciousness AND
(2) generalized, tonic, clonic, tonic–clonic, or or atonic motor
manifestations.
Level 2 of diagnostic certainty
history of unconsciousness AND
(1) generalized, tonic, clonic, tonic–clonic, or atonic motor manifestations.
Level 3 of diagnostic certainty
(1) history of unconsciousness AND
(2) other generalized motor manifestations
(1) Bonhoeffer J, Menkes J, Gold MS, de Souza-Brito G, Fisher M, et
al. (2004) Generalized convulsive seizure as an adverse event
following immunization: case definition and guidelines for data
collection, analysis, and presentation. Vaccine 22 (5–6): 557–562
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12.9 Sepsis
S/N Event Medical (case) definition References
10 Sepsis “Sepsis refers to Systemic Inflammatory Response Syndrome (SIRS) in the
presence of or as a result of suspected or proven infection”
“Systemic Inflammatory Response Syndrome (SIRS) is a widespread
inflammatory response that may or may not be associated with infection. The
presence of two or more of the following criteria (one of which must be
abnormal temperature or leukocyte count) defines SIRS”:
Core temperature (measured by rectal, bladder, oral, or central probe)
of >38.5ºC or <36ºC
Tachycardia, defined as a mean heart rate >2 standard deviations
above normal for age, or for children <1 year of age, bradycardia
defined as a mean heart rate <10th percentile for age
Mean respiratory rate >2 standard deviations above normal for age
Leukocyte count elevated or depressed for age, or >10 percent
immature neutrophils
(1) Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005:2–8
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12.10 Sudden death
S/N Event Medical (case) definition References
11 sudden death
Two events will be considered here:
(1) Sudden death
(2) Sudden cardiac death
Sudden death
Two definitions will be considered for sudden death:
(1) Unwitnessed death occurring within 24hrs of being seen alive and
functioning normally.
(2) Natural, unexpected death within 1 hour of the onset of symptoms. Four
temporal elements have to be considered in the use of this definition:
prodromes, onset of the terminal event, cardiac arrest, and biological
death. The 1-hour definition refers to the period between onset of the
terminal event, that is, acute changes in cardiovascular status, and
cardiac arrest. The biological legal death can occur days or weeks after
the cardiac arrest, as patients can survive with irreversible brain damage
and life support
Sudden cardiac death (SCD)
Sudden cardiac death (SCD) is said to have occurred when there is sudden
cessation of cardiac activity so that the victim becomes unresponsive, with no normal breathing and no signs of circulation, thereby leading to death (if corrective measures are not taken rapidly)
Cardiac arrest should be used to signify an event as described above, that is reversed, usually by CPR and/or defibrillation or cardioversion, or cardiac pacing. Sudden cardiac death should not be used to describe events that are not fatal."
(1) C. van der Werf, I. van Langen, A.A. Wilde. Sudden death in the young: what do we know about it and how to prevent? Circ Arrhythm Electrophysiol, 3 (2010), pp. 96–104
(2) UpToDate. Overview of sudden cardiac arrest and sudden cardiac death. 2013 [cited 2014 19th June]; Available from: http://www.uptodate.com/contents/overview-of-sudden-cardiac-arrest-and-sudden-cardiac-death?source=search_result&search=overview+of+sudden+cardiac+arrest+and+sudden+cardiac+death&selectedTitle=1~150.
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12.11 Sudden infant death
S/N Event Medical (case) definition
References
12 sudden infant death syndrome (SIDS)
“sudden infant death syndrome (SIDS) is defined as the sudden death of an
infant younger than one year of age, which remains unexplained after a
thorough case investigation, including performance of a complete autopsy,
examination of the death scene, and review of the clinical history”.
“This definition emphasizes the necessity of autopsy, death scene investigation,
and review of the clinical history when making the diagnosis of SIDS, to exclude
other explanations for the sudden unexpected infant death that can mimic
SIDS”.
(1) CDC(1996) Sudden infant death syndrome—United States, 1983–94. MMWR Morb Mortal Wkly Rep 45:859–863
(2) Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol.1991;11 :677– 684
12.12 Suicide
S/N Event Medical (case) definition References
13 suicide completed suicide
Death caused by self-directed injurious behavior with any intent to die as a result
of the behavior.
suicide attempt
A non-fatal self-directed potentially injurious behavior with any intent to die as a
result of the behavior. A suicide attempt may or may not result in injury.
(1) Crosby AE, Ortega L, Melanson C. Self-directed Violence Surveillance: Uniform Definitions and Recommended Data Elements, Version 1.0. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2011
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12.13 Thrombocytopenia
S/N Event Medical (case) definition References
14 Thrombocytopenia Thrombocytopenia can be defined as follows:
(1) Level 1 of diagnostic certainty (confirmed TP):
Platelet count less than 150×109 L−1
AND
confirmed by blood smear examination OR the presence of
clinical signs and symptoms of spontaneous bleeding.
(2) Level 2 of diagnostic certainty (unconfirmed TP): Platelet
count less than 150×109 L−1
Drug-induced thrombocytopenia (DITP) should be suspected in a
patient who presents with new onset of thrombocytopenia without an
obvious cause other than drug ingestion. A patient with recurrent
episodes of acute thrombocytopenia should be suspected of having a
drug-induced etiology. A detailed history, including all of the
medications being taken by the patient, is essential. This should
include all prescribed drugs, over-the-counter medications, herbal
preparations, folk remedies, quinine-containing beverages, and recent
vaccinations.
(1) Wise RP, Bonhoeffer J, Beeler J, et al. Thrombocytopenia: Case
definition and guidelines for collection, analysis, and presentation
of immunization safety data. Vaccine 2007; 25: 5717–5724
(2) Royer, D. J., George, J. N. and Terrell, D. R. (2010),
Thrombocytopenia as an adverse effect of complementary and
alternative medicines, herbal remedies, nutritional supplements,
foods, and beverages. European Journal of Haematology, 84: 421–
429
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12.14 Venous thromboembolism
S/N
Event Medical (case) definition References
15 venous thromboembolism
Two manifestations of thromboembolism will be considered:
(1) Deep venous thrombosis (DVT)
(2) Pulmonary thromboembolism (PE)
deep venous thrombosis (DVT)
This is characterized by:
Leg pain
Inguinal or abdominal pain
Swelling, and reddish or purple discoloration of the legs
Palpable cord (reflecting a thrombosed vein),
Ipsilateral edema
Warmth, and/or superficial venous dilation
“Positive” result on compression ultrasonography
“Positive” result on impedance plethysmography
“Positive” result on contrast venography (reference test).
pulmonary thromboembolism (PE)
This is characterized by:
Pleuritic chest pain
Tachypnea
Cough
Tachycardia
Acute dyspnea
Sudden collapse
Leukocytosis
Increased erythrocyte sedimentation rate (ESR)
Elevated serum LDH or AST (SGOT) with a normal serum bilirubin
Arterial blood gases: hypoxemia, hypocapnia, and respiratory
alkalosis
(1) UpToDate. Pathogenesis and clinical manifestations of venous
thrombosis and thromboembolism in infants and children. 2013
[cited 2014 19th June]; Available from:
http://www.uptodate.com/contents/pathogenesis-and-clinical-
manifestations-of-venous-thrombosis-and-thromboembolism-in-
infants-and-
children?source=search_result&search=pathogenesis+and+clinical
+manifestation+of+thrombosis+and+thromboembolism+in+children
&selectedTitle=1~150.
(2) Lensing AWA, Prandoni P, Prins HR, Büller HR. Deep-vein
thrombosis. Lancet. 1999;353:479-485.
(3) Hirsh J, Hull RD, Raskob GE. Clinical features and diagnosis of
venous thrombosis. J Am Coll Cardiol 1986;8:114B-27B
(4) Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical
assessment of deep-vein thrombosis . Lancet . 1995;;345:1326-
1330.
(5) Kahn SR, Joseph L, Abenhaim L, Leclerc JR. Clinical prediction of
deep vein thrombosis in patients with leg symptoms. Thromb
Haemost. 1999;81:353-7
(6) Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. ABC of
arterial and venous disease. Non-invasive methods of arterial and
venous assessment. Br Med J 2000;320:698–701.
(7) Hull R, Taylor DW, Hirsh J, Sackett DL, Powers P, Turpie AGG,
Walker ID: Impedance plethysmography: The relationship between
venous filling and sensitivity and specificity for proximal vein
thrombosis. Circulation 58:898, 1978
(8) Hull R, Hirsh J, Sackett DL, Taylor DW, Carter C, Turpie AG,
Powers P, Gent M: Clinical validity of a negative venogram in
patients with clinically suspected venous thrombosis. Circulation.
1981; 64(3):622.
(9) Lensing AW, Büller HR, Prandoni P, Batchelor D, Molenaar AH,
Cogo A, Vigo M, Huisman PM, ten Cate JW. Contrast venography,
the gold standard for the diagnosis of deep-vein thrombosis:
improvement in observer agreement. Thromb Haemost.
1992;67(1):8.
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S/N
Event Medical (case) definition References
(10) Buck JR, Connors RH, Coon WW, Weintraub WH, Wesley JR,
Coran AG. Pulmonary embolism in children. J Pediatr Surg.
1981;16(3):385.
(11) Byard RW, Cutz E. Sudden and unexpected death in infancy and
childhood due to pulmonary thromboembolism. An autopsy study.
Arch Pathol Lab Med. 1990;114(2):142.
(12)Matthew DJ, Levin M. Pulmonary thromboembolism in children.
Intensive Care Med. 1986;12(6):404.
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12.15 ventricular arrhythmia
S/N
Event Medical (case) definition References
16 ventricular arrhythmia
Three events will be considered:
(1) Ventricular Tachycardia
(2) Ventricular Fibrillation
(3) Bradycardia
ventricular tachycardia
This can be defined on the basis of heart rate and ECG findings.
On the basis of heart rate:
>180 beats/minute (regular) in infants and young children
> 120 beats/minute (regular) in older children/adolescents (indicate
tachycardia generally)
On the basis of ECG, the following features apply:
Ventricular rate is >120 beats per minute and regular
P waves are often not identifiable, may have AV dissociation, or may
have retrograde depolarization
QRS is typically wide (>0.09 sec)
T waves are often opposite in polarity from the QRS complex
ventricular fibrillation (VF)
It is characterized by rapid, chaotic, and asynchronous contraction of the
LV.
The surface electrogram of VF reveals a rapid, irregular, dysmorphic
pattern with no clearly defined QRS complex.
bradycardia
Normally, the value for average heart rates varies with age. Younger patients
usually have higher heart rates which decrease to adult values by the late
teenage years.
Bradycardia can be established by either using 12-lead electrocardiogram
(ECG) or by 24-hour ambulatory monitoring.
On the basis of 12-lead electrocardiogram (ECG):
Newborn to 3 years: < 100 beats/minute
3 - 9 years: < 60 beats/ minute
(1) UpToDate. Causes of wide QRS complex tachycardia in children.
2014 [cited 2014 19th June]; Available from:
http://www.uptodate.com/contents/causes-of-wide-qrs-complex-
tachycardia-in-
children?source=machineLearning&search=causes+of+wide+qrs+t
achycardia+in+children&selectedTitle=1~150§ionRank=1&anc
hor=H3#H3.
(2) Rho RW, Page RL. Chapter 42. Ventricular Arrhythmias. In: Fuster
V, Walsh RA, Harrington RA, eds. Hurst's The Heart. 13th ed. New
York: McGraw-Hill; 2011.
http://www.accessmedicine.com/content.aspx?aID=7814365.
Accessed October 4, 2012
(3) Michaelson M, Engle MA. Congenital complete heart block: An
international study of the natural history. In: Cardiovascular Clinics,
Brest AN, Engle MA (Eds), FA Davis, Philadelphia 1972. p.85
(4) Kugler JD. Sinus node dysfunction. In: Pediatric Arrhythmias:
Electrophysiology and Pacing, Gillette PC, Garson AG Jr (Eds),
WB Saunders, Philadelphia 1990. p.250.
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S/N
Event Medical (case) definition References
9 – 16 years: < 50 beats per minute
On the basis of 24-hour ambulatory monitoring:
Newborns – 2 years: < 60 beats/minute while asleep and < 80
beats/ minute while awake
2 – 6 years: < 60 beats per minute
6 – 11 years: < 45 beats/ minute
> 11 years (adolescents): < 40 beats/minute
> 11 years who are well-trained athletes: < 30 beats per minute
N.B The 24-hour ambulatory guidelines vary from the ECG guidelines as they
include the slower heart rates that occur normally at rest and sleep
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12.16 Anaphylaxis as AEFI
S/N Event Case definition References
1 Anaphylaxis See Brighton Collaboration case definition Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data.
Rüggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, de Souza Brito G, Heininger U, Imoukhuede B, Khamesipour A, Erlewyn-Lajeunesse M, Martin S, Mäkelä M, Nell P, Pool V, Simpson N; Brighton Collaboration Anaphylaxis Working Group.
Vaccine. 2007 Aug 1;25(31):5675-84. Epub 2007 Mar 12.
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12.17 Thrombocytopenia
S/N Event Case definition References
2 Thrombocytopenia See Brighton Collaboration case definition Thrombocytopenia: case definition and guidelines for collection, analysis, and presentation of immunization safety data.
Wise RP1, Bonhoeffer J, Beeler J, Donato H, Downie P, Matthews D, Pool V, Riise-Bergsaker M, Tapiainen T, Varricchio F; Brighton Collaboration Thrombocytopenia Working Group.
Vaccine. 2007 Aug 1;25(31):5717-24. Epub 2007 Mar 12.
12.18 (Febrile) seizures
S/N Event Case definition References
3 (Febrile) seizures
See Brighton Collaboration case definition Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation.
Bonhoeffer J1, Menkes J, Gold MS, de Souza-Brito G, Fisher MC, Halsey N, Vermeer P; Brighton Collaboration Seizure Working Group.
Vaccine. 2004 Jan 26;22(5-6):557-62.
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12.19 Disseminated BCGitis
S/N Event Case definition References
4 Disseminated BCGitis
It is a recognized but rare consequence of BCG vaccination traditionally seen in individuals with severe
cellular immune deficiencies.
The case definition was created with information from the resources listed under references.
Level 1
1. BCG cultured and identified by biochemical methods at least.
2. Dissemination evidenced by either A or B.
A. A positive blood or bone marrow culture.
B. Evidence of infection at two or more anatomic sites beyond the region of vaccination. Evidence of
infection includes a positive culture or histopathologic demonstration of acid-fast bacilli. Examples of
acceptable sites include the following: lymph node nodes beyond the ipsilateral axillary lymph nodes;
one or more cutaneous abscesses beyond the region of vaccination; osteomyelitis at one or more sites;
brain or CSF; lung biopsy specimen, sputum, pleura and/or pleural fluid, or gastric aspirate; liver;
spleen; intestine and/or stool; and kidney and/or urine. Multiple isolates from the same organ system
are counted only once. For example, infection of multiple distant lymph nodes constitutes one site.
Isolation of BCG from both sputum and pleural fluid constitutes one site.
3. A systemic syndrome compatible with mycobacterial disease. Typical cases include fever, weight loss,
anemia, and death.
Level 2
Clinical signs of infection at two or more anatomic sites (see above) beyond the region of vaccination OR systemic syndrome compatible with mycobacterial disease following BCG vaccination
Remark: For case identification in databases (algorithm): Further classification into
- reported disseminated BCGitis with insufficient evidence to meet the case definition +/- respective
treatment (potentially referrals to specialists?).
Adapted from: Talbot EA, et al.
Disseminated bacille Calmette-Guérin
disease after vaccination: case report and
review. Clin Infect Dis. 1997;24(6):1139-46.
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12.20 Hypotonic hyporesponsive episode
S/N Event Case definition References
5 Hypotonic hyporesponsive episode
See Brighton Collaboration case definition Hypotonic-hyporesponsive episode (HHE) as an adverse event following immunization in early childhood: case definition and guidelines for data collection, analysis, and presentation.
Buettcher M, Heininger U, Braun M, Bonhoeffer J, Halperin S, Heijbel H, de Menezes Martins R, Vermeer-de Bondt P; Brighton Collaboration HHE Working Group.
Vaccine. 2007 Aug 1;25(31):5875-81. Epub 2007 May 8.
12.21 Encephalitis
S/N Event Case definition References
6 Encephalitis See Brighton Collaboration case definition Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data.
Sejvar JJ, Kohl KS, Bilynsky R, Blumberg D, Cvetkovich T, Galama J, Gidudu J, Katikaneni L, Khuri-Bulos N, Oleske J, Tapiainen T, Wiznitzer M; Brighton Collaboration Encephalitis Working Group.
Vaccine. 2007 Aug 1;25(31):5771-92. Epub 2007 May 11.
12.22 Intussusception
S/N Event Case definition References
7 Intussusception See Brighton Collaboration case definition Acute intussusception in infants and children as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation.
Bines JE1, Kohl KS, Forster J, Zanardi LR, Davis RL, Hansen J, Murphy TM, Music S, Niu M, Varricchio F, Vermeer P, Wong EJ; Brighton Collaboration Intussusception Working Group.
Vaccine. 2004 Jan 26;22(5-6):569-74.
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12.23 Vaccine-associated paralytic poliomyelitis (VAPP)
S/N Event Case definition References
8 Vaccine-associated paralytic poliomyelitis (VAPP)
There is no official case definition for VAPP. The current definition was created with
information from the two resources listed under references.
VAPP is a flaccid paralysis for a minimum of 60 days after the vaccination with oral
polio vaccine (OPV) or after contact with a person who had recently been
vaccinated. The paralysis is caused by mutation of the attenuated virus during
passage of the intestines.
Level 1:
residual weakness 60 days after the onset of paralysis vaccine-related poliovirus isolated from stool sample no wild poliovirus isolated from stool sample receipt of oral polio vaccine 4-40 days before onset of paralysis OR 4-40 days
beforehand contact with person who had received OPV 4 -84 days before the case’s paralysis began
Level 2:
residual weakness 60 days after the onset of paralysis vaccine-related poliovirus isolated from stool sample unknown if wild poliovirus in stool sample receipt of OPV 4-40 days before onset of paralysis OR 4-40 days beforehand
contact with person who had received OPV 4 -84 days before the case’s paralysis began
Level 3:
residual weakness 60 days after the onset of paralysis receipt of OPV 4-40 days before onset of paralysis OR 4-40 days beforehand
contact with person who had received OPV 4 -84 days before the case’s paralysis began
Remark: For case identification in databases (algorithm): Further classification into
- reported VAPP with insufficient evidence to meet the case definition +/- respective
treatment (potentially referrals to specialists?).
[1] Bull World Health Organ. 2002;80(3):210-6. Vaccine-associated paralytic poliomyelitis in India during 1999: decreased risk despite massive use of oral polio vaccine. Kohler KA, Banerjee K, Gary Hlady W, Andrus JK, Sutter RW. [2]http://www.paho.org/english/ad/fch/im/PolioCaseDefinition.htm [47] Impfratgeber – Impfempfehlungen für Kinder, Jugendliche und Erwachsene. Heininger U. 7. Auflage – Bremen: UNI-MED, 2013
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12.24 Disseminated Oka VZV
S/N Event Case definition References
9 Disseminated Oka VZV
There is no official case definition for disseminated Oka Varicella
Zoster virus (VZV). The current definition was created with
information from the following two resources listed under
references.
without organ involvement
Level 1:
disseminated (more than one dermatome) rash (with vesicles, maculopapules, and scabs in varying stages)
within 42 days after vaccination or after contact with vaccinated person
skin biopsy or vesicular fluid with vaccination strain no wild type virus in skin biopsy immunocompromised? Level 2:
disseminated (more than one dermatome) rash (with vesicles, maculopapules, and scabs in varying stages)
within 42 days after vaccination or after contact with vaccinated person
skin biopsy or vesicular fluid with vaccination strain unknown if wild type virus in skin biopsy or wild type virus in
skin biopsy
Level 3:
disseminated (more than one dermatome) rash (with vesicles, maculopapules, and scabs in varying stages)
within 42 days after vaccination or after contact with vaccinated person
no skin biopsy or vesicular fluid
with organ involvement
Level 1:
pneumonia, meningitis or hepatitis and potentially
[1] IOM, Report of the Institute of Medicine: Adverse Effects of Vaccines: Evidence and causality (2012). [2] Galea SA, Sweet A, Beninger P, et al. The safety profile of varicella vaccine: a 10-year review. J Infect Dis. 2008;197 Suppl 2:S165-9.
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S/N Event Case definition References
disseminated rash (with vesicles, maculopapules, and scabs in varying stages)
within 10 days to 2 months after vaccination or after contact with vaccinated person
with vaccination strain in bronchoalveolar, CSF or liver biopsy no wild type virus in bronchoalveolar, CSF or liver biopsy immunocompromised? Level 2:
pneumonia, meningitis or hepatitis and potentially disseminated rash (with vesicles, maculopapules, and scabs in varying stages)
within 10 days to 2 months after vaccination or after contact with vaccinated person
with vaccination strain in bronchoalveolar, CSF or liver biopsy unknown if wild type virus in bronchoalveolar, CSF or liver
biopsy
Level 3:
pneumonia, meningitis or hepatitis and potentially disseminated rash (with vesicles, maculopapules, and scabs in varying stages)
within 10 days to 2 months after vaccination or after contact with vaccinated person
no skin biopsy
Remark: For case identification in databases (algorithm): Further
classification into
- reported disseminated Oka VZV with insufficient evidence to
meet the case definition +/- respective treatment (potentially
referrals to specialists?).
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12.25 Arthritis
S/N Event Case definition References
10 Arthritis There is no BC case definition for arthritis or arthralgia as an
adverse event following immunization. The CIOMS report –
Reporting adverse drug reactions 1999 does not include case
definitions for any kind of arthritis either. One of the reasons may
be that there are many different forms of arthritis. Furthermore,
arthralgia as such is not a diagnosis but a symptom and literally
means joint pain. The causes are varied and it is mostly
subjective.
Arthropathy is a further event which has been mentioned in
association with vaccines, e.g. in the IOM report ‘adverse effects
of vaccines: evidence and causality (2012)’. Arthropathy per se
means a disease of a joint, regardless of the cause, hence
arthritis is also a form of arthropathy which involves inflammation
of one or more joints.
Harmonisation in this field would be helpful.
The term arthritis and arthralgia following immunization may stem
from arthritis and arthralgia which has been described following
rubella vaccination. The mechanism of this joint inflammation
was supposed to be direct infection of the synovial tissue by the
virus or induction of autoimmunity.
Regardless of the type of arthritis, the symptoms include
- joint pain - joint swelling
- joint stiffness
Depending on the type of arthritis apart from clinical symptoms, further tests will be done for diagnosis, e.g. radiology, lab tests (e.g. rheumatoid factor for rheumatoid arthritis).
The approach should be broad, i.e. new disease,
induction/excerbation of inflammatory/autoimmune disease,
[1] Wikipedia ‘Arthralgia’: http://en.wikipedia.org/wiki/Arthralgia (accessed April 18, 2013) [2] Wikipedia ‘Arthritis’: http://en.wikipedia.org/wiki/Arthritis (accessed April 18, 2013) [47] Wikipedia ‘Arthropathy’ http://en.wikipedia.org/wiki/Arthropathy (accessed April 18, 2013) [4] IOM Report ‘Adverse Effects of Vaccines: Evidence and Causality (2012) [5] CIOMS ‘Reporting Adverse Drug Reactions’ (1999) [6] Vaccines. Eds. Plotkin S, Orenstein W, Offit P. Fifth edition. Elsevier 2008. CDC, the National Arthritis Data Workgroup has put together codes of diseases of what might be considered to be arthritis or a related rheumatologic condition. The list is quite broad http://www.cdc.gov/arthritis/data_statistics/case_definition/adult.htm.
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S/N Event Case definition References
arthropathy should be included, e.g.
- rheumatoid arthritis
- psoriatic arthritis - Reiter’s disease/reactive arthritis -
Not to be included:
- arthritis with known cause, e.g. bacterial arthritis
- osteoarthritis - myalgia/myositis - gout
- spondylitis - Behcet’s syndrome - vascular disorders - polyneuropathy
12.26 Guillain Barré Syndrome
S/N
Event Case definition References
11 Guillain Barré Syndrome
See Brighton Collaboration case definition Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.
Sejvar JJ, Kohl KS, Gidudu J, Amato A, Bakshi N, Baxter R, Burwen DR, Cornblath DR, Cleerbout J, Edwards KM, Heininger U, Hughes R, Khuri-Bulos N, Korinthenberg R, Law BJ, Munro U, Maltezou HC, Nell P, Oleske J, Sparks R, Velentgas P, Vermeer P, Wiznitzer M; Brighton Collaboration GBS Working Group.
Vaccine. 2011 Jan 10;29(3):599-612. doi: 10.1016/j.vaccine.2010.06.003.
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12.27 Wheezing
S/N Event Case definition References
12 Wheezing Wheezing is a symptom and common in respiratory diseases in children. It
may be benign or self-limiting or a symptom of a significant respiratory
disease, commonly asthma. Wheeze is the end result of narrowing of
intrathoracic airways and expiratory flow limitation and may hence have
different underlying mechanisms.
A wheeze is a continuous musical sound heard during chest auscultation
that lasts longer than 250 msec. It can be high-pitched or low-pitched,
consist of single or multiple notes, and occur during inspiration or
expiration.
A Wheeze in children might be defined differently:
episodic wheeze = during discrete time periods, often in association with
clinical evidence of a viral cold, wheeze absent between episodes
multiple trigger wheeze = shows discrete exacerbations, but also symptoms
between episodes
transient wheeze = commenced before age of 3, to have disappeared by
age of 6; episodic or multi-trigger
persistent wheeze = symptoms continued until the age >=6; episodic or
multi-trigger
late-onset wheeze = start after age of 3; episodic or multitrigger
Diseases with wheezing as clinical sign such as asthma, obstructive
bronchitis will be included in the search for codes in case wheezing is not
recorded as such in certain databases.
[1] Fakhoury K. Approach to wheezing in children. www.uptodate.com. Accessed April 19, 2013. [2] Brand PL. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008;32(4):1096-110.
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12.28 IDDM
S/N Event Case definition References
13 Insulin dependent diabetes mellitus
Type 1 diabetes mellitus (T1DM) is most commonly diagnosed in childhood,
only about one-fourth of cases in adulthood. Most common types of diabetes
are T1DM and type II diabetes mellitus (T2DM). The initial step of diagnosis
is to diagnose diabetes. The second step is to differentiate T1DM
characterized primarily by insulin deficiency from other causes of diabetes
based upon the clinical presentation of the patient and laboratory studies.
Diagnosis of DM
HbA1C ≥6.5% OR Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) on more than one
occasion. Fasting is defined as no caloric intake for at least 8 h OR Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral
glucose tolerance test OR Random venous plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic
symptoms of hyperglycemia (polydypsia, polyuria, weight loss, blurry vision)
Classic symptoms of hyperglycemia or hyperglycemic crisis or diabetic ketoacidosis
Differentiation of T1DM from T2DM
T1DM
Age at presentation Throughout childhood
Weight 20-25% overweight; often recent history of weight loss
Acanthosis nigricans 12%
Insulin resistance, hypertension, dyslipidemia, polycystic ovary syndrome
Less likely
Ketosis at onset Common
Affected relative 5-10%
Female:male 1:1
HLA-DR3/4 Strong association
Ethnicity Most common non-Hispanic white
Insulin secretion Decreased/absent
[1] Lynne L Levitsky, Madhusmita Misra. Epidemiology, presentation, and
diagnosis of type 1 diabetes mellitus in children and adolescents.
www.uptodate.com. Accessed April 18, 2013.
[2] David K McCulloch. Diagnosis of diabetes mellitus. www.uptodate.com.
Accessed April 18, 2013.
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S/N Event Case definition References
Insulin sensitivity Normal when controlled
Insulin dependence Permanent
Pancreatic antibodies yes
T2DM
Age at presentation Puberty
Weight >80% obese
Acanthosis nigricans 50-90%
Insulin resistance, hypertension, dyslipidemia, polycystic ovary syndrome
frequently
Ketosis at onset About one-third
Affected relative 75-90%
Female:male Ca. 2:1
HLA-DR3/4 No association
Ethnicity All
Insulin secretion Variable
Insulin sensitivity Decreased
Insulin dependence Episodic
Pancreatic antibodies no
Remark: in databases we might need to go via the code T1DM or T2DM and
the treatment to differentiate the two types
12.29 Bell’s palsy
S/N Event Case definition References
14 Bell’s palsy See draft Brighton Collaboration case definition For reference, contact [email protected]