Report on terminology mapping and AEFI/ADE definitions

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

GRiP – Global Research in Paediatrics

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



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



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



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.

http://www.grip-network.org/



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



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



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.



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



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.

http://www.nlm.nih.gov/research/umls/



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)

http://www.imi-protect.eu/

http://www.sos-nsaids-project.org/

http://www.aritmo-project.org/



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]).



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’.



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.



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

https://brightoncollaboration.org/public/who-we-are.html

https://brightoncollaboration.org/public/who-we-are.html

http://www.cioms.ch/



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)



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



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



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.


ICD10CM code; walk up one level in ICD10CM hierarchy and check for an ICD10 code in that CUI.


ICD10CM code; walk up two levels in ICD10CM hierarchy and check for an ICD10 code in that CUI.


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.



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.



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.

http://www.ncbi.nlm.nih.gov/pubmed?term=Talbot%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=9195072

http://www.ncbi.nlm.nih.gov/pubmed/?term=Talbot+EA%2C+Perkins+MD%2C+Silva+SF%2C+Frothingham+R.+Disseminated+Bacille+Calmette%E2%80%94Guerin+disease+after+vaccination%3A+case+report+and+review.+Clin+Infect+Dis+1997%3B24%3A1139%E2%80%9446.



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



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)



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



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



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.



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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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.



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.



12.2 Agranulocytosis


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


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



12.4 bullous eruptions


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.


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.


128. Accessed October 2, 2012.




(4) Pathologic analysis shows full-thickness necrosis of epidermis associated

with mild mononuclear cell infiltrate



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.

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







S/N


- 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.



12.6 Psychosis


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.

http://www.uptodate.com/contents/overview-of-psychosis?source=search_result&search=overview+of+psychosis&selectedTitle=1~150





12.7 QT prolongation

S/N


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.

http://www.uptodate.com/contents/image?imageKey=CARD/78934&topicKey=CARD%2F1053&source=preview&rank=undefined

http://www.uptodate.com/contents/image?imageKey=CARD/78934&topicKey=CARD%2F1053&source=preview&rank=undefined



12.8 Seizure


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.


history of unconsciousness AND

(1) generalized, tonic, clonic, tonic–clonic, or atonic motor manifestations.


(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



12.9 Sepsis


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



12.10 Sudden death


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.

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






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


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



12.13 Thrombocytopenia


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



12.14 Venous thromboembolism

S/N


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.

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








S/N


(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.



12.15 ventricular arrhythmia

S/N


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&sectionRank=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.

http://www.uptodate.com/contents/causes-of-wide-qrs-complex-tachycardia-in-children?source=machineLearning&search=causes+of+wide+qrs+tachycardia+in+children&selectedTitle=1~150&sectionRank=1&anchor=H3#H3







S/N


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



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.

http://www.ncbi.nlm.nih.gov/pubmed/17448577




12.17 Thrombocytopenia


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


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.

http://www.ncbi.nlm.nih.gov/pubmed?term=Wise%20RP%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Bonhoeffer%20J%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Beeler%20J%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Donato%20H%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Downie%20P%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Matthews%20D%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Pool%20V%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Riise-Bergsaker%20M%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Tapiainen%20T%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Varricchio%20F%5BAuthor%5D&cauthor=true&cauthor_uid=17493712

http://www.ncbi.nlm.nih.gov/pubmed?term=Brighton%20Collaboration%20Thrombocytopenia%20Working%20Group%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=thrombocytopenia+AND+wise+AND+bonhoeffer

http://www.ncbi.nlm.nih.gov/pubmed?term=Bonhoeffer%20J%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=Menkes%20J%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=Gold%20MS%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=de%20Souza-Brito%20G%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=Fisher%20MC%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=Halsey%20N%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=Vermeer%20P%5BAuthor%5D&cauthor=true&cauthor_uid=14741144

http://www.ncbi.nlm.nih.gov/pubmed?term=Brighton%20Collaboration%20Seizure%20Working%20Group%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=Brighton%20Collaboration%20Seizure%20Working%20Group%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=seizure+AND+bonhoeffer+AND+menkes



12.19 Disseminated BCGitis


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.

http://www.ncbi.nlm.nih.gov/pubmed?term=Talbot%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=9195072

http://www.ncbi.nlm.nih.gov/pubmed/?term=Talbot+EA%2C+Perkins+MD%2C+Silva+SF%2C+Frothingham+R.+Disseminated+Bacille+Calmette%E2%80%94Guerin+disease+after+vaccination%3A+case+report+and+review.+Clin+Infect+Dis+1997%3B24%3A1139%E2%80%9446.



12.20 Hypotonic hyporesponsive episode


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


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


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.







http://www.ncbi.nlm.nih.gov/pubmed?term=Bines%20JE%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Kohl%20KS%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Forster%20J%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Zanardi%20LR%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Davis%20RL%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Hansen%20J%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Murphy%20TM%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Music%20S%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Music%20S%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Niu%20M%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Varricchio%20F%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Vermeer%20P%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Wong%20EJ%5BAuthor%5D&cauthor=true&cauthor_uid=14741146

http://www.ncbi.nlm.nih.gov/pubmed?term=Brighton%20Collaboration%20Intussusception%20Working%20Group%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=Brighton%20Collaboration%20Intussusception%20Working%20Group%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=bines+AND+kohl+AND+foster



12.23 Vaccine-associated paralytic poliomyelitis (VAPP)


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

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kohler+KA%2C+Banerjee+K%2C+Hlady+WG%2C+Andrus+JK%2C+Sutter+RW.+Vaccine-+associated+paralytic+poliomyelitis+in+India+during+1999%3A+decreased+risk+despite+massive+use+of+oral+polio+vaccine.+Bull+World+Health+Organ+2002%3B+80%3A+210-6.

http://www.ncbi.nlm.nih.gov/pubmed?term=Kohler%20KA%5BAuthor%5D&cauthor=true&cauthor_uid=11984607

http://www.ncbi.nlm.nih.gov/pubmed?term=Kohler%20KA%5BAuthor%5D&cauthor=true&cauthor_uid=11984607

http://www.ncbi.nlm.nih.gov/pubmed?term=Banerjee%20K%5BAuthor%5D&cauthor=true&cauthor_uid=11984607

http://www.ncbi.nlm.nih.gov/pubmed?term=Gary%20Hlady%20W%5BAuthor%5D&cauthor=true&cauthor_uid=11984607

http://www.ncbi.nlm.nih.gov/pubmed?term=Andrus%20JK%5BAuthor%5D&cauthor=true&cauthor_uid=11984607

http://www.ncbi.nlm.nih.gov/pubmed?term=Sutter%20RW%5BAuthor%5D&cauthor=true&cauthor_uid=11984607

http://www.paho.org/english/ad/fch/im/PolioCaseDefinition.htm



12.24 Disseminated Oka VZV


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:



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:



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.

http://www.ncbi.nlm.nih.gov/pubmed?term=Galea%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=18419392

http://www.ncbi.nlm.nih.gov/pubmed?term=Sweet%20A%5BAuthor%5D&cauthor=true&cauthor_uid=18419392

http://www.ncbi.nlm.nih.gov/pubmed?term=Beninger%20P%5BAuthor%5D&cauthor=true&cauthor_uid=18419392

http://www.ncbi.nlm.nih.gov/pubmed/?term=The+Safety+Profile+of+Varicella+Vaccine%3A+A+10-Year+Review




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)


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)


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?).



12.25 Arthritis


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.

http://en.wikipedia.org/wiki/Arthralgia

http://en.wikipedia.org/wiki/Arthropathy

http://www.cdc.gov/arthritis/data_statistics/case_definition/adult.htm




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.





12.27 Wheezing


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.

http://www.uptodate.com/

http://www.ncbi.nlm.nih.gov/pubmed/?term=Definition%2C+assessment+and+treatment+of+wheezing+disorders+in+preschool+children%3A+an+evidence-based+approach



12.28 IDDM


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.

http://www.uptodate.com/contents/epidemiology-presentation-and-diagnosis-of-type-1-diabetes-mellitus-in-children-and-adolescents/contributors

http://www.uptodate.com/contents/epidemiology-presentation-and-diagnosis-of-type-1-diabetes-mellitus-in-children-and-adolescents/contributors






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


14 Bell’s palsy See draft Brighton Collaboration case definition For reference, contact [email protected]

Report on terminology mapping and AEFI/ADE definitions

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