Population-level impact of Pneumococcal Conjugate Vaccines in … · 2018-12-06 · 3 Objectives...

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634446

Population-level impact of Pneumococcal Conjugate Vaccines in older adults

Generic protocol for conducting before and after studies on

Invasive Pneumococcal Disease and Pneumococcal pneumonia

WP nr: 3

Version: V2.2-updated

Date: 26/04/2018

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Document prepared by I-MOVE+ partners involved in pneumococcal vaccines studies from WP3 and WP4, coordinated by THL and EpiConcept.

Adapted in parts from the SpIDnet Generic Protocol to measure PCV impact in children developed under the European Centre for Disease Prevention and Control – funded project SpIDnet “Assessing the impact of vaccination with the conjugate vaccines on the epidemiology of the invasive pneumococcal disease in Europe”, ECDC/2012/038, and discussions during SpIDnet expert meetings (Madrid 2012, Paris 2013, Prague 2013).

Version history:

Version number Date Type document Comments

V1.0 31 Jul 2015 Original document Document submitted for partners’ comments and to EC as part of deliverable D3.1.

V2.0 30 Oct 2015 Original document Document including partners’ comments and decisions of the First technical meeting (Copenhagen, Sep 2015). This version was used as basis for site specific protocols and submitted as part of deliverable D3.2.

V2.1 15 Dec 2016 Amendment Version amended with the decisions of the second technical meeting (Paris, September 2016) on definitions of outcomes and underlying conditions based on ICD codes. Analysis based on IPD surveillance remained unchanged except for IPD clinical presentation categories.

V2.2 15 Dec 2017 Amendment Version amended with the decisions of the third technical meeting (Utrecht, October 2017) to include additional analysis on IPD by high risk conditions and pneumonia outcomes based on ICD codes.

V2.2-updated 26 Apr 2018 Update Version 2.2 with an update of Table 4 revised after the initial data collection in March 2018.

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Table of contents

1 Introduction .............................................................................................................................. 8

1.1 Definition of vaccination effects ................................................................................................... 9

1.1.1 Overall effect ......................................................................................................................... 9

1.1.2 Indirect effect ........................................................................................................................ 9

1.1.3 Total effect ............................................................................................................................ 9

1.2 Rationale...................................................................................................................................... 10

2 Background of the protocol ...................................................................................................... 13

3 Objectives ................................................................................................................................ 14

3.1 Overall objective .......................................................................................................................... 14

3.2 Specific objectives ....................................................................................................................... 14

4 Methods .................................................................................................................................. 15

4.1 Study design ................................................................................................................................ 15

4.2 Study setting ................................................................................................................................ 15

4.3 Study population ......................................................................................................................... 15

4.4 Study period ................................................................................................................................ 15

4.4.1 Definitions of periods before and after the PCV introduction ............................................ 15

4.5 Outcomes .................................................................................................................................... 16

4.5.1 Case definitions ................................................................................................................... 16

4.6 Laboratory methods .................................................................................................................... 17

4.7 Data source and collection .......................................................................................................... 18

4.7.1 Cases (numerator) ............................................................................................................... 18

4.7.2 Denominator ....................................................................................................................... 18

Additional information to be collected for results interpretation ...................................................... 18

4.7.3 Vaccination coverage .......................................................................................................... 18

4.7.4 Other information ............................................................................................................... 18

4.8 Data management ....................................................................................................................... 19

4.9 Sample size .................................................................................................................................. 19

5 Analysis ................................................................................................................................... 21

5.1 Data checking .............................................................................................................................. 21

5.2 Descriptive analysis ..................................................................................................................... 21

5.3 Measure of impact ...................................................................................................................... 21

5.4 Pooled analysis ............................................................................................................................ 22

5.5 Adjustments ................................................................................................................................ 22

6 Limitations ............................................................................................................................... 24

6.1 Study design related .................................................................................................................... 24

6.2 Sample size .................................................................................................................................. 24

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6.3 Pre-existing vaccination .............................................................................................................. 24

6.4 Case identification and serotyping .............................................................................................. 25

7 Ethical approval ....................................................................................................................... 25

8 Human resources ..................................................................................................................... 25

Annex 1: Impact analysis of pneumococcal vaccines using register-based data .................................. 48

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List of abbreviations

Ag Antigen, referring to the laboratory method to detect Streptococcus pneumoniae antigen

AMS(NS) Antimicrobial susceptibility or non-susceptibility according to context

CAP Community acquired pneumonia

CSF Cerebrospinal fluid

EARS-net European Antimicrobial Resistance Surveillance Network

EC European Commission

ECDC European Centre for Disease Prevention and Control, Stockholm, Sweden

EU/EEA European Union/European Economic Area

ICU Intensive care unit

IPD Invasive Pneumococcal Disease

MS Member States

OR Odds Ratio

NIP National Immunisation Plan

NRC National Reference Centre for Pneumococci in a country

PCR Polymerase Chain Reaction

PCV Pneumococcal conjugate vaccine (according to the number of serotypes covered: PCV7, PCV10, PCV13)

PPV23 Pneumococcal polysaccharide vaccine 23-valent

SAGE WHO Strategic Advisory Group of Experts

Sp Streptococcus pneumoniae

VE Vaccine Effectiveness

VI Vaccination Programme Impact

WHO World Health Organization

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Glossary

Term Definition

Antimicrobial susceptibility

In this context, used as the capacity of antibiotic/antimicrobial treatment to successfully inhibit the bacterial growing, according to clinical breakpoints of the standards used

Antimicrobial non-susceptibility

Intermediate susceptibility or resistance to an antimicrobial as defined by the standards used

CAP Community Acquired Pneumonia

CLSI Clinical and Laboratory Standards Institute, international standards that describe the methods and clinical breakpoints for antimicrobial susceptibility testing

Completeness of the surveillance system

The proportion of all cases with no missing variable or information

Comprehensive surveillance system

A population-based surveillance system implying notifications from all possible reporting sites

Coverage of the surveillance system

The proportion of the population effectively under surveillance compared to the total population of the country

EUCAST European Committee on Antimicrobial Susceptibility Testing, European standards for antimicrobial susceptibility testing (http://www.srga.org/Eucastwt/eucastdefinitions.htm)

Herd immunity The proportion of subjects with immunity in a given population where a vaccine is offered1

Herd effect The reduction of infection or disease in the unimmunised segment as a result of immunising a proportion of the population2

ICD International Statistical Classification of Diseases and Related Health Problems, used as discharge diagnostic codes or for coding causes of death. The 9th or 10th revision are currently used in most countries

Impact of a vaccination programme

The measure of effects of a specific vaccination programme in a specific population, which include overall, indirect and total effect against the target disease

IPD Invasive pneumococcal disease, defined as isolation of Streptococcus pneumoniae or the detection of Streptococcus pneumoniae nucleic acid or antigen from a normally sterile side

1 John TJ, Samuel R. Herd immunity and herd effect: new insights and definitions. Eur. J. Epidemiol. 2000: 16 (7): 601–6. doi:10.1023/A:1007626510002. PMID 11078115 2 Ibid.1

http://www/

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Term Definition

MIC Minimum inhibitory concentration, a method for antimicrobial susceptibility testing

MLST Multilocus sequence typing

Sentinel surveillance system

A surveillance system that involves collecting data from a sample of reporting sites

Sensitivity

(of the surveillance system)

The proportion of cases reported by the surveillance system out of the total number of cases meeting the same case definition in the entire population. Also called the degree of ascertainment or the exhaustiveness of the surveillance system

Surveillance site Surveillance system (in a country) participating in the I-MOVE+ project.

Surveillance unit Hospital/laboratory reporting cases to a surveillance site included in the I-MOVE+ project

Vaccination coverage The proportion of the eligible population which is effectively vaccinated. Vaccine coverage should be defined by schedule (number of doses or complete schedule)

Vaccination registry Electronic database where vaccination data are recorded. It usually includes patient unique identifier; age; sex; vaccine type; vaccination date; vaccine brand/ manufacturer; vaccine lot number

VE Vaccine effectiveness, defined as the measure of the direct effect of vaccination against target disease when used under field conditions

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1 Introduction

Streptococcus pneumoniae is a Gram-positive diplococcus bacterium causing a wide spectrum of illness either by invading the bloodstream or by mucosal contiguity. Based on capsule polysaccharide composition, more than ninety serotypes of Streptococcus pneumoniae have been identified. These serotypes differ not only in prevalence by area and over time but also in pathogenicity and age distribution.

Invasive pneumococcal disease (IPD), defined as the isolation of Streptococcus pneumoniae or the detection of nucleic acid or antigen of Streptococcus pneumoniae from a normally sterile fluid, may present different clinical conditions such as meningitis, bacteraemic pneumonia, bacteraemia without focus, septic shock, and other less frequent conditions such as arthritis, peritonitis, etc. Transmitted by contiguity to middle ear, sinuses or other locations of the respiratory tract, Streptococcus pneumoniae can also cause non-invasive diseases such as acute otitis media, sinusitis or pneumonia. Streptococcus pneumoniae nasopharyngeal colonization, particularly in young children, represent the main reservoir of pneumococci and the primary means of transmission to susceptible individuals. As recent acquisition of Streptococcus pneumoniae in nasopharynx is thought to precede episodes of pneumococcal disease, carriage plays a key role in the epidemiology of pneumococcus.

Two major groups of vaccines are currently available to protect against Streptococcus pneumoniae: polysaccharide vaccine (23-valent vaccine - PPSV23) and more recently pneumococcal conjugate vaccines (PCVs). PPSV23, licensed in 1983, is generally recommended for use in the elderly as well as adults and children ≥2 years with underlying medical conditions (risk groups)3. Pneumococcal conjugate vaccines4 (PCV7, PCV10 and PCV13) covering the 7, 10 and 13 serotypes most frequently causing IPD in developed countries during pre-vaccine era, were licensed in the European Union (EU) in 2001 (PCV7), and in 2009 (PCV10 and PCV13) for the use in children under five years old, with PCV10 and PCV13 replacing PCV7. PCV13 was approved for use in adults in 2011, and in children up to 17 years in November 2012. Currently, PCV13 is licensed for prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants, children and adolescents from 6 weeks to 17 years of age, as well as for the prevention of invasive disease and pneumonia caused by Streptococcus pneumoniae in adults ≥18 years of age and the elderly5. Most EU countries have introduced PCV vaccines for routine infant vaccination, but vaccination policies widely vary across member states in terms of vaccine (PCV 10/13), dose schedule (2+1 or 3+1 doses) and target groups (risk groups only or universal vaccination)6,7.

3 WHO, 23-valent pneumococcal polysaccharide vaccine WHO position paper – 2008, WER 2008; 83: 373–384 4 WHO, Pneumococcal vaccines – WHO position paper -2012, WER 2012; 14; 87:, 129–144 5 European Medicines Agency. Prevenar 13: EPAR – Product information. Annex I - Summary of product characteristics. 12/05/2015. 6 ECDC, Report of Survey for identifying potential study sites for active IPD surveillance in the EU/EAA, 2013. 7 ECDC and Venice II, Impact of childhood pneumococcal vaccination programmes and activities for pneumococcal vaccines in the EU and EEA \EFTA countries. Available from http://venice.cineca.org/VENICE_Survey_PNC_1_2012-02-24.pdf

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1.1 Definition of vaccination effects

In epidemiology, effect is the amount of change in a population‘s disease frequency caused by a specific factor. Absolute effects are differences in incidences rates, incidence proportions, prevalence, or incidence time. Relative effects involve ratios of these measures8. Effects in vaccinology measure various absolute or relative changes in incidences observed between populations exposed and not exposed to an intervention (vaccination).

For the purpose of this document, the following terms will be used, based on Halloran9 description of vaccination effects (Figure 1).

1.1.1 Overall effect

The overall effect is the effect of the vaccination programme in the entire population, including vaccinated and unvaccinated. To measure the overall effect, the overall (average) incidence of disease (or other outcome) of the population in which there is a vaccination programme is compared to the incidence of disease (or other outcome) in a completely unvaccinated population (Figure 1).

1.1.2 Indirect effect

The indirect effect is the population-level effect on the unvaccinated portion within a population with a vaccination programme. This type of effect is usually estimated by comparing the incidence of disease (or other outcomes) in the unvaccinated portion of a population in which some individuals have been vaccinated, with the incidence of disease (or other outcomes) in a completely unvaccinated population (Figure 1).The indirect effect can be measured by comparing the incidence rates of disease (outcome) in a group never targeted for vaccination before and after the introduction of the vaccination programme. For age-group-specific estimates, the age-groups of interest can vary according to time since introduction of vaccination. For example, unless a catch up campaign is conducted, two years after vaccination, the indirect effect can be measured by comparing outcome rates in those older than two years before and after the introduction of the vaccination programme. Three years after vaccination, the comparison can be made among those aged more than three years; and so on.

1.1.3 Total effect

The total effect of a vaccination programme measures the population-level effect of vaccination on the vaccinated portion of a population. This can be estimated by comparing the incidence of disease (or other outcome) in the vaccinated portion of a population in which some individuals have been vaccinated, with the incidence of disease (or other outcomes) in a completely unvaccinated population (Figure 1).

8 Rothman KJ, Epidemiology – An introduction; Oxford University Press, 2002 9 Halloran ME, Longini Jr IM, Struchiner CJ. Design and Analysis of Vaccine Studies. Series: Statistics for Biology and Health 2010, XVIII, 389 p. Hardcover, ISBN 978-0-387-40313-7

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For the purpose of this document, the term “impact” refers to overall, indirect and total effect of vaccination as the term “effectiveness” refers only to the direct effect of vaccination under field conditions10.

An attempt to present the types of effects according to the availability of the childhood and adult vaccination is presented in the Figure 2. The draft will be discussed in the expert meeting to reach a consensus regarding the effects measured under this project (Figure 2 – to be further discussed in the expert meeting).

1.2 Rationale

A total of 1.6 million deaths due to pneumococcal disease occur annually worldwide among all ages11. Despite the decreases in vaccine type IPD rates due to herd effects from routine childhood PCV introduction, substantial burden of pneumococcal disease remains in older adults.

ECDC/Venice II latest estimate of PCV introduction in the 29 EU/EEA MS reported that 24/29 countries had already included PCV in the immunisation programme: 13 (54%) universally recommended, five (21%) recommended to risk groups and six (25%) recommended both universally in children<2 years and in risk groups ≥2 years, and 10 countries included a catch-up campaign. In addition 23/25 respondents to the ECDC/Venice II survey acknowledged the presence in the country of at least an IPD surveillance system and the report presented data on 27 surveillance systems. Of these, 24 are organised at the national level and 25 are comprehensive12.

This protocol presents a generic approach for conducting PCV impact studies among older adult population by using the before and after design with data provided by several routine surveillance systems in Europe. The prerequisite for conducting these studies is an established IPD surveillance system which uses a specific, laboratory confirmed outcome according to EU 2012 case definition13.

Studies on non-laboratory confirmed outcomes14 or those conducted by linking different electronic databases: hospital discharge databases (ICD codes) with laboratory or vaccination registries can follow the same protocol, specificities being addressed in the annexes of the present document.

10 Hanquet G, Valenciano M, Simondon F, Moren A. Vaccine effects and impact of vaccination programmes in post-licensure studies. Vaccine 2013; doi:10.1016/j.vaccine.2013.07.006 11 WHO. The global burden of disease: 2004 update. Geneva: World Health Organization; 2008. 12 ECDC and Venice II, Impact of childhood pneumococcal vaccination programmes and activities for pneumococcal vaccines in the EU and EEA \EFTA countries. Available from http://venice.cineca.org/VENICE_Survey_PNC_1_2012-02-24.pdf 13 European Commission, Commission Implementing Decision 2012/506/EU of 8 August 2012 amending Decision 2002/253/EC laying down case definitions for reporting communicable diseases to the Community network under Decision No 2119/98/EC of the European Parliament and of the Council (notified under document C(2012) 5538) 14 WHO, Measuring impact of Streptococcus pneumoniae and Haemophilus influenzae type b conjugate vaccination, WHO/IVB/12.08, September 2012

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Figure 1: Diagram on vaccination effect adapted from Halloran et al [ibid. 6]:

R=rate or risk in vaccinated (v) or unvaccinated (u)

u

uindirect

R

RVE

2

11

u

aveoverall

R

RVE

2

11

Intervention

Population: 1

Control

Population: 2

Vac

f

R1v

Nonvac

1-f

R1u

Overall

Nonvac

R2u

IndirectDirect

u

vdirect

R

RVE

1

11

Total

u

vtotal

R

RVE

2

11

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Figure 2. Different possible effects by periods and vaccine availability

A)

B)

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2 Background of the protocol

I-MOVE+ project is part of the EC work programme PHC 17 – 2014: “Personalising health and care”, “Comparing the effectiveness of existing healthcare interventions in the elderly”.

The objectives of the I-MOVE+ network are to identify, pilot test, use, and disseminate in and beyond the EU the best study designs to measure, in near real time the effectiveness and impact of vaccines used in the elderly population to prevent influenza and pneumococcal infections.

As part of I-MOVE+, we measure the impact of available pneumococcal vaccines against IPD and CAP in the elderly population in order to determine the best study designs and data sources to provide evidence for informing public health actions at regional, national and supranational levels.

This generic protocol will be adapted to the specific context of each partner site.

The following information for the specific study setting should be reviewed and provided:

date of introduction of the vaccine(s) in routine childhood vaccination programmes and among the elderly (PPSV23 and/or PCV13);

vaccination schedules for children and/or adults;

target groups for vaccination (universal/ risk group);

estimated vaccination coverage;

data sources for pneumococcal disease outcomes (i.e. laboratory surveillance, hospital surveillance, primary care surveillance);

sources to document different factors that may influence the results interpretation;

ethical/ consent requirements;

► Each study site will provide a description of the specific background for the country/region: introduction of vaccine(s), calendar, vaccination coverage, organisation of the surveillance system (case definition, laboratory confirmation and serotyping, reporting flow, data collected, reports on evaluations, any references of published articles, etc.).

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3 Objectives

3.1 Overall objective

To estimate the population-level impact of pneumococcal conjugate vaccination programmes on invasive pneumococcal disease (IPD) burden among adults 65 years of age and older. This will be accomplished by comparing population-based rates of IPD before and after conjugate vaccine introduction (pre-PCV7 or PCV7 periods vs. PCV10/13 period) at each study site.

► Each study site to specify the effect measure to be used. According to the recommendation and uptake of PCV13 in older adults at each study site, the overall and/or indirect effect of vaccination programmes will be measured (Figure 2).

3.2 Specific objectives

• Estimate the reduction in the incidence among older adults ≥65 years of age, by IPD related outcome due to routine childhood PCV programmes (herd protection, i.e. indirect effect);

• Understand the timing and magnitude of potential increase in disease from non-vaccine serotypes (replacement disease).

By using as indicators the number and rate of IPD reported by all surveillance units among the elderly age groups;

And by:

• Eligibility for vaccination (eligible/non-eligible age groups, high risk groups);

• Serotype category (all serotypes, vaccine serotypes (PCV7, PCV10non7, PCV13non10, PPSV23nonPCV13), vaccine-related, non-vaccine (nonPPSV23non6A), specific serotypes);

(See Table 1 – Serotypes contained in different pneumococcal vaccines)

• Clinical presentation (meningitis, bacteraemic pneumonia, bacteraemia, other clinical presentations);

• Antimicrobial susceptibility (susceptible, non-susceptible);

• Severity.

Table 1: Streptococcus pneumoniae serotypes by outcome

Vaccine Serotypes

PCV7 4, 6B, 9V, 14, 18C, 19F, 23F

PCV10non7 1, 5, 7F

PCV13non10 3, 6A, 19A

PPV23nonPCV13 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F

PPV23 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F

► Each study site will adapt the above objectives to the IPD surveillance in their country/area and the recommendations for PCV7 and PCV10/13 vaccination in childhood and adult vaccination programmes.

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4 Methods

4.1 Study design

Population-based before and after study, comparing IPD rates during the pre-PCV/PCV7 periods with the period post-PCV10/13 introduction. The periods before introduction of the PCV10/13 vaccination (pre-PCV and PCV7 periods) will be considered for reference periods.

4.2 Study setting

The study is embedded in the routine IPD surveillance system, using the available data sources and databases.

The particularities of studies based on hospital discharge registries are described in the Annex 1.

► Each study site to define the study setting according to the data sources of the IPD surveillance system or the organisation of the reporting system for IPD;

► Description of the surveillance units used for case ascertainment: hospitals, laboratories, clinical networks;

► Number of participating units, proportion out of the total number of existing institutions (e.g. participating hospitals/ total number of hospitals);

► Representativeness of the surveillance units reporting IPD cases in the 65 years and older population.

4.3 Study population

The study population comprises all community dwelling individuals ≥65 years of age who are residents of the catchment area of the laboratory/ hospitals participating in the already set up surveillance system, for whom information is collected for surveillance purposes.

► Each study site to state the study population (65 years of age and older).

4.4 Study period

The study period depends on the date when PCV was introduced in the country or when the IPD surveillance system was set up. Efforts should be made to extract data for sufficiently long reference (baseline) periods to account for changes in medical and diagnostic practices and surveillance activities.

4.4.1 Definitions of periods before and after the PCV introduction

Pre-PCV period: XX years (at least two) before introduction of the PCV vaccine in the country or beginning of universal childhood PCV vaccination programme (the number of years will depend on the data available). Note that a longer pre-PCV baseline period allows a better assessment of secular trends.

PCV7 period (where applicable): XX years before introduction of childhood PCV10/13 vaccination programme in countries in which PCV7 vaccination was available (the number of years will depend on the data available).

Post-PCV10/13 period: years starting from childhood PCV10/13 introduction in the country.

Transitional periods: In countries where the PCV vaccine was introduced progressively in children, the first year(s) in which the vaccine was available but low vaccination coverage (i.e.

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<40%) was achieved may be considered as “transitional period” between periods with no vaccine available and periods with high vaccine coverage (i.e. years with vaccine available prior to universal introduction).

► Each study site to describe the study periods: pre-PCV, PCV7, transition, post-PCV10/13 periods. The most years included in the pre-PCV period, the better the secular trends could be taken into account in the interpretation of the results.

4.5 Outcomes

The primary outcome of interest is laboratory confirmed IPD (isolation or detection of Streptococcus pneumoniae from a normally sterile site) or ICD coded (for hospital discharge registries studies described in Annex 1).

Secondary outcomes may include:

1. IPD cases due to vaccine, vaccine-related, non-vaccine related or specific serotypes. The following categories will be considered: PCV7, PCV10non7, PCV13non10, PPV23nonPCV13, nonPPV23non6A according to the serotypes included in each vaccine (Table 1)

2. IPD cases by high risk group (high risk immunocompromised, high risk immunocompetent, no high risk conditions, other conditions – site specific) according to Table 4.

3. [Clinical manifestation] of vaccine serotype disease. In this context, clinical manifestation can be: pneumococcal meningitis, bacteremic pneumonia, bacteraemia, other clinical manifestations

4. IPD cases susceptible or non-susceptible to antimicrobials 5. IPD severity: IPD related death in 30 days since the disease onset/diagnosis of current episode

or intra-hospital deaths. 6. All cause pneumonia, SpCAP and non-specific pneumonia according to the ICD codes (Annex

1).

4.5.1 Case definitions

IPD is defined according to the ECDC case definition used for surveillance purposes15 :

PNEUMOCOCCAL INVASIVE DISEASE(S) (Streptococcus pneumoniae)

Clinical criteria

Not relevant for surveillance purposes

Laboratory criteria

At least one of the following three:

Isolation of Streptococcus pneumoniae from a normally sterile site

Detection of Streptococcus pneumoniae nucleic acid from a normally sterile site

Detection of Streptococcus pneumoniae antigen from a normally sterile site

15 European Commission, Commission Decision 2008/426/EC of 28 April 2008 amending Decision 2002/253/EC laying down case definitions for reporting communicable diseases to the Community network under Decision No 2119/98/EC of the European Parliament and of the Council (notified under document number C(2008) 1589)

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Epidemiological criteria

NA

Case classification

A. Possible case

NA

B. Probable case

NA

C. Confirmed case

Any person meeting the laboratory criteria

For the primary outcome (all type IPD), a case is defined as a patient with laboratory confirmed IPD according to the ECDC case definition.

For secondary outcomes, a case is defined as above for the primary outcome, and additional data availability:

1. Pneumococcal serotype is determined 2. Comorbidity group identified as none, immunocompetent, immunocompromised conditions

(see Annex 1, table 4) 3. The clinical presentation is identified as: meningitis, bacteraemic pneumonia and

bacteraemia, other clinical manifestations 4. Antimicrobial susceptibility is investigated and the classification is done according to the MIC

of each antimicrobial using EUCAST breakpoints 5. IPD death within 30 days since disease onset/diagnosis or intra-hospital death. 6. Pneumonia outcomes (see Annex 1, tables 1.2 and 1.3)

► Each study site to state the case definitions for primary and secondary outcomes according to data available in the surveillance system.

4.6 Laboratory methods

To fulfil the IPD case definition, cases should be laboratory confirmed by culture or PCR/Ag testing. In addition, for the secondary outcomes, serotyping and antimicrobial testing are needed.

● Serotyping of isolates is usually done at the reference laboratory using capsular reaction testing (Quellung test), gel diffusion with type-specific antisera or PCR. If the culture is negative and pneumococcus cannot be isolated, PCR is an alternative for identification and serotyping.

● Antimicrobial susceptibility testing should be done for all isolates for at least the following antimicrobials: penicillin, macrolide, and cephalosporin. The EUCAST clinical breakpoints used will be used for classification in susceptible/non-susceptible (non-susceptible is defined as intermediate resistant strain according to EUCAST).

Specimen collection for each technique, storage and transportation guidelines are specified in each IPD surveillance system (to be included as reference).

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► Each study site to describe how specimens are collected, transported and types of tests performed for confirmation and serotyping or refer to the surveillance guidelines in place. When confirmation and serotyping was done by PCR, the method and the algorithms used should also be described. The sensitivity and specificity of all tests should be provided.

► For antimicrobial susceptibility testing, MIC should be determined and EUCAST breakpoints according to antimicrobial should be used for interpretation. At least three antimicrobial classes should be investigated: betalactam (penicillin, cephalosporin), macrolide (erythromycin), floroquinolone (cipro/ levofloxacin).

4.7 Data source and collection

4.7.1 Cases (numerator)

Data will be extracted from existing surveillance database. In countries with a unique identifier in place, investigators should be able to link various databases. For each variable, the database source and its characteristics should be recorded. Anonymised, individual data for a minimum set of variables will be extracted. If individual case data are not available, aggregated database by age group and serotype categories can be used.

In case data is extracted directly from hospital discharge registries the outcomes presented in Annex 1 should be used.

4.7.2 Denominator

Population data can be extracted from population statistics or birth registers in hospital catchment areas or available census results. Changes in population of the surveillance catchment area should be recorded.

Data collected for denominators includes population by age group and year. If the study population is considered to be stable during a year, the annual census could provide the denominator.

Additional information to be collected for results interpretation

4.7.3 Vaccination coverage

Estimates of vaccination uptake can be obtained from vaccine sales or distribution, vaccination registries, and specific coverage surveys in the surveillance catchment areas. Vaccination coverage over time should be recorded in the target age group for PPSV23 and PCV13 (if recommended) as well as for childhood vaccination programmes (if possible annual coverage).

4.7.4 Other information

Interviews with experts can be conducted to gain information on IPD testing over time (tests used, changes over time), case detection and ascertainment, site-specific particularities (e.g. outbreaks, vaccine trials), medical practices (case management protocols, criteria for taking blood culture, etc.). These data may not be directly analysed, but will help in the interpretation of results by explaining possible variations in trend.

► Each study site to specify data to be extracted and the source for numerator, denominator, vaccination

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coverage and additional information gathered.

4.8 Data management

► Each study site to describe all procedures for data management:

Who extracts data?

Who validates data and how?

How, by whom and when are data stored?

Who links databases?

How are data extracted?

Who analyses data?

Softwares used?

4.9 Sample size

The studies will require sufficient power to detect the impact of PCV vaccination. The achievable power of each study should be calculated taking into account the following parameters (Figure 3):

the observed rate of the selected outcome in the reference period (pre-PCV/PCV7)

the expected effect to be detected

an alpha error of 0.05

a power of 80% or 90%

If the achievable sample size is too low to assure representativeness of the data and meaningful results, the study should be reconsidered.

► Each study site to estimate the power of the study.

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Figure 3: Sample size calculation taken into account the pre-PCV incidence (low=10/100,000, moderate=40/100,000, high=80/100,000, very high=110/100,000), percentage change to be reached with different power scenarios (A)β=0.8 and B)β=0.9)

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5 Analysis

5.1 Data checking

Data will be collected on reported IPD cases. Data will be checked to find outliers, implausible or missing information. As much as possible, data should be completed or validated against the data source.

Completeness of surveillance data is important in estimating the IPD incidence by relevant time periods. Changes in surveillance data completeness can influence the measurement of impact and the power of the study. Therefore, these changes should be recorded and missing data should be taken into account. Handling of missing serotype data will be discussed and determined by the WP3 expert panel.

► Each study site to describe data checking and the management of missing data.

5.2 Descriptive analysis

IPD cases will be described by time period, age group and serotype categories. Baseline characteristics by periods will be compared using the chi-square test, Fisher’s exact test, t-test or the Mann-Whitney test (depending on the nature of the variable and the sample size) if individual data provided.

Incidence by period will be calculated according to the data available from the surveillance system:

Numerator = laboratory confirmed IPD cases by year, age group

Denominator = population in the study catchment area by year, age group

Number of cases (by year and outcome) as well as the corresponding denominator should be presented (similar to Tables 3). Incidence may be adjusted for surveillance system sensitivity (both under-reporting and coverage) if reliable data are available.

Graph presentation of yearly number of cases or incidence is recommended. If a long time period is available smoothing procedures using 52 weeks moving average to describe long term trends may be used.

► Each study site to present the descriptive analysis plan.

5.3 Measure of impact

The methods used for comparing IPD rates between reference periods and post-PCV10/13 years depend on available data and should be specified for each study site.

The impact (see also 16) may be computed as:

the reduction in the mean number of cases in the post-PCV10/13 period compared with the reference periods, expressed as absolute numbers or percentage change in the number of cases with corresponding 95% CI;

the reduction in the cumulative incidence or rate in the post-PCV10/13 period compared with the reference periods, expressed as rate/risk difference with the corresponding 95% CI;

16 Hanquet G, Valenciano M, Simondon F, Moren A. Vaccine effects and impact of vaccination programmes in post-licensure studies. Vaccine 2013; doi:10.1016/j.vaccine.2013.07.006

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the relative reduction in the incidence proportion or rate in the post-PCV10/13 period compared to the reference periods, expressed as a percentage change in incidence or an incidence rate/risk ratio with the corresponding 95% CI.

On the basis of estimates of pneumococcal vaccination uptake among individuals 65 years of age and older, we can describe (Figure 2 A, B):

an overall effect: the measure of impact in the age group ≥65 years of age in a population where a proportion of people in this age group and in the paediatric age group is vaccinated with PCV13 compared with the same population before the introduction of the vaccination programmes;

indirect effect: the measure of impact of childhood conjugate vaccination programme among persons ≥65 years of age in the absence of direct PCV13 vaccination programme in older adults, compared to the same population before the introduction of the childhood vaccination programme;

► Each study site to specify the indicators for each of the effects measured in the elderly (Figure 2 A and B) and the methods used for calculation of the confidence intervals.

5.4 Pooled analysis

Individual or aggregated data will be shared for conducting a pooled analysis, using the Table 2 and 3 format. If feasible, and dependent on data quality, these data may be analysed to compute pooled impact measures. Individual data or lower aggregation data (monthly) may be submitted for additional analyses according to site specific approvals to allow a more thorough time series analysis.

► Each study site to prepare the data for submission according tables 2 and 3.

5.5 Adjustments

Several factors should be taken into account in interpreting the results. If possible, adjustments for these factors could be considered17:

Challenge Methods used in studies Comment/limitation

Adjusting for changes in case detection

Calculate number of cases per 1000 blood cultures

This indicator cannot be directly used for impact estimation (not an incidence). Availability of blood culturing data

Compare to other IPD trends, e.g. compare non-meningitis to meningitis syndromes

Trends in meningitis do not follow automatically trends in non-meningitis if serotypes more prone to cause meningitis vary

Compare IPD trends with trends of an internal marker (i.e. other disease detected by same ways but not targeted by intervention)

No adjustment made on this basis, except for UK that developed an “inflation factor” based on the pre-vaccination trends in total IPD (validated by increases also seen for other bacterial infections). These trends were only extrapolated

17 Based on a review made by Hanquet and discussed during SpIDnet expert meeting in Paris 2013.

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four years after which no further increases were assumed Mostly described under Discussion or in non-impact studies

If changes in test, stratify impact by test (e.g. by culture and non-culture)

Cannot correct if culture is not systematically done or if pre-admission antibiotics

Adjust for changes in “ascertainment”

Calculate inflation factor and apply it retrospectively to predict previous incidence

Assumes that any IPD increases is due to increased ascertainment

Adjust for changes in syndromes covered

Stratify impact by syndrome Adjust for serotype distribution if other dataset with unbiased syndrome %

Difficult if differential impact by syndrome

Adjust for changes in sensitivity of surveillance system

Estimate sensitivity and adjust incidence accordingly (pre and post)

Methods: capture-recapture mostly, comparison between datasets, few other methods

If coverage is known, estimate under-reporting factor by year, based on audit, review of cases, other source etc.

For sentinel or incomplete systems, does not take into account the cases not reported by the units (missed cases)

Adjust for changes in admission criteria

Compare with trend of other conditions to assess changes in admission criteria/coding. Trends in overall hospitalization rates.

E.g. urinary tract infections, all cause hospitalisations

Adjust for secular trends or other trends

Make assumption and model expected number of cases without vaccination based on pre-vaccine data, using different techniques (e.g. linear regression)

Requires sufficiently long pre-vaccine period Usually assumed linear trend Can also correct for changes in detection or reporting, however only short term predictions are likely to be valid

Adjust for missing data Apply distribution of serotypes/cases with information to serotypes/cases without information Exclude periods with high % of missing data Multiple imputation method?

Assume similar distribution. Can be partly assessed by looking at whether distribution of known variables are similar Can we use multiple imputation methods on outcome variables?

Adjust for pre and post population and case differences

Use corresponding denominator Stratify by or adjust for age (e.g. 65-74, 75-84, 85+ years) Stratify by or adjust for comorbidities (Charlson index)

Require annually updated population Stratification reduces power, may also use adjustment

Pooling from heterogeneous sites

Assess differences across sites May be easier to collect site variable than individual variables. Model difficult to test (require independent site incidences?).

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Use regression methods with site variables to calculate pooled incidence

► Each study site to specify the adjustments according to availability of additional data in consultation with the WP3 expert panel.

6 Limitations

6.1 Study design related

In studies comparing pre and post intervention, the main limitation is that the effect measured can be due to other factors not related to vaccination as presented above in the section 4.4. Therefore, different factors should be considered, such as:

changes in case detection and ascertainment

changes in sensitivity of the surveillance system

secular trends

changes in medical practices and in health seeking behaviour

other factors that may influence IPD incidence

Efforts to collect information on all the potential factors that can explain the changes should be described.

► Each study site to describe changes in the reporting, medical practice that may have occurred in the study period. If possible, pre-vaccination trends should be identified and taken into account in the interpretation of measures of impact.

6.2 Sample size

If achieved sample size does not meet the planned one, large confidence intervals will limit the possible interpretation of results. In this case, several years need to be aggregated in order to reach a sufficient number of cases for precise results.

► Each study site to describe the limitations related to the sample size.

6.3 Pre-existing vaccination

PCV vaccination may have begun earlier in some regions or a country, and a certain coverage may have been achieved before the vaccine’s universal introduction in a country. It is the case in the countries where the vaccine was first introduced for risk groups or recommended by professional associations or large clinical trials were conducted. Therefore these years should be included in the transition periods, analysed separately and taken into account in the result interpretation. Not taking into account the pre-existing vaccine use in the target population could lead to an underestimation of the impact of the vaccine.

► Each study site to describe the limitations related to the pre-existing vaccination in the study area.

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6.4 Case identification and serotyping

Laboratory-based case identification implies good specificity and sensitivity of the case definition. Moving from the culture-based case confirmation (low sensitivity, high specificity) to PCR (higher sensitivity, high specificity) will increase the number of IPD cases identified and underestimates the impact estimate. In addition increase in testing and serotyping will also underestimate impact. However it can also help identify new or emerging serotypes causing IPD. This has a high importance in identifying replacement.

► Each study site to describe the potential limitations related to laboratory testing.

7 Ethical approval

► Each study site to describe the procedures to obtain the approval of the national / ethics committee if such approval is required according to national law.

8 Human resources

The roles and responsibilities of the members of the investigation team should be described: principal investigator, assistant, data manager, etc.

► Each study site to describe the team members’ roles and responsibilities.

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Table 2: List of variables, coding, definitions and data sources as collected in IPD surveillance

Variable name Name of the variable in the

site specific database

Variable label Type Values and coding Definition Comments

siteid Site identification Unique ID AAA Surveillance site identification

recordid Record identification code

Unique ID string Surveillance unit identification and record identification code

datenotif Date of notification Date dd/mm/yyyy Date when the case is notified the first time to the site level

residence Residence in the catchment area

Numeric 0-no

1-yes

9-unknown

Residence in the catchment area of the surveillance unit reporting to the system

ageyears Age of the case in years Numeric ### Age of patient in years as reported at the site level in years at time of hospital admission

sex Gender Code 0-female

1-male

9-unknown

Gender of the reported case

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dateadm Date of the admission in the hospital

Date dd/mm/yyyy Date when the case was admitted to the hospital

datedis Date of the discharge from the hospital

Date dd/mm/yyyy Date when the case was discharged from the hospital

outcome Outcome Code 0-alive

1-deceased

9-unknown

Information on survival at the end of hospitalisation: alive, deceased, unknown

datedeath Date of death Date dd/mm/yyyy Date of death of the admitted patient (if outcome==1)

clinic Clinical entity Multiple choice 0-unknown

1-meningitis

2-pneumonia

3-

4-bacteremia

5-

6- 9-other, specify

Clinical manifestation of the IPD case

This multiple-choice variable can be collected as such or each clinical entity can be entered separately using variables 12-20. If clinic =9, variable 20 (otherclin) specifies other clinical entities of IPD not listed

meningitis Pneumococcal meningitis

Code 0-no

1-yes

9-unknown

A case presenting with lab confirmed pneumococcal meningitis

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pneumonia invasive pneumococcal pneumonia

Code 0-no

1-yes

9-unknown

A case presenting with lab confirmed pneumococcal pneumonia

bacteremia Bacteremia without known focus of infection

Code 0-no

1-yes

9-unknown

A case presenting with lab confirmed bacteremia (blood stream infection) without known focus of infection

otherclin Other clinical entities Text String20 Other clinical entities of the IPD case

Please specify other clinical entity for the IPD cases

icuadm Admission in the ICU Code 0-no

1-yes

9-unknown

A lab confirmed case who needed admission in the ICU during the pneumococcal episode

datediag Date of diagnosis Date dd/mm/yyyy Date when the diagnosis was made, should be the same with the identification/confirmation of the

serotype Serotype identified Text String3

PEN – pending

NTP – non-typeable

UKN - unknown

Serotype identified

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micpeni MIC to penicillin Numeric ##.### MIC to penicillin in µg/ml If not tested, the variable will be left blank

mic[macrolid] MIC to macrolide Numeric ##.## MIC to macrolide in µg/ml [please specify the antimicrobial used: Erythromycin, Azithromycin, Clarithromycin, etc.]

If not tested, the variable will be left blank

mic[cepha] MIC to cephalosporin Numeric ##.## MIC to cephalosporin in µg/ml [please specify the antimicrobial used: Cefotaxime, Ceftriaxone, etc]

If not tested, the variable will be left blank

mic[antimicrobial]

MIC to antimicrobial Numeric ##.## MIC to different other antimicrobial tested

Please specify the antimicrobial using specific variables

nbdosepcv13 Number doses PCV13 Numeric # Number doses PCV13

dosepcv13 PCV13 vaccination Code 0-no

1-yes

9-unknown

Vaccination with PCV13

datepcv13 Date of vaccination with first dose PCV

date dd/mm/yyyy Date of latest dose PCV

nbdoseppv Number doses PPSV23 Numeric # Number doses PPSV23

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doseppv PPSV23 vaccination Code 0-no

1-yes

9-unknown

Vaccination with PPSV23

dateppv Date vaccination with PPSV23

date dd/mm/yyyy Date of vaccination with PPSV23 for the latest and previous dose if available

underdis Underlying diseases Code 0-no

1-yes

9-unknown

Presence of at least one underlying disease which represents high risk groups for getting IPD

This variable can be collected as such or by specifying conditions 52-59

underdistype Underlying diseases by immune status

Code 0-no

1-immunocompetent

2-immunocompromissed

9-unknown

Underlying diseases by immune status

For definitions please refer to table 4

cardiovasc Cardiovascular diseases Code 0-no

1-yes

9-unknown

Patient was diagnosed with a chronic cardiovascular disease: see table 4 for ICD codes

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respdis Respiratory diseases Code 0-no

1-yes

9-unknown

Patient was diagnosed with a chronic respiratory disease or asthma: see table 4 for ICD codes

rendis Renal diseases Code 0-no

1-yes

9-unknown

Patient was diagnosed with a chronic renal disease including nephrotic syndrome: see table 4 for ICD codes

immunodef Immunodeficiency Code 0-no

1-yes

9-unknown

Patient was diagnosed with an acquired or congenital immunodeficiency: see table 4 for ICD codes

hiv Human immunodeficiency virus (HIV) disease

Code 0-no

1-yes

9-unknown

See table 4

leukemia Lymphoid and myeloid leukaemia; multiple myeloma

Code 0-no

1-yes

9-unknown

See table 4

lymphoma Hodgkin lymphoma, Follicular lymphoma, Non-follicular lymphoma, MatureT/NK-cell lymphoma, Other and

Code 0-no

1-yes

9-unknown

See table 4

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unspecified types of non-Hodgkin lymphoma

transplant Solid organ transplat Code 0-no

1-yes

9-unknown

See table 4

malignancy Generalized malignancy Code 0-no

1-yes

9-unknown

See table 4

immunomed Immunosuppressing medication

Code 0-no

1-yes

9-unknown

See table 4

diabetes Diabetes mellitus Code 0-no

1-yes

9-unknown

Patient was diagnosed with diabetes mellitus type 1 or 2: see table 4 for ICD codes

asplenia Asplenia or splenectomised

Code 0-no

1-yes

9-unknown

Patient with functional or anatomical asplenia / splenectomy in the clinical history: see table 4 for ICD codes

sicklemia Sickle cell disease Code 0-no

1-yes

9-unknown

Patient with sickle cell disease in the clinical history: see table 4 for ICD codes

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Also include: Thalassemia, Other haemoglobinopathies

csfleak Cerebrospinal fluid (CSF) leak

Code 0-no

1-yes

9-unknown

See table 4

cohlear Cochlear implant Code 0-no

1-yes

9-unknown

See table 4

alcoholism Alcoholism Code 0-no

1-yes

9-unknown

See table 4

liverdis Liver chronic disease including cirrhosis

Code 0-no

1-yes

9-unknown

See table 4

smoking Cigarette smoking Code 0-no

1-yes

9-unknown

See table 4

institutionalised Institutionalized persons

Code 0-no

1-yes

9-unknown

See table 4

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► Each study site to describe the data available for cases according to the data collection in IPD surveillance.

otherdis Other underlying disease

Text string20 Specify other underlying conditions included in the recommendation for PCV/PPV vaccination in a specific site

fluvac Influenza vaccination Code 0-no

1-yes

9-unknown

Influenza vaccination for the current season

Other variables Please include all other variables collected in the site-specific surveillance system important for pooled analysis

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Table 3: Data to be collected for pooled analysis Please fill in the table by each group included in the study, according to the calendar years (from January –December of each year) or epi years (August - July)

A) IPD ☐ Culture positive; ☐ All cases (include culture, PCR and Ag positive)

Site: ______________Age group: ☐ ≥65 years ☐ 65-74 years; ☐ 75-84 years ☐ ≥85 years

Variable

Years*

Pre-vaccination

(please add additional years if needed)

Post-vaccination PCV7 (please add additional years if needed)

Post-vaccination PCV10/13


Year 6 Year 5 Year 4 Year3 Year 2 Year 1 Year 1 Year 2 Year ... Year 1 Year 2 Year… etc

Year

PCV Vaccine PCV7, PCV10 or PCV13

NA NA NA NA NA NA

PCV coverage Percentage vaccination

NA NA NA NA NA NA

PPV23 vaccine PPV23 recommendation Yes/No; if yes, high risk, all elderly

PPV23 coverage

Percentage vaccination

Population Number of inhabitants in the age group

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All type IPD Number of cases

IPD serotyped Number of cases

PCV7 IPD Number of cases

PCV10 non PCV7 IPD

Number of cases

PCV13 non PCV10 IPD

Number of cases

PPV23nonPCV13

Number of cases

nonPPV23

non6A IPD Number of cases

Serotype specific IPD (at least 3, 7F, 19A)

Number of cases by serotype

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B) Clinical presentations for IPD cases: ☐ Yes; ☐ No, If yes: ☐ Culture positive; ☐ All cases (include culture, PCR and Ag positive)

Site: ____________ Age group: ☐ ≥65 years ☐ 65-74 years; ☐ 75-84 years ☐ ≥85 years

Variable

Years*

Pre-vaccination Post-vaccination PCV7 Post-vaccination PCV10/13

Year 6 Year 5 Year 4 Year3 Year 2 Year 1 Year 1 Year 2 Year … Year 1 Year 2 Year …

Year

All type meningitis Number of cases

Meningitis serotyped Number of cases

PCV7 Meningitis Number of cases

PCV10 non PCV7 Meningitis Number of cases

PCV13 non PCV10 Meningitis Number of cases

PPV23 non PCV13 Meningitis Number of cases

nonPPV23 non6A Meningitis Number of cases

Serotype specific meningitis Number of cases

All type invasive pneumonia Number of cases

Invasive pneumonia serotyped

Number of cases

PCV7 invasive pneumonia Number of cases

PCV10 non PCV7 invasive pneumonia

Number of cases

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PCV13 non PCV10 invasive pneumonia

Number of cases

PPV23 non PCV13 invasive pneumonia

Number of cases

nonPPV23 non6A invasive pneumonia

Number of cases

Serotype specific pneumonia Number of cases

All type Bacteraemia Number of cases

Bacteraemia serotyped Number of cases

PCV7 Bacteraemia Number of cases

PCV10 non PCV7 Bacteraemia Number of cases

PCV13 non PCV10 Bacteraemia

Number of cases

PPV23 non PCV13 non6A Bacteraemia

Number of cases

nonPPV23 Bacteraemia Number of cases

Serotype specific bacteremia Number of cases

*Invasive pneumonia including empyema

**Bacteraemia without focus

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C) Antimicrobial non-susceptibility IPD (AMNS: intermediate and resistant according to EUCAST version 3.1.): ☐ Yes; ☐ No

If yes: ☐ Culture positive; ☐ All cases (include culture, PCR for Ery?)

Site: ___________ Age group: ☐ ≥65 years ☐ 65-74 years; ☐ 75-84 years ☐ ≥85 years

Variable

Years*

Unit



Year

AMNS Peni all type IPD Number of cases

AMNS Peni serotyped IPD Number of cases

AMNS Peni PCV7 IPD Number of cases

AMNS Peni

PCV10 non PCV7 IPD

Number of cases

AMNS Peni

PCV13 non PCV10 IPD

Number of cases

AMNS Peni

PPV23 non PCV13 IPD

Number of cases

AMNS Peni nonPPV23 non6A IPD

Number of cases

AMNS Peni serotype specific IPD

Number of cases

AMNS ERY All type IPD Number of cases

AMNS ERY Serotyped IPD Number of cases

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AMNS ERY PCV7 IPD Number of cases

AMNS ERY

PCV10 non PCV7 IPD

Number of cases

AMNS ERY

PCV13 non PCV10 IPD

Number of cases

AMNS ERY

PPV23 non PCV13 IPD

Number of cases

AMNS ERY nonPPV23non6A IPD

Number of cases

AMNS ERY Serotype specific IPD

Number of cases

AMNS Cepha All type IPD Number of cases

AMNS Cepha Serotyped IPD Number of cases

AMNS Cepha PCV7 IPD Number of cases

AMNS Cepha

PCV10 non PCV7 IPD

Number of cases

AMNS Cepha

PCV13 non PCV10 IPD

Number of cases

AMNS Cepha

PPV23 non PCV13 IPD

Number of cases

AMNS Cepha nonPPV23non6A IPD

Number of cases

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AMNS Cepha Serotype specific IPD

Number of cases

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D) Severity of IPD cases (defined as IPD deaths at 30 days): ☐ Yes; ☐ No; (defined as intra-hospital IPD deaths): ☐ Yes; ☐ No

If yes, ☐ Culture positive; ☐ All cases (include culture, PCR and Ag positive)

Site: _____________ Age group: ☐ ≥65 years ☐ 65-74 years; ☐ 75-84 years ☐ ≥85 years

Variable

Years*



Year

Severe All type IPD Number of cases

Severe IPD serotyped

Number of cases

Severe PCV7 IPD Number of cases

Severe PCV10 non PCV7 IPD

Number of cases

Severe PCV13 non PCV10 IPD

Number of cases

Severe PPV23 non PCV13 IPD

Number of cases

Severe nonPPV23non6A IPD

Number of cases

Serotype specific severe IPD

Number of cases

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E) IPD by high risk conditions (HRC) ☐ No HRC; ☐ Immunocompetent HRC ☐ Immunocompromised HRC ☐ Other HRC


Variable

Years*

Pre-vaccination





Year 6 Year 5 Year 4 Year3 Year 2 Year 1 Year 2 2009 Year 1 Year 2 Year… etc

Year


NA NA NA NA NA NA


NA NA NA NA NA NA


PPV23 coverage



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All type Number of cases

IPD serotyped Number of cases

PCV7 Number of cases

PCV10 non PCV7

Number of cases

PCV13 non PCV10

Number of cases

PPV23nonPCV13

Number of cases

nonPPV23

non6A Number of cases

Serotype specific IPD (at least 3, 7F, 19A)

Number of cases by serotype

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F) Other pneumococcal outcomes (defined in Annex 1) and control conditions


Variable

Years*

Pre-vaccination





Year 6 Year 5 Year 4 Year3 Year 2 Year 1 Year 2 2009 Year 1 Year 2 Year… etc

Year


NA NA NA NA NA NA


NA NA NA NA NA NA


PPV23 coverage



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All cause pneumonia

Number of cases

Pneumococcal pneumonia

Number of cases

Unspecified pneumonia

Number of cases

All cause hospitalisation

Number of cases

Other control conditions (e.g. urinary tract infections)

Number of cases

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G) Additional data to be collected: sensitivity of the IPD surveillance systems and blood culture practices

Site: __________________

Sensitivity of the surveillance system ever calculated: ☐ Yes; ☐ No

Sensitivity of the surveillance system pre-vaccination available? ☐ Yes; ☐ No o Year when it was investigated: _____ o Percentage Se pre-vaccination:______ o Methods used for measuring Se pre-vaccination:________________________________________________________________________

________________________________________________________________________ ________________________________________________________________________

o Please provide references (articles/reports in which Se is presented)

Sensitivity of the surveillance system post-vaccination available? ☐ Yes; ☐ No o Year when it was investigated: _____ o Percentage Se post-vaccination:______ o Methods used for measuring Se post-vaccination:________________________________________________________________________

________________________________________________________________________ ________________________________________________________________________

o Please provide references (articles/reports in which Se is presented)

Blood culture practices investigated?

Please describe practices pre-vaccination: ______________________________________________________________________________

______________________________________________________________________________

______________________________________________________________________________

Please describe practices post-vaccination ______________________________________________________________________________

______________________________________________________________________________

______________________________________________________________________________

Please include references helping interpretation of impact data according to the blood culture practices.

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Annex 1: Impact analysis of pneumococcal vaccines using register-based data

Overview For impact analyses, data from hospital discharge registries can be used to measure changes in register-based pneumonia and IPD. When doing so, the analyses will be performed similarly as if using surveillance database. Cases will be extracted from hospital discharge registries using the following case definitions. Denominators (population data) and measure of impact are defined according to the Generic impact protocol.

Outcomes

Three outcomes will be used:

1. Invasive pneumococcal disease (clinical) 2. Pneumococcal pneumonia 3. All cause pneumonia 4. Unspecified pneumonia

All-cause hospitalizations and/or other conditions (e.g. urinary tract infections) will serve as a comparison group.

Episode definition

If possible, an episode definition of 90 days will be used for pneumonia outcomes. An episode starts from index notification with pneumonia-related ICD-9/10 code and all care notifications within 90 days are combined into one episode.

Table 1.1. Clinical Invasive pneumococcal disease

ICD-9 Code ICD-10 Code Diagnosis in Text

038

003.1

995.91

A40, A41 Streptococcal sepsis; other sepsis

041 A49 Bacterial infection of unspecified site

320 G00 Bacterial meningitis, not elsewhere classified

711 M00 Pyogenic arthritis

420 I30.1 Infective pericarditis

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041.09 B95.3 S. pneumoniae as the cause of diseases classified to other chapters

041.09 B95.4 Other Streptococcus as the cause of diseases classified to other chapters

041.00 B95.5 Unspecified Streptococcus as the cause of diseases classified to other chapters

995.91 and 790.7 Sepsis with bacteremia ??

Table 1.2. Pneumococcal pneumonia


481 J13 Pneumonia due to S. pneumoniae

Table 1.3. All-cause pneumonia


487.0, 480 J10.0, J11.0, J12.0-12.3, J12.8-12.9, J17.1

Viral pneumonia

481, 482 (except for 482.89), 483.1

J13, J14, J15.0-15.8, J16.0, J17.0

Bacterial pneumonia (specified)

483.2, 484.7, 484.8 J16.8, J17.2, J17.3, J17.8

Pneumonia due to fungal, parasitic, or other infectious disease

482.9 J15.9 Bacterial pneumonia, unspecified

485 J18.0-18.2 Bronchopneumonia, unspecified; lobar pneumonia, unspecified; , hypostatic pneumonia, unspecified

486 J18.8-J18.9 Other pneumonia, organism unspecified; pneumonia, unspecified

510 J86 Pyothorax (Incl. Empyema)

Table 1.4. Unspecified pneumonia


486 J18.8-J18.9 Other pneumonia, organism unspecified; pneumonia, unspecified

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Core risk conditions based on ICD codes

Table 4. Risk conditions for pneumococcal diseases and the corresponding ICD-9 and 10-codes.

Risk conditions Description ICD-9 Code ICD-10 Code

Immunocompromised persons

Congenital/acquired immunodeficiency

135, 279 D80-D89

Human immunodeficiency virus (HIV) disease

042 B20-B24

Chronic kidney disease

585 N18

Nephrotic syndrome 581 N04

Leukemia Lymphoid and myeloid leukemia; multiple myeloma

203 – 206

202.9

C91-C92, C93, C96.9

C90

Lymphoma Hodgkin lymphoma, Follicular lymphoma, Non-follicular lymphoma, MatureT/NK-cell lymphoma, Other and unspecified types of non-Hodgkin lymphoma

200 - 202 C81, C82, C83, C84, C85

Generalized malignancy (Metastatic solid tumors)

Malignant neoplasms of ill-defined, other secondary and unspecified sites

195-199 C76-C80

Immunosuppressing medication

No specific ICD-10 codes

Solid Organ Transplant

Transplanted organ and tissue status

V42 Z94

Functional or anatomical asplenia

Thalassemia, Sickle cell disorders, Other haemoglobinopathies,

282, 289.4-5 D56, D57, D58.2, D73

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Diseases of the spleen (including anatomical asplenia)

Immunocompetent persons

Cerebrospinal fluid (CSF) leak

349.81, 388.61 G96.0

Cochlear implant 431 Z96.21

Chronic heart disease Chronic ischemic heart disease, Cardiomyopathy, Heart failure

412 – 414, 425, 428 I25, I42, I50

Chronic lung disease Emphysema, Other COPD, Asthma

492, 493 J43, J44, J45

Diabetes mellitus Type 1 Diabetes, Type 2 Diabetes, Malnutrition-related diabetes, Other specified diabetes, Unspecified diabetes

250 E10, E11, E12, E13, E14

Alcoholism Mental and behavioral disorders due to use of alcohol, Degeneration of nervous system due to alcohol, Alcoholic polyneuropathy, Alcoholic myopathy, Alcoholic cardiomyopathy, Alcoholic gastritis, Alcoholic liver disease, Alcohol-induced acute pancreatitis, Alcohol-induced chronic pancreatitis, Maternal care for (suspected) damage to fetus from alcohol,

305, 281, 357.5, 425.5, 535.30-31, 571, 655

F10, G31.2*, G62.1, G72.1*, I42.6, K29.2, K70, K85.2*, K86.0*, O35.4

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Chronic liver disease, cirrhosis

Hepatic failure, NES, Chronic hepatitis, NES, Fibrosis and cirrhosis, Other diseases of liver, Malignancy of liver

155, 470 – 474

572.4, 573.9

K72, K73, K74, K76.7, K76.9, C22

Cigarette smoking Tobacco use, Mental disorders due to tobacco

300.51 292.89 Z72.0*, F17.2, F17.3*

Institutionalized persons

Nursing homes and long-term facilities

No specific ICD-10 codes

Other ICD codes Site specific conditions included in the high-risk groups for pneumococcal infection

*No corresponding code results

Note that codes are not always completely concordant. To be interpreted in the site-specific context.

► Each study site to describe the ICD codes used for outcome and high risk conditions. All site should provide for each code percentage of all diagnoses in reference cohorts as described in Palmu et al 2015

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Version track changes

Version number

Date published

Text in original document Changes included in the amended version

Comments

V2.1 15 Dec 2016

Page 14: Specific objective:

Estimate the reduction in the burden among older adults ≥65 years of age, by IPD related outcome due to routine infant PCV programmes

Page 14: Specific objective:

Estimate the reduction in the incidence among older adults ≥65 years of age, by IPD related outcome due to routine childhood PCV programmes

Avoid the overlap with WP5.

Page 14 (specific objectives)

Page 17 (secondary outcomes)

Page 18 (Case definitions for secondary outcomes)

Table 3

“serotype category nonPPSV23”

Modified as “serotype category nonPPSV23non6A”

Avoid the overlap with the PCV13 category.

Page 14 (specific objectives)

Page 17 (secondary outcomes)


Table 2 and 3

“Clinical presentation (meningitis, pneumonia, sepsis)”

Modified by “Clinical presentation (meningitis, bacteraemic pneumonia, bacteraemia, other clinical presentations)”

Note that bacteraemia covers all bacteremia and not only bacteremia without focus (because in Denmark no difference between bacteremia and bacteremic pneumonia can be made)

Decision during the technical meeting (Paris,

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September 2016) because the definition of sepsis is not homogenous over the sites.

Page 17 (secondary outcomes): Severe IPD


“Severity is assessed according to ICU admission AND/OR intra-hospital death”

Modified as:

“IPD severity: IPD related death in 30 days since the disease onset/diagnosis of current episode or IPD related intra-hospital deaths”

Decision during the technical meeting (Paris, September 2016)

Annex 1

Case definition according to Palmu 2015

Register-based pneumonia

Case definition hierarchy based on register data:

1.Any hospital-diagnosed pneumonia

Any register-based event with an ICD10 diagnosis compatible with pneumonia: J10.0, J11.0, J12 to J18, J85.1 and J86

OR

Any register-based event with an ICD9 diagnosis compatible with pneumonia:480, 481, 482, 483, 485, 486, 487, 510, 513, 518.81, 511.1

Modified providing Definition of clinical IPD, SpCAP and all cause pneumonia using ICD codes

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2. Any hospital-treated pneumonia

#1 and hospitalization at least overnight 3. Confirmed hospital-treated primary pneumonia

#2 and final primary discharge diagnosis for pneumonia (ICD10/ICD9 as in #1)

4. Confirmed hospital-treated primary bacterial pneumonia

#2 and final primary discharge diagnosis for pneumonia (ICD10: J13, J14, J15, or J18 OR ICD9: 481, 482, 483, 486)

5. Any hospital-diagnosed pneumococcal pneumonia

Any register-based event with an ICD10 diagnosis compatible with pneumococcal pneumonia: J13

OR

Any register-based event with an ICD9 diagnosis compatible with pneumococcal pneumonia: 481

6. Empyema

hospital-treated ICD10 code J86 OR ICD9 code 510 and hospitalization at least overnight

Clinically suspected IPD

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Clinically suspected IPD has been defined and PCV10 vaccine impact estimated in Palmu 201518 using the following case-definitions:

1. Register-based non–laboratory confirmed IPD or unspecified sepsis: admission or discharge notification with ICD10 or ICD9 code compatible with invasive pneumococcal disease or unspecified sepsis (Table 4) assigned in the hospital discharge register without confirmation as IPD by laboratory assays (isolation of S pneumoniae and/or detection of pneumococcal DNA or antigen from a normally sterile site).

2. Register-based non–laboratory confirmed IPD: ICD10 or ICD9 code compatible with IPD assigned in the hospital discharge register as final discharge diagnosis (Table 4) without confirmation as IPD by laboratory assays. This is a subgroup of the more sensitive case definition as defined above.

18 Palmu A. A., Kilpi T. M., Rinta-Kokko H., Nohynek H., Toropainen M., Nuorti P., Jokinen J. Pneumococcal Conjugate Vaccine and Clinically Suspected Invasive Pneumococcal

Disease. Pediatrics 2015: 136(1), pp. e22 -e27. doi: 10.1542/peds.2015-0458 http://pediatrics.aappublications.org/content/136/1/e22.long

http://pediatrics.aappublications.org/content/136/1/e22.long

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V2.2 15 Dec 2017

Pneumonia outcomes added as secondary objectives, outcomes and data collection tool (Table 3)

Table 3, E) becomes Table 3, G)

Additional table included in the Table 3: F) Pneumonia outcome.

Decision during the technical meeting (Utrecht, October 2017)

15 Dec 2017

Annex 1

Outcome definitions:

- unspecified pneumonia definition added - comparison group of total hospitalizations and other

control condition added.

Episode definition for pneumococcal outcomes added.

Episode definition and Table 1.4. including unspecified pneumonia codes added


15 Dec 2017

Inclusion in Table 3: a data collection tool for IPD by high risk conditions

Table 3, E) becomes Table 3, G)

Additional table included in the Table 3: E) IPD by high risk conditions.


V2.2-updated

26 Apr 2018

ICD codes revised according to sites comments after HRC data collection in March 2018

Additional ICD codes added to Table 4: C93: Monocytic leukaemia C96.9: Malignant neoplasm of lymphoid, haematopoietic and related tissue, unspecified C76-C80: Malignant neoplasms of ill-defined, secondary and unspecified sites

ICD codes revised according to sites comments after HRC data collection in March 2018

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ICD code for cochlear implant corrected: Z96.21 instead of Z96.1

ICD code for hepato-renal syndrome was corrected K76.7 instead of K76.

Population-level impact of Pneumococcal Conjugate Vaccines in … · 2018-12-06 · 3 Objectives...

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