Global Literature Review of Haemophilus Influenzae Type B and Streptococcus Pneumoniae Invasive Disease Among Children Less Than Five Years of Age 1980–2005

Home , Miss Spain 2009

WHO/IVB/09.02 ORIGINAL: ENGLISH

Global literature review of Haemophilus influenzae type b and Streptococcus pneumoniae invasive disease among children less than five years of age 1980–2005

Immunization, Vaccines and Biologicals WHO/IVB/09.02 ORIGINAL: ENGLISH

Global literature review of Haemophilus influenzae type b and Streptococcus pneumoniae invasive disease among children less than five years of age 1980–2005

Immunization, Vaccines and Biologicals WHO/IVB/09.02 ORIGINAL: English

Global literature review of Haemophilus influenzae type b and Streptococcus pneumoniae invasive disease among children less than five years of age 1980–2005 The Department of Immunization, Vaccines and Biologicals thanks the donors whose unspecified financial support has made the production of this document possible.

This publication was produced for the Immunization, Vaccines and Biologicals, WHO, by: Maria Deloria Knoll1, Katherine L. O’Brien1, Emily Henkle1, Ellen Lee1, James P. Watt2, Natalie McCall1, Punam Mangtani2

1 GAVI Alliance’s PneumoADIP, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA 2 GAVI Alliance’s Hib Initiative, London School of Hygiene and Tropical Medicine, London, United Kingdom

Ordering code: WHO/IVB/09.02 Printed: March 2009

This publication is available on the Internet at: http://whqlibdoc.who.int/hq/2009/WHO_IVB_09.02_eng.pdf

Copies of this document as well as additional materials on immunization, vaccines and biologicals may be requested from:

World Health Organization Department of Immunization, Vaccines and Biologicals CH-1211 Geneva 27, Switzerland

• Fax: + 41 22 791 4227 • Email: [email protected] •

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication.

Printed by the WHO Document Production Services, Geneva, Switzerland

ii Contents

Abbreviations and acronyms...... v Authorship and acknowledgements...... vii Executive summary...... xi 1. Introduction...... 1 2. Methods ...... 2 2.1 Literature search strategy ...... 2 2.2 Screening and article retrieval...... 4 2.3 Exclusion criteria...... 6 2.4 Abstractor training...... 7 2.5 Article abstraction process...... 7 2.6 Information abstracted ...... 8 2.7 Data entry...... 12 2.8 Data cleaning ...... 12 2.9 Qualitative assessment of meningitis incidence...... 14 3. Other inputs for analysis...... 18 3.1 Country classifications...... 18 3.2 Geographic and mortality strata used...... 18 4. Results...... 20 4.1 Hib studies ...... 21 4.2 Spn studies ...... 24 4.3 Hib meningitis...... 26 4.4 Spn meningitis...... 37 4.5 Comparison of Hib and Spn meningitis incidence data...... 49 4.6 Hib non-pneumonia, non-meningitis invasive disease...... 57 4.7 Spn non-pneumonia, non-meningitis invasive disease...... 59 5. Discussion...... 62 5.1 Clinical standards for case definitions and classification...... 62 5.2 Limitations of Hib and Spn incidence studies ...... 64 5.3 Data sparsity and reporting inconsistencies in the published literature.....66 5.4 Adjusted incidence data ...... 66 5.5 Foreign language papers ...... 67 6. References...... 68

iii 7. Annexes...... 69 Annex 1: Search strategies...... 70 Annex 2: Article screening instructions...... 81 Annex 3: Data Abstraction Form (DAF)...... 85 Annex 4: Member States by WHO Region...... 108 Annex 5: Countries and territories by United Nations region...... 109 Annex 6: Study characteristics and key data from Hib studies entering the meningitis and NPNM analytic database...... 110 Annex 7: Study characteristics and key data from Spn studies entering the meningitis and NPNM analytic database...... 128 Annex 8: References for studies with evaluable outcome data...... 145

iv Abbreviations and acronyms

AFR WHO African Region AMR WHO Region of the Americas CFR Case-fatality ratio CSF Cerebrospinal fluid DAF Data Abstraction Form EMR WHO Eastern Mediterranean Region EUR WHO European Region Independent Expert Panel Ad Hoc Expert Review Committee for the Global Burden of Hib and Pneumococcal Disease HELLIS Health Literature, Library and Information Services Hi Haemophilus influenzae Hib Haemophilus influenzae type b HibRAT Hib Rapid Assessment Tool IBIS Invasive Bacterial Infections Surveillance IMCI integrated management of childhood infections IMEMR Index Medicus for the WHO Eastern Mediterranean Region IMSEAR Index Medicus for the WHO South-East Asia Region Invasive disease Organism identified from a normally sterile site, such as blood, cerebral spinal fluid, or pleural fluid JHBSPH Johns Hopkins Bloomberg School of Public Health LILACS Latin American and Caribbean Health Sciences Information LP lumbar puncture LSHTM London School of Hygiene and Tropical Medicine NPNM Non-pneumonia, non-meningitis PCR polymerase chain reaction SEAR WHO South-East Asia Region Spn Streptococcus pneumoniae UNICEF United Nations Children’s Fund WHO World Health Organization Working Group Global Burden of Hib and Pneumococcal Disease Working Group WPR WHO Western Pacific Region

v vi Authorship and acknowledgements

This work was performed collaboratively by WHO, the PneumoADIP and the Hib Initiative. The PneumoADIP and the Hib Initiative are funded in full by the GAVI Alliance, and The Vaccine Fund.

Hib and Spn Global Disease Burden Working Group

Core Working Group Members: World Health Organization: Thomas Cherian, Lara J. Wolfson Johns Hopkins Bloomberg School of Public Health: Maria Deloria Knoll, Orin S. Levine, Katherine L. O’Brien, James P. Watt London School of Hygiene and Tropical Medicine: Kim Mulholland

Extended Working Group Members: World Health Organization: Maureen Birmingham Johns Hopkins Bloomberg School of Public Health: Emily Henkle, Ellen Lee, Natalie McCall, Jennifer Moïsi, Suyan Tian London School of Hygiene and Tropical Medicine: Punam Mangtani

Acknowledgments

Literature Review: Johns Hopkins Bloomberg School of Public Health: Neelam Ahmed, Bethany Baer, Bianca Bell, Will Checkley, Cynthia Fisher, Yatin Gadgil, Shivam Gupta, Erin Kish, Rachel Lestz, Natalie McCall, Shaun Morris, Riyadh Muhammad, Roopal Patel, Sarah Polk, Stephanie S. Renegold, Hasan Shahib, Melissa Seaman, Jesse Sturm, Andrea Sutherland, Andre Wattiaux, Chizoba Wonodi Center for Disease Control: Brendan Flannery, Vishnu Sneller, Michael Wiederhold London School of Hygiene and Tropical Medicine: Venetia Clarke, Andreia Costa Santos, Isaac C. Fung, Hiwot Haile-Selassie, Kenneth Lee, Hong Huay Lin, Jennifer Palmer, Emily Robinson, Susanna Scott, Beth Temple, Maria VanKerkhove

vii Translation: Olga Alexinskaya (Freelance Russian interpreter/translator, Russia; Russian translation), Ezra Barzilay (Centers for Disease Control and Prevention, USA; Greek translation), Tomoya Saito (Johns Hopkins Bloomberg School of Public Health, USA; Japanese translation), Mark Schapiro (US Department of State, Italy; Italian translation), Jana Shaw (The Children’s Clinic, USA; Czech translation), Masja Straetemans (Centers for Disease Control and Prevention, USA; Dutch translation) Country Consultation: London School of Hygiene and Tropical Medicine: Ulla Griffiths World Health Organization: Marta Gacic Dobo Johns Hopkins Bloomberg School of Public Health: Lois Privor-Dumm

Additional Support: Johns Hopkins Bloomberg School of Public Health: Chantelle Boudreaux , LaTia Brinkley, Kimberly Carlton, Ed Chan, Zunera Gilani, Lindsay Grant, Rana Hajjeh, Avanti Johnson, Kimberly Johnson, Walt Jones, Rula Khoury, Benedicta Kim, Lawrence Moulton, Sharmila Shetty, Katherine Williams London School of Hygiene and Tropical Medicine: Karen Edmond, Claudia Da Silva, Keith Branson World Health Organization: Thomas Allen, Anthony Burton, Ximena Laurie, Kenji Shibuya, Martin Weber

Sharing unpublished data: Jay Berkley Steve Black Abdullah Brooks Felicity Cutts Rosanna Lagos Shabir Madhi Hanna Nohynek Anthony Scott Samir Saha Mark Steinhoff

viii The authors wish to thank the Independent Expert Review Panel of the Global Burden of Hib and Spn Disease Project for reviewing proposed approaches and methodology for estimating Hib and Spn disease burden, and whose recommendations directly impacted the literature search strategy. Dr Zulfiqar Ahmed BHUTTA, Professor, Pediatrics and Child Health, The Aga Khan University, Pakistan Dr Claire BROOME, Consultant, USA Dr Harry CAMPBELL, Department of Public Health Sciences, Edinburgh University Dr Daniel CHANDRAMOHAN, Disease Control and Vector Biology Unit, London School of Hygiene and Tropical Medicine, United Kingdom Dr Paul FINE, Professor of Communicable Disease, Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom Dr Bradford GESSNER, Agence de Médecine Préventive (AMP) a l’Institut Pasteur, Paris, France Dr Bryan GRENFELL, Biology Department, The Pennsylvania State University, USA Dr Alan R. HINMAN, All Kids Count, Task Force for Child Survival and Development, Decatur, GA, USA Dr Keith KLUGMAN, Department of International Health, Emory University, Atlanta, GA, USA Dr Julie LEGLER, Department of Mathematics, Statistics and Computer Science, St. Olaf College, USA Dr Walt ORENSTEIN, Emory Vaccine Center, Emory University, USA Dr Hanna NOHYNEK, Department of Vaccines, National Public Health Institute, Finland Dr Anne Schuchat, Centers for Disease Control and Prevention, USA Professor Peter SMITH, London School of Hygiene and Tropical Medicine, United Kingdom Dr Cynthia WHITNEY, Centers for Disease Control and Prevention, USA

ix x Executive summary

Introduction:

Estimates of Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (pneumococcus, Spn) global disease burden among children less than five years of age are needed for major policy decisions regarding prevention and treatment priorities. In particular, vaccine policy decisions are a major priority of global health organizations. To this end, a comprehensive literature review of published and unpublished reports of Hib and pneumococcal disease among children less than five years of age was undertaken to provide input parameters for a World Health Organization (WHO) modelling study directed at estimating global, regional, sub-regional and country level Hib and pneumococcal disease burden. This document describes the literature search method and the data abstraction tools, and provides a descriptive analysis of the reports identified by the literature search. The data from this literature search was then used to populate models to estimate the global disease burden of Hib and Spn. The literature review and modelling work was carried out between 2005 and 2007. The methods and results of the models themselves are published elsewhere (Wolfson, 2009; O’Brien, 2009; Watt, 2009).

Literature search methodology:

Using a comprehensive set of search terms formulated with the assistance of a professional librarian at the WHO, nine databases were searched for articles on Hib or Spn disease published between 1 January 1980 and 31 December 2005. A total of 15 099 citations were identified. The titles and abstracts of these citations (where available) were reviewed to exclude those which were unlikely to contain relevant disease burden information. The full text of the remaining 1900 citations was reviewed for inclusion and exclusion criteria. Articles were sought which had information on any of the following: meningitis or any invasive disease incidence; meningitis, non-pneumonia/non-meningitis or any invasive disease case-fatality ratio; age distribution of invasive disease cases, or invasive disease syndrome distribution. In addition to these disease-specific parameters, information was also abstracted from the papers on the study methodology, so that a quality assessment could be done of the data reported in the paper.

Literature review results:

Of the 1900 articles reviewed, 336 studies had evaluable key extracted outcomes (205 reported Hib data, 211 reported Spn data, and 80 of the 336 studies reported on both Hib and Spn disease). Of these 336 studies, 266 provided data for at least one variable in the meningitis or non-pneumonia, non-meningitis (NPNM) model; 176 provided data on Hib disease, 164 provided data on Spn disease, and 74 of the 266 studies provided data on both Hib and Spn disease.

xi Hib studies:

General: A total of 205 studies provided evaluable Hib data. Most studies were from the WHO European Region (EUR, N = 65) and the WHO Region of the Americas (AMR, N = 49); fewer studies were from the WHO African Region (AFR, N = 33) and the WHO Western Pacific Region (WPR, N = 35), and fewest were from the WHO Eastern Mediterranean Region (EMR, N = 12) and the WHO South-East Asia Region (SEAR, N = 11).

Meningitis incidence: Of the 205 Hib studies, 110 (54%) provided meningitis incidence data. Of these, few (N = 20, 18%) reported meningitis incidence adjusted for recognized under-detection biases. Although most of the world’s under-5 population lives in countries within AFR and SEAR, these regions had only 12 and 4 Hib meningitis incidence studies respectively, compared with 41 in EUR, and 22 in AMR. Only 59 (54%) studies were assessed to be of sufficient quality to include in the model.

Meningitis CFR: Sixty-two studies (30%) provided case-fatality ratio (CFR) data for any syndrome, 55 (89%) of which reported Hib meningitis CFRs with representation from all regions. Both the greatest absolute CFR and the greatest range of CFRs measured were from AFR and SEAR.

NPNM: There were 27 studies which provided data on the relative distribution of invasive Hib meningitis cases to NPNM cases (invasive Hib disease that was classified as other than meningitis or pneumonia). Studies were available from every region, but no region had more than nine studies. There were fewer NPNM cases relative to the number of meningitis cases, the difference of which increased with increasing mortality. There were only five studies which provided data on both NPNM CFR and meningitis CFR.

Spn studies:

General: A total of 211 studies provided evaluable Spn data. Most studies with Spn data were from EUR (N = 65) and AMR (N = 68); fewer studies were from AFR (N = 32) and WPR (N = 33), and the least were from EMR (N = 8) and SEAR (N = 5).

Meningitis incidence: Out of 211 studies, 90 (43%) provided meningitis incidence data. Of these, none reported meningitis incidence adjusted for recognized under-detection biases, but five reported information that could be used by the reviewers to adjust the estimates. Similarly to Hib meningitis incidence studies, most Spn meningitis incidence studies were from EUR (N = 41) and AMR (N = 24); only 10 and 13 studies were from AFR and EMR, respectively, only two studies were from EMR, and there were none from SEAR. Of the 90 Spn meningitis incidence studies, 51 (57%) were assessed to be of sufficient quality to be included in the model.

Meningitis CFR: Of the 60 (28%) Spn studies reporting CFRs for any Spn syndrome, 34 reported CFRs for meningitis. All regions were represented, with the highest CFR observed in AFR and SEAR.

xii NPNM: There were 38 Spn studies providing information on the relative distribution of Spn NPNM cases to meningitis cases. Studies were available from every region except EMR. Non-severe NPNM was documented only in the very low mortality strata. There were more NPNM cases relative to meningitis cases reported in very low mortality countries and more meningitis cases relative to NPNM cases for all other mortality strata. There were only two studies with NPNM CFR and meningitis CFR, from AFR and AMR.

Summary:

There is a large body of literature on serious, invasive, Hib and Spn disease among children less than five years of age, representing all regions of the world. These data provide measures of meningitis incidence, case and syndrome distributions, and CFRs for various severe syndromes of interest. With rigorous literature review criteria and a systematic approach to identifying reports, a comprehensive literature database has been established from which models were constructed of Hib and Spn disease burden among children less than five years. However, Hib and Spn disease burden estimates remain limited by the number and representativeness of studies from some regions of the world, as well as the lack of consistency of information provided in the reports and the quality of surveillance (i.e. case ascertainment and laboratory diagnosis) on which the studies report. Efforts to improve the quality of disease surveillance and the consistency and quality of surveillance reporting will improve the input parameters for such models in the future.

xiii 1. Introduction

This document describes the literature review, data abstraction, and descriptive analysis of the data which was used in models to estimate the global disease burden of Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Spn) among children less than five years of age in the year 2000. This work was carried out between 2005 and 2007.

In a 2002 World Health Organization (WHO) report, Bennett and colleagues presented a summary and analysis of published and unpublished literature on Hib disease in the pre-immunization era, with particular focus on Hib meningitis incidence, age distribution and case-fatality ratios (Bennett, 2002). This analysis included literature published between 1970 and October 2001. From 2004 to 2005, the WHO collaborated with PneumoADIP, the Hib Initiative, and Johns Hopkins Bloomberg School of Public Health (JHBSPH) to update this literature search on Hib disease, and to conduct a new literature search on Spn disease. The objective of this review was to estimate the global burden of Hib and Spn disease using models based on data from the existing literature. In June 2005, the results of the literature searches were presented to an Ad Hoc Expert Review Committee for the Global Burden of Hib and Pneumococcal Disease (Independent Expert Panel) convened by WHO to review the proposed approach and methodology for estimating Hib and Spn disease burden. The Independent Expert Panel made a number of recommendations to the Global Burden of Hib and Pneumococcal Disease Working Group (Working Group) about the modelling methodology. To implement those recommendations, it was necessary to conduct a revised literature search for Hib and Spn. The Working Group aimed to consolidate information extracted from past literature search efforts in a standardized format and to incorporate new information, which may have been missed by the previous reviews or made available after the database for the June 2005 meeting had closed. This effort included implementing the Independent Expert Panel’s recommendation to incorporate data quality-assessments of the studies identified through the literature review.

This report provides the documentation and summary of that systematic, revised literature review conducted between 2005 and 2006.

WHO/IVB/09.02 1 2. Methods

2.1 Literature search strategy

The literature search included articles published between January 1980 and November 2005, inclusive.

2.1.1 Strategy for Hib and Spn literature search A professional librarian at WHO identified potentially relevant references by systematically searching the published literature using a defined search strategy. This search strategy was modified according to the features of each database. Specific search strategies are described in detail in Section 5.1.2 for Hib, Section 5.1.3 for Spn and Annex 10.1. The results of the literature search were compiled into a password-protected online database of identified references maintained at JHBSPH. Figure 1 depicts the flow of activities and number of references identified at each step. At the last step, articles that presented data from more than one country were treated as a separate study for each country represented.

Figure 1: Summary of references identified and studies abstracted

15 099 Hib & Spn references identified from database search and title/abstract screened + 32 HibRATs* + 12 references identified from grey literature search and country consultation process

1331 duplicate 54 unable to 3285 met criteria for full text review citations obtain full text

1899 undergo full text review 1000 screened out for lack of applicable data 216 fail to meet primary outcome 899 enter data abstraction process 352 excluded for criteria, partial data meeting at least abstracted one exclusion 332 articles (336 stumeet criteria criteria for at least one extracted outcome and contain evaluable datadies)

* HibRAT = Hib Rapid Assessment Tool (Feikin, 2004; WHO, 2001)

2 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 2.1.2 Databases searched All databases listed below were searched for both Hib and Spn literature, with the exception of the Pascal database, which was used for the Hib search only. The WHO subscription for the Pascal database expired between the time of the Hib search and Spn search. Furthermore, due to the limited number of unique Hib articles identified through the use of this database, the Working Group decided to omit Pascal for the Spn literature search. All languages were considered in the literature search. A detailed description of the database search criteria can be found in Annex 10.1. 1) Medline (US Library of Medicine) and Embase (Elsevier Science). 2) CAB Health (CAB International). 3) Cochrane (Cochrane Collaboration). 4) Pascal (Institut de l’Information Scientifique et Technique) – Hib search only. 5) Biosis (Thomson Scientific). 6) Regional databases: a) African Index Medicus; b) Index Medicus for the WHO Eastern Mediterranean Region (IMEMR); c) Latin American and Caribbean Health Sciences Information (LILACS) database produced by BIREME, the Latin American and Caribbean Center on Health Sciences Information; d) Health Literature, Library and Information Services (HELLIS), which also contains Index Medicus for the South-East Asia Region (IMSEAR).

2.1.3 Hib literature search strategy for each database 1) Medline and Embase (Annex 1.1). 2) HELLIS: search terms used were “Haemophilus”, “Hemophilus”, “Hib” or “Hib disease”. 3) Biosis (Annex 1.2). 4) CAB (Annex 1.3). 5) Africa Index Medicus: search terms used were “meningitis”, “meningite”, “Haemophilus”, “Hemophilus”, “Hib”, “bacteraemia”, “bacteremia” or “sepsis”. 6) Cochrane (Annex 1.4). 7) LILACS: search terms used were “Haemophilus influenzae”, “Hemophilus influenzae” or “Hib”. 8) Pascal (Annex 1.5). 9) IMEMR: search terms used were “Haemophilus”, “Hemophilus” or “Hib”.

WHO/IVB/09.02 3 2.1.4 Spn literature search strategy for each database 1) Medline and Embase (Annex 1.6). 2) HELLIS: search terms used were “Pneumococcal” or “pneumococcus” or “Streptococcus pneumoniae” or “pneumococci” or “S. pneumoniae” or “(pneumococcal invasive disease)”. 3) Biosis (Annex 1.7). 4) CAB (Annex 1.8). 5) Africa Index Medicus: search terms used were “Pneumococcal” or “pneumococcus” or “Streptococcus pneumoniae”. 6) Cochrane (Annex 1.9). 7) LILACS: search terms used were “Pneumococcal”, “pneumococcus” or “pneumococci” or “Streptococcus pneumoniae”. 8) IMEMR: search terms used were “Pneumococcal”, “pneumococcus” or “Streptococcus pneumoniae”.

2.1.5 Unpublished (“grey”) literature Through personal correspondence, the Working Group sought data from investigators of unpublished but potentially relevant studies. Reports of WHO consultations using the Hib Rapid Assessment Tool (HibRAT) were included in this category. The HibRAT provides an estimate of Hib disease burden in settings where rigorous, long-term studies have not been performed. The HibRAT uses as much local data as possible to generate country or population-specific Hib disease burden estimates (Feikin, 2004; WHO, 2001).

2.2 Screening and article retrieval

To determine whether studies identified through the literature search were eligible for data abstraction, individuals were trained to review all titles and abstracts (when available) of the references identified for potential relevance. Studies deemed not relevant were screened out at this step, leaving studies considered potentially relevant, and studies whose relevance was unknown based on the title and abstract. References in languages other than English were “screened in” if a translation for the title and abstract was not available. The objective of this step was to reduce the workload of retrieving complete references which were obviously not relevant to the project, without losing articles that might have relevant data. Notations were made in the online database to identify the citations retained or excluded at this step. The criteria used for screening are specified in Sections 5.2 and 5.3 and the specific instructions for screening references are available in Annex 2.

Because a summary of 1970–2001 published and unpublished literature on Hib disease was available for comparison (Bennett, 2002), the results of the Hib literature search were screened by one individual only. The Spn references were screened twice to ensure only potentially relevant articles were selected. Approximately 80% of the Spn citations identified by the literature search were screened by two individuals. Of the dually screened articles, there was agreement between the two screeners on whether to include or exclude the article in 87% of cases. Among the 13% of references with discrepant screening status, only 21% were ultimately screened in through an adjudication process (2.6% of the total). This demonstrates that the screening process effectively eliminated irrelevant references and was unlikely to miss potentially useful articles.

4 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Screeners and data abstractors reviewed full text articles to complete the screening process using the same screening criteria described above. The availability of the full text allowed screeners and data extractors to eliminate articles which clearly did not provide the information of primary interest, but that did not provide sufficient information in the title/abstract to confidently screen them out. If an article had been screened in based on title/abstract review but subsequently excluded based on the screening of the full text of the article, the article was sent to a second reviewer. If the second reviewer decided to include the article for data extraction, an adjudicator evaluated the discrepancy, and their decision was considered final.

Examples of articles screened in During the screening process, references deemed potentially relevant and screened in were those which included any of the following data. 1) Incidence in children under 15 years of age for: a) Hib meningitis, pneumonia, or non-pneumonia/non-meningitis (e.g. sepsis, bacteraemia, septic arthritis, epiglottitis, etc.) invasive disease (organism identified from a normally sterile site, such as blood, cerebral spinal fluid, or pleural fluid); b) Spn meningitis, pneumonia, or non-meningitis/non-pneumonia invasive disease. 2) Age distribution of cases of invasive Hib or invasive Spn disease. 3) Case-fatality ratios of invasive Hib or invasive Spn disease. 4) Distribution of Hib and Spn disease syndromes (i.e. proportion of cases due to meningitis, pneumonia, sepsis, or other invasive disease). 5) Etiology by syndrome (i.e. proportion of all meningitis or other invasive disease by bacterial etiology, if organisms isolated include Hib and/or Spn).

Although the objective of the project was to estimate Hib and Spn disease burden in children less than five years of age, all articles were screened in that included relevant data from children less than 15 years of age.

Examples of articles screened out Articles containing only the types of data listed below were screened out during the screening process. 1) A case report (single case). 2) Antimicrobial resistance studies. 3) Vaccine immunogenicity and safety studies. 4) Nasopharyngeal carriage studies. 5) Molecular characterization of bacterial strains. 6) Policy papers. 7) Studies of disease only among adults. 8) Studies of species other than Haemophilus influenzae (Hi) or Spn. 9) Studies including only children less than one year of age. 10) Studies with isolates only from non-sterile sites. 11) Review articles with no original data.

WHO/IVB/09.02 5 The online reference database specifies the screening status for each identified reference. Screeners distinguished review articles in the online database to facilitate their rapid identification and retrieval for other purposes, for example to check for additional references.

2.3 Exclusion criteria

Following the screening process, data abstractors reviewed the remaining studies and applied exclusion criteria that eliminated studies with the following characteristics from complete data extraction. 1) There was “substantial use” (defined as coverage > 25%) of Hib or Spn conjugate vaccines in the study population either before or during the study period, and there were no data in that reference from the period prior to vaccine introduction or widespread use of vaccine, since the objective of this analysis was to estimate disease burden prior to vaccine introduction. 2) The study report included cases occurring prior to 1980; such studies were deemed too old to include epidemiologically relevant data given the possibility for major changes in disease patterns, and improvements in diagnostic tools over time. 3) The study involved less than 12 months of case ascertainment, and therefore does not account for possible seasonality of disease. 4) The data reported were from a specific sub-population of children (e.g. distinct racial/ethnic background, shared medical condition believed to change the risk of disease such as HIV infection) only, with no information about the general population. As the focus of the Working Group was data which could be generalized to the whole country, studies reporting data only for sub-populations such as Native American or Australian Aboriginal children were excluded. If a study reported data both for the general population and a select sub-population, the study was included; if the data for the populations were reported separately, the reviewer would extract data regarding the general population only. 5) The data reported were not grouped into any of the three following age categories: 1 (±1 month) to 11 month olds (±1 month); 1 (±1 month) to 23 month olds (±1 month); or 1 (±1 month) to 59 month olds (±1 year) (some variability in age categorization was accepted if it was not expected to significantly affect parameter estimates): since the objective was to obtain under-5 parameters, these had to be directly available in the article or calculable from under-1 or under-2 parameters.

There were 352 articles excluded for at least one of the reasons above (Figure 1).

2.3.1 Exclusion criteria for specific variables Additional exclusion criteria were applied to determine if data on disease incidence, age distribution of cases, distribution of syndromes, or case-fatality ratios could be abstracted (refer to Annex 3 to view the Data Abstraction Form). The criteria below were applied as exclusion criteria.

6 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Incidence: • <20 000 child-years of observation on average for each one-year age stratum, unless the area under study was an entire country, in which case the size of the entire population for that age group could be included. Age distribution, syndrome distribution: • <30 cases of either Hib or Spn invasive disease in children less than five years of age.

2.4 Abstractor training

All individuals trained to screen references or abstract data had graduate training in medicine and/or epidemiology. All individuals were trained in the objectives and process of screening and data abstraction prior to working on the project. A total of 44 individuals were trained to work on the project. This large number of abstractors was needed because of the extensive screening process instituted, and the time required to complete the data abstraction (approximately one to two hours per full text article).

Multiple training sessions were conducted at JHBSPH and LSHTM from October 2005 to May 2006. With the exception of three individuals who attended data abstraction training via teleconference, all training was conducted in person over one- to three- day sessions. Training sessions included presentations, sample studies for screening and select studies for “practice” data abstraction. To practice the data abstraction process, all data abstractors were assigned the same three studies as a means of comparing the accuracy of the different abstractors and assessing the heterogeneity between them.

2.5 Article abstraction process

A standardized Data Abstraction Form (DAF) was developed through collaboration between the WHO, PneumoADIP, and the Hib Initiative (refer to Annex 3 to view DAF). The abstraction form first prompted the reviewer to apply specific exclusion criteria to studies that had been “screened-in”. These initial exclusion criteria, listed in Section 5.3, determined if abstraction of the complete article was appropriate. If the article met any of the exclusion criteria, it was excluded and data abstraction stopped.

For all studies screened-in after application of the exclusion criteria, data abstractors completed structured abstraction of the full article. Data on the study design, population, and case definitions were abstracted from all articles. If a study met the additional inclusion criteria for abstraction of at least one category of data (e.g. disease incidence, age distribution of cases, distribution of syndromes, or case-fatality ratios), information about the study’s data quality was collected. For all studies, data abstractors were asked to indicate if the references cited contained other potentially relevant articles.

WHO/IVB/09.02 7 2.6 Information abstracted

(Refer to Annex 3 to view the Data Abstraction Form).

2.6.1 Location of study The number and names of countries included in the study were recorded. If a paper described a multi-country study, and if possible, data from each of the countries were abstracted separately. However, some papers describing a multi-country study reported only aggregated data making the distinction between each country’s data impossible. In these cases, the names of all countries included and the aggregate data were recorded. The abstractors indicated if case-ascertainment occurred throughout the country or on a sub-national level (e.g. a district or county), and recorded the names of the areas involved (e.g. name of city or county of the study). Information about the study setting (e.g. rural, urban, etc.) as described by the authors was also collected.

2.6.2 Study design Data abstractors characterized study design by indicating if data collection was prospective or retrospective, active or passive surveillance, and hospital-based or community-based case ascertainment. If the study was hospital-based, the number and type of hospitals involved were recorded.

2.6.3 Study population The lower age limit for children included in the study, whether HIV prevalence was reported, and the under-5 mortality rate of the study population, were recorded when available. Other information collected included the availability and use of Hib or pneumococcal vaccine, and the proportion of subjects who received antibiotics prior to presentation or specimen collection.

2.6.4 Case definitions Data abstractors indicated the syndrome of Hi or Spn invasive disease measured and the specific laboratory methods used to characterize children as cases of invasive disease (e.g. culture, latex agglutination, polymerase chain reaction). For studies of invasive Hib disease, abstractors indicated if the authors specified that all Hi isolates were typed, if only some isolates were typed and the others were assumed to be type b, or if no typing was done and all isolates were assumed to be type b.

Hib and Spn invasive syndromes were extracted as reported in the article, with invasive disease defined as an organism identified from a normally sterile site, such as blood, cerebral spinal fluid, or pleural fluid. Syndromes of interest were all invasive disease, all non-meningitis invasive disease, meningitis, pneumonia, or non-pneumonia/non- meningitis (e.g. sepsis, bacteraemia, septic arthritis, epiglottitis, etc.) invasive disease.

2.6.5 Years of surveillance If a study provided incidence data, the month and year of the start and end dates of surveillance period were recorded.

8 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 2.6.6 Incidence The data abstractors were prompted to determine if incidence data could be abstracted from each study. If a study did not report Hib or Spn invasive disease incidence, the data abstractor skipped to questions about the age and syndrome distribution reported in the study.

If incidence data were reported, the abstractor then had to determine if the study met the minimum number of child-years of observation for incidence data abstraction. This minimum was established to ensure that incidence estimates would have sufficient precision to be justifiably included in the model. Child-years of observation were calculated by multiplying the average population of children less than five years of age in the area of the study and the number of years of the study. To be included for data abstraction, the study had to include, on average, a minimum 20 000 child-years of observation for each one-year age stratum. For example, if the study included children less than five years, a minimum of 100 000 child-years of observation were required for the study to be included for incidence data abstraction. If the study included only children less than two years, a minimum of 40 000 child-years of observation were required. The criterion of 20 000 child-years per one-year age stratum was an average. Therefore, if a study of children under five years included a total of 100 000 child-years of observation, but had only 15 000 child-years for children under one year, the study would be included. Alternatively, if the area under study was an entire country, the size of the entire population for that age group could be included (e.g. the entire population of children less than five years, or the entire population of children less than two years), even if the minimum number of child-years was not met. In this way, studies from smaller countries could be included for abstraction. If the study did not meet the minimum criterion for child-years of observation, the data abstractor did not abstract data about disease incidence.

Incidence for all age strata and all disease syndromes reported in a study were recorded. Three age strata (< 5 years, < 2 years, < 1 year) were particularly important, as they were the age strata used for data analysis. If incidence within these age strata were not reported but could be calculated using the available data, the calculated values were recorded.

If a study reported incidence data for a special sub-population (e.g. children with HIV infection) as well as the general population, data for the general population only were recorded. This literature search was not used to determine differences in disease risk or mortality in HIV positive children compared to HIV negative children. Wolfson and colleagues describe the separate literature seaches and the products of these searches in another publication (Wolfson, 2009).

Incidence rates adjusted to account for study limitations were also recorded if reported by the authors, as well as the reason for the adjustment (i.e. cases missed because they did not come to a study facility or were not evaluated, diagnostic tests were not done, or results were culture-negative but probably bacterial disease).

WHO/IVB/09.02 9 2.6.7 Age distribution/syndrome distribution If a study provided incidence data, age and syndrome distribution, data were usually abstracted with the incidence data. For the remaining studies, to abstract age distribution or syndrome distribution, a minimum of 30 cases of either Hib or Spn invasive disease in children under age five was required. This minimum number of cases was chosen to maintain statistical validity for the distribution of cases across age groups. If a study did not meet this criterion, and did not report incidence data, no further information was abstracted.

To abstract age distribution data, the study must report the proportion of Hib and/or Spn invasive disease occurring in any age group of children less than five years. If data for children under five years were provided without further description of age sub-categories (e.g. under two years, under one year), these data were not abstracted.

To abstract syndrome distribution data, the study must report the distribution of Hib and/or Spn invasive disease by syndrome for any age group among children less than five years. If a study provided incidence data for all Hib invasive disease, without further characterization of the distinct syndromes, it could not be used in the model. At minimum, the manuscript had to provide data for two different categories of invasive disease (e.g. meningitis and all other invasive disease) to have syndrome distribution data abstracted. If age or syndrome distribution data could not be abstracted, the abstractor then evaluated the study for abstraction of case-fatality ratio data.

2.6.8 Case-fatality ratio Data abstractors evaluated all studies including cases of Hib or Spn invasive disease to determine if case-fatality ratio (CFR) data could be abstracted. To calculate the CFR, the study needed to provide the number of cases due to the disease of interest (denominator), and the number of deaths among those cases (numerator). If CFRs were not reported by the authors but the relevant data for children under five years were available, abstractors calculated and recorded the CFRs. The abstractors were instructed to record for the denominator only the cases for which mortality outcome (i.e. alive or dead) was known. If the manuscript did not provide this information, CFR could not be calculated, and this variable was left blank for this study. Initially a minimum of 30 cases with evaluable death outcome was anticipated as criteria for inclusion in the analytic database, but this was later expanded to a minimum of 25.

2.6.9 Data quality measurements Objective questions about the quality of the study design and methods were included in the Data Abstraction Form (Sections 5.9.2 to 5.9.3, and Annex 3). The series of objective questions served as a guide for the trained reviewer to make the subjective assessment of data quality as consistent across reviewers as possible. For case ascertainment, reviewers were asked to characterize the participating paediatric hospitals, to describe care-seeking patterns within the study area, and to assess the potential impact of these care-seeking practices on case ascertainment. For laboratory methods, reviewers were encouraged to consider possible limitations in specimen handling and transport, and in diagnostic techniques. The subjective assessment involved one question each about case ascertainment, diagnostic methods, and the population denominator used for incidence-rate calculations as expressed in the questions shown in Figure 2.

10 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Figure 2: Subjective data collected for determination of quality scores

CASE ASCERTAINMENT Select the response that best describes your judgment of whether the case ascertainment methods were likely to miss a significant proportion of cases, for any of the disease syndromes studied.  Unlikely to have missed a significant proportion of cases  May have missed a significant proportion of cases but results adjusted accordingly  May have missed a significant proportion of cases, results not adjusted  Unable to determine

DIAGNOSTIC METHODS In your opinion, the diagnostic methods described for the study were:  Likely to be reliable  Unlikely to be reliable  Unable to determine reliability

POPULATION SOURCE Does the study specify the source for the population data provided?  Yes (answer question 53a)  No, source of population data not specified (skip to question 54)  No population data provided (skip to question 56) If yes, did the population denominator come from a reliable source (e.g. current census)?  Ye s  No  Unable to determine

2.6.10 Spn non-pneumonia, non-meningitis: additional data collected Spn non-pneumonia, non-meningitis (NPNM) cases were differentiated into “severe” and “non-severe” (occult bacteraemia that was detected in countries where it is standard clinical practice to obtain blood culture in every febrile young child). All studies that reported cases and deaths from Spn NPNM syndromes were re-reviewed by a single Extended Working Group member and cases were separated out into “severe” and “non-severe”. The proportion of severe cases was calculated and abstracted for each article. When it was not possible to decide on the basis of the published paper which proportion of cases were “severe” and “non-severe”, authors were contacted for further details. “Severe” cases of NPNM were defined as:

WHO/IVB/09.02 11 • patients who were hospitalized; • patients who had a localized invasive infection (myocarditis, septic arthritis, peritonitis, cellulitis, etc.); • all NPNM cases from high and very high mortality countries where it is not routine to collect blood cultures in every young patient with a high fever. • All papers from Africa that reported sufficient NPNM cases were categorized as “severe”.

2.7 Data entry

Abstractors entered data in a Microsoft InfoPath database, which was available online through the JHBSPH password-protected web portal. Paper copies of the DAF were available because abstractors occasionally could not enter data online themselves, and would need to send paper copies to study staff in Baltimore, Maryland, for data entry.

2.8 Data cleaning

2.8.1 Review of discrepancies and adjudication If a data abstractor determined an article met criteria for abstraction of either disease incidence, age distribution of cases, distribution of syndromes, or CFR, the article was assigned to a second reviewer for repeat data abstraction. If the second reviewer determined the study did not meet criteria for abstraction of these data, or if the numeric data abstracted by the two reviewers differed, an adjudicator evaluated the discrepancy to determine the final result.

For studies published in English, French, German, Italian, Portuguese and Spanish, duplicate review was done as described above. For studies published in other languages, only one review was possible due to the limited number of appropriately trained individuals available to read the articles. The reports from the WHO HibRAT were reviewed by a trained individual familiar with the assessment tool’s methodology, and any useable data was adjudicated by a second trained individual.

Due to time and budgetary constraints, data cleaning efforts focused on the variables of most importance — those influencing the results of the meta-analyses. Data on incidence, CFR, age distribution, or syndrome distribution, were adjudicated by (at least) one of the members of the Extended Working Group. The following steps were taken, looking at the hard copies of the data tables side-by–side. 1) If both abstractors recorded the same numbers, the data was marked as acceptable. 2) If the numbers recorded by both abstractors were the same, but additional age or syndrome strata were recorded by one abstractor, the data abstraction with more information was accepted, as long as the data from that abstractor were internally consistent. 3) If the abstractors did not agree, the full article was retrieved and the correct results were determined by the adjudicator.

12 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 The data quality score was a composite of the subjective responses from both abstractors and therefore did not require adjudication (Section 5.9.2), as were all open response variables. All other variables were drawn from the form of the abstractor deemed more complete or correct in steps two and three above, or chosen randomly if both abstractors were acceptable. It was felt that the abstractor who was more correct and detailed for the key variables would also be more correct in abstracting the remaining data. Other key variables used in the analysis (country, midpoint year of study) were occasionally missing and were obtained from the original article.

2.8.2 Elimination of articles for studies with multiple publications The country and dates of surveillance were reviewed for articles contributing to the analysis. Possible overlapping surveillance time-periods or reporting of surveillance data in more than one article were identified. Seven articles were eliminated due to overlaps. Several articles were published in Spanish and English; if identical data were presented, the English language article was used.

2.8.3 Identification of missing papers 1) Papers identified by comparison with the previous work by Bennett and colleagues. The citations that were identified in the literature search were first compared with those cited in the previous work by Bennett and colleagues. Of the citations in the the previous work by Bennett and colleagues, 23 Hib and four Spn articles were found that had not been identified by the 2005–2006 literature search. These were reviewed, and it was found that 18 Hib articles and two Spn articles did not meet the literature search criteria (unpublished articles, review articles etc.). There were five Hib and two Spn articles that had been missed by the literature search despite meeting all the requisite criteria. These articles were then retrieved, screened and abstracted, and were applicable.

2) Papers identified by expert review of articles. At two dates, October 2006 and February 2007, a list of studies providing meningitis CFR and incidence data for analysis were circulated to a group of five experts in the fields of Hib and Spn research, and to the Working Group, in order to identify important studies which were absent from the list. Twenty-five articles missing from Hib or Spn meningitis CFR or incidence analysis identified by the experts and the Working Group were again reviewed to confirm the reason for exclusion. As a result of this process, one article was added that had been published after the literature search process was concluded, and two unpublished data sources were added. For three vaccine trial articles, the authors were contacted to obtain data that allowed their data to be included in the model.

WHO/IVB/09.02 13 3) Papers identified through country consultation. A further source of data was obtained through the country consultation process. Letters were sent to each country in August 2007 with provisional Hib and Spn disease burden estimates and data sources of these estimates. Countries were offered the opportunity to bring to our attention additional sources of local data for review and possible addition to the database. Four data sources were identified during this process. One foreign language article was identified that had been indexed after the original search was completed; one country provided acceptable Ministry of Health data in time for addition to the database; one article identified in the literature review had been erroneously excluded, and a HibRAT with acceptable data was included despite the fact that the resulting peer-reviewed publication was excluded.

2.8.4 Non-pneumonia, non-meningitis (NPNM) 1) Review of all NPNM CFR articles. All of the articles for which information on NPNM CFR had been abstracted were reviewed. For Spn, a CFR of zero to “non-severe” NPNM patients was assigned, and only the CFR from patients with severe NPNM illness was used in the analysis. All Hib NPNM cases were categorized as “severe” so no additional severity data was collected. NPNM CFRs were excluded from studies where there were fewer than 25 cases reported.

2) Missing NPNM data. The papers reporting NPNM cases were assessed for the presence of additional variables required for the model. If any NPNM information was missing from an article deemed to have NPNM data, authors of papers included in the analysis were contacted to obtain: • the proportion of Spn NPNM cases that was “severe” and “non-severe”. An approximate proportion with “severe” and “non-severe” disease from an author was acceptable. All authors were able to stratify cases using this nomenclature. • The outcome of patients with “severe” Spn NPNM. This allowed the calculation of CFR for patients with “severe” NPNM SP infection only. • The age distribution (under-1, under-2, under-5) of cases and deaths due to NPNM. • The number of deaths in each age category for articles that reported large case series of NPNM, but did not provide CFRs.

2.9 Qualitative assessment of meningitis incidence

Estimates of childhood meningitis incidence incorporate the number of observed meningitis cases (numerator) and the population of children from which the cases originated (denominator). Inaccuracies with either of these elements can make estimates of meningitis incidence difficult to interpret or compare with other studies. Identification of cases involves two separate activities. Firstly, cases of suspected meningitis must be identified (i.e. case ascertainment). Secondly, appropriate tests must be done to determine the presence of meningitis and to identify its etiology (i.e. diagnostic tests).

14 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 2.9.1 Selection of articles Criteria were established a priori to exclude studies likely to have results of limited comparability due to small size, limited diagnostic methods, and seasonal variation. These exclusion criteria are detailed in Section 5.3.

2.9.2 Data quality categories The original approach for evaluating study quality included assessment of the methods used to determine the numerator and denominator for meningitis incidence calculations. However, because only half the studies provided enough information to evaluate the denominator used, no studies were excluded based on the assessment of the denominator. It was felt that this would unacceptably curtail an already sparse dataset.

To evaluate the numerator, abstractors were asked to subjectively assess case ascertainment and diagnostic methods (see section 5.6.9 for more detail). The following were considered important indicators of the likelihood of missing cases: not all hospitals in the study area that admitted children under five for treatment of bacteraemia, pneumonia, or meningitis were included in surveillance; some patients from the study area may have sought care outside the study area; laboratory specimens were not collected for all potential cases; laboratory testing was not performed for all specimens collected; some laboratory/medical records were not available or review of records was incomplete; there was inconsistent recruitment of cases in hospital (recruitment was not 24 hours/day, 7 days/week); study was not conducted in all areas of the facility where potential cases received care; some subjects refused to participate, and there were limitations in diagnostic methods (i.e. poor handling and transport of specimens, poor laboratory techniques). The likely quality of the diagnostic testing was also considered in the light of the type of study conducted; whether it was a prospective study with good quality control, was conducted in an area with generally high-quality health services, was conducted at a research institution or other facility with resources appropriate for study, or was conducted in an area with generally limited health services and facilities. When evaluating the care-seeking patterns, abstractors took the authors’ assessment of whether impact on case ascertainment was likely to be substantial or have little impact.

Based on the information available, the abstractors made a subjective decision on whether the laboratory and case-ascertainment methods were likely to be reliable or not.

Meningitis incidence studies were categorized into the following three groups, in order of decreasing quality. • Category “A”: Both reviewers judged the case ascertainment and laboratory methods to be reliable. • Category “B”: One reviewer judged case ascertainment and/or laboratory methods to be unreliable or un-evaluable. • Category “C”: Both reviewers judged either case ascertainment or laboratory methods to be unreliable or un-evaluable.

WHO/IVB/09.02 15 Figure 3: Categorization of study quality by assessment of case ascertainment and diagnostic methods by two reviewers

Case ascertainment* Not reliable/ Laboratory methods* Reliable/ Reliable/ Reviewer A unable to adjusted adjusted determine Not reliable/ Not reliable/ Reliable/ Reviewer A Reviewer B Reviewer B unable to unable to adjusted determine determine Reliable Reliable A B C Not reliable/ Reliable unable to B B C determine Not reliable/ Not reliable/ unable to unable to C C C determine determine

* Refer to Figure 2 for exact wording of questions used to determine quality scores.

Category “C” studies were excluded from the meta-analysis of meningitis incidence. For all CFR estimates and the estimate of the ratio of NPNM cases to meningitis cases, no exclusion was made based on the meningitis incidence quality category.

2.9.3 Data quality review It was recognized that in this initial scoring process, studies where access to care was a limitation of the setting itself (and not of the study design) were categorized as “C”. Those “C” studies were re-reviewed where the study setting was a potential limitation on the access to care (refer to bullet list below) for two reasons — some under-ascertainment was judged to be acceptable as this was the only way to include in the analysis additional geographically representative high mortality data, and mortality estimates are adjusted for access to care, therefore, even if the incidence is underestimated through inclusion of these studies, the mortality estimate will be less affected. “C” quality studies re-reviewed included the following. • Studies that had received a “C” score for case ascertainment and an “A” or a “B” score for diagnostic methods. • Studies from (United Nations regions) Africa and Asia with an “A” or “B” score for diagnostic methods, regardless of their original case ascertainment score. • Studies with an “A” or “B” diagnostic methods score that reported data on culture-negative purulent meningitis regardless of their original case ascertainment score.

16 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Studies were assigned a final case ascertainment score based on refined criteria and, if possible, incidence was adjusted as described below. • Studies that did not miss cases or that may have missed cases but provided an adjustment for this source of under-ascertainment were re-classified as “A”. In some cases, adjusted incidence was recalculated based on adjustment factors available in the paper (e.g. “only 85% of eligible children had a lumbar puncture done”, solution: adjust for the missed 15%). • Studies that used optimal case ascertainment methods but necessarily missed cases due to limitations in access to care in the setting where they were conducted. These studies were re-classified as “B” to avoid excluding all papers from high mortality regions from the analysis. The mortality estimates for these and all other papers are adjusted for access to care. • Studies that missed cases because of flawed methodology and for which no adjustment was possible were classified as “C”.

The Working Group re-reviewed 108 papers for case ascertainment and assigned a score which was considered final. Ten papers with an initial case ascertainment score of “C” were re-categorized as “A”. Six of the ten were found to have good case ascertainment, one presented data adjusted for case ascertainment issues, and three reported adjustment factors that were used to compute adjusted incidence. Of these ten, three were from the African region and four from Asia. In addition, two papers from Africa (the Republic of the Gambia) that were initially scored “C” were re-categorized as “B”.

Final study quality scores by region and incidence are shown in Figure 5 (for Hib studies) and in Figure 9 (for Spn studies). In summary, a total of 59 (54%) Hib studies and 51 (57%) Spn studies with meningitis incidence were evaluated to be of “A” or “B” quality.

WHO/IVB/09.02 17 3. Other inputs for analysis

3.1 Country classifications

Countries were characterized by region and mortality status using two methods: one for analytic purposes and one for the reporting of results. For the purpose of reporting results, all summary statistics for articles and all disease burden estimates were grouped by region using WHO-defined geo-political strata (Annex 4) and under-5 mortality strata. However, because these strata do not adequately reflect the epidemiology of Spn and Hib disease in some countries, different groupings were used in the modelling of disease burden (Section 6.2).

3.2 Geographic and mortality strata used

Strata were defined by geographic and under-5 mortality criteria in order to group together countries that would have similar patterns of Hib and Spn disease epidemiology. When imputing values for countries where no Hib or Spn data was available, values from “neighbouring” countries within the same stratum were used, and this seemed most applicable to the disease epidemiology of that country.

Geographic strata For the purpose of the Hib and Spn disease burden model, geographic groupings were required that: (a) reflected geographic proximity; (b) had a fine level of detail to allow step-wise aggregation; (c) defined groups geographically proximate to countries with potential differences in disease epidemiology. Several available definitions of geographic groupings were considered which were available through the World Bank, United Nations Children’s Fund (UNICEF), WHO, and the United Nations (UN), and it was determined that the UN definition of six regions and 21 geographic sub-regions best met the needs (Annex 5). At the sub-regional level, the African countries were further separated into those that were and were not in the so-called “Meningitis Belt” in response to the Independent Expert Panel’s suggestion, since meningitis surveillance in those countries may differ from that in other non-meningitis belt countries. Countries in the “Meningitis Belt” include the Republic of Benin, Burkina Faso, the Republic of Cameroon, the Central African Republic, the Republics respectively of Chad and of the Côte d’Ivoire, Eritrea, the Federal Democratic Republic of Ethiopia, the Republics respectively of Gambia, Ghana, Guinea-Bissau, Kenya and Mali, the Islamic Republic of Mauritania, the Republic of the Niger, the Federal Republic of Nigeria, the Republics respectively of Senegal and Sudan, the Togolese Republic, and the Republic of Uganda.

18 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Mortality strata Studies were assigned the mortality strata of the country where the study occurred during the midpoint year of the study. The rationale of grouping the countries not only by geographic proximity but also on mortality strata was that the risk of Hib and Spn disease among children was likely to be associated with general health status and access to care, both of which would be reflected in under-5 mortality figures. Numeric under-5 mortality estimates were obtained from the 2005 United Nations Children’s Fund (UNICEF) State of the World’s Children Report rather than using the combination of child and adult mortality data used to generate WHO mortality regions (UNICEF 2004). Under-5 mortality rates were reported for 1980, 1990, 1995, 2000 and 2003. A time series of estimates for each country was generated by extrapolating the mortality rates for years between the intervals. The “low”, “medium”, “high” and “very high” under-5 mortality strata were defined based on consensus of the working group members as less than 30, 30–75, 75–150 and more than 150 deaths per 1000 live births, respectively.

WHO/IVB/09.02 19 4. Results

Of the 15 099 articles identified in the literature search (including at least 1331 duplicates), the inclusion/exclusion criteria, article abstraction, and cleaning process yielded 336 unique studies with evaluable extracted outcomes for consideration in the analysis; 205 studies contained Hib data and 211 studies contained Spn data (i.e. there were 80 studies that contained data for both Hib and Spn, 125 with Hib data only, and 131 with Spn data only). Of these, 266 studies contained key extracted outcomes and (176 Hib and 164 Spn) entered the meningitis and NPNM analytic database (with 74 containing data for Hib and Spn, 102 with Hib data only, and 90 with Spn data only). All but 13 Hib, six Spn articles, and two with both, contributed to at least one of the final meningitis and NPNM models (described in detail in the methods paper [Wolfson, 2009]). Note that more than one article may provide information on a single study, and one article may report more than one study (for example, if an article reports on more than one country, each country is considered a separate study).

Figure 4: Summary of references identified and studies abstracted (continued from Figure 1)

332 articles (336 studies) meet criteria for at 70 articles (70 studies) least one extracted outcome and contain that have no data for the evaluable data meningitis and NPNM models

21 articles (21 studies) 262 articles (266 studies) enter meningitis with C quality incidence and NPNM analytic database (all A, B and C data that have no other quality incidence studies are included) data for the models

241 articles (245 studies) used for final meningitis and NPNM modelling

20 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 4.1 Hib studies

[Refer to Annex 8 for a list of Hib studies with evaluable extracted outcomes and Annex 6 for key Hib outcome data in the analytic database.]

Of 205 studies that reported evaluable Hib key extracted outcomes, the majority came from EUR (N = 65) and AMR (N = 49) and the least from SEAR (N = 11) and EMR (N = 12) (Table 1 and Map 1). Approximately 65% of the studies in the database provided data on incidence of invasive Hib disease (N = 134 with adjusted and/or unadjusted estimates). A similar percentage described the age distribution of cases (N = 139, 68%). Thirty percent of Hib studies reported data on CFRs due to invasive Hib disease (N = 62), but few studies described how cases (N = 27) or CFRs (N = 5) were distributed by syndrome. In general, these findings were consistent across regions, with the exception of studies reporting incidence data; these were less common in EMR and SEAR (only four and three studies, respectively), most common in EUR, AMR and WPR (65%–75% of studies in those regions, 24–50 studies in each region), and AFR was in the middle with 14 studies (42% of all AFR studies).

Map 1: Number of studies with evaluable key extracted Hib outcomes in each country

Number of studies:

0 1 2-5 6-19

WHO/IVB/09.02 21 Few (24/134) studies that reported incidence adjusted those estimates (or provided the necessary information to calculate adjusted estimates), to account for under-detection of cases due to limitations of the study. Those studies that did adjust accounted for cases missed because they did not come to a study facility, cases not included because diagnostic tests were not done, or negative culture results that were probable bacterial disease.

Most of the Hib studies reported Hib meningitis incidence and fewer reported on other variables considered for the disease burden model. There were at least three times as many studies with Hib meningitis incidence data than for any other Hib syndrome in every region — of all studies with any incidence data, 82% contained meningitis incidence data compared to 9% for invasive pneumonia (N = 19) and 8% for NPNM data (N = 18). Studies providing data on the age distribution of pneumonia cases were also particularly rare, only 6.3% overall compared with 57% for meningitis.

22 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 1: Number of studies with evaluable Hib data for each of the key extracted outcomes considered for the global disease burden model, by WHO region

Key extracted WHO Regions (%) Total outcomes AFR AMR EMR EUR SEAR WPR Incidence, 127 14 (11) 32 (25) 4 (3) 50 (39) 3 (2) 24 (19) unadjusted All invasive 56 5 (9) 15 (27) 1 (2) 26 (46) 0 (0) 9 (16) Meningitis 103 12 (12) 22 (21) 4 (4) 40 (39) 2 (2) 23 (22) Pneumonia 18 4 (22) 4 (22) 1 (6) 7 (39) 0 (0) 2 (11) NPNM 18 3 (17) 4 (22) 1 (6) 7 (39) 0 (0) 3 (17) Incidence, 24 2 (8) 4 (17) 4 (17) 6 (25) 2 (8) 6 (25) adjusted* All invasive 5 0 (0) 2 (40) 0 (0) 1 (20) 0 (0) 2 (40) Meningitis† 21 1 (5) 2 (10) 4 (20) 6 (29) 3 (14) 5 (24) Pneumonia 1 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) NPNM 0 ------Age 139 26 (19) 32 (23) 8 (6) 45 (32) 8 (6) 20 (14) distribution All invasive 38 3 (8) 8 (21) 0 (0) 16 (42) 3 (8) 8 (21) Meningitis 115 24 (21) 22 (19) 8 (7) 37 (32) 7 (6) 17 (15) Pneumonia 13 2 (15) 3 (23) 1 (8) 3 (23) 2 (15) 2 (15) NPNM 10 0 (0) 2 (20) 1 (10) 4 (40) 1 (10) 2 (20) Syndrome distribution of cases 27 4 (15) 7 (26) 1 (4) 9 (33) 2 (7) 4 (15) (NPNM and meningitis)‡ Syndrome distribution of CFRs 5 0 (0) 1 (20) 0 (0) 2 (40) 0 (0) 2 (40) (NPNM and meningitis)§ Case-fatality 62 12 (19) 16 (26) 3 (5) 14 (23) 3 (5) 14 (23) ratio All invasive 13 3 (23) 1 (8) 0 (0) 5 (38) 1 (8) 3 (23) Meningitis 55 10 (18) 15 (27) 3 (5) 12 (22) 3 (5) 12 (22) Pneumonia 1 0 (0) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) NPNM 6 0 (0) 1 (17) 0 (0) 2 (33) 0 (0) 3 (50) Total 205 33 49 12 65 11 35 (any data)

* Adjusted to account for under-detection of cases due to limitations of the study. † Eight studies provided adjusted estimates only; all other studies with adjusted data also provided unadjusted data. Refer to Table 10 for a line listing of the Hib meningitis incidence studies. ‡ From the distribution of syndromes from each study, 27 studies had a syndrome distribution of cases that included cases of NPNM and meningitis. § From the distribution of syndromes from each study, five studies had a syndrome distribution of CFRs that included CFRs for NPNM and meningitis.

WHO/IVB/09.02 23 4.2 Spn studies

[Refer to Annex 8 for a list of Spn studies with evaluable extracted outcomes and Annex 7 for key Spn outcome data in the analytic database.]

There were 211 studies that had evaluable Spn extracted outcomes, with the majority from AMR (N = 68) and EUR (N = 65) and very few studies from SEAR (N = 5) and EMR (N = 8) (Table 2 and Map 2), as was observed for Hib. The characterization of Spn studies was remarkably similar to Hib studies with respect to the distribution of the type of primary outcome data of interest available. Most studies provided data on incidence of invasive Spn disease (55%, N = 117) and age distribution (77%, N = 162). Data on the CFR of invasive Spn disease were reported in 28% (N = 60) of papers, and few papers described the syndrome distribution of cases (18%, N = 38) or the syndrome distribution of CFRs (1%, N = 2). While in general these findings were similar across regions, the number of studies reporting incidence data in EMR and SEAR was grossly inadequate (two and one study, respectively), and EUR and AMR dominated (N = 65 and 68 studies, respectively).

Map 2: Number of studies with evaluable key extracted Spn outcomes in each country

Number of studies:

0 1 2-5 6-19

Only five of the studies reporting Spn incidence provided the necessary information to adjust estimates to account for under-detection of isolates.

24 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 As seen for Hib studies, the majority of all Spn data on the extracted outcomes of interest pertained to meningitis. There were about three times as many studies with Spn meningitis data as for any other Spn syndrome for every outcome. This trend was similar across all regions. Very few studies had data on invasive Spn pneumonia incidence; EMR had no invasive Spn pneumonia data for any primary outcome of interest, SEAR only had data on the age distribution of invasive Spn pneumonia cases (two studies) and the CFR of invasive Spn pneumonia (one study), and EUR, with the most data on invasive Spn pneumonia incidence, had only 12 studies. Table 2: Number of studies with evaluable Spn data for each of the extracted outcomes considered for the global disease burden model, by WHO region

Key extracted WHO Regions (%) Total outcomes AFR AMR EMR EUR SEAR WPR Incidence, 117 13 (11) 33 (28) 2 (2) 52 (44) 0 (0) 17 (15) unadjusted All invasive 59 5 (8) 17 (29) 0 (0) 29 (49) 0 (0) 8 (14) Meningitis 90 10 (11) 24 (27) 2 (2) 41 (46) 0 (0) 13 (14) Pneumonia 31 5 (16) 8 (26) 0 (0) 12 (39) 0 (0) 6 (19) NPNM 23 2 (17) 7 (30) 0 (0) 8 (35) 0 (0) 6 (26) Incidence, adjusted* Meningitis† 5 1 (20) 3 (60) 0 (0) 0 (0) 0 (0) 1 (20) Age distribution 162 26 (16) 48 (30) 8 (5) 52 (32) 5 (3) 23 (14) All invasive 64 3 (5) 20 (31) 3 (5) 25 (39) 0 (0) 13 (20) Meningitis 117 24 (21) 28 (24) 5 (4) 39 (33) 5 (4) 16 (14) Pneumonia 33 3 (9) 14 (42) 0 (0) 6 (18) 2 (6) 8 (24) NPNM 28 4 (14) 9 (32) 0 (0) 6 (21) 3 (11) 6 (21) Syndrome distribution of cases 38 4 (11) 15 (39) 0 12 (32) 3 (8) 4 (1) (NPNM and meningitis)‡ Syndrome distribution of CFRs 2 1 (50) 0 (0) 0 0 (0) 0 (0) 1 (50) (NPNM and meningitis)§ Case-fatality 60 8 (13) 27 (45) 1 12 (20) 1 (2) 11 (18) ratio All invasive 25 1 (4) 10 (40) 0 8 (32) 0 (0) 6 (24) Meningitis 34 6 (18) 16 (47) 1 5 (15) 1 (3) 5 (15) Pneumonia 13 3 (23) 9 (69) 0 0 (0) 0 (0) 1 (8) NPNM 7 2 (29) 3 (43) 0 1 (14) 0 (0) 1 (14) Total 211 32 68 8 65 5 33 (any data)

* Adjusted to account for under-detection of cases due to limitations of the study. † Refer to Table 18 for a line listing of the Spn meningitis incidence studies. ‡ From the distribution of syndromes from each study, 38 studies had a syndrome distribution of cases that included cases of NPNM and meningitis. § From the distribution of syndromes from each study, two studies had a syndrome distribution of CFRs that included CFRs for NPNM and meningitis.

WHO/IVB/09.02 25 4.3 Hib meningitis

4.3.1 Hib meningitis incidence data and study quality Of the 205 studies that provided evaluable extracted outcomes considered for one or more variables in the Hib models, 126 (61%) had incidence data on any syndrome (Table 1), almost all on meningitis incidence (N = 103, 82%). Only 20 (16%) of the studies reporting meningitis incidence were adjusted for limitations of the study (e.g. cases missed because they did not come to a study facility, cases not included because diagnostic tests were not done, or culture results that were negative but were probable bacterial disease). Most of the Hib studies with meningitis incidence data were from EUR (N = 41), AMR (N = 22), and WPR (N = 24) (Table 3, Map 3 and Map 4). Only 12 studies from AFR contributed meningitis incidence data, and even fewer were available from EMR (N = 7) and SEAR (N = 4). Thus, the regions with the largest number of children under five years of age and with the highest mortality in that age group (SEAR and AFR), were under-represented.

Table 3: Number and percentage of studies with Hib meningitis incidence data, by WHO region

WHO Region Study statistics AFR AMR EMR EUR SEAR WPR Total Number of studies with Hib 12 22 7 41 4 24 110 meningitis incidence data Number of studies with Hib meningitis incidence data 10 12 5 16 3 13 59 included in analysis Percentage of studies within the region included in 83.3 54.5 71.4 39.0 75 54.2 53.6 analysis

Map 3: Number of studies with Hib meningitis incidence data in each country

Number of studies:

0 1 2-5 6-9

26 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Map 4: Number of studies with included Hib meningitis incidence data in each country

Number of studies:

0 1

2-5

The quality of the studies was considered, and “C” quality studies were excluded from the model analysis (Section 5.9.3). The number of studies rated “A” or “B” quality that were included in analysis is shown in Table 3. Figure 5 shows the distribution of Hib meningitis incidence studies stratified by WHO region and study quality. All regions had “A”, “B” and “C” quality studies. Although the AFR, EMR and SEAR had the fewest number of studies, most of these were of “A” or “B” quality and thus included in the analysis. Conversely, regions that had the most studies (AMR, EUR and WPR), also had the greatest proportion excluded from analyses — roughly 40%–60% of studies were of “C” quality. EUR had the most studies of any region (N = 41), but only 39% were documented to be of sufficient quality for inclusion and so the actual number of studies included in analysis from this region is on a par with those from AMR and WPR.

WHO/IVB/09.02 27 Figure 5: Number of Hib meningitis incidence studies by data quality and WHO Region

C 25

15 C C

Number of studies 10 A B A B B A B 5 A A C B C A B C 0

AFR AMR EMR EUR SEAR WPR

WHO Region

Most of the studies with Hib meningitis incidence data came from countries with very low mortality (Refer to Annex 4 for a list of countries by mortality strata) (Figure 6). There was only one “A” quality study from high or very high mortality countries, but every mortality strata had multiple “B” and “C” quality studies.

Figure 6: Number of Hib meningitis incidence studies by data quality and mortality strata

40 C 35

25 A

20 B

15 Number of studies 10 C

A B B 5 B C A C 0 very low medium high very high

Mortality strata

28 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 4.3.2 Hib meningitis incidence data by study method Vaccine probe studies provide the best estimation of Hib disease burden. In these trials, a vaccine with a known efficacy against microbiologically-confirmed disease is administered to part of the study population and not to the other. If the vaccine efficacy against microbiologically-confirmed disease is 100%, the burden of disease due to that organism is the difference in disease incidence between the vaccinated and unvaccinated groups (i.e. the rate difference, also called the attributable risk or rate).

Vaccine probe studies, the gold standard for estimating Hib meningitis incidence, were conducted in two of the six regions. Approximately half of the studies with Hib meningitis incidence data were retrospective in design (N = 55, 51%), the majority of which were excluded from analyses based on insufficient quality (N = 35, 64%). The next most frequent study types were prospective that employed active surveillance (N = 38, 35%). Prospective studies were less likely to be excluded because of poor quality (“C” score) than were retrospective studies.

Table 4: Type of study method used in studies with evaluable Hib meningitis incidence data, by WHO region

WHO Region Study method Total AFR AMR EMR EUR SEAR WPR All studies 110 12 22 7 41 4 23 Vaccine probe 2 0 0 0 0 1 1 Prospective, active 39 7 10 3 13 1 5 surveillance Prospective, passive 11 1 2 0 5 1 2 surveillance Prospective, other 2 0 0 1 0 0 1 Retrospective 55 4 10 3 23 1 14 Unknown 1 0 0 0 0 0 1 Included in analysis* 59 10 12 5* 16 3 13 Vaccine probe 2 0 0 0 0 1 1 Prospective, active 30 6 6 3 10 1 4 surveillance Prospective, passive 7 1 2 0 3 1 0 surveillance Prospective, other 0 0 0 0 0 0 0 Retrospective 20 3 4 2 3 0 8 Excluded from analysis* 50 2 10 2 25 1 10 Prospective, active 9 1 4 0 3 0 1 surveillance Prospective, passive 4 0 0 0 2 0 2 surveillance Prospective, other 2 0 0 1 0 0 1 Retrospective 35 1 6 1 20 1 6 Unknown 1 0 0 0 0 0 1

* Quality “A” and “B” studies were included in analysis and quality “C” studies were excluded (Section 5.6.9).

WHO/IVB/09.02 29 While all regions had several countries contributing data to estimate Hib meningitis incidence, the absolute number of countries with data included in analyses in each region was very small, ranging from three to eight countries (Table 5 and Map 5). At best, this represented only 30% of all countries in a region, which was in SEAR and WPR where there is felt to be the most diversity in populations. The lowest proportion of countries in a region represented in analyses was AFR (11%), where most of the meningitis deaths occur.

Table 5: The number and percent of countries with Hib meningitis incidence data, by WHO region

WHO Region Country statistics AFR AMR EMR EUR SEAR WPR Total number of countries in the 47 35 22 52 11 27 region

Number of countries with Hib 6 7 7 21 4 13 meningitis incidence data Number of countries with Hib meningitis incidence data included 5 6 5 8 3 8 in analysis Percentage of countries within the 10.6 17.1 22.7 15.4 27.3 29.6 region represented in analysis

Map 5: Countries with and without Hib meningitis data

Data included (35 countries) Data included (23 countries) Data included (137 countries)

The types of surveillance conducted for the 110 studies with evaluable Hib meningitis incidence data were primarily hospital-based (overall, 57%) as opposed to either community-based, which described the fewest studies (2%), or outpatient (30%) (Table 6). This was true in every region. The type of surveillance was not related to whether the study was excluded or included in analyses, as all types were equally included and excluded.

30 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 6: Study population assessed in studies with evaluable Hib meningitis incidence data, by region

WHO Region Study population Total AFR AMR EMR EUR SEAR WPR All studies 110 12 22 7 41 4 24 Community (any) 2 1 1 0 0 0 0 Outpatient (any) 33 4 7 0 14 2 6 Hospital only 63 7 12 6 20 2 16 Unknown 12 0 2 1 7 0 2 Included in analysis 59 10 12 5 16 3 13 Community (any) 1 1 0 0 0 0 0 Outpatient (any) 18 4 2 0 6 2 4 Hospital only 33 5 8 4 7 1 8 Unknown 7 0 2 1 3 0 1 Excluded from analysis 51 2 10 2 25 1 11 Community (any) 1 0 1 0 0 0 0 Outpatient (any) 15 0 5 0 8 0 2 Hospital only 30 2 4 2 13 1 8 Unknown 5 0 0 0 4 0 1

4.3.3 Extrapolation of Hib meningitis incidence for studies without data in the age group < 5 years of age The majority of studies reporting Hib meningitis incidence for any age group <5 years of age had data for that entire age group (94%) (Table 7). Studies that only presented under-1 or under-2 incidence rates required having their under-5 incidence estimated based on ratios of cases under-1:under-5 or under-2:under-5 observed in other studies. Approximately 50% of studies with incidence data were excluded because of poor quality, resulting in 59 studies included in analysis, three of which required extrapolation because they only presented under-1 or under-2 incidence rates (two from AFR and one from SEAR). There were also four “C” quality studies (one AMR, one EMR, and two EUR) for which this extrapolation was made.

WHO/IVB/09.02 31 Table 7: Number of studies with Hib meningitis incidence data, by age group where incidence is available and by WHO region

WHO Region Age Total AFR AMR EMR EUR SEAR WPR All studies <1 50 8 9 2 20 1 10 <2 34 1 7 2 15 0 9 <5 103 10 21 6 39 3 24 <1 or <2 only (extrapolated <5)* 7 2 1 1 2 1 0 Total 110 12 22 7 41 4 24 Included in analysis <1 26 6 3 2 10 1 4 <2 19 1 5 2 7 0 4 <5 56 8 12 5 16 2 13 <1 or <2 only (extrapolated <5)* 3 2 0 0 0 1 0 Total 59 10 12 5 16 3 13 Excluded from analysis <1 24 2 6 0 10 0 6 <2 15 0 2 0 8 0 5 <5 47 2 9 1 23 1 11 <1 or <2 only (extrapolated <5)* 4 0 1 1 2 0 0 Total 51 2 10 2 25 1 11

* Only under-1 or under-2 incidence is available, no under-5 incidence; data were extrapolated to estimate under-5 incidence.

Distribution of meningitis cases across age groups may be more similar between countries with similar mortality than from countries within the same region but of differing mortality strata. When a study presented only under-1 or under-2 incidence data, an under-5 incidence was extrapolated using the age distribution of meningitis cases. This process is described in more detail in the methods paper [Wolfson, 2008]. Extrapolation of included studies was needed for studies from medium and high mortality countries only. Table 8 below shows the three included studies requiring extrapolation by mortality strata of the country.

32 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 8: The number of studies with Hib meningitis incidence data available for age groups less than one year or less than two years only (no data for age less than five years) by mortality strata of the country

Number of Mortality strata* Age studies Very Low Medium High

<1 only 2 0 1 (AFR) 1 (AFR) Included <2 only 1 0 1 (SEAR) 0 <1 only 1 0 1 (AMR) 0 Excluded <2 only 2 2 (EMR, EUR) 0 0 <1 and <2 only 1 1 (EUR) 0 0 * Refer to section 6.2 for a description of mortality strata.

The number of studies that described the age distribution of meningitis cases used for this extrapolation is presented in Table 9 by region and mortality stratum of the countries within the region. The included studies needing extrapolation were from AFR and SEAR, and from medium and high mortality strata. Included studies needing extrapolation needed both under-1:under-5 and under-2:under-5 case ratios from other studies in the corresponding mortality strata, which was populated by data from both SEAR and AFR.

Table 9: Studies that described the age distribution for cases of Hib meningitis, by mortality strata and WHO region

WHO Region Mortality strata* Total AFR AMR EMR EUR SEAR WPR Very high <1:<5 15 15 0 0 0 0 0 <2:<5 3 3 0 0 0 0 0 High <1:<5 6 3 1 0 0 1 1 <2:<5 1 0 0 0 0 1 0 Medium <1:<5 17 1 7 2 2 3 2 <2:<5 15 0 8 3 0 3 1 Very low <1:<5 53 0 7 4 28 1 13 <2:<5 45 0 6 5 22 0 12 * Refer to section 6.2 for a description of country mortality strata.

WHO/IVB/09.02 33 4.3.4 Effect of quality score on Hib meningitis incidence The median incidence of Hib meningitis reported in “C” studies was lower than the median incidence reported in “A/B” studies in AFR, SEAR and WPR; it was similar to the median incidence in “A/B” studies in AMR, EUR and EMR (Figure 7).

Figure 7: Incidence of Hib meningitis in children under five years of age (adjusted where possible) in studies included (“A/B”) versus excluded (“C”) from analysis, by region*†‡

100

20 Incidence (per 100 000) 0 8 2 12 9 5 1 16 23 2 1 13 11

A/B C A/B C A/B C A/B C A/B C A/B C

AFR AMR EMR EUR SEAR WPR

Number of studies, quality score & WHO region

* Hib meningitis incidence estimates are not official WHO estimates, but are summaries of available data from the literature review. † Excludes seven studies that did not present under-5 data (Table 8). ‡ Boxplot key: grey box = interquartile range (IQR), Red dot = median, Range bars = minimum and maximum values.

4.3.5 Effect of adjustment on Hib meningitis incidence Adjusted Hib meningitis incidence data was available for 20 studies. Eight of these were estimated using a modelling process (HibRAT) that inherently incorporates the adjustments made to data resulting from surveillance studies (N = 7) or was from a vaccine probe trial (N = 1) where cases prevented by Hib vaccine far exceeds the number of invasive cases that can be detected through culture-based surveillance methods. Unadjusted meningitis incidence was not abstracted from the HibRATs. Therefore, only 12 studies had both unadjusted and adjusted incidence data available to evaluate the effect of adjustment.

In all studies with unadjusted and adjusted data, the adjustment resulted in an increase in the Hib meningitis incidence estimate, demonstrating that the use of unadjusted data leads to underestimation of the true burden of disease. The increase in incidence from unadjusted to adjusted estimates ranged from 1.3/100 000 to 64.7/100 000 for children less than five years of age. This equates to fold-rises in incidence of 1.1 to 4.3 (Table 10). The broad variability of the adjustment factor precludes applying a uniform adjustment to studies that do not themselves provide study-specific information to adjust the reported meningitis incidence rate.

34 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 10: Studies reporting adjusted Hib meningitis incidence rates or reporting data sufficient to adjust the reported unadjusted meningitis incidence rates

Fold WHO Age Unadjusted Adjusted increase Country Reference** Region group incidence incidence (adjusted/ unadjusted)

AFR South Africa Madhi (2002) <1† 106 117.66* 1.1 Dominican Gomez (2000) <5 13.4 17.4* 1.3 Republic AMR Guatemala Asturias (2003) <5 13.8 15.9* 1.2

Egypt‡ Watt (1999) <5 - 23.1 -

EMR Iran‡ Nelson <5 - 9 -

Pakistan‡ Al Awaidy (2003) <5 - 16.3 - Bosnia and Al Awaidy (2004) <5 - 14.7 - Herzegovina‡ Kojouharova Bulgaria <5 6.1 8.4 1.4 (2002) Livartowski France <5 14.7 17 1.2 (1989) EUR France Reinert (1993) <5 13.4 14.77 1.1 De Jonghe Luxembourg <5 11 12.7 1.2 (1995) Ukraine‡ Platanov (2003) <5 - 8 -

Indonesia Gessner (2005) <2 - 67 -

SEAR Nepal‡ Russell (2003) <5 - 5.4 - Rerks-Ngarm Thailand <5 3.8 9.8 2.6 (2004) Australia McIntyre (1991) <5 19.7 22.9* 1.2

Fiji‡ Wilson (2003) <5 19.7 84.4 4.3

WPR Mongolia Watt (2004) <5 28 38 1.4 Republic of Kim (2004) <5 5.98 10.8* 1.8 Korea Samoa‡ Carapetis (2002) <5 - 83.8 -

* Adjusted incidence was not provided directly by the authors but was based on data sufficient to adjust the reported unadjusted incidence rates. ** See Annex 8 for full reference. † <1 = under age one year, <2 = under age two years, <5 = under age five years. ‡ HibRat = Hib Rapid Assessment Tool (Feikin, 2004; WHO, 2001).

WHO/IVB/09.02 35 4.3.6 Hib meningitis case-fatality ratio Fifty-five studies reported case-fatality ratios (CFR) for Hib meningitis. The CFR data from all studies was included regardless of whether they had incidence data, and regardless of the quality scoring of the incidence data. [Note: CFR from “C” quality studies were similar to those from “A” and “B” quality studies (data not shown).] While all regions had CFR data (Table 1 and Map 6), there were very few studies from the EMR and SEAR with CFR for Hib meningitis. In none of the regions were data available from more than 14 studies.

Map 6: Number of studies with Hib meningitis CFR data in each country

Number of studies:

2-5

Hib meningitis CFRs were highest in AFR, followed by SEAR and AMR (Figure 8). CFRs reported in the different studies varied widely in AFR and were more consistent across studies in other regions.

36 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Figure 8: Hib meningitis CFRs by WHO region*†‡

5050

4040

3030

2020

Case-fatality ratio

Case fatality ratio 10 10

0 101014 2 10 22 1212

AFR AMR EMR EUR SEAR WPR AFRAMREMREURSEARWPR

Number of studies & WHO Region Number of studies & WHO region

* CFRs for the age category of <5 years of age. † CFR estimates summarize data from the literature review and are not official WHO estimates. ‡ Boxplot key: grey box = interquartile range; dot = median; range bars = minimum and maximum values.

4.4 Spn meningitis

4.4.1 Spn meningitis incidence data by study quality Of the 211 studies that provided data for one or more variables in the Spn models, 117 (53%) had incidence data on any syndrome (Table 2), of which almost all were meningitis (N = 90, 77%). None of the Spn studies reported an adjusted meningitis incidence estimate. However, five studies provided sufficient information to adjust the published incidence estimate (see Table 18 for list of studies). Examples of such information include the proportion of cases that presented to the hospital but did not have a lumbar puncture, and the proportion of cases that were likely to be treated at non-study hospitals, etc. Most of the studies with Spn meningitis incidence data were from EUR (N = 41), AMR (N = 24), and WPR (N = 13). Only ten studies from AFR contributed meningitis incidence data, and fewer were available from EMR (N = 2). No studies were available from SEAR (N = 0) (Table 11, Map 7 and 8). The regions with the largest number of children under five years of age and the highest mortality (SEAR and AFR) were under-represented, as were children from EMR.

WHO/IVB/09.02 37 Table 11: Number and percent of studies with Spn meningitis incidence data, by WHO region

WHO Region Study statistics AFR AMR EMR EUR SEAR WPR Total Number of studies with Spn 10 24 2 41 0 13 90 meningitis incidence data Number of studies with Spn meningitis incidence data 7 13 1 20 0 10 51 included in analysis Percentage of studies within 70.0 54.2 50.0 48.8 - 76.9 56.7 the region included in analysis

Map 7: Number of studies with Spn meningitis incidence data in each country

Number of studies: 0 1 2-5

6-12

38 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Map 8: Number of studies with included Spn meningitis incidence data by country

Number of studies: 0 1 2-5

Studies were evaluated for quality. Those studies of “C” quality were excluded from the Spn global disease burden model analysis (Section 5.6.9). Figure 9 shows the distribution of Spn meningitis incidence studies stratified by WHO region and study quality. All regions with data had “A”, “B” and “C” quality studies. Although AFR had the fewest number of studies, most of these were of “A” or “B” quality and included in the model. The majority of studies from WPR were also included in the model. Conversely, in regions that had the greatest number of published studies (AMR and EUR), a greater proportion of those studies were of “C” quality (approximately 50% compared to approximately 30% in AFR and WPR).

WHO/IVB/09.02 39 Figure 9: Number of Spn meningitis incidence studies by data quality and WHO region

C 20

C A B 10 A

Number of studies B A B 5 C B C A A C 0 AFRAMREMREURSEARWPR

WHO region

Similarly to Hib, most of the studies with Spn meningitis incidence data came from countries with very low mortality (Refer to Annex 4 for list of countries by mortality strata, Figure 10). There were no “A” quality studies from high or very high mortality countries, but every mortality strata had multiple “B” quality studies and at least one “C” quality study.

Figure 10: Number of Spn meningitis incidence studies by data quality and mortality strata

C 30

25 A 20 B 15

Number of studies 10 C 5 A B B B C C 0

very low medium high very high

Mortality strata

40 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 4.4.2 Spn meningitis incidence data by study method Vaccine probe studies, also the gold standard for estimating Spn meningitis incidence, were conducted in one of the six WHO regions (AFR). Slightly less than half the studies with Spn meningitis incidence data were retrospective in design (N = 41, 46%), and the majority of these were excluded from analyses based on insufficient quality (N = 25, 66%). The next most frequent study types were prospective that employed active surveillance (N = 35, 39%). The prospective studies were less likely to be excluded because of poor quality (“C” score) than the retrospective studies.

Table 12: Type of study method used in studies with evaluable Spn meningitis incidence data, by WHO region

WHO Region Study method Total AFR AMR EMR EUR SEAR WPR All studies 90 10 24 2 41 0 12 Vaccine probe 2 2 0 0 0 0 0 Prospective, active surveillance 35 4 12 1 14 0 4 Prospective, passive surveillance 8 1 1 0 3 0 3 Prospective, other 3 0 1 0 2 0 0 Retrospective 41 3 10 1 22 0 5 Missing 1 0 0 0 0 0 1 Included in analysis* 51 7 13 1 20 0 10 Vaccine probe 2 2 0 0 0 0 0 Prospective, active surveillance 28 3 8 1 12 0 4 Prospective, passive surveillance 4 0 1 0 1 0 2 Prospective, other 1 0 0 0 1 0 0 Retrospective 16 2 4 0 6 0 4 Excluded from analysis* 38 3 11 1 21 0 2 Prospective, active surveillance 7 1 4 0 2 0 0 Prospective, passive surveillance 4 1 0 0 2 0 1 Prospective, other 2 0 1 0 1 0 0 Retrospective 25 1 6 1 16 0 1 Missing 1 0 0 0 0 0 1

* Quality “A” and “B” studies were included in analysis and quality “C” studies were excluded (Section 5.6.9).

As previously mentioned, no country in SEAR had data on Spn meningitis incidence and only one country in EMR had data (Table 13 and Map 9). The proportion of countries contributing Spn meningitis incidence data for the other regions ranged from 11% (AFR) to 23% (EUR) (5–12 countries per region). Results were similar to the number of countries providing Hib meningitis data for all regions except EMR and SEAR, for which more countries had Hib meningitis incidence data than Spn meningitis incidence data.

WHO/IVB/09.02 41 Table 13: Number and percentage of countries in the region with Spn meningitis incidence data, by WHO region

WHO Region Country statistics AFR AMR EMR EUR SEAR WPR

Total number of countries in the region 47 35 22 52 11 27

Number of countries with Spn meningitis 6 9 1 16 0 8 incidence data Number of countries with Spn meningitis 5 6 1 12 0 6 incidence data included in analysis Percentage of countries within the region 10.6 17.1 4.5 23.1 0.0 22.2 represented in analysis

Map 9: Countries with and without Spn meningitis incidence data

Data included (30 countries) Data included (10 countries) Data included (155 countries)

The type of surveillance conducted for studies with evaluable Spn meningitis incidence data was primarily hospital-based (overall, 58%) as opposed to either community- based (2%) or outpatient studies (29%) (Table 14). This was true in every region with incidence data. The type of surveillance conducted was not strongly related to whether the study was excluded or included in analyses; however, slightly more hospital-based studies were included (63%).

42 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 14: Study population assessed in studies with evaluable Spn meningitis incidence data, by WHO region

WHO Region Study population Total AFR AMR EMR EUR SEAR WPR All studies 90* 10 24 2 41 0 13

Community (any) 2 1 1 0 0 0 0

Outpatient (any) 26 2 9 0 13 0 2

Hospital only 52 7 14 1 22 0 8

Unknown 10 0 0 1 6 0 3

Included in analysis 51 7 13 1 20 0 10

Community (any) 1 1 0 0 0 0 0

Outpatient (any) 13 2 4 0 5 0 2

Hospital only 33 4 9 0 14 0 6

Unknown 4 0 0 1 1 0 2

Excluded from analysis 39 3 11 1 21 0 3

Community (any) 1 0 1 0 0 0 0

Outpatient (any) 13 0 5 0 8 0 0

Hospital only 19 3 5 1 8 0 2

Unknown 6 0 0 0 5 0 1 Total 360 40 96 8 164 0 52 * Number of studies.

4.4.3 Extrapolation of Spn meningitis incidence for studies without data in the age group <5 years of age The majority of studies reporting Spn meningitis incidence for any age group <5 years of age had data for that entire age group (88%) (Table 15). Studies that only reported under-1 or under-2 meningitis incidence rates required having their under-5 meningitis incidence rate estimated based on the ratio of under-1:under-5 or under-2:under-5 rates observed in other studies. Forty-three percent of studies were excluded because of poor quality, resulting in 51 studies included in the analysis, eight of which required extrapolation because they only presented under-1 or under-2 incidence rates (four from AFR, three from AMR and one from EUR). There were also three “C” quality studies in EUR for which this extrapolation was made.

WHO/IVB/09.02 43 Table 15: Number of studies with Spn meningitis incidence data, by age group where incidence is available and WHO region

WHO Region Age Total AFR AMR EMR EUR SEAR WPR All studies <1 41 4 10 2 22 0 3 <2 41 1 7 2 25 0 6 <5 79 6 21 2 37 0 13 <1 or <2 only (extrapolated <5)* 11 4 3 0 2 0 0 Total 90 10 24 2 41 0 13 Included in analysis <1 23 2 4 1 14 0 2 <2 25 1 3 1 16 0 4 <5 43 3 10 1 19 0 10 <1 or <2 only (extrapolated <5)* 8 4 3 0 1 0 0 Total 51 7 13 1 20 0 10 Excluded from analysis <1 18 2 6 1 8 0 1 <2 16 0 4 1 9 0 2 <5 36 3 11 1 18 0 3 <1 or <2 only (extrapolated <5)* 3 0 0 0 3 0 0 Total 39 3 11 1 21 0 3 * Only under-1 or under-2 incidence is available, no under-5 incidence; data were extrapolated to estimate under-5 incidence.

The distribution of meningitis cases across age groups may be more similar between countries with similar mortality than between countries within the same region but of differing mortality strata. Table 16 below shows the eight included studies requiring imputation of the under-5 Spn meningitis incidence rate, by the mortality strata of the country of the study. Extrapolation was needed for studies from all but the “Very High” mortality countries.

44 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 16: The number of studies with Spn meningitis incidence available for age groups less than one year or less than two years only (no data for age less than five years) by mortality strata of the country

Number of Mortality strata* Age studies Very Low Medium High <2 only 7 4 (AMR,EUR) 2 (AFR) 1 (AFR) Included <1 and <2 only 1 0 0 1 (AFR) <1 only 1 1 (EUR) 0 0 Excluded <2 only 2 2 (EUR) 0 0 * Refer to section 6.2 for a description of mortality strata.

The number of studies that described the age distribution of meningitis cases available for extrapolation is presented in Table 17. The studies needing extrapolation were from AFR, AMR and EUR. Studies needing extrapolation used primarily under-2: under-5 case ratios from studies in corresponding mortality strata, which were available for these regions in at least one of those mortality strata.

Table 17: Studies that provided data on the age distribution for cases of Spn meningitis data, by mortality strata and WHO region

WHO Region Mortality strata* Total AFR AMR EMR EUR SEAR WPR Very high <1:<5 21 14 0 0 0 0 7 <2:<5 6 6 0 0 0 0 0 High <1:<5 5 3 1 0 0 0 1 <2:<5 4 1 0 0 0 2 1 Medium <1:<5 16 1 6 3 2 2 2 <2:<5 13 0 6 4 0 2 1 Very low <1:<5 40 0 14 1 25 0 0 <2:<5 53 0 12 1 28 0 12 * Refer to section 6.2 for a description of mortality strata.

WHO/IVB/09.02 45 4.4.4 Effect of quality score on Spn meningitis incidence Although for Hib meningitis incidence studies a similar trend was observed across regions in the relationship of “A/B” quality studies and “C” quality studies, the relationship of “A/B” quality studies and “C” quality studies varied across regions for Spn meningitis incidence (Figure 11). In general, the median incidence of Spn meningitis in “C” studies was lower than the median incidence in “A/B” studies in AFR, AMR and WPR, similar to the median incidence in “A/B” studies in EUR, and higher than the median incidence in “A/B” studies in EMR.

Figure 11: Incidence of Spn meningitis in children under five years of age (adjusted where possible) in studies included (“A/B”) versus excluded (“C”) by WHO region*

6060

5050

4040

3030

2020

1010 Incidence (per 100 000) Incidence (per 100 000) 0 333 10 11 11 1919 180 0 010 103 A/B C A/B C A/B C A/B C A/B C A/B C A/BCA/BCA/BCA/BCA/BCA/BC AFR AMR EMR EUR SEAR WPR AFRAMREMREURSEARWPR

NumberNumber of ofstudies, studies, quality quality score score & & WHO WHO regionRegion

* Spn meningitis incidence estimates are not official WHO estimates, but are summaries of available data from the literature review. Excludes 11 studies that did not have under-5 data (Table 16). Boxplot key: grey box = interquartile range (IQR); red dot = median; range bars = minimum and maximum values.

4.4.5 Effect of adjustment on Spn meningitis incidence Only five studies provided sufficient information to adjust the published Spn meningitis incidence estimates — three of these were from AMR, one from AFR and one from WPR.

46 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 In all studies with unadjusted and adjusted data, the adjustment leads to an increase in the Spn meningitis incidence estimate, demonstrating that the use of unadjusted data only leads to underestimates of the true burden of disease. The increase in incidence from unadjusted to adjusted estimates ranged from 1.3/100 000 to 2.4/100 000 children under five years of age. This represents a 1.0 to 1.8 fold-rise in incidence of Spn meningitis rates (Table 18). Although the adjustment factor had lower variability than it did for Hib meningitis incidence, it was judged unwise to apply a uniform adjustment to studies that do not provide study-specific data to adjust the Spn meningitis incidence data reported.

Table 18: Studies reporting data sufficient to adjust the reported unadjusted meningitis incidence rates

Fold Under-5 Under-5 increase WHO Region Country Reference* unadjusted adjusted (adjusted/ incidence incidence unadjusted)

Brazil Reis (2002) 24.7 25.9 1.0 AMR Dominican Gomez (2000) 5.2 7.3 1.4 Republic Asturias Guatemala 16.3 18.7 1.1 (2003) Campbell AFR Mali 13.4 15.6 1.2 (2004) Republic of WPR Kim (2004) 2.13 3.8 1.8 Korea * See Annex 8 for full reference.

4.4.6 Spn meningitis case-fatality ratio Thirty-four studies reported CFRs for Spn meningitis. All regions except EMR had CFR data, and SEAR had only one study with CFR data, as was observed for studies providing Spn meningitis incidence data (Table 2 and Map 10). AMR had the most data (16 studies), but no other region had more than six published studies.

WHO/IVB/09.02 47 Map 10: Number of studies with Spn meningitis CFR data in each country

Number of studies: 0 1 2-5

Spn meningitis CFRs were highest in AFR, followed by SEAR and AMR (Figure 12). Observed CFRs varied widely in AMR and were more consistent across studies in other regions.

Figure 12: Spn meningitis CFRs by WHO region*

7070

6060

5050

4040

3030

2020

Case-fatality ratio 1010

00 4 11 0 4 1 3 4 11 0 4 1 3 AFRAMREMREURSEARWPR AFR AMR EMR EUR SEAR WPR

Number of studies & WHO region

* CFRs for the age category of <5 years of age. Spn meningitis CFR estimates are not official WHO estimates, but are summaries of available key extracted outcomes from the literature review. Boxplot key: grey box = interquartile range (IQR); red dot = median; range bars = minimum and maximum values.

48 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 4.5 Comparison of Hib and Spn meningitis incidence data

The number of studies that had data on any evaluable endpoint of interest was remarkably similar between Hib and Spn in each region (Figure 13. and Tables 7.1.1 and 7.2.1). AMR and EUR had the largest number of studies, and EMR and SEAR had the least number for both pathogens.

Figure 13: Number of studies with any evaluable extracted outcomes on Hib and Spn by WHO region

30 Number of studies 20

0 AFR AMR EMR EUR SEAR WPR

WHO region

Hib Spn

The number of studies that had data on meningitis incidence was also similar between Hib and Spn in AFR, AMR and EUR, but there were more Hib studies in EMR, SEAR, (which had no Spn meningitis incidence studies) and WPR (Figure 14). The number of studies with meningitis incidence data that were included in analysis was similar for Hib and Spn in each region, again with the exception of SEAR, with no Spn studies and only one Spn study in EMR. No region had more than 20 studies for either pathogen, and regions with the most studies were those with the fewest number of under-5 deaths (EUR and AMR).

WHO/IVB/09.02 49 Figure 14: Number of Hib and Spn meningitis incidence studies included and excluded in the analysis by WHO region

45 40 35 30 25 20 15 10

Number of studies 5 0 Hib Spn Hib Spn Hib Spn Hib Spn Hib Spn Hib Spn

AFR AMR EMR EUR SEAR WPR

WHO region

Excluded Included

At most, 12 countries in any region provided meningitis incidence data that were included in analysis (Figure 15). All regions had at least three countries with Hib data, but two regions were significantly lacking in Spn meningitis incidence data; zero countries from SEAR and only one country from EMR had Spn meningitis data. Spn data was available and included in the analysis for more countries in EUR compared to Hib data; the number of countries with data included in the analysis was the same for Spn and Hib in AFR and AMR.

50 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Figure 15: Number of countries with Hib and Spn meningitis incidence data included in analysis by WHO region

Number of studies 4

0 AFR AMR EMR EUR SEAR WPR WHO region

Excluded Included

There were more studies that provided data on CFRs for Hib meningitis than for Spn, except AMR which had a similar number of studies for Spn and Hib. AMR was also the region with the greatest number of studies providing meningitis CFR data.

WHO/IVB/09.02 51 Figure 16: Number of studies with Hib and Spn meningitis CFR data by WHO region

6 Number of studies 4

AFR AMR EMR EUR SEAR WPR WHO region

Hib Spn

4.5.1 Number of Hib and Spn studies by publication year Studies reporting data on Hib meningitis incidence tended to be published in earlier years than studies reporting Spn meninigitis incidence. Publication of studies in the database increased for both Hib and Spn after 1981 to a maximum of 17 studies in any one year for Hib, and 26 for Spn. The low numbers of studies at or near 1981 is likely to reflect in part the exclusion of studies with cases prior to 1980. Since 1999, the number of studies with meningitis incidence data has been similar for Hib and Spn, and declined steadily to zero-to-one studies in 2004 and 2005 for both. Unlike for Hib in which the number of studies providing meningitis incidence data was relatively stable year-to-year, there was a clear peak for Spn between 1995 and 1998.

4.5.2 Number of Hib and Spn studies by midpoint year of study Studies with evaluable extracted outcomes on any of the endpoints of interest tended to be from surveillance conducted in earlier years for Hib relative to Spn (Figure 17). The number of studies with Hib data was greatest from 1985 to 1995, and then declined slowly but steadily thereafter. Studies with Spn data by contrast rose steadily in number to a clear peak in 1997 and then declined to numbers similar to the Hib studies after 1999. There was a surge in Spn studies from 1995 to 1998, just prior to introduction of pneumococcal conjugate vaccine in the United States of America in 2000.

52 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Figure 17: Number of Hib and Spn studies by midpoint year of study

5 Number of studies 0

Year

Excluded Included

Studies that reported data on meningitis incidence tended to be from more recent surveillance for Spn compared to Hib (Figure 18). Studies in the database increased for both Hib and Spn to approximately three to seven studies per year after 1985, with peaks up to nine studies in any one year for Hib, and 11 studies for Spn. The low number of studies at or near 1981 probably reflects the exclusion of studies with cases prior to 1980. Since 1997 for Spn, and 2000 for Hib, the number of studies with meningitis incidence data has declined steadily to zero and one study, respectively, in 2004. Unlike Hib, in which the number of studies providing meningitis incidence data was relatively stable year-to-year, there was clear peak for Spn between 1997 and 1998.

WHO/IVB/09.02 53 Figure 18: Number of Hib and Spn meningitis incidence studies by midpoint year of study

4 Number of studies 2

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year

Excluded Included

Figure 19 below shows the number of studies with Hib and Spn meningitis incidence data by their midpoint year of the surveillance conducted separately for each WHO region. All regions had Hib and Spn data from studies throughout the entire calendar period of data collection, except SEAR which had only recent data for Hib, and no data for Spn, and EMR which had only recent Spn data. Prior to 1995, the number of studies with Hib meningitis incidence data was generally greater than Spn studies in every region. The large peak in Spn studies observed in Figure 18 was primarily the result of a large number of studies conducted in AMR. Similarly, there were a large number of studies with Hib data published in AMR at that time. By contrast, in EUR, the number of studies with Hib meningitis data fell to the lowest numbers for that region during this time period, probably the result of Hib vaccine introduction in many EUR countries, while the number of Spn studies remained at a steady rate. After the year 2000, studies in AMR fell to zero because Spn and Hib vaccine were both in routine use and therefore met exclusion criteria, while all other regions continued to have studies included in the dataset since pneumococcal conjugate vaccine was not introduced until later.

54 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Figures 19: Number of studies with Hib and Spn meningitis incidence data by midpoint year of surveillance and WHO region

AFR AMR 6 6

5 5

4 4

3 3

2 2 Number of studies Number of studies Number of studies

1 1

0 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year

Spn Hib Spn Hib

EMR EUR 6 6 5 5

4 4

3 3

2 2 Number of studies Number of studies 1 1 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Year

Spn Hib Spn Hib

SEAR WPR 6 6

5 5

4 4

3 3

2 2 Number of studies Number of studies Number of studies

1 1

0 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Year

Spn Hib Spn Hib

Trends in the number of meningitis incidence studies that were included in analysis were more similar between Hib and Spn than for all studies with meningitis data, with peaks in the number of studies being conducted in the late 1980s and in the late 1990s/early 2000s (Figure 20). The number of Spn studies increased to an average of 3.0 per year after 1992 compared to 1.3 per year prior to 1992. By contrast, Hib studies were more stable, with 2.9 studies conducted per year prior to 1993, compared with 2.4 per year after 1993.

WHO/IVB/09.02 55 Figure 20: Number of Hib and Spn meningitis incidence studies included in analysis by midpoint year of study

2 Number of studies

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year

Spn Hib

Spn studies were notably fewer in AFR and EMR compared to Hib studies, particularly in the earlier years (Figure 21). SEAR, which had no Spn studies, also did not have Hib studies until recently. In AMR, EUR and WPR, distribution of Hib and Spn studies over the literature review period were generally similar.

56 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Figure 21: Number of Hib and Spn meningitis studies included in analysis by midpoint year of study

AFR AMR 4 4

3 3

2 2 Number of studies Number of studies 1 Number of studies 1

0 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Year

Spn Hib Spn Hib

EMR EUR 4 4

3 3

2 2

Number of studies 1 Number of studies 1

0 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Year

Spn Hib Spn Hib

SEAR WPR 4 4

3 3

2 2 Number of studies Number of studies Number of studies 1 1

0 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Year

Spn Hib Spn Hib

4.6 Hib non-pneumonia, non-meningitis invasive disease

There were 27 studies that reported the syndrome distribution of Hib NPNM cases to meningitis cases (Table 19). The NPNM analysis also derived cases of NPNM if all invasive disease, meningitis and pneumonia data were available. There were eight studies that presented the distribution of cases ranging from Hib NPNM to meningitis among children less than one year of age, eight among children less than two years, and 25 among children less than five years of age.

WHO/IVB/09.02 57 Table 19: Number of studies reporting the syndrome distribution of Hib NPNM cases to meningitis cases by WHO region

WHO Region Studies Total AFR AMR EMR EUR SEAR WPR

Number of studies 4 7 1 9 2 4 27

Percentage of total 14.8 25.9 3.7 33.3 7.41 14.8 100 studies

Figure 22 shows the range and median of Hib NPNM/meningitis ratio by mortality strata and the number of studies that contributed to the analysis within each mortality strata. Most of the data available on Hib NPNM/meningitis ratio comes from countries in the very low mortality strata. The Hib NPNM/meningitis ratios are all below 1.0 indicating that cases of Hib meningitis always exceeded the number of Hib NPNM cases in these papers. This is consistent with prior knowledge that Hib disease is known to cause mainly meningitis and pneumonia. There is little variation across mortality strata, although a subtle trend can be observed towards a lower Hib NPNM/meningitis ratio in higher mortality countries.

Figure 22: Hib NPNM:meningitis case ratio median and range for studies according to NPNM case severity and mortality strata*

0.1 Median and range

0.01 17 (13) 7 (7) 1 (1) 2 (1)

very low medium high very high

Number of studies (countries) and mortality strata

* Key: red dot = median; range bars = minimum and maximum values.

There were only five studies that provided CFRs for both Hib NPNM and meningitis for children less than five years of age, with a denominator consisting of at least 25 cases to allow direct comparison of the CFRs for these two syndromes (Table 20).

58 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 20: Number of studies that reported both Hib NPNM and meningitis CFR from at least 25 cases by WHO region

WHO Region Studies Total AFR AMR EMR EUR SEAR WPR Number of studies 0 1 0 2 0 2 5 Percentage of total studies 0 20 0 40 0 40 100

There were no data meeting these criteria from AFR, EMR and SEAR, and the data from the other regions were all from low mortality countries (Table 21). NPNM CFRs ranged between 0 and 3.9 (Table 21), and were in the same range but always lower than the meningitis CFR.

Table 21: Line list of CFRs and denominators for studies with both Hib NPNM and meningitis CFR (and at least 25 cases each)

Hib NPNM Hib meningitis Hib meningitis Country Hib NPNM CFR number of cases number of cases CFR (denominator) (denominator)

Australia 0.00 3.7 117 135 Australia 0.80 2.5 128 79 United Kingdom 3.90 4.1 51 195 United Kingdom 3.54 4.9 113 284 United States 0.00 4.0 228 457

4.7 Spn non-pneumonia, non-meningitis invasive disease

There were 38 studies that reported the syndrome distribution of Spn NPNM cases to meningitis cases directly or from which the syndrome distribution was inferred when cases of all invasive disease, meningitis, and pneumonia were available (Table 23). There were nine studies that presented the syndrome distribution of Spn NPNM and meningitis cases in children less than one year, 24 among children less than two years and 31 among children less than five years of age.

Table 22: Number of studies that reported the syndrome distribution of Spn NPNM cases to meningitis cases by WHO region

WHO Region Studies Total AFR AMR EMR EUR SEAR WPR Number of studies 4 15 0 12 3 4 38 Percentage of total studies 10.5 39.5 0 31.6 7.9 10.5 100

WHO/IVB/09.02 59 Figure 23 shows the range and median of the ratio of Spn NPNM cases to meningitis cases according to mortality strata and disease severity of NPNM cases, with the number of studies and countries contributing to each. As expected, non-severe NPNM was documented only in the very low mortality strata. The distribution of cases differed by mortality strata, with more NPNM cases relative to meningitis cases in the very low mortality countries, regardless of NPNM severity, and fewer NPNM cases relative to meningitis cases in medium, high and very high mortality countries. Overall, there is a wider variation in the range of NPNM:meningitis ratio for Spn than for Hib.

Figure 23: Spn NPNM meningitis case ratio median and range for studies according to NPNM case severity and mortality strata

100

0.1 Median and range 0.01

very low very low medium high very high 11(6) 27(14) 4(3) 3(2) 3(3)

Non-severe Severe

Number of studies (countries) and mortality strata

There were two studies that provided CFRs for both Spn NPNM and meningitis in children less than five years, with a denominator of at least 25 cases for each syndrome to allow for comparison of CFRs (Table 24). Since there were only two studies that provided CFRs from both Spn NPNM and meningitis (one in Kenya and one in the United States), it is difficult to draw general conclusions from this data. However, the CFR for Spn NPNM differed considerably between the two studies (Table 25). One explanation may be the heterogeneity of syndromes, and severity of these syndromes which are included in the NPNM category.

Table 23: Number of studies that reported Spn NPNM CFR and meningitis CFR by WHO region

WHO Region Studies Total AFR AMR EMR EUR SEAR WPR Number of studies 1 1 0 0 0 0 2 Percentage of total 50 50 0 0 0 0 100 studies

60 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 24: Line list of CFRs and denominators for studies with both Spn NPNM and meningitis CFR (with at least 25 cases each)

Spn NPNM Spn meningitis Spn NPNM Spn meningitis Country number of cases number of cases CFR CFR (denominator) (denominator)

Kenya 29.00 38.4 36 39 United States 0.59 11.0 169 27

WHO/IVB/09.02 61 5. Discussion

The search identified 336 unique studies with evaluable extracted outcomes for consideration in the analysis to estimate Hib and Spn disease burden. The number of studies found with evaluable extracted outcomes for Hib was similar to that of Spn — 205 and 211 studies, respectively. However, while the syndromes caused by these two diseases are very similar, only 24% of the studies contained evaluable extracted outcomes for both Hib and Spn.

Efforts to identify these studies were extensive, with over 15 000 published articles investigated, from nine databases, and the full text reviewed from almost 2000 articles. The process to identify and abstract these articles and to evaluate and clean the database required a large team of people (over 70 people participated in the process), and took over two years to complete.

This literature review provided data to populate the meningitis and NPNM disease burden models. However, the literature search was not used to generate the pneumonia model inputs or to determine differences in disease risk or mortality in HIV-positive children compared to HIV-negative children. Wolfson and colleagues describe the separate literature seaches and the products of those searches in another publication (Wolfson, 2009).

5.1 Clinical standards for case definitions and classification

Studies identified through the literature review used a wide variety of case definitions for meningitis and pneumonia, and these were sometimes very different from the standards recommended by WHO. Keeping track of such heterogeneity across studies was one of the reasons a quality review was instituted. For the purpose of clinical case management, case definitions may differ from one setting to another; however, when definitions used for surveillance vary widely, it makes comparison across studies problematic. To promote uniform standards in clinical case ascertainment used for surveillance, the WHO has recommended the following definitions for meningitis and for pneumonia in children (WHO, 2003; WHO, 1999).

62 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Meningitis Suspected: Any person with sudden onset of fever (>38.5 °C rectal or >38.0 °C axillary) and one of the following signs: neck stiffness, altered consciousness or other meningeal sign.

Probable: A suspected case with cerebrospinal fluid (CSF) examination showing at least one of the following: • turbid appearance; • leukocytosis (>100 cells/mm3); • leukocytosis (10–100 cells/ mm3) AND either an elevated protein (>100 mg/dl) or decreased glucose (<40 mg/dl).

Confirmed: A case that is laboratory-confirmed by growing (i.e. culturing) or identifying (i.e. by Gram stain or antigen detection methods) a bacterial pathogen (Hib, pneumococcus or meningococcus) in the CSF or from the blood, in a child with a clinical syndrome consistent with bacterial meningitis (WHO, 2003).

Pneumonia case definitions and classification Pneumonia: • Symptoms: cough or difficult breathing, and • signs: breathing >50 breaths per minute for infant aged two months to less than one year, breathing >40 per minute for child aged one to five years, and no chest indrawing, stridor or danger signs.

Severe pneumonia: • Symptoms: cough or difficult breathing plus any general danger sign or chest indrawing or stridor in a calm child. • General danger signs for children aged two months to five years: unable to drink or breastfeed; vomits everything; convulsions; lethargy or unconscious (WHO, 1999).

Clinical diagnosis of meningitis is more straightforward than that of pneumonia. The definition of pneumonia is based on the integrated management of childhood infections (IMCI) approach, which includes other acute lower respiratory tract infections and lacks specificity. In addition, etiological diagnosis of bacterial pathogens is easier in CSF than in blood. While pneumonia constitutes a larger fraction of the Hib and pneumococcal disease spectrum, surveillance of meningitis yields more accurate disease burden estimates compared to surveillance of pneumonia.

WHO/IVB/09.02 63 There is a need to update the current WHO recommended case definitions for probable and confirmed meningitis to include etiologic detection by use of PCR and possibly BinaxNOW® — an immunochromatographic antigen test to detect Streptococcus pneumoniae. The most recent WHO recommendations mention only blood culture and antigen detection of bacterial pathogens (WHO, 2003). However, since the publication of these guidelines in 2003, diagnostic technology has advanced. Polymerase chain reaction (PCR) has been validated for use in CSF and shown to be more sensitive than culture. Given its increasing use for CSF testing, even in resource- poor settings, there is a need to incorporate PCR diagnostics into the WHO standard case definitions for meningitis syndrome.

In this meta-analysis, invasive Hib and Spn cases were classified that were neither meningitis nor pneumonia, as non-pneumonia, non-meningitis (NPNM) syndrome. Cases in this category are largely confirmed cases of invasive Hib or Spn disease with no locus of infection (i.e. bacteraemia), or in the case of Hib, other clinical presentations such as cellulitis, septic arthritis and epiglottitis. Variability in blood- culturing practices across sites may lead to differences in observed incidence and CFRs of Spn NPNM syndromes. For example, a setting with limited capacity for blood culture will probably obtain cultures only among the sickest children, leading to higher CFRs compared to a setting with a high capacity. To account for this potential confounding the Spn analysis was stratified by “severe” and “non-severe” NPNM cases ofStreptococcus pneumoniae. This NPNM classification is used for the first time in this review. A standardized approach to reporting cases by syndrome would provide significant benefit for future surveillance reports and disease burden estimation projects.

5.2 Limitations of Hib and Spn incidence studies

The disease burden due to Hib and Spn is difficult to estimate. Estimates of Hib and Spn incidence are directly related to the microbiologic capacity to perform blood and CSF cultures, including training, experience, and access to optimal materials. In many countries this capacity is wholly lacking. Even in studies where active surveillance is undertaken, there may be limitations in case ascertainment and laboratory diagnosis. Estimating incidence of pneumonia is particularly problematic because such a small proportion of disease is bacteraemic, and lung aspirates, which are more sensitive, are rarely done. For meningitis, several procedures and appropriate tests must be performed for diagnosis, and to identify the pathogen-specific etiology. Meningitis has multiple causes, and laboratory confirmation of disease etiology is needed to confirm a case of Spn or Hib. Complete case ascertainment is very difficult to achieve so the majority of meningitis cases have unknown or unconfirmed etiology. Challenges with both case ascertainment and microbiology may lead meningitis incidence figures in some studies to be a gross underdetection of the real disease burden.

64 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Some common difficulties with case ascertainment are: • some cases are not treated in hospital; • some hospitals serving the study population may not be included in surveillance; • cases may be given an alternative diagnosis; for example, some children with possible meningitis are diagnosed as having febrile convulsions associated with another infectious disease; • cases with a clinical diagnosis of meningitis may not have diagnostic testing done; • cases may present at times when study staff are not available; • children in the study population may seek care outside the area (e.g. some cases may travel to large cities for care).

Common limitations of lab detection include the following. • Lumbar puncture must be done to collect cerebrospinal fluid (CSF). • Analysis of CSF must be done to diagnose meningitis. A variety of findings in CSF are suggestive of bacterial meningitis. Different studies use different case definitions for meningitis cases that are likely to have a bacterial etiology. • For culture results to be accurate, specimens must be collected before antibiotics are administered and done asceptically to avoid contamination. Culture results may be falsely negative if a specimen is collected after antibiotic administration. • Concentration of pathogen in CSF may be insufficient for detection at the time of lumbar puncture (LP). Supplemental blood cultures and follow-up LPs may increase detection. • CSF and blood specimens must be handled appropriately (e.g. specimen transport, storage). • CSF and blood specimens must be cultured using appropriate methods. • CSF and blood specimens must be cultured using the appropriate reagents. • Non-culture tests, such as bacterial antigen detection, or PCR, can be done on CSF to increase sensitivity.

Common problems with the denominator data include: • the source of population data is unreliable or out of date; • the study is carried out in a setting where the population is very difficult to estimate (for example, a highly mobile population); • cases that are not from the population at risk are included in the numerator.

WHO/IVB/09.02 65 5.3 Data sparsity and reporting inconsistencies in the published literature

The majority of studies that contributed data to primary endpoints of interest for both Hib and Spn were from AMR and EUR, while very few studies were available from SEAR and EMR. Unfortunately, many of the studies in all regions (25% to 50%) were deemed to be of insufficient quality for inclusion in analysis, which reduced even further the available data in all regions.

For both Hib and Spn, most of the data published for any outcome measure pertained to meningitis. Even though both Hib and Spn cause more cases and deaths due to pneumonia than meningitis, there were at least three times as many studies with evaluable meningitis data than for any other syndrome, in every region. It is well known that a significant proportion of pneumonia cases will have no etiology detected even when sample collection and laboratory methods are optimized. The inherent challenge is in obtaining a body fluid specimen from the site of infection (i.e. the lung). It is not surprising therefore that most of the surveillance literature focuses on those syndromes, such as meningitis, where a body fluid specimen can be collected from the site of infection.

Along with data sparsity, one of the limitations of this project was the heterogeneity of studies included for data abstraction and analysis. Apart from the differences in study design and methodology, studies were highly variable with regard to how data were reported. Among studies with incidence data, for example, abstractors often had to closely review the available data, and calculate one of the necessary inputs (e.g. the denominator). With the number of calculations required, it was not possible to verify with study authors the accuracy of the values obtained by the abstractors. However, for studies reviewed by two abstractors, discrepancies between the abstractors justified a review by a third individual who adjudicated the results.

5.4 Adjusted incidence data

Few studies (18% for Hib and less than 5% for Spn) reporting meningitis incidence were adjusted for limitations of the study, such as cases missed because they did not come to a study facility, cases not included because diagnostic tests were not done, or having negative culture results that were probable bacterial disease. In all studies with unadjusted and adjusted data, the adjustment resulted in an increase in the meningitis incidence estimate, demonstrating that the use of unadjusted data only leads to an underestimation of the true burden of disease. Because the amount of adjustment varied from study to study and is relative to the extent of the cases missed (not specified in the publications that were not adjusted), adjustment could not be applied to the majority of the studies. This means that any model using estimates of invasive meningitis incidence as a parameter, will result in an underestimation of the model outputs, potentially quite substantially.

66 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Those studies providing adjusted results attempt to address limitations in case ascertainment and/or diagnostic testing that could result in underestimates of disease burden. For example, the WHO HibRAT for the estimation of Hib meningitis incidence includes two adjustments that have been adopted in some recent studies (WHO, 2001; Rerks-Ngarm, 2004). Firstly, there is an adjustment for children who do not have lumbar puncture, which accounts for children who do not reach a study hospital or who do reach a hospital but who do not undergo lumbar puncture. Secondly, there is an adjustment for probable bacterial meningitis cases that do not have a pathogen identified to account for difficulties in specimen handling and testing in the laboratory. This adjustment also accounts for cases that might have false negative culture results because antibiotics are administered before lumbar puncture is done.

5.5 Foreign language papers

Most studies published in languages other than English were reviewed by two data abstractors. However, for a limited number of languages there was no individual, or only one trained individual who could screen and abstract data. In these cases, studies were excluded (if no translation could be obtained), or in the case of a limited number of trained reviewers, studies were reviewed only once instead of the standard double-abstraction.

WHO/IVB/09.02 67 6. References

Bennett JV et al. Haemophilus influenzae type b (Hib) meningitis in the pre-vaccine era: a global review of incidence, age distributions, and case-fatality rates. Geneva, World Health Organization, 2002. WHO/V&B/02.18. Available at: http://whqlibdoc.who.int/hq/2002/WHO_V&B_02.18.pdf Feikin DR et al. Rapid assessment tool for Haemophilus influenzae type b disease in developing countries. Emerging Infectious Diseases, 2004, 10(7):1270–1276. O’Brien KL et al. The global burden of disease due to Streptococcus pneumoniae in children less than 5 years of age. [submitted], 2009. Rerks-Ngarm S et al. Prospective population-based incidence of Haemophilus influenzae type b meningitis in Thailand. Vaccine, 2004, 22(8):975–983. State of the World’s Children 2005 — Childhood under threat. New York, United Nations Children’s Fund, 2004. Available at: http://www.unicef.org/ publications/files/SOWC_2005_(English).pdf. Watt JP et al. The global burden of disease due to Haemophilus influenzae, type b in children less than 5 years of age, [submitted], 2009. WHO-recommended surveillance standards. Geneva, World Health Organization, 1999. WHO/CDS/CSR/ISR/99.2. Available at: http://www.who.int/csr/resources/ publications/surveillance/whocdscsrisr992.pdf. Estimating the local burden of Haemophilus influenzae type b (Hib) disease preventable by vaccination: a rapid assessment tool. Geneva, World Health Organization, 2001. WHO/V&B/01.27. Available at: http://www.who.int/vaccines-documents/ DocsPDF01/www625.pdf. WHO-recommended surveillance standards for surveillance of selected vaccine- preventable diseases. Geneva, World Health Organization, 2003. WHO/V&B/03.01. Available at: http://www.who.int/vaccines-documents/DocsPDF06/843.pdf. Wolfson LJ et al. Methods to estimate the global burden of disease due to Haemophilus influenzae type b and Streptococcus pneumoniae in children less than five years of age, [submitted], 2009.

68 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 7. Annexes

Annex 1. Search strategies ...... 70 1. Search strategy for Hib articles in Embase/Medline ...... 70 2. Search strategy for Hib articles in Biosis...... 72 3. Search strategy for Hib articles in CAB Abstracts...... 73 4. Search strategy for Hib articles in Cochrane Library conducted in October 2005...... 74 5. Search strategy for Hib articles in Pascal BioMed conducted in October 2005...... 74 6. Search strategy for Spn articles in Embase/Medline ...... 76 7. Search strategy for Spn articles in Biosis...... 78 8. Search strategy for Spn articles in CAB...... 79 9. Search strategy for Spn articles in COCHRANE ...... 80 Annex 2. Article screening instructions...... 81 Annex 3. Data Abstraction Form (DAF)...... 85 Annex 4. Member States by WHO Region...... 108 Annex 5. Countries and territories by United Nations region...... 109 Annex 6. Study characteristics and key data from Hib studies entering the meningitis and NPNM analytic database...... 110 Annex 7. Study characteristics and key data from Spn studies entering the meningitis and NPNM analytic database...... 128 Annex 8. References for studies with evaluable outcome data...... 145

WHO/IVB/09.02 69 Annex 1: Search strategies

1. Search strategy for Hib articles in Embase/Medline

Step 1 (‘haemophilus influenzae type b’/exp OR ‘haemophilus influenzae type b’) OR (‘diphtheria pertussis poliomyelitis tetanus haemophilus influenzae type b hepatitis b vaccine’/exp OR ‘diphtheria pertussis poliomyelitis tetanus Haemophilus influenzae type b hepatitis b vaccine’) OR (‘diphtheria pertussis tetanus haemophilus influenzae type b vaccine’/exp OR ‘diphtheria pertussis tetanus haemophilus influenzae type b vaccine’) OR (‘dtp haemophilus influenzae type b vaccine’/exp OR ‘dtp haemophilus influenzae type b vaccine’) OR (‘diphtheria pertussis tetanus haemophilus influenzae type b vaccine’/exp OR ‘diphtheria pertussis tetanus haemophilus influenzae type b vaccine’) OR (‘haemophilus influenzae type b’/exp OR ‘haemophilus influenzae type b’) OR (‘haemophilus influenzae type b dtp vaccine’/exp OR ‘haemophilus influenzae type b dtp vaccine’) OR (‘haemophilus influenzae type b hepatitis b vaccine’/exp OR ‘haemophilus influenzae type b hepatitis b vaccine’) OR (‘haemophilus influenzae type b vaccine’/exp OR ‘Haemophilus influenzae type b vaccine’) OR (‘hepatitis b Haemophilus influenzae type b vaccine’/exp OR ‘hepatitis b Haemophilus influenzae type b vaccine’) OR (‘hib ompc’/exp OR ‘hib ompc’) OR (‘hib vax’/exp OR ‘hib vax’) OR ‘h influenzae’ OR ‘hib disease’ OR ‘hib infection’ OR ‘hib immuni’ OR ‘hemophilius influ’ OR (‘Haemophilus influenzae’/exp OR ‘Haemophilus influenzae’) OR (‘hemophilus influenzae’/exp OR ‘hemophilus influenzae’) OR (‘hemophilus influenzae’/exp OR ‘hemophilus influenzae’) OR (‘Haemophilus influenzae’/exp OR ‘Haemophilus influenzae’) AND [1980–2005]/py

Step 2 (‘purulent meningitis’/exp OR ‘purulent meningitis’) OR (‘bacterial meningitis’/exp OR ‘bacterial meningitis’) OR (‘meningitis, bacterial’/exp OR ‘meningitis, bacterial’) OR ‘meningitis and bacterial’ OR ‘bacterial meningitides’ OR ‘bacterial meningitides’ OR ((‘bacterial infection’/exp OR ‘bacterial infection’) AND (‘meningitis’/exp OR ‘meningitis’)) OR (‘bacterial pneumonia’/exp OR ‘bacterial pneumonia’) OR ((‘bacterial infection’/exp OR ‘bacterial infection’) AND (‘respiratory tract disease’/exp OR ‘respiratory tract disease’)) OR (‘bacteremia’/exp OR ‘bacteremia’) OR (‘septicemia’/ exp OR ‘septicemia’) AND (‘bacteraemia’/exp OR ‘bacteraemia’) OR (‘septicemia’/ exp OR ‘septicemia’) OR (‘septicaemia’/exp OR ‘septicaemia’) OR (‘sepsis’/exp OR ‘sepsis’) OR ‘lower respiratory tract infection ‘/exp OR ‘lower respiratory tract infection ‘) OR (‘lung infection’/exp OR ‘lung infection’) OR (‘infectious pneumonia’/ exp OR ‘infectious pneumonia’) OR (‘community acquired pneumonia’/exp OR ‘community acquired pneumonia’) OR (‘lobar pneumonia’/exp OR ‘lobar pneumonia’) OR (‘bacterial pneumonia’/exp OR ‘bacterial pneumonia’) OR (‘pneumonia’/exp

70 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 OR ‘pneumonia’) OR ‘bacteraemic pneumonia’ OR arli AND [1980–2005]/py # 2 (‘purulent meningitis’/exp OR ‘purulent meningitis’) OR (‘bacterial meningitis’/exp OR ‘bacterial meningitis’) OR (‘meningitis, bacterial’/exp OR ‘meningitis, bacterial’) OR ‘meningitis and bacterial’ OR ‘bacterial meningitides’ OR ‘bacterial meningitides’ OR ((‘bacterial infection’/exp OR ‘bacterial infection’) AND (‘meningitis’/exp OR ‘meningitis’)) OR (‘bacterial pneumonia’/exp OR ‘bacterial pneumonia’) OR ((‘bacterial infection’/exp OR ‘bacterial infection’) AND (‘respiratory tract disease’/exp OR ‘respiratory tract disease’)) OR (‘bacteremia’/exp OR ‘bacteremia’) OR (‘septicemia’/ exp OR ‘septicemia’) AND (‘bacteraemia’/exp OR ‘bacteraemia’) OR (‘septicemia’/ exp OR ‘septicemia’) OR (‘septicaemia’/exp OR ‘septicaemia’) OR (‘sepsis’/exp OR ‘sepsis’) OR (‘lower respiratory tract infection ‘/exp OR ‘lower respiratory tract infection ‘) OR (‘lung infection’/exp OR ‘lung infection’) OR (‘infectious pneumonia’/ exp OR ‘infectious pneumonia’) OR (‘community acquired pneumonia’/exp OR ‘community acquired pneumonia’) OR (‘lobar pneumonia’/exp OR ‘lobar pneumonia’) OR (‘bacterial pneumonia’/exp OR ‘bacterial pneumonia’) OR (‘pneumonia’/exp OR ‘pneumonia’) OR ‘bacteraemic pneumonia’ OR dol AND [1980–2005]/py

Step 3 (1 AND 2) Step 4 ‘meningitis, hemophilius’ OR ‘hemophilius meningitis’ OR ‘meningitis, haemophilius’ AND ‘haemophilius meningitis’ OR ‘hib pneumonia’ OR ‘hib meningitis’ OR ‘invasive hib’ AND [1980–2005]/py # 4 ‘meningitis, hemophilius’ OR ‘hemophilius meningitis’ OR ‘meningitis, haemophilius’ AND ‘haemophilius meningitis’ OR ‘hib pneumonia’ OR ‘hib meningitis’ OR ‘invasive hib’ AND [1980–2005]/py

Step 5 (4 OR 3) Step 6 (‘child’/exp OR ‘child’) OR (‘children’/exp OR ‘children’) OR (‘youth’/exp OR ‘youth’) OR youth* OR newborn* OR (‘newborn’/exp OR ‘newborn’) OR ‘new born’ OR ‘young people’ OR (‘childhood disease’/exp OR ‘childhood disease’) OR ‘childhood disease’ OR (‘baby’/exp OR ‘baby’) OR babies OR (‘infant’/exp OR ‘infant’) OR infant* OR juvenile* OR (‘juvenile’/exp OR ‘juvenile’) AND dolesce* OR childhood* OR toddler* OR kid OR kids OR ‘young patient’ OR dolescent* OR (‘adolescence’/ exp OR ‘adolescence’) OR boy* OR girl* OR teenager* OR ‘young age’ OR pediatr* OR paediatr* OR (‘child death’/exp OR ‘child death’) OR (‘child health’/exp OR ‘child health’) OR (‘child care’/exp OR ‘child care’) OR (‘childhood mortality’/exp OR ‘childhood mortality’) OR (‘child hospitalization’/exp OR ‘child hospitalization’) OR (‘pediatric hospital’/exp OR ‘pediatric hospital’) AND [1980–2005]/py # 6 (‘child’/ exp OR ‘child’) OR (‘children’/exp OR ‘children’) OR (‘youth’/exp OR ‘youth’) OR youth* OR newborn* OR (‘newborn’/exp OR ‘newborn’) OR ‘new born’ OR ‘young people’ OR (‘childhood disease’/exp OR ‘childhood disease’) OR ‘childhood disease’ OR (‘baby’/exp OR ‘baby’) OR babies OR (‘infant’/exp OR ‘infant’) OR infant* OR juvenile* OR (‘juvenile’/exp OR ‘juvenile’) AND dolesce* OR childhood* OR toddler* OR kid OR kids OR ‘young patient’ OR dolescent* OR (‘adolescence’/exp OR ‘adolescence’) OR boy* OR girl* OR teenager* OR ‘young age’ OR pediatr* OR paediatr* OR (‘child death’/exp OR ‘child death’) OR (‘child health’/exp OR ‘child health’) OR (‘child care’/exp OR ‘child care’) OR (‘childhood mortality’/exp OR ‘childhood mortality’) OR (‘child hospitalization’/exp OR ‘child hospitalization’) OR (‘pediatric hospital’/exp OR ‘pediatric hospital’) AND [1980–2005]/py

WHO/IVB/09.02 71 Step 7 (5 AND 6) Step 8 Limit 5 to ([newborn]/lim OR [infant]/lim OR [preschool]/lim OR [school]/lim OR [child]/lim OR [adolescent]/lim) #8 #3 OR #4 AND ([newborn]/lim OR [infant]/lim OR [preschool]/lim OR [school]/lim OR [child]/lim OR [adolescent]/lim)

Step 9 (8 OR 7) Step 10 ‘case report’/exp

Step 11 (9 NOT 10) Total number of citations 2213 conducted on the http://www.embase.com interface on Thursday 6 October 2005 at 09:00

2. Search strategy for Hib articles in Biosis

BIOSIS Previews <1997 to 2003> BIOSIS Previews <2005 Week 01 to 2005 Week 44> BIOSIS Previews <2004> Searched October 2005 (OVID Interface)

Step 1 (‘Haemophilus influenzae type b’ OR ‘diphtheria pertussis poliomyelitis tetanus Haemophilus influenzae type b hepatitis b vaccine’ OR ‘diphtheria pertussis tetanus Haemophilus influenzae type b vaccine’ OR ‘dtp Haemophilus influenzae type b vaccine’ OR ‘Haemophilus influenzae type b’ OR ‘Haemophilus influenzae type b dtp vaccine’ OR ‘Haemophilus influenzae type b hepatitis b vaccine’ OR ‘Haemophilus influenzae type b vaccine’

‘hepatitis b Haemophilus influenzae type b vaccine’) OR ‘hib ompc’ OR ‘hib vax’ OR ‘h influenzae’ OR ‘hib disease*’ OR ‘hib infection*’ OR ‘hib immuni*’ OR ‘hemophilius influ*’ OR ‘Haemophilus influenzae’ OR ‘hemophilus influenzae’ OR ‘hemophilus influenzae’ OR ‘Haemophilus influenzae’) AND [1980–2005]/py

Step 2 (‘purulent meningitis’ OR ‘bacterial meningitis’ OR ‘meningitis, bacterial’ OR ( ‘meningitis and bacterial’) OR ‘bacterial meningitides’ OR ((‘bacterial infection’ OR ‘bacterial infection*’) AND (‘meningitis’ OR ‘meningitis’)) OR (‘bacterial pneumonia’ OR ‘bacterial pneumonia’) OR ((‘bacterial infection’ OR ‘bacterial infection’) AND (‘respiratory tract disease’ OR ‘respiratory tract disease’)) OR ‘bacteremia’ OR ‘septicemia’ OR ‘septicaemia’ OR ‘sepsis’ OR ‘lower respiratory tract infection’ OR ‘lung infection’ OR ‘infectious pneumonia’ OR ‘community acquired pneumonia’ OR ‘lobar pneumonia’ OR ‘bacterial pneumonia’ OR ‘pneumonia’ OR ‘bacteraemic pneumonia’ OR arli )AND [1980–2005]/py

72 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Step 3 (1 AND 2) Step 4 (‘meningitis, hemophilius’ OR ‘meningitis, haemophilius’ AND ‘haemophilius meningitis’ OR ‘hib pneumonia’ OR ‘hib meningitis’ OR ‘invasive hib’) AND [1980–2005]/py

Step 5 (4 OR 3)

3. Search strategy for Hib articles in CAB Abstracts

1973 to September 2005 (Ovid Interface); search performed October 2005

Step 1 (‘haemophilus influenzae type b’ OR ‘diphtheria pertussis poliomyelitis tetanus haemophilus influenzae type b hepatitis b vaccine’ OR ‘diphtheria pertussis tetanus haemophilus influenzae type b vaccine’ OR ‘dtp haemophilus influenzae type b vaccine’ OR ‘haemophilus influenzae type b’ OR ‘haemophilus influenzae type b dtp vaccine’ OR ‘haemophilus influenzae type b hepatitis b vaccine’ OR ‘haemophilus influenzae type b vaccine’ ‘hepatitis b haemophilus influenzae type b vaccine’) OR ‘hib ompc’ OR ‘hib vax’ OR ‘h influenzae’ OR ‘hib disease*’ OR ‘hib infection*’ OR ‘hib immuni*’ OR ‘hemophilius influ*’ OR ‘haemophilus influenzae’ OR ‘hemophilus influenzae’ OR ‘hemophilus influenzae’ OR ‘haemophilus influenzae’)

AND [1980–2005]/py

Step 2 (‘purulent meningitis’ OR ‘bacterial meningitis’ OR ‘meningitis, bacterial’ OR (‘meningitis and bacterial’) OR ‘bacterial meningitides’ OR ((‘bacterial infection’ OR ‘bacterial infection*’) AND (‘meningitis’ OR ‘meningitis’)) OR (‘bacterial pneumonia’ OR ‘bacterial pneumonia’) OR ((‘bacterial infection’ OR ‘bacterial infection’) AND (‘respiratory tract disease’ OR ‘respiratory tract disease’)) OR ‘bacteremia’ OR ‘septicemia’ OR ‘septicaemia’ OR ‘sepsis’ OR ‘lower respiratory tract infection ‘OR ‘lung infection’ OR ‘infectious pneumonia’ OR ‘community acquired pneumonia’ OR

‘lobar pneumonia’ OR ‘bacterial pneumonia’ OR ‘pneumonia’ OR ‘bacteraemic pneumonia’ OR ril )AND [1980–2005]/py

Step 3 (1 AND 2) Step 4 (‘meningitis, hemophilius’ OR ‘meningitis, haemophilius’ AND ‘haemophilius meningitis’ OR ‘hib pneumonia’ OR ‘hib meningitis’ OR ‘invasive hib’) AND [1980–2005]/py

Step 5 (4 OR 3)

WHO/IVB/09.02 73 4. Search strategy for Hib articles in Cochrane Library conducted in October 2005

Step 1 - Search results 1 (1069 citations) “Haemophilus influenzae type b” OR “diphtheria pertussis poliomyelitis tetanus Haemophilus influenzae type b hepatitis b vaccine” OR “diphtheria pertussis tetanus Haemophilus influenzae type b vaccine” OR “dtp Haemophilus influenzae type b vaccine” OR “Haemophilus influenzae type b” OR “Haemophilus influenzae type b dtp vaccine” OR “Haemophilus influenzae type b hepatitis b vaccine” OR “Haemophilus influenzae type b vaccine” OR “hepatitis b Haemophilus influenzae type b vaccine” OR “hib ompc” OR “hib vax” OR “h influenzae” OR “hib disease*” OR “hib infection*” OR “hib immuni*” OR “hemophilius influ*” OR “Haemophilus influenzae” OR “hemophilus influenzae” OR “hemophilus influenzae” OR “Haemophilus influenzae”

Step 2 - Search Results 2 (7627 citations) “purulent meningitis” OR “bacterial meningitis” OR “meningitis, bacterial” OR (“meningitis and bacterial”) OR “bacterial meningitides” OR ((“bacterial infection” OR “bacterial infection*”) AND (“meningitis” OR “meningitis”)) OR (“bacterial pneumonia” OR “bacterial pneumonia”) OR ((“bacterial infection” OR “bacterial infection”) AND (“respiratory tract disease” OR “respiratory tract disease*”)) OR “bacteremia” OR “septicemia” OR “septicaemia” OR “sepsis” OR “lower respiratory tract infection” OR “lung infection” OR “infectious pneumonia” OR “community acquired pneumonia” OR “lobar pneumonia” OR “bacterial pneumonia” OR “pneumonia” OR “bacteraemic pneumonia” OR arli

Step 3 - Combine Steps 1 and 2 (260 citations) Step 4 - Search results (31 citations) “meningitis, hemophilius” OR “meningitis, haemophilius” OR “haemophilius meningitis” OR “hib pneumonia” OR “hib meningitis” OR “invasive hib”

Combine (Step 4 OR Step 3) (279 citations)

5. Search strategy for Hib articles in Pascal BioMed conducted in October 2005

Pascal BioMed (2005/01-2005/09,2003–2004,2001–2002,1999–2000,1997–1998, 1994–1996,1991–1993, 1987–1990. Searched October 2005 (WebSpirs Interface)

74 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 ‘hepatitis b Haemophilus influenzae type b vaccine’) OR ‘hib ompc’ OR ‘hib vax’ OR ‘h influenzae’ OR ‘hib disease*’ OR ‘hib infection*’ OR ‘hib immuni*’ OR ‘hemophilius influ*’ OR ‘Haemophilus influenzae’ OR ‘hemophilus influenzae’ OR ‘hemophilus influenzae’ OR ‘Haemophilus influenzae’) AND [1980–2005]/py

Step 2

(‘purulent meningitis’ OR ‘bacterial meningitis’ OR ‘meningitis, bacterial’ OR (meningitis and bacterial’) OR ‘bacterial meningitides’ OR ((‘bacterial infection’ OR ‘bacterial infection*’) AND (‘meningitis’ OR ‘meningitis’)) OR (‘bacterial pneumonia’ OR ‘bacterial pneumonia’) OR ((‘bacterial infection’ OR ‘bacterial infection’) AND (‘respiratory tract disease’ OR ‘respiratory tract disease’)) OR ‘bacteremia’ OR ‘septicemia’ OR ‘septicaemia’ OR ‘sepsis’ OR ‘lower respiratory tract infection’ OR ‘lung infection’ OR ‘infectious pneumonia’ OR ‘community acquired pneumonia’ OR ‘lobar pneumonia’ OR ‘bacterial pneumonia’ OR ‘pneumonia’ OR ‘bacteraemic pneumonia’ OR arli )AND [1980–2005]/py

Step 5 (4 OR 3)

WHO/IVB/09.02 75 6. Search strategy for Spn articles in Embase/Medline

Search queries

No. Query Results Date (‘lower respiratory tract infection’/exp OR ‘lower respiratory tract infection’) OR ‘lower respiratory tract infection’ OR (‘lung infection’/exp OR ‘lung infection’) OR ‘lung infection’ OR (‘infectious pneumonia’/exp OR ‘infectious pneumonia’) OR ‘infectious pneumonia’ OR (‘bacterial pneumonia’/exp OR ‘bacterial pneumonia’) OR ‘bacterial pneumonia’ OR (‘community acquired pneumonia’/exp OR ‘community acquired pneumonia’) OR ‘community 153 153 #1 17 November 2005 acquired pneumonia’ OR (‘lobar pneumonia’/exp OR ‘lobar pneumonia’) OR ‘lobar pneumonia’ OR (‘pneumonia’/ exp OR ‘pneumonia’) OR ‘pneumonia’ OR ‘bacteraemic pneumonia’ OR ‘bacteraemic pneumonia’ OR arli OR ‘infectious pneumopath’ OR (‘streptococcus infection’/exp OR ‘streptococcus infection’) OR ‘streptococcus infection’ OR (‘bacterial meningitis’/exp OR ‘bacterial meningitis’) OR ‘bacterial meningit’ AND [1980–2005]/py (‘Streptococcus pneumoniae’/exp OR ‘Streptococcus pneumoniae’) OR (‘diplococcus pneumoniae’/exp OR ‘diplococcus pneumoniae’) OR (‘pneumococcus’/ exp OR ‘pneumococcus’) OR ‘s pneumoniae’ OR pneumococci OR (‘pneumococcus vaccine’/exp OR ‘pneumococcus vaccine’) OR ‘pneumococcus vaccine’ OR (‘pneumococcus polysaccharide’/exp OR ‘pneumococcus polysaccharide’) OR ‘pneumococcal conjugate’ OR (‘pneumovax 23’/exp OR ‘pneumovax 17 November 2005 #2 25 790 23’) OR (‘prevnar’/exp OR ‘prevnar’) OR ‘pneumococcal heptavalent conjugate’ OR ‘pneumococcal heptavalent conjugate’ OR (‘pnu-imune 23’/exp OR ‘pnu-imune 23’) OR ‘ 7-valent pncompc vaccine’ OR ‘seven-valent pneumococcal ps-meningococcal ompc conjugate vaccine’ OR ‘pncrm7’ OR ‘mnc-crm197’ OR ‘mncc’ OR ‘pneumococcal polysaccharide vaccine’ OR (‘pneumovax’/exp OR ‘pneumovax’) OR ‘pnu-imune vaccine’ AND [1980–2005]/py #3 #1 AND #2 11 392 17 November 2005 ‘Streptococcus pneumoniae meningitis’ OR (‘pneumococcal meningitis’/exp OR ‘pneumococcal meningitis’) OR (‘meningitis, pneumococcal’/exp OR ‘meningitis, pneumococcal’) OR (‘pneumococcal meningitis’/exp OR ‘pneumococcal meningitis’) OR (‘pneumococcal pneumonia’/exp OR ‘pneumococcal #4 10 921 17 November 2005 pneumonia’) OR ‘pneumococcal bacteraemia’ OR ‘invasive pneumococcal disease’ OR ‘pneumococcal mortalit’ OR ‘pneumococcal invasive disease’ OR ‘pneumococcal *5 pneumonia’ OR ‘pneumococcal *5 meningitis’ OR ‘pneumococcal *5 bacteraemia’ OR ‘pneumococcal *5 invasive’ AND [1980–2005]/py #5 #6 #3 OR #4 18 683 17 November 2005

76 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 No. Query Results Date ((‘child’/exp OR ‘child’) OR (‘child’/exp OR ‘child’)) OR ((‘children’/exp OR ‘children’) OR (‘children’/exp OR ‘children’)) OR child* OR ((‘youth’/exp OR ‘youth’) OR (‘youth’/exp OR ‘youth’)) OR youth* OR newborn* OR ((‘newborn’/exp OR ‘newborn’) OR (‘newborn’/exp OR ‘newborn’)) OR ‘new born’ OR ‘young people’ OR ((‘childhood disease’/exp OR ‘childhood disease’) OR (‘childhood disease’/exp OR ‘childhood disease’)) OR (‘childhood disease’/exp OR ‘childhood disease’) OR ((‘baby’/exp OR ‘baby’) OR (‘baby’/exp OR ‘baby’)) OR babies OR ((‘infant’/exp OR ‘infant’) OR (‘infant’/exp OR ‘infant’)) OR infant* OR juvenile* OR ((‘juvenile’/ exp OR ‘juvenile’) OR (‘juvenile’/exp OR ‘juvenile’)) OR juvenille* OR childhood* OR toddler* OR kid OR kids 17 November 2005 #7 OR ‘young patient’ OR adolescen* OR ((‘adolescence’/ 1 795 097 exp OR ‘adolescence’) OR (‘adolescence’/exp OR ‘adolescence’)) OR boy* OR girl* OR teenager* OR ‘young age’ OR pediatr* OR paediatr* OR ((‘child death’/ exp OR ‘child death’) OR (‘child death’/exp OR ‘child death’)) OR ((‘child health’/exp OR ‘child health’) OR (‘child health’/exp OR ‘child health’)) OR ((‘child care’/ exp OR ‘child care’) OR (‘child care’/exp OR ‘child care’)) OR ((‘childhood mortality’/exp OR ‘childhood mortality’) OR (‘childhood mortality’/exp OR ‘childhood mortality’)) OR ((‘child hospitalization’/exp OR ‘child hospitalization’) OR (‘child hospitalization’/exp OR ‘child hospitalization’)) OR ((‘pediatric hospital’/exp OR ‘pediatric hospital’) OR (‘pediatric hospital’/exp OR ‘pediatric hospital’)) AND [1980–2005]/py #8 #6 AND #7 8423 17 November 2005 #3 OR #4 AND ([newborn]/lim OR [infant]/lim OR 6481 #9 [preschool]/lim OR [school]/lim OR [child]/lim OR 17 November 2005 [adolescent]/lim) #10 #8 OR #9 8423 17 November 2005 1 221 465 #11 case report /exp AND [1980–2005]/py 17 November 2005

#12 #10 NOT #11 6994 17 November 2005

WHO/IVB/09.02 77 7. Search strategy for Spn articles in Biosis

Set 1 “lower respiratory tract infection” or “lower respiratory tract infection$” or “lung infection” or “lung infection$” or “infectious pneumonia” or “infectious pneumonia$” or “bacterial pneumonia” or “bacterial pneumonia$” or “community acquired pneumonia” or “community acquired pneumonia$” or “lobar pneumonia” or “lobar pneumonia$” or “pneumonia” or “pneumonia$” or “bacteraemic pneumonia” or “bacteraemic pneumonia$” or ARLI or “infectious pneumopath$” or “Streptococcus infection” or “Streptococcus infection$” or “bacterial meningitis” or “bacterial meningit$”

Set 2 “Streptococcus pneumoniae” or “Diplococcus pneumoniae” or “Pneumococcus” or “s pneumoniae” or Pneumococci or “Pneumococcus vaccine” or “Pneumococcus vaccine$” or “pneumococcus polysaccharide” or “pneumococcal conjugate$” or “Pneumovax 23” or Prevnar or “pneumococcal heptavalent conjugate” or “pneumococcal heptavalent conjugate$” or “Pnu-Imune 23” or “7-valent PncOMPC vaccine” or “seven-valent pneumococcal PS-meningococcal OMPC conjugate vaccine$” or “PNCRM7” or “Mnc-CRM197” or “MnCC” or “Pneumococcal Polysaccharide Vaccine$” or “Pneumovax” or “Pnu-Imune Vaccine$”

Set 3 “Streptococcus pneumoniae Meningitis” or “Pneumococcal Meningitis” or “Meningitis, Pneumococcal” or “Pneumococcal Meningitis” or “Pneumococcal pneumonia” or “Pneumococcal bacteraemia” or “Invasive pneumococcal disease$” or “Pneumococcal mortalit$” or “Pneumococcal invasive disease$” or “pneumococcal adj5 pneumonia” or “pneumococcal adj5 meningitis” or “pneumococcal adj5 bacteraemia” or “Pneumococcal adj5 invasive”

Set 4 (‘child’/exp OR ‘child’) OR (‘children’/exp OR ‘children’) OR child$ OR (‘youth’/exp OR ‘youth’) OR youth$ OR newborn$ OR (‘newborn’/exp OR ‘newborn’) OR ‘new born’ OR ‘young people’ OR (‘childhood disease’/exp OR ‘childhood disease’) OR ‘childhood disease’ OR (‘baby’/exp OR ‘baby’) OR babies OR (‘infant’/exp OR ‘infant’) OR infant$ OR juvenile$ OR (‘juvenile’/exp OR ‘juvenile’) OR juvenille$ OR childhood$ OR toddler$ OR kid OR kids OR ‘young patient’ OR adolescen$ OR (‘adolescence’/exp OR ‘adolescence’) OR boy$ OR girl$ OR teenager$ OR ‘young age’ OR pediatr$ OR paediatr$ OR (‘child death’/exp OR ‘child death’) OR (‘child health’/exp OR ‘child health’) OR (‘child care’/exp OR ‘child care’) OR (‘childhood mortality’/exp OR ‘childhood mortality’) OR (‘child hospitalization’/exp OR ‘child hospitalization’) OR (‘pediatric hospital’/exp OR ‘pediatric hospital’)

78 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 8. Search strategy for Spn articles in CAB

WHO/IVB/09.02 79 9. Search strategy for Spn articles in COCHRANE

“lower respiratory tract infection” or “lower respiratory tract infection*” or “lung infection” or “lung infection*” or “infectious pneumonia” or “infectious pneumonia*” or “bacterial pneumonia” or “bacterial pneumonia*” or “community acquired pneumonia” or “community acquired pneumonia*” or “lobar pneumonia” or “lobar pneumonia*” or “pneumonia” or “pneumonia*” or “bacteraemic pneumonia” or “bacteraemic pneumonia*” or ARLI or “infectious pneumopath*” or “Streptococcus infection” or “Streptococcus infection*” or “bacterial meningitis” or “bacterial meningit*” or “Streptococcus pneumoniae” or “Diplococcus pneumoniae” or “Pneumococcus” or “s pneumoniae” or Pneumococci or “Pneumococcus vaccine” or “Pneumococcus vaccine*” or “pneumococcus polysaccharide” or “pneumococcal conjugate*” or “Pneumovax 23” or Prevnar or “pneumococcal heptavalent conjugate” or “pneumococcal heptavalent conjugate*” or “Pnu-Imune 23” or “Pnu Imune 23”or “ 7-valent PncOMPC vaccine” or “7 valent PncOMPC vaccine” or “seven valent pneumococcal PS meningococcal OMPC conjugate vaccine*” or “seven- valent pneumococcal PS-meningococcal OMPC conjugate vaccine*” or “PNCRM7” or “Mnc-CRM197” or “MnCC” or “Pneumococcal Polysaccharide Vaccine*” or “Pneumovax” or “Pnu-Imune Vaccine*” or “Streptococcus pneumoniae Meningitis” or “Pneumococcal Meningitis” or “Meningitis, Pneumococcal” or “Pneumococcal Meningitis” or “Pneumococcal pneumonia” or “Pneumococcal bacteraemia” or “Invasive pneumococcal disease*” or “Pneumococcal mortalit*” or “Pneumococcal invasive disease*” or “pneumococcalNEAR/5 pneumonia” or “pneumococcal NEAR/5 meningitis” or “pneumococcal NEAR/5 bacteraemia” or “Pneumococcal NEAR/5 invasive”

80 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Annex 2: Article screening instructions

The procedure for collecting all the published data follows a series of steps as follows: 1) Literature search: Systematically search the published literature to identify articles based on a defined search strategy. 2) Identify potentially relevant articles (Screening): Review the titles and abstracts (when available) of the articles identified in the previous step to remove articles which obviously are not relevant, leaving those which are classified as “potentially relevant” (or whose relevance is unknown based on the title and abstract). The objective of this step is to reduce the workload of retrieving articles that are obviously not relevant based on titles and abstracts, without losing sensitivity. 3) Retrieve the full text of all the potentially relevant articles (=screened articles). 4) Identify relevant articles: Screen again all potentially relevant articles to identify those for structured abstraction, using the same criteria as in Step 2. This fourth step is to eliminate, with the benefit of having the full article text available, those articles which clearly do not provide the information of primary interest (i.e., incidence rates, case-fatality rates). This step likely will eliminate only a small number of articles, as the bulk of the screening occurred in Step 2. 5) Assess eligibility of screened articles: Complete the first 2 pages of abstraction form for articles screened in; these 2 pages describe inclusion/exclusion criteria for the studies (e.g., year of case detection, vaccine use in the population, number of months of case ascertainment, cases from sub-group populations) and will determine if further data abstraction is appropriate. 6) Complete abstraction of eligible articles: For articles meeting inclusion criteria in Step 5, do structured abstraction of methods, results, and data quality, as well as bibliography check for other potentially relevant articles not yet identified.

This document describes the procedure for step 2.

WHO/IVB/09.02 81 Persons screening articles will be provided with a spreadsheet listing the ID # for all references which require screening, and another file with titles/abstracts for these references. This spreadsheet includes columns in which to indicate whether articles should be abstracted or excluded. The articles should be reviewed and placed into one of 5 categories: 1) Include: Reference has relevant data (as described below), should be retrieved for review/abstraction; 2) Review: Reference is a review article and has no primary data. It will not be pulled for abstraction but should be tracked as it may be reviewed later; 3) Exclude: Reference does not have relevant data and is not a review article; 4) Exclude pneumonia etiology: Reference does not have relevant data and is not a review article, but may have data on pneumonia etiology in childhood. 5) Foreign language: Reference is in another language (specify language). If screener is able to make a decision about the article based on the abstract, indicate which of the first 4 categories is appropriate, and also include the language of the article in column 5.

Screening: Categories of Articles (A-E)

A. INCLUDE Articles should be ABSTRACTED if they have any data that are relevant for the study. Relevant data include: 1) Incidence of invasive disease in children for: a) Hib meningitis b) Hib pneumonia c) Hib non-meningitis, non-pneumonia invasive disease (i.e., sepsis, bacteremia, septic arthritis, epiglottitis, etc.) d) pneumococcal meningitis e) pneumococcal pneumonia f) pneumococcal non-meningitis, non-pneumonia invasive disease (i.e., sepsis, bacteremia, septic arthritis, epiglottitis, etc.)

2) Age distribution of cases of invasive Hib or pneumococcal disease 3) Case fatality rates of invasive Hib or pneumococcal disease 4) Distribution of Hib and pneumococcal disease syndromes (i.e., what proportion of cases are meningitis, pneumonia, sepsis, other invasive disease)

82 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 5) Etiology data by syndrome - Some studies are by syndrome (e.g. meningitis or other invasive disease) and what was found proportionally by etiology. These studies may be useful for plausibility checks, they may provide CFR by syndrome/pathogen, and some of these may have a denominator that we could infer or get. a) proportion of all meningitis that is Hib and/or pneumococcus b) proportion of all invasive disease that is Hib and/or pneumococcus

Note: Pneumonia etiology studies should placed in category D below

B. REVIEW These are review articles and will not be pulled for abstraction. However, these references should be distinguished as a separate category because review articles might provide empirical data not published in journals captured by the search strategy. This category provides us with an option to retrieve review articles and check if their references have been included or missed by the search strategy. (An example of such an article is the review by Heikki Peltola on Hib in Africa, which has a massive number of useful references.)

EXCLUDE This category is for references without relevant data or references that are not review articles. Examples of types of articles which will be excluded (unless they have relevant data): 1) A case report (i.e. a single case) 2) Antimicrobial resistance studies 3) Vaccine immunogenicity and safety studies 4) Nasopharyngeal carriage studies 5) Molecular characterization of bacterial strains 6) Policy papers (except if the article might also provide primary disease burden data from specified countries) 7) Disease only among adults 8) Articles that don’t specifically coverH. influenzae or pneumococcus- e.g. other types of Haemophilus or syndromic studies. Do include studies of H. influenzae, even if no information about typing is provided, as long as the other criteria are met. 9) Studies including only children less than one year of age (e.g., studies of neonates) 10) Studies with isolates only from non-sterile sites.

WHO/IVB/09.02 83 There may be several variations of studies encountered: a) Papers with isolates from sterile sites only  Include; b) Papers with isolates from both sterile and non-sterile sites, and the data can be separated into these 2 groups  Abstract data for the sterile sites only; c) Papers with isolates from both sterile and non-sterile sites, and data from each cannot be separated  Exclude; d) Papers with isolates only from non-sterile isolates  Exclude. Urine antigen should be treated as a non-sterile site isolate. The only exception would be a study with an overwhelming majority of sterile site isolates, and a very small number of non-sterile site isolates that were included for some compelling reason. For these types of studies, the paper should be screened in so the article can be reviewed and discussed with the rest of the group.

C. EXCLUDED (PNEUMONIA ETIOLOGY) These references include studies that attempt to identify the etiology of pneumonia in children using lung tap, serology, or other methods. These articles should be excluded but marked as pneumonia etiology studies; they may be retrieved for review later. Select this category only if the article has data on children under age 5 years and if they include Hib and/or S. pneumo (otherwise select category C).

D. FOREIGN LANGUAGE If the article is not in English, write in the space provided the language of the article (if language is not known, indicate “Unknown”).

***Note on screening of and abstracting data from case series with < 30 cases*** As noted in Category C, a case report of a single case should be excluded during screening. A study with more than one case can be included, provided the article’s content is appropriate for abstraction. However, once screened in, if a study does not meet criteria for abstraction of incidence data AND there are fewer than 30 cases included in the study, other data such as age/syndrome distribution and case fatality data will not be abstracted. In this situation, the data abstraction form should be started, but only limited information will be abstracted (see below).

If there are NO incidence data and there are 2-29 cases reported in a case series: a) Complete Section A (Inclusion Criteria) Questions 1-7. b) Skip Sections B (Study Design), C (Study Population), D (Case Definition) c) Skip to Section E (Incidence Data) and answer Question 25 (“Does the manuscript report incidence data…”). The answer to either Q25 or Q26 will be “No.” d) Skip to Section F (Age and Disease Syndrome Distribution Data) and answer Question 34 (“Does the manuscript report a total of 30 or more cases…”). The response should be “No.” e) Skip to the last question of the form (Question 61) and end/submit the form.

84 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Annex 3: Data Abstraction Form (DAF)

1. Study ID number ______

Section A. Inclusion criteria

2. Is this a randomized controlled trial to test the effectiveness of Hib or pneumococcal vaccine?  Yes (skip to question 5)  No (continue to question 3) If study presents Hib data, answer question 3; if study presents S. pneumo data, answer question 4.

3. Was there any use of Hib vaccine before or at any time during the study period?  Yes (answer question 3a)  No (skip to question 4)  Unknown (skip to question 4)

3a. Was Hib vaccine coverage 25% or higher for children under 5 years of age, and/or was there substantial use of Hib vaccine in the study population?  Yes (continue to question 3b)  No (skip to question 4)  Unknown (skip to question 4) 3b. Does the paper include any data on Hib disease reduction following widespread use of the vaccine?  Yes  No 3c. Are any data available from the period before vaccine coverage reached 25%, or before vaccine use became substantial?  Yes (continue to question 4)  No (STUDY EXCLUDED for Hib data abstraction, continue to question 4)

WHO/IVB/09.02 85 4. Was there any use of pneumococcal conjugate vaccine before or at any time during the study period?  Yes (answer question 4a)  No (skip to question 5)  Unknown (skip to question 5)

4a. Was pneumococcal conjugate vaccine coverage 25% or higher for children under 5 years of age, and/or was there substantial use of pneumococcal conjugate vaccine in the study population?  Yes (continue to question 4b)  No (skip to question 5)  Unknown (skip to question 5) 4b. Does the paper include any data on S. pneumo disease reduction following widespread use of the vaccine?  Yes  No 4c. Are any data available from the period before vaccine coverage reached 25%, or before vaccine use became substantial?  Yes (continue to question 5)  No (STUDY EXCLUDED for S. pneumo data abstraction)

NOTE 1:

If study is excluded for both Hib and S. pneumo data abstraction, skip to end of form and answer question 61.

5. Did all reported cases occur after 1979?  Yes  No (STOP – EXCLUDE, skip to question 61)

6. Are there at least 12 months of case ascertainment?  Yes  No (STOP – EXCLUDE, skip to question 61)  Unknown (STOP – EXCLUDE, skip to question 61)

86 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 7. Does the manuscript provide data for any subpopulation of children (e.g., HIV infection, sickle cell disease, racial/demographic groups, etc.)?  Yes (answer question 7a)  No (skip to Section B)

7a. What distinguished the sub-population from the general study population?  HIV infection  Shared medical condition other than HIV (e.g., sickle cell disease)  Different ethnic/racial background (e.g., Native Americans)  Displaced population  Degree of antibiotic use  Other (specify in 7b) 7b. If “Other,” describe the sub-population(s) [text] 7c. Are data about the general study population available also?  Yes (continue to section B)  No (STOP – EXCLUDE, skip to question 61)

NOTE 2:

If the study is included: Complete sections B, C, and D. If study is excluded: Skip to end of form to question 61.

Section B. Study Design

8. Are data from more than one country presented?  Yes (answer question 8a)  No (skip to question 9) 8a. How many countries are included in the study? [numeric] 8b. Can data be distinguished by individual country?  Yes (skip to question 9; a separate abstraction form should be completed for each country whose data meet inclusion criteria )  No (complete question 8c) 8c. If data cannot be distinguished by individual country, indicate all the countries included in the study [text]

9. Describe the geographic area under study:  Whole country  Portion of country  Unknown

WHO/IVB/09.02 87 10. In which country did the study take place? [picklist of countries, include multi- country as option]

11. If the study was located in a portion of a country, indicate the name of the area where it was located. [text]

12. How is the study area described? (select one)  Rural setting  Urban and/or peri-urban setting  Mixed rural/urban setting  Unknown

13. Were cases identified in hospitals?  Yes (Answer question 13a, 13b, and 13c)  No (Skip to question 14)  Unknown (Skip to question 14) 13a. Is the number of hospitals included in the study known?  Yes  No (Skip to question 13c) 13b. If the number of hospitals is known, specify the number here __ __ 13c. Type of hospitals included in study (check all that apply):  Tertiary care or referral hospital, or specialized research hospital  Regional, district, or local hospital (or primary and secondary care hospitals)  Other type of hospital (specify in question 13d)  Unknown 13d. Describe the other type(s) of hospital included in the study [text]

14. Were cases identified among children who presented to outpatient facilities (and who may not have been admitted to the hospital)?  Yes  No  Unknown

15. Were cases identified from children in the home setting?  Yes  No  Unknown

88 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 16. Describe data collection (check all that apply):  Retrospective  Prospective (answer question 16a) 16a. If prospective, indicate type of data collection (check all that apply)  Active surveillance  Passive surveillance  Other (specify in question 16b)  Unknown 16b. If “Other,” specify data collection method [text]

Section C. Study Population

17. Are neonates (infants less than 1 month old) included?  Yes (skip to question 18)  No (answer question 17a)  Unknown (skip to question 18) 17a. If neonates are not included, is the lower age limit for surveillance known?  Yes (specify in question 17b)  No (skip to question 18) 17b. Specify the lower age limit in months (include ½ month as “0.5”) __ __ . __

18. Is HIV prevalence described in the manuscript?  Yes  No

19. Does the manuscript describe the under-5 mortality rate for the area under study?  Yes, in numeric terms (answer questions 19a and 19b)  Yes, in general terms (answer questions 19a and 19c)  No (skip to question 20) 19a. What is the source for the under-5 mortality rate? [text] 19b. What is the under-5 mortality rate?  More than 150 deaths per 1000 live births  75 to 150 deaths per 1000 live births  30-74 deaths per 1000 live births  Less than 30 deaths per 1000 live births 19c. How is the under-5 mortality rate (U5MR) characterized? [text]

WHO/IVB/09.02 89 20. Was Hib vaccine available to the population under study during the period of data collection (i.e., available via private market but not through national immunization program)?  Yes (Answer question 20a)  No (Skip to question 21)  Not applicable - Randomized trial of Hib vaccine (Skip to question 21)  Unknown (Skip to question 21) 20a. Was information about the proportion of the population who received Hib vaccine provided?  Yes, in numeric terms (Complete question 20b)  Yes, in general terms (descriptive, not numeric (Complete Q20c)  No (Skip to Question 21) 20b. Enter the numeric estimate of the proportion of the population vaccinated with Hib, if provided __ __ % 20c. If no numeric estimate is provided but the proportion vaccinated with Hib is described, indicate description here (i.e., “few,” “most”) [text]

21. Was S. pneumo vaccine available to the population under study during the period of data collection? (i.e., available via private market but not through national immunization program)?  Yes (Answer question 21a)  No (Skip to question 22)  Not applicable - Randomized trial of pneumococcal conjugate vaccine (Skip to question 22)  Unknown (Skip to question 22) 21a. Was information about the proportion of the population who received S. pneumo vaccine provided?  Yes, in numeric terms (Complete question 21b)  Yes, in general terms (descriptive, not numeric (Complete Q21c)  No (Skip to Question 22) 21b. Enter the numeric estimate of the proportion of population vaccinated with S. pneumo, if provided __ __ % 21c. If no numeric estimate is provided but the proportion vaccinated with S. pneumo is described, indicate description here (i.e., “few,” “most”) [text]

90 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 22. Does the manuscript indicate the proportion of subjects who received antibiotics prior to presentation or specimen collection?  Yes, in numeric terms (Complete question 22a)  Yes, in general terms (Complete Question 22b)  No (Skip to Question 23) 22a. If a numeric estimate for the proportion was provided, enter it here __% 22b. If no numeric estimate is provided but the proportion of subjects who received antibiotics is described, enter the description here (e.g., “few”)

Section D. Case Definitions

23. Which Hib and/or S. pneumo invasive disease(s) was measured? (check all that apply)  Meningitis  Pneumonia  Non-pneumonia, non-meningitis invasive disease  All invasive disease other than meningitis (check here if pneumonia cases were not distinguished from other syndromes)  All invasive disease (check only if cases were not stratified by syndrome)

24. Case definition includes patients with positive result for (check all that apply):  Blood specimens, by culture  CSF specimens, by culture  CSF specimens, by non-culture method (e.g., PCR, latex agglutination)  Other (non-blood, non-CSF) normally sterile fluid specimens (e.g., pleural fluid, joint fluid, peritoneal fluid) by culture  Other normally sterile fluid specimens, by non-culture method  Other laboratory tests (specify in question 24a) 24a. Specify other laboratory test(s) [text] 24b. Indicate which of the following describe the data abstracted from this study:  No data presented on H. influenzae or Hib invasive disease  Presents data on H. influenzae invasive disease, no serotyping was done (for these papers, assume all H. influenzae invasive disease = Hib  Presents data on H. influenzae type b invasive disease, states all isolates were serotyped  Presents data on H. influenzae type b invasive disease, states some isolates were serotyped and others were assumed to be type b  Presents data on H. influenzae, type b invasive disease, but does not state whether serotyping was done

WHO/IVB/09.02 91 Section E: Incidence Data

Answer the following questions to determine if Section E (Incidence Data) should be completed for the manuscript. 25. Does the manuscript report incidence, or data that can be used to calculate incidence, for Hib and/or S. pneumo invasive disease for any age group among children under age 5 years?  Yes (answer question 26)  No (skip to Section F)

26. Does the study involve at least 20,000 child-years per one-year age group of overall observations, or does it include the size of the entire population of the age group in the country under study? (This criterion does not apply to clinical trials.) For example: If incidence is for 0-11 months  at least 20,000 child-years of observation, or all children <1 year in the country are included; If incidence is for 0-23 months  at least 40,000 child years of observation, or all children <2 years in the country are included; If incidence is for 0-59 months  at least 100,000 child years of observation, or all children <5 years in the country are included  YES, for either Hib or S. pneumo (Continue to Question 27, complete Section E)  NO, for both Hib and S. pneumo (Skip to Section F, starting with Q#34)  Not applicable – study is a clinical trial (Continue to Q#27, complete Section E)  Unknown (Skip to section F, Q#34)

NOTE 3:

If the response for Hib and S. pneumo is “No,” skip to Section F. If the response for either Hib or S. pneumo is “Yes,” continue with Section E.

27. Start date of data collection in study; if no month is provided, use “07” for month [format mm/yyyy] 28. End date of data collection in study; if no month is provided, use “07” for month [format mm/yyyy] 29. Is the number of child-years of observation reported, or can it be calculated from data provided?  Yes (answer questions 29a)  No (skip to question 30) 29a. Enter the total number of child-years of observation in children under 5. If the study is a randomized trial, report this for the control group only. [numeric]

92 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Section E1. Incidence data for surveillance studies

If incidence data will be abstracted, complete Section E1 (starts with question 30).

30. Complete the following table for all incidence data reported in the manuscript, or for data which may be used to calculate incidence. If these data are provided by multiple age categories (e.g, children under 5 years and children under 2 years), include all information as separate entries in the table. Specify age in months. If neonates are included, or if it is not known if neonates are included, indicate lowest age as “00 months.” When available (either reported or derived from data provided), data should be recorded for the following age strata: • lowest age to 59 months (<5 years) • lowest age to 23 months (<2 years) • lowest age to 11 months (<1 year) If there are data for the general population, as well as data stratified for sub-groups (e.g. children infected/not infected with HIV), enter data for the overall population only. If the study is a vaccine trial, report data for the control group only, and for the group with the lowest minimum age (i.e., intent-to-treat analysis or children not fully vaccinated with 3 doses). This group will have the broadest age range. If the authors report adjusted incidence rates only, skip to question 31.

30a. Hib disease(select one) [picklist]

Age range reported Calculation of incidence rate

Incidence Lowest Highest No. of Denominator rate per age age cases (child-years) 100,000 (mths) (mths) child years

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[add rows if needed]

WHO/IVB/09.02 93 30b. S. pneumo disease (select one) [picklist]

Age range reported Calculation of incidence rate

Incidence Lowest Highest No. of Denominator rate per age age cases (child-years) 100,000 child (mths) (mths) years

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[add rows if needed]

31. Does the manuscript report disease incidence for children under age 5 years adjusted for any limitations?  Yes (complete question 31a and/or 31b, then read Note 4)  No (skip to Note 4) Complete the following table for all adjusted incidence data reported in the manuscript. If there are data for the general population, as well as data stratified for sub-groups (e.g. children infected and not infected with HIV), enter data for the overall population only. If the study is a vaccine trial, report data for the control group only, and for the group with the lowest minimum age (i.e., intent-to-treat analysis or children not fully vaccinated with 3 doses).

For the column titled, “Type of adjustment for this rate,” the picklist will be: 1. Case ascertainment (cases missed because they did not come to a study facility or were missed) 2. Diagnostic techniques (cases not included because diagnostic tests not done or adjustments made for culture-negative, probable bacterial disease) 3. Both (1) and (2). 4. Other type of adjustment (Specify in Question 31b or 31d)

94 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 31a. Hib disease (select all that apply) [picklist]

Age range reported Adjustments to incidence rate

Type of Adjusted Lowest Highest adjustment for Incidence rate age age this rate [indicate per 100,000 child (mths) (mths) # from list above] –years

 Meningitis

 Pneumonia

 Non-pneumonia, non- meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[add rows if needed]

31b. If “Other type of adjustment,” specify adjustment here

WHO/IVB/09.02 95 31c. S. pneumo disease (select all that apply) [picklist]

Age range reported Adjustments to incidence rate

Type of Adjusted Lowest Highest adjustment for Incidence rate age age this rate [indicate per 100,000 child (mths) (mths) # from list above] –years

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[add rows if needed]

31d. If “Other type of adjustment,” specify adjustment here

NOTE 4:

If the manuscript reports findings from a vaccine-probe study, in which the incidence of vaccine-preventable clinical disease with unconfirmed etiology is reported, complete Section E2. Otherwise, skip to Section G.

Section E2: Incidence data from vaccine probe studies

32. Intervention administered (check all that apply)  Hib vaccine  S. pneumo vaccine

96 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 33. Complete following table for all categories of clinical disease. These will represent either Hib clinical disease or S. pneumo clinical disease depending on which vaccine was evaluated in the study. If these data are reported in multiple age strata (e.g, children under 5 years, children under 2 years), include all information as separate entries in the table. Specify age in months. If neonates are included, or if it is not known if neonates are included, indicate lowest age as “00 months.” When available (either reported or derived from data provided), data should be recorded for the following age strata:  lowest age to 59 months (<5 years)  lowest age to 23 months (<2 years)  lowest age to 11 months (<1 year) If there are data for the general population, as well as data stratified for sub- groups (e.g. children infected and not infected with HIV), enter data for the overall population only.

33a. Clinical outcome (select all that apply)

Incidence per 100,000 Age range child-years Lowest Highest Intervention Control age age Group group (mths) (mths)

 Hospitalization for pneumonia

 WHO-defined severe pneumonia

 Radiographic findings consistent with WHO criteria for diagnosis of pneumonia

 Radiologically-confirmed pneumonia

 Any infiltrate on chest x-ray

 Clinical signs/symptoms of pneumonia

WHO/IVB/09.02 97 Incidence per 100,000 Age range child-years Lowest Highest Intervention Control age age Group group (mths) (mths)

 Total pneumonia deaths

 Hospitalization for meningitis

 CSF findings suggestive of bacterial meningitis

 Lumbar puncture done

 Clinical signs/symptoms of meningitis

 Total meningitis deaths

33b.  Other (specify in 33b)

[additional rows added as needed]

33b. If the clinical disease outcome measured is not among the options provided, specify the outcome in the space provided above [text]

NOTE 5:

If Section E1 (± Section E2) has been completed, skip to Section G.

98 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Section F. Age and Disease Syndrome Distribution Data

Answer the following questions to determine if Section F (Age and Disease Syndrome Distribution Data) should be completed for the manuscript.

34. Does the manuscript report a total of 30 or more cases of either Hib or S. pneumoniae invasive disease among children less than 5 years of age?  Yes (answer question 35)  No (age/syndrome distribution and/or case fatality data cannot be abstracted, skip to section H)

35. Does the manuscript provide data that can be used to determine the proportion of Hib and/or S. pneumo invasive disease occurring in any age group of children under 5 years (e.g., proportion of Hib disease in children under age 2 years)?  Yes  No

36. Does the study provide information about the distribution of disease syndromes caused by Hib and/or S. pneumoniae for any age group of children under 5 years? (e.g., what proportion of invasive Hib disease is meningitis, what proportion is pneumonia, etc.?)  Yes  No

NOTE 6:

If the response to either question 35 or 36 is “Yes,” complete Section F. If the response to both questions 35 and 36 is “No,” skip to section G.

37. Complete the following table to indicate the number of cases reported in each age stratum, for each invasive disease syndrome. If these data are reported in multiple age strata (e.g, children under 5 years, children under 2 years), include all information as separate entries in the table. Specify age in months. If neonates are included, or if it is not known if neonates are included, indicate lowest age as “00 months.” Take note of how the highest age is described [e.g, children 5 years and under (0-71 months), vs. children under 5 years (0-59 months)]. Record all age categories given, including those over 59 months of age. When available (either reported or derived from data provided), data should be recorded for the following age strata: • lowest age to 59 months (<5 years) • lowest age to 23 months (<2 years) • lowest age to 11 months (<1 year) If data are not provided by syndrome, mark the option for “All invasive disease.”

WHO/IVB/09.02 99 37a. Hib disease (select all that apply) [picklist]

Age range reported (months) Number of cases Lowest age Highest age

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[additional rows added as needed]

37b. S. pneumo disease (select all that apply) [picklist]

Age range reported (months) Number of cases Lowest age Highest age

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[additional rows added as needed]

100 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Section G. Case Fatality Data

Answer the following question to determine if Section G (Case Fatality Data) should be completed for the manuscript.

38. Does the manuscript provide case fatality ratios, or data that can be used to calculate case fatality ratios, for disease due to Hib and/or S. pneumo in children under age 5 years?  Yes (complete section G)  No (skip to section H)

39. Is the proportion of cases with known mortality outcome provided?  Yes (answer question 39a)  No (skip to question 40)

39a. What is the proportion of cases with known outcome? For vaccine probe studies or randomized trials, include this proportion for control group only. [numeric] 39b. If the proportion of cases with known outcome is < 100%, for what reason is the outcome unknown for the remainder of cases?  A random sample was selected for follow-up  Reasons other than follow-up of random sample, does not seem to lead to bias  Reasons other than follow-up of random sample, likely to lead to bias  Unknown

40. Complete the following table of case-fatality ratios (CFR) for each invasive disease syndrome, for each age strata reported for children 59 months and younger. If these data are reported in multiple age strata (e.g, children under 5 years, children under 2 years), include all information as separate entries in the table. Specify age in months. If neonates are included, or if it is not known if neonates are included, indicate lowest age as “00 months.” Take note of how the highest age is described [e.g, children 5 years and under (0-71 months), vs. children under 5 years (0-59 months)]. When available (either reported or calculated), data should be recorded for the following age strata:  lowest age to 59 months (<5 years)  lowest age to 23 months (<2 years)  lowest age to 11 months (<1 year)

WHO/IVB/09.02 101 40a. Hib disease (select all that apply) [picklist]

Age range reported Case fatality data Number of Lowest Highest cases with Case age age known mortality fatality (mths) (mths) outcome ratio (%) (denominator)

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[additional rows added as needed]

40b. S. pneumo disease (select all that apply) [picklist]

Age range reported Case fatality data Number of Lowest Highest cases with Case age age known mortality fatality (mths) (mths) outcome ratio (%) (denominator)

 Meningitis

 Pneumonia

 Non-pneumonia, non-meningitis invasive disease

 All invasive disease other than meningitis

 All invasive disease

[additional rows added as needed]

102 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 If Sections E, F, and G could not be completed (no data were abstracted), skip Section H and go to Question 61 at the end.

Section H. Quality Assessment

Complete for all studies abstracted. Note that any methodological issues that could have resulted in 20% or more of cases being missed should be considered “significant.” i. Numerator/Case ascertainment 41. Characterize the participating pediatric hospitals (defined as any hospital where children under 5 are admitted for treatment of bacteraemia, pneumonia, meningitis), as described in the manuscript. (select one)  All [pediatric hospitals] in study area included  Some [pediatric hospitals] in study area not included, results adjusted accordingly  Some not included, authors state the effect was not significant  Some not included, authors state the effect may have been significant  Some not included, no discussion of the effect  No hospital-based case-ascertainment used  Unable to determine/no information provided by authors

42. Select the response that best describes care-seeking of patients with any of the syndromes studied, as described in the manuscript. (check all that apply)  Unlikely to seek care outside study area  May have sought care outside study area (answer question 42a)  May not have sought any care (answer question 42a)  Unable to determine/no information provided by authors (skip to question 43)

42a. Did the authors characterize the potential impact of these care-seeking patterns?  Authors state the effect was not significant  Authors state the effect may have been significant, results adjusted accordingly  Authors state the effect may have been significant, no adjustment  Authors do not discuss potential impact

WHO/IVB/09.02 103 43. Indicate which, if any, of the following potential problems with case ascertainment may apply to this study. (check all that apply)  Laboratory specimens not collected for all potential cases, or laboratory testing not performed for all specimens collected  Some laboratory/medical records not available, or review of records was incomplete  Inconsistent recruitment of cases in hospital (recruitment not 24-hours/ day, 7 days/week)  Study was not conducted in all areas of facility where potential cases received care  Some subjects refused to participate  None of the above  Other (specify in question 43a)  Unable to determine

43a. Specify other potential problems with case ascertainment [text] 44. Select the response that best describes your judgment of whether the case ascertainment methods were likely to miss a significant proportion of cases, for any of the disease syndromes studied.  Unlikely to have missed a significant proportion of cases  May have missed a significant proportion of cases but results adjusted accordingly  May have missed a significant proportion of cases, results not adjusted  Unable to determine

45. Describe limitations of case ascertainment methods, including any numeric estimate of the limitations (e.g., % of children presenting who did not have lumbar puncture). ii. Numerator/Diagnostic methods 46. Do the authors acknowledge any limitations in diagnostic methods (i.e., handling and transport of specimens, laboratory techniques)?  Yes (describe in question 47)  No

47. Describe limitations of diagnostic methods used [text] 48. In your opinion, the diagnostic methods described for the study were:  Likely to be reliable  Unlikely to be reliable  Unable to determine reliability

104 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 49. Select reasons for your judgment about the quality of diagnostic testing (check all that apply)  Prospective study with good quality control  Study conducted in area with generally high-quality health services  Study conducted at research institution or other facility with resources appropriate for study  Study conducted in area with generally limited health services and facilities  Other (specify in question 49a)

49a. Specify reason for your judgment about the quality of diagnostic testing

NOTE 7:

If the study does not report any data about Hib and/or S. pneumo meningitis, skip to question 53. If meningitis data were reported, continue to question 50.

50. Are you able to determine the proportion of probable (as defined by the authors, see guide) bacterial meningitis cases with confirmed etiology?  Yes  No 50a. Enter proportion of probable bacterial meningitis with confirmed etiology

51. Are you able to determine the proportion of meningitis cases with confirmed etiology that were due to Hib and pneumococcus combined? ______%  Yes  No 51a. Enter proportion of meningitis cases with confirmed etiology that were due to Hib and S. pneumo combined.

52. Were any adjustments made to account for limitations in diagnostic methods, or for culture-negative, probable bacterial meningitis?  Yes  No

WHO/IVB/09.02 105 iii. Population/Denominator data 53. Does the study specify the source for the population data provided?  Yes (answer question 53a)  No, source of population data not specified(skip to question 54)  No population data provided (skip to question 56) 53a. If yes, did the population denominator come from a reliable source (e.g., current census)?  Yes  No  Unable to determine

54. For incidence calculations, does the denominator represent a population to which all the cases (numerator) belong?  Yes  No  Unknown

55. Include comments on the population data provided in the manuscript [text] iv. Time Period 56. Is the study longitudinal and are study data presented in a way that permits estimation of results from different time periods?  Yes (complete questions 56a and 56b)  No (skip to question 57)

56a. If yes, indicate time period with most accurate results for Hib and S. pneumo, if appropriate [text] 56b. Indicate the reason why you think this time period is most accurate [text] v. Other 57. Indicate any other factors that may have affected the accuracy of study results (i.e., study done in 2 populations, one of which was clearly biased)? [text] 58. Can estimates be calculated for a portion of the study results (from a portion of the study period or from a subpopulation) that are more accurate than the overall results?  Yes (answer question 58a)  No 58a. Specify the most accurate portion [text]

106 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 59. Does the manuscript indicate that the results from this study are also reported in another reference?  Yes (specify in question 59a)  No 59a. Specify which reference(s) report the same results as those reported in this manuscript (use the reference numbers from the manuscript itself)

60. Does the manuscript mention other references with potentially relevant data for abstraction?  Yes (specify in question 60a)  No 60a. Specify which reference(s) may include potentially relevant data (use the reference numbers from the manuscript itself) [For database: field set so anyone can use it, even if the study is excluded and you stopped answering questions before this page.] 61. Are there additional comments for this study? If the study was excluded, but the paper warrants additional review (e.g., a good quality 5-year study that started in 1979, doesn’t meet inclusion criteria but may provide useful data), indicate this here.

WHO/IVB/09.02 107 Annex 4: Member States by WHO Region

These regional groupings of countries were used in the results section of this publication.

Region WHO Member States Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Cape Verde, Central African Republic, Comoros, Congo, Côte d’Ivoire, Democratic Republic of the AFR Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, South Africa, Swaziland, Togo, Uganda, United Republic of Tanzania, Zambia, Zimbabwe Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Bolivia, Brazil, Canada, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, AMR Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, United States of America, Uruguay, Venezuela (Bolivarian Republic of)

EMR Afghanistan, Bahrain, Cyprus, Djibouti, Egypt, Iraq, Iran (Islamic Republic of), Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates, Yemen

Albania, Andorra, Armenia, Austria, Azerbaijan, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, EUR Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Luxembourg, Malta, Monaco, Montenegro, Netherlands, Norway, Poland, Portugal, Republic of Moldova, Romania, Russian Federation, San Marino, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Tajikistan, The former Yugoslav Republic of Macedonia, Turkey, Turkmenistan, Ukraine, United Kingdom of Great Britain and Northern Ireland, Uzbekistan

Bangladesh, Bhutan, Democratic People’s Republic of Korea, India, Indonesia, SEAR Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste

Australia, Brunei Darussalam, Cambodia, China, Cook Islands, Fiji, Japan, WPR Kiribati, Lao People’s Democratic Republic, Malaysia, Marshall Islands, Micronesia (Federated States of), Mongolia, Nauru, New Zealand, Niue, Palau, Papua New Guinea, Philippines, Republic of Korea, Samoa, Singapore, Solomon Islands, Tonga, Tuvalu, Vanuatu, Viet Nam

Source: WHO (2001) http://www.who.int/quantifying_ehimpacts/global/ebdcountgroup/en/index.html

Sub-regions: AFR=African; AMR=Americas; EMR=Eastern Mediterranean; EUR=European; SEAR=South-East Asia; WPR=Western Pacific.

108 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Annex 5: Countries and territories by United Nations region

These regional groupings of countries were used in analysis.

United Nations Countries in region region Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Cape Verde, Central African Republic,

Chad, Comoros, Congo, Côte d´Ivoire, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Africa Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Libyan Arab Jamahiriya, Madagascar, Malawi, Mali, Mauritania, Mauritius, Morocco, Mozambique, Namibia, Nigeria, Niger, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, Somalia, South Africa, Sudan, Swaziland, Togo, Tunisia, Uganda, United Republic of Tanzania, Zambia, Zimbabwe

Afghanistan, Armenia, Azerbaijan, Bahrain, Bangladesh, Bhutan, Brunei Darussalam, Democratic People’s Republic of Korea, Cambodia, China, Cyprus, Georgia, India, Indonesia, Iran (Islamic Republic of), Iraq, Israel, Japan, Jordan, Kazakhstan, Kyrgyzstan, Kuwait, Lao People’s Democratic Asia Republic, Lebanon, Malaysia, Maldives, Myanmar, Mongolia, Nepal, Oman, Pakistan, Philippines, Qatar, Republic of Korea, Saudi Arabia, Singapore, Sri Lanka, Syrian Arab Republic, Tajikistan, Thailand, Timor-Leste, Turkey, Turkmenistan, United Arab Emirates, Uzbekistan, Viet Nam, Yemen Albania, Andorra, Austria, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Europe Luxembourg, Malta, Monaco, Montenegro, Netherlands, Norway, Poland, Portugal, Republic of Moldova, Romania, Russian Federation, San Marino, Slovakia, Slovenia, Spain, Sweden, Switzerland, The former Yugoslav Republic of Macedonia, Ukraine, United Kingdom, Serbia and Montenegro

Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Latin America Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, and the Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Saint Lucia, Saint Caribbean Kitts and Nevis, Saint Vincent and The Grenadines, Suriname, Trinidad and Tobago, Uruguay, Venezuela

North America Canada, United States of America

Australia, Cook Islands, Fiji, Kiribati, Marshall Islands, Micronesia Oceania (Federated States of), New Zealand, Nauru, Niue, Palau, Papua New Guinea, Samoa, Solomon Islands, Tonga, Tuvalu, Vanuatu

Source: The United Nations Country Classification. http://www.un.org/esa/population/publications/WPP2004/WPP2004_Vol3_Final/Preface_TOC_ ExpNotes.pdf. Accessed 30 March 2009.

WHO/IVB/09.02 109 Annex 6: Study characteristics and key data from Hib studies entering the meningitis and NPNM analytic database

Annex 6 lists studies containing data that entered the Hib (N = 176) meningitis and NPNM analytic databases. The list includes articles that were eventually excluded from meningitis incidence analysis due to poor quality scores. An electronic dataset containing most of the data presented here in Annex 6 is available on the WHO website at: http://www.who.int/immunization_monitoring/burden/en/. The figure below describes the Annex 6 subset of all studies presented in this document (Annex 8 contains the complete list of studies).

Figure: Summary of references included in Hib meningitis and NPNM analytic database (continued from Figure 1)

332 articles (336 studies) meet criteria Studies with for at least one extracted outcome and Studies without only key Spn contain evaluable data evaluable key outcomes (Annex 8) Hib outcomes

Annex 6 contains the 176 Hib studies that entered the meningitis and NPNM analytic database

From the 332 articles (336 studies) with evaluable outcome data, there were 205 studies identified with any Hib outcome data. The highlighted outcomes in the table below indicate the key outcomes that were included in the meningitis and NPNM analytic database. Annex 6 lists the studies that had evaluable data for these key outcomes, by country, and grouped by WHO region.

110 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 1: All extracted outcomes and among these the key outcomes (highlighted) entering the analytic database

Extracted outcomes (N = 205) Incidence All invasive Meningitis Pneumonia NPNM Age distribution All invasive Meningitis Pneumonia NPNM Syndrome distribution of cases (NPNM and meningitis) Syndrome distribution of CFRs (NPNM and meningitis) Case-fatality ratio All invasive Meningitis Pneumonia NPNM

WHO/IVB/09.02 111

<2 ratio (%)

Case-fatality

10 <5 Hib NPNM

<2 cases Number of

<5 (adj)

47 41 34 57 74 60 28 27 <5 Incidence

<2 (per 100 000)

97 <1 239 105 222 297 218 104

22 26 16 37 <5

(%) <2 Hib Meningitis

<1 Case-fatality ratio

95 78 21 77 20 <5 111 141 122

<2 Number of cases

19 27 42 64 64 <1 120 104

11 011 11 93 137 47 924 84 231 67 163 37 344 annual studies 191 220 225 787 Estimated <5 children for incidence population of average study High High High year) strata (study midpoint Very High Very Very High Very Very High Very Very High Very Very High Very Very High Very <5 Mortality year 2003 1988 2002 1991 1992 1986 2000 1994 2003 Study midpoint midpoint 3 1 2 4.9 2.9 1.9 1.9 2.6 13.7 (years) Duration Year Year 2002 1986 2002 1990 1985 1985 2000 1993 2002 started (2005) Tall (1992) Tall Reference Sow (2005) Yaro (2006) Yaro Bijlmer (1990) Cowgill (2006) Adegbola (1996) Adegbola (1999) Mulholland (1997) Parent du Chatelet Banjul 2 cities Table 2: Study characteristics and key data from Hib studies entering the meningitis NPNM analytic database Table Bamako Western Western Study site Kilifi District Bobo-Dioulasso Bobo-Dioulasso 4 districts, Banjul AFR studies with incidence data Mali Faso Faso Faso Kenya Burkina Burkina Burkina Gambia Gambia Gambia Gambia Country WHO African Region (AFR) WHO

112 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<5 Hib NPNM

<2 cases Number of

<5 (adj)

34 49 <5 Incidence

<2 (per 100 000) 116

<1 118 112 211

24 38 44 35 <5

24 (%) <2 Hib Meningitis

44 <1 Case-fatality ratio

51 78 32 74 31 65 22 <5 611 117 140

42 <2 586 Number of cases

29 26 51 22 95 27 54 16 <1 530 125

84 801 annual studies 248 418 Estimated <5 children for incidence population of average study High year) strata (study Medium Medium midpoint Very High Very Very High Very Very High Very Very High Very Very High Very Very High Very Very High Very Very High Very <5 Mortality year 1992 1983 1989 1997 1997 1997 1987 1992 1991 1986 1994 Study midpoint midpoint

0.9 0.9 14.8 (years) Duration Year Year 1991 1982 1981 1997 1996 1995 1985 1990 1989 1985 1993 started (1985) Reference Madhi (2002) Koko (2000) Muhe (1999) Gedlu (1995) Orega (1997) Hussey (1994) de Bary (1990) Bernard-Bonnin Fonkoua (2001) Campagne (1999) Faye-Kette (2003) S oweto Niamey Abidjan Gondar Abidjan Yaoundé Yaoundé Libreville Study site Cape Town Cape Addis Ababa Addis Lagunes Region AFR studies without incidence data Côte Côte Côte Niger Gabon dÍvoire dÍvoire dÍvoire Ethiopia Ethiopia Country Cameroon Cameroon outh Africa S outh outh Africa S outh

WHO/IVB/09.02 113

<2 ratio (%) Case-fatality

<5 Hib NPNM

<2 cases Number of

<5 (adj)

<5 Incidence

<2 (per 100 000)

43 <5

(%) <2 Hib Meningitis

<1 Case-fatality ratio

94 10 38 <5 109 121

49 46 49 21 35 <2 35 Number of cases

91 79 41 37 44 18 28 <1 19 102

annual studies Estimated <5 children for incidence population of average study High High High High High High year) strata (study midpoint Very High Very Very High Very Very High Very Very High Very Very High Very <5 Mortality year 1995 1985 1990 1999 1992 1988 1999 1985 1996 1987 1990 Study midpoint midpoint

(years) Duration Year Year 1995 1983 1989 1998 1990 1987 1998 1985 1996 1985 1989 started (2004) (1994) Reference Cisse (1989) Nesbitt (1988) Palmer (1999) Onyemelukwe Migliani (2002) Akpede (1994) Molyneux (1998) Razafindralambo Atakouma (1995) O'Dempsey (1994) Goetghebuer (2000) Dakar Banjul Nairobi Nsukka Division Blantyre Western Study site Benin City Enugu and Upper River Lomé-Tokoin Antananarivo Antananarivo Togo Kenya Malawi Nigeria Nigeria Gambia Gambia Gambia S enegal Country Madagascar Madagascar

114 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<1 8

24 <5 Hib NPNM

<2 cases Number of

<5 (adj)

5 11 26 20 17 28 15 51 17 <5 Incidence

27 54 33 93 39 <2 (per 100 000)

37 63 10 47 63 <1

20 13 16 16 15 <5

16 (%) <2 Hib Meningitis

22 16 <1 Case-fatality ratio

22 83 26 <5 218 152 194 242 152

65 24 <2 215 120 Number of cases

78 18 <1 154 170

34 849 66 565 77 819 annual studies 555 646 164 761 302 280 102 537 3 703 548 Estimated <5 children for incidence population of average study High year) strata (study Medium Medium Medium Medium Medium Medium Medium Very Low Very Very Low Very midpoint <5 Mortality year 1988 1983 1994 1998 1998 1995 1998 1986 1991 1997 Study midpoint midpoint 7 7.9 0.9 2.4 5.9 0.9 4.5 2.9 2.9 1.9 (years) Duration Year Year 1985 1983 1992 1995 1998 1992 1996 1985 1990 1997 started Reference Weiss (2001) Weiss Lagos (1996) Torres (1995) Torres Ribeiro (2003) Lucena (1996) S imoes (2004) Rezende (1989) Ferreccio (1990) Kmetzsch (2003) Takemura (2001) Takemura Bahia do S ol S alvador S antiago S antiago Tucuman Campinas S ao Paulo Study site Rio Grande Goias S tate Parana S tate AMR studies with incidence data Chile Chile Brazil Brazil Brazil Brazil Brazil Brazil Brazil Country Argentina WHO Region of the Americas (AMR) WHO Region of the

WHO/IVB/09.02 115

<2 ratio (%)

Case-fatality

12 <5 228 Hib NPNM

4 <2 cases Number of

4 <1

17 16 <5 (adj) 13 46 19 40 57 17 22 23 17 13 13 14 <5 Incidence

31 31 <2 (per 100 000)

34 63 34 52 34 <1

14 <5

(%) <2 Hib Meningitis

12 19 <1 Case-fatality ratio 51 79 41 44 17 <5 457 127 139 686 199 1334 55721

93 41 <2 Number of cases

51 55 35 <1 115 334 36 714 53 730 annual studies 410 000 512 683 151 023 383 868 277 618 359 536 859 695 952 865 7 514 507 Estimated 20 116 551 20 116 <5 children for incidence population of average study year) strata (study Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1986 1983 1989 1983 1983 1998 1985 1998 1999 1997 1995 1989 Study midpoint midpoint 1 7 5 1.9 0.9 0.9 1.9 0.9 2.9 2.3 5.9 0.9 (years) Duration Year Year 1986 1983 1989 1980 1983 1998 1983 1998 1998 1996 1993 1989 started Dickinson Reference Cochi (1986) Adams (1993) Gomez (2000) Walling (1991) Walling Murphy (1992) Leguen (1991) Asturias (2003) Loughlin (1995) Meneses (2001) Dickinson (2001) Dickinson (2002) S choendorf (1994) region Kansas 2 states 20 states Study site Whole country Whole country Whole country Whole country Whole country Massachusetts Guatemala City National District Atlanta, Georgia Cuba Cuba Cuba Cuba S tates S tates S tates S tates S tates S tates United United United United United United Country Republic Dominican Guatemala

116 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

9 31 <5 Hib NPNM

<2 cases Number of

<5 (adj)

<5 Incidence

<2 (per 100 000)

11 19 15 18 <5

17 (%) <2 Hib Meningitis

<1 Case-fatality ratio

36 33 81 37 65 <5 628 171 219 192

32 29 21 31 <2 154 204 168 Number of cases

19 21 19 <1 160 302 133

annual studies Estimated <5 children for incidence population of average study year) strata (study Medium Medium Medium Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1993 1992 1995 1988 1992 2000 1989 1985 1992 1985 1991 Study midpoint midpoint

(years) Duration Year Year 1989 1988 1993 1983 1989 2000 1988 1984 1989 1984 1990 started (2000) Reference Diaz (2001) Nascimento- Otero (1988) Ferraz (1996) Burgos (1988) Barton-Forbes Chávez (1996) Boehme (1993) Flannery (2007) Carvalho (1998) Chavez P (1994) Chavez P Miranzi S de (2003) 2 cities Medina Valdivia Medellin S alvador S antiago S antiago Study site Minas Gerais Whole country Temuco region Temuco Federal District AMR studies without incidence data Chile Chile Chile Chile Chile Brazil Brazil Brazil Brazil Jamaica Country Colombia

WHO/IVB/09.02 117

<2 ratio (%)

Case-fatality

4 <5 Hib NPNM

<2 cases Number of

4 <1

23 23 16 <5 (adj)

17 14 16 <5 Incidence

37 34 31 <2 (per 100 000)

57 54 <1

16 <5

16 (%) <2 Hib Meningitis

22 <1 Case-fatality ratio

58 23 68 17 49 13 <5 109

54 23 96 16 40 12 <2 Number of cases

8 43 52 13 <1

99 300 40 944 annual studies 179 182 Estimated <5 children for incidence population of average study High year) strata (study Medium Medium Medium Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 2000 1987 1986 1984 1999 2000 2001 1993 1984 2002 1988 Study midpoint midpoint

1 1.9 0.9 1.6 1.2 6.9 2.0 (years) Duration Year Year 1999 1985 1984 1980 1999 1999 2000 1991 1981 2002 1987 started (1995) Nelson Reference Castaneda Zaki (1990) Watt (1999) Watt Coant (1992) S osa-Iglesias Novelli (1989) Soltani (2005) Narvaez (1990) Basualdo (2004) Al Awaidy (2003) Awaidy Al Al-Mazrou (2004) 6 cities Puebla Farwania Asunción New York New Study site 4 provinces 2 provinces Mexico City 1 governorate Whole country Punjab Province EMR studies with incidence data Iran Qatar S audi Egypt S tates Arabia United Kuwait Mexico Mexico Tunisia ((Islamic Country Pakistan Paraguay Republic of)

WHO Eastern Mediterranean Region (EMR)

118 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<5 Hib NPNM

<2 cases Number of

15 <5 (adj)

11 21 <5 Incidence

35 <2 (per 100 000)

23 20 <1

2 2

(%) <2 Hib Meningitis

<1 Case-fatality ratio

27 60 36 42 59 <5 146

24 44 57 24 42 54 24 <2 Number of cases

43 34 40 12 <1

17 635 annual studies 452 550 Estimated <5 children for incidence population of average study year) strata (study Medium Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1984 1990 1987 1983 1987 1984 1991 1990 2002 Study midpoint midpoint

3 6 9.9 1.5 (years) Duration Year Year 1982 1984 1985 1982 1983 1980 1990 1988 2002 started Reference Vutuc (1995) Vutuc Daoud (1989) Rauter (1994) Azubuike (1990) Almuneef (1998) Abanamy (1991) Al Awaidy (2004) Awaidy Al Abomelha (1988) van Hoeck (1997) Tabuk Riyadh Riyadh Eastern Hospital Antwerp Farwania Study site Styria state Whole country Whole country EUR studies with incidence data EMR studies without incidence data S audi S audi S audi S audi Arabia Arabia Arabia Arabia Kuwait Austria Austria Belgium Country Bosnia and

WHO European Region (EUR) Herzegovina

WHO/IVB/09.02 119

<2 ratio (%) Case-fatality

71 33 <5 109 Hib NPNM

20 87 <2 cases Number of

17 15 <5 (adj) 6 9 3 8 19 43 18 15 13 27 22 18 <5 Incidence

44 26 17 40 42 <2 (per 100 000)

67 12 65 28 12 14 66 65 <1 2

3 4

3 7

(%) <2 Hib Meningitis

<1 Case-fatality ratio 21 42 55 28 42 <5 110 280 349 123 177 142 169

10 96 50 25 41 <2 266 135 158 Number of cases 8

11 56 75 28 10 34 <1 204 247 122 41 841 86 162 52 018 annual studies 519 225 142 305 244 933 120 872 132 805 493 748 949 577 175 395 525 000 Estimated <5 children for incidence population of average study year) strata (study Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1990 1998 1992 1983 1985 2001 1994 1993 1985 1986 1994 1983 Study midpoint midpoint 2 2 1 2.9 2.4 7.9 6.9 9.9 0.9 4.9 4.9 10.9 (years) Duration Year Year 1988 1997 1989 1980 1980 2001 1994 1992 1985 1984 1988 1981 started (2002) (1990) Reference Kojouharova Halfon-Yaniv Halfon-Yaniv Tsolia (1998) Tsolia Dagan (1994) Dagan (1999) Pizzuti (1998) Dagan (1992) Peltola (1992) Reinert (1993) Lebedova (2003) Kristensen (1990) Livartowski (1989) Naples Athens Helsinki 6 regions Study site The Negev Whole country Whole country 2 departments Whole country 2 departments Whole country Whole country Italy Israel Israel Israel Israel Czech France France Greece Finland Bulgaria Country Republic Denmark

120 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<5 Hib NPNM

<2 cases Number of

13 <5 (adj) 4

4 3 7 8 11 11 28 17 31 13 <5 Incidence

8 9

54 18 <2 (per 100 000)

4 36 12 <1

(%) <2 Hib Meningitis

<1 Case-fatality ratio

35 18 31 29 39 20 37 73 17 13 <5 423

11 37 17 58 <2 318 Number of cases

7 12 33 <1

87 167 55 769 23 186 85 438 annual studies 761 602 105 491 189 216 252 987 124 960 2 911 176 2 911 Estimated <5 children for incidence population of average study year) strata (study Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1988 1996 1987 1989 1990 1994 1993 1994 1987 1994 1999 2001 Study midpoint midpoint 2 5 4 7 1 2 1.9 5.9 1.9 1.9 2.1 14.5 (years) Duration Year Year 1987 1996 1985 1987 1988 1991 1993 1994 1980 1994 1998 2000 started (1995) Reference Berg (1996) Luca (2004) D'Alessandro Zielinski (2001) Chironna (1998) Novakova (1999) Hugosson (1995) De Jonghe (1995) Kostiukova (1992) Villo S irerol (2004) Villo S quarcione (1999) S oult Rubio (1994) Puglia S eville Kielce, Madrid 8 districts 2 districts Study site Bydgoszcz 3 provinces Luxembourg National and regional data Whole country S t. Petersburg Orebro County Grand Duchy of Italy Italy Italy S pain S pain Poland S weden S weden Russian S lovakia Country Romania Federation Luxembourg

WHO/IVB/09.02 121

<2 ratio (%)

Case-fatality

51 <5 114 205 1038 Hib NPNM

71 29 <2 cases Number of

40 19 <1

<5 (adj)

31 16 20 25 24 22 24 24 19 22 14 22 <5 Incidence

37 46 45 <2 (per 100 000)

31 40 58 55 43 32 <1

6 <5

(%) <2 Hib Meningitis

8 <1 Case-fatality ratio

57 99 <5 118 440 477 508 284 138 145 130 357 1041

<2 377 221 105 109 Number of cases

31 60 48 50 <1 206 184 139

88 423 61 489 53 713 45 764 annual studies 646 359 491 372 181 592 299 008 170 880 178 829 173 841 2 783 326 Estimated <5 children for incidence population of average study year) strata (study Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1989 1982 1991 1986 1992 2001 1986 1985 1992 1985 1992 1984 1988 Study midpoint midpoint 4 2 16 10 2.9 2.9 3.4 9.9 3.9 0.9 9.9 6.9 13.9 (years) Duration Year Year 1987 1981 1983 1980 1991 2001 1985 1981 1990 1980 1991 1980 1985 started (1989) Reference Booy (1993) Kyaw (2002) Slack (1998) Urwin (1996) Howard (1991) Tudor-Williams Tudor-Williams Trollfors (1987) Trollfors Coggins (1993) Fortnum (1993) Platanov (2003) Olowokure (2000) Garpenholt (1996) Muhlemann (1996) Wales district Oxford Oxford England S cotland Glasgow 2 regions 5 regions, Study site Nottingham Thames area Kiev, Donetsk Kiev, Whole country Whole country Gwynedd and West Midlands West United United United United United United United United United Ukraine S weden S weden Country Kingdom Kingdom Kingdom Kingdom Kingdom Kingdom Kingdom Kingdom Kingdom S witzerland

122 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<5 Hib NPNM

<2 cases Number of

<5 (adj)

<5 Incidence

<2 (per 100 000)

(%) <2 Hib Meningitis

11 <1 Case-fatality ratio

36 40 40 56 78 89 46 38 <5 110

34 33 38 82 37 98 <2 Number of cases

19 13 20 26 31 34 51 17 51 27 <1

annual studies Estimated <5 children for incidence population of average study year) strata (study Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1990 1991 1984 1982 1983 1989 1982 1989 1997 1988 1992 Study midpoint midpoint

(years) Duration Year Year 1987 1988 1983 1980 1981 1985 1980 1987 1997 1988 1984 started (1994) (1998) Reference Villa-Alcazar Villa-Alcazar Ticca (1997) Ticca Cellesi (1995) Martinez Leon Corcaci (2002) Demina (1983) Demina (1986) Rosenthal (1988) Deviatkina (1990) Christensen (1988) Skoczynska (2000) Iasi Rome Madrid Malaga Eastern Moscow Moscow Moscow Study site The Negev 6 provinces Whole country EUR studies without incidence data Italy Italy Israel S pain S pain Poland Russian Russian Russian Country Romania Denmark Federation Federation Federation

WHO/IVB/09.02 123

<2 ratio (%)

Case-fatality

pc <5 Hib NPNM

11 pc <2 cases Number of

pc <1

10 <5 (adj)

20 <5 Incidence

67 <2 (per 100 000)

18 <1

22 16 <5

pc (%) <2 Hib Meningitis

20 <1 Case-fatality ratio

pc 36 39 48 <5 277 7

pc 29 38 <2 257 Number of cases

30 <1 pc* 191

annual studies 114 696 114 179 103 Estimated <5 children for incidence population of average study High High High year) strata (study Medium Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 2000 2004 1989 1990 1985 2000 2001 1995 1986 2005 Study midpoint midpoint 4 1

0.9 (years) Duration Year Year 1998 2004 1987 1987 1981 2000 2000 1993 1985 2003 started (2004) (2002) Reference WHO(2002) S aha (1997) S ingh (1992) Rerks-Ngarm Russell (2003) communication Saha, personal Gessner (2005) de Louvois (1991) Juan Martin (1993) Terai Wales Dhaka Vellore 6 cities Dhaka, Mirzapur Study site Chittagong, Phitsanulok England and Lampang and Not described Lombok Island Colombo District India India S pain Nepal United Country Thailand Kingdom S ri Lanka Indonesia Bangladesh Bangladesh s EAR studies without incidence data outh-East Asia Region ( S EAR) WHO S outh-East s EAR studies with incidence data

124 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<5 117 Hib NPNM

51 <2 cases Number of

20 <1

23 <5 (adj)

11 31 25 20 19 25 32 33 <5 Incidence

60 36 47 <2 (per 100 000)

59 38 39 44 <1

6 5 <5

(%) <2 Hib Meningitis

<1 Case-fatality ratio

48 25 44 <5 144 135 229 225 257 186

37 98 38 <2 216 167 Number of cases

18 18 54 35 77 <1 186

22 639 95 956 80 365 annual studies 115 859 115 235 516 243 002 303 647 132 924 Estimated <5 children for incidence population of average study year) strata (study Medium Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1985 1987 1989 1991 1986 1986 1987 1986 1987 1986 Study midpoint midpoint

5 6 6.9 2.9 2.9 2.9 4.9 (years) Duration Year Year 1980 1984 1987 1990 1985 1980 1985 1985 1984 1984 started (1994) Reference Yang (1996) Yang Bower (1994) Gilbert (1990) Hanna (1991) el S aadi (1993) McIntyre (1991) McIntyre (1993) Likitnukul (1994) McGregor (1992) Chotpitayasunondh Chotpitayasunondh Victoria Sydney Sydney Western Western Bangkok Bangkok S outhern Hefei City Canberra, Study site Queanbeyan WPR studies with incidence data China Country Thailand Thailand Australia Australia Australia Australia Australia Australia Australia

WHO Western Pacific Region (WPR) WHO Western

WHO/IVB/09.02 125

<2 ratio (%)

Case-fatality

<5 189 Hib NPNM

<2 cases Number of

11 38 84 <5 (adj) 6 2 6 1 2 6 5 28 20 38 27 27 95 <5 Incidence 7

14 <2 (per 100 000) 204 4

18 10 <1 337

11 13 <5

(%) <2 Hib Meningitis

<1 Case-fatality ratio 11 14 34 89 25 50 37 22 89 66 <5 118 121 465 6

89 19 66 <2 108 Number of cases 2

59 13 35 95 <1 61 738 20 105 94 898 65 050 42 694 annual studies 103 811 396 023 399 774 187 986 426 168 291 865 1 650 905 1 414 876 Estimated <5 children for incidence population of average study year) strata (study Medium Medium Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 2000 1988 1999 2003 1996 1990 1992 1988 1997 1984 1994 1990 1995 Study midpoint midpoint 4 1 9 1 2.3 4.9 2.9 1.2 2.9 1.9 6.9 5.9 2.9 (years) Duration Year Year 1999 1986 1997 2002 1996 1989 1992 1984 1997 1981 1994 1988 1994 started Reference Lau (1995) Kim (2004) Watt (2004) Watt Voss (1989) Voss S hao (2004) Chen (1999) Wilson (2003) Wilson (2002) Kamiya (1998) Nakano (2001) Anglaret (1993) Ishikawa (1996) Limcangco (2000) Taiwan Taiwan Jeonbuk Province Auckland Study site Ulaanbaatar 6 prefectures Whole country Whole country Whole country Central Manila Mie Prefecture Aichi Prefecture Hong Kong S AR Fiji New New New S AR China China Korea Japan Japan Japan China, Zealand Zealand Country Mongolia Caledonia Philippines Hong Kong Republic of

126 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

<2 ratio (%)

Case-fatality

<5 116 Hib NPNM

55 <2 cases Number of

19 <1

84 <5 (adj)

12 <5 Incidence

27 <2 (per 100 000)

33 <1

14 <5

(%) <2 Hib Meningitis

<1 Case-fatality ratio

46 23 46 79 39 48 23 43 24 <5

32 26 55 66 46 16 <2 Number of cases

11 11 19 19 26 35 41 22 <1

31 915 annual studies 280 268 Estimated <5 children for incidence population of average study High year) strata (study Medium Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very Very Low Very midpoint <5 Mortality year 1991 1990 1996 2000 1989 2001 1988 1990 2003 1996 1991 Study midpoint midpoint

1.9 (years) Duration Year Year 1986 1986 1994 2000 1988 2000 1984 1985 2000 1995 1989 started (1999) Reference Lee (1998) Kim (1998) Anh (2006) Tran (2004) Tran Kuriki (1995) Gilbert (1995) S akata (2000) Nik Khairulddin Ishiwada (2004) Lehmann (1999) Carapetis (2002) S eoul S eoul Hanoi Eastern Malaysia Hakkaido Kelantan, Highlands Melbourne Study site 11 hospitals 11 Whole country Aichi Prefecture Ho-Chi Minh City WPR studies without incidence data Korea Korea Japan Japan Japan S amoa Guinea * pc = personal communication Country Australia Malaysia Viet Nam Viet Viet Nam Viet Republic of Republic of Papua New

WHO/IVB/09.02 127 Annex 7: Study characteristics and key data from Spn studies entering the meningitis and NPNM analytic database

Annex 7 lists studies containing data that entered the Spn (N = 164) meningitis and NPNM analytic databases. The list includes articles that were eventually excluded from meningitis incidence analysis due to poor quality scores. An electronic dataset containing most of the data presented here in Annex 7 is available on the WHO websiteat: http://www.who.int/immunization_monitoring/burden/en/. The figure below describes the Annex 7 subset of all studies presented in this document (Annex 8 contains the complete list of studies).

Figure: Summary of references included in Spn meningitis and NPNM analytic database (continued from Figure 1)

332 articles (336 studies) meet criteria Studies with for at least one extracted outcome and Studies without only key Hib contain evaluable data evaluable key outcomes (Annex 8) Spn outcomes

Annex 7 contains the 164 Spn studies that entered the meningitis and NPNM analytic database

From the 332 articles (336 studies) with evaluable outcome data, there were 211 studies identified with any Spn outcome data. The table below indicates all outcomes extracted and the key outcomes (highlighted) that were included in the meningitis and NPNM analytic database. Annex 7 lists the studies with evaluable data for these key Spn outcomes, by country, and grouped by WHO region.

128 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 1: All extracted outcomes and among those the key outcomes (highlighted) entering the analytic database

Extracted outcomes (N = 211) Incidence All invasive Meningitis Pneumonia NPNM Age distribution All invasive Meningitis Pneumonia NPNM Syndrome distribution of cases (NPNM and meningitis) Syndrome distribution of CFRs (NPNM and meningitis) Case-fatality ratio All invasive Meningitis Pneumonia NPNM

WHO/IVB/09.02 129

pc <5

(%) <2

<1 Case-fatality ratio

<5 Spn NPNM

5 <2 cases Number of

<5 15.6 (adj)

<5 56.4 52.3 26.4 13.4 38.2 Incidence

11 pc 40 90 73 <2 (per 100 000)

pc 95 43 42 <1 150

55 52 38 <5

<2 Spn Meningitis

58 <1 Case-fatality ratio (%)

22 39 29 21 <5 133 100 477

pc 22 <2 450

Number of cases 38 19 19 <1 pc* 373

study 47 924 34 827 84 016 annual studies 191 220 216 585 248 418 average Estimated <5 children for incidence population of <5 Very Very Very Very Very Very Very Very High High High High High High High year) strata (study Medium Medium Medium Mortality midpoint year 1988 2002 1994 2000 2002 1989 2002 1992 1998 1999 Study midpoint 1 1 2 4.9 2.6 3.9 3.7 0.9 3.7 14.8 (years) Duration Duration Year Year 1986 2002 1993 1998 2002 1981 2000 1991 1997 1998 started (2005) Tall (1992) Tall Reference Usen (1998) Cutts (2005) Madhi (2000) Berkley (2005) Hussey (1997) Klugman (2003) Campbell (2004) Campagne (1999) Parent du Chatelet Table 2: Study characteristics and key data from Spn studies entering the meningitis NPNM analytic database Table Bobo- 2 cities Soweto Soweto Niamey Bamako Western Dioulasso 2 divisions Study site Cape Town Cape Kilifi District Mali Faso Faso Niger Kenya Burkina Burkina Gambia Gambia Country South Africa South South Africa South South Africa South WHO African Region (AFR) WHO AFR studies with incidence data

130 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

(%) <2

<1 Case-fatality ratio

11 <5 Spn NPNM

11 <2 cases Number of

<5 (adj)

<5 Incidence

<2 (per 100 000)

39 <5

41 29 <2 Spn Meningitis

41 <1 Case-fatality ratio (%)

11 11 59 67 33 89 71 33 <5 103 120

9 49 28 <2

8 Number of cases 41 45 27 57 56 18 75 24 <1 101

study annual studies average Estimated <5 children for incidence population of <5 Very Very Very Very Very Very Very Very Very Very Very Very Very Very High High High High High High High High High High High year) strata (study Mortality midpoint year 1983 1997 1986 1997 1987 1991 1995 1992 1990 1985 1990 Study midpoint

(years) Duration Duration Year Year 1982 1996 1985 1995 1985 1989 1995 1990 1989 1985 1989 started (1985) (2000) Reference Koko (2000) Goetghebuer Orega (1997) Nesbitt (1988) Palmer (1999) de Bary (1990) Bernard-Bonnin Fonkoua (2001) Faye-Kette (2003) O'Dempsey (1994) O'Dempsey (1996) Banjul Region Nairobi Abidjan Abidjan Division Division Western Lagunes Yaoundé Yaoundé Libreville Study site Upper River Upper River Kenya Gabon Gambia Gambia Gambia Gambia Country Cameroon Cameroon Côte dÍvoire Côte dÍvoire Côte dÍvoire AFR studies without incidence data

WHO/IVB/09.02 131

(%) <2

<1 Case-fatality ratio

57 <5 Spn NPNM

39 <2 cases Number of

<5 (adj)

15 <5 8.7 Incidence

18 34 <2 (per 100 000)

28 <1

<2 Spn Meningitis

<1 Case-fatality ratio (%)

30 18 13 33 68 36 45 <5

6 11 18 51 24 33 44 <2 9

Number of cases 11 13 13 46 16 63 28 <1

study 77 819 annual studies 102 537 average Estimated <5 children for incidence population of <5 Very Very Very Very Very Very Very Very Very Very Very Very High High High High High High High High year) strata (study Medium Medium Mortality midpoint year 1991 1999 1997 1990 1985 2002 1987 1988 1990 1991 Study midpoint

1.9 2.9 (years) Duration Duration Year Year 1989 1998 1997 1987 1983 2001 1985 1987 1989 1990 started (1994) Reference Roca (2006) Cisse (1989) Weiss (2001) Weiss Emele (2000) Onyemelukwe Lucena (1996) Migliani (2002) Akpede (1994) Ozumba (1995) Atakouma (1995) Bahia Dakar Enugu District Sokoto Manhica Campinas Benin City Study site Enugu State Lomé-Tokoin Antananarivo Togo Brazil Brazil Nigeria Nigeria Nigeria Nigeria Senegal Country Madagascar Mozambique WHO Region of the Americas (AMR) WHO Region of the AMR studies with incidence data

132 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

(%) <2

<1 Case-fatality ratio

27 <5 226 Spn NPNM

21 <2 162 cases Number of

<1 112

<5 25.9 (adj) 4

8 5 12 <5 1.1 4.4 5.3 1.3 2.9 24.7 15.2 Incidence

9 2

33 12 <2 (per 100 000)

13 12 47 19 10 32 14 <1

60 23 15 <5

<2 Spn Meningitis

54 <1 Case-fatality ratio (%)

4 20 31 44 43 <5 148 242 216 157 153

66 34 <2 215 198

Number of cases 19 98 26 <1 3.2 101 154 155

study annual studies 586 112 302 280 277 618 546 164 489 067 913 430 944 625 157 997 average 3 704 641 Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very High year) strata (study Medium Medium Medium Medium Mortality midpoint year 1998 1995 1983 1999 1996 1986 1997 1998 1995 1997 1989 1997 Study midpoint 7 5.9 0.9 2.9 4.9 2.9 6.9 6.9 5.9 2.8 0.9 3.9 (years) Duration Duration Year Year 1995 1992 1983 1998 1994 1994 1985 1995 1993 1995 1989 1995 started (2003) Dickinson Ko (2000) Reference Reis (2002) Simoes (2004) Leguen (1991) Ulloa-Gutierrez Lagos Z (2001) Bjornson (2002) Rezende (1989) Meneses (2001) Ferreccio (1990) Dickinson (2002) Takemura (2001) Takemura region 9 cities Salvador Santiago Salvador Sao Paulo Study site Goias State Metropolitan Parana State Whole country Whole country Whole country Whole country Chile Chile Cuba Cuba Cuba Brazil Brazil Brazil Brazil Brazil Canada Country Costa Rica

WHO/IVB/09.02 133

<5 0.59

(%) <2 0.7

<1 Case-fatality ratio

54 <5 169 2622 Spn NPNM

53 <2 135 2086 cases Number of

<1 912

<5 7.3 18.7 (adj) 4

34 <5 5.2 2.8 4.7 10.4 16.3 10.4 Incidence

8 12 22 19 <2 (per 100 000)

18 37 <1

11 37 33 <5 4.5

33 12 <2 3.9 Spn Meningitis

4 <1 Case-fatality ratio (%)

17 19 46 16 27 <5 190 105 182

16 25 12 <2 157

Number of cases 12 21 <1 113

study 36 714 52 785 annual studies 359 536 125 370 321 583 410 000 average 7 514 507 Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Medium Medium Mortality midpoint year 1998 1997 1997 1986 1987 1988 1995 1996 1985 1989 Study midpoint 7 1 5 11 0.9 2.3 4.9 0.9 3.9 0.9 (years) Duration Duration Year Year 1998 1996 1994 1986 1982 1986 1995 1995 1983 1989 started Reference Liptak (1997) Pastor (1998) Adams (1993) Gomez (2000) Camou (2003) Walling (1991) Walling Asturias (2003) Loughlin (1995) Davidson (1994) Robinson (2001) City Texas Alaska 5 cities Kansas National 20 states New York New Study site Guatemala Whole country District Region Massachusetts States States States States States States States United United United United United United United Uruguay Country Republic Dominican Guatemala

134 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

pc <5

pc (%) <2

pc <1 Case-fatality ratio

pc <5 142 276 Spn NPNM

pc <2 cases Number of

pc <1

<5 (adj)

<5 Incidence

<2 (per 100 000)

29 17 <5

<2 38.7 Spn Meningitis

34 28 <1 Case-fatality ratio (%)

pc 26 36 17 58 <5 294 528 154

25 31 14 58 <2 130

Number of cases 11 44 25 29 40 <1 111

study annual studies average Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very High year) strata (study Medium Medium Medium Medium Medium Mortality midpoint year 1997 1994 1992 1984 2002 1991 1989 1996 1985 2000 1988 1993 Study midpoint

(years) Duration Duration

Year Year 1993 1993 1988 1980 1999 1989 1988 1994 1984 1983 1989 started Reference Diaz (2001) Silva (1990) Nascimento- Burgos (1988) Kertesz (1998) Berezin (1996) Berezin (2002) Boehme (1993) communication) Flannery (2007) Carvalho (1998) Lagos (personal Ruvinsky (2002) Chavez P (1994) Chavez P Santa 8 cities Valdivia Catarina Santiago Salvador Santiago Santiago Sao Paulo Sao Paulo Study site Whole country Whole country Temuco region Temuco Chile Chile Chile Chile Chile Brazil Brazil Brazil Brazil Brazil Country Argentina Argentina AMR studies without incidence data

WHO/IVB/09.02 135

pc <5

(%) <2

<1 Case-fatality ratio

pc pc 14 85 26 52 <5 768 Spn NPNM

61 44 <2 pc* 607 1178 cases Number of

45 33 <1 311

<5 (adj)

<5 Incidence

<2 (per 100 000)

19 24 <5

<2 8.5 Spn Meningitis

<1 Case-fatality ratio (%)

pc 22 18 42 89 <5 104 361 149 191 199 153

20 34 75 71 <2 277 264 132

Number of cases 15 64 46 <1 113 242 138 102

study annual studies average Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Medium Medium Mortality midpoint year 1995 1985 1997 1996 1997 1984 1996 1998 1995 1997 1995 1996 1995 Study midpoint

(years) Duration Duration Year Year 1994 1984 1994 1994 1994 1980 1993 1995 1994 1994 1991 1994 1993 started (2002) (2001) Reference Castaneda King (2003) Ríos (1999) Buckingham Otero (1988) Hortal Palma Hortal (1997) Kaplan (2002) Kaplan (1998) Agudelo (1999) Agudelo (2000) Agudelo (2001) Narvaez (1990) Black (personal communication) 3 cities 8 cities Bogotá 8 states 8 states Medellin Northern California Memphis, Study site Tennessee Mexico City 7 departments 7 departments 3 departments Whole country States States States States States United United United United United Mexico Uruguay Uruguay Country Colombia Colombia Colombia Colombia Colombia

136 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

(%) <2

<1 Case-fatality ratio

<5 Spn NPNM

<2 cases Number of

<5 (adj)

6 <5 6.7 3.4 5.7 17.4 Incidence

6 8 28 13 15 <2 (per 100 000)

50 24 24 <1

12 <5

<2 Spn Meningitis

<1 Case-fatality ratio (%) 9 6 21 21 23 34 20 <5 133 5 4 17 16 19 24 18 <2 105

Number of cases 15 13 18 88 14 <1

study 21 639 17 635 58 532 annual studies 179 182 500 082 average Estimated <5 children for incidence population of <5 Low Low Low Low Very Very Very Very Very Very Very Very year) strata (study Medium Medium Medium Medium Mortality midpoint year 1998 2000 1984 1988 1983 1987 2002 1990 Study midpoint

6 5.6 1.9 9.9 1.9 (years) Duration Duration Year Year 1995 1999 1982 1980 1982 1983 2001 1988 started (2004) Reference Abid (1999) Rauter (1994) Rendi-Wagner Rendi-Wagner Azubuike (1990) Almuneef (2001) Abomelha (1988) Al-Mazrou (2004) van Hoeck (1997) Tabuk Riyadh Eastern Antwerp Study site Styria state 4 provinces Casablanca Whole country Austria Austria Belgium Country Morocco Saudi Arabia Saudi Saudi Arabia Saudi Saudi Arabia Saudi Saudi Arabia Saudi WHO Eastern Mediterranean Region (EMR) EMR studies with incidence data EMR studies without incidence data WHO European Region (EUR) EUR studies with incidence data

WHO/IVB/09.02 137

(%) <2

<1 2.1 Case-fatality ratio

<5 308 288 Spn NPNM

<2 220 218 cases Number of

88 <1

<5 (adj) 1 <5 6.7 4.6 1.3 2.1 5.5 2.3 3.4 8.2 3.9 3.7 5.3 Incidence 1 5 5

7 7 2 12 14 12 <2 (per 100 000) 2 7

3 11 17 10 18 <1

<2 Spn Meningitis

<1 Case-fatality ratio (%) 5

23 34 93 10 65 87 25 <5 324 307 650 7

17 30 93 77 16 <2 286 230 505

Number of cases 14 21 87 59 12 <1 202 157

study 79 903 annual studies 141 901 366 162 404 485 343 875 424 982 252 987 562 583 949 577 average 4 125 179 4 392 640 Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Mortality midpoint year 1998 1990 1997 1987 2001 1994 1993 1994 1997 1999 1990 1994 Study midpoint 4 4 4 2 2.4 4.9 0.9 1.9 9.9 1.9 2.9 18.9 (years) Duration Duration Year Year 1997 1981 1995 1985 2001 1994 1991 1990 1997 1997 1988 1994 started (2002) Reference Kojouharova Kaltoft (2000) Gaillat (1998) Dagan (1994) Pizzuti (1998) Eskola (1992) Chironna (1998) von Kries (2000) von Kries (2002) D'Ancona (2005) Spanjaard (2000) Konradsen (2002) Puglia Puglia Naples 6 regions Piedmont, Study site Whole country Whole country Whole country Whole country 7 departments Whole country Whole country Whole country Italy Italy Italy Israel France Finland Bulgaria Country Denmark Denmark Germany Germany Netherlands

138 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

(%) <2

<1 Case-fatality ratio

<5 Spn NPNM

40 83 36 <2 cases Number of

<5 (adj)

<5 3.5 4.9 1.3 9.2 5.2 4.4 2.5 2.4 Incidence

8 6 6 7 9 4 4 14 15 15 <2 (per 100 000) 2

4 11 22 <1

<2 Spn Meningitis

<1 Case-fatality ratio (%) 6

7 7

6 25 12 14 17 <5 0.39

6 8 3 4 5 11 17 23 13 <2 0.7 3

Number of cases 14 10 <1 0.6

study 85 438 62 834 19 290 15 249 34 259 annual studies 101 329 771 766 average Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Mortality midpoint year 2001 1987 1995 1999 2002 1998 1996 1991 1994 1998 1998 1996 Study midpoint 2 5 3 7 4 2.1 2.9 8.4 6.9 0.9 10.9 20.9 (years) Duration Duration Year Year 2000 1985 1990 1998 2001 1997 1992 1981 1991 1996 1995 1996 started (2002) (2002) (2002) Reference Luca (2004) Espin (2002) Perez (2002) Pineda (2002) Diez-Domingo Bernaola Iturbe Gonzalez (2003) Iglesias Sanchez Kostiukova (1992) Villo Sirerol (2004) Villo Dominguez (2002) Soult Rubio (2005) Gijon Seville Murcia Madrid Navarra Valencia 2 districts Catalonia Cantabria Barcelona Study site Guipuzcoa Pais Vasco, Pais Vasco, St. Petersburg Spain Spain Spain Spain Spain Spain Spain Spain Spain Spain Russian Country Romania Federation

WHO/IVB/09.02 139

(%) <2

<1 Case-fatality ratio

86 <5 Spn NPNM

64 32 <2 cases Number of

<5 (adj)

<5 4.1 3.1 2.7 3.5 3.8 4.6 6.3 7.4 5.5 6.6 3.7 Incidence 6

10 10 13 <2 (per 100 000)

11 16 18 18 13 13 13 <1

14 20 <5

13 <2 Spn Meningitis

9 12 <1 Case-fatality ratio (%)

62 93 23 44 19 30 20 <5 118 280 449 1.65

57 92 72 38 16 <2 385

Number of cases 48 26 10 21 <1 0.8 188 307 177

study 88 423 45 764 38 615 annual studies 761 602 380 016 903 925 204 993 697 592 average 3 557 505 3 325 275 Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Mortality midpoint year 1989 1994 1999 1992 1997 2000 1992 1997 1984 1988 1988 1986 Study midpoint 1 2 14 9.9 2.9 2.9 2.9 2.9 2.9 4.4 9.9 1.8 (years) Duration Duration Year Year 1985 1993 1998 1991 1996 2000 1991 1995 1980 1981 1987 1985 started (1997) (1998) Reference Dahl (2001) Berg (1996) Laurichesse Miller (2000) Urwin (1996) Jones (1997) Venetz (1998) Venetz Casado Flores Casado (2002) Fortnum (1993) Sleeman (2001) de Louvois (1991) Wales Wales Wales Wales region district except region, region, Geneva Thames Thames England England 5 regions 5 regions Study site Nottingham England and England and England and England and Southwestern Whole country Whole country Spain Spain United United United United United United United Sweden Sweden Country Kingdom Kingdom Kingdom Kingdom Kingdom Kingdom Kingdom Switzerland

140 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

(%) <2

<1 Case-fatality ratio

22 36 49 <5 134 Spn NPNM

25 42 <2 cases Number of

13 20 <1

<5 (adj)

<5 4.1 Incidence

<2 (per 100 000)

10 <1

<2 Spn Meningitis

<1 Case-fatality ratio (%) 7

39 22 15 29 34 56 <5 245 219

12 20 44 15 <2

7 3

Number of cases 17 19 12 33 12 <1 129

study annual studies 195 568 333 714 average Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Medium Medium Mortality midpoint year 1993 1999 1991 1988 1997 1982 1982 2000 1997 1988 1991 Study midpoint

16 5.6 (years) Duration Duration Year Year 1991 1999 1983 1997 1980 1980 1999 1995 1988 1980 1988 started (2000) (2000) (1998) Reference Syriopoulou Skoczynska Kyaw (2002) Kyaw (2003) Martinez Leon Demina (1983) Demina (1986) Jenssen (2000) Shackley (2000) McIntosh (2003) Deviatkina (1990) Oxford Athens Malaga Moscow Moscow Moscow England Scotland Scotland 3 counties Study site Whole country Spain United United United United Poland Greece Norway Russian Russian Russian Country Kingdom Kingdom Kingdom Kingdom Federation Federation Federation EUR studies without incidence data

WHO/IVB/09.02 141

(%) <2

<1 Case-fatality ratio

pc pc 31 38 84 <5 Spn NPNM

pc pc 21 26 <2 cases Number of

pc <1

<5 (adj)

<5 6.3 5.6 4.1 10.9 Incidence

12 25 <2 (per 100 000)

pc <5 8.3

pc <2 Spn Meningitis

pc <1 Case-fatality ratio (%)

pc pc 13 13 17 36 42 <5 189

11 pc pc 15 31 <2 164 106

Number of cases pc 98 <1 141

study 19 409 33 493 annual studies 115 737 115 339 546 average Estimated <5 children for incidence population of <5 Low Low Low Low Very Very Very Very Very Very High High year) strata (study Medium Medium Medium Mortality midpoint year 1990 1985 1996 1997 2001 2005 1986 1995 1995 Study midpoint

6.9 0.9 4.9 (years) Duration Duration Year Year 1987 1980 1994 2001 1992 2003 1984 1993 1993 started (1994) Liu (2003) Reference Saha (1997) Fagan (2001) Hanna (1991) Christie (2002) Saha (personal INCLEN (1999) communication) communication) Chotpitayasunondh Chotpitayasunondh Steinhoff (personal Steinhoff Dhaka 6 cities 6 cities Dhaka, Victoria Western Bangkok Mirzapur Far North Tasmania Study site Chittagong, Queensland India India Country Thailand Australia Australia Australia Australia Bangladesh Bangladesh WHO South-East Asia Region (SEAR) WHO South-East SEAR studies without incidence data WHO Western Pacific Region (WPR) WHO Western WPR studies with incidence data

142 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005

(%) <2

<1 Case-fatality ratio

23 <5 667 436 Spn NPNM

20 42 <2 cases Number of

<5 3.8 (adj)

1 25 <5 6.4 3.5 2.1 0.8 2.1 9.8 10.5 Incidence

13 23 <2 (per 100 000)

29 <1

16 <5 4.3

19 <2 5.3 Spn Meningitis

<1 Case-fatality ratio (%) 5 5 5

96 46 36 47 38 19 62 <5

3 79 31 20 31 57 <2

2 Number of cases 79 23 41 <1

study 71 315 80 365 61 738 70 842 annual studies 103 811 330 509 187 986 426 168 average 1 451 365 Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very Very year) strata (study Medium Medium Mortality midpoint year 1999 2002 1989 1998 1991 1992 1996 1988 2003 1988 2000 Study midpoint

9 4.5 0.9 2.9 8.9 2.9 8.9 2.3 (years) Duration Duration Year Year 1997 2002 1997 1990 1992 1994 1984 1984 2002 1984 1999 started Reference Kim (2004) Watt (2004) Watt Voss (1994) Voss Yang (1996) Yang Sung (1997) Roche (2003) Wilson (2003) Krause (2000) McIntyre (2003) McIntyre (2000) Ishikawa (1996) New East Aichi Wales Sydney, Sydney, Territory Illawarra Jeonbuk Northern Province Hunter & Auckland Hefei City Territories Territories Prefecture Study site New South Ulaanbaatar Whole country Whole country Fiji New China Korea Japan Zealand Country Australia Australia Australia Australia Mongolia Kong SAR Republic of China, Hong WPR studies without incidence data

WHO/IVB/09.02 143

<5 2.4

(%) <2 7.1

<1 Case-fatality ratio

37 20 <5 373 125 Spn NPNM

31 85 17 <2 cases Number of

87 <1

<5 (adj)

<5 Incidence

<2 (per 100 000)

<2 Spn Meningitis

20 <1 Case-fatality ratio (%) 7

5 62 13 24 15 52 63 32 <5 118 4

4 7

87 19 54 26 <2

6 Number of cases 18 43 53 21 <1 116

study annual studies average Estimated <5 children for incidence population of <5 Low Low Low Low Low Low Low Very Very Very Very Very Very Very Very Very Very Very Very Very Very High High year) strata (study Medium Medium Mortality midpoint year 1994 1987 1991 1996 1983 1992 2003 1987 1991 1982 1990 Study midpoint

(years) Duration Duration Year Year 1988 1981 1986 1995 1982 1992 2003 1985 1989 1980 1986 started Reference Lee (1998) Kim (1998) Tran (1998) Tran Sato (2001) Shen (1989) Davis (1995) Roche (2004) Gratten (1985) Trotman (1995) Trotman Lehmann (1999) Andresen (2004) City areas Seoul Seoul Central Sydney Eastern provinces 1 territory, 1 territory, Highlands Prefecture Kanagawa Study site 4 cities, 18 Ho Chi Minh Queanbeyan The highland Whole country * pc = personal communication China Korea Korea Japan Guinea Guinea Country Australia Australia Australia Australia Viet Nam Viet Republic of Republic of Papua New Papua New

144 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Annex 8: References for studies with evaluable outcome data

Annex 8 lists all studies (332 articles containing 336 studies) that were considered evaluable for any outcome. The articles in Annexes 6 and 7 are found in Annex 8, as well as additional articles that do not contain key outcomes (Tables 7.1.1 (Hib) and 7.1.2 (Spn)). The figure below describes the set of data included in Annex 8.

Figure: Summary of references and studies abstracted (continued from Figure 1)

332 articles (336 studies) meet criteria for at least one extracted outcome and contain evaluable data

Of the articles identified with evaluable data, 332 articles (336 studies) contained key outcome data. Annex 8 lists any article that had an evaluable Hib and/or Spn outcome by country and grouped by WHO region.

WHO/IVB/09.02 145 Table 1: All studies with evaluable outcome data

Extracted outcomes (N = 332) Incidence All invasive Meningitis Pneumonia NPNM Age distribution All invasive Meningitis Pneumonia NPNM Syndrome distribution of cases (NPNM and meningitis) Syndrome distribution of CFRs (NPNM and meningitis) Case-fatality ratio All invasive Meningitis Pneumonia NPNM

Table 2: Studies from the WHO African Region (AFR) with evaluable outcome data

Countries and Type of data Citation other areas in article Parent du Chatelet I et al. Bacterial meningitis in Burkina Faso: surveillance using field-based polymerase chain Burkina Faso reaction testing. Clinical Infectious Diseases: an official Hib Spn publication of the Infectious Diseases Society of America, 2005, 40(1):17–25.

Tall FR et al. Haemophilus influenzae meningitis in a hospital Burkina Faso in Burkina-Faso. Médecine et Maladies Infectieuses, 1992, Hib Spn 22(12):1173–1177.

Yaro S et al. The epidemiology of Haemophilus influenzae Burkina Faso type b meningitis in Burkina Faso. The Pediatric Infectious Hib Disease Journal, 2006, 25(5):415–419.

Bernard-Bonnin AC, Ekoe T. [Purulent meningitis in children in Yaoundé: epidemiological and prognostic aspects]. Cameroon Hib Spn Annales de la Société belge de médecine tropicale, 1985, 65(1):59–68. Fonkoua MC et al. [Bacterial meningitis in Yaoundé Cameroon (Cameroon) in 1999–2000]. Bulletin de la Société de Hib Spn pathologie exotique (1990), 2001, 94(4):300–303. de Bary JB et al. [Purulent meningitis at a semi-rural hospital Côte d´Ivoire in the forest area of the Ivory Coast]. Bulletin de la Société Hib Spn de pathologie exotique (1990), 1990;83(4):460–467.

146 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article

Faye-Kette H et al. [Agents of community acquired purulent meningitis in the child: epidemiologic trends in Abidjan, Côte Côte d´Ivoire Hib Spn d’Ivoire, from the year 1995 to 2000]. Bulletin de la Société de pathologie exotique (1990), 2003, 96(4):313–316.

Orega M et al. Les meningites purulentes de l’enfant à Abidjan (À propos de 521 cas). [Purulent meningitis in Côte d´Ivoire children in Abidjan (a case-series including 521 cases).] Hib Spn

Médecine d’Afrique Noire, 1997, 44(4). Gedlu E, Rahlenbeck SI. Pyogenic meningitis in children in Ethiopia north-western Ethiopia. Annals of Tropical Paediatrics, 1995, Hib 15(3):243–247. Muhe L, Klugman KP. Pneumococcal and Haemophilus influenzae meningitis in a children’s hospital in Ethiopia: Ethiopia Hib serotypes and susceptibility patterns. Tropical Medicine and International Health: TM & IH, 1999, 4(6):421–427.

Koko J et al. Bacterial meningitis in children in Libreville, Gabon Gabon. Epidemiologic, therapeutic and prognostic features. Hib Spn Médecine et Maladies Infectieuses, 2000, 30(1):50–56.

Adegbola RA et al. Haemophilus influenzae type b disease in the western region of The Gambia: background surveillance Gambia Hib for a vaccine efficacy trial. Annals of Tropical Paediatrics, 1996, 16(2):103–111.

Adegbola RA et al. Haemophilus influenzae type b meningitis Gambia in The Gambia after introduction of a conjugate vaccine. Hib Lancet, 1999, 354(9184):1091–1092.

Bijlmer HA et al. The epidemiology of Haemophilus influenzae meningitis in children under five years of age Gambia Hib in The Gambia, West Africa. The Journal of Infectious Diseases, 1990, 161(6):1210–1215.

Cutts FT et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive Gambia pneumococcal disease in The Gambia: randomized, Spn double-blind, placebo-controlled trial. Lancet, 2005, 365(9465):1139–1146.

Goetghebuer T et al. Outcome of meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae Gambia Hib Spn type b in children in The Gambia. Tropical Medicine and International Health: TM & IH, 2000, 5(3):207–213.

WHO/IVB/09.02 147 Countries and Type of data Citation other areas in article

Mulholland K et al. Randomized trial of Haemophilus influenzae type-b tetanus protein conjugate vaccine Gambia Hib [corrected] for prevention of pneumonia and meningitis in Gambian infants. Lancet, 1997, 349(9060):1191–1197.

O’Dempsey TJ et al. Importance of enteric bacteria as a cause of pneumonia, meningitis and septicemia among Gambia children in a rural community in The Gambia, West Africa. Hib Spn The Pediatric Infectious Disease Journal, 1994, 13(2):122– 128.

O’Dempsey TJ et al. Pneumococcal disease among children Gambia in a rural area of west Africa. The Pediatric Infectious Spn Disease Journal, 1996, 15(5):431–437.

Palmer A et al. Acute bacterial meningitis in The Gambia: a Gambia four-year review of paediatric hospital admissions. Journal of Hib Spn Tropical Pediatrics, 1999, 45(1):51–53.

Usen S et al. Epidemiology of invasive pneumococcal Gambia disease in the Western Region, The Gambia. The Pediatric Hib Spn Infectious Disease Journal, 1998, 17(1):23–28.

Berkley JA et al. Bacteremia among children admitted to Kenya a rural hospital in Kenya. The New England Journal of Spn Medicine, 2005, 352(1):39–47.

Cowgill KD et al. Effectiveness of Haemophilus influenzae type b conjugate vaccine introduction into routine childhood Kenya Hib immunization in Kenya. JAMA: the journal of the American Medical Association, 2006, 296(6):671–678.

Nesbitt A et al. Pyogenic meningitis in Nairobi children. Kenya Hib Spn East African Medical Journal, 1988, 65(3):189–196.

Migliani R et al. [Non-tubercular bacterial meningitis in children in Antananarivo, Madagascar]. Archives de Madagascar Hib Spn pédiatrie : organe officiel de la Sociéte Française de Pédiatrie, 2002, 9(9):892–897.

Razafindralambo M et al. [Haemophilus influenzae, the second cause of bacterial meningitis in children in Madagascar Hib Madagascar]. Bulletin de la Société de pathologie exotique (1990), 2004, 97(2):100–103.

Molyneux E et al. Acute bacterial meningitis in children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi Hib Malawi in 1996–97. Tropical Medicine and International Health: TM & IH, 1998, 3(8):610–618.

148 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article

Campbell JD et al. Invasive pneumococcal infections Mali among hospitalized children in Bamako, Mali. The Pediatric Spn Infectious Disease Journal, 2004, 23(7):642–649.

Sow SO et al. Burden of invasive disease caused by Haemophilus influenzae type b in Bamako, Mali: impetus for Mali routine infant immunization with conjugate vaccine. Hib The Pediatric Infectious Disease Journal, 2005, 24(6):533–537.

Roca A et al. Invasive pneumococcal disease in children Mozambique <5 years of age in rural Mozambique. Tropical Medicine and Spn International Health: TM & IH, 2006, 11(9):1422–1431.

Campagne G et al. Epidemiology of bacterial meningitis Niger in Niamey, Niger, 1981–96. Bulletin of the World Health Hib Spn Organization, 1999, 77(6):499–508.

Akpede O et al. Childhood bacterial meningitis beyond the neonatal period in southern Nigeria: changes in Nigeria Hib Spn organisms/antibiotic susceptibility. East African Medical Journal, 1994, 71(1):14–20. Emele FE. Etiologic spectrum and pattern of antimicrobial Nigeria drug susceptibility in bacterial meningitis in Sokoto, Nigeria. Spn Acta Paediatrica, 2000, 89(8):942–946. Onyemelukwe NF. Haemophilus influenzae meningitis in Nigeria parts of eastern Nigeria. East African Medical Journal, 1994, Hib Spn 71(2):129–131. Ozumba UC. Acute bacterial meningitis in Enugu, Nigeria. Nigeria 1 April 1989 to 31 March 1993. The Central African Journal Spn of Medicine, 1995, 41(2):54–59.

Cisse MF et al. [Bacterial meningitis in a pediatric hospital Senegal in a tropical zone]. Médecine tropicale : revue du corps de Hib Spn santé colonial, 1989, 49(3):265–269.

Hussey G et al. Epidemiology of invasive Haemophilus South Africa influenzae infections in Cape Town, South Africa. Annals of Hib Tropical Paediatrics, 1994, 14(2):97–103.

Hussey G et al. Epidemiology of post-neonatal bacterial South Africa meningitis in Cape Town children. South African Medical Spn Journal, 1997, 87(1):51–56.

Karstaedt AS, Khoosal M, Crewe-Brown HH. Pneumococcal bacteremia during a decade in children in Soweto, South Africa Spn South Africa. The Pediatric Infectious Disease Journal, 2000, 19(5):454–457.

WHO/IVB/09.02 149 Countries and Type of data Citation other areas in article Klugman KP et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV South Africa Spn infection. The New England Journal of Medicine, 2003, 349(14):1341–1348.

Madhi SA et al. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency South Africa Hib Spn virus type 1-infected children. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, (2000a), 31(1):170–176.

Madhi SA et al. Impact of human immunodeficiency virus type 1 on the disease spectrum of Streptococcus South Africa Spn pneumoniae in South African children. The Pediatric Infectious Disease Journal, (2000b), 19(12):1141–1147.

Madhi SA et al. Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with a South Africa high prevalence of human immunodeficiency virus type 1 Hib infection. The Pediatric Infectious Disease Journal, 2002, 21(4):315–321.

Madhi SA et al. The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia South Africa in HIV-infected and -uninfected children. Clinical infectious Spn diseases: an official publication of the Infectious Diseases Society of America, 2005, 40(10):1511–1518.

Atakouma DY et al. Aspects cliniques, bacteriologiques, thérapeutiques et évolutifs des meningites aigues purulentes du nourisson dans le service de pédiatrie du CHU de Lomé-Tokoin (Togo). [Clinical, bacteriological, Togo Hib Spn treatment and outcome characteristics of acute purulent meningitis in infants in the University Hospital pediatric ward in Lome-Tokoin (Togo)] Médecine d’Afrique Noire, 1995, 42(5):270–275.

150 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 3: Studies from the WHO Region of the Americas (AMR) with evaluable outcome data

Countries and Type of data Citation other areas in article Abate H, Falaschi A, García B. Enfermedad invasiva por Haemophilus influenzae b: disminución de la incidencia en la Argentina era postvaccinal. [Invasive disease caused by Haemophilus Hib influenzae b: decreasing incidence in the post vaccination era.] Archivos Argentinos de Pediatría, 2003, 101(1):26–30. Hortal M et al. [Impact of Streptococcus pneumoniae on pneumonia in Latin American children. SIREVA-Vigia Group]. Argentina Spn Revista Panamericana de Salud Pública = Pan American journal of Public Health, 2000, 8(3):185–195.

Kertesz DA et al. Invasive Streptococcus pneumoniae infection in Latin American children: results of the Pan Argentina American Health Organization Surveillance Study. Clinical Spn infectious diseases: an official publication of the Infectious Diseases Society of America, 1998, 26(6):1355–1361.

Ruvinsky R et al. [Streptococcus pneumoniae pneumococcal Argentina infections - epidemiology]. Archivos Argentinos de Pediatría, Spn 2002, 100(1):31–43.

Torres A et al. Infecciones invasivas por Haemophilus influenzae tipo b (Hib) en Tucumbn-Argentina. Argentina [Haemophilus influenzae type b (Hib) invasive infection in Hib Tucumbn-Argentina.] Archivos Argentinos de Pediatría, 1995, 93(4):238–244. Berezin EN et al. Streptococcus pneumoniae penicillin- nonsusceptible strains in invasive infections in Sao Paulo, Brazil Spn Brazil. The Pediatric Infectious Disease Journal, 1996, 15(11):1051–1053.

Berezin EN et al. [Pneumococcal meningitis in children: Brazil clinical findings, most frequent serotypes and outcome]. Spn Jornal de Pediatria, 2002, 78(1):19–23.

Ferraz LR et al. Ocorrencia de meningites por Neisseria meningitidis, Haemophilus influenzae e Streptococcus pneumoniae no Distrito Federal, no periodo de 1989 a 1995 Brazil [Incidence of meningitis resulting from Neisseria meningitis, Hib Haemophilus influenzae and Streptococcus pneumoniae in Distrito Federal between 1989 and 1995]. Revista de Saúde do Distrito Federal, 1996, 7(1):19–24.

Flannery B (personal communication). In: Brazil Ministry of Brazil Hib Spn Health Country Letter Response, 2007.

Hortal M et al. [Impact of Streptococcus pneumoniae on pneumonia in Latin American children. SIREVA-Vigia Group]. Brazil Spn Revista Panamericana de Salud Pública = Pan American journal of Public Health, 2000, 8(3):185–195.

WHO/IVB/09.02 151 Countries and Type of data Citation other areas in article

Kmetzsch C et al. Occurrence of Haemophylus influenzae Brazil B meningitis after the implementation of a mass vaccination Hib program. Jornal de Pediatria, 2003, 79(6):530–536.

Ko AI et al. Clonally related penicillin-nonsusceptible Streptococcus pneumoniae serotype 14 from cases of Brazil meningitis in Salvador, Brazil. Clinical infectious diseases: Spn an official publication of the Infectious Diseases Society of America, 2000, 30(1):78–86.

Lucena R et al. [Clinical and laboratorial characteristics Brazil of bacterial meningitis in children]. Arquivos de Neuro- Hib Spn Psiquiatria, 1996, 54(4):571–576.

Mantese OC et al. [Prevalence of serotypes and antimicrobial Brazil resistance of invasive strains of Streptococcus pneumoniae]. Spn Jornal de Pediatria, 2003, 79(6):537–542.

Miranzi Sde S, Camacho LA, Valente JG. [Haemophilus influenzae type b: epidemiological situation in the State of Brazil Minas Gerais, Brazil, 1993–1997]. Cadernos de saúde pública Hib / Ministério da Saúde, Fundação Oswaldo Cruz, Escola Nacional de Saúde Pública, 2003, 19(5):1267–1275.

Nascimento-Carvalho CM, Moreno-Carvalho OA. Brazil [Etiology of bacterial meningitis in a cohort from Salvador, Hib Spn Bahia]. Arquivos de Neuro-Psiquiatria, 1998, 56(1):83–87.

Reis JN et al. Population-based survey of antimicrobial susceptibility and serotype distribution of Streptococcus Brazil Spn pneumoniae from meningitis patients in Salvador, Brazil. Journal of Clinical Microbiology, 2002, 40(1):275–277.

Rezende MA, Succi RCdM. Meningites no Estado de Säo Paulo nos anos de 1980 a 1983. [Meningitis in the State of Brazil Hib Spn Säo Paulo between 1980 and 1983.] Pediatria Moderna 1989, 24(3):113–120.

Ribeiro GS et al. Prevention of Haemophilus influenzae type b (Hib) meningitis and emergence of serotype replacement with Brazil Hib type a strains after introduction of Hib immunization in Brazil. The Journal of Infectious Diseases, 2003, 187(1):109–116.

Silva RJ et al. Fatores prognosticos na meningite pneumococcica. [Prognostic factors for pneumococcal Brazil Spn meningitis.] ACM: Arquivos Catarinenses de Medicina, 1990, 19(3):185–188.

Simoes LL et al. [Impact of Haemophilus influenzae b (Hib) Brazil vaccination on meningitis in Central Brazil]. Revista de Saúde Hib Spn Pública, 2004, 38(5):664–670.

152 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Takemura NS, Andrade SM. [Haemophilus influenzae type b Brazil meningitis in the state of Parana, Brazil]. Jornal de Pediatria, Hib Spn 2001, 77(5):387–392. Weiss DP, Coplan P, Guess H. Epidemiology of bacterial Brazil meningitis among children in Brazil, 1997–1998. Revista de Hib Spn Saúde Pública, 2001, 35(3):249–255.

Bigham M et al. Epidemiology, antibiotic susceptibility, and serotype distribution of Streptococcus pneumoniae associated with invasive pneumococcal disease in British Canada Spn Columbia — A call to strengthen public health pneumococcal immunization programs. The Canadian Journal of Infectious Diseases, 2003, 14(5):261–266.

Bjornson G et al. Population-based incidence rate of invasive pneumococcal infection in children: Vancouver, 1994–1998. Canada Spn Canada Communicable Disease Report, 2000, 26(18): 149–151; discussion 151–152.

Bjornson GL, Scheifele DW, Halperin SA. Population-based epidemiology of invasive pneumococcal infection in children in Canada nine urban centers in Canada, 1994 through 1998. Spn The Pediatric Infectious Disease Journal, 2002, 21(10): 947–950.

Jette LP et al. Surveillance of invasive Streptococcus pneumoniae infection in the province of Quebec, Canada, Canada from 1996 to 1998: serotype distribution, antimicrobial Spn susceptibility, and clinical characteristics. Journal of Clinical Microbiology, 2001, 39(2):733–737.

Vaudry W, Talling D. Invasive pneumococcal infection in first Canada nations children in northern Alberta. Canada Communicable Spn Disease Report , 2002, 28(20):165–172. Banfi PA, Valenzuela B, Lagos ZR. Vacuna anti Haemophilus influenzae b: impacto epidemiológico en Chile. [Vaccination Chile against Haemophilus influenzae b: epidemiologic impact Hib in Chile.] Revista Chilena de Infectología, 1999, 16(Suppl. 1):S56–S63.

Boehme C et al. [Three years of acute bacterial meningitis in Chile the pediatric service at the Temuco Regional Hospital]. Hib Spn Revista Médica de Chile, 1993, 121(6):633–638.

Burgos R et al. [Bacterial meningitis: identification of the Chile etiologic agent by latex agglutination]. Revista Chilena de Hib Spn Pediatría, 1988, 59(2):88–93.

Chavez PA et al. [Acute Bacterial Meningitis: A 10 Years Chile Experience]. Revista Chilena de Infectología: órgano oficial de Hib Spn la Sociedad Chilena de Infectología, 1994, 11(2):92–98. Chávez P et al. Infecciones invasoras por Haemophilus influenzae b. [Invasive infections with Haemophilus influenzae Chile Hib b.] Revista Chilena de Infectología: órgano oficial de la Sociedad Chilena de Infectología, 1996, 13(1):27–33.

WHO/IVB/09.02 153 Countries and Type of data Citation other areas in article

Diaz JM et al. [Trends of etiology of acute bacterial meningitis in Chilean children from 1989 to 1998. Impact of the anti-H Chile Hib Spn influenzae type b vaccine]. Revista Médica de Chile, 2001, 129(7):719–726.

Ferreccio C et al. A population-based retrospective assessment of the disease burden resulting from invasive Chile Haemophilus influenzae in infants and young children in Hib Spn Santiago, Chile. The Pediatric Infectious Disease Journal, 1990, 9(7):488–494.

Lagos R et al. Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T conjugate Chile vaccine: practicality and effectiveness in preventing invasive Hib Haemophilus influenzae type b infections. The Pediatric Infectious Disease Journal, 1996, 15(3):216–222.

Lagos R et al. Population-based surveillance for hospitalized and ambulatory pediatric invasive pneumococcal disease in Chile Spn Santiago, Chile. The Pediatric Infectious Disease Journal, 2002, 21(12):1115–1123.

Chile Lagos R (personal communication). 2006. Spn

Lagos Z R et al. [Epidemiology of Streptococcus pneumoniae invasive diseases in Chilean children: Clinical and Public Chile Health Perspectives.] Revista Chilena de Infectología: Spn órgano oficial de la Sociedad Chilena de Infectología, 2001, 18(s1):15–21. Agudelo CI et al. Vigilancia por el laboratorio de Streptococcus pneumoniae, aislado de procesos invasores en niños menores de 5 años: actualización de los datos Colombia 1994–2000. Spn [Laboratory surveillance of Streptococcus pneumoniae, isolated from invasive sites in children less than 5 years: report from 1994–2000.] Biomédica , 2001, 21:192–199. Agudelo CI, Muñoz N, De la Hoz F. Evaluacion rapida del impacto de la vacuna contra Haemophilus influenzae serotipo b en Colombia. [Impact assessment of vaccination against Colombia Spn Haemophilus influenzae type b in Colombia.] Revista Panamericana de Salud Pública = Pan American journal of Public Health, 2000, 8(3):181–184.

Agudelo CI, Muñoz N, De la Hoz F. Evaluación rápida del impacto de la Vacuna contra Haemophilus influenzae serotipo Colombia b en Colombia. [Impact assessment of vaccination against Spn Haemophilus influenzae type b in Colombia.] Revista de la Sociedad Boliviana de Pediatría, 2001, 40(1):9–11.

154 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article

Hortal M et al. [Impact of Streptococcus pneumoniae on pneumonia in Latin American children. SIREVA-Vigia Group]. Colombia Spn Revista Panamericana de Salud Pública = Pan American journal of Public Health, 2000, 8(3):185–195.

Otero R et al. Meningitis bacteriana aguda en ninos: estudio clinico y bacteriologico en el hospital infantil de Medellin. Colombia [Bacterial meningitis in children: clinical and bacteriologic Hib Spn study in the children’s hospital of Medellin.] Iatreia, 1988, 1(2):69–76. Ríos AM et al., pneumoniae yGCdTeS. Impacto de la resistencia a antimicrobianos y de serotipos de Streptococcus pneumoniae en la mortalidad de niños menores de 5 años con enfermedad invasora. [Impact of antimicrobial resistance Colombia Spn and serotypes of Streptococcus pneumoniae on mortality of children under 5 years of age with invasive disease.] Revista Panamericana de Salud Pública = Pan American journal of Public Health, 1999, 5(2):69–76.

Ulloa-Gutierrez R et al. Invasive pneumococcal disease in Costa Rica Costa Rican children: a seven year survey. The Pediatric Spn Infectious Disease Journal, 2003, 22(12):1069–1074.

Dickinson FO et al. [Impact of vaccination against Haemophilus influenzae type b in Cuba.] Revista Cuba Hib Panamericana de Salud Pública = Pan American journal of Public Health, 2001, 10(3):169–73.

Dickinson M, Félix O, Perez R. Las meningoencefalitis bacterianas en la población infantil cubana. [Bacterial Cuba Hib Spn meningoencephalitis in a Cuban population of children.] Revista Cubana de Pediatría, 2002, 74(2):106–114. Dickinson Meneses FO, Pérez Rodríguez AE. Meningoencefalitis bacterianas en Cuba. Cuba Hib Spn [Bacterial meningoencephalitis in Cuba.] Revista Cubana de Higiene y Epidemiología, 2001, 39(2):86–94.

Leguen CE et al. Non-meningococcal bacterial meningitis in Cuba the Republic of Cuba 1989. Revista de Sanidad e Higiene Hib Spn Pública, 1991, 65(6):521–527.

Gomez E et al. Population-based surveillance for bacterial Dominican meningitis in the Dominican Republic: implications for control Hib Spn Republic by vaccination. Epidemiology and Infection, 2000, 125(3): 549–554.

Asturias EJ et al. Meningitis and pneumonia in Guatemalan children: the importance of Haemophilus influenzae type b Guatemala and Streptococcus pneumoniae. Revista Panamericana de Hib Spn Salud Pública = Pan American journal of Public Health, 2003, 14(6):377–384.

WHO/IVB/09.02 155 Countries and Type of data Citation other areas in article Barton-Forbes MA, Samms-Vaughan M, Irons B. Epidemiology of Haemophilus influenzae invasive disease in Jamaica Hib Jamaica, 1990–1993. The West Indian Medical Journal, 2000, 49(3):200–204.

Castaneda Narvaez JL et al. Current aspects of bacterial Mexico Hib Spn meningitis. Revista Mexicana de Pediatria, 1990, 57(3).

Hortal M et al. [Impact of Streptococcus pneumoniae on pneumonia in Latin American children. SIREVA-Vigia Group]. Mexico Spn Revista Panamericana de Salud Pública = Pan American journal of Public Health, 2000, 8(3):185–195.

Sosa-Iglesias EG et al. [Haemophilus influenzae infections Mexico in 2 hospitals in the city of Puebla, Mexico]. Revista Hib Latinoamericana de Microbiología, 1995, 37(3):189–199.

Basualdo W, Arbo A. Invasive Haemophilus influenzae type Paraguay b infections in children in Paraguay. Archives of Medical Hib Research, 2004, 35(2):126–133. Instituto Nacional de Salud (Perú). Vigilancia epidemiológica centinela de Haemophilus influenzae y Streptococcus pneumoniae en menores de 5 años en el Perú. Peru [Sentinel surveillance of Haemophilus influenzae and Spn Streptococcus pneumoniae in children less than 5 years old in Peru.] Revista Peruana de Medicina Experimental y Salud Publica, 2003, 20(3):150–155.

Adams WG et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA: United States Hib Spn the journal of the American Medical Association, 1993, 269(2):221–226.

United States Black R (personal communication), 2006. Spn

Buckingham SC et al. Pneumococcal meningitis in children: relationship of antibiotic resistance to clinical characteristics United States Spn and outcomes. The Pediatric Infectious Disease Journal, 2001, 20(9):837–843.

Byington CL et al. Temporal trends of invasive disease due to Streptococcus pneumoniae among children in the United States intermountain west: emergence of nonvaccine serogroups. Spn Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 2005, 41(1):21–29.

Campbell JF et al. Pneumococcal bacteremia in Hawaii: United States initial findings of a pneumococcal disease prevention project. Spn Hawaii Medical Journal, 1989, 48(12):513–514; 517–518.

156 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article

Coant PN et al. Blood culture results as determinants in the United States organism identification of bacterial meningitis. Hib Pediatric Emergency Care, 1992, 8(4):200–205.

Cochi SL et al. Primary invasive Haemophilus influenzae type United States b disease: a population-based assessment of risk factors. Hib The Journal of Pediatrics, 1986, 108(6):887–896.

Cooper TA, Bandy U. Invasive disease attributed to United States Streptococcus pneumoniae, 1998–1999. Medicine and Spn Health, Rhode Island, 2001, 84(1):24–25.

Davidson M et al. The epidemiology of invasive pneumococcal disease in Alaska, 1986–1990 — ethnic differences and United States Spn opportunities for prevention. The Journal of Infectious Diseases, 1994, 170(2):368–376.

From the Centers for Disease Control and Prevention. Progress toward elimination of Haemophilus influenzae type b United States disease among infants and children — United States, Hib 1987–1993. JAMA: the journal of the American Medical Association, 1994, 271(16):1231–1232.

Greenberg DP et al. Protective efficacy ofHaemophilus influenzae type b polysaccharide and conjugate vaccines in United States Hib children 18 months of age and older. JAMA: the journal of the American Medical Association, 1991, 265(8):987–992.

Gustafson TL et al. Statewide survey of the antimicrobial susceptibilities of Haemophilus influenzae producing invasive United States Hib disease in Tennessee. Pediatric Infectious Disease, 1983, 2(2):119–122.

Harrison LH et al. A day care-based study of the efficacy of United States Haemophilus b polysaccharide vaccine. JAMA: the journal of Hib the American Medical Association, 1988, 260(10):1413–1418.

Istre GR et al. Invasive disease due to Streptococcus pneumoniae in an area with a high rate of relative penicillin United States Spn resistance. The Journal of Infectious Diseases, 1987, 156(5):732–735.

Kaplan SL et al. Three-year multicenter surveillance of United States systemic pneumococcal infections in children. Pediatrics, Spn 1998, 102(3 Pt. 1):538–545.

Kaplan SL et al. Six year multicenter surveillance of invasive United States pneumococcal infections in children. The Pediatric Infectious Spn Disease Journal, 2002, 21(2):141–147.

WHO/IVB/09.02 157 Countries and Type of data Citation other areas in article King MD et al. Recurrent invasive pneumococcal disease: a population-based assessment. Clinical infectious diseases: United States Spn an official publication of the Infectious Diseases Society of America, 2003, 37(8):1029–1036.

Liptak GS et al. Decline of pediatric admissions with Haemophilus influenzae type b in New York State, 1982 United States Spn through 1993: relation to immunizations. The Journal of Pediatrics, 1997, 130(6):923–930.

Loughlin AM, Marchant CD, Lett SM. The changing epidemiology of invasive bacterial infections in Massachusetts United States Hib Spn children, 1984 through 1991. American Journal of Public Health, 1995, 85(3):392–394.

Makintubee S, Istre GR, Ward JI. Transmission of invasive United States Haemophilus influenzae type b disease in day care settings. Hib The Journal of Pediatrics, 1987, 111(2):180–186.

Murphy TV et al. Invasive Haemophilus influenzae type b disease in children less than 5 years of age in Minnesota and United States Hib in Dallas County, Texas, 1983–1984. The Journal of Infectious Diseases, 1992, 165(Suppl. 1):S7–S10.

Murphy TV et al. Declining incidence of Haemophilus influenzae type b disease since introduction of vaccination. United States Hib JAMA: the journal of the American Medical Association, 1993, 269(2):246–248. Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease in Dallas County, Texas: results from population- United States based surveillance in 1995. Clinical infectious diseases: Spn an official publication of the Infectious Diseases Society of America, 1998, 26(3):590–595. Rathore MH et al. Haemophilus influenzae type B invasive disease in urban and rural children: immunization patterns United States Hib and prevalence of disease. The Southern Medical Journal, 1994, 87(11):1083–1087.

Robinson KA et al. Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995–1998: United States opportunities for prevention in the conjugate vaccine era. Spn JAMA: the journal of the American Medical Association, 2001, 285(13):1729–1735.

Schoendorf KC et al. National trends in Haemophilus United States influenzae meningitis mortality and hospitalization among Hib children, 1980 through 1991. Pediatrics, 1994, 3(4):663–668. Schutze GE, Tucker NC, Mason EO, Jr. Impact of the United States conjugate pneumococcal vaccine in Arkansas. The Pediatric Spn Infectious Disease Journal, 2004, 23(12):1125–1129.

158 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article

Singleton R et al. Experience with the prevention of invasive Haemophilus influenzae type b disease by vaccination in United States Hib Alaska: the impact of persistent oropharyngeal carriage. The Journal of Pediatrics, 2000, 137(3):313–320.

Totapally BR, Walsh WT. Pneumococcal bacteremia in United States childhood: a 6-year experience in a community hospital. Spn Chest, 1998, 113(5):1207–1214. Walling AD et al. The epidemiology of bacterial meningitis. United States The Journal of the American Board of Family Practice / Hib Spn American Board of Family Practice, 1991, 4(5):307–311. Whitney CG et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate United States Spn vaccine. The New England Journal of Medicine, 2003, 348(18):1737–1746.

Camou T et al. Invasive pneumococcal diseases in Uruguayan children: comparison between serotype Uruguay Spn distribution and conjugate vaccine formulations. Vaccine, 2003, 21(17–18):2093–2096. Hortal M et al. Capsular type distribution and susceptibility to antibiotics of Streptococcus pneumoniae clinical strains Uruguay isolated from Uruguayan children with systemic infectionS. Spn pneumococcus Study Group. Microbial drug resistance (Larchmont, N.Y.), 1997, 3(2):159–163. Hortal M et al. [Impact of Streptococcus pneumoniae on pneumonia in Latin American children. SIREVA-Vigia Group]. Uruguay Spn Revista Panamericana de Salud Pública = Pan American journal of Public Health, 2000, 8(3):185–195.

Hortal Palma M et al. Vigilancia de las neumococcias del nino hospitalizado: so prevencion especifica (1994–2000). Uruguay [Pneumococcal surveillance in hospitalized children: specific Spn prevention (1994–2000).] Revista Médica del Uruguay, 2002, 18(1):66–75.

Nascimento-Carvalho CM, Moreno-Carvalho OA. Etiology of bacterial meningitis among children aged 2–59 months in Uruguay Salvador, Northeast Brazil, before and after routine use of Hib Haemophilus influenzae type B vaccine. Arquivos de Neuro- Psiquiatria, 2004, 62(2A):250–252.

Amnesty de Valbuena A, Sansone D, Torres G. Neumonía por Venezuela Haemophilus influenzae tipo B en niños: estudio de 5 años. Hib Investigación Clínica, 1988, 29(2):79–92.

WHO/IVB/09.02 159 Table 4: Studies from the WHO Eastern Mediterranean Region (EMR) with evaluable outcome data

Countries and Type of data Citation other areas in article Watt J, Gayed AS. Introduction of routine vaccination against Haemophilus influenzea Type b: a cost-benefit analysis. Egypt Hib Unpublished report, World Health Organization Rapid Assessment Tool, 1999.

Nelson CB, Mohsni E. Iran - estimation of disease burden Iran (Islamic due to Hib. Unpublished report, World Health Organization Hib Republic of) Rapid Assessment Tool, 2000. Daoud AS, Zaki M, al-Saleh QA. Prolonged and secondary Kuwait fever in childhood bacterial meningitis. European Journal of Hib Pediatrics, 1989, 149(2):114–116.

Zaki M et al. Childhood bacterial meningitis in Kuwait. The Kuwait Hib Journal of Tropical Medicine and Hygiene, 1990, 93(1):7–11.

Abid A et al. Pneumococcal meningitis in children. La Morocco Semaine des hôpitaux de Paris, 1999, 75(35–36):1308– Spn 1315.

Moustaoui N et al. Serotypes, biotypes and antimicrobial susceptibilities of Haemophilus influenzae isolated from invasive disease in children in Casablanca. Clinical Morocco Spn Microbiology and Infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2000, 6(1):48–49.

Al Awaidy S. Estimation of Hib Disease Burden in Pakistan. Pakistan Unpublished report, World Health Organization Rapid Hib Assessment Tool, 2003. Novelli VM et al. Haemophilus influenzae type b disease in Qatar an Arab Gulf state. The Pediatric Infectious Disease Journal, Hib 1989, 8(12):886–887.

Abanamy A et al. Childhood bacterial meningitis in Riyadh. Saudi Arabia Hib Annals of Saudi Medicine, 1991, 11(6):628–632.

Abomelha A et al. Childhood bacterial meningitis. Annals of Saudi Arabia Hib Spn Saudi Medicine, 1988, 8(4):274–278.

Al-Aqeeli AA, Guy ML, Al-Jumaah SA. Streptococcus pneumoniae resistance to penicillin and ceftriaxone in a Saudi Arabia Spn tertiary care center in Saudi Arabia. Saudi Medical Journal, 2002, 23(4):400–404.

Al-Mazrou YY et al. Haemophilus type B meningitis in Saudi Saudi Arabia children under 5 years old. Journal of Tropical Pediatrics, Hib Spn 2004, 50(3):131–136.

Almuneef M et al. Childhood bacterial meningitis in Saudi Saudi Arabia Hib Arabia. The Journal of Infection, 1998, 36(2):157–160.

160 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Almuneef M et al. Bacterial meningitis in Saudi Arabia: the impact of Haemophilus influenzae type b vaccination. Saudi Arabia Spn Journal of Chemotherapy (Florence, Italy), 2001, 13(Suppl. 1):S34–S39.

Azubuike JC. Childhood bacterial meningitis in Tabuk, Saudi Saudi Arabia Hib Spn Arabia. Annals of Saudi Medicine, 1990, 10(2):145–148.

Kambal AM, Abdullah AM. Childhood pneumococcal Saudi Arabia bacteraemia in Riyadh, Saudi Arabia. Annals of Tropical Spn Paediatrics, 1997, 17(3):245–251.

Soltani MS et al. [Epidemiology of Haemophilus influenzae Tunisia meningitis in Tunisia]. Eastern Mediterranean Health Journal, Hib 2005, 11(1–2):14–27.

Table 5: Studies from the WHO European Region (EUR) with evaluable outcome data

Countries and Type of data Citation other areas in article

Rauter L, Mutz I. [Haemophilus influenzae meningitis 1983 to Austria 1992 — epidemiology and sequelae of the disease]. Wiener Hib Spn Klinische Wochenschrift, 1994, 106(7):187–192.

Rendi-Wagner P et al. Prospective surveillance of incidence, serotypes and antimicrobial susceptibility of invasive Austria Streptococcus pneumoniae among hospitalized children in Spn Austria. The Journal of Antimicrobial Chemotherapy, 2004, 53(5):826–831.

Vutuc C, Kunze M. [Haemophilus influenzae meningitis Austria in Austria: 1990–1992 incidence]. Wiener Klinische Hib Wochenschrift, 1995, 107(8):256–257.

Ducoffre G et al. [Trends in pneumococcal infections in Belgium Belgium from 1986 to 1991]. Acta Clinica Belgica, 1993, Spn 48(3):148–155.

van Hoeck KJ et al. A retrospective epidemiological study of Belgium bacterial meningitis in an urban area in Belgium. European Hib Spn Journal of Pediatrics, 1997, 156(4):288–291.

Bosnia and Al Awaidy S, Afsar O, Tulisov A. Estimation of Hib disease Hib Herzegovina burden in Bosnia and Herzegovina. 2004.

Kojouharova M et al. Epidemiology of meningitis due to Haemophilus influenzae type b in children in Bulgaria: a Bulgaria Hib Spn prospective, population-based surveillance study. Bulletin of the World Health Organization, 2002, 80(9):690–695.

WHO/IVB/09.02 161 Countries and Type of data Citation other areas in article Kriz P, Lebedova V, Benes C. Large decrease in incidence of invasive Haemophilus influenzae b disease following Czech introduction of routine vaccination in the Czech Republic. Hib Republic Euro Surveillance: European communicable disease bulletin, 2005, 10(7):E050728 4.

Lebedova V, Krizova P. The 2001 serological survey in Czech the Czech Republic — Hib invasive disease Haemophilus Hib Republic influenzae b. Central European Journal of Public Health, 2003, (Suppl. 11):S25–S30.

Christensen AC, Frederiksen W. [Etiology of bacterial Denmark Hib meningitis]. Ugeskrift for Laeger, 1988, 150(11):655–657.

Kaltoft MS, Zeuthen N, Konradsen HB. Epidemiology of invasive pneumococcal infections in children aged 0–6 years Denmark Spn in Denmark: a 19-year nationwide surveillance study. Acta Paediatrica. Supplementum, 2000, 89(435):3–10.

Konradsen HB, Kaltoft MS. Invasive pneumococcal infections in Denmark from 1995 to 1999: epidemiology, serotypes, and Denmark Spn resistance. Clinical and Diagnostic Laboratory Immunology, 2002, 9(2):358–365.

Kristensen K et al. Epidemiology of Haemophilus influenzae type b infections among children in Denmark in 1985 and Denmark Hib 1986. Acta Paediatrica Scandinavica, 1990, 79(6–7):587– 592.

Nielsen SV, Henrichsen J. Incidence of invasive pneumococcal disease and distribution of capsular types Denmark Spn of pneumococci in Denmark, 1989–94. Epidemiology and Infection, 1996, 117(3):411–416. Baer M, Vuento R, Vesikari T. Increase in bacteraemic Finland pneumococcal infections in children. Lancet, 1995, Spn 345(8950):661.

Eskola J et al. Epidemiology of invasive pneumococcal Finland infections in children in Finland. JAMA: the journal of the Spn American Medical Association, 1992, 268(23):3323–27.

Peltola H, Kilpi T, Anttila M. Rapid disappearance of Haemophilus influenzae type b meningitis after routine Finland Hib childhood immunization with conjugate vaccines. Lancet, 1992, 340(8819):592–594.

Saarinen M et al. Spectrum of 2836 cases of invasive bacterial or fungal infections in children: results of prospective nationwide five-year surveillance in Finland. Finland Hib Spn Finnish Pediatric Invasive Infection Study Group. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 1995, 21(5):1134–1144.

Takala AK et al. Risk factors of invasive Haemophilus Finland influenzae type b disease among children in Finland. The Hib Journal of Pediatrics, 1989, 115(5 Pt. 1):694–701.

162 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Gaillat J. [Epidemiology of systemic Streptococcus France pneumoniae infections]. La Presse Médicale, 1998, 27(Suppl. Spn 1):S9–S16. Laurichesse H et al. Clinical characteristics and outcome of patients with invasive pneumococcal disease, Puy-de- Dome, France, 1994–1998. European Journal of Clinical France Spn Microbiology & Infectious Diseases: official publication of the European Society of Clinical Microbiology, 2001, 20(5):299– 308.

Livartowski A et al. [Epidemiology of Haemophilus influenzae France type b meningitis in two French departments]. Archives Hib Françaises de Pédiatrie, 1989, 46(3):175–179.

Reinert P et al. Epidemiology of Haemophilus influenzae type France Hib b disease in France. Vaccine, 1993, 11 (Suppl. 1):S38–S42.

von Kries R et al. Proportion of invasive pneumococcal infections in German children preventable by pneumococcal Germany conjugate vaccines. Clinical infectious diseases: an official Spn publication of the Infectious Diseases Society of America, 2000, 31(2):482–487.

von Kries R et al. Prediction of the potential benefit of different pneumococcal conjugate vaccines on invasive Germany Spn pneumococcal disease in German children. The Pediatric Infectious Disease Journal, 2002, 21(11):1017–1023.

Syriopoulou V et al. Epidemiology of invasive childhood Greece pneumococcal infections in Greece. Acta Paediatrica. Spn Supplementum, 2000, 89(435):30–34.

Tsolia MN et al. Epidemiology of invasive Haemophilus influenzae type b infections among children in Greece before Greece Hib the introduction of immunization. Scandinavian Journal of Infectious Diseases, 1998, 30(2):165–168.

Dagan R. A two-year prospective, nationwide study to determine the epidemiology and impact of invasive childhood Haemophilus influenzae type b infection in Israel. The Israel Hib Israeli Pediatric Bacteremia and Meningitis Group. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 1992, 15(4):720–725. Dagan R et al. Epidemiology of pediatric meningitis caused by Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis in Israel: a 3-year Israel Hib Spn nationwide prospective study. Israeli Pediatric Bacteremia and Meningitis Group. The Journal of Infectious Diseases, 1994, 169(4):912–916.

WHO/IVB/09.02 163 Countries and Type of data Citation other areas in article

Dagan R et al. Effectiveness of a nationwide infant immunization program against Haemophilus influenzae Israel Hib Spn b. The Israeli Pediatric Bacteremia and Meningitis Group. Vaccine, 1999, 17(2):134–141.

Fraser D et al. A decade (1989–1998) of pediatric invasive pneumococcal disease in two populations residing in one Israel geographic location: implications for vaccine choice. Clinical Spn infectious diseases: an official publication of the Infectious Diseases Society of America, 2001, 33(4):421–427.

Halfon-Yaniv I, Dagan R. Epidemiology of invasive Haemophilus influenzae type b infections in Bedouins and Israel Hib Jews in southern Israel. The Pediatric Infectious Disease Journal, 1990, 9(5):321–326.

Rosenthal J et al. Differences in the epidemiology of childhood community-acquired bacterial meningitis between Israel two ethnic populations cohabiting in one geographic area. Hib The Pediatric Infectious Disease Journal, 1988, 7(9):630– 633.

Cellesi C et al. Retrospective survey on the epidemiology of H. influenzae type B meningitis in Italy (1987–91). The Italy New Microbiologica: official journal of the Italian Society for Hib Medical, Odontoiatric, and Clinical Microbiology (SIMMOC), 1995, 18(2):183–186.

Chironna M et al. [Haemophilus influenzae type b meningitis in Apulia. Retrospective study from the years 1994–1995]. Italy Hib Spn Annali di Igiene: Medicina Preventiva e di Comunità, 1998, 10(3):131–136. Ciofi degli Atti ML et al.Haemophilus influenzae invasive disease in Italy, 1997–1998. European Journal of Clinical Italy Microbiology & Infectious Diseases: official publication of the Hib European Society of Clinical Microbiology, 2001, 20(6):436– 437. D’Alessandro D, Biasio LR, Fara GM. [Incidence of Haemophilus influenzae type b meningitis in Italy. Preliminary Italy Hib results]. Annali di Igiene: Medicina Preventiva e di Comunità, 1995, 7(5):319–327.

D’Ancona F et al. Incidence of vaccine preventable Italy pneumococcal invasive infections and blood culture practices Spn in Italy. Vaccine, 2005, 23(19):2494–2500.

Pizzuti R et al. [Haemophilus influenzae type b meningitis in the city and district of Naples: a retrospective study on Italy Hib Spn hospitalizations in the period 1987–1995]. Annali di Igiene: Medicina Preventiva e di Comunità, 1998, 10(3):137–146. Squarcione S, Pompa MG, D’Alessandro D. National Italy Surveillance System and Hib meningitis incidence in Italy. Hib European Journal of Epidemiology, 1999, 15(7):685–686.

164 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Ticca F et al. [Haemophilus influenzae type b in meningitis: antibiotic resistance in pediatric patients]. Le Infezioni in Italy Medicina: rivista periodica di Eziologia, Epidemiologia, Hib Diagnostica, Clinica e Terapia delle Patologie Infettive, 1997, 5(2):96–99.

De Jonghe M, Glaesener G. [Type B Haemophilus influenzae infections. Experience at the Pediatric Hospital of Luxembourg Hib Luxembourg]. Bulletin de la Société des Sciences Médicales du Grand-Duché de Luxembourg, 1995, 132(2):17–20.

Spanjaard L et al. Epidemiology of meningitis and bacteraemia due to Streptococcus pneumoniae in The Netherlands Spn Netherlands. Acta Paediatrica. Supplementum, 2000, 89(435):22–26.

Jenssen KT et al. [Invasive pneumococcal infections in children from Troms, Nordland and Sor-Trondelag 1980–95]. Norway Spn Tidsskrift for den Norske Laegeforening, 2000, 120(3):308– 311.

Skoczynska A et al. Characteristics of the major etiologic agents of bacterial meningitis isolated in Poland in 1997– Poland Hib Spn 1998. Microbial drug resistance (Larchmont, N.Y.), 2000, 6(2):147–153.

Zielinski A, Tomaszunas-Blaszczyk J, Kuklinska D. Epidemiology of childhood bacterial meningitis in Poland. Incidence of bacterial meningitis with special reference to Poland Haemophilus influenzae type b among children 0–59 months Hib old in the former Kielce and Bydgoszcz districts in Poland in 1998–1999. European Journal of Epidemiology, 2001, 17(8):779–782.

Corcaci C et al. Hemophilus influenzae meningitis— the experience of infectious diseases department between 1984– Romania Hib 2001. Revista Medico-Chiruricala A Societatii de Medici si Naturalisti Din Iasi (Iasi), 2002, 107(2):348–351.

Luca V et al. Incidence and etiological agents of bacterial meningitis among children <5 years of age in two districts Romania of Romania. European Journal of Clinical Microbiology & Hib Spn Infectious Diseases: official publication of the European Society of Clinical Microbiology, 2004, 23(7):523–528. Demina AA et al. Etiology of purulent bacterial meningitis. Russian Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii, Hib Spn Federation 1983:3–6. Demina AA et al. Surveillance of meningococcal infections Russian and other forms of purulent meningitis: a 4-year study in Hib Spn Federation the USSR. Bulletin of the World Health Organization, 1986, 64(2):263–269.

WHO/IVB/09.02 165 Countries and Type of data Citation other areas in article

Deviatkina NP et al. [The characteristics of suppurative Russian meningitis morbidity caused by Streptococcus pneumoniae Hib Spn Federation and Haemophilus influenza type B]. Zhurnal Mikrobiologii, Eepidemiologii, i Immunobiologii, 1990(1):45–49.

Kostiukova NN et al. [The etiological structure of Russian acute bacterial meningitis in different regions]. Zhurnal Hib Spn Federation Mikrobiologii, Epidemiologii, i Immunobiologii, 1992(7–8):14– 17. Novakova E, Gessner BD, Olear V. Incidence of Haemophilus influenzae type b meningitis among children less than 5 years of age in Slovakia. European Journal Slovakia Hib of Clinical Microbiology & Infectious Diseases: official publication of the European Society of Clinical Microbiology, 1999, 18(6):409–413.

Paragi M et al. Possibility of application of new Slovenia pneumococcal conjugate vaccines in children in Slovenia. Hib Spn Vaccine, 2003, 21(32):4708–4714.

Bernaola Iturbe E et al. [Study of the incidence of invasive pneumococcal disease in neonates and children aged less Spain Spn than 5 years in the Basque country and Navarre (Spain)]. Anales Españoles de Pediatría, 2002, 57(4):301–309.

Casado Flores J et al. [Multicenter prospective study on Spain severe bacterial meningitis in children]. Anales Españoles de Spn Pediatría, 1997, 47(5):466–472.

Casado Flores J et al. Prevalence of pneumococcal Spain meningitis in Spain. Anales Españoles de Pediatría, 2002, Spn 56(1):5–9.

Diez-Domingo J et al. Epidemiology of invasive Spain Streptococcus pneumoniae infections in children in Spain, Spn 1996–1998. The Journal of Infection, 2002, 45(3):139–143.

Dominguez A et al. The epidemiology of invasive Spain Streptococcus pneumoniae disease in Catalonia (Spain). A Spn hospital-based study. Vaccine, 2002, 20(23–24):2989–2994.

Espin MI et al. [Invasive pneumococcal disease in children Spain in the region of Murcia (Spain)]. Gaceta Sanitaria / Spn S.E.S.P.A.S., 2002, 16(5):385–391.

166 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article

Goicoechea-Saez M et al. [Invasive pneumococcal disease Spain in children in the Community of Valencia, Spain]. Gaceta Spn Sanitaria / S.E.S.P.A.S., 2003, 17(6):458–465.

Gonzalez A et al. [Incidence of invasive pneumococcal disease in Cantabria, Spain, [1995–2001] and implications Spain Spn for the childhood inmunization schedule]. Gaceta Sanitaria / S.E.S.P.A.S., 2003, 17(6):453–457.

Iglesias Sanchez L et al. [Epidemiology of invasive pneumococcal disease in children in Gipuzkoa (Spain) Spain Spn from 1981 to 2001]. Anales Españoles de Pediatría, 2002, 57(5):401–407.

Juan Martin F, Campos Calleja C. Invasive Haemophilus Spain influenzae type B infections in children (1981–1990). Anales Hib Españoles de Pediatría, 1993, 39(2):111–115.

Latorre C, Sierra M, Lite J. [Prospective study of the invasive strains of Streptococcus pneumoniae isolated in 16 Spain Spn hospitals in Cataluna, Spain]. Enfermedades Infecciosas y Microbiología Clínica, 1999, 17(6):286–291.

Martinez Leon M et al. [Bacterial meningitis. Clinical- Spain epidemiological study. Review of 8 years (1988–1995)]. Hib Spn Anales Españoles de Pediatría, 1998, 48(3):277–282.

Perez MC et al. Predictive factors for invasive pneumococcal Spain disease: A case-control study. Anales Españoles de Spn Pediatría, 2002, 57(4):310–316.

Pineda Solas V et al. [Bacteremic pneumococcal Spain pneumonia]. Anales Españoles de Pediatría, 2002, Spn 57(5):408–413.

Pineda V et al. Epidemiology of invasive Streptococcus Spain pneumoniae infections in children in an area of Barcelona, Spn Spain. Acta Paediatrica, 2002, 91(11):1251–1256.

Pocheville Gurutzeta I et al. [Invasive disease caused Spain by Streptococcus pneumoniae: a 7-year study]. Anales Spn Españoles de Pediatría, 1997, 47(2):151–155.

Soult Rubio JA et al. Haemophilus influenzae type B Spain meningitis. A retrospective study. Anales Españoles de Hib Pediatría, 1994, 40(6):443–448.

WHO/IVB/09.02 167 Countries and Type of data Citation other areas in article

Soult Rubio JA et al. Pneumococcal sepsis and meningitis, Spain 2001–2003: Incidence, clinical features and identification of Spn serotypes. Acta Pediátrica Española, 2005, 63(1):8–13.

Villa-Alcazar M et al. Haemophilus influenzae meningitis: Spain a disease on the increase that may be prevented. Revista Hib Española de Pediatría, 1994, 50(300):529–535.

Villo Sirerol N et al. [Streptococcus pneumoniae and Haemophilus influenzae serotype B invasive disease. A 12- Spain Hib Spn year retrospective study]. Anales de Pediatría (Barcelona, Spain: 2003), 2004, 61(2):150–155.

Berg S et al. Incidence and prognosis of meningitis due to Haemophilus influenzae, Streptococcus pneumoniae and Sweden Hib Spn Neisseria meningitidis in Sweden. Scandinavian Journal of Infectious Diseases, 1996, 28(3):247–252.

Dahl MS et al. Invasive pneumococcal infections in Southwestern Sweden: a second follow-up period of 15 Sweden Spn years. Scandinavian Journal of Infectious Diseases, 2001, 33(9):667–672. Ekdahl K, Martensson A, Kamme C. Bacteraemic pneumococcal infections in Southern Sweden 1981–96: Sweden trends in incidence, mortality, age-distribution, serogroups Spn and penicillin-resistance. Scandinavian Journal of Infectious Diseases, 1998, 30(3):257–262.

Garpenholt O et al. The impact of Haemophilus influenzae Sweden type b vaccination in Sweden. Scandinavian Journal of Hib Infectious Diseases, 1996, 28(2):165–169.

Hugosson S et al. Invasive Haemophilus influenzae disease: epidemiology and clinical spectrum before large-scale H. Sweden Hib influenzae type b vaccination. Scandinavian Journal of Infectious Diseases, 1995, 27(1):63–67.

Trollfors B et al. Haemophilus influenzae meningitis in Sweden Sweden 1981–1983. Archives of Disease in Childhood, 1987, Hib 62(12):1220–1223.

Muhlemann K et al. Invasive Haemophilus influenzae disease and epiglottitis among Swiss children from 1980 to 1993: Switzerland evidence for herd immunity among older age groups. The Hib Swiss Haemophilus influenzae Study Group. Scandinavian Journal of Infectious Diseases, 1996, 8(3):265–268.

168 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Venetz I, Schopfer K, Muhlemann K. Paediatric, invasive pneumococcal disease in Switzerland, 1985–1994. Swiss Switzerland Spn Pneumococcal Study Group. International Journal of Epidemiology, 1998, 27(6):1101–1104. Platanov A, Cowgill K, Linehan M. Haemophilus influenzae Ukraine type b (Hib) disease burden in Ukraine: WHO Hib Rapid Hib Assessment Tool, Unpublished report, 2003. A survey of invasive Haemophilus influenzae infections — United England and Wales. Canada Communicable Disease Report, Hib Kingdom 1992, 18(6):42–47.

Anderson EC et al. Epidemiology of invasive Haemophilus United influenzae infections in England and Wales in the pre- Hib Kingdom vaccination era (1990–2). Epidemiology and Infection, 1995, 115(1):89–100.

Booy R et al. Invasive Haemophilus influenzae type b United disease in the Oxford region (1985–91). Archives of Disease Hib Kingdom in Childhood, 1993, 69(2):225–228.

Coggins A, Shepherd CW, Cockburn F. Epidemiology United of Haemophilus type b invasive disease in childhood in Hib Kingdom Glasgow. Scottish Medical Journal, 1993, 38(1):18–20. de Louvois J et al. Infantile meningitis in England and Wales: United a two year study. Archives of Disease in Childhood, 1991, Hib Spn Kingdom 66(5):603–607. Fallon RJ, Reid D. Haemophilus influenzae type b invasive United disease. BMJ (Clinical research ed.), 1991, 303(6811):1203– Hib Kingdom 1204.

United Fortnum HM, Davis AC. Epidemiology of bacterial meningitis. Hib Spn Kingdom Archives of Disease in Childhood, 1993, 68(6):763–767.

Grant CC et al. Invasive pneumococcal disease in Oxford, United 1985–2001: a retrospective case series. Archives of Disease Spn Kingdom in Childhood, 2003, 88(8):712–714.

Howard AJ et al. Epidemiology of Haemophilus influenzae United type b invasive disease in Wales. BMJ (Clinical research Hib Kingdom ed.), 1991, 303(6800):441–445.

Jones IR et al. Social deprivation and bacterial meningitis in United north east Thames region: three year study using small area Spn Kingdom statistics. BMJ (Clinical research ed.), 1997, 314(7083):794– 795.

Kyaw MH et al. The changing epidemiology of bacterial United meningitis and invasive non-meningitic bacterial disease in Hib Spn Kingdom Scotland during the period 1983–99. Scandinavian Journal of Infectious Diseases, (2002a), 34(4):289–298. Kyaw MH et al. Incidence of invasive pneumococcal disease United in Scotland, 1988–99. Epidemiology and Infection, (2002b), Spn Kingdom 128(2):139–147.

WHO/IVB/09.02 169 Countries and Type of data Citation other areas in article Kyaw MH et al. Invasive pneumococcal disease in Scotland, 1999–2001: use of record linkage to explore associations United between patients and disease in relation to future vaccination Spn Kingdom policy. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 2003, 37(10):1283–1291.

Laurichesse H et al. Pneumococcal bacteraemia United and meningitis in England and Wales, 1993 to 1995. Spn Kingdom Communicable Disease and Public Health / PHLS, 1998, 1(1):22–27.

McIntosh ED. How many episodes of hospital care might United be prevented by widespread uptake of pneumococcal Spn Kingdom conjugate vaccine? Archives of Disease in Childhood, 2003, 88(10):859–861.

Miller E et al. Epidemiology of invasive and other United pneumococcal disease in children in England and Wales Spn Kingdom 1996–1998. Acta Paediatrica. Supplementum, 2000, 89(435):11–16.

Olowokure B et al. Decrease in effectiveness of routine surveillance of Haemophilus influenzae disease after United introduction of conjugate vaccine: comparison of routine Hib Kingdom reporting with active surveillance system. BMJ (Clinical research ed.), 2000, 321(7263):731–732.

Quigley C et al. Haemophilus influenzae type b disease United in North-West England. The Journal of Infection, 1993, Hib Kingdom 26(2):215–220.

Ramsay ME et al. Estimating Haemophilus influenzae type United b vaccine effectiveness in England and Wales by use of the Hib Kingdom screening method. The Journal of Infectious Diseases, 2003, 188(4):481–485. Shackley F et al. Outcome of invasive pneumococcal United disease: a UK based study. Oxford Pneumococcal Spn Kingdom Surveillance Group. Archives of Disease in Childhood, 2000, 83(3):231–233. Slack MP et al. Enhanced surveillance of invasive United Haemophilus influenzae disease in England, 1990 to 1996: Hib Kingdom impact of conjugate vaccines. The Pediatric Infectious Disease Journal, 1998, 17(Suppl. 9):S204–S207.

Sleeman K et al. Invasive pneumococcal disease in United England and Wales: vaccination implications. The Journal of Spn Kingdom Infectious Diseases, 2001, 183(2):239–246.

Tudor-Williams G et al. Haemophilus influenzae type United b disease in the Oxford region. Archives of Disease in Hib Kingdom Childhood, 1989, 64(4):517–519.

Urwin G et al. Pneumococcal meningitis in the North East United Thames Region UK: epidemiology and molecular analysis of Hib Spn Kingdom isolates. Epidemiology and Infection, 1996, 117(1):95–102.

170 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Table 6: Studies from the WHO South-East Asia Region (SEAR) with evaluable outcome data

Countries and Type of data Citation other areas in article Saha S, personal communication. PneumoADIP sponsored Bangladesh Hib Spn ICDDRB surveillance sites in Bangladesh, 2007.

Saha SK et al. The increasing burden of disease in Bangladesh Bangladeshi children due to Haemophilus influenzae type b Hib Spn meningitis. Annals of Tropical Paediatrics, 1997, 17(1):5–8.

Saha SK et al. Invasive Haemophilus influenzae type Bangladesh B diseases in Bangladesh, with increased resistance to Hib antibiotics. The Journal of Pediatrics, 2005, 146(2):227–233.

Are Haemophilus influenzae infections a significant problem in India? A prospective study and review. Clinical infectious India Hib diseases: an official publication of the Infectious Diseases Society of America, 2002, 34(7):949–957. Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India. Invasive India Bacterial Infection Surveillance (IBIS) Group, International Spn Clinical Epidemiology Network (INCLEN). Lancet, 1999, 353(9160):1216–1221. Singh R et al. Occurrence of multiple antimicrobial resistance India among Haemophilus influenzae type b causing meningitis. Hib The Indian Journal of Medical Research, 1992, 95:230–233.

India Steinhoff M, (personal communication), 2007. Spn

Gessner BD et al. Incidences of vaccine-preventable Haemophilus influenzae type b pneumonia and meningitis in Indonesia Hib Indonesian children: hamlet-randomized vaccine-probe trial. Lancet , 2005, 365(9453):43–52.

Russell F et al. The Burden of Haemophilus influenzae Nepal Type B (Hib), in Nepal. Unpublished report, World Health Hib Organization Rapid Assesment Tool, 2003.

Burden of Haemophilus influenzae b (Hib) disease Sri Lanka study — Sri Lanka. Geneva, WHO report SE / ICP / IVD / Hib 506 / XF / 02 / U, 2002.

Chotpitayasunondh T. Bacterial meningitis in children: etiology and clinical features, an 11-year review of 618 Thailand Hib Spn cases. The Southeast Asian Journal of Tropical Medicine and Public Health, 1994, 25(1):107–115.

Likitnukul S. Systemic Haemophilus influenzae disease Thailand in Thai children. The Southeast Asian Journal of Tropical Hib Medicine and Public Health, 1994, 25(4):672–627.

Rerks-Ngarm S et al. Prospective population-based Thailand incidence of Haemophilus influenzae type b meningitis in Hib Thailand. Vaccine, 2004, 22(8):975–983.

WHO/IVB/09.02 171 Table 7: Studies from the WHO Western Pacific Region (WPR) with evaluable outcome data

Countries and Type of data Citation other areas in article Andresen DN, Collignon PJ. Invasive pneumococcal disease in the Australian Capital Territory and Queanbeyan region: Australia Spn do high infant rates reflect more disease or better detection? Journal of Paediatrics and Child Health, 2004, 40(4):184–188.

Bower C et al. Sequelae of Haemophilus influenzae type b meningitis in aboriginal and non-aboriginal children under 5 Australia Hib years of age. Journal of Paediatrics and Child Health, 2004, 1994, 30(5):393–397.

Bower C et al. Measuring the impact of conjugate vaccines on invasive Haemophilus influenzae type b infection in Western Australia Hib Australia. Australian and New Zealand Journal of Public Health, 1998, 22(1):67–72.

Christie DJ et al. Childhood invasive pneumococcal disease Australia in Tasmania, 1994–2000. Journal of Paediatrics and Child Spn Health, 2002, 38(5):445–449.

Davis CW, McIntyre PB. Invasive pneumococcal infection Australia in children, 1981–92: a hospital-based study. Journal of Spn Paediatrics and Child Health, 1995, 31(4):317–322.

Fagan RL et al. The epidemiology of invasive pneumococcal Australia disease in children in Far North Queensland. Journal of Spn Paediatrics and Child Health, 2001, 37(6):571–575.

Gilbert GL, Clements DA, Broughton SJ. Haemophilus influenzae type b infections in Victoria, Australia, 1985 Australia Hib to 1987. The Pediatric Infectious Disease Journal, 1990, 9(4):252–257.

Gilbert GL, Johnson PD, Clements DA. Clinical manifestations and outcome of Haemophilus influenzae type Australia Hib b disease. Journal of Paediatrics and Child Health, 1995, 31(2):99–104. Gilmour R. EpiReview: invasive pneumococcal disease, Australia NSW, 2002. New South Wales Public Health Bulletin, 2005, Spn 16(1–2):26–30.

Gratten M et al. Seroepidemiology of invasive pneumococcal Australia disease in Queensland, 1990 to 1997. Communicable Spn Diseases Intelligence, 1998, 22(12):265–269.

Hanna JN, Wild BE. Bacterial meningitis in children under Australia five years of age in Western Australia. The Medical Journal of Hib Spn Australia, 1991, 155(3):160–164. Hogg GG, Strachan JE, Lester RA. Invasive pneumococcal Australia disease in the population of Victoria. The Medical Journal of Spn Australia, 2000, 173(Suppl.):S32–S35.

172 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Krause VL, Reid SJ, Merianos A. Invasive pneumococcal Australia disease in the Northern Territory of Australia, 1994–1998. The Spn Medical Journal of Australia, 2000, 173(Suppl.):S27–S31.

Liu M et al. Invasive pneumococcal disease among children Australia in Victoria. Communicable Diseases Intelligence, 2003, Spn 27(3):362–366.

McGregor AR et al. Invasive Haemophilus influenzae infection Australia in the Australian Capital Territory region. The Medical Journal Hib of Australia, 1992, 156(8):569–572.

McIntyre P, Gilmour R, Watson M. Differences in the epidemiology of invasive pneumococcal disease, metropolitan Australia Spn NSW, 1997–2001. New South Wales Public Health Bulletin, 2003, 14(4–5):85–89.

McIntyre P et al. The outcome of childhood Haemophilus Australia influenzae meningitis. A population based study. The Medical Hib Journal of Australia, 1993, 159(11–12):766–772.

McIntyre PB, Leeder SR, Irwig LM. Invasive Haemophilus influenzae type b disease in Sydney children 1985–1987: a Australia Hib population-based study. The Medical Journal of Australia, 1991, 154(12):832–837.

McIntyre PB et al. Blood cultures in hospitalized children. The Australia Hib Spn Medical Journal of Australia, 1987, 147(10):485–489.

McIntyre PB et al. Epidemiology of invasive pneumococcal Australia disease in urban New South Wales, 1997–1999. The Medical Spn Journal of Australia, 2000, 173(Suppl.):S22–S26.

Roche P et al. Invasive pneumococcal disease in Australia, Australia 2002. Communicable Diseases Intelligence, 2003, 27(4):466– Spn 477.

Roche P et al. Invasive pneumococcal disease in Australia, Australia 2003. Communicable Diseases Intelligence, 2004, 28(4):441– Spn 454.

el Saadi O, Cameron AS. Epidemiology of Haemophilus Australia influenzae type b (Hib) meningitis in South Australia. The Hib Medical Journal of Australia, 1993, 159(7):494–495.

The Vaccine Impact Surveillance Network — Invasive Pneumococcal Study Group. Are current recommendations Australia for pneumococcal vaccination appropriate for Western Spn Australia? The Medical Journal of Australia, 2000, 173 (Suppl.):S36–S40.

WHO/IVB/09.02 173 Countries and Type of data Citation other areas in article Trotman J, Hughes B, Mollison L. Invasive pneumococcal disease in central Australia. Clinical infectious diseases: Australia Spn an official publication of the Infectious Diseases Society of America, 1995, 20(6):1553–1556.

Shen SJ. [Serotypes and epidemiological study of China pneumococcal infection in 18 provinces (cities) in China]. Spn Zhonghua Liu Xing Bing Xue Za Zhi, 1989, 10(3):133–137.

Yang Y et al. Acute bacterial meningitis in children in China Hefei, China 1990–1992. Chinese Medical Journal, 1996, Hib Spn 109(5):385–388. Yu CH, Chiu NC, Huang FY. Invasive pneumococcal infection China in children. The Southeast Asian Journal of Tropical Medicine Spn and Public Health, 2001, 32(1):126–131.

Lau YL et al. Invasive Haemophilus influenzae type b China, Hong infections in children hospitalized in Hong Kong, 1986–1990. Hib Kong SAR Hong Kong Hib Study Group. Acta Paediatrica, 1995, 84(2):173–176.

Sung RY et al. Meningitis in Hong Kong children, with China, Hong special reference to the infrequency of haemophilus and Spn Kong SAR meningococcal infection. Journal of Paediatrics and Child Health, 1997, 33(4):296–299.

Chen MK et al. Prospective surveillance of children with invasive Haemophilus influenzae disease in Taiwan. Journal Taiwan*, China Hib of Microbiology, Immunology, and Infection, 1999, 32(4):257– 260.

Siu LK et al. Epidemiology of invasive pneumococcal infection in Taiwan: antibiotic resistance, serogroup distribution, and Taiwan*, China Spn ribotypes analyses. Microbial drug resistance (Larchmont, N.Y.), 2002, 8(3):201–208.

Wilson N et al. Estimating the Haemophilus influenzae type Fiji b (Hib) disease burden and the impact of Hib vaccine in Fiji. Hib Spn Vaccine, 2003, 21(17–18):1907–1912.

Ishikawa T et al. Epidemiology of bacterial meningitis in Japan children: Aichi Prefecture, Japan, 1984–1993. Pediatric Hib Spn Neurology, 1996, 14(3):244–250.

Ishiwada N, Cao LD, Kohno Y. PCR-based capsular serotype determination of Haemophilus influenzae strains recovered from Japanese paediatric patients with invasive infection. Japan Hib Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2004, 10(10):895–898.

Kamiya H et al. Childhood bacterial meningitis in Japan. Japan The Pediatric Infectious Disease Journal, 1998, 17(Suppl. Hib 9):S183–S185.

174 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 Countries and Type of data Citation other areas in article Kuriki M et al. [Acute encephalitis and bacterial meningitis in children in Aichi Prefecture (1984–1993)]. Nippon Koshu Japan Hib Eisei Zasshi = Japanese Journal of Public Health, 1995, 42(5):338–345.

Nakano T et al. Incidence of Haemophilus influenzae type b meningitis in Mie Prefecture, Japan. Pediatrics International: Japan Hib official journal of the Japan Pediatric Society,2001, 43(3):323–324. Sakata H, Maruyama S. [A study of bacterial meningitis in Hokkaido between 1994 and 1998]. Kansenshogaku Zasshi. Japan Hib The Journal of the Japanese Association for Infectious Diseases, 2000, 74(4):339–44. Sato A et al. [Clinical study of 33 children with systemic pneumococcal infections]. Kansenshogaku Zasshi. The Japan Spn Journal of the Japanese Association for Infectious Diseases, 2001, 75(12):1007–1013.

Nik Khairulddin NY, Choo KE, Johari MR. Epidemiology of Haemophilus influenzae invasive disease in hospitalised Malaysia Hib Kelantanese children, 1985–1994. Singapore Medical Journal, 1999, 40(2):96–100. Watt J. Burden of Haemophilus influenzae b (Hib) disease Mongolia study — Mongolia. Geneva, WHO report WP / ICP / EPI / 5.2 Hib Spn / 001 / XZ / 04, 2004.

Anglaret X et al. Invasive Haemophilus influenzae disease of New Caledonia Melanesian and Caucasian children in New Caledonia. The Hib Pediatric Infectious Disease Journal, 1993, 12(10):888–889.

Voss L, Lennon D, Gillies M. Haemophilus influenzae type New Zealand b disease in Auckland children 1981–87. The New Zealand Hib Medical Journal, 1989, 102(865):149–151.

Voss L et al. Invasive pneumococcal disease in a pediatric New Zealand population, Auckland, New Zealand. The Pediatric Infectious Spn Disease Journal, 1994, 13(10):873–878.

Wilson N et al. The beneficial impact of Hib vaccine on New Zealand disease rates in New Zealand children. The New Zealand Hib Medical Journal, 2002, 115(1159):U122.

Gratten M et al. The aetiology of purulent meningitis in Papua New highland children: a bacteriological study. Papua and New Spn Guinea Guinea Medical Journal, 1985, 28(4):233–240.

Lehmann D et al. Aetiology and clinical signs of bacterial Papua New meningitis in children admitted to Goroka Base Hospital, Hib Spn Guinea Papua New Guinea, 1989–1992. Annals of Tropical Paediatrics, 1999, 19(1):21–32.

WHO/IVB/09.02 175 Countries and Type of data Citation other areas in article Limcangco MR, Salole EG, Armour CL. Epidemiology of Haemophilus influenzae type b meningitis in Manila, Philippines Hib Philippines, 1994 to 1996. The Pediatric Infectious Disease Journal, 2000, 19(1):7–11.

Kim JS et al. Incidence of Haemophilus influenzae type b and Republic of other invasive diseases in South Korean children. Vaccine, Hib Spn Korea 2004, 22(29–30):3952–3962.

Kim KH et al. The causative organisms of bacterial meningitis Republic of in Korean children, 1986–1995. Journal of Korean Medical Hib Spn Korea Science, 1998, 13(1):60–64.

Lee HJ. Epidemiology of systemic Haemophilus influenzae Republic of disease in Korean children. The Pediatric Infectious Disease Hib Spn Korea Journal, 1998, 17(Suppl. 9):S185–S189. Carapetis J. Estimating the burden of Haemophilus influenzae type b, congenital rubella syndrome and mumps in Samoa. Samoa Hib Unpublished report, World Health Organization Rapid Assessment Tool, 2002.

Lee YS et al. Invasive Haemophilus influenzae type b Singapore infections in Singapore children: a hospital-based study. Hib Journal of Paediatrics and Child Health, 2000, 36(2):125–127.

Anh DD et al. Haemophilus influenzae type B meningitis among children in Hanoi, Viet Nam: epidemiologic patterns Viet Nam and estimates of H. Influenzae type B disease burden. The Hib American Journal of Tropical Medicine and Hygiene, 2006, 74(3):509–515.

Tran TT et al. The etiology of bacterial pneumonia and Viet Nam meningitis in Vietnam. The Pediatric Infectious Disease Spn Journal, 1998, 17(Suppl. 9):S192–S194.

Tran TT et al. [Role of Haemophilus influenzae b and pneumococcus in bacterial meningitis in Viet Nam (1995– Viet Nam Hib 1997)]. Archives de pédiatrie : organe officiel de la Sociéte Française de Pédiatrie, 2004, 11(4):373–374.

* Publication of this contribution is not intended to signify any attribution to “Taiwan” other than as a Province of China and to “Hong Kong” other than as a Special Administrative Region of China. Therefore, references to “Taiwan” and to “Hong Kong” in this publication, including in the bibliography, should be interpreted respectively as “China (Province of Taiwan)” and “Hong Kong, Special Administrative Region”.

176 Global literature review of Hib and Spn invasive disease among children less than five years of age, 1980–2005 WHO/IVB/09.02 177 The World Health Organization has provided The Quality, Safety and Standards team technical support to its Member States in the focuses on supporting the use of vaccines, field of vaccine-preventable diseases since other biological products and immunization- 1975. The office carrying out this function related equipment that meet current inter- at WHO headquarters is the Department of national norms and standards of quality Immunization, Vaccines and Biologicals (IVB). and safety. Activities cover: i ) setting norms and standards and establishing reference IVB’s mission is the achievement of a world preparation materials; ii ) ensuring the use of in which all people at risk are protected quality vaccines and immunization equipment against vaccine-preventable diseases. through prequalification activities and The Department covers a range of activities strengthening national regulatory authorities; including research and development, and iii ) monitoring, assessing and responding standard-setting, vaccine regulation and to immunization safety issues of global quality, vaccine supply and immunization concern. financing, and immunization system strengthening. The Expanded Programme on Immunization focuses on maximizing access to high These activities are carried out by three quality immunization services, accelerating technical units: the Initiative for Vaccine disease control and linking to other health Research; the Quality, Safety and Standards interventions that can be delivered during team; and the Expanded Programme on immunization contacts. Activities cover: Immunization. i ) immunization systems strengthening, including expansion of immunization services The Initiative for Vaccine Research guides, beyond the infant age group; ii ) accelerated facilitates and provides a vision for worldwide control of measles and maternal and vaccine and immunization technology neonatal tetanus; iii ) introduction of new and research and development efforts. It focuses underutilized vaccines; iv ) vaccine supply on current and emerging diseases of global and immunization financing; and v ) disease public health importance, including pandemic surveillance and immunization coverage influenza. Its main activities cover: i ) research monitoring for tracking global progress. and development of key candidate vaccines; ii ) implementation research to promote The Director’s Office directs the work of evidence-based decision-making on the these units through oversight of immunization early introduction of new vaccines; and iii ) programme policy, planning, coordination and promotion of the development, evaluation management. It also mobilizes resources and and future availability of HIV, tuberculosis carries out communication, advocacy and and malaria vaccines. media-related work.

Department of Immunization, Vaccines and Biologicals Family and Community Health

World Health Organization 20, Avenue Appia CH-1211 Geneva 27 Switzerland E-mail: [email protected] Web site: http://www.who.int/immunization/en/