REPORT FOR WHO-COORDINATED IBVPD SURVEILLANCE NETWORK,

LABORATORY TECHNICAL WORKING GROUP MEETING

EXECUTIVE SUMMARY MEETING REPORT

WHO-Coordinated IBVPD Surveillance Network

Laboratory Technical Working Group Meeting

29th-30th October 2014

Geneva, Switzerland

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CONTENTS

Background ................................................................................................................................................... 3

Objectives ..................................................................................................................................................... 3

Background documents in participant file .................................................................................................. 4

Meeting summary ........................................................................................................................................ 4

Network overview and regional updates ......................................................................................... 4 Improving data quality of the IBVPD laboratory network ............................................................... 5

Quality Assurance and Quality Control ............................................................................................ 6

Optimization of laboratory procedures in the network .................................................................. 7

Annex 1: Meeting agenda ............................................................................................................................ 9

Annex 2: List of participants ...................................................................................................................... 12

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BACKGROUND

In 2011 the WHO established a laboratory Technical Working Group (TWG) to provide technical

guidance throughout the WHO-Coordinated Global Invasive Bacterial Vaccine Preventable Disease (IB-

VPD) Network, for strengthening the laboratory capacities related to the identification and

serotyping/serogrouping of Streptococcus pneumoniae (Spn), Haemophilus influenzae (HI) and Neisseria

meningitidis (Nm) and the improvement of the quality of laboratory data collected through the

surveillance network.

In 2013, a Strategic Review of the IB-VPD network was carried out and the findings were presented at a

meeting in Geneva and the resulting recommendations from the review to strengthen the IB-VPD

surveillance network and the strategic plan from this review was endorsed by the Strategic Advisory

Group of Experts on Immunization Epidemiology (SAGE EPI) technical oversight body.

The laboratory TWG was convened in October 2014 to assess the status of the implementation of the

Strategic Review recommendations, to gain a better understanding of regional and specific lab related

issues, to provide guidance on how to improve the data quality of the IB-VPD laboratory network by

development of a strategy for more standard reporting from regional and national reference

laboratories performing PCR testing and the data linkage between clinical and laboratory data. The

group also discussed how to better optimize the laboratory procedures in the network and strengthen

the Quality Assurance (QA) and Quality Control (QC) systems.

Some of the key achievements from 2013 – 2014 include the implementation of Performance Measures

at all levels. In the area of monitoring laboratory performance, achievements include a continued

external quality assessment (EQA) global programme and implementation of global external quality

control QC system between the Global and regional reference labs (RRLs). Regions have started the

transition to case-based reporting of RRLs data and linkages between these data and the sentinel site (SS)

data have improved.

MEETING OBJECTIVES

To review the regional updates for the status of the recommendations from the strategic review,

the flow of samples and information, the monitoring of lab performances and the site

assessments.

To review any 2013 data quality issues and ways to improve laboratory data. These include the

use of standard RRL reporting forms, introduction to the web-based tool and addressing data

quality issues at the sentinel site level for missing information and availability of reagents.

To review the External Quality Assessment (EQA) and Quality Control (QC) programmes and to

define the way forward.

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Optimisation of lab procedures, addressing the challenges of bacteriology capacities at the site

level and the molecular testing capacities of the regional laboratories.

BACKGROUND DOCUMENTS IN PARTICIPANT FILE

October 2014 update on status of action points of the 2014 WHO Management Framework

Reference laboratory process and performance metrics

Draft IBD Lab Variables ST/SG for the Regional Reference Labs

List of participants

Meeting agenda

MEETING SUMMARY

I. Network overview and regional updates

The meeting began with a global overview of the network and the global status of the implementation

of the strategic review recommendations.

Overall there has been a lot of progress with completion of 26 out of 30 iTAG recommendations that

were to be implemented by the first year.

The objective of the network has changed from documenting and measuring diseases to monitoring

vaccine impact, providing a good baseline before vaccine introduction in countries. An important

component of this process is sharing case base data and the linking of laboratory and clinical data. The

main achievements that were highlighted in the global and regional updates included:

Progress and transition to case based reporting; case-based 2013 data was received from 6 out

of 9 RRLs and one sentinel site laboratory

Continued monitoring of laboratory performance at all levels of the laboratory network and

distribution of External Quality Assessment (EQA) proficiency testing panels globally

Implementation of a global quality control programme for confirmatory testing between the

global and regional reference labs

Improved referral systems between sentinel sites laboratories (SSLs) and the RRLs for either

confirmatory testing or PCR for diagnosis and serotyping/serogrouping (ST/SG)

Development of a new web based tool to improve data collection and bridge linkages between

data collected at all levels of the surveillance network.

Some of the current challenges that need additional resources and capacity building activities are in the

areas of sample referral and testing, such as specimen storage, testing capacities at RRL, shipping

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logistics, regulations (Material Transfer Agreement (MTA), Import permit), site visits and trainings, the

data management system and low rates of bacterial isolation at country level.

There is still a need to improve linkage between data for all laboratory testing done at SSL and RRL levels

and the clinical database. The use of a unique patient ID number when samples are referred for lab

testing is still a challenge.

II. Improving data quality of the IBVPD laboratory network

An overview of the RRL 2013 data consolidation and analysis processes showed that huge efforts have

been made to improve the quality of laboratory data collected through the surveillance network. 3144

samples from Meningitis Surveillance were received and tested at the RRLs in 2013. Of these 1003 (32%)

were positives for one of the three pathogens (Spn, HI or Nm). ST/SG data could be assigned to 833

(83%) of positive cases. PCR data from RRL shows an important increase in diagnostic yield of bacterial

meningitis. This highlighted the importance of developing a strategy to prioritize retrospective linkages

between RRL and SS data.

Linking of the RRL data with clinical database from sentinel sites could be done on samples that were

reported in the RRL databases with a unique ID number; these represented around 30% of 2013 data

reported from RRLs.

One of the challenges that were addressed is the quality and categorization of the samples that are

referred to the RRL. Information to categorize the samples into the Probable Bacterial Meningitis1 (PBM)

cases (WBC, glucose and protein) and results of initial laboratory testing (culture, Gram stain and Rapid

diagnostic tests (RDT)) are often missing. WHO reinforces its recommendation that SSL send ALL

suspected meningitis cases to the RRL till more data can be linked and more analysis can be done to

assess the use of prioritization algorithm for samples referral.

The group emphasized the importance of linkage between data quality and availability /use of the

necessary quality controlled laboratory reagents, supplies and equipment at the sentinel site level (use

of sheep blood for culture, TI media for cerebrospinal fluid (CSF) transport, RDT kits to provide quick

feedbacks to clinicians, availability of incubators and freezers etc.).

There have been improved linkages between RRL and clinical databases for the 2013 data with 6 out of 9

having reported case-based data. However there are still challenges in the data management system

such as the inconsistent use of the unique ID number or missing information on lab testing performed at

the sentinel site level. These limit the data analysis and comparison between sentinel site lab testing

results and RRL results.

1 Definition of PBM: A suspected meningitis case (as defined above) with 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) Note: if protein and glucose results are not available, diagnose using the first two conditions (i.e. turbid appearance or leukocytosis > 100 cells/mm

3)

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WHO has started the development of a web based system to bridge the gap between laboratory and

epidemiological data and improve surveillance data. The system is being pilot tested in PAHO and SEARO

and more regions showed interest in pilot testing it. This would improve the data check, cleaning,

analysis and feedback mechanisms throughout the year.

The standard form for reporting PCR data from reference laboratories and sentinel sites performing PCR

was reviewed and the group recommended WHO to revise and distribute the form to all labs reporting

PCR by end of 2014.

Recommendations to improve laboratory data quality are:

Caution in reporting the non-typeable (NT) and non-groupable; distinction between real NT and

NT because of methods limitations

Standard use of the drop down options that are listed in the reporting form; Include comments

whenever it is necessary to explain the final result

RRLs to receive lab testing results from referring sentinel sites for a better tackling of

discrepancies and improved feedbacks mechanisms

Active data analysis and feedback mechanisms throughout the year

The web based tool to be pilot tested at RRL in coordination with ROs that are interested in

implementing the system

Data consolidation at regional level before submission to WHO HQ

III. Quality assurance and quality control

1. EQA

In 2014, WHO coordinated the global External Quality Assessment (EQA) programme in coordination

with the National EQA Unit at the Public Health England (PHE). The EQA for IBVPD provides proficiency

testing panels to assess diagnostic capabilities at sentinel site level to identify Spn, HI and Nm (Culture,

Microscopy and RDT). AMST was included in the testing but did not count into the overall scoring as

WHO does not provide technical support for these tests. Serotyping/serogrouping capacities are

assessed for labs that have the capacities to do it. Preliminary 2014 results from sentinel sites and RRLs

showed a high level of performance in the labs that submitted results. Data summary is as follows:

o 109 labs were included in participant list received from ROs o 90 labs did submit results o 83 had passing score of >75% o 7 labs failed the EQA exercise o 19 labs did not submit results

The RRLs received more challenging proficiency testing (PT) panels and were assessed on the methods

for genotypic characterization. All except one RRL had >90% passing score. One RRL had 82% score.

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Challenges of 2014 EQA survey included holding back by customs of the infectious diseases PT panels

and delays in panels deliveries to the labs which resulted in postponing the closing date of the survey

and delays in data analysis and feedbacks.

Recommendations to improve the EQA in 2015:

WHO to continue the EQA to monitor lab performance globally

WHO to avoid contracting with different suppliers every year to decrease challenges and build

capacities consistently

Timelines to be set up and agreed upon in January-February 2015 and quicker turnover of the

process so corrective actions can be implemented quickly

Next EQA survey to be ready by May 2015; WHO to provide updated and correct information on

participant labs 2 months in advance to the survey

2. QC for confirmatory testing between RRL and GRL

Preliminary results of the first year of implementing global external QC programme for confirmatory

between the RRLs and CDC Global Reference Lab (GRL) showed a high level of concordance

identification and ST/SG of Spn, HI and Nm by PCR. Data of 6/9 RRLs were summarized and discussion on

general concordance and typical discrepant results were addressed. The average of concordance

between the RRL and CDC GRL results was 91% for pathogen detection and 93% for ST/SG, which

indicated a very high performance of the RRLs. Some of the common reasons for the discrepancies seen

could be transcriptional errors, differing sample conditions, differences in interpretation of PCR results (

as in the lack of standardized Cycle Threshold (CT) cut-off values for the target genes or use of the

human RNaseP gene in the interpretive scheme), and unequivocal starting volume of extraction.

Recommendations on QC for confirmatory testing:

The QC is an useful exercise for RRLs and GRL so WHO to continue its monitoring in 2015

RRLs to continue sending 50 specimens to GRL and additional difficult samples can be sent but

will not be included in the scoring

Discrepant results will be discussed, followed by troubleshooting and a third lab will test this if

no consensus is reached (Refer to WHO guidelines developed in 2013)

The timing of the QC worked well but development of timeline table from CDC GRL for 2015 is

needed and that will be distributed to RRLs through WHO and ROs.

IV. Optimizing the use of laboratory procedures in the network

The TWG addressed the availability and use of WHO recommended laboratory procedures at all levels

and reinforced the need of building bacteriology capacity based on the findings from the site

assessments and efforts to improve bacterial isolation rates at the sentinel site level. Regions provided

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inputs on their procurement system and challenges are mainly noticed in AFR and EUR for procuring lab

supplies and ensuring their availability at the country level in a timely manner.

CDC GRL presented a new direct PCR procedure without DNA extractions on CSF for the detection of

bacterial meningitis pathogens plus RNaseP and ST/SG of Hib, NmA, B, C, W, X and Y. The group

emphasized the added value of the implementation of this new technique for surveillance purposes,

especially in labs that receive large volume of samples as the traditional PCR and DNA extraction are

time consuming and requires extensive manipulation that can introduce cross-contamination..

The optimization of reporting PCR data was also discussed and the CT cut-off values to report the PCR

results for target genes as well as RNaseP human genes were determined by the group.

Recommendations for optimal use of lab procedures in the network:

The Direct PCR to be validated in RRLs that are interested in using it for surveillance

The cut off point for the CT values used for target genes should be adopted as below 35 being

positive and above 35 being negative (equivocal between 36-40 to be diluted when possible).

For RNaseP standardization, first test for pathogens target genes as a priority. If this is negative

(>35) then test for RNaseP and if RNaseP>35 then report it as inconclusive; the cut off is 35.

A list of lab equipment/ supplies for sentinel sites and RL, including estimated quantities needed

by year, to be compiled in consultation with ROs for submission into the WHO catalogue.

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ANNEX1: MEETING AGENDA

Meeting for WHO-Coordinated IBVPD Surveillance Network Laboratory Technical Working Group

October 29-30, 2014

Wednesday 29 October 2014 Chair: Dr. Anne Von Gottberg Rapporteur: Sapna Manglani

Session I. Network overview and regional updates 9:00-10:30

1. Welcome and Introductions 2. Network overview and Global status of implementation of

strategic review recommendations 3. Meeting objectives and expected outcomes 4. Regional Updates to include: (20 Min per presentation)

o Network overview with data flow and referral of samples between different lab levels

o Status of implementing the strategic review recommendations

o Monitoring of labs performance, regional activities to improve lab performance and quality assurance systems

o site assessments and main findings associated to it o Procurement of lab supplies

AFR

AMR

M. Agocs /F.

Serhan

ROs lab

coordinators /RRLs

10:30-11:00 COFFEE BREAK

11:00-12:30 Regional Updates on status of strategic review recommendations 5. EMR 6. EUR 7. SEAR 8. WPR

ROs lab coordinators/ RRLs

12:30-14:00 LUNCH

Session II. Improve data quality of IBVPD laboratory network

14:00-16:30

Data quality issues

Overview of RRL data consolidation and analysis

F. Serhan

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process; progress and challenges

RRL process and performance indicators

Linking RRL lab data with clinical data from sentinel sites: use of unique ID number

Discussion:

Linkage between data quality and availability/use of the necessary quality controlled laboratory lab reagents/supplies as well as equipment at sentinel site level (use of sheep blood, TI media, RDT kits, incubators and freezers etc..)

Main recommendations

J. Murray S. Singh Group discussions

15:30-16:00 COFFEE BREAK

16:30-17:30

Introduction to web based system: bridging lab and epi data Discussions: rolling out the web-based system, experience from PAHO and SEARO

D. Jackson N. Noblet

17:30 END DAY 1

Thursday 30 October 2014 Chair: Dr. Mary Slack

Rapporteur: Sapna Manglani Session III. Quality assurance and quality control

9:00-10:30

1. EQA (60 min)

2014 results

Feedbacks from group on 2014 survey

Way forward and how to improve

Corrective actions and main recommendations 2. Quality Control for confirmatory testing (30 min):

Results of confirmatory testing at GRL

C. Walton M. Slack Group discussions M. Ouattara

10:30-11:00 COFFEE BREAK

11:00-12:30 2. Quality Control to be continued (90min)

Discussion and strategy on way forward for global QC programme

Regional QC systems

Main recommendations

Group discussions

12:30-14:00 LUNCH

Session IV. Optimize use of laboratory procedures in the network

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14:00-16:30 a. Availability and use of WHO recommended laboratory procedures at all levels

b. Building bacteriology capacity in country: main challenges seen from site assessments and how to improve weak areas (45 min)

c. New and updated laboratory procedures (45 min)

Direct PCR on CSF

Updated protocols

Discussion on relevance for the network

Recommendations

d. Brief description of WHO Laboratory Manual for identification and serotyping of Spn in carriage studies (10 min)

Coffee break in between

F. Serhan Group discussions S. Schwartz T. Cherian

17:00-17:30 Summary of recommendations and meeting conclusions

17:30 Meeting Closing

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ANNEX 2: LIST OF PARTICIPANTS

REGIONAL REFERENCE LAB PARTICIPANTS Martin Antonio RRL/IBVPD Regional pneumococcal Reference Laboratory Medical Research Council Banjul Gambia E-mail: mantonio@mrc.gm María Cristina Brandileone RRL/IBVPD Instituto Adolfo Lutz Setor de bacterias Piogenicas e Toxigenicas Avenida Doutor Arnaldo, 355 Sao Paolo Brazil E-mail: brandi@ial.sp.gov.br Songmee Bae RRL/IBVPD 187 Osongsaengmyeong2(i)-ro Osong-eup Cheongwon-gun Chungbuk Republic of Korea E-mail: Songmee@hanmail.net Carolina Duarte Valderrama RRL/IBVPD Instituto Nacional de Salud Avenida calle 26 51- 20 Bogota Colombia E-mail: cduarte@ins.gov.co Linda de Gouveia RRL/IBVPD National Institute for Communicable Disease Block no 1 Modderfontein Road Private Bag X4, Sandringham 2132 Johannesburg South Africa E-mail : lindad@ncid.ac.za Janet Strachan RRL/IBVPD Microbiological Diagnostic Unit University of Melbourne Melbourne Australia E-mail : janetes@unimelb.edu.au

Balaji Veeraraghavan RRL/IBVPD Christian Medical College Tamil Nadu Vellore India E-mail : vbalaji@cmcvellore.ac.in Anne Von Gottberg RRL/IBVPD National Institute for Communicable Disease Block no 1 Modderfontein Road Private Bag X4, Sandringham 2132 Johannesburg South Africa E-mail : annev@nicd.ac.za Elena Voropaeva RRL/IBVPD Laboratory of Clinical Microbiology and Biotechnology Gabrichevsky Research Institute for Epidemiology and Microbiology Admiral Makarov Street 10 125212 Moscow Russia E-mail : yegorovaea@gmail.com

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GLOBAL REFERENCE LABORATORY Rana Hajjeh Centers for Disease Control and Prevention Atlanta, GA 30333 USA E-mail: rfh5@cdc.gov Mahamoudou Ouattara Centers for Disease Control and Prevention Atlanta, GA 30333 USA E-mail: xbi0@cdc.gov Stéphanie Schwartz Global Reference Laboratory Centers for Disease Control and Prevention Atlanta, GA 30333 USA E-mail: zqd3@cdc.gov Chris Van Beneden Centers for Disease Control and Prevention Atlanta, GA 30333 USA E-mail: cav7@cdc.gov Xin Wang (Unable to attend) Centers for Disease Control and Prevention Atlanta, GA 30333 USA E-mail: gqe8@cdc.gov

OTHER PARTNERS Dave Jackson Canadian Primary Care Sentinel Surveillance network Alberta, Calgary Canada E-mail: dave@newlevelthinking.com Nathanael Noblet Canadian Primary Care Sentinel Surveillance network Alberta, Calgary Canada E-mail: nathanael@noblet.ca Samir Saha Department of Microbiology Bangladesh Institute of Child Health Dhaka Shishu Hospital Sher-E-Bangla Nagar. City, Dhaka – 1207, Bangladesh E-mail: sksaha@bangla.net Mary Slack Hampden House, Clifton Hampden Abingdon, OX14 3EG Oxfordshrie, United Kingdom E-mail: mpeslack@gmail.com Christine Walton Public Health England Wellington House 133-155 Waterloo Road London , United Kingdom E-mail: Christine.Walton@phe.gov.uk

REGIONAL STAFF AFRO Jason Mwenda WHO Office Regional Office for Africa P.O. Box No. 6 Cite du Djoue Brazzaville, Congo E-mail: mwendaj@who.int AMRO - PAHO Lucia de Oliveira Pan American Health Organization 525 23rd Street, N.W. Washington, DC 20037-2895 USA E-mail: oliveiral@who.int Ana Belen Ibarz Pavon Pan American Health Organization 525 23rd Street, N.W. Washington, DC 20037-2895 USA E-mail: ibarza@paho.org Claudia Ortiz Pan American Health Organization 525 23rd Street, N.W. Washington, DC 20037-2895 USA E-mail: ortizcla@who.int Gloria Rey Pan American Health Organization 525 23rd Street, N.W. Washington, DC 20037-2895 USA E-mail: reyg@who.int Alvaro Whittenbury Pan American Health Organization 525 23rd Street, N.W. Washington, DC 20037-2895 USA E-mail: whittemburya@paho.org EMRO Hinda Ahmed WHO Office for the Eastern Mediterranean Abdul Razzak El Sanhouri Street P.O. Box 7608 Nasr City Cairo 11371, Egypt E-mail: ahmedh@who.int Hossam Ashmony WHO Office for the Eastern Mediterranean Abdul Razzak El Sanhouri Street P.O. Box 7608 Nasr City Cairo 11371, Egypt E-mail: ashmonyh@who.int

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EURO Dovile Videbaek WHO Office for Europe 8, Scherfigsvej Copenhagen Denmark E-mail: videbaekd@who.int Annemarie Wasley WHO Office for Europe 8, Scherfigsvej Copenhagen Denmark E-mail: wasleya@who.int

SEARO Samir Saha Child Health Research Foundation Department of Microbiology Dhaka Shishu Hospital Sher-e-Bangla Nagar Dhaka -1215 Bangladesh E-mail: samirk.sks@gmail.com Pushpa Ranjan Wijesinghe World Health Organization Regional Office for South-East Asia I.P Estate, Ring Road New Delhi India E-mail: wijesinghep@who.int

WPRO Kimberley Fox WHO Office for the Western Pacific United Nations Avenue P.O. Box 2932 1000 Manila Philippines E-mail: foxk@who.int Varja Grabovac WHO Office for the Western Pacific United Nations Avenue P.O. Box 2932 1000 Manila Philippines E-mail: grabovacv@wpro.who.int

WHO HEADQUARTERS STAFF Mary Agocs Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: agocsm@who.int Thomas Cherian Department of Immunization, Vaccines and Biologicals Avenue Appia, 20 1211 Geneva 27 Switzerland, E-mail: cheriant@who.int

Carine Cruz Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: cruzca@who.int Marta Gacic Dobo Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: gacicdobom@who.int Ana Maria Henao Restrepo Department of Immunization, Vaccines and Biologicals Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: henaorestrepoa@who.int Sapna Manglani Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland, E-mail: manglanis@who.int Jillian Muray Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: murrayj@who.int Tomoka Nakamura Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: nakamurat@who.int Fatima Serhan Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: serhanfa@who.int Simar Singh Department of Immunization, Vaccines and Biologicals Expanded Programme on Immunization Avenue Appia, 20 1211 Geneva 27 Switzerland E-mail: singhs@who.int