Public Health Laboratories for Alert and Response A WHO Guidance Document
WHO Library Cataloguing in Publication Data Public health laboratories for alert and response: a WHO guidance document 1. Laboratories - standards. 2. Public health. 3. Disease outbreaks. 4. Quality control. I. World Health Organization Regional Office for the Western Pacific. ISBN 978 92 9061 586 6 (NLM Classification: WA 23) World Health Organization 2012 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; e-mail: bookorders@who.int). 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; e-mail: permissions@who.int). For WHO Western Pacific Regional Publications, request for permission to reproduce should be addressed to the Publications Office, World Health Organization, Regional Office for the Western Pacific, P.O. Box 2932, 1000, Manila, Philippines, (fax: +632 521 1036, e-mail: publications@wpro.who.int). 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.
A WHO Guidance Document Contents Acknowledgements.... iv Abbreviations.... v 1. Introduction.... 1 2. Public health laboratory system... 3 2.1 Core functions of public health laboratories... 6 2.1.1 Support public health surveillance.... 6 2.1.2 Support outbreak response.... 8 2.1.3 Act as a national resource and coordinating centre.... 9 3. Factors to consider when establishing public health laboratories... 11 3.1 Syndromic approach to laboratory testing.... 11 3.2 Diagnostic capability... 11 3.3 Staffing... 13 3.4 Physical structure, equipment and supplies.... 13 3.5 Biosafety.... 13 3.6 Laboratory information management system.... 14 4. Quality assurance..................................................15 4.1 External quality assessment.... 15 4.2 Quality control........................................ 16 4.3 International quality standards.... 17 References.... 18 iii
Public Health Laboratories for Alert and Response Acknowledgements The authors would like to acknowledge the following experts for their contributions to the preparation of this guidance document: Dr Chua Kaw Bing, Temasek Life Sciences Laboratory, Singapore; Dr Abdul Rasid Kasri, Ministry of Health, Malaysia; Ms Supawat Krongkaew, National Institute of Health, Thailand; Dr Raymond Lin, Ministry of Health, Singapore; Dr Yoshitsugu Miyazaki, National Institute of Infectious Diseases, Japan; and Dr Feng Zijian, Centers for Disease Control, China. iv
A WHO Guidance Document Abbreviations AMR APSED EID EQA HFMD IHR ISO JE NIID NIH PCR WHO antimicrobial resistance Asia Pacific Strategy for Emerging Diseases emerging infectious disease external quality assurance hand, foot and mouth disease International Health Regulations International Organization for Standardization Japanese encephalitis National Institute of Infectious Diseases National Institute of Health polymerase chain reaction World Health Organization v
1 Introduction Emerging infectious diseases (EIDs), including diseases caused by antimicrobial-resistant pathogens, can potentially cause regional and global outbreaks. The International Health Regulations, also known as IHR (2005), provide the legal framework for collective action by WHO and Member States to prepare for and respond to EIDs that may cross borders and pose threats to health security. 1 To ensure early recognition of EIDs, and to minimize their impact on health, society and economies, WHO and its Member States are strengthening national and regional capacity to rapidly and accurately identify causative pathogens. Reliable and timely laboratory diagnosis is a crucial component of such capacity. The Asia Pacific Strategy for Emerging Diseases (APSED) was launched in 2005 as a common strategic framework for countries and areas in the 1
Public Health Laboratories for Alert and Response Western Pacific and South-East Asian Regions to strengthen their capacity to manage and respond to emerging disease threats, and to meet the core capacity requirements under IHR (2005). The updated strategy, APSED (2010), consists of eight focus areas to assist Member States in the region to develop and implement core capacities. 2 Focus area two of this strategy is laboratory strengthening, which strongly contributes to other core capacities such as surveillance, risk assessment and outbreak response (Figure 1). The purpose of this guidance document is to assist Member States in establishing a public health diagnostic laboratory network to support surveillance activities and enhance rapid detection and response to EID outbreaks. This document describes the public health laboratory system, its core functions, and factors to consider when establishing such a system. Figure 1: The relationship between surveillance, risk assessment and outbreak response for emerging infectious diseases Event-based Surveillance Clusters of disease Rumors of unexplained deaths Time frame for reporting: Immediate Indicator-based Surveillance Sentinel and laboratory-based Time frame for reporting: Weekly or monthly Risk Assessment Response National and subnational capacities to respond to alerts 2
A WHO Guidance Document 2 Public health laboratory system Health laboratory services, which have been detailed in the Asia Pacific Strategy for Strengthening Health Laboratory Services (2012 2015), 3 are instrumental to health systems. Public health laboratories play an important role in providing these services. A public health laboratory is broadly defined as a government laboratory funded by public money that performs activities related to protection, support and promotion of health-related matters. Public health laboratories can be classified into three categories: 1. diagnostic laboratories, including: a. hospital-based laboratories, and b. community-based laboratories; 2. reference laboratories; and 3. research laboratories. 3
Public Health Laboratories for Alert and Response Non-public health diagnostic laboratories are referred to as clinical laboratories in this document. An integrated public health laboratory system, which includes a network of all three categories of laboratories (diagnostic, reference and research), aims to improve laboratory capacity and efficiency to support surveillance and outbreak response. It also serves to harmonize the different laboratories in order to enhance and complement their individual roles. Public health diagnostic laboratories are at the base of an integrated public health laboratory system (Figure 2). 4 They are close to the point of patient care and serve as the first line of support for epidemiological surveillance and response, including the confirmation of known diseases and the recognition of novel or (re-)emerging diseases. Just as in clinical practice, where the general practitioner is the first point of contact for patients before referral to specialists, the diagnostic laboratory is the point of entry for a specimen before being sent to a pathogen-specific laboratory. Public health diagnostic laboratories should be able to identify a range of pathogens commonly associated with a clinical condition, using readily available reagents and methods. Difficult or unusual cases, as well as cases with negative results, may then be referred to a reference laboratory for more specialized investigations (Figure 2). The establishment of an in-country public health laboratory system is important for an effective and rapid response to new infections with epidemic or pandemic potential. The integrated system will include reference laboratories that are able to identify pathogens of public health significance. 4
A WHO Guidance Document Figure 2: Schematic representation of an integrated public health laboratory system in Country X Reference Laboratory International Not characterized EQA programmes Country X Not characterized Reference Laboratory Reference Laboratory National level EQA programmes Biosafety PHDL PHDL PHDL Sub-national level Notes: Public health diagnostic laboratories (indicated as PHDL) are at the base (subnational level) of the network. Specimens are sent to reference laboratories at the national level and, if necessary, to a reference laboratory outside the country. External quality assessment (EQA) programmes provided by national and international reference laboratories assure the quality of diagnostic tests conducted at the subnational and national levels, respectively. 5
Public Health Laboratories for Alert and Response Laboratories in a functional network communicate with each other, with epidemiology departments and with higher authorities, e.g. government or relevant ministries. The aim of the network is to provide advice and share expertise to strengthen national and regional capacity for surveillance and timely response. The approach used to establish a national public health laboratory network depends very much on a country s structure, size, demography, financial resources, availability of human expertise and technological resources. For a country with a small population size, the national public health diagnostic laboratory could merge with one of the clinical laboratories for optimal function and sustainability. 2.1 Core functions of public health laboratories The sections below explain the following core functions of public health laboratories: 1. support public health surveillance; 2. support outbreak response; and 3. act as a national resource and coordinating centre. 2.1.1 Support public health surveillance Public health diagnostic laboratories support surveillance by monitoring the presence of pathogens and disease trends. They are responsible for providing guidance related to collecting appropriate patient specimens, selecting and performing diagnostic tests, further typing of agents such as antimicrobial resistance (AMR), and, in case the causative agent cannot be characterized on site, referral of the specimens to reference laboratories (Figure 2). 6
A WHO Guidance Document Case study 1: Laboratory networks in Japan during an outbreak response A major outbreak of febrile encephalitis affecting pigs and humans in peninsular Malaysia in 1998 1999 resulted in the death of 105 humans and the eventual culling of about 1.1 million pigs. The outbreak, which initially affected pig farm workers, Before was officially pandemic reported influenza September A(H1N1) cases 1998, were in the detected suburb in of Japan, Ipoh, the National capital Institute city of Perak of Infectious state, situated Diseases in the (NIID) north-western and subnational part of (regional) peninsular laboratories were Malaysia. trained From on this the epicentre, use of polymerase the outbreak chain spread reaction to other (PCR) parts for detection of peninsular of pandemic Malaysia influenza and reached A(H1N1) Singapore strains. by NIID March supported 1999. As the soon subnational as the outbreak laboratories was with the recognized provision in late of 1998, a detection the Ministry package, of Health consisting of Malaysia of the protocols, carried out primers various and enzymes measures specific to control for pandemic a JE epidemic, influenza but A(H1N1). they failed The to control subnational the disease. laboratories The tested all discovery clinical of Nipah samples, virus but as the only causative specimens agent with of positive the outbreak or ambiguous in mid-march results 1999 were sent was a significant to NIID for turning confirmatory point testing. instituting Thanks the to correct this subnational control measures laboratory and network, terminating specimens the outbreak. were tested As a close lesson to learnt, the front-line Malaysia and now the undertakes surveillance laboratory system was testing updated using clinical without symptoms delay. With and surge epidemiological capacity of findings human resources rather than across the country, following the the burden previous on NIID practice has been of disease-specific reduced. use of diagnostics. 5 7
Public Health Laboratories for Alert and Response National reference laboratories are encouraged to train and build capacity at the subnational level to build surge capacity in case of a disease outbreak. They need to ensure that laboratory standards, including biosafety, are maintained at the subnational level. EQA programmes for diagnosis of EIDs, organized by the national laboratories, need to be conducted to ensure accurate and reliable diagnosis. 2.1.2 Support outbreak response In the event of an outbreak of EID, public health diagnostic laboratories will play a crucial role in supporting hospital-based clinical laboratories with the timely identification of the causative agent to ensure the rapid institution of appropriate control measures. Following the detection of the causative pathogen of an outbreak, the public health diagnostic laboratory should refer the pathogen to national or regional reference laboratories for confirmation or identification, or for further characterization. In the event of an outbreak of EID due to a novel pathogen, a system needs to be in place to enable the timely characterization of the pathogen for appropriate response. This referral system will be based on the existing surveillance system but will use standard operating procedures for rapid referral of specimens, will prioritize outbreak specimens for testing and will ensure round-the-clock availability of staff. Such a system should also include a mechanism for surge capacity to scale up diagnostic support. For any disease outbreak, known pathogens are always present along with the causative agent of the outbreak. Thus, epidemiological information, clinical features as well as pathological findings need to be correlated with laboratory findings in order to build enough evidence for the final 8
A WHO Guidance Document diagnosis of the causative pathogen. Therefore, as in the case of public health surveillance work, clinicians, epidemiologists, clinical laboratories and public health diagnostic laboratories have to work together to ensure early detection and response to EID threats. 2.1.3 Act as a national resource and coordinating centre An integrated public health laboratory system requires well-structured organization, strong leadership and streamlined coordination to function optimally and sustainably. The national public health laboratory or national public reference laboratory can act as the country s resource and coordinating centre for all laboratory-related matters. It can act as a resource pool for the country s laboratory expertise and maintain close links with public health experts in country as well as with regional and international reference systems. The national public health laboratory should support the development and implementation of national laboratory policy, establish and coordinate a functional national laboratory quality system, provide training in diagnostic techniques and biosafety procedures, and monitor AMR, where applicable. 9
Public Health Laboratories for Alert and Response Case study 2: The Thai National Institute of Health and support of subnational public health laboratories in Thailand The National Institute of Health (NIH) is the national public health reference laboratory of Thailand. It supports 14 regional medical science centres with subnational public health laboratories. During outbreak situations, NIH participates in the national emergency operation centre organized by the Department of Disease Control, Ministry of Public Health. For laboratory issues, NIH organizes videoconferences with subnational laboratories to discuss how to support epidemiological surveillance and outbreak response. NIH organizes training workshops and refresher courses for staff of the subnational laboratories and provides support in terms of guidelines, standard operating procedures, reagents, quality control samples, and transport media for influenza A(H1N1)pdm09, EHEC O 104, and hand, foot and mouth disease (HFMD). Molecular techniques for all pathogens were transferred to subnational laboratories. Previously, samples that tested positive by PCR were transferred to NIH for confirmation, isolation and typing, but these techniques are now available at subnational laboratories. All laboratory results are sent to NIH for collation and analysis, and policy-makers are informed on a daily basis. Between outbreaks, NIH conducts nationwide proficiency testing to ensure laboratories maintain competency in testing methods. 10
3 Factors to consider when establishing public health laboratories 3.1 Syndromic approach to laboratory testing Generally, public health laboratories focus on specific agents, such as Japanese encephalitis (JE) or influenza, rather than on clinical presentation, such as encephalitis or pneumonia. To enhance detection and identification of diseases that cause outbreaks, a system must be built to identify a full range of pathogens based on clinical presentation and epidemiological findings. 3.2 Diagnostic capability Each laboratory performs only a certain number of diagnostic tests. Each type of diagnostic test has its advantages and disadvantages in terms of cost, technological sophistication, sensitivity and specificity, as well as result interpretation. Laboratory tests should be carefully selected to help public health specialists make the correct diagnosis. 11
Public Health Laboratories for Alert and Response Case study 3: A lesson from Malaysia A major outbreak of febrile encephalitis affecting pigs and humans in peninsular Malaysia in 1998 1999 resulted in the death of 105 humans and the eventual culling of about 1.1 million pigs. The outbreak, which initially affected pig farm workers, was officially reported in September 1998, in the suburb of Ipoh, the capital city of Perak state, situated in the north-western part of peninsular Malaysia. From this epicentre, the outbreak spread to other parts of peninsular Malaysia and reached Singapore by March 1999. As soon as the outbreak was recognized in late 1998, the Ministry of Health of Malaysia carried out various measures to control a JE epidemic, but they failed to control the disease. The discovery of Nipah virus as the causative agent of the outbreak in mid-march 1999 was a significant turning point in instituting the correct control measures and terminating the outbreak. As a lesson learnt, Malaysia now undertakes laboratory testing using clinical symptoms and epidemiological findings rather than following the previous practice of disease-specific use of diagnostics. 5 12
A WHO Guidance Document With the increasing concern for AMR, laboratory-based surveillance for AMR is becoming more important. There is a need for laboratories that can detect the presence of resistance, as well as reference facilities able to identify important new resistance genes. AMR surveillance data may be used to inform clinical management, educate medical practitioners about antibiotic prescribing practices and monitor the effectiveness of infection control activities. 3.3 Staffing Laboratories need staff who possess the necessary technical skills to deliver an effective quality of service. A comprehensive programme should be developed at the country level to assess training needs and provide training. Staff training should cover new technologies along with upgrading known methods. 3.4 Physical structure, equipment and supplies The national coordinating centre should ensure that laboratories are built according to standards required for their function, and that they incorporate appropriate biosafety measures. 3.5 Biosafety Staff who work with infectious microbiological agents are at risk of laboratory-acquired infection and of accidentally spreading infectious material to the public. Hence, laboratory staff need to be aware of potential hazards and should be trained in the safe handling of such 13
Public Health Laboratories for Alert and Response materials. Biosafety involves good staff training, the availability of standard operating procedures, staff competence in risk management, appropriate containment equipment, proper facility design, correct operation and maintenance, and administrative considerations to minimize the risk of worker injury or illness or environmental contamination. 6 Biosafety practices must be engaged at every step from sample collection, transportation, processing and testing, to storage and waste management. Errors in any one part of the chain will result in risks to biosafety. Biosafety requires appropriate physical infrastructure, including engineering controls and equipment maintenance. 3.6 Laboratory information management system A laboratory information management system would enhance alert and response as it allows for the capture, analysis and storage of laboratory surveillance data, and ensures timely sharing of relevant data with those who need to be informed for public health action. The system may be electronic, allowing for real-time communication with hospitals and epidemiology units, or it may be paper-based but with provisions, allowing for the timely alerting of relevant parties involved in follow-up control action. 14
4 Quality assurance Laboratory quality assurance is the process whereby the quality of laboratory reports can be guaranteed. Laboratory quality assurance is a combination of quality control and internal and external quality assessment. Quality control covers the analytical part of quality assurance. Recent documents describe the main requirements and the implementation of laboratory quality standards. 7,8 The sections below describe EQA, quality control and quality standards in more detail. 4.1 External quality assessment EQA is the assessment of the quality of laboratory performance by comparing test results between laboratories. Oftentimes, several laboratories are provided with identical sets of coded samples and controls (or proficiency test panel) that have been prepared by a reference laboratory. Once the tests have been completed the laboratories send the results to the reference laboratory to determine the accuracy of the 15
Public Health Laboratories for Alert and Response individual laboratories. Examples of diseases for which EQA programmes exist are influenza, measles, tuberculosis and polio. EQA can be conducted at an international level, but it may be difficult for some countries to participate because such programmes can be expensive and shipments may encounter customs delays. As an alternative, national reference laboratories can organize in-country EQA programmes. Many pathogens, due to their unusual nature or occurrence in only developing countries, do not have corresponding EQA programmes. Therefore, other avenues need to be explored to assess quality, such as inter-laboratory exchange of clinical specimens or control materials such as isolates, DNA or positive specimens. 4.2 Quality control Quality control aims to verify test results and to reduce errors in the performance of tests to a minimum. It covers all aspects of microbiological testing, including reagents, equipment and procedures, related to, for example, preparation of culture media or AMR testing. Reagents must be clearly labelled, stored, and used before their expiry date. Equipment must undergo regular cleaning, servicing and maintenance in order to remain in good working order. Establishing and following standard operating procedures are important to ensuring quality control. 16
A WHO Guidance Document 4.3 International quality standards The International Organization for Standardization (ISO) has developed standards for quality management of medical laboratories (ISO 15189) and measurement laboratories (ISO 17025). Public health laboratories should strive to be in compliance with these standards. 17
Public Health Laboratories for Alert and Response References 1. International Health Regulations (2005), Second Edition. Geneva, WHO, 2008. 2. Asia Pacific Strategy for Emerging Diseases (2010). WHO Regional Offices for South-East Asia and the Western Pacific, 2010. 3. Asia Pacific Strategy for Strengthening Health Laboratory Services (2010 2015). WHO Regional Offices for South-East Asia and the Western Pacific, 2010. 4. Informal Consultation on a Draft Asia Pacific Laboratory Action Plan (2011 2015) for Emerging Infectious Diseases, Manila, Philippines, 19 20 May 2011. 5. Syndromic Notifications and Laboratory Investigation Manual. Kuala Lumpur, Ministry of Health Malaysia, 2007. 6. Laboratory Biosafety Manual, Third Edition. Geneva, WHO, 2004. 7. Laboratory Quality Standards and their Implementation. WHO Regional Offices for South-East Asia and the Western Pacific, 2011. 8. Laboratory Quality Management System Handbook. Geneva, WHO, 2011. 18
WHO Western Pacific Region PUBLICATION ISBN-13 978 92 9061 586 6