Background documentation
Given current evidence and consensus, the Stop TB Partnership Laboratory Strengthening Subgroup, partner organizations, laboratory experts and the Strategic and Technical Advisory Group for tuberculosis recently endorsed the following WHO policies:
1. The revision of the definition of a new sputum smear positive pulmonary TB case, based on the presence of at least one acid fast bacillus (AFB) in at least one sputum sample in countries with a well functioning external quality assurance system.
2. The reduction of the number of specimens to be examined for screening of TB cases from three to two in places where workload is very high and human resources are limited. (If both smears are negative, then the algorithm for sputum negative cases applies.)
3. The use of liquid culture and rapid species identification to address the needs for culture and drug susceptibility testing (DST), based on a country specific comprehensive plan for laboratory capacity strengthening. The use of liquid cultures and rapid species identification to be implemented as a step-wise approach.
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The definition of a new sputum smear positive pulmonary TB case [pdf 144kb]
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The reduction of the number of specimens [pdf 144kb]
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Liquid culture background document [pdf 336kb]
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Strategic and Technical Advisory Group for TB (STAG-TB)
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Proposal for a revision of the case definition of "Sputum Smear-Positive Tuberculosis" [pdf 1.99Mb]
Background document prepared by Hans L. Rieder and Armand Van Deun
Definition of a new sputum smear-positive TB case
The revised definition of a new sputum smear-positive pulmonary TB case is based on the presence of at least one acid fast bacilli (AFB+) in at least one sputum sample in countries with a well functioning external quality assurance (EQA) system.
Detailed background information [pdf 144kb]
Proposal for a revision of the case definition of "Sputum Smear-Positive Tuberculosis" [pdf 1.99Mb]
Background document prepared by Hans L. Rieder and Armand Van Deun
As highlighted in the Stop TB Strategy, quality-assured bacteriological examination is an essential element for diagnosis and management of TB patients harbouring susceptible or resistant bacilli. During the last two years, an increasing number of countries are scaling up external quality assurance programmes for smear microscopy by means of blinded re-checking of slides. As a result, the quality of smear microscopy examination reached a satisfactory level in some countries. Evidence suggests that countries with a functional EQA system have very low frequency of false positive cases.
A number of key meetings and workshops were held where the TB case definition was discussed. These meetings included the Stop TB Partnership Laboratory Strengthening Subgroup (SLCS), an expert group meeting organized by the UNION held in Belgium and a technical expert workshop held in the Netherlands. Recent scientific evidence [Ref. 1,2] was reviewed and it was concluded that where a functional EQA for smear microscopy is in place, the finding of a single AFB in at least one single sputum smear examination in a TB suspect would satisfy the criterion to report a patient as having "sputum smear-positive tuberculosis" and to subsequently start treatment.
It should be noted that the definition of bacteriological failures has not been reviewed; hence, no change in definition of failure cases is proposed at this stage.
1. Mase S, Ramsay A, Ng N, Henry M, Hopewell PC, Cunningham J, Urbanczik R, Perkins M, Aziz MA, Pai M. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis 2007;11(5):485-95)
2. Bonnet M, Ramsay A, Gagnidze L, Githui W, Guerin PJ, Varaine F. Reducing the number of sputa examined, and thresholds for positivity: An opportunity to optimize smear microscopy. Accepted for publication, Int J Tuberc Lung Dis
Reduction of number of smears for the diagnosis of pulmonary TB
WHO recommends the number of specimens to be examined for screening of TB cases can be reduced from three to two, in places where a well-functioning external quality assurance (EQA) system exists, where the workload is very high and human resources are limited.
Detailed background information [pdf 144kb]
The WHO Stop TB Strategy and the Global Plan to Stop TB, 2006-2015 recognizes the weakness of the health system as one of the greatest challenges to TB control and indeed to the achievement of the Millenium Development Goals (MDGs) in general. The Global Plan also recognizes that patients, particularly poor patients, face economic barriers in accessing TB control services and that patients with TB in many resource-limited settings face long and sometimes costly pathways to diagnosis. In most of these countries, the laboratory services are often neglected and may be considered to be among the weakest components of the health system.
The challenge is particularly great in sub-Saharan Africa, where the direct and indirect effects of the HIV epidemic exacerbate the human resource crisis and compound the essential but neglected component of adequate TB diagnostic capacity within the health system.
The current international policy on TB case detection recommends the examination of three sputum smears for the diagnosis of pulmonary tuberculosis (PTB). The present definition of a smear-positive case states "Tuberculosis in a patient with at least two initial sputum smear examinations (direct smear microscopy) positive for acid fast bacilli (AFB+)". [Ref. 1,2]
A systematic review of 37 eligible studies that quantified the incremental diagnostic yield of serial sputum specimens was performed by Mase et al and published recently. [Ref. 3] The results clearly demonstrated that the vast majority of TB cases (on average 85.8%) was detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%. [Ref. 3]
In a recent study conducted in Kenya, Bonnet et al. demonstrated that decreasing the number of smears examined for the detection of new pulmonary TB cases lead to a reduction of patient's visits to a clinic and the laboratory workload. Examining only two smears could therefore alleviate the workload of laboratories - particularly in countries with a high microscopy workload - by one third. [Ref. 4]
It is expected that microscopic analysis of two sputum smear samples will improve case findings through enhanced quality of service, decreased time for diagnosis and initiation of treatment and decreased number of patients dropping out of the diagnostic pathway.
However, the reduction of the number of specimens examined for screening TB patients from three to two specimens should only be recommended in settings with a well-established laboratory network, a fully functional EQA programme for smear microscopy including on-site evaluation with the feed-back mechanism and where the workload is very high and human resources are limited. [Ref. 5]
1. World Health Organization. Framework for effective tuberculosis control. World Health Organization Document 1994; WHO/TB/94.179:1-7.
2. World Health Organization, International Union Against Tuberculosis and Lung Disease, Royal Netherlands Tuberculosis Association. Revised international definitions in tuberculosis control. Int J Tuberc Lung Dis 2001;5:213-5.
3.Mase S, Ramsay A, Ng N, Henry M, Hopewell PC, Cunningham J, Urbanczik R, Perkins M, Aziz MA, Pai M. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis 2007;11(5):485-95.
4. Bonnet M, Ramsay A, Gagnidze L, Githui W, Guerin PJ, Varaine F. Reducing the number of sputa examined, and thresholds for positivity: An opportunity to optimize smear microscopy. Accepted for publication, Int J Tuberc Lung Dis.
5. External quality assessment for AFB smear microscopy [pdf 631kb]
The use of liquid medium for culture and DST
WHO recommends, as a step-wise approach:
1. The use of liquid medium for culture and DST in middle- and low-income countries.
2. The rapid species identification to address the needs for culture and drug susceptibility testing (DST).
Taking into consideration that liquid systems will be implemented in a phased manner, integrated into a country specific comprehensive plan for laboratory capacity strengthening and addressing the following key issues:
Detailed background information [pdf 336kb]
International TB laboratory experts and representatives of partner organizations recommend the use of TB liquid culture and DST in low income settings. Liquid culture systems are the standard of care for TB diagnosis and patient management in industrialized countries.
Liquid culture and DST systems are more complex and sensitive than solid culture and DST media. Increased bacterial contamination and an increased frequency of nontuberculous mycobacterial (NTM) isolation must be addressed. A rapid method to differentiate M. tuberculosis complex from other mycobacterial species is essential.
Laboratory diagnosis of TB largely relies on the direct microscopic examination of sputum specimens. However, the technique, although specific, has low and variable sensitivity and cannot identify drug-resistant strains. Mycobacterial culture is more sensitive but growth of TB bacilli on traditional solid medium requires 4-8 weeks and consequently delays appropriate treatment in the absence of a confirmed diagnosis.
Expanding culture capacity is urgently needed to address challenges due to the epidemics of HIV-associated TB and drug resistant TB, especially in resource-limited settings.
Liquid culture systems reduce the delays in obtaining results to days rather than weeks. For DST, the delay may be reduced to as little as 10 days, compared to 28-42 days with conventional solid media. Liquid systems are more sensitive for detection of mycobacteria and may increase the case yield by 10% over solid media. With increased sensitivity and reduced delays, liquid systems may contribute significantly to improved patient management.
Liquid systems are, however, more prone to contamination by other micro-organisms. In experienced laboratories, approximately 5-10% of specimens cannot yield results because of contamination. Procedures to prevent cross-contamination (due to carryover of bacilli from positive to negative specimens) should also be strictly followed, especially where more positive specimens are processed in high-incidence countries.
The decision to implement a liquid culture and DST system should be based on need and be consistent with a country’s plan for TB laboratory capacity strengthening and expansion. Such plans should be considered only in countries with a strong network of quality-assured microscopy.
In most circumstances, the first priority would be to implement the system in the NRL, assuming that the NRL is currently supervising quality-assured (QA) microscopy of the laboratory network and performing QA TB culture and DST. This would provide valuable experience that could be applied if a decision were made to scale up the system. In those countries where a liquid culture and DST system is currently in use at the NRL, the decision to scale up should be informed by the accumulated experience at the NRL with the liquid culture system.
Subsequent expansion of liquid culture and DST capacity would logically be to regional TB culture and DST laboratories. The extent of scale up should be determined by need and availability of funding, and again consistent with a national laboratory plan.
It is imperative that all mycobacterial isolates be speciated at least to the level of M. tuberculosis complex vs. NTM. When using liquid culture, with the expectation that time-to-detection will be significantly reduced, it is also imperative that a rapid and affordable method of species identification be used. Where identification of NTM is needed, standard biochemical tests or other methods can be considered.
Ministries of Health and their partners urgently require guidance from WHO on the use of liquid culture and other means to improve diagnostic capacity. Based on an expert consultation organized by WHO (26 March 2007) with key experts and agencies in this field, and building on recent comprehensive review of available evidence regarding the efficacy, effectiveness and feasibility of implementing liquid culture technology in high TB burden settings, recommendations were made.
1. Adoption of liquid culture systems should be decided by Ministries of Health in the context of a comprehensive and detailed country plan for TB laboratory capacity strengthening.
2. Country plans for expansion of TB culture and drug-susceptibility testing (DST) should be based on a strong network of quality-assured microscopy, the cornerstone for TB diagnosis.
3. Laboratories should have demonstrated experience in culture and DST using conventional methods.
4. Phased implementation is recommended with the National Reference Laboratory (NRL) as a first priority and further scale-up to regional laboratories based on the NRL experience and consistent with the national country plan.
5. Adequate infrastructure and equipment should be provided, especially regarding laboratory biosafety. Specimen processing for culture purposes has to be performed in appropriate Biological Safety Cabinets (BSCs), at least in Biosafety Level 2 (BSL2) facilities. Processing of cultures for conventional species identification, subculturing and phenotypic DST must be performed in BSL3 facilities [Ref. 9], since culture suspensions required for these activities generate highly infectious aerosols with a high concentrations of TB bacilli. The successful establishment, staffing and maintenance of BSL3 laboratories is demanding and costly.
6. Commercial liquid culture systems must include a detailed commercial sales contract which guarantees ample and continuous supply, optimal shipment conditions and logistics for custom clearance.
7. A customer support plan should detail measures that guarantee - by the supplier - equipment installation, maintenance, reparation and provision of training, training materials and technical support.
WHO will include the use of liquid culture in all relevant technical documents (e.g. Standard Operational Procedures, training material for culture and DST) and will support countries in assessing their needs and building capacity to use liquid cultures.
1. Bemer P, Palicova F, Rusch-Gerdes S, Drugeon HB, Pfyffer GE. Multicenter evaluation of fully automated BACTEC Mycobacteria Growth Indicator Tube 960 system for susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 2002;40(1):150-4
2. Johansen IS, Thomsen VO, Marjamaki M, Sosnovskaja A, Lundgren B. Rapid, automated, nonradiometric susceptibility testing of Mycobacterium tuberculosis complex to four first-line antituberculous drugs used in standard short-course chemotherapy. Diagn Microbiol Infect Dis 2004;50(2):103-7.
3. Scarparo C, Ricordi P, Ruggiero G, Piccoli P. Evaluation of the fully automated BACTEC MGIT 960 system for testing susceptibility of Mycobacterium tuberculosis to pyrazinamide, streptomycin, isoniazid, rifampin, and ethambutol and comparison with the radiometric BACTEC 460TB method. J Clin Microbiol 2004;42(3):1109-14.
4. Bemer P, Bodmer T, Munzinger J, Perrin M, Vincent V, Drugeon HB. Multicenter evaluation of the MB/BACT system for susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 2004;42:1030-4.
5. Werngren J, Klintz L, Hoffner SE. Evaluation of a novel kit for use with the BacT/ALERT 3D system for drug susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 2006;44(6):2130-2.
6. Kruuner A, Yates MD, Drobniewski FA. Evaluation of MGIT 960-based antimicrobial testing and determination of critical concentrations of first- and second-line antimicrobial drugs with drug-resistant clinical strains of Mycobacterium tuberculosis. J Clin Microbiol 2006;44(3):811-8.
7. Rusch-Gerdes S, Pfyffer GE, Casal M, Chadwick M, Siddiqi S. Multicenter laboratory validation of the BACTEC MGIT 960 technique for testing susceptibilities of Mycobacterium tuberculosis to classical second-line drugs and newer antimicrobials. J Clin Microbiol 2006;44(3):688-92.
8. Systematic review of fully automated liquid culture tests. Chapter 14 In "A systematic review of rapid diagnostic tests for the detection of tuberculosis infection", J. Dinnes (ed), Health Technology Assessment 2007;vol. 11:No 3.
9. Laboratory Biosafety Manual, Third Edition [pdf 1309kb]
Moving research findings into new WHO policies
Today’s technologies for tuberculosis (TB) control—medicines, diagnostics, and vaccines—are decades old, and improvements in these technologies or new technologies altogether would accelerate TB control efforts worldwide. “Retooling” TB control is the process for adopting and introducing new and improved health technologies with the goal of maximizing their widespread use, while minimizing delays. A pivotal point in retooling is when a global policy is revised or created to encompass a new technology or strategy.
A primary source of global health policy is the World Health Organization (WHO). As WHO is governed by Member States, WHO policy is commonly the foundation for country-level technical decisions. The majority of countries may not take up new tools or strategies that are not endorsed by the WHO, even when they are effective. WHO strongly supports TB retooling efforts and works towards the rapid and widespread dissemination and use of new technologies to combat TB and eliminate the disease. In addition to its role in policy setting, WHO can facilitate the translation of policy into practice through its normative, technical assistance, and monitoring functions at the country level.
A widespread and common understanding of the process that WHO utilizes to move research evidence into policy is critical to ensure that all product developers or researchers have similar access to the policy-making process, and to enable countries to access objective information on all new, improved and existing technologies.
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