Improving diagnosis TB laboratory strengthening

Role of laboratory services in TB control Laboratory services perform crosscutting activities for the three implementation working groups (DEWG, DOTS-Plus, TB/HIV) Diagnosis of all TB cases (e.g., SM(+), SM (-), extrapulmonary, HIV co-infected, drug resistant) Monitoring patient's response to treatment Participation in TB surveillance; notification/prevalence of TB; DRS Assistance in selecting effective treatment regimens: MDR-TB Human resource development including training Operational research

Consequences of poor lab performance Unreliable diagnosis results: over/under diagnosing of TB patients Individual level: Undiagnosed TB cases: (disease transmission, death) Mismanagement of patients (MDR-TB) Over diagnosed patients: (bear the effects of long & unnecessary treatment, disease stigma) National/Global level: Low case detection, Continuous transmission and Ultimately poorly performing TB control programme

Situation Analysis (22 HBCs) 18 countries have National Reference Laboratory (NRL) to oversee the organization and performance of the network; however some NRLs are weak and not fully functional 18 HBCs claim to have EQA scheme for smear microscopy; however, majority report it's limited coverage and suboptimal quality 14 countries perform culture at the national/regional level according to nationally-defined specifications, which are not always consistent with international recommendations. In addition, the quality of culture is unknown Major impediments to perform diagnostic tests (especially culture and DST): inadequate equipment and infrastructure limited technical knowledge Insufficient human and financial resources

Stop TB Strategy and laboratory Pursuing quality DOTS expansion and enhancement Political commitment Case detection through quality-assured bacteriology Standardised treatment, with supervision and patient support Effective drug supply system Monitoring system and impact evaluation Addressing TB/HIV and MDR-TB Contributing to health system strengthening Engaging all care providers Empowering patients and communities Enabling and promoting research 14

Improving diagnosis- planning framework Activities: Organization of TB laboratory network (prevalence and population distribution) Provide laboratory equipment supplies and reagents Implement quality assurance programme for smear microscopy, culture and DST Promote human resource development Meetings and Workshops Support technical assistance Promote operational research Expedite the diagnosis of smear negative & extrapulmonary TB in high HIV prevalence areas

Peripheral level (Level 1) Located at primary health centers or district hospitals Activities: Sputum collection Smear microscopy Recording and reporting Slide collection for EQA Manpower: ≤ 1(2) worker(s); >2-3 / <20 smears per day Population coverage: 100-200K

Intermediate level (Level-2) Located at regional health institutions including hospitals Activities: Services to clinics: FM/ZN smear microscopy Culture / ID of MTB; referral services Support activities: (supply of reagents/materials, training; EQA for smear microscopy including supervision) Manpower: 2-3 workers (only for TB work) Population Coverage: 500 - 1,500K

Central level (Level 3) Part of the central public health laboratory, research laboratory, or upgraded laboratory in the country’s principal tuberculosis institution Activities: National reference laboratory for the TB program, Development of standardized manuals and guidelines Training External Quality Assurance Perform: smear microscopy, culture and DST

Generally 3 levels in a TB lab network All functions of level 1 and 2 Identification of mycobacteria other than MTB DST of M. Tuberculosis laboratory equipment services and maintenance Laboratory manuals and guidelines for all lab services Primary link with NTP Supervision of intermediate QA of culture and microscopy Training of intermediate organization of DRS Operational and applied research All functions of level 1 fluorescence microscopy (optional) Digestion and decontamination of specimens Culture and identification of MTB Training of staff Support and supervision of peripheral staff for microscopy Preparation and distribution of reagents QA and panel testing of microscopy Manpower: 2-3 only for TB Coverage: 500K-1.500K Receipt of specimens Preparation and staining of smears ZN microscopy /recording Reporting of results Maintenance of lab register Management of reagents and supplies Internal QC Participation in EQA system Manpower: 1-2 staff Coverage: 100-200K Internal and External Quality Assurance at all levels

External Quality Assessment Early warning-system for problems Measure of laboratory quality Valuable benchmarking tool (standardization and traceability) Indicator of where to direct improvement efforts Monitor of changes in technology and testing practices (evaluation component)

Quality Assurance Programme Components Supervision Rechecking/panel testing Internal quality control

Strengthen the national capacity to perform culture for diagnostic purposes

Epidemiological and programmatic conditions have changed The number of repeatedly sputum negative TB cases is increasing, mainly due to the HIV epidemic Many countries are implementing DRS and monitoring MDR trends Second line drugs are available and a growing number of countries implement DOTS-Plus strategy Culture is increasingly used even in resource limited countries

Estimated cost of culture (LJ method) & DST (proportion method) per laboratory Capital investment per laboratory: 200,000$US Consumables, media and pure substances for 1000 cultures and DST: 22,000$US Training: national & international: 20,000$US EQA for culture and DST: 5,000$US/ year Staff salaries

Proposed approach to strengthen capacity to perform culture Develop/strengthen the capacity to perform culture at the intermediate level as an essential component of DOTS expansion Initially, 1 culture facility should be established per ~ 3 to 5 million population Introducing culture in step wise approach to cover all eligible population by 2015 (number of facilities will depend on the national policy)

Smear microscopy optimizations Outcomes of expert consultation meeting (1-2 September 2005) The meeting was organized to discuss the outcomes of the systematic literature review to determine the strength of existing data, identify knowledge gaps, and define a research agenda regarding the following issues: Fluorescence microscopy (45 studies) Sputum processing methods (83 studies) Number of sputum smears per TB suspect (41 studies)

Fluorescent microscopy (FM) Findings: Improve the sensitivity of sputum microscopy by 10% Shorten time of diagnosis Reduce laboratory workload; FM recommended to be used in high volume settings >100 smears Recommendations: Countries wishing to implement FM at the peripheral level, in lower volume settings, should do so within the context of operational research FM may be considered at all levels in high HIV prevalence countries Collaboration with TDR, FIND on operation research to further evaluate applicability, sustainability of this technology

Fluorescent microscopy Close collaboration with FIND and WHO on evaluation of the LED portable fluorescent microscope

Sputum processing methods Findings: Use of different chemicals and methodology Moderate sensitivity improvement Serious concerns regarding the use of centrifuge and bio-safety issues Recommendations: Concentration methods not recommended Sedimentation may be promising and less problematic to implement; however, multi-centre studies are required to investigate the performance and feasibility with standardised method Collaboration with TDR and FIND on design and implementation of operational research to evaluate sedimentation methods.

Number of sputum smears per TB suspect Findings: The results indicated limited incremental yield of the 3rd sputum examination (2-5%) However, there was some bias in studies design and difference in case definition Points to be considered: Dilemma on improving sensitivity (more false positive) or specificity Workload issues (more time allocation for examination of slide => improved output) Recommendation: The questions should be studied in the context of case definition (this topic will be presented and discussed during the upcoming STAG meeting)