1. Diagnosis of Smear negative pulmonary TB in high HIV settings: RESEARCH PRIORITIES Haileyesus Getahun, Stop TB, WHO. Expert consultation on TB/HIV research priorities,14-15 February 2005, Geneva, Switzerland

2. Smear negative pulmonary TB At least three negative sputum specimens for AFB AND Radiographic abnormalities consistent with active TB AND No response to a course of broad spectrum antibiotics AND Clinician decision to treat with a full course of TB drugs

3. Differential diagnoses in PLWHA Bacterial pneumonia Kaposis sarcoma Pneumocystis carinii pneumonia Cryptococossis Nocardiosis Penicilliosis Melioidosis Histoplasmosis Etc..

4. Magnitude of SN- pulmonary TB in PLWHA Significant increase in incidence in HIV+ Inferior treatment outcomes than HIV- In published data SN- in PLWHA ranges from 24-61% ( 28% in 7763 patients) However, –Institution based (poor health coverage) studies –Biased towards smear positives –In autopsy TB causes 14-54% of PWA deaths

5. Global TB data end of 2003

6. Global TB data, end 2003

9. Proportion smear negative of all pulmonary cases with HIV prevalence in selected sub-Sahara African countries, 2003.

10. SN- pulmonary TB in NTP Diagnosis of smear negative pulmonary TB in resource constrained settings is difficult. Less attention by NTP to document treatment outcome of SN- cases. SN- is an important component of TB that needs more urgent attention by NTP

11. WHO-Diagnostic Algorithm

12. Diagnostic algorithm Algorithm adapted from WHO Key parameters include –AFB sputum smear examinations –Diagnostic antibiotic trial (s) –CXR –Medical officer's judgement –Group discussion of the case (peer review) Best scenario assumption= 11-34 days Few studies address delay in diagnosis among PLWHA (Thailand and Zimbabwe) Other suggested clinical predictors include weight loss and anaemia.

13. Sputum smear microscopy If sensitivity improved-it is more valuable tool Positive threshold –Reported as 1+-3+ when >10 AFB/100 HPF –< 10 AFB/HPF reported in exact numbers – Scanty:" competent authority" to decide (c.f) Fluorescence microscopy –Increase ZN yield (15% and 18%) –15X more field scanned in the same period than ZN –Reduce time needed (4 mt vs 10 mts) –Cost effective- $40 (on 2 sputa) vs $57(ZN 3 sputa) –Limitations: Economic, require electricity, naturally fluorescent particles

14. Bleach method Most widely studied method Centrifugation and sedimentation

15. Bleach method 95% CI of relative improvement of sensitivity

16. Bleach method Most widely studied method Centrifugation and sedimentation Used in 3 countries under routine NTP Additional processing time is the limitation Sensitivity 3850% among PLWHA Most studies in hospital or research settings Technique is not standardised.

17. Sputum Culture 5-10 x more expensive Selective recommendation (? Underutilised) Sophisticated facilities and expertise Contamination (1-4%) Takes 6-8 weeks MGIT –8-20 vs 20-26 days –The same facilities –Expensive –More contamination

18. Intensified TB case finding Early detection of cases through intensive case detection Practical Approach to Lung Health (PAL) improves efficiency of resp services and improves TB case detection Involvement of community members is very important

19. Conclusion Expedite the search for new and rapid tools However, in the meantime Research should be focused –To immediately inform changes in policy and practice (e.g. rapid and effective diagnostic algorithm) –To hasten the expansion and utility of existing diagnostic methods (e.g. bleach, culture facilities in peripheral settings) –To inform the development of appropriate technologies for resource constrained settings (e.g. culture facility using solar energy)