Barriers on implementation of rapid methods of TB diagnosis

Transcription

1 Barriers on implementation of rapid methods of TB diagnosis Turid Mannsåker National Reference Laboratory for Mycobacteria Norwegian Institute of Public Health

2 TB in Norway around 1900: Among the highest rates in Europe In the 1970s: TB disease is slow TB diagnosis is slow TB patients are old TB will soon be gone NO HURRY! TST Chest X-ray Smear microscopy Culture and DST on solid medium

3 Now very low incidence in native Norwegians thanks to 1940: Diagnostic x-ray routine 1947: Mandatory screening (x-ray, TST) and BCG vaccination 1952: Ambulatory x-ray units And: Isolation of diagnosed patients Standardized drug treatment regime Notification system Well organized health care system

4 Notified TB i Norway Foreign born Norwegian born

5 Joint ECDC/WHO Regional Office for Europe joint Tuberculosis Country Visit, 2011 From the report; Suggested follow-up actions: Assess and evaluate the feasibility and need of the new rapid diagnostic tools for TB control. My comment: recognition of cases of TB infection should be the main issue since all new cases are subject to infection control measures until drug susceptibility testing is performed and effect of treatment is documented. Any cost-effective, reliable and sensitive PCR method for direct detection of MTBc in clinical specimens would do, together with microscopy.

6 Globally: Diagnostic delay is on the agenda More extensive use of rapid diagnostics of pulmonary TB important for: high incidence areas (much transmission) with poor facilities for isolation of contagious patients (even more transmission) and a high rate of drug resistant TB (dangerous tansmission)

7 Rapid diagnosis of pulmonary TB TBc detection directly in sputum / BAL (good quality specimen!) Smear microscopy Conventional PCR (RT PCR, in-house or commercial) Line Probe Assay (LIPA, PCR-based) Xpert MTB/RIF (RT PCR) (Culture in liquid medium in stead of solid) Sero-immunological, not yet

8 Smear microscopy Widely integrated in global TB diagnosis Simple and cheap, - if you have: microscope light source trained personnel But: Low sensitivity (spec. HIV+!) and specificity (Poor identification and differentiation from NTM)

9 Rapid diagnosis of pulmonary TB TBc detection directly in sputum / BAL (good quality specimen!) Smear microscopy Conventional PCR (RT PCR, in-house or commercial) Line Probe Assay (LIPA, PCR-based) Xpert MTB/RIF (RT PCR) (Culture in liquid medium instead of solid) Sero-immunological, not yet

10 Conventional RT PCR detection of MTB complex in clinical specimens Much used in high- and middel-income countries. Suited for MTBc detection in smear positive specimens or when highly suspected TB - if you have: suitable laboratory fascilities and equipment trained personnel But: Expensive tests

11 Rapid diagnosis of pulmonary TB TBc detection directly in sputum / BAL (good quality specimen!) Smear microscopy Conventional PCR (RT PCR, in-house or commercial Line Probe Assay (LIPA, PCR-based) Xpert MTB/RIF (RT PCR) (Culture in liquid medium instead of solid) Sero-immunological, not yet

12 Line Probe Assay on clinical specimens LIPA much used in high- and middle-income countries - most for identification of cultured strains. Highly specific genetic detection of MTB complex and rifampicin resistance - if you have got suitable laboratory facilities PCR equipment trained personnel But: Expensive tests

13 Rapid diagnosis of pulmonary TB TBc detection directly in sputum / BAL (good quality specimen!) Smear microscopy Conventional PCR (RT PCR, in-house or commercial) Line Probe Assay (LIPA, PCR-based) Xpert MTB/RIF (RT PCR) (Culture in liquid medium instead of solid) Sero-immunological, not yet

14 Automated integrated RT PCR and rifampicin resistance detection (Xpert MTB/RIF assay) Fully automated integrated procedure for sample processing, PCR and analysis of the PCR fragment if you have got GeneXpert system unit But: Expensive equipment Expensive tests

15 Smear microscopy MTBc RT PCR LIPA Xpert MTB/RIF Hands on-time xxxxx xxx xxx x Test rapidity xxxx xxx xx xxxx Spec. lab. fascilitiy xx xxx xxx x Training xxx xxxx xxxx x Cost equip.+test x xxx xxx xxxxx

16 Plenty of buts: Smear microscopy Sub-optimal sensitivity and specificity Poor identification and differentiation from NTM RT PCR detection Special equipment in suited fascilities Line Probe Assay Special equipment in suited fascilities Expensive kits Xpert MTB/RIF Expensive equipment Expensive kits - and all need stable power supply!

17 Xpert MTB/RIF is widely promoted by WHO No wonder they want it! WHO likes it most (=can afford it)? Well-funded laboratories in low-endemic (TB and HIV), highincome countries. WHO needs it most? Poorly equipped laboratories in high-endemic (TB, MDR and HIV), low-income countries. WHO supports purchase of equipment and kits

18 GenXpert system: Simple procedure decontaminated sputum samples 1. Inoculate media and prepare smear from deposit 2. Add 1.5ml Sample Reagent to 0.5ml deposit 3. Shake then stand10 min. 5. Transfer the 2ml to cartridge 4. Shake then stand further 5 minutes Begin Test

19 In essence about money! WHO gets it? Hospital laboratories / research centers with added use of the system (MRSA) Centers with honest connections to funding sources and stable electrical supply, temperature control, storage fascilities Not necessarily where clinical specimens, or TB patients, are easily collected?

20 In essence about money! - but also about politics and health care policy Example: Introduction of direct detection of MTB complex in sputum in TB Hospital in high-endemic area in WHO Eastern Europe Region some years ago: - Extensive experience and high quality performance of smear microscopy - Implemented liquid culture and 1.st line DST - Competent, clever and brave HCWs (clinic and lab.) But..

21 Buraucracy years before permission and funding for PCR-lab in the hospital Frequent changes of key persons in regional health authority Unwillingness to take advise from international community Staff replacements in the hospital (nepotism??) Challenging cooperation with prison hospital authorities «Brain drain» - Trained personnel moved for career reasons

22 Our dream: Highly sensitive, simple, cheap and rapid screening test for active pulmonary TB Needed for high-incidence countries with decentralized organisation of poorly funded and staffed health care centers and high rate of drug-resistance and high incidence of HIV The consequence of positive rapid test result should be decided before the patient goes back home!

23 Photo: C Holm-Hansen

24 Photo: C Holm-Hansen

25 How can our dream come true in locations where it matters the most? Maybe by... On-site sensitive screening test on saliva specimens and quick referral to diagnostic center for more specific test LIPA or Xpert MTB/RIF for rapid spesific diagnosis of MTB complex and rifampicin resistance Treatment and drug regime decided (and started) before patient goes home Not realistic??

26 Vietnam 4 Ag Rv3881c Rv0934 Rv1886 Rv0831 S+C+H- Community Controls MFI Ag 1 Ag 2 Ag 3 Ag 4 Carol Holm-Hansen et al Bioplex-results on serum-samples

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29 Most important Funding of further research on simple on-site test methods Supporting implementation of Xpert MTB RIF where it is most needed and actually makes a difference (without money lost on the way!) Functioning laboratory networks in all regions

30 AND.. Continue support of laboratory based diagnostics and surveillance of MTB/MDR by competence building quality assurance of laboratory methods continue Reference Laboratory Network BECAUSE.. Crucial to perform culture and correct DST Crucial to perform molecular epidemiology surveillance

31 When will we be on the top of hill?