Diagnosis of Smear negative pulmonary TB in

high HIV settings:

RESEARCH PRIORITIESHaileyesus Getahun, Stop TB, WHO.

Expert consultation on TB/HIV research priorities,14-15 February 2005, Geneva, Switzerland

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

Differential diagnoses in PLWHA

• Bacterial pneumonia• Kaposis sarcoma• Pneumocystis carinii pneumonia• Cryptococossis • Nocardiosis• Penicilliosis• Melioidosis• Histoplasmosis • Etc..

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

Global TB data end of 2003

SS+

SS+

SS+

SS+

SS+

SS+

SS-

SS-

SS-

SS-

SS-

EP

EP

EPEP

EP

EP

SS-

0%

10%

20%

30%

40%

50%

60%

70%

India

Mya

nmar

Thaila

nd

Cambod

ia

China

Viet N

am

Global TB data, end 2003

SS+

SS+

SS+

SS+

SS+

SS+

SS+

SS-

SS-SS-

SS-

SS-

SS-

SS-

EPEP

EP

EP

EP

EPEP

0%

10%

20%

30%

40%

50%

60%

70%

Kenya

Moz

ambiq

ue

Niger

ia

South

Afri

ca

UR Tan

zani

a

Zambia

Zimba

bwe

Global TB data, end 2003

SS+

SS+

SS+

SS+

SS+

SS+

SS-SS-

SS-

SS-

SS-

SS-EP EP

EP

EP

EP

EP

0%

10%

20%

30%

40%

50%

USA

Germ

any

Portu

gal

Japan

Singa

pore

Nethe

rlands

Global TB data, end 2003

SS+

SS+

SS+

SS+

SS+

SS+

SS-

SS-

SS-

SS-

SS-

SS-

EP

EP

EP

EP EP

EP

0

10

20

30

40

50

60

AFR AMR EMR EUR SEA WPR

Regions

Per

cen

t

Proportion smear negative of all pulmonary cases with HIV

prevalence in selected sub-Sahara African countries, 2003.

R2 = 0.1601

2.0

2.5

3.0

3.5

4.0

4.5

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

% HIV Prevalence in Adult (log)

Pro

po

rtio

n s

mea

r n

eag

ativ

e o

f al

l p

ulm

on

ary

case

s (l

og

)

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

WHO-Diagnostic Algorithm

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.

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

Bleach method

• Most widely studied method

• Centrifugation and sedimentation

Bleach method95% CI of relative improvement of sensitivity

Bleach method

• Most widely studied method

• Centrifugation and sedimentation

• Used in 3 countries under routine NTP

• Additional processing time is the limitation

• Sensitivity 38→50% among PLWHA

• Most studies in hospital or research settings

• Technique is not standardised.

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

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

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)