A novel TB diagnostic algorithm using

automated microscopy achieves

high sensitivity while reducing the volume

of Xpert MTB/RIF testing

N Ismail

SV Omar, J Lewis, D Dowdy, D Clark,

M v/d Meulen, S Kennedy, G Churchyard

Background

• “For better or worse microscopy is here to stay

…”

– Could we improve this test?

• GXP has proven to an excellent diagnostic tool

but uptake has been limited

– Could we use a screening strategy to reduce the

number of test while maintaining performance

and thus increase uptake?

Automated Microscopy• TBDx® is a computer-aided detection (CAD) system

to automatically detect and count TB AFB on

digitized fields of view using “signature mapping”

Further improvements ….

Aims

• Evaluate the diagnostic

performance of the

improved TBDx as a stand

alone tool

• Evaluate the diagnostic

performance a novel

diagnostics algorithm

combining TBDx with the

GXP

Methods

• Setting: NTBRL, Johannesburg, South Africa

• Samples: Consecutive sputum from patients with symptoms of TB and not on treatment

• Gold standards:

– Culture:

• MGIT 960

– Auramine Smear Microscopy

• Microscopy : technician with >40years experience

• Confirmatory microscopy: technologist >40years experience

– All pos and ~ 10% random negative

Specimen processing

decontamination, centrifugation,

and standardization

Standardized pellet (2ml)

0.5 mL 200 µL remnant

Culture and DST Slide smears Stored 2-8oC

Produced, heated and fixed

then stained

Routine microscopy

TBDx GXP for all TBDx pos

& GXP ~10% TBDx neg

Economic methods

(prelim)

Cost Assumptions:

Smear: $2.25 (Shah et al)

TBDx: Smear + $2.99

(possible high-volume price)

GXP: $17.18 (Vassall et al)

Treatment for TB: $610

(WHO notification from SA)

Compare Algorithms:

TBDx positive -> treat (GXP

for RIF if desired)

TBDx scanty -> confirm with

GXP

TBDx negative -> no

treatment

Laboratory Methods

Results

• 1006 samples were directly comparable

(smear/culture/GXP)

– 204 were excluded; contamination, missing results

or NTMs

• Positivity rate: 10.6%

• Scanty: 36%

• ≥1+: 65%

The ROC curve (smear vs TBDx)

TBDx vs Culture

• Sensitivity and specificity of smear and TBDx (with different cut-offs) compared to gold standard of culture.

0%

20%

40%

60%

80%

100%

sme

ar

1+

2+

3+

4+

5+

6+

7+

8+

9+

TBDx cut-off

sensitivity

specificity

TBDx vs Culture

0%

20%

40%

60%

80%

100%

no

rma

l

sca

nty

1

sca

nty

2

sca

nty

3

sca

nty

4

sca

nty

5

sca

nty

7

sca

nty

8

sca

nty

9 P+

P+

+

P+

++

730 158 26 7 8 1 4 2 1 14 26 29

% c

ult

ure

po

siti

ve

fo

r M

TB

TBDx result (and number with result below)

TBDx > GXP

TBDX, TBDx(scanty)>GXP

sensitivity specificity PPV NPV

number of GXP

needed

(n=1,006)

smear 68.2% 99.2% 91.3% 96.3% 0

1+ 77.6% 98.8% 88.3% 97.4% 207

2+ 72.9% 99.3% 92.9% 96.9% 49

3+ 68.2% 99.3% 92.4% 96.3% 23

4+ 66.4% 99.3% 92.2% 96.1% 16

5+ 64.5% 99.3% 92.0% 95.9% 8

6+ 64.5% 99.3% 92.0% 95.9% 7

7+ 64.5% 99.3% 92.0% 95.9% 7

8+ 63.6% 99.6% 94.4% 95.8% 3

9+ 62.6% 99.7% 95.7% 95.7% 1

Preliminary Economic Evaluation(1006 patients tested)

Algorithm Confirmed TB

Cases

Diagnosed

(n = 107)

Culture

Negative,

Test Pos.

GXP

Tests*

Diagnostic

Costs

Treatment

Costs**

Total Costs Incr. Cost

Smear 73 (68%) 7 0 $2,300 $48,800 $51,100 ref

TBDx (S2) 78 (73%) 4 49/118 $6,100 $50,000 $56,100 $5,000

TBDx (S1) 83 (78%) 9 207/276 $8,800 $56,100 $64,900 $13,800

GXP 93 (87%)*** 27*** 1006 $17,300 $73,200 $90,500 $39,400

* The second number includes testing of positive results for RIF testing

** Excludes additional costs of treating MDR-TB

*** Estimated, as not all samples were tested with TBDx

Conclusion

• TBDx as a stand alone test provides equivalent sensitivity and specificity to a microscopy standard of >80years of experience

• TBDx provides a useful screening tool to GXP and could achieve high sensitivity

– 77% with 75% less GXP testing

– 73% with 90% less GXP testing

• Limitations of the study:

– used digested and decontaminated sediments

– high microscopy standard and low prevalence cohort

RecommendationDemonstration studies in different settings to confirm our

findings. Potential applications …

1. Can afford GXP on all

– Use Technology for Treatment monitoring

2. Limited budget for GXP

– Rif Resistance not a concern• Automated microscopy followed by GXP in scanty cases

– Rif resistance is a concern• Automated microscopy followed by GXP in all cases

3. No budget for GXP

– Automated microscopy or

– Automated microscopy confirmations at central locations