(2)

Tuberculin skin test

2014.6.25

2

THE POSTTT 2015 TB STRATEGY

3Source Global strategy and targets for tuberculosis prevention, care and control after 2015, 2013 , WHO

Post-2015 Global TB Strategy

4

(200505-5-2012)

5

6

(DOTS)

A (Level A) 2 70%60%B (Level B) 60%C (Level C) 60%

: 2012

1323712634

DOTS,

, ?

11111111111111123381111111111222222222222222222222222222

7

ProphylaxisINH 1

9

90%

+DOTS

Source: Interventions for Tuberculosis Control and Elimination, IUATLD 2002

LTBIBI2008 LTBI ( )–

•– 13 X

– 13 1986

(2012 4 )–

• 9 INH–

• 1986

9

Tools for Screening LTBI• TST--- Currently recommended for identifying LTBI (DTH) ->

Sensitivity and Specificity of TSTs ---no “gold standard” (estimated sensitivity 80~96%).

• QuantiFERON-TB-- (Quantiferon-TB Gold, Cellestis, Carnegie, Australia) EMA and FDA-approved diagnostic test quantifies IFN-γreleased by sensitized lymphocytes in whole blood (* QFT has not been adequately evaluated in children < 5 years / immunocompromised patients/ Persons recently exposed to M. tuberculosis/ seiral tests.)MMWR Recomm Rep. 2003;52(RR-2):15–18) (MMWR Recomm Rep 2005;54(RR15):49-55) (MMWR Recomm Rep 2010;55(RR-5):1-25)

• Enzyme-Linked Immunospot – (T-Spot.TB, Oxford Immunotec, Abingdon, UK) EMA and FDA-approved -> detects IFN-γ secreted by ESAT-6-specific T cells in PBMC. ESAT-6 is a secreted antigen specifically expressed by the TB complex but absent in strains of M bovis & most NTM.

11

S Ferebee et al Am Rev Respir Dis 1962

RISK OF TB AMONG HOUSEHOLD CONTACTS B AMONG HOUSEHOLD CDURING FIRST YEAR

0

5

10

15

20

25

30

<5 >5<9 >10<14 >15<19 >20 CXR

TST (MM)

TB C

ASE

S / 1

,000

6,496/32 1,445/12 2,240/23 1,280/16 801/16 308/8

Factors Associated With False-Negative or False-Positive TST

Reactions

Pediatric Tuberculosis Collaborative Group.Pediatrics 2004;114;1175-201-Table 12

Factors That May Influence the Effect of BCG Immunization on the

TST

Pediatric Tuberculosis Collaborative Group.Pediatrics 2004;114;1175-201. Table 13.

Selected Studies Assessing the Effect of Selected Studies Assessing the Effect of BCG Immunization on TST Reactivity

Pediatric Tuberculosis Collaborative Group.Pediatrics 2004;114;1175-201. Table 14.

BCG and TST in Taiwan

• Tokyo 172 • 0.05mg/0.1ml •

––

1.5cm

•–– AIDS–

• 1951 –• 1965 – (1966 72.2%)• 1975 -- 8.73%,

86.5%• 2001 –

98.15%• 1997 -- ,

-> ( RT23 1TU : 4~7% -> 0.5~1% )

5mm

10mm

15mm

Figure 4 4 Rates of positive TSTs determined by cutu -t-off Figure 44 Rates of positive TSTs determineRpoints of 10 mm or the proposed new cut

mineuu -

d by cuut ff ofoednett--off values (N) in points

highints

ghgh-of 10 mm or the propos nts

hh--risk (Group 3) and lowopoww-

sed new cuut ff values (ofospoww--risk children (Group 1).

Chan PC et al. IJTLD 2008;12:1401-6

The correlation between TST size and The correlation between TST size andTB incidence in children contacts

TST size / cutoff points

Follow-up number

Case No

TB incidence /100000

RR P value

TST >=10mm 970 20 2053 22.4 (8.4-59.5) <0.001*TST < 10mm 5465 5 91TST>=15mm 335 16 4776 32.4(14.4-73.0) <0.001*TST<15mm 6104 9 147

TST>=18mm 172 11 5294 28.7(13.2-62.1) <0.001*

TST<18mm 6267 14 176

TST <5mm 3939 4 102 1

TST 5-9mm 1526 1 66 0.6 (0.07-5.8) 1

TST 10-15mm 639 4 626 6.2(1.5-24.6) 0.017*

TST 15-18mm 163 5 3067 30.2 (8.2-111.1) <0.001*

TST 18-20mm 55 3 5455 53.8(12.3-232.6) <0.001*

TST >20mm 117 8 6837 67.1(20.6-222.2) <0.001*

* p< 0.05; 12 (DOH97-DC-1502)

Multivariate Cox Proportional Hazards Multivariate Cox Proportional Hazards Model for Tuberculosis Risk among Child del for Tuber

Contactsrculosis Risk among Cber

ss (n= 9411, < 13 years)

Chan PC et al. Am J Respir Crit Care Med. 2014;189(2):203-213

TST ; 13

25

LTBIBITBBITLT

Chan PC et al. Am J Respir Crit Care Med. 2014;189(2):203-213 26

LTBIBI <1332010

Chiou MY, The Efficacy of Latent TB Infection Treatment in children. 2010 Annual Meeting of Taiwan Society of Pulmonary and Critical Care Medicine

LTBIBI

, , , <13 89% (60-97%), >=13 84% (57-95%)

102 (DOH102-DC-2302)28

Shorts of TST

• the TST is neither specific, as the antigens present in PPD cross-react with BCG and environmental mycobacteria

• Nor sensitive, due to anergy in those individuals with a compromised immune system (such as HIV, iatrogenic immunosuppression and children).

• Can not distinguish recent/remote LTBI, active TB.

Why We Still Use TST as a Diagnostic Tool in Taiwan

• Program aimed at contacts of TB, high prevalence of LTBI rate can increase PPV of tool itself

• Cheap and available national wide• For younger population, only one dose of BCG

has been exposed -> Effect on TST waning as time goes by

• For younger population, recent infection is more likely than remote infection, and the severity of TB disease itself outweighs the problem of low specificity

About TST and IGRA for latent tuberculosis infection

interferon-� release assayIGRA

Wang J-Y, et al. Interferon-gamma release assay and Rifampicin therapy for household contacts of tuberculosis. J Infect (2012), doi:10.1016/j.jinf.2011.11.028

The Positive rate with TST (10mm,15mm, 18mm) rate with TSand QFT

TSFTFT-

T (10mm,15TTSTTTTTTTTTTTTTTTT--TTTTTTTTTTTTTTTTTTTTT IT vs. Age

2008/6~ 10 inmates LTBI study (not TB contacts), Taiwan : 2384Chan PC et al. Int J Tuberc Lung Dis. 2012;16(5):633-8.

Concordance between TST & QFTFT-TTTTTTTTTTT-TTTTTTTTTTT IT, Concordance between TST & QFFTT TIStratified by BCG Scar Numbers

PPD10 vs. QFT PPD15 vs. QFT PPD18 vs. QFT

Scar No Kappa, agreement Kappa, agreement Kappa, agreement

0 + 1 0.1246, 45.4% 0.2475, 63.8% 0.2388, 72.2%

>=2 0.061, 33.1% 0.1477, 60.1% 0.1979, 79.6%

0 0.2607, 61.8% 0.3845,69.3% 0.3331, 67.9%

1 0.1075, 42.1% 0.2165, 62.6% 0.2055, 73%

2 0.0604, 33.1% 0.1401, 59.7% 0.203, 76.7%

3 0.0888, 36.4% 0.5217, 77.3% -0.082, 72.7%

Chan PC et al. Int J Tuberc Lung Dis. 2012;16(5):633-8.

909 HIV inmates for diagnosis of LTBI with TST & T-SPOT.TB

• After a median follow-up duration of 2.97 years, 5 patients (0.55%) developed active TB.

• All 5 patients had dual positive TST and T-SPOT.TB results at baseline.

• The incidence of active TB among our participants (excluding patients taking IPT) was 0.17/100 person-year (PY); 95% CI, 0.003-0.29/100 PY.

Yang CH et al. Plos one 2013:8; e73069

Number Needed to Treat

• According to our results, the number needed to treat to prevent one subsequent TB case among patients with a positive TST, a positive T-SPOT.TB and dual positive results was 35, 22 and 8 respectively.

• If we adopt the strategy that patients with either a positive TST results or a positive T-SPOT.TB test should receive IPT, there will be 30.8% of the enrollee put on treatment. If we choose dual positive results as criteria for IPT, then only 8.9% of the enrollee will be put on treatment, and this strategy already covers all the active TB patients developed during the follow-up.

N N % N % N %

20007 302 134 86

<=9 9165 72 0.79 14 0.15 8 0.09

10-19 6139 54 0.88 14 0.23 8 0.13

20-29 1481 39 2.63 16 1.08 9 0.61

30-39 879 37 4.21 22 2.5 18 2.05

40-49 930 38 4.09 27 2.9 14 1.51

50-59 716 32 4.47 24 3.35 16 2.23

60-69 330 19 5.76 11 3.33 10 3.03

70-79 191 9 4.71 5 2.62 3 1.57

80-89 157 2 1.27 1 0.64 0 0

102(DOH102-DC-2302)

40

20133 11-1--1000 1333 1333-3-2552500LTBI

133 1333BILTBLTBL BBIBI

41

Utilize the TST & IGRA for LTBI Dx in contacts in Taiwan

• Using TST in contacts with only one BCG vaccination at newborn is proper

• False positive rate could be high in adults with BCG booster beyond infancy

• More efficient to treat recent LTBI than remote LTBI => concomitant TST + IGRA maybe better from the point of specificity for those with more than 2 BCG vaccination

• For immunocompromised, TST or IGRA positive maybe better from the point of sensitivity but dual positive still works in HIV patients with high risk of TB under the medical care system.

Exclude Active TB is the most important thing!!!

CAN YOU IMAGINEA WORLD WITHOUT TB ?

WE CAN.Chan Pei-Chun, M.D,MPH.

Medical Officer of Taiwan CDCemail: pcanita.tw@cdc.gov.tw

website: www.cdc.gov.tw