Mantoux ?a? IGRA st? d?????s? t?? f?

1
Mantoux ?a? IGRA st? d?????s? t?? f?µat??s??
sta pa?d?? a?t?pa??? ? s??e???te?
Seµ?????? ?a?d?at????? ???µ??e?? Tessa??????, 14
Feß???a???? 2014

• ?. ?s????
• A?ap?. ?a????t??a
• ?? ?a?d?at???? ??????? ?a?ep?st?µ??? ??????

2
????s? a?t??????µe??? s?µfe???t??

• S?µµet??? se s???d??a Vianex
• Honoraria GSK
• X??µat?d?t?s? e?e???t???? p??t???????
• Pfizer, GSK, ELPEN
• Advisory Boards GSK, Pfizer
• S?µµet??? se e?e???t??? p????aµµa eta??e?a?
  Pfizer, AbbVie

?a???a s?et??? µe t? s?µe???? pa???s?as?
3
? ep?d?µ??????a t?? f?µat??s?? pa???sµ?a

530,000
74,000
F?µat??s? se pa?d??
170,000
http//www.who.int/tb/publications/global_report/e
n/
4
??e???? t?? f?µat??s??
5
F?µat??s? ap? t?? ???es? st? ??s?
???
10 st??? e?????e?
6
? s?µas?a t?? ?a??????sa? f?µat??s?? st??
ep?d?µ??????a t?? ??s??
??e???? ?? ?9 ? 106 pe??pt?se??

• ?e?aµe?? a??pt???? ???? pe??pt?se?? e?e???? ??s??
• ? d?????s? ?a? ? a?t?µet?p?s? t?? ?a??????sa? ??
  e??a? s?µa?t??? ??a t? µe????t??? ??e??? t??
  ??s??

?a??????sa f?µat??s? 1/3 t?? p????sµ?? t??
??? (2 d?se?at?µµ???a ?????p??) ??e? µ?????e? µe
t? M. tuberculosis
7
????µas?e? ??a t? d?????s? t?? f?µat??s??
??????s? e?e???? ?a? ?a??????sa? ??
??????s? e?e???? ??
???s?- d?a???st???? µ???d??
?????ß????????? µ???d??

• TST
• IGRAs (Interferon gamma release assays)
• ??????????

• ????os??p???
• e??tas? ep????sµat??
• ?a??????e?a
• ????a??? µ???d??
• ???e? ?p? µe??t?

8
??????s? f?µat??s?????s?d?a???st???? µ???d??

• TST
• IGRAs (Interferon
• gamma release assays)

?a?aµ??? e?d???? ??a t? µ???ßa?t???d?? a??s?a???
apa?t?se?? t??
?- ?eµf???tt????
9
???s??????? ß?s? t?? IGRAs
10
??d???t?ta t?? a?t?????? a?????a µe t? e?d?? t??
µ???ßa?t???d???
Andersen, et al. Lancet 2000356(9235)1099.
11
?eta-a?a??se?? t?? IGRAs sta pa?d??
12
??????S?? ????ST?S?? () ????ST?S?? () ????ST?S?? ()
??????S?? ???e? ?????? e?s?d?µat?? ???e? ?aµ???? e?s?d?µat?? ??e? ?? ???e?
QFT, QFT-IT 86 (78-94) (N15) 58 (28-87) (N2) 83 (75-92)
T.SPOT.TB 86 (67-100) (N6) 77 (23-100) (N3) 84 (63-100)
TST 81 (73-90) (N14) 70 (45-94) (N4) 80 (70-90)
?????????? () ?????????? () ?????????? ()
??????S?? ???e? ?????? e?s?d?µat?? (N15) ???e? ?aµ???? e?s?d?µat?? (N2) ??e? ?? ???e?
QFT, QFT-IT 91 (74-100) 94 (74-100) 91 (78-100)
T.SPOT.TB 95 (84-100) 93 (83-100) 94 (87-100)
TST 79 (39-100) 93 (77-100) 85 (63-100)
S?st?µat??? a?as??p?s? ?a? µeta-a????s? t??
e?a?s??s?a? ?a? e?d???t?ta? t?? IGRAs st?
d?????s? t?? e?e???? ??s?? (ep?ßeßa??µ???? ?a?
p??a???) sta pa?d??.
13
????p?st?a t?? IGRAs sta pa?d?? ?a??????sa TB
S?????s? ?antoux ?a? IGRAs st? d?????s? t??
?a??????sa? ?? a?????a µe t? ßa?µ? ???es??
HIC high income countries
LMIC low-middle income countries
Regression slopes for exposure gradients
Mandalakas AM et al Int J Tuberc Lung Dis 2011
14
????p?st?a t?? IGRAs sta pa?d?? ?a??????sa TB
S?????s? ap?te??sµat?? t?? d?af???? d???µas???
a?????a µe t?? ???es? ? µ? (d???t?µ??? /-) st?
Mtb
????µas?a Pooled effects ?dds Ratio (Random) (95CI)
TST 5 mm 1.3 (0.72.7)
TST 10 mm 1.9 (0.983.8)
TST 15 mm 1.8 (0.75.0)
QFT-G/QFT-GIT 3.5 (1.96.7)
T-SPOT.TB 1.3 (0.82.3)
Mandalakas AM et al Int J Tuberc Lung Dis 2011
15
IGRAs ?a? ?a??????sa TB?a????????e? µe??te?
pa?a???????s??p?s?? ap? t??? IGRA() ?a
a?apt????? ??s?

• N 104 pa?d?? (lt 16 et)-pa?a???????s? ?2 ?????a
• ?st????? epaf??
• ??e???? µe QFT ?a? TST - de? ??aßa? ?e?ape?a
• N21, QFT () ? 6/21 e?e??? ??s? (PPV
  28, 95 CI 16-75)
• 3/7 ?????a? lt 5 et?? (PPV 43)
• (s?????t??? ?? e?????e? µe QFT 10)
• N40, TST gt5mm () ? 6/40 e?e??? ??s? (PPV
  15) P0,33
• Negative Predictive value 100 ?a???a pa?d? µe
  QFT(-) de ??s?se

Diel R, Am J Respir Crit Care Med, 2011
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???ß?e?? a??pt???? e?e???? ??s?? µe ß?s? t?? IGRA
???pt??? e?e???? ??s?? IGRA () vs IGRA (-)
2,1 f???? s????te?? (95 CI 1,293,46) TST 10
mm vs TST (-) 1,60 f???? s????te??
(0,942,72) ?µ?? s?µa?t??? µe?a??te??? a???µ??
at?µ?? ????? TST ()
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? ???s? t?? IGRAs sta pa?d??

• ????p?st?a t?? IGRAs se µ???? pa?d?? (lt 5 et) ?a?
  a??s??atesta?µ????? as?e?e?? ??e???eta?
  pe??ss?te?? µe??t?
• - ? ap??sd????st? ap?t??esµa
  
  (? IFN? pa?a????
  µet? d???e?s? µe PHA)
• S???? d?af??et??? ap?t??esµa ap? t? Mantoux
  s????te?a TST() /IGRA (-)
• ?t?pa µ???ßa?t???d?a, BCG, ?aµ???te??
  e?a?s??s?a?

Haustein T et al Pediatr Infect Dis J 2009 Connel
TG et al Pediatr Infect Dis J 2010
18
?p??e??e? ? µ???? ?????a t? ap?t??esµa t?? QFT-IT
?at? t?? ??e??? ??a ?a??????sa ???

• ?? ap??sd????st? ap?t??esµa e??a? p?? s???? sta
  µ???? pa?d??
• ?a µ???? pa?d?? µe ?a??????sa ?? pa??????
  ??te?fe???? ? ?? s???e?t??se?? t?? e??a?
  ?????te?e? se s?????s? µe ta µe?a??te?a pa?d??
• ?e? d?ap?st??eta? ?????te?? s????t?ta as?µf???a?
  ap?te?esµ?t?? TST ?a? QFT-IT is sta µ????te?a
  pa?d??

?p??t?s? sta a?t????a t?? f?µat??s??
?p??t?s? st? µ?t?????
Interferon ? concentration (IU/ml)
r0.14 plt0.0001
Age (years)
Age (years)
r-0.18 p0.009
Critselis E J Pediatrics 2012 Pavic I et al
Pediatr Infect Dis J 2011 Lewisohn DA et al
PLoS One 2008
19
????? ? ????? t?? IGRAs st? d?????s? t??
f?µat??s?? sta pa?d??

• ?a?d?? µ????? ?????a? ? a??s??atesta?µ??a,
  ?d?a?te?a e?? s?ßa?? ??s?? se s??d?asµ? µe t?
  Mantoux ?ste ?a a????e? ? e?a?s??s?a
• ?e?a??te?a, a??s?epa???, s?ßa?? ??s?? (-),
  ?d?a?te?a e?? BCG()
  a?t? t?? Mantoux - a???s? t?? e?d???t?ta?
  t?? d?????s??

• ?? IGRAs de? ????? ??s? st? µ????ß????????
  ep?ßeßa??µ??? ??s?
• ?? a???t??? ap?t??esµa IGRA de? ap???e?e?
  e?e??? ? ?a??????sa TB
• ?? IGRAs de? µp????? ?a ?????? d?????s? µeta??
  e?e???? ?a? ?a??????sa? TB

? ???s? t??? de? s???st?ta? ap? t?? ?.?.? se
?aµ???? ?a? µ?s?? e?s?d?µat?? ???e?
http//guidance.nice.org.uk/CG117/Guidance
CDC MMWR 2010 ECDC 2011 Red Book, AAP 2009
http//www.who.int/tb/features_archive/igra_fact
sheet_oct2011.pdf Amanatidou A et al Eur J Clin
Microbiol 2012 Tsolia M et al PIDJ 2010
20

• ?a?d?? lt 5et??
• ???t?µ?ta? ? TST
• ?? IGRA µp????? ?a ???s?µ?p??????? se
  s??d?asµ? ??a ?a a????e? ? e?a?s??s?a

• S??d?asµ??
• Mantoux ?a? IGRA
• Se a???µ??? ???d??? ??a ???µ???/??s?/?a?? ??ßas?
• ???a?? e?e???? ??s??

• ???t?µ??ta? ?? IGRAs
• BCG eµß???asµ????
• G? a?t??? p?? de? ?a epa???????

• Mantoux ? IGRA
• ??e?e???s? epaf??
• ?pa??e?µat??? ???es?

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?ate????t???e? ?d???e? NICE 2011 (UK)

• ?????? ???d???? pa?d?? lt 5 et??
• (epaf??, µeta??ste? ap? e?d?µ???? ???e? )
• TST p??t?? e?????? ?a? ??????s? ?e?ape?a? ??a
  ?a??????sa ?? e?? ?et??? (af?? ap???e?ste? ?
  e?e???? ??s??)
• ??e????e?a IGRA e?? TST (-) ?ste ?a a????e? ?
  e?a?s??s?a ? ?e?ape?a e?? TST ? IGRA ?et???

22
??t?µet?p?s? pa?d??? lt 5 et?? ?
a??s??atesta?µ???? as?e??? p?? ????? ???e? se
epaf? µe p?s???ta
Mantoux- /IGRA-
IGRA ? ?antoux ? 5mm
a/a ???a???, ?st????? (s?µpt?µata), ???????
e??tas?
a/a ???a???, ??????? e??tas?
?a????????
F?s????????
?a????????
F?s????????
??t?µ?s? ??a e?e??? ?? ?a? ?e?ape?a
??a??? ???
??t?µ?s? ?a? ?e?ape?a ??a e?e??? ??
(8-10 ???)
Te?ape?a ?a??????sa? ??
?pa?????? Mantoux/IGRA
IGRA ? Mantoux ? 5mm
Mantoux - /IGRA-
Te?ape?a ?a??????sa? ??
??a??p? ??? BCG?
CDC, MMWR 2005 54 (RR15) CDC, MMWR 201059
(RR50)
23
??t?µet?p?s? pa?d??? gt 5 et?? ?a? e??????? p??
????? ???e? se epaf? µe p?s???ta
A
B
G
TST-/IGRA-
IGRA/TST or TST-
TST/IGRA-
a/a ???a???, ??????? e??tas?
a/a ???a???, ??????? e??tas?
?st?????, ??????? e??tas?
?a????????
F?s????????
?a????????
F?s????????
S?µpt?µata s?µßat? µe ??
????? s?µpt?µata s?µßat? µe ??
?et? 8-10 eßd
??t?µ?s?/?e?ape?a ??a e?e??? ??
Te?ape?a ?a??????sa?
??at?µ??e?eta? ?a?a???????s? ????? ?e?ape?a
st?? pe??ss?te?e? pe??pt?se??
??t?µ?s?/ ?e?ape?a ??a e?e??? ??
??t?µ?s?/ ?e?ape?a ??a e?e??? ??

?pa?????? TST/IGRA
TST/IGRA-
IGRA
TST-/IGRA-
STOP pe?a?t??? ??e????
?p?? ?
?p?? G
CDC, MMWR 2005 54 (RR15) CDC, MMWR 201059
(RR50)
24
?? µ????? t?? IGRAs?

• ??d?de?µ??? de?µat??? d???µas?a C-tb
  ??as??d?asµ??? ESAT-6 and CFP10
• (Statens Serum Institute)

• IP-10 se ?a?t? f??t???

Tuuminen T BMJ OPEN 2012 Aaybe MG ERJ 2013
25
LTBI
HCs
TB
Hierarchical cluster analysis of 116
genes prediction error 11 for TB vs LTBI vs
healhty controls Set of 9 genes prediction error
of 9 for TB vs LTBI and prediction
error of 17 and 23 in previous adult cohorts
26
S?µp??asµa

• ?? IGRAs µp????? ?a ???s?µe?s??? ?? µ?a p??s?et?
  e??tas? ??a t? d?????s? t?? f?µat??s??
• ?e? fa??eta? ?a ????? ?????te?? e?a?s??s?a se
  s?????s? µe t? Mantoux ????? ?µ?? ?????te??
  e?d???t?ta st?? a?ept??µ??e? ???e? ??a t??
  e?t?µ?s? BCG () at?µ?? ? a?t?? µe ???µ??? ap?
  ?t?pa µ???ßa?t???d?a
• ??e???eta? ?a a?apt?????? ??e? µ???d?? p?? ?a
  ????? µe?a??te?? a???ße?a st? d?????s? t??
  e?e???? ?a? t?? ?a??????sa? ??

27
???a??st?
28

• MANTOUX
• ??e??e?t?µata
• ?aµ??? ??st??
• de? apa?te? e??p??sµ??? e??ast????
• ?e???e?t?µata
• apa?te?ta? epa?e??tas?
• ?p??e?µe????t?ta st?? a?????s?
• ?e??µ??? e?d???t?ta se eµß???asµ????? µe BCG ?
  ???µ??? ap? ?t?pa µ???ßa?t???d?a
• ?e??µ??? e?a?s??s?a se µ???? pa?d?? ?
  a??s??atesta?µ??a

• IGRAS
• ??e??e?t?µata
• ?pa?te?ta? µ?a µ??? ep?s?e??
• ??? e?d??? e??tas? se eµß???asµ??a µe BCG pa?d??
  ? ???µ??? ap? ?t?pa µ???ßa?t???d?a
• ?e???e?t?µata
• ?pa?te? e??p??sµ??? e??ast????
• ?e??µ??? e?a?s??s?a se µ???? pa?d?? ?
  a??s??atesta?µ??a

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Management of household contacts
NICE Guidelines 2011
Contacts lt 2 yrs
Neonates
BCG ()
BCG (-)
Initiate INH ?3 mos
TST
TST
Repeat TST
TST?15
TSTlt15
TST (6)
TST (lt6)
Repeat TST, IGRA in 6w
INH ? 6 w
Evaluate for active TB
Evaluate for active TB
TST (-)
TST ()
Repeat TST and IGRA
Repeat IGRA
Evaluate for active TB
active TB ruled out
active TB ruled out
either test positive
either test ()
If both negative
active TB ruled out
active TB ruled out
Treat for LTBI
active TB ruled out
Treat for LTBI

• D/C treatment
• BCG

Treat for LTBI
Treat for LTBI
Treat for LTBI
30
Management of household contacts
Contacts 2- 5 yrs
TST
TST (lt6)
TST (6)
Evaluate for active TB
Repeat TST and IGRA in 6 weeks
active TB ruled out
either test ()
Treat for LTBI
active TB ruled out
Treat for LTBI