Transcript TB or not TB - האתר הרשמי של האיגוד

TB or not TB ?
Mahmoud Abu-Shakra
Rheumatic disease Unit
Soroka Medical Center
Beer-Sheva
The Issue:
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For patients treated with TNFi agents:
When to diagnose LTBI.
When to treat with anti-TB agents.
How we diagnose LTBI?
LTBI is diagnosed mainly by:
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Tuberculin Skin Testing (TST)
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CXR
Skin testing with PPD (TST)
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Used in screening for M. Tuberculosis infection
Low sensitivity and low specificity for active TB
Positive test is seen in patients:
Have been infected with MT
Sensitized by BCG
False negative reaction is common in IS patients and
those with active TB
Interpretation of TST results:
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Treatment of LTBI reduces the risk of active
TB in > 90% of cases.
Guidelines for positive of skin test
reaction (ATS)
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Induration >15 mm – Persons with no risk
factors
> 10 mm
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Recent arrival from high prevalence countries
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Resident and employees of high risk
categories (prisons, nursing homes,…)
Injection drug users
Mycobacteriology Lab personnel.
Chronic diseases: DM, silicosis, CRF,
Lymphoma, leukemia, gastrectomy)
Children <4,
Children and adolescents exposed to adults
in high risk categories
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> 5 mm
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HIV
Recent contact to TB
Fibrotic changes on CXR consistent with old
TB
Organ transplant
IS therapy equivalent to 15 mg/d prednisone
for > 1month
BCG and TST results
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BCG vaccination induces PPD reactivity, (3-19 mm).
Most of the reactivity wane over 10 years.
If subjects vaccinated in infancy, TST is the same for
vaccinated and non-vaccinated after 5 yrs.
If vaccinated at entry to primary school, TST wane more slowly
If PPD performed >15 years after BCG, interpret TST as for
unvaccinated persons.
If there is baseline TST, increase in TST reactivity > 10 mm
suggests positivity
If there is no baseline, interpret as for unvaccinated
Booster Phenomenon
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Increased tuberculin reaction upon retesting
Results from recall of waned CMI.
Anamnestic serologic response
Maximal if the interval between 1st and 2nd
test is between 1-5 weeks
Less frequent if the interval > 90 days
TST and Booster phenomenon
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Persons in old TB and those who received
BCG- TST results may be false negative ( <
2 mm)
A 2nd TST in 1-3 weeks is indicated
2-steps TST is important in those who have
not had a test in the prior 12 months and who
will be subject to regular testing.
> 5 mm
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IS therapy equivalent to 15 mg/d prednisone
for > 1month
What is the risk of TB for patients on >
15 prednisone ?
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Case-control study of TB cases during 19902001 using General Practice Research
Database in the UK.
4 controls for each case of first time
diagnosis of TB
497 new cases of TB and 1966 controls
derived from 16,629,041 PY.
Arthritis Care and Research 2006,55:19-26
Variable
Current use CS
< 15 mg
> 15 mg
Non biologic anti-rheumatic*
Smoker
BMI < 20
DM
OR
4.9
2.8
7.7
2.0
1.6
2.8
3.8
*AZA, gold, cytoxan, Cellcept, sulfasalazine, MTX, cyclosporine, and PCA
Are TNFi immune-suppresser?
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Most cases of TB among patient treated with
TNFi are the result of activation of LTBI and
not d/t primary TB.
TB associated with TNFi is disseminated
(X12) (24%), extra-pulmonary (X3) (56%),
and atypical presentation.
Median time from TNFi therapy and TB
diagnosis was 12 weeks.
TB, TNF and Mice
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TNF and 55 kDa TNF-r are necessary conditions for protection
against murine TB infection. (Immunity, 1995;2:561)
In the anti-TNF treated mice:
Granuloma formation was delayed
20% lacked epithelioid cells in the liver
Less organized,
AFB were 10-50 fold higher
Extensive necrosis in the lungs.
TNF neutralization with mAb results in disease reactivity in
mice persistently infected 6 months previously with TB (Inf and
Immun. 2001)
Effects of TNF
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TNF is involved in the regulation of apoptosis of cells
infected with M. Tuberculosis
TNF promotes the maturation of DC, thereby
inducing the transport of MT antigens to the lymph
nodes and the priming of the T-cells subsets that
traffic the site of infection
TNF induced antimicrobial activity of murine
macrophages
TNF directs the movement of leucocytes
(Ann Rheum Dis, 2005;64:24-8)
TNFi and TB in humans
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Early reports-USA
Incidence
RA + TNFi
24.4/100000
RA-TNFi
6.1/100000
Jerrold Ellner at Boston- 9 fold increase of
TB in TNFi treated in US
(NEJM 2001;345:1098)
TB cases in Spain
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All Cases (pre)
(Post)
RA only
Pre
post
(Arthrits and Rheum 2005;52:1766)
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Rate/100,000
522
117
564
95
OR
21
4.7
22.6
3.8
Risk of TB in RA patients
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RR of TB in RA
No TNFi
With TNFi
J Rheum 2007;34:706
Arthritis and Rheum 2005;52:1986-92
Sweden
2
8
Korea
9
30
Humira RA clinical Trials
Rate/100 PY
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Pre-screening
Post Screening
1.3
0.15
Risk of TB after screening
Spain
OR
 All TB cases
4.7
 RA patients
3.8
 Lack of compliance with
recommendation
7
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(Arthitis Care and Res 2007;57:756)
Yes- TNFi are IS
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The increased risk of TB among TNFi treated
is mainly the result of TNFi therapy and not
the disease state.
Is Repeated TST indicated?
In the START study 7 cases of active TB
developed despite negative TST at screening
2 other patients developed TB with positive
TST at screening. (one with TST of 6)
Arthritis and Rheumatisim 2006;54:1075-86.
Repeated TST following therapy with
TNFi- Soroka Data
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Patients with RA, AS and PsA receiving TNFi
therapy and who had not received therapy
for LTBI
All patients underwent a second TST
Conversion was defined as an increase of 6
mm of induration between the screening and
the second test.
Am J Resp Crit Care Med 1999;159:15-21
Preliminary results
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40 patients were assessed.
First TST: 25 < 5 mm
15 > 5 mm
Second TST: 21 < 5 mm
19 > 5 mm
Eight (20%) had an increase of 6 mm
between readings with 4 having an increase
of 10 mm.
Change in TST reading
2nd TST
1 > 5mm
3 converters
3-4
5
2> 5mm
2 converters
>5
15
3 converters
2 reverters
once positive is always positive-incorrect
Once positive –no longer useful -correct
TST reading
0-2
1st TST
20
Boosting vs. conversion
2 step testing is indicated in this group to avoid
interpreting the boost as new infection
Summary
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The risk of secondary TB following TNFi
therapy is more than 15 mg of prednisone
Before therapy perform TST
If TST > 5 mm diagnose and treat LTBI.
If TST <5 mm perform 2nd test 1 week later
If TST is negative look for old TB in CXR
For patients with negative TST consider
annual testing of TST.
Think TB
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Look for TB associated symptoms
Treat recent contact with patients with TB
Look for extra-pulmonary and atypical
disease.
Evaluation should be rigorous including NGT
and bronchoscopy