1

LATENT TB IN ADULTS

by
Assoc. Prof. Pang Yong Kek
 LEARNING OBJECTIVES
2

• To learn about the definition & diagnosis of

LTBI

• To learn about the investigations & algorithm

of investigations of LTBI

• To learn about the treatment target groups &

treatment regimens of LTBI
 ESTIMATED INCIDENCE OF ACTIVE TB

3 WHO, Global TB Report, 2011

 INTRODUCTION
4

• In high TB prevalence areas, many have been

exposed to infectious TB through:

o a direct contact with a known index case

or

o inadvertent exposure to an unsuspected active TB

patient.
 INTRODUCTION
5

 Some will acquire the infection.

 But, many of those infected will develop adequate

immunity to keep the infection at bay.

 Hence, only a small number will eventually develop

active disease.

 Those infected but remain asymptomatic are said to

have Latent TB Infection (LTBI).
 PATHOGENESIS OF TB
6

Charles Bryan MD.

Infectious Disease.
Chapter Five.
Mycobacterial Diseases.
http://pathmicro.med.sc.e
du
7 WHAT IS LTBI?
 LTBI
8

LTBI is diagnosed when an individual:

 shows positive reaction to the TST/IGRA

but

 does not have any clinical, bacteriological (if

done), or radiographic evidence of active TB
 DIAGNOSTIC CRITERIA
9

 No symptoms to suggest active disease

 Normal CXR (usually)

 Negative sputum smear for AFB (if collected)

 “Positive” TST (Mantoux Test)/IGRA

 DIAGNOSTIC CRITERIA
10

If the CXR is abnormal,

• ensure no changes are seen on repeat CXR (≥ 6

months apart)

• repeat sputum induction or BAL for AFB smear &

culture should be considered, even if no changes are
seen on repeat CXR
 DIAGNOSTIC CRITERIA
11

Remark:

• Calcified nodular lesions (calcified granulomas) &

apical or basal pleural thickening pose a lower risk
for future progression to active TB

→ Hence, does not require treatment

 WHY TREATMENT OF LTBI IS
12
NECESSARY?
 TB CONTROL PROGRAMME
13

 We know that:
• early detection & prompt treatment of active
TB (esp. infectious TB), constitute one of the
most important strategies to control TB
 UNIQUE FEATURES OF TB
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 However, the signs & symptoms of active TB, are

usually quite subtle in early stage.

 Consequently, it will not alert the victims to seek

early medical attention.

 The lack of florid symptoms & signs often elude

early detection by the health care providers.
 UNIQUE FEATURES OF TB
15

 Besides, MTB does not immediately debilitate the

host.
 This allows the hosts to remain active &
mobile spreading the infection.

Animation taken from:

http://www.fw-ac-
deptofhealth.com/images/tbanim2.gif
 UNIQUE FEATURES OF TB
16

 Once infected,
many could mount sufficient immune response &
control the disease.

 Only about 5 - 10% developed reactivation in

later part of their lives.
17 SO, WHY BOTHER?
 TREATMENT OF LTBI
18

 When LTBI reactivated, it will spread the disease in

the community.

 LTBI Rx prevents this sporadic reactivation &

dissemination of TB.

 Thus,it is certainly an essential component of TB

control in the community.
 Symptoms

Biopsy Signs

Diagnosis
of Active
TB
PCR CXR

Sputum
Culture
AFB

19
 TST Diagnosis
of LTBI IGRA

• Dependent on the
demonstration of
host immune
response toward
tuberculous
proteins.
20
 TUBERCULIN SKIN TEST (TST)
21

Robert Koch 1843 -1910

Pioneered the
Tuberculin Skin Test
 PRINCIPLE OF TST
22

 TST is based on the principle of delayed-type

hypersensitivity response to intradermal inoculation
of PPD, or tuberculin.
 TUBERCULIN SKIN TEST (TST)
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• However, interpretation of TST posts a big

challenge to the healthcare professionals.
 THE SHORTCOMINGS OF TST
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Tuberculin contains
>200 proteins, widely
shared among the TB
mycobacteria.

BCG NTM
 THE SHORTCOMINGS OF TST
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• Due to this cross-reactivity, it has a poor specificity in

population which have been extensively vaccinated
with BCG.

• Furthermore, NTM infection is relatively common in

tropical countries - further compound the diagnosis.
 NEW TESTS - IGRA
26

 Recently, with the invention of 2 new tests, collectively

known as IGRA
• QuantiFERON-Gold-In-Tube (QFT-GIT) test
• Elispot test (T-SPOT)
 the prospect of differentiating LTBI from BCG
vaccination/NTM infection has becoming promising.
 PRINCIPLE OF IGRA
27

2 to 3 specific antigens are utilised,

1. ESAT-6 (early secretory antigenic target-6)
2. CFP-10 (culture-filtrate protein-10)
3. TB 7.7 (only in QFT test)
• expressed in M. tuberculosis complex,
• absent from all strains of BCG & majority of NTM
 PRINCIPLE OF IGRA
28

 Because ESAT-6 & CFP-10 is not shared by

BCG & most NTM, T-cells of individuals with
BCG vaccination or NTM infection alone, will
not be stimulated to produce interferon-γ.

TB

BCG NTM
 PRINCIPLE OF IGRA
29

 Circulating T-cells of infected individuals are sensitised to TB

antigens (which include ESAT-6 & CFP-10).

 When the T-cells are incubated with these 2 antigens in the

lab, they are stimulated to secrete interferon-γ.

 The interferon-γ could be measured by:-

 ELISA technique (Quantiferon Test)

 ELISPOT technique (T-SPOT)

 QUANTIFERON TEST
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 T-SPOT
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 SENSITIVITY & SPECIFICITY
OF IGRA
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 Although this test is more specific, it still

cannot overcome the limitation that

 the test result is dependent on the immune

status of the tested individuals
 WHO SHOULD BE TESTED?
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 Only individuals who are at high risk of acquiring

LTBI or developing TB reactivation should be
investigated.

 Treatment might be considered for those who are

positive for LTBI.
 POSITIVE TST FOR LTBI
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Positive TST Type of Individuals

(Measurement)
≥5 mm • HIV-infected persons

• Organ transplant recipients

• Persons who are immunosuppressed for

other reasons (such as those taking the
equivalent of >15 mg/day of prednisolone
for ≥1 month or taking TNF-α antagonists)
 POSITIVE TST FOR LTBI
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Positive TST Type of Individuals

(Measurement)
≥10 mm • Close contacts

• Recent immigrants (< 2 years)

• Injecting drug users

• Residents & employees of high risk

congregate settings(such as correctional
facilities, nursing homes, homeless
shelters, hospitals & other healthcare
facilities)

• Persons with fibrotic changes on CXR

 POSITIVE TST FOR LTBI
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Positive TST Type of Individuals

(Measurement)
≥15 mm • Individuals from countries with low
incidence of TB
 WHO SHOULD BE TESTED?
37

• The goal of testing – to identify persons who are

going to benefit most from treatment.

• A pre-test evaluation should be made to identify

these individuals.

• There are two broad categories of individuals

1. Persons who have recent close contact
2. Immunocompromised individuals
 WHO ELSE SHOULD BE SCREENED?
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1. Individuals who are at increased risk of acquiring

TB infection (e.g. prison-warden, nursing home
residents/workers, intravenous drug users &
healthcare workers)

2. Immunocompromised individuals who are at

increased risk of reactivation (e.g. HIV infection,
patients on immunosuppresants, patients with
advanced organ failure)
 ALGORITHM FOR SCREENING &
TREATMENT
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Target individuals - screen for symptoms of

active TB

• If active TB suspected - CXR & sputum

direct smear & Mantoux test

• If otherwise – TST (Mantoux test)

• TST <5 mm – no further test
• TST ≥5 mm, may proceed with IGRA test
 PROPOSED ALGORITHM
OF SCREENING & Close contacts
TREATMENT OF LTBI

Immune competent Immune

individuals compromised
individuals

TST TST Work-up for active

TST ≥ 10 mm TB
< 5 mm 5 – 9 mm

IGRA test IGRA Test

Active TB Active TB ruled out
negative positive confirmed

S&S / CXR / Consider

S&S / CXR / prophylactic Rx
sputum positive sputum negative irrespective of LTBI
status

Active TB Latent TB

Active TB Rx
LTBI Rx

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 SHORTCOMING OF THIS ALGORITHM
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 Lack of longitudinal study that treatment of LTBI

using TST/IGRA is effective in preventing disease
reactivation in high burden countries.

 A study of this nature is desperately required.

 WHAT IS THE ADVANTAGE OF
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TARGETED SCREENING?

Active
TB

Latent
TB
 THE OCCULT TARGETS ARE FLAGGED!
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 ADVANTAGES OF TARGETED CONTACT
SCREENING
44

1. A positive TST is more likely to indicate LTBI - less

false positive result.

2. They are likely to benefit most from the treatment -

reactivation risk is higher in recent contact.

3. Besides, they may be more likely to accept therapy

& adhere to it.
 ANTITB REGIMENS FOR LTBI
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Drugs Duration Interval Completion criteria

Isoniazid 6-9 Daily  180 doses in 9 months (6-

months month regimen)
 270 doses in 12 months (9-
month regimen)

Isoniazid + 4 months Daily  120 doses within 6 months

rifampicin
Rifampicin 4 months Daily  120 doses within 6 months

Isoniazid & 3 months Once weekly  12 doses

rifapentine*

• *Rifapentine is not currently registered in Malaysia.

• *Its use should be restricted to those on DOT
 TAKE HOME MESSAGES
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1. Sporadic reactivation is a cause of continuous

dissemination of TB in Malaysia.

2. Treatment of LTBI may be incorporated into TB

elimination programme.

3. Nonetheless, longitudinal study is needed to prove

the long-term effectiveness of this strategy.
47 THANK YOU
ykpang@ummc.edu.my
