CHEST Special Features

GLOBAL MEDICINE

Relevance of Latent TB Infection in

Areas of High TB Prevalence
Surendra K. Sharma, MD, PhD; Sandeep Mohanan, MD; and Abhishek Sharma, MBBS

About one-third of the world population has latent TB infection (LTBI), the majority of which is
distributed in 22 high-burden countries. Early diagnosis and treatment of active TB remains the
top priority in resource-poor countries with high TB prevalence. Notwithstanding, because LTBI
contributes significantly to the pool of active TB cases later on, its diagnosis and treatment is essen-
tial, especially in high-risk groups. The lack of a gold standard and several limitations of currently
available tools, namely the tuberculin skin test and interferon-g release assays, are major con-
straints for LTBI diagnosis. In areas with high TB prevalence, interferon-g release assays have
not shown superiority over the conventional tuberculin skin test and are yet to be systematically
studied. Decisions regarding LTBI treatment with isoniazid preventive therapy should be made,
keeping in mind the high prevalence of isoniazid resistance in these settings. Although efforts
to shorten the LTBI treatment duration are encouraging, most trials have focused on adher-
ence and toxicity. Future trials on short-duration regimens in high-burden settings should address
drug efficacy issues as well. LTBI management, therefore, should comprise a targeted screen-
ing approach and individualization of LTBI treatment protocols. In addition, efforts should
focus on airborne infection control measures in high-burden countries. A high prevalence of
drug-resistant TB, the HIV epidemic, and delays in the diagnosis of active TB cases are other
major concerns in areas of high TB prevalence. There is ample space for further research in these
countries, whose outcomes may strengthen future national guidelines.
CHEST 2012; 142(3):761–773

Abbreviations: ART 5 antiretroviral therapy; BCG 5 Bacillus Calmette-Guérin; CDC 5 Centers for Disease Control
and Prevention; HBC 5 high-burden country; HCW 5 health-care worker; IGRA 5 interferon-g release assay; INH 5 iso-
niazid; IPT 5 isoniazid preventive therapy; LTBI 5 latent TB infection; MDR 5 multidrug resistant; Mtb 5 Mycobacterium
tuberculosis; NTM 5 nontubercular mycobacteria; TST 5 tuberculin skin test; WHO 5 World Health Organization

Latent TB infection (LTBI) is the presence of

Mycobacterium tuberculosis (Mtb) in an individ-
ual without clinical, imaging, or microbiologic evi-
dence of active disease. Based on the tuberculin skin
test (TST), which is also known as the Mantoux test,
approximately one-third of the world population is
Manuscript received January 17, 2012; revision accepted May 11,
2012.
Affiliations: From the Department of Internal Medicine
(Drs S. K. Sharma, Mohanan, and A. Sharma), All India Institute
of Medical Sciences, New Delhi, India; and Medical University-
Pleven (Dr A. Sharma), Pleven, Bulgaria.
Correspondence to: Surendra K. Sharma, MD, PhD, Depart-
ment of Medicine, All India Institute of Medical Sciences, New
Delhi 110 029, India; e-mail: sksharma.aiims@gmail.com
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-0142
believed to have LTBI.1 This burden is distributed
largely among resource-poor countries. LTBI preva-
lence rates of up to 79% have been noted, with an
annual risk of TB infection ranging from 0.5% to
14.3% among health-care workers (HCWs) in resource-
limited countries.2 Poverty, malnutrition, tropical
infections, addictions, overcrowding, illiteracy, poorly
functioning health-care systems, and political imbal-
ance are important contributors to this situation.
Worldwide, TB prevalence seems to be decreasing;
about 12 million TB cases were estimated in 2010
(178 cases per 100,000 population).1 According to the
World Health Organization (WHO), 82% of this global
burden is distributed among 22 high-burden countries
(HBCs).1 The highest prevalence was estimated in
African countries, such as South Africa and Congo
Republic, and southeast Asian countries, like Cambodia

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 and Myanmar. India holds the global rank-one position
in the total estimated cases of TB (. 3.4 million), fol-
lowed by China, South Africa, Nigeria, and Indonesia.
Although treatment of active TB is the overriding
priority in TB control, the diagnosis and treatment
of LTBI is equally important because it significantly
contributes to active cases later on. Several guide-
lines are available for LTBI management, but from
the priority point of view, these are applicable only
to countries with low TB prevalence. In areas with
high TB prevalence, the enormous number of sub-
jects with LTBI who would have to be screened and
treated would have to be balanced against the lim-
ited resources available for treating active TB cases.
Repeated exogenous infections due to persistent
mycobacterial sources in the environment along with
poor airborne infection control policies further com-
plicate this situation. The administration of Bacillus
Calmette-Guérin (BCG) vaccination early in life, which
so far has been the prime strategy, has done little to
solve this predicament. Thus, decisions regarding the
diagnosis and treatment of LTBI should address the
various high-risk groups within the population. This
is known as targeted screening, and it holds the key
in implementing focused therapy. In addition to
socioeconomic concerns, the presence of high-level
background isoniazid (INH) resistance and several
uncertainties regarding diagnosis and treatment have
hampered formal synthesis of guidelines for LTBI
management in resource-limited countries.
Immunopathogenesis and Risk Factors
Various outcomes following exposure to Mtb are
depicted in Figure 1. In the general population, the
lifetime risk of progression from LTBI to active dis-
ease is about 5% to 10%; with HIV coinfection, this
rises to 30% (annual risk, 10%).5 The pathogenic state
of bacterial infection and probability of reactivation
depend on the balance between host immunity and
the influence of exogenous factors (Fig 2). It was
previously suggested that Mtb exists in a dormant
state during LTBI, which may later be resuscitated
to actively growing bacilli by certain resuscitation-
promoting factors.7 However, perspectives propose a
dynamic relationship, between a quiescent and an
active state having bidirectional shifts, depending on
the mycobacterial load and virulence, and the host’s
immune mileu.8 This concept suggests that a bulk of
the so-called latent infection may actually be asymp-
tomatic active infection. Future research may help to
develop novel vaccines against LTBI persistence and
reactivation.9
In addition to immune mechanisms, several latency-
related genes, such as a crystalline (acr) and s factor
(sigF), have been identified.10 Genetic determinants
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associated with the susceptibility of developing TB
have also been identified and include the natural
resistance-associated macrophage protein (NRAMP),
vitamin-D receptor (VDR), and nitric oxide synthase
(NOS2A). Their polymorphisms may play a signifi-
cant role in populous HBCs.11
Growing urbanization, explosive economic growth,
and aggressive medical treatment in developing coun-
tries have led to a surge in altered immunologic states
and diseases that multiply TB reactivation risk (Table 1).
Added to the background environmental Mtb persis-
tence, these tend to push the present goals of TB
control farther away. This review deals with the pre-
sent principles of LTBI diagnosis and treatment and
their role in controlling the TB epidemic in HBCs.
Diagnosis of LTBI
Even as TB continues to intimidate the human race
since time immemorial, the lack of a gold standard
test for LTBI diagnosis remains a major impediment
in recognizing the population at risk. Contact investi-
gation promptly identifies new sources of environ-
mental transmission and is the best method to isolate
the person at risk. This should ideally be incorporated
into national programs, but inadequate finances and
lack of trained human resources limit such reforms
in several countries. The TST, . 100 years old, is still
the most widely used tool. Even though the advent of
interferon-g release assays (IGRAs) has shown promise
in overcoming several drawbacks of the TST,13 as its
utility unfolds, the presumed superiority of IGRAs seem
to diminish, particularly for high-TB-burden settings.
Tuberculin Skin Test
TST quantifies the cell-mediated immune response
using a protein derivative of the bacilli to elicit delayed-
type hypersensitivity. Table 2 shows criteria for inter-
pretation of TST in various clinical settings. When
a smaller reaction is used as a cutoff for TST posi-
tivity, sensitivity increases for those who are at high-
est risk for reactivation TB. However, TST specificity
decreases with increased BCG vaccination coverage
and presence of environmental nontubercular myco-
bacteria (NTM).
Currently, one-time BCG vaccination at birth is a
routine practice of national programs in developing
countries. Although it is not possible to distinguish
between a tuberculin reaction that is caused by true
infection vs that caused by BCG, only 8% of subjects
who receive the BCG vaccine at birth have a positive
TST result 15 years later.15 Accordingly, the history
of BCG vaccination may be ignored when TST is
interpreted in adults.16 Similarly, the older the child,
the lesser the probability for the reaction to be con-
founded by prior BCG administration.
Special Features
 Figure 1. Outcomes following exposure to Mycobacterium tuberculosis in an individual: scope for
interventions in TB disease control. Following environmental exposure with M tuberculosis, about 30% of
individuals become infected. Out of these, 5% to 10% progress to primary pulmonary TB, whereas the
rest (90%-95%) undergo containment but persist to LTBI because a balance strikes between protective
host immunity and bacterial virulence. The lifetime reactivation risk is about 10%, 20%,3,4 30%,5 and
40%3,4 for healthy adults, children aged , 5 years, people with HIV, and children aged , 2 years, respec-
tively. Various other high-risk clinical settings, such as administration of biologic agents or steroids,
chronic renal failure, diabetes mellitus, and so forth (see Table 1) tilt this balance in favor of increased
bacterial multiplication. The reactivation risk is greatest after the first 2 years of exposure. TB reactiva-
tion may express in the form of pulmonary, extrapulmonary, or miliary TB. Pulmonary TB cases again
perpetuate the cycle of environmental transmission. Thus, interventions to decrease global TB burden
can be considered at the following three levels: (1) airborne infection control, (2) intensive case finding
and treatment, and (3) diagnosis and treatment of latent infection. LTBI 5 latent TB infection.

Various studies conducted in India show NTM
prevalence rates varying from 1% to 28%, with
Mycobacterium fortuitum and Mycobacterium chelonae
being the most common isolates.17 Most individuals
harboring LTBI (due to Mtb) elicit a larger reaction
compared with that with NTM antigens, especially
when there is a history of contact. Sometimes, it may
be difficult to distinguish the reactions induced by
Mycobacterium bovis from Mtb. However, M bovis
infections have become relatively rare in India because
of the practice of boiling milk, although this may not
be the case in many African nations.
Interferon-g Release Assays
The IGRAs are a new class of in vitro assays that
measure interferon-g released by effector T cells fol-
lowing stimulation with Mtb antigens (namely ESAT-6,
CFP-10, and TB7.7). The QuantiFERON-TB Gold
In-Tube (Cellestis) and the T-SPOT.TB (Oxford

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 Figure 2. Immune mechanisms of containment and persistence of M tuberculosis. Following infection, dendritic cells prime T lympho-
cytes, which recruit and activate macrophages; this contains the initial phase of bacterial multiplication. Failure of this containment process
results in primary TB. Viable bacteria may persist either within focal lesions or outside a focal lesion. Within focal lesions, they may either
exist as sequestered foci or may be walled off by fibrosis and calcification. When outside focal lesions they are held in check by host immu-
nity. DC-SIGN 5 dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin; IFN-g 5 interferon-g; MHC 5 major
histocompatibility complex; TCR 5 T-cell antigen receptor; TLR-2 5 toll-like receptor 2; TNF-a 5 tumor necrosis factor-a. See Figure 1
legend for expansion of other abbreviation. (Reprinted with permission from Stewart et al.6)

Immunotec) tests are now widely used in the devel-
oped world. The growing economies of developing
nations have made them a lucrative market for com-
mercial IGRAs. This has led to the indiscriminate use
of IGRAs, even for diagnosis of active TB, where they
play no role.18,19 This should be highly discouraged
because several controversies still exist regarding their
operational value, such as their discordance with the
TST,20 role in immunocompromised subgroups,21 role
in HCWs,22 role of serial testing,23 and ability to iden-
tify people who are likely to progress to active TB.24
In high-burden settings, IGRAs tend to have
decreased sensitivity because of the confounding
effects of malnutrition, NTM exposure (especially
Mycobacterium kansasii and Mycobacterium marinum),
leprosy, and parasitic and other tropical infections
that may alter the host’s T helper 1/T helper 2 cell bal-
ance. Additionally, in such settings, IGRAs seem to
Table 1—Relative Risk of Reactivation TB in Various
Clinical Settings
Clinical Setting Relative Risk
AIDS
HIV infection
Solid organ transplantation (renal)
Silicosis
Jejunoileal bypass
Chronic renal failure on dialysis
Carcinoma of head and neck
Abnormal chest radiograph with upper-lobe
fibronodular disease typical of healed TB infection
TNF-a inhibitor therapy
Glucocorticoid therapy
Children aged , 4 y
Diabetes mellitus
Gastrectomy
Smoker (1 pack/d)
TNF-a 5 tumor necrosis factor-a. (Adapted with permission from
Lobue and Menzies.12)
detect recent as well as remote T-cell responses.
Dheda et al4 reported a pooled sensitivity of
about 77% for the QuantiFERON-Gold test to detect
culture-confirmed TB, but when analyzed separately
for high- and low-burden areas, it was 69% and 86%,
respectively. In individuals with immunodeficiency,
the sensitivity of IGRAs decreases with higher degrees
of immunosuppression.25 A meta-analysis on the value
of IGRAs in active pulmonary TB found pooled sen-
sitivities in the range of 84% to 88% for both the
QuantiFERON-Gold and T-SPOT.TB tests in individ-
uals without HIV, but the same decreased to 65% to
68% in individuals with HIV infection18 (Figs 3, 4).
As noted earlier, Mtb persistence and reinfection
is a major concern in IGRA interpretation. Likewise,
strong IFN-g responses persisted even after 6 months
of INH therapy in Indian HCWs,26 implying contin-
uous nosocomial exposure, although high levels of
INH resistance may also contribute. This raises doubts
about the practical value of the currently recom-
mended LTBI treatment regimen in high-burden
settings. Further, cost of IGRAs is another factor that
makes it less preferable to TST. Future studies should
110-170 focus on improved versions of these tests that are
50-110 more user friendly and cost-effective. Table 3 com-
20-74
30
pares the utility of IGRAs and TST.
27-63
10-25 TST, IGRA, or Both?
16
6-19 Accumulated evidence at present suggests that in
HBCs, neither IGRAs nor TST accurately identify
1.7-9 people who will benefit from treatment. A systematic
4.9
review on their predictive value by Rangaka et al24
2.2-5
2-3.6 reported false-positive rates . 50% for both. Despite
2-5 its several limitations, the TST still remains a simple
2-3 and cost-effective tool for both epidemiologic research
and TB control. Accordingly, the latest European
Centre for Disease Prevention and Control guidelines32

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 Table 2—Criteria for TST Positivity in Various
Clinical Settings
Width of Induration Positive Reaction
ⱖ 5 mm People with HIV infection
Close contacts of patients with active TB
Patients with iatrogenic immunosuppressiona
Patients having fibrotic changes in chest
radiograph suggestive of old TB
Chronic medical disease increasing
susceptibility to infectionb
ⱖ 10 mm Residents and staff of long-term-care
facilities
Homeless people
IV drug users
Health-care workers
Recent TST conversion (increase by 10 mm
over past 2 y)
Children aged , 4 y
ⱖ 15 mm People with no particular risk factors
Data from Reference 14. TST 5 tuberculin skin test.
aOrgan transplant recipients, people taking biologic agents or steroids
(equivalent of 15 mg/d prednisolone for . 1 mo).
bPatients with silicosis, diabetes mellitus, chronic renal failure, lym-
phoreticular/solid malignancies, or gastrectomy/ileojejunal bypass or
with a weight loss of ⱖ 10% of ideal body weight.
and a policy statement issued by the WHO19 dis-
courage the use of IGRAs over TST, especially in
high-prevalence settings. A two-step strategy using a
combination of TST and IGRA in sequence has been
suggested by the National Institute for Health and
Clinical Excellence33 and European Centre for Disease
Prevention and Control32 guidelines, especially for
very-high-risk groups, such as those with HIV infec-
tion with low CD4 cell counts (, 200/mm), in low-
prevalence settings. However, for countries with high
Figure 3. Pooled sensitivity of QFT-GIT and TSPOT among peo-
ple with HIV infection with confirmed active pulmonary TB from
various studies conducted in low- and middle-income countries.
QFT-GIT 5 QuantiFERON-TB Gold In-Tube; TSPOT 5 T-SPOT.
TB. (Reprinted with permission from Metcalfe et al.18)
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TB prevalence, further evidence is required before
this can be routinely recommended.
Treatment of LTBI
Before considering treatment of LTBI, a meticu-
lous assessment to rule out active TB is mandatory;
otherwise the patient may develop complications in
the form of emergence of drug-resistant strains, dis-
ease progression, and mortality. Many popular LTBI
regimens have been described in the past 2 decades,
broadly, isoniazid preventive therapy (IPT) and short-
course rifamycin-containing regimens (Table 4 ).
However, the overall efficacy of various regimens is
thwarted by issues concerning adherence, duration
of protection, and drug toxicity.
A Cochrane meta-analysis that examined the per-
formance of 6- and 12-month INH therapy (300 mg
daily) in people without HIV reported 60% effi-
cacy, which was only slightly higher for the 12-month
regimen.39 One person was saved from developing
active TB when 35 people were treated with INH for
6 months.39 However, a major practical difficulty for
IPT, especially among people with low socioeconomic
status, is poor adherence. It is important to under-
stand that if proper adherence is ensured, 12-month
INH therapy is definitely more effective than 6-month
INH therapy.37 The WHO currently recommends
IPT for LTBI treatment at a daily dose of 5 mg/kg
(max 300 mg/kg) for at least 6 months and ideally
for 9 months.40 Table 4 summarizes and compares
short-course LTBI treatment regimens with IPT.
The reported Three Months of Weekly Rifapentine
and Isoniazid for M Tuberculosis Infection study
(PREVENT TB) showed that a directly observed
weekly regimen of rifapentine (900 mg) and INH
(maximum dose 900 mg) for 12 weeks was noninfe-
rior to 9 months of IPT and had better adherence
rates than the latter.36 Accordingly, the Centers for
Disease Control and Prevention (CDC) revised its
treatment guidelines for people aged . 12 years in
countries with low and medium TB prevalence. Fur-
ther clinical trials are required to demonstrate the
efficacy and cost-effectiveness of this regimen for
high-prevalence settings.
It has long been argued that in developing coun-
tries, available resources should be conserved for
managing active TB. In populous nations like India
or China, the prospects of treating the majority of
the population over 6 or 9 months seem unfeasible
and nonproductive. In addition, high-prevalence rates
of INH resistance in these countries, ranging from
10% to 39%,41,42 preclude widespread use of INH
monotherapy for LTBI. Failure of IPT because of
the emergence of drug-resistant strains has been
reported.43 However, the fear of emergence of drug
CHEST / 142 / 3 / SEPTEMBER 2012 765
 In addition, 6-month IPT had only a limited role
compared with extended therapy for 36 months in
the high-TB-burden setting of Botswana among indi-
viduals with HIV.47 This again emphasizes the priority
of individual TB case management and environmen-
tal infection control above LTBI treatment in resource-
limited countries. Once the decision to treat LTBI
has been made, the choice of regimen has to be indi-
vidualized based on toxicity risk, pill burden, and
clinical setting. Effective information, education, and
counseling activities along with directly observed pre-
ventive therapy48 may help to achieve higher comple-
tion rates.

Pertinent Issues in Endemic Countries

Figure 4. Pooled sensitivity of QFT-GIT and TSPOT among
people without HIV infection with confirmed active pulmonary
TB from various studies conducted in low- and middle-income
countries. See Figure 3 legend for expansion of abbreviations.
(Reprinted with permission from Metcalfe et al.18)
resistance should not hamper the administration of
IPT to high-risk groups provided that the importance
of ruling out active TB and continued drug resis-
tance surveillance is emphasized.44,45 Further, sys-
tematic background INH resistance mapping should
be carried out in these countries.
Although definite data on the duration of effective-
ness of LTBI treatment are lacking, risk of reexposure
and degree of immunosuppression are major deter-
minants of the waning protection with time. A study
in the setting of high TB-HIV prevalence in Zambia
revealed durability of protection for at least 2.5 years.46
LTBI and the HIV Epidemic
Globally, about 13% of TB cases occur among
people with HIV (. 50% in some African countries).1
Figure 5 illustrates global TB-HIV coinfection rates.
People with HIV infection and Mtb have a roughly
30% lifetime reactivation risk, and this increases with
disease progression.5 This is further complicated by
late presentation and significant delay in accessing
antiretroviral therapy (ART) in resource-limited coun-
tries. Therefore, in the HBCs, prevention of TB is
sine qua non to reduce the morbidity and mortality
attributed to HIV infection. Exogenous infection
plays a significant role in HIV-associated TB in set-
tings of high TB prevalence.49 Continuous environ-
mental exposure to Mtb also increases the chance of
TB reactivation by increasing the total host mycobac-
terial load.50 Unfortunately, only DNA fingerprinting
technology can distinguish reinfection vs reactivation

Table 3—Comparison of the Utility of TST and IGRAs in Areas of High TB Endemicity

Characteristics TST IGRA

Sensitivity4,24,27,28, a 72%-100% QFT-GIT test, 69%
T-SPOT.TB test, 72%-90%
Specificity24,27, a,b 41%-97% 50%-99%
Quantity of evidence Abundant Fewer
Material costs Inexpensive Costly
Reporting Patient needs to return after 2 d Single visit
Interpretation Subjective to technique and observer bias Yes/no answer (may also be indeterminate)
Predictive value for reactivation TB Poor Poor
Resource input Minimum laboratory equipment, but manpower Requires laboratory expertise, expensive
and cold storage required equipment, and phlebotomy facilities
HIV population29 Overall sensitivity less than that for Sensitivity wanes with the progression of
immunocompetent population disease; overall performance is similar to TST
Pediatric population30,31 More sensitive, preferred Less-sensitive and more-indeterminate results
IGRA 5 interferon-g release assay; LTBI 5 latent TB infection; QFT-GIT 5 QuantiFERON-TB Gold In-Tube. See Table 2 legend for expansion of
other abbreviation.
aData are based on comparison studies among active TB cases. Absolute sensitivity and specificity for LTBI cannot be obtained in the absence

of a gold standard. TST sensitivity is higher for a lower cutoff for positivity.
bSpecificity tends to be relatively lower for TST in the Bacillus Calmette-Guérin-vaccinated cohort in low-prevalence countries. In adults from

high-burden countries, the specificity of TST tends to be higher (due to waning Bacillus Calmette-Guérin effect), and that of IGRAs tends to be
lower because of repeated infections.

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 Table 4—Summary of Various Popular Regimens That Have Been Used for LTBI Treatment
Regimen Efficacy
Daily H: 6 mo 69%
Daily H: 9-12 mo 90%-93%
Daily RH: 3-4 mo Equal to 6-mo H
Daily RZa: 2 mo Equal to 9- to 12-mo H
Daily R: 3-4 mo34 65%
Twice-weekly RH: 3 mo35, b Equal to 6-mo H
Weekly RH: 3 mo35,36, b Equal to 9-mo H
H 5 isoniazid 5 mg/kg; R 5 rifampicin 10 mg/kg; Z 5 pyrazinamide. See Table 3 legend for expansion of other abbreviation. (Adapted with permis-
sion from Menzies et al.37)
aRZ regimen is no longer recommended because of high incidence of drug toxicity.38
bIn the weekly and twice-weekly regimens, H and R were used at doses of 900 mg each.35
TB and is not easily available in resource-limited set-
tings.51 Several issues complicate TB diagnosis in the
setting of HIV coinfection, which can also create con-
fusion in differentiating latent from active disease
(Table 5).
The influence of HIV disease stage on the efficacy
of LTBI treatment is still not known and warrants
further study. The recommendation of WHO to ini-
tiate ART at a CD4 cell count of 350/mm3 may signif-
icantly bring down TB reactivation rates by restoring
immunity at an earlier stage of the disease. Resource-
limited countries need to undertake IPT feasibility
studies to evaluate the impact of this recommendation.
Nevertheless, a study conducted in Brazil reported
efficacy of IPT, regardless of the CD4 cell count, in
addition to the protective effect offered by ART.56
Unlike the situation in low-prevalence countries,
studies among individuals with HIV in high-burden
settings have shown poor concordance between the
TST and IGRAs, with only modest predictive values
for either.29,57 Increased number of indeterminate
test results and reduced sensitivity at lower CD4 cell
counts were reported with IGRAs.25 Among the two
commercially available kits, a higher sensitivity was
reported with T-SPOT.TB (about 72%) than with the
QuantiFERON-TB Gold In-Tube (about 61%).29
Table 6 describes the major lacunae identified in the
interpretation of IGRAs in the population with HIV
infection. Based on available evidence, IGRAs cur-
rently cannot be recommended over TST to screen
people living with HIV for eligibility to receive IPT
in high-TB-prevalence areas.19
For intensified case finding, WHO recognizes that
the absence of four symptoms, namely fever, current
cough, night sweats, and weight loss, has a nega-
tive predictive value of 97.7% for active TB in high
TB-HIV coinfection areas and that such patients can
be safely treated for LTBI.45,59 This holds true irre-
spective of the degree of immunosuppression, people
receiving ART, people with a history of TB, and preg-
nant women.59 A Cochrane meta-analysis among
patients with HIV infection revealed a 32% reduction
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Adherence Incidence of Drug-Induced Hepatitis
50% 1%-5%
, 50% 1%-5%
Slightly better (by 6%) than 9- to 12-mo H 1%-5%
Slightly better (by 6%) than 9- to 12-mo H 3%-5%
Much better (by 22%) than 9- to 12-mo H , 1%
95% 2.4%
82%-96% 0.4%-1.5%
in the risk of developing TB with any LTBI treatment
regimen, which increased to 62% when the TST result
was positive.60 However, IPT was found to be rela-
tively safer than the combination regimens. Significant
pharmacokinetic drug interactions and additive toxic-
ities with ART preclude the use of rifamycin-containing
combination regimens as the first choice for LTBI
treatment. Accordingly, current WHO guidelines
for resource-limited countries strongly recommend
at least 6-month INH therapy for both adults and
children, regardless of TST, after excluding active TB.45
It also conditionally recommends a 36-month IPT
regimen in high-prevalence settings, although adher-
ence issues may interfere with treatment completion.
Among people with HIV, IPT was found to reduce
the risk of reactivation by 82% when given immedi-
ately after cure of a first TB episode61 and by 55%
when given for a history of cured TB.62 Accordingly,
WHO guidelines advocate secondary prevention with
INH for patients with HIV who have successfully
completed their TB treatment.45
The fear of developing drug-resistant TB is one of
the arguments cited for not offering INH for latent
TB-HIV coinfection in endemic settings. However,
this was not noted in a large prospective study from
Figure 5. Prevalence of HIV in new TB cases reported in 2010.
(Reprinted with permission from the World Health Organization.1)
CHEST / 142 / 3 / SEPTEMBER 2012 767
 Table 5—Difficulties in the Diagnosis of TB in People
With TB-HIV Coinfection in Endemic Countries
Characteristic Reference
Increased prevalence of asymptomatic active TB that
may preclude symptom-based diagnosis
Increased rates of occult disseminated TB that may
cause gross underestimation of the true prevalence
Higher incidence of extrapulmonary TB compared
with the non-HIV population
More frequent sputum smear-negative active TB cases
Higher proportion of TST-negative TB infection
See Table 2 legend for expansion of abbreviation.
South Africa63 and, therefore, should not be a hin-
drance to the use of IPT in developing nations.45 In
countries with high prevalence of INH resistance,
IPT provision may have to be based on regional resis-
tance mapping, as mentioned previously. In response
to the dual epidemic, the WHO highlights interven-
tions like ART provision and the three Is for HIV/TB,
namely intensified TB case finding, infection control,
and IPT, as part of prevention, care, and treatment
services.64 With the current scale-up of ART services,
future trials on LTBI treatment should assess the
duration of protection, cost-effectiveness, and value
of combination with ART.
LTBI and Drug Resistance
Globally, about 3.6% of incident TB cases are mul-
tidrug resistant (MDR) (ie, resistant to INH and
rifampicin), one-half of which are estimated to occur
in China and India.65 Estimates in India reveal that
up to 20% of patients with TB who are retreated, have
relapsed, or have previously defaulted are infected
with MDR isolates.66 Household contacts of patients
with MDR TB are at high risk of infection, particularly
in the first 2 years.67 A prospective study from Peru
observed 4,500 household contacts of patients with
MDR-TB and revealed the high probability of devel-
oping MDR-TB over a period of 4 years.68 This exposes
limitations of current guidelines on the duration of
contact monitoring in this scenario. The prevalence
Table 6—Knowledge Gaps Restricting the Use of IGRAs
in the Diagnosis of TB-HIV Coinfection
Knowledge Gap
Accuracy and reliability for the diagnosis of LTBI
Value in predicting who to treat
Identification of cutoff points for various ranges of CD4 cell counts
Prognostic ability to predict progression from latent to active disease
Role in monitoring response to treatment in latent and active disease
Feasibility, acceptability, and cost-effectiveness
Role in point-of-care setting compared with TST for diagnosing
latent disease
Data from Pai et al.58 See Table 2-4 legends for expansion of
abbreviations.
768
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of active TB in household contacts of patients with
MDR-TB range from 1.9% in adults to up to 11.2%
in children.67,69,70 The Revised National TB Control
Program of India advocates early diagnosis and treat-
52
ment in symptomatic contacts of patients with MDR-TB
53 as an important element of TB prevention. However,
the insurgence of extensively drug-resistant strains
54,55 and reports on the appearance of totally drug-resistant
strains are further blows to TB-control measures.
55
54
A paucity of evidence-based guidelines for the
treatment of LTBI in MDR-TB contacts is very much
acknowledged. A careful evaluation to assess the
reactivation risk should be made, and a combination
regimen should be started, considering the resistance
profile of the suspected Mtb isolates in question, for
6 to 12 months. LTBI-proven contacts of INH mono-
resistant TB have been successfully treated with the
4-month rifampicin regimen.16,34 Among the fluoro-
quinolones, moxifloxacin is a promising drug for the
treatment of both active TB infection and LTBI.71
Unfortunately, their unrestricted use for community-
acquired pneumonia has facilitated the entry of drug-
resistant strains by inadvertent monotherapy for
unsuspected TB.72 In high-prevalence countries, flu-
oroquinolone use should be safeguarded through
strict regulatory policies to prevent weakening of
the drug arsenal. Newer promising molecules, such as
TMC-207, SQ109, PA-824, and FAS20013, have potent
in vitro bactericidal action against MDR-TB and latent
TB isolates.38,51 These molecules are being evaluated
in phase 1 and 2 clinical trials but have a long way to
go before they see daylight in developing nations.
LTBI in Children
Childhood TB has been neglected in national TB
control programs for a long time. In high-burden set-
tings, reactivation rates of up to 40% are observed
in children aged , 2 years, with most occurring in
the first year following infection.4 The importance of
LTBI diagnosis and treatment in this cohort, there-
fore, should be acknowledged in view of children’s
developing immune systems, especially for those
aged ⱕ 5 years.33 In children, IGRAs perform poorly
in terms of sensitivity30 and provide more indeter-
minate results,31 and the specificity is not better for a
higher cutoff for a positive TST result.30 In those who
received BCG at birth, . 50% will have a negative
TST result at age 9 to 12 months and almost all will
be negative by 5 years of age.73 Currently, TST is
the more-valuable and cost-effective tool for LTBI
diagnosis in children living in high-prevalence coun-
tries, regardless of BCG status,74,75 and should not be
replaced by IGRAs.19
The CDC,76 WHO,44 and National Institute for
Health and Clinical Excellence30 guidelines recommend
Special Features
 at least 6 months of IPT (10 mg/kg daily) for children
with LTBI. However, a trial failed to reveal signifi-
cant survival benefits in children with HIV coinfec-
tion.77 The Revised National TB Control Program
guidelines in India recommend treatment of all close
household contacts aged , 6 years with 6 months of
IPT (5 mg/kg daily), regardless of BCG vaccination
status.78 However, operational analyses in develop-
ing countries have revealed that less than one-fourth
of the deserving pediatric population receives screen-
ing and IPT services.79,80 This must be dealt with strict
surveillance protocols and education of field-level
staff and program managers in national TB-control
programs.
Relevance of Airborne Infection Control
Measures to LTBI Management
Rapid expansion of medical therapeutics in devel-
oping countries has greatly amplified the susceptible
population for reactivation TB. HCWs from endemic
countries were found to have an annual risk of TB
infection of 8.4% (range, 2.7%-14%).81 In addition,
the prevalence of diseases impairing host immunity,
such as diabetes mellitus and chronic renal disease,
are ever increasing. However, routine screening and
treatment of LTBI is not currently advisable in HBCs,
especially because of the large population they repre-
sent and the increased risks for drug toxicity. Hence,
decisions regarding LTBI treatment should be indi-
vidualized until large-scale studies have conclusively
shown favorable results in specific risk groups. A
summary of evidence for the diagnosis and treatment
of LTBI in various iatrogenic risk groups appears in
Table 7.
The overwhelming danger of reinfection and mul-
tiplying risk groups underscore the need for com-
mensurate airborne infection control measures. To
tackle this, the CDC has proposed the following
three-level hierarchy: (1) administrative control,
(2) environmental control, and (3) respiratory protec-
tion control.76 Administrative control is the prompt
identification, segregation, triaging, and case manage-
ment at the facility level, a prerequisite for further
control measures. Environmental (airborne infection)
control works on the principle of dilution of infectious
particles through natural or mechanical methods. Sug-
gested basic recommendations are summarized in
Table 8. Additionally, future design of health-care
facilities should consider patient flow patterns and
isolation strategies to minimize the spread of airborne
nosocomial infections. Particular attention should be
given to facilities that provide integrated TB-HIV
management services and to those that deal with
drug-resistant TB.90 Respiratory protection devices,
pertaining mainly to people who are at highest risk
(laboratory staff and various categories of health-care
providers [eg, ICU staff, bronchoscope operators,
thoracic surgeons]), include N95 and FFP2 masks.
Individual guidelines on airborne infection control
have now come up in several developing nations.90
Political commitment is essential to plan, control, and
supervise these measures at the community level for
a good TB control program.
Conclusion
In developing countries, the problem of high TB
burden sometimes eclipses the real issues of poor
reliability of diagnostic tools and treatment-related
concerns. Delayed diagnosis of active TB cases and
the emergence of MDR-TB strains are additional
issues. The moral argument that every infected person
deserves treatment, just as in other chronic diseases
like HIV and hypertension, may be overshadowed by
the real problem of scarce resources, but this matter of
contention seems largely one of political commitment

Table 7—Evidence-Based Updates on the Diagnosis and Management of LTBI in Selected High-Risk Groups

Risk Factor Diagnostic Protocola Treatment Regimen

Organ transplantation b82,83 TST and IGRAs perform similarly 9- to 12-mo H
Hemodialysis16,84,85 IGRAs preferred to TST (two -step testing may be advisable) 9-mo H
Biologic therapyc86-88 IGRAs preferred to TST (TST if effect of BCG is minor) Preferred, 9- to 12-mo H; alternative, 3-mo HR
Health-care workersd23,77 No evidence for superiority of either TST or IGRA, but Preferred, 9-mo H; alternatives, 6-mo H or 4-mo R
one-time IGRA may prevent excess false positives and
thus overtreatment in low burden settings
BCG 5 Bacillus Calmette-Guérin. See Table 1-4 legends for expansion of other abbreviations.
aA person is considered to be infected if he or she has a history of TB or if the chest radiograph shows suggestive infiltrates despite negative
immunologic test results. Recommendations supporting IGRAs are based primarily on studies conducted in low-burden countries and cannot be
extrapolated to high-burden settings where IGRAs, in general, have not been shown to be superior to TST. Large-scale studies that are conducted
exclusively in these selected risk groups may reveal their exact role in endemic settings.
bIncreased toxicity has been reported with the H regimen following liver transplantation.83,84

cBiologic agents include anti-TNF-a therapy, especially infliximab, and monoclonal antibodies against various immune mediators, which are used

against inflammatory diseases or malignancies.

dSerial testing for health-care workers is not advised in high-prevalence settings.23

journal.publications.chestnet.org CHEST / 142 / 3 / SEPTEMBER 2012 769

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 Table 8—Basic Recommendations on Environmental
Control of Airborne Infection
Recommendation
Adequate natural ventilation in all patient-care zones of health-care
facilities should exist.
Requirements for natural ventilation are an hourly average
ventilation rate of the following:
160 L/s per patient for isolation rooms (minimum of 80 L/s
per patient)
60 L/s per patient for general wards and outpatient departments
2.5 L/s/m3 for corridors and spaces not used for fixed patient care
Alternative modes such as hybrid (mixed-mode) ventilation,
mechanical ventilation, ultraviolet germicidal irradiation
devices, and use of HEPA filters should be considered
when natural ventilation is inadequate.
The airflow should start from the source and be directed outdoors.
Data from Atkinson et al.89 HEPA 5 high-efficiency particulate air.
rather than one purely of finances. Nevertheless, eco-
nomic evaluations are necessary to justify the diver-
sion of money and trained human resources. Despite
these obstacles, the success seen among individuals
with HIV infection suggest that targeted screening
and therapy, especially for young children and other
high-risk groups, which have so far been ignored,
should be pursued. Rather than comprehensive cov-
erage, individualization of treatment protocols would
be a step in the right direction. However, prudence
should be maintained to ensure that LTBI treatment
does not divert resources from treatment of active TB
or from offering ART services to needy patients. The
need for systematic trials focusing on high-risk groups
in resource-limited settings is very much felt, and this
may help to formulate clear-cut individual national
guidelines on LTBI management in the future.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article.
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