Most individuals who get exposed to Mycobacterium tuberculosis (MTB) manage to eliminate
or contain the infection using host T-cell immune defenses. However, some MTB bacilli
may remain viable (latent) and “reactivate” later to cause active TB disease. This
state is called latent TB infection (LTBI). Although LTBI and active TB disease are
part of a dynamic spectrum,[1] people with LTBI are asymptomatic and not infectious.
For example, nearly 50% of doctors and health care workers in India will test positive
on the Mantoux tuberculin skin test, but a majority will not display any TB symptoms,
or develop active TB disease.[2] Such individuals, presumably, have LTBI. However,
some health care workers may go on to develop symptoms, and if found to have active
TB require the standard four-drug short course anti-TB therapy.
Identification and treatment (i.e. preventive therapy or prophylaxis) of LTBI can
substantially reduce the risk of development of active disease (by as much as 60%),
and is an important TB control strategy in low-TB incidence settings where reactivation
disease usually accounts for the majority of non-imported TB disease[3] For example,
LTBI screening and treatment is a major component of TB control programs in both USA
and Canada, and large numbers of individuals are tested for LTBI and treated with
isoniazid for 9 months.
The goal of testing for LTBI is to identify individuals who are at an increased risk
for the development of active TB; these individuals would benefit most from treatment
of LTBI. There is no diagnostic gold standard for LTBI and all existing tests are
immunological tests that provide indirect evidence of sensitization of the host to
TB antigens.
There are two available tests for identification of LTBI: Tuberculin skin test (TST)
and interferon-gamma release assays (IGRA). TST is usually performed using the Mantoux
skin test method, and purified protein derivative (PPD) is the antigen injected intradermally.
Skin induration is read after a period of 48-72 h.
IGRAs are done in vitro, and instead of PPD, they use highly specific peptides from
two main antigens-early secreted antigenic target (ESAT6) and culture filtrate protein
(CFP10). Commercial IGRAs include QuantiFERON-TB Gold In Tube (Qiagen, Valencia, CA,
USA), and T-SPOT. TB (Oxford Immunotec, UK). Both TST and IGRA depend on cell-mediated
immunity (memory T-cell response), and a positive result suggests that the patient
has been exposed and sensitized to MTB in the past.
A detailed recent review of these tests is available elsewhere.[4] Briefly, published
data suggest that both TST and IGRA are acceptable, but somewhat imperfect tests.
Both represent indirect markers of MTB exposure and measure a cellular immune response
to MTB (read as mm induration with the TST, and amount of interferon-gamma released
by T-cells in IGRAs). Neither test can accurately differentiate between LTBI and active
TB. Neither test can resolve the various stages within the spectrum of MTB infection.
Both TST and IGRA have reduced sensitivity in immunocompromised patients (e.g., people
living with HIV/AIDS), and have low predictive value for progression to active TB.
In other words, a majority of individuals with positive TST or IGRA results will not
progress to active TB disease.[5]
Tuberculin skin test surveys in India show a very high annual risk of TB infection.[6]
Given the very high TB burden of active TB in India, it is not surprising that nearly
40% of Indians are estimated to be latently infected.[7] Given the large number of
latently infected individuals in the country, the Revised National TB Control Program
(RNTCP) does not give priority to LTBI detection and treatment in the public sector.
This is true for most high TB burden countries around the world.
For high-burden countries such as India, what should be the approach toward the management
of LTBI? In 2014, World Health Organization (WHO) published its first comprehensive
guideline on management of latent TB infection.[8] This guideline offers a clear,
evidence-based algorithm [Figure 1].[8]
Figure 1
World Health Organization algorithm for latent tuberculosis infection management.
Source: Adapted from WHO, Geneva[8]
As shown in the algorithm, WHO recommends that only selected risk groups should be
evaluated for LTBI.[8] These include people living with HIV, adult and child contacts
of pulmonary TB cases, patients initiating anti-tumor necrosis factor (TNF-alpha)
treatment, patients with end-stage renal failure on dialysis, patients preparing for
organ or hematologic transplantation, and patients with silicosis. The rationale for
giving priority to these subgroups is that they are at a very high risk of progressing
from latent infection to active disease, and this progression could be prevented by
treating LTBI.
If an individual has any of the above risk factors, the WHO algorithm requires that
they be assessed for TB symptoms. If any TB symptom is present (e.g., cough, fever,
weight loss, hemoptysis, night sweats), then the focus should be on diagnosing active
TB using WHO and RNTCP-endorsed microbiological tests such as smear microscopy, TB
cultures, and molecular tests as Xpert MTB/RIF (Cepheid Inc, Sunnyvale, CA, USA),
and line probe assays as Genotype MTBDR plus (Hain Life Science, Nehren, Germany).
Chest radiography can also be used as part of the work-up for active TB. If the individual
has no symptoms, then WHO recommends that either TST or an IGRA be used to test for
LTBI in high-income and upper middle-income countries with estimated TB incidence
less than 100 per 100 000. TST is preferred and IGRA should not replace TST in low-income
and other middle-income countries.[8]
If either TST or IGRA is positive, then the next step is to rule out active disease,
before starting LTBI treatment. This is done by getting chest radiography done. If
the radiogram shows any abnormalities, then it is critical to investigate for active
TB, using smear microscopy, TB cultures, and molecular tests. If the radiogram is
normal and the individual has no symptoms, then the likelihood of active TB is very
low, and LTBI treatment can be initiated.
What are the drug regimens available for LTBI treatment? Unlike active TB where four
drugs are required in the intensive phase, the burden of bacteria in LTBI is quite
low. So, even a single TB drug is sufficient. As shown in the WHO algorithm, treatment
options recommended by WHO include 6-9 months of isoniazid, 3-month regimen of weekly
rifapentine plus isoniazid, or 3-4 months isoniazid plus rifampicin, or 3-4 months
rifampicin alone.[8] All regimens are known to be efficacious, but adherence can be
poor with longer regimens such as 9 months of isoniazid.[3] Rifampicin containing
regimens may be more suitable in populations with a high background level of isoniazid
monoresistance.
Regardless of the regimen used for LTBI, it is important to ensure adherence, and
provide patients adequate counseling about why they are being treated for LTBI (despite
not having symptoms), likely adverse events, and monthly follow-up visits. The risk
of toxicity is highest with isoniazid, especially in older individuals, and those
who consume alcohol.[3]
In India, there is concern that tests such as Mantoux and IGRAs (e.g., TB Gold, TB
Platinum) are being misused for active TB diagnosis.[9] The WHO algorithm clearly
shows that when doctors suspect active TB, they should test for active TB, not screen
for LTBI. In fact, the Standards for TB Care in India (STCI) clearly state that both
TST and IGRAs should not be used for the diagnosis of active TB in high endemic settings
such as India.[10] If IGRAs are used for active TB diagnosis, this will result in
significant overdiagnosis of TB, because of the high background prevalence of LTBI
in India. In children, STCI suggests that the Mantoux test may have some value as
a test for infection, in addition to chest radiography, symptoms, history of contact,
and other microbiological investigations (e.g., gastric juice acid fast bacilli and
Xpert MTB/RIF).[10]
In conclusion, LTBI screening must be restricted to specific high-risk populations
in India, where the benefits of LTBI treatment outweigh any risks. Although either
TST or IGRA can be used for LTBI screening, it is important to make sure that these
tests are not used for active TB diagnosis. For persons with symptoms or abnormal
chest radiograms, physicians should order smears, cultures, and molecular tests (these
tests are now available in the public sector, and made more affordable in the private
sector in India via the Initiative for Promoting and Affordable Quality TB Tests (IPAQT
- www.ipaqt.org)). If LTBI is diagnosed, then physicians must rule out TB disease
with chest radiography before starting one of the recommended drug regimens. It is
important to ensure adherence, and provide adequate counseling to ensure that patients
do not stop therapy prematurely.