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infectious diseases Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Infectious Diseases Board
Review Manual is a study guide for fellows
and practicing physicians preparing for board
exam­inations in infectious diseases. Each man­
ual reviews a topic essential to current prac­
tice in the subspecialty of infectious diseases.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
editorial director
Debra Dreger
SENIOR EDITOR
Bobbie Lewis
associate EDITOR
Diagnosis and Treatment of
Latent Tuberculosis Infection
Contributors: Edward D. Chan, MD
Department of Medicine
National Jewish Medical and Research Center
Denver, CO
Kathryn Chmura, BA
Department of Medicine
National Jewish Medical and Research Center
Denver, CO
Tricia Faggioli
EDITORial assistant
Farrawh Charles
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
PRODUCTION Director
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PRODUCTION associate
Kathryn K. Johnson
ADVERTISING/PROJECT director
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sales & marketing manager
Deborah D. Chavis
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Internal Medicine.
Endorsed by the
Association for Hospital
Medical Education
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Cover Illustration by May Cheney
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Infectious Diseases Volume 10, Part 2 Infectious Diseases Board Review Manual
Diagnosis and Treatment of Latent Tuberculosis Infection
Edward D. Chan, MD, and Kathryn Chmura, BA
“[I]n the treatment of Consumption, . . . in the commencement
[it] is easy to cure and difficult to understand; but when it has
neither been discovered in due time nor treated upon a proper
principle, it becomes easy to understand and difficult to cure.”
–Niccolo Machiavelli (1469–1527)
Introduction
The World Health Organization estimates that one
third of the world’s population is latently infected with
Mycobacterium tuberculosis.1 From this pool, approximately 9 million active tuberculosis (TB) cases emerge
annually, resulting in 2 to 3 million deaths and making
TB the second most common cause of death by a single
infectious agent in the world.2 The AIDS epidemic is
responsible for the rise in TB cases in many parts of the
world (in approximately 1.5 million active TB cases per
year there is co-infection with HIV), and co-infection
with both agents contributes significantly to TB-related
mortality. Ninety-five percent of cases of TB occur in
the developing world. Annual incidence rates exceed
300 cases per 100,000 persons in much of sub-Saharan
Africa, the Indonesian and Philippine archipelagos,
Afghanistan, Bolivia, and Peru.1,3 Areas with the highest
incidence include the most populous nations of India
(1.9 million cases/yr) and China (1.4 million cases/yr).
In North America, cases occur disproportionately among
foreign-born individuals from TB-endemic countries,
HIV-infected persons, institutionalized persons, and minorities. The United States saw a decline in TB cases up
to the early 1980s due mostly to public health programs,
but HIV/AIDS, immigration, and waning TB programs
led to a resurgence of TB in the late 1980s and early
1990s.4 The annual incidence is now declining again, but
as TB becomes less frequent in this country, decreased
awareness of disease manifestations may lead to delays in
diagnosis and treatment.
As indicated by the opening quotation, hundreds of
years before the cause of TB was elucidated it was recognized that TB may exist in 2 different forms: infection
and disease. Infection occurs by airborne transmission
Hospital Physician Board Review Manual
of tubercle bacilli from person to person. Primary infection is usually asymptomatic but may present with mild
nonspecific symptoms, symptoms of acute pneumonia,
or severe disseminated disease. After primary infection,
M. tuberculosis spreads from the lungs to hilar lymph
nodes and then throughout the bloodstream, generally
resulting in latent TB infection (LTBI) (Figure 1). Most
cases of active TB are due to reactivation of latent infection. Reactivation TB is typically a chronic destructive
pneumonia with cavitation and fibrosis involving the
lung apices and superior segments of lower lobes. This
paper focuses on the diagnosis and treatment of LTBI
as opposed to management of active disease. Treatment
of active TB is discussed in a recent publication and the
latest (2003) guidelines from the American Thoracic
Society (ATS)/Centers for Disease Control and Prevention/Infectious Diseases Society of America.5,6
CASE STUDY
INITIAL PRESENTATION
A 50-year-old woman who works as a nursing assistant at a nursing home receives a tuberculin skin test
using 5 units of purified protein derivative (PPD) as
part of an annual screening program. After 72 hours,
the diameter of the induration is 14 mm, whereas it was
3 mm the previous year. She is asymptomatic, healthy,
and does not use tobacco or alcohol. She is not on any
medications and is HIV-negative.
• What are the exogenous risk factors for TB infection?
• What are the endogenous risk factors for reactivation TB?
RISK FACTORS
Close contact with a person who has pulmonary TB
represents the single most important risk factor for TB
transmission. Factors associated with a high burden of
tubercle bacilli further increase this risk and include
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Alveolus
Tubercle bacilli are
ingested by alveolar
macrophages
and proliferate in them
Intracellular
bacilli spread
to hilar nodes
Occult
dissemination
resulting in
latent infection
Active TB
Figure 1. Graphic representation of a primary tuberculosis (TB) infection and occult dissemination. After ingestion of Mycobacterium
tuberculosis by mononuclear phagocytes in the alveoli, a largely asymptomatic dissemination of the tubercle bacilli occurs when infected
cells migrate throughout the body, particularly to the lung apices, kidneys, bone growth plates, and the vertebrae, resulting in latent
infection. In normal hosts, the risk of progression to active TB in a newly infected individual is ~ 5% for the first year and ~ 5% for the
remaining lifetime.
exposure to individuals with cavitary pulmonary TB,
laryngeal TB, and untreated or inadequately treated
TB. Surroundings that facilitate TB transmission include places with indoor crowding such as nursing
homes, schools, and prisons.
In otherwise healthy individuals, the lifetime risk for
progression from LTBI to active TB is approximately
5% within the first year of infection and 5% for the
remainder of the lifetime of the individual. However,
certain individuals are at significantly increased risk
for reactivation TB. Perhaps the single most important
host risk factor for reactivation TB is co-infection with
HIV, where the estimated rate of reactivation is approximately 5% to 10% per year.7 Nursing home residents
also are at increased risk for reactivation due to waning
immunity from aging, malnutrition, comorbid illnesses,
and/or use of immunosuppressive medications.8 Other
particularly high-risk individuals include those with
upper lobe fibronodular scarring, suggesting evidence
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of prior untreated TB, recent immigrants from regions
endemic for TB, and subjects with silicosis, chronic
kidney disease, gastrectomy, malnutrition, diabetes mellitus, organ transplantation, certain malignancies, and
immunosuppressive drug use, in particular, prednisone
(≥ 15 mg/day for ≥ 1 month) and tumor necrosis factor-a (TNF-a) antagonists.7
• Who are candidates for tuberculin skin testing?
CRITERIA FOR SCREENING
Testing should be performed on groups with a high
risk for TB infection. The most important individuals
to test are close contacts of an active case of TB, especially if the exposure occurred prior to treatment of
the index case. Others include HIV-infected persons,
recent immigrants from countries with high rates of TB
infection, homeless persons, health care workers, residents or employees of long-term care facilities, as well
Infectious Diseases Volume 10, Part 2 D i a g n o s i s a n d Tr e a t m e n t o f L a t e n t Tu b e r c u l o s i s I n f e c t i o n
Table. Criteria for Selecting Individuals for Isoniazid
Preventive Therapy Based on Diameter of Tuberculin
Reaction
Criteria for
Positivity
Patient Groups
≥ 5 mm
Recent close contacts to an active case of TB
HIV-positive persons
Persons with apical fibronodular disease consistent
with prior healed TB
Organ transplant recipients
≥ 15 mg/day of prednisone use for ≥ 1 month
TNF-α antagonists
≥ 10 mm
Recent skin test converters (≥ 10 mm increase within
2 yr)
Foreign-born persons in U.S. < 5 yr from highprevalence regions such as Asia, Africa, and Latin
America
High-risk groups (alcohol abusers, intravenous drug
abusers, homeless persons, nursing home patients,
prisoners, employees of hospitals or other health
care facilities, children)
Persons with medical risk factors (diabetes, silicosis,
immunosuppressive therapy, prolonged corticosteroid
therapy, chronic kidney disease, gastrec­tomy, jejunalileal bypass, malnutrition, certain malignancies)
≥ 15 mm
All others; essentially, those who are considered low
risk. In general, these individuals should not be
tested in the first place.
TB = tuberculosis; TNF-a = tumor necrosis factor-a.
as other individuals with the endogenous and exogenous risk factors described previously.9 While there are
no prospective studies for screening diabetic patients
for LTBI, they are clearly at increased risk and thus it is
prudent to perform tuberculin skin testing on diabetic
patients, especially those who are insulin-dependent,
poorly controlled, and/or in a population where TB is
relatively more prevalent.
In patients who are considered for treatment with
anti-TNF-a agents (eg, infliximab, an antibody directed
against TNF-a, or etanercept, a soluble form of p75
TNF-a receptor), tuberculin skin testing should be
performed.10 If positive, probably at a criteria of 5 mm
or greater, patients should be treated for LTBI prior
to receiving anti-TNF-a therapy. Even with this preventive measure, reactivation TB has been described in
patients who received anti-TNF-a agents.
In recently exposed individuals who are historically
known to be PPD-positive, preventive therapy can probably be withheld unless the subjects are HIV-positive.
The rationale for this is that a number of case studies
have shown that previous LTBI appears to protect individuals from developing TB from a new infection. All
persons with LTBI should be clinically monitored for
Hospital Physician Board Review Manual
signs and symptoms that would indicate progression to
active disease, such as fever, anorexia, weight loss, and
any unexplained respiratory symptoms, whether they
are treated or not.
• What is the general algorithm for screening for latent infection?
APPROACH TO POSITIVE SKIN TEST RESULT
One important tenet in testing for LTBI is that if
the skin test result is positive, treatment usually is indicated (ie, “the decision to test is a decision to treat”).
Thus, low-risk individuals (Table) should not be tested
because the likelihood that a positive test represents
a true TB infection is small based on the combined
effects of low pretest probability and the observation
that infection with nontuberculous mycobacteria can
cause a false-positive PPD result. The tuberculin skin
test should be performed by injecting intradermally
0.1 mL of 5 tuberculin units of PPD into the volar
surface of the forearm (Figure 2A). In many countries
outside the United States, a tuberculin formulation
known as RT-23 at a dose of 2 tuberculin units is often
used. A 27-gauge needle is used to produce a wheal
6 to 10 mm in diameter. The diameter of the induration and not erythema is measured after 48 to 72 hours
(Figure 2B), although it can be accurately read up to a
week later. Only trained personnel should determine
the degree of induration, as it has been shown that patients’ own evaluations of their test results are generally
inaccurate.11 Three different diameters of induration
are used as threshold values for treatment depending on host risk factors (Table). If both skin test result
and review of symptoms are negative, treatment is not
indicated (Figure 3) except in 2 instances. One exception is in children aged younger than 5 years or any
children with additional risk factors for development
of TB and known exposure to an active case (ie, even if
the initial PPD skin test and chest radiograph are negative, empiric prophylactic therapy is recommended for
at least 3 months).12 The tuberculin skin test is then
repeated after 3 months and if negative, treatment can
be discontinued; if the second tuberculin skin test is
positive, isoniazid treatment should be continued for
a total of 9 months. The other exception is the HIVpositive individual with a negative PPD test who has had
a close contact exposure to an active case (ie, because
the risk of progression to active disease is so high, these
patients should be treated for LTBI despite a negative
tuberculin skin test). If either skin test or symptom review is positive, a chest radiograph should be obtained
and if abnormal, the individual should be ruled out
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Induration diameter
Erythema diameter
Tense tuberculin wheal
Epidermis
Needle
1.2 mm approx
Dermis
A
B
Subcutaneous tissue
Figure 2. (A) The tuberculin skin test is performed by injecting 0.1 mL of 5 tuberculin units of purified protein derivative intradermally.
(B) An example of a positive tuberculin skin test on the volar surface of a forearm. The diameter of the induration should be measured
and recorded in millimeters. Erroneously measuring the diameter of the erythema instead will overestimate the true reaction size. (Photos
obtained and slightly modified from a poster published by the Centers for Disease Control and Prevention.)
for active TB with serial sputum for acid-fast staining
and culture for mycobacteria (Figure 3). If the chest
radiograph is normal in an asymptomatic person with
a positive PPD test, then the patient is a candidate for
LTBI treatment.
The tuberculin skin test is not 100% sensitive for TB
infection, and even among individuals with documented TB and no immunosuppression, up to 20% will have
negative results on tuberculin skin testing. Testing with
control antigens such as mumps and candida is not
recommended since anergy testing lacks standardization, reproducibility, and positive predictive value for
risk of M. tuberculosis infection and because reactivity to
control antigens but not to PPD does not exclude TB
infection.13
• What is the effect of previous bacille CalmetteGuerin (BCG) vaccine on the tuberculin skin test
and its interpretation?
The BCG vaccine was developed in 1924 from an
attenuated strain of Mycobacterium bovis. It is used in
many parts of the world but not in the United States.
While BCG may cause a false-positive tuberculin skin
test, most noninfected persons vaccinated with BCG
are in fact skin test–negative to PPD, especially if they
were vaccinated during infancy or early childhood.14
Thus, it has been recommended that prior BCG vaccination should not be a factor in either initiating or
interpreting the skin test (ie, if the tuberculin skin test
is positive, it is attributed to M. tuberculosis infection and
the history of prior BCG is ignored). In patients with
prior BCG vaccination, more recently developed bloodbased assays for interferon-γ (IFNγ) appear to have
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increased specificity for diagnosing LTBI.15–17 These
IFNg-release assays are based on the principle that
memory T cells in the blood, if they have been exposed
to M. tuberculosis in the past, release larger amounts
of IFNγ upon in vitro stimulation with M. tuberculosis–
specific antigens (eg, ESAT-6 or CFP-10) than T cells
from individuals who have not been previously exposed
to M. tuberculosis.
Two IFNγ-release assays are commercially available
and both are based on the principle outlined above.
The new tests are Quantiferon-TB (Cellestis Limited,
Australia) and T-SPOT.TB (Oxford Immunotec, UK).
The newest generation of the Quantiferon uses an “intube” method wherein either the ESAT-6 or CFP-10 antigen is already present in the blood-drawing tube. After
the drawn blood is incu bated with an M. tuberculosis
antigen for 16 to 24 hours at 37oC, IFNγ levels are measured by ELISA (enzyme-linked immunosorbent assay).
The test result is considered positive if the IFNγ level in
the tube containing M. tuberculosis antigen minus the
IFNγ level in the control tube containing no antigen is
0.35 IU/mL or greater. As shown in Figure 4, the technique for T-SPOT.TB as compared with Quantiferon
is different, although the principle is the same. For
T-SPOT.TB, 250,000 peripheral blood mononuclear
cells are aliquoted into each well of a 96-well tissue culture plate and performed as described in the Figure 4
legend. After incubation for 16 to 24 hours, the test result is considered positive if the patient sample stimulated with M. tuberculosis antigen has 6 or more spots (cells)
compared with the unstimulated patient sample. Both
IFNγ-release assays have sensitivities that are similar to
tuberculin skin test, although T-SPOT.TB is likely to be
Infectious Diseases Volume 10, Part 2 D i a g n o s i s a n d Tr e a t m e n t o f L a t e n t Tu b e r c u l o s i s I n f e c t i o n
At-risk adult
Tuberculin skin test (TST)
+
symptom review (ROS)
Negative TST and
negative ROS
Positive TST or
positive ROS
High-risk exposure within 3 mos?
Chest radiograph
No
Yes
Treatment not
indicated
Normal
Abnormal
Candidate for
treatment of latent
tuberculosis infection
Evaluate for
active tuberculosis
Figure 3. Tuberculosis screening flowchart.
more sensitive than either tuberculin skin test or Quantiferon in patients who are lymphopenic due to advanced
HIV infection or to cytotoxic agents. Specificities for
Quantiferon and T-SPOT.TB in BCG-vaccinated persons
with low risk of TB exposure are excellent, on the order
of 96% to 99% and 86% to 99%, respectively.18,19 Similar to the tuberculin skin test, neither Quantiferon nor
T-SPOT.TB are able to distinguish active TB from LTBI.
• Can one induce induration in an uninfected person
with serial PPD skin testing?
No. PPD is not sensitizing.
• What is the booster phenomenon?
• What is the epidemiologic basis for treatment of
LTBI?
The booster phenomenon describes an initial negative skin test that upon subsequent testing is positive
even though the person is not newly infected. This
apparent conversion is actually a reflection of a prior
LTBI in which waning immunity resulted in a falsenegative initial skin test. Two-step testing, in which a
negative test is followed by a second test 1 week later,
helps reduce the likelihood that boosted reactions will
be interpreted as a new conversion should the person
be retested at a later date (as in annual screening programs). Tuberculin positivity only after boosting is more
common in the elderly, BCG vaccinees, and in persons
exposed to nontuberculous mycobacteria. Persons with
a booster response are at lower risk of reactivation than
recent converters. Persons who will undergo annual
tuberculin skin test (eg, health care workers) should
undergo 2-step testing on initial evaluation.
Hospital Physician Board Review Manual
EVALUATION AND TREATMENT
The case patient’s induration response to PPD showed
an increase of 11 mm. Given her occupational risk of TB
infection, the patient is started on treatment for LTBI.
Based on a number of clinical trials, many of which
were double-blind and placebo-controlled, there is compelling epidemiologic evidence that treatment of LTBI is
efficacious in preventing disease provided patients adhere
to treatment.20 The rationale for treating LTBI is not only
to prevent active TB in the individual but also as a public
health measure since most active TB cases are derived
from the pool of LTBI. This beneficial public health effect of isoniazid preventive therapy is schematically shown
in an initial 1963 Ferebee model21 updated by Iseman13
(Figure 5). As shown in this theoretical model, isoniazid
decreases the number of cases of reactivation TB leading
to a decrease in secondary TB infection and disease.
• What is the standard recommended treatment for
LTBI?
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ESAT-6 or CFP-10
Wash
Add enzymeconjugated
anti-IFNγ Add substrate
antibody for detection
Lymphocytes
IFNγ
A
Anti-IFNγ ab
Anti-IFNγ ab
B
Each spot = the
“footprint” of
1 IFNγ-producing cell
Figure 4. Basic technique of the T-SPOT.TB assay. After peripheral blood mononuclear cells (PBMCs) are isolated from blood, they are
washed and counted and 250,000 cells are added to a well of a 96-well tissue culture plate that is precoated with anti-interferon-γ (IFNγ)
antibody. Either ESAT-6 or CFP-10 Mycobacterium tuberculosis antigen is added to the well. A negative control well is one in which no
M. tuberculosis antigen is added. After washing, an enzyme-conjugated anti-IFNγ antibody is added. In cells that produce IFNγ in response to
stimulation with an M. tuberculosis antigen, dark-colored spots are generated by the catalytic action of the conjugated enzyme on the colo­
rimetric substrate; they are essentially footprints of the antigen-specific effector T cells in the sample. For example, in illustration A, the
result would be 2 spots. Shown in B is an actual well in a T-SPOT.TB assay that demonstrates numerous IFNγ-producing lymphocytes.
TREATMENT
The preferred treatment of LTBI is 9 months of
isoniazid.7,22 Two isoniazid regimens may be used:
5 mg/kg (maximum dose, 300 mg) daily for 9 months
(preferable for self-administration) or 15 mg/kg (maximum dose, 900 mg) twice weekly for 9 months (preferable for directly observed preventive therapy). For
those who are not infected with HIV, do not have
fibrotic lesions on chest radiograph, and are older than
18 years, a shorter regimen consisting of 6 months of
isoniazid 5 mg/kg (maximum dose, 300 mg) once daily
or 15 mg/kg (maximum dose, 900 mg) twice weekly
are acceptable but inferior alternatives to the 9-month
regimen. For individuals with exposure to isoniazidresistant TB or who are intolerant to isoniazid, rifampin
600 mg once daily for 4 months is recommended.
FOLLOW-UP
The patient is nonadherent with daily isoniazid
therapy. Based on the 2000 ATS guidelines,7 an infectious disease consultant recommends rifampin 600 mg
once daily and pyrazinamide (PZA) 2 g once daily for
2 months.
• Would you follow the consultant’s recommendations?
MATCHING TREATMENT REGIMEN TO THE PATIENT
This consultant’s recommendations should not be
followed. Initially, based on 3 randomized trials in HIVinfected individuals comparing isoniazid preventive
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therapy (6–12 months) with 2 months of rifampinPZA, the latter regimen was found to be as efficacious
as isoniazid without any apparent increase risk of
adverse effects.23–25 Thus, to help improve compliance by shortening the length of therapy, 2 months
of rifampin-PZA once daily or rifampin-PZA twice
weekly for 2 to 3 months was recommended as a viable
alternative.7 However, soon after the publication of the
2000 ATS guidelines, this 2-drug regimen was found
to have a significantly greater risk of grade 3 hepatitis
(liver enzymes > 5 times normal) or grade 4 hepatitis
(liver enzymes > 10 times normal or > 5 times normal
with compatible symptoms) with an initial report of
5 deaths from severe liver injury.26,27 As a result, the
2-month regimen of rifampin and PZA can no longer
be recommended. Indeed, revised guidelines issued
warning that the 2-month rifampin-PZA combination
should be used with extreme caution and not be used
in patients with alcoholism, chronic liver disease, or
those with a history of isoniazid-induced liver toxicity.26
The most recent recommendation from the Centers
for Disease Control and Prevention also emphasize
that rifampin-PZA should not be offered for treatment
of LTBI.28 In contrast to HIV-negative subjects, where
the risk of hepatotoxicity of rifampin-PZA is greater
than with isoniazid alone, the rifampin-PZA regimen
appears to be as safe as isoniazid monotherapy in
HIV-positive individuals.29 For individuals who are
nevertheless put on rifampin-PZA dual therapy, stricter
monitoring also was recommended: (1) no more than
a 2-week supply of rifampin-PZA should be given;
Infectious Diseases Volume 10, Part 2 D i a g n o s i s a n d Tr e a t m e n t o f L a t e n t Tu b e r c u l o s i s I n f e c t i o n
10 m­illion infected
10 million infected
1 in 600
reactivate
1 in 1000
reactivate
16,000
reactivation
48,000
newly
infected
20,000 cases
annually
4000 new
TB cases
10,000
reactivation
1 in 12 with
TB
30,000
newly
infected
250 m­illion uninfected
A
12,500 cases
annually
2500 new
TB cases
1 in 12 with
TB
250 million uninfected
B
Figure 5. Illustration depicting (A) the theoretical cycle of development of tuberculosis (TB) infection and disease without isoniazid (INH)
prophylaxis, and (B) reduction of reactivation disease, secondary infection, and secondary disease due to the effect of INH prophylaxis
of an entire infected U.S. population (1998).
(2) patients should be evaluated closely for symptoms
and signs of hepatitis such as anorexia, nausea, emesis,
abdominal pain, and jaundice; and (3) liver function
tests should be obtained before starting therapy and
at 2, 4, and 6 weeks after initiation of treatment, even
in asymptomatic individuals.26,30 Thus, in the case patient, other measures to improve adherence (eg, isoniazid twice weekly under directly observed preventive
therapy) should be tried before resorting to the riskier
rifampin-PZA regimen.
While it is not clear why the incidence of hepatitis
with the rifampin-PZA combination appears to be
greater than that with rifampin-PZA plus isoniazid,
used for active TB, impaired host immunity during active disease may account for the decreased risk of liver
injury even in those who received the 3-drug regimen.31
A decreased host immune response also is used to explain why treatment was not associated with a relatively
alarming risk of hepatitis in the initial studies examining the use of rifampin-PZA in HIV-positive patients.31
While not mutually exclusive, an alternative explanation for the increased risk of hepatitis with rifampinPZA is that perhaps PZA in the absence of isoniazid
may be metabolized to more hepatotoxic metabolites
(M. Iseman, personal communication, December
2003). This interesting hypothesis is indirectly supported by the observation that the use of a fluoroquinolone
plus PZA for LTBI due to a multidrug-resistant strain of
M. tuberculosis in New York City and California also was
associated with an unacceptable risk of hepatitis.32,33
Despite these concerns about rifampin-PZA hepatotoxicity, Stout and colleagues30 recently suggested that the
Hospital Physician Board Review Manual
rifampin-PZA regimen may be useful for high-risk, traditionally nonadherent groups (61% of their 114 patients
were homeless and 17% drank alcohol excessively), albeit
cautioning the need for close monitoring. However, the
rate of confirmed and suspected cases of hepatitis in their
cohort was 5.3%.30 In an accompanying editorial, Jasmer
and Daley31 evaluated 5 separate rifampin-PZA regimen
studies comprising over 1300 patients and found the
overall frequency of grade 3 or 4 hepatitis to be 5.8%.
This relatively high incidence of significant hepatitis is
unacceptable as it is 19- to 53-fold greater than that seen
with isoniazid preventive therapy, where the incidence of
at least grade 3 hepatitis is estimated to be approximately
0.1% to 0.3%.34 Jasmer and Daley also questioned the
claim of improved compliance with the shorter regimen
by identifying a multicenter study that showed that there
was no difference in the proportion of patients who
completed therapy with 2 months of rifampin-PZA versus
the 6 months of isoniazid (61% versus 57%, respectively;
P > 0.2).27
• What is the recommended treatment of LTBI due to
multidrug-resistant M. tuberculosis in someone with a
PPD skin test conversion?
MULTIDRUG-RESISTANT TB
Prospective studies evaluating the treatment of LTBI
caused by a presumed multidrug-resistant TB strain
are lacking and thus such treatment is controversial.
As previously noted, in high school students and teachers from Orange County, California33 and health care
workers at Lincoln Hospital in Bronx, New York32
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who were exposed to multidrug-resistant TB and were
treated with ofloxacin and PZA, there was an unacceptably high risk of hepatitis (approximately 25%–32%).
HIV-negative persons can be treated with drugs to
which the tubercle bacilli is susceptible or observed
for the development of active TB. HIV-positive persons
should be treated with at least 2 drugs to which the
strain is susceptible because the risk of progression to
active TB is so high in this population. Alternatively,
fluoroquinolone monotherapy without PZA may be
considered with the caveat that long-term efficacy data
on these treatments are lacking.7 Other recommended
options include PZA-ethambutol or fluoroquinoloneethambutol regimens.35
suboptimal, as may be seen in homeless persons, alcoholics, or intravenous drug abusers, pyridoxine may
decrease the incidence of isoniazid-induced peripheral neuropathy. Pyridoxine is also recommenced in
pregnant women, persons with seizure disorders and
in other conditions in which neuropathy is common
(eg, diabetes, uremia, HIV infection). The dose of pyridoxine should be less than or equal to 10 mg per day,
because larger doses may antagonize isoniazid itself.39
Indeed, very large doses of pyridoxine are recommended as an antidote for isoniazid overdose.40
• What are the adverse effects of isoniazid and who is
at high risk of developing them?
MONITORING FOR DRUG TOXICITIES
Review of symptoms and physical examinations
are the cornerstone of monitoring for drug toxicities
with subsequent clinically indicated laboratory testing
for confirmation (eg, liver function tests such as AST,
alanine aminotransferase, alkaline phosphatase, and
bilirubin). However, certain individuals should have
liver function testing obtained at baseline and periodically during treatment, including HIV-infected subjects,
pregnant women and those at least 3 months postpartum, alcoholics, patients with liver disease, or individuals taking other potentially hepatotoxic medications.7
The major adverse effects of isoniazid are hepatitis,
peripheral neuropathy, anaphylaxis, and psychosis,
while minor side effects include headache, rash, nausea, and nonspecific abdominal pain not necessarily
associated with hepatitis.36–38 Risk of isoniazid-associated
hepatitis (defined as symptoms consistent with hepatitis, aspartate aminotransferases [AST] levels ≥ 5 times
normal levels, and resolution of signs and symptoms of
hepatotoxicity after withdrawal of isoniazid) is 0.1% in
persons younger than age 35 years and approximately
0.2% to 0.3% in persons aged 35 or older.34 Risk increases with age, current alcohol use, ingestion of other
hepatotoxic drugs, and chronic hepatitis B or C infection. For the standard isoniazid regimen for LTBI, baseline and follow-up liver function tests are not routinely
indicated except for those individuals with HIV infection, pregnancy, or history of chronic liver disease or in
those who regularly drink alcohol.7 Subjects should be
evaluated monthly for adherence to the regimen and to
uncover any symptoms suggestive of hepatitis. Patients
should abstain from alcohol and other potential hepatotoxins. Clinical signs of hepatitis such as fever, fatigue,
nausea, vomiting, and jaundice should be monitored.
Mild elevations of hepatic transaminases are common
and in the absence of symptoms do not necessarily
require interruption of medication. If AST and alanine
aminotransferase levels are 5 times the upper limit of
normal, or if 3 times normal with compatible symptoms,
then isoniazid should be discontinued.
• Should vitamin B6 be given with isoniazid preventive
therapy and, if so, what is the recommended dose?
Vitamin B6 (pyridoxine) is not routinely recommended with isoniazid preventive therapy in individuals with adequate nutrition. However, when the diet is
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• What is the recommendation for monitoring for
drug toxicity in the treatment of LTBI?
SUMMARY
One third of the world’s population is latently infected with M. tuberculosis. From this pool, approximately
9 million active TB cases emerge annually, resulting in
2 to 3 million deaths and making TB the second most
common cause of death by a single infectious agent in
the world. In otherwise healthy individuals with LTBI,
the lifetime risk for active TB is approximately 5% within
the first year of infection and 5% for the remainder of
the lifetime of the individual. Perhaps the single most
important host risk factor for reactivation TB is coinfection with HIV, where the estimated rate of reactivation
is approximately 5% to 10% per year. Other particularly high-risk individuals include those with upper lobe
fibronodular scarring, recent immigrants from regions
endemic for TB, nursing home residents, and persons
with silicosis, chronic kidney disease, gastrectomy, malnutrition, diabetes mellitus, organ transplantation, or
immunosuppressive use. Testing for latent infection involves administering 0.1 mL of 5 tuberculin units of PPD
(or 0.1 mL of 2 tuberculin units of RT-23, available in
many places outside the United States) intradermally and
Infectious Diseases Volume 10, Part 2 D i a g n o s i s a n d Tr e a t m e n t o f L a t e n t Tu b e r c u l o s i s I n f e c t i o n
measuring the diameter of induration at 48 to 72 hours.
There is compelling epidemiologic evidence that treatment for LTBI decreases the development of active TB.
The preferred treatment regimen of LTBI is 9 months of
isoniazid for those with normal chest radiographs. Correctly diagnosing and treating individuals with LTBI are
important cornerstones to curbing the scourge of TB.
Acknowledgment
The authors thank Drs. Marian Goble, Carol Welsh,
Brian Fouty, and Michael Iseman for critical review of
the manuscript.
13. Mandell GL, Bennett JE, Dolin R, editors. Principles and
practice of infectious diseases. 6th ed. London: Churchill
Livingstone; 2004:2860.
14. Menzies R, Vissandjee B. Effect of bacille Calmette-Guerin
vaccination on tuberculin reactivity. Am Rev Respir Dis
1992;145:621–5.
15. Mori T, Sakatani M, Yamagishi F, et al. Specific detection
of tuberculosis infection: an interferon-a-based assay using
new antigens. Am J Respir Crit Care Med 2004;170:59–64.
16. Brock I, Weldingh K, Lillebaek T, et al. Comparison of
tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Respir Crit Care Med 2004;170:65–9.
17. Barnes PF. Diagnosing latent tuberculosis infection: turning
glitter to gold. Am J Respir Crit Care Med 2004;170:5,6.
REFERENCES
18. Richeldi L. An update on the diagnosis of tuberculosis
infection. Am J Respir Crit Care Med 2006;174:736–42.
1. Raviglione MC, Snider DEJ, Kochi A. Global epidemiology
of tuberculosis. Morbidity and mortality of a worldwide
epidemic. JAMA 1995;273:220–6.
19. Menzies D, Pai M, Comstock G. Meta-analysis: new tests for
the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern
Med 2007;146:340–54.
2. Lienhardt C, Rodrigues LC. Estimation of the impact of
human immunodeficiency virus infection on tuberculosis: tuberculosis risks re-visited? Int J Tuberc Lung Dis
1997;1:196–204.
20. Iseman MD. A clinician’s guide to tuberculosis. Philadelphia: Lippincott, Williams & Wilkins; 2000:355–97.
3. WHO report: global tuberculosis control: surveillance,
planning, financing. Geneva: World Health Organization;
2002.
21. Ferebee SH. An epidemiological model of tuberculosis in
the United States. TB control: with present methods? with
BCG vaccination? or with isoniazid prophylaxis? NTA Bull
1967;53:4–7.
4. Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM.
Epidemiology of tuberculosis in the United States, 1985
through 1992. JAMA 1992;272:535–9.
22. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults. Int
J Tuberc Lung Dis 1999;3:847–50.
5. Blumberg HM, Burman WJ, Chaisson RE, et al. American
Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of
tuberculosis. Am J Respir Crit Care Med 2003;167:603–62.
23. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and
pyrazinamide vs isoniazid for prevention of tuberculosis
in HIV-infected persons: an international randomized
trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adults AIDS Clinical Trials Group,
the Pan American Health Organization, and the Centers
for Disease Control and Prevention Study Group. JAMA
2000;283:1445–50.
6. Chan ED, Iseman MD. Current medical treatment for
tuberculosis. BMJ 2002;325:1282–6.
7. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Pt
2):S221–47.
8. Stead WW, Lofgren JP, Warren E, Thomas C. Tuberculosis
as an endemic and nosocomial infection among the elderly in nursing homes. N Engl J Med 1985;312:1483–7.
9. Small PM, Fujiwara PI. Management of tuberculosis in the
United States. N Engl J Med 2001;345:189–200.
10. Ellerin T, Rubin RH, Weinblatt ME. Infections and antitumor necrosis factor a therapy. Arth Rheum 2003;48:3013–
22.
11. Howard TP, Solomon DA. Reading the tuberculin skin test:
Who, when, and how? Arch Intern Med 1988;148:2457–9.
12. Starke JR. Mycobacterium tuberculosis. In: Rudolph CD,
Rudolph AM, Hostetter MK, et al, editors. Rudolph’s ped­
iatrics. 21st ed. Philadelphia: McGraw-Hill, Medical Pub
Division; 2003:949–59.
10 Hospital Physician Board Review Manual
24. Halsey NA, Coberly JS, Desormeaux J, et al. Randomised
trial of isoniazid versus rifampicin and pyrazinamide for
prevention of tuberculosis in HIV-1 infection. Lancet
1998;351:786–92.
25. Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice weekly
tuberculosis preventive therapy in HIV infection in Zambia. AIDS 1998;12:2447–57.
26. Centers for Disease Control and Prevention. Update: fatal
and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions
in the American Thoracic Society/CDC recommendations—United States, 2001. MMWR Morb Mortal Wkly
Rep 2001;50:733–5.
27. Jasmer RM, Saukkonen JJ, Blumberg HM, et al. Shortcourse rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical
www.turner-white.com
D i a g n o s i s a n d Tr e a t m e n t o f L a t e n t Tu b e r c u l o s i s I n f e c t i o n
trial. Ann Intern Med 2002;137:640–7.
28. Centers for Disease Control and Prevention (CDC); American Thoracic Society. Update: adverse event data and
revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for
treatment of latent tuberculosis infection—United States,
2003. MMWR Morb Mortal Wkly Rep 2003;52:735–9.
29. Gordin FM, Cohn DL, Matts JP, et al. Hepatotoxicity of
rifampin and pyrazinamide in the treatment of latent
tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons? Clin Infect Dis
2004;39:561–5.
30. Stout JE, Engemann JJ, Cheng AC, et al. Safety of 2 months
of rifampin and pyrazinamide for treatment of latent tuberculosis. Am J Respir Crit Care Med 2003;167:824–7.
31. Jasmer RM, Daley CL. Rifampin and pyrazinamide for
treatment of latent tuberculosis infection: is it safe? Am J
Respir Crit Care Med 2003;167:809–12.
32. Horn DL, Hewlett D Jr, Alfalla C, et al. Limited tolerance of
ofloxacin and pyrazinamide prophylaxis against tuberculosis. N Engl J Med 1994;330:1241.
33. Ridzon R, Meador J, Maxwell R, et al. Asymptomatic
hepatitis in persons who received alternative preventive
therapy with pyrazinamide and ofloxacin. Clin Infect Dis
1997;24:1264–5.
34. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from
a Public Health Tuberculosis Clinic. JAMA 1999;281:1014–
8.
35. Management of persons exposed to multidrug-resistant tuberculosis. MMWR Recomm Rep 1992;41(RR-11):61–71.
36. Alao AO, Yolles JC. Isoniazid-induced psychosis. Ann Pharmacother 1998;32:889–91.
37. Crook M. Isoniazid-induced anaphylaxis. J Clin Pharmacol
2003;43:545–6.
38. LoBue PA, Moser KS. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am J Respir Crit Care
Med 2003;168:443–7.
39. Snider DE Jr. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980;4:191–6.
40. Chan ED, Terada LS, Kortbeek J, Winston BW. Bedside
critical care manual. 2nd ed. Philadelphia: Hanley & Belfus; 2002:102–3.
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