tuberculosis

Annals of Internal Medicine䊛
In the Clinic®
Tuberculosis
A
lthough tuberculosis (TB) rates remain
low in the United States, 10.4 million
people were diagnosed and 1.4 million
died of the disease worldwide in 2015. The past
decade has seen major advances in prevention,
diagnosis, and treatment. New diagnostics to
detect latent TB infection (LTBI) and clinical disease have been developed, and new drugs,
particularly for drug-resistant TB, have become
increasingly available. Despite these advances,
in 2014 TB surpassed HIV/AIDS as the deadliest
infectious disease in the world (1), and it continues to be the leading killer of persons infected
with HIV globally.
The CME quiz is available at Annals.org. Complete the quiz to earn up to 1.5 CME credits.
Physician Writer
Karen R. Jacobson, MD,
MPH
doi:10.7326/AITC201702070
CME Objective: To review current evidence for screening and prevention, diagnosis, and
treatment of tuberculosis.
Funding Source: American College of Physicians.
Acknowledgment: The author thanks Elizabeth J. Ragan for administrative and technical
support on this manuscript and Dr. Patricio Escalante, writer of the earlier version.
With the assistance of additional physician writers, the editors of Annals of Internal Medicine
develop In the Clinic using MKSAP and other resources of the American College of
Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical
guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.
Disclosures: Dr. Jacobson, ACP Contributing Author, has disclosed no conflicts of interest.
The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms
.do?msNum=M16-2138.
© 2017 American College of Physicians
Screening and Prevention
Diagnosis
Treatment
Tool Kit
Patient Information
In the United States, 9421 TB
cases (3 cases per 100 000 persons) were reported in 2014, a
69% decrease since a resurgence
in 1992 (2). Sixty-six percent of
these cases occurred in foreignborn persons, a rate of infection
13 times that of U.S.-born persons (2). Racial and ethnic
groups are disproportionately
affected—the highest rates of
infection occur among Asians as
well as native Hawaiians and
other Pacific
Islanders. Building on the momentum of new scientific discoveries, the World Health Organization (WHO) published the
END TB Strategy in 2014, which
aims to reduce TB incidence
and deaths by 90% and 95%,
respectively, by 2035 (3).
Screening and Prevention
1. World Health Organization. Global Tuberculosis
Report 2016. Geneva:
World Health Organization; 2016.
2. Centers for Disease Control and Prevention. Fact
Sheet: Trends in tuberculosis. 2014. Accessed at
www.cdc.gov/tb
/publications/factsheets
/statistics/tbtrends.htm
on 20 December 2016.
3. World Health Organization. The END TB Strategy:
Global strategy and targets for tuberculosis prevention, care and control
after 2015. Geneva: World
Health Organization;
2014. Accessed at www
.who.int/tb/strategy
/End_TB_Strategy.pdf
?ua=1 on 20 December
2016.
4. Alvarez GG, Van Dyk DD,
Davies N, Aaron SD, Cameron DW, Desjardins M,
et al. The feasibility of the
interferon gamma release
assay and predictors of
discordance with the tuberculin skin test for the
diagnosis of latent tuberculosis infection in a remote aboriginal community. PLoS One. 2014;9:
e111986. [PMID:
25386908]
5. Ribeiro-Rodrigues R, Kim
S, Coelho da Silva FD,
Uzelac A, Collins L, Palaci
M, et al. Discordance of
tuberculin skin test and
interferon gamma release
assay in recently exposed
household contacts of
pulmonary TB cases in
Brazil. PLoS One. 2014;9:
e96564. [PMID:
24819060] http://dx.doi
.org/10.1371/journal.pone
.0096564 on 20 December 2016.
6. European Centre for Disease Prevention and Control. Management of contacts of MDR TB and XDR
TB patients. Stockholm:
European Centre for Disease Prevention and Control; 2012.
姝 2017 American College of Physicians
Who should be screened for
latent TB infection?
TB is caused by the acid-fast bacillus (AFB) Mycobacterium tuberculosis, which is transmitted
through airborne respiratory
droplets from the throat and
lungs of persons with active respiratory disease. When M tuberculosis droplets are inhaled and
delivered to the terminal airways,
macrophages ingest the mycobacteria, which continue to multiply intracellularly and can potentially spread to other organs
through the lymphatic system
and bloodstream. Most TBinfected persons remain asymptomatic and enter the latency
phase (LTBI). They have a 10%
lifetime risk for progressing from
latent to active TB; half of that risk
is progression during the first 2
years after infection (“primary
progression”).
The goal of LTBI testing is to
identify and treat persons at increased risk for TB. These persons include contacts of an individual with known infectious
pulmonary TB, those at high risk
for potential exposure, and those
at high risk for rapid disease progression regardless of known TB
contact (see the Box). Risk for
primary progression in the first 2
years after infection is agedependent— children younger
than 2 years have the highest
risk. Thus, particular attention
should be paid to LTBI screening
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In the Clinic
and treatment in young children
(4, 5).
If the results of the first test after
exposure of close contacts of a
known case patient with TB (persons from the same household
sharing common habitation
rooms, or those with prolonged
and frequent exposure in such
settings as workplaces, schools,
prisons, hospitals, and some social settings) (6) are negative, the
test should be repeated in 8 –12
weeks to confirm lack of conversion to positive results.
What tests are used to screen
for TB infection?
The 2 tests used to detect TB are
the Mantoux tuberculin skin test
(TST) and interferon-␥–release
assays (IGRAs). Neither test can
distinguish between latent and
active disease, and neither is appropriate as the sole investigation for active disease (Table 1).
Both tests are based on cellmediated immunity and thus are
more likely to yield false-negative
results in persons with advanced
immunosuppression.
The TST has been used for more
than 100 years. Purified protein
derivative (PPD) is injected intradermally (usually into the inner
surface of the forearm). The patient returns in 48 –72 hours, and
the test is read by assessing the
transverse diameter of induration
(not erythema). Positive results
indicate a delayed-type hyper-
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7 February 2017
sensitivity response mediated by
T lymphocytes. To increase the
specificity of the test, criteria for
positivity are based on the patient's risk factors for M tuberculosis infection (Table 1).
The largest threshold (≥15 mm
induration) has the lowest sensitivity but the highest specificity
and is therefore useful to evaluate patients in regions with high
prevalence of nontuberculous
mycobacterium rather than
M tuberculosis, such as the
United States. False-negative results are more common in patients with recent TB infection,
age younger than 6 months,
overwhelming active TB, recent
vaccination with a live virus (e.g.,
measles), recent viral infection
(e.g., measles or varicella), and
anergy. False-positive results can
be caused by a history of bacille
Calmette-Guérin (BCG) vaccination or infection with nontuberculous mycobacterium. People who
received the BCG vaccine should
have their TST interpreted according to standard criteria, although recent BCG vaccination
can be an indication for IGRA
testing instead. For patients who
received the BCG vaccine when
they were younger than 1 year,
no discernible effect on TST remains after 10 or more years (7).
Patients with remote exposure to
TB may initially have a negative
TST result that can become positive several weeks later. This is
called the “booster effect” and is
considered a true-positive result.
It is more common in elderly persons, although it may also occur
more often in persons with a history of BCG or nontuberculous
mycobacteria. For this reason,
current guidelines recommend a
2-step initial TST for all health
care workers, with the second
test done on the opposite forearm 7–21 days after initial negative results (8). Two-step testing
7 February 2017
is not required when IGRA is
used (9).
The Centers for Disease Control
and Prevention (CDC) now endorses IGRAs, including the
QuantiFERON-TB Gold In-Tube
(QFT) (Qiagen) and the
T-SPOT.TB (Oxford Immunotec),
in nearly all clinical settings
where TST is recommended (8,
10). One exception is children
younger than 5 years, for whom
some experts recommend both
tests for increased specificity.
IGRAs indicate sensitization to
M tuberculosis by measuring the
release of interferon-␥ in the
blood by T cells as a response to
M tuberculosis–associated antigen and do not require a second
patient visit. The initially higher
cost of IGRAs should be taken
into account. These tests are considered to be as sensitive as but
more specific than TSTs because
persons who have other nontuberculous mycobacterium infections or have had BCG do not
have positive results. IGRAs are
preferred to TSTs in persons who
received BCG as treatment for
cancer or as a vaccine and in those
who are less likely to return for a
test reading in 48 –72 hours (11).
Once a person has a positive TST
or IGRA result, repeated testing
has no clinical utility. Unless suspicion for error in interpretation
or performance of the first test is
high, a positive result should be
considered a true positive. In a
patient with a known positive TST
result, repeated testing can result
in a more severe, and at times necrotic, inflammatory response (12).
Risk Factors for TB Infection
or Progression to Disease
After Infection
Persons with HIV infection
Patients with other
immunocompromising
conditions, including organ
transplant recipients and
others with illnesses that
require immunosuppressive
therapy (the equivalent of
≥15 mg of prednisone per
day for ≥4 wk, which
includes most persons
receiving tumor necrosis
factor-␣ antagonists)
Persons recently in close contact
with a person with active TB
Persons with fibrotic changes on
chest radiography consistent
with old TB
Recent (<5 y) arrivals from
high-prevalence countries
Mycobacteriology laboratory
personnel
Residents or employees in
high-risk settings, such as
prisons and jails, nursing
homes and other long-term
facilities for elderly persons,
hospitals and other health
care facilities, residential
facilities for patients with
AIDS, and homeless shelters
Injection drug users, users of
other drugs (e.g., crack
cocaine), and tobacco
smokers
Persons with clinical conditions
that put them at high risk for
active disease (including
diabetes mellitus; silicosis,
intestinal bypass, gastrectomy,
or other type of bariatric
surgery; cancer of the head
and neck; chronic
malabsorption syndromes;
end-stage renal disease;
hematologic cancer; and
body weight ≥10% below
ideal level)
Children aged ≤4 years exposed
to adults with TB
Two challenges for providers are
how to interpret discordance between results on TST and IGRA
and how to interpret reversions if
a test is repeated. Historically,
stable TST converters (i.e., those
who do not revert with later testing) had significantly larger areas
of induration than reverters at the
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In the Clinic
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姝 2017 American College of Physicians
Table 1. Interpretation of Tuberculin Skin Test Results: Criteria for Tuberculin Positivity by Risk Group,
According to Size of Induration, in Millimeters*
≥5
≥10
≥15
HIV-positive persons
Recent contacts of persons with active
TB
Persons with fibrotic changes on
chest X-ray consistent with old TB
Patients who have had organ
transplantation and other
immunosuppressive conditions
(receiving equivalent of ≥15 mg
prednisone/d for >4 wk)
Recent (<5 y) arrivals from high-prevalence TB countries
Injection drug users
Residents or employees of high-risk congregate settings,
such as prisons and jails, nursing homes and other
long-term facilities for elderly persons, health care
facilities, residential facilities for AIDS patients,
homeless shelters
Persons with comorbid conditions that place them at
high risk for TB (silicosis, diabetes mellitus, severe
kidney disease, certain types of cancer, some intestinal
conditions)
Mycobacteriology laboratory personnel
Children aged ≤4 y
Persons with no risk
factors for TB
TB = tuberculosis.
* Data from reference 2.
time of TST conversion (13), making the larger threshold in most
U.S.-based populations more
likely to be true-positive. More
concerning has been that rates of
serial conversion from negative
to positive IGRA results among
health care workers in North
America have been reported at
nearly an order of magnitude
higher than historical or concurrent TST conversion rates (14 –
16), accompanied by high rates
(>60%) of reversion on subsequent testing.
7. Farhat M, Greenaway C,
Pai M, Menzies D. Falsepositive tuberculin skin
tests: what is the absolute
effect of BCG and nontuberculous mycobacteria?
Int J Tuberc Lung Dis.
2006;10:1192-204.
[PMID: 17131776]
8. Centers for Disease Control and Prevention. Latent
Tuberculosis Infection: A
Guide for Primary Health
Care Providers. 2014.
Accessed at www.cdc.gov
/tb/publications
/ltbi/diagnosis.htm on
20 December 2016.
9. QIAGEN. Frequently Asked
Questions: QuantiFERON®
-TB Gold. 2013. Accessed
at http://usa.quantiferon
.com/irm/content/pdfs
/FAQ_QFT_HCP-US_EN
_1113_H_LR.pdf on 20
December 2016.
10. Mazurek GH, Jereb J,
Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for
using interferon gamma
release assays to detect
Mycobacterium tuberculosis infection—United
States, 2010. MMWR
Recomm Rep. 2010;59:
1-25. [PMID: 20577159]
姝 2017 American College of Physicians
Hypotheses for IGRA variability in
a single patient have included
that initial conversion followed by
reversion may reflect exposure
that does not lead to persistent
infection (17); operational reasons for variability in results on
the QFT, including manufacturing and processing issues; analytic variability; and host immunologic changes over time (18).
Recent studies have also found
evidence of positive QFT results
after TST in the prior 6 months,
so such proximate dual testing
should be particularly avoided
(16, 17).
For these reasons, providers
should use the LTBI test that
best fits their patient's needs
and generally should use only
one.
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In the Clinic
What can patients do to
decrease the likelihood of
infecting others?
TB patients have been shown to
infect up to 10 –15 other people
over the course of a year. However, once a patient has received
effective therapy for 2 weeks, risk
for transmission is nearly, if not
completely, eliminated (19 –21).
Therefore, prompt identification
of patients with active TB is critical to prevent transmission.
Prevention of spread in hospitals
includes respiratory isolation of
patients with confirmed or suspected TB (22). Staff who come in
contact with an infectious or suspected infectious patient should
wear previously fitted particulate
respirators (N95 masks). Patients
suspected of having TB can be
removed from isolation after 3
sputum smears, collected at least
8 hours apart, are confirmed to
be negative and an alternative
diagnosis has been made (22).
Patients with confirmed TB can
usually be removed from isolation
once they begin adequate therapy; show a significant clinical response; and are negative for AFB
on 3 sputum smears, also obtained at least 8 hours apart (22).
Patients who are not too ill can
be sent home after initiation of
therapy, although they must be
Annals of Internal Medicine
7 February 2017
isolated from outsiders. Healthy
adults residing in the home have
probably been exposed for
weeks to months before diagnosis of the infected patient and are
unlikely to benefit from isolation
(23). However, if there are highrisk contacts in the household
(i.e., children aged <5 years or
immunocompromised persons),
TB patients should reside elsewhere until they meet criteria for
noninfection (22).
The BCG vaccine is not used in the
United States. However, knowledge of whether persons born in
other countries received the vaccine, at what age, and whether
they received a booster is particularly helpful when deciding which
LTBI diagnostic test to use. An interactive Web site lists BCG vaccine practices in 180 countries
(www.bcgatlas.org) (24).
For patients with latent TB
infection, what can be done to
decrease the likelihood of
developing active disease?
Patients with evidence of LTBI
(i.e., positive results on IGRA or
TST), in whom active TB has been
excluded, should be offered prophylaxis. Patients at greater risk
for active disease should be particularly encouraged to take prophylaxis, including those with HIV
infection, close contacts of persons with active TB in the past 2
years (especially infants and children aged <5 years), those who
have fibrotic changes on a chest
radiograph consistent with old
TB, those with medical conditions
known to increase risk (e.g., diabetes mellitus; silicosis; organ
transplantation; immunosuppressive therapy, such as the equivalent of >15 mg of prednisone per
day for ≥1 month; and receipt of
tumor necrosis factor-␣ antagonists), those who inject illicit
drugs and other high-risk substance users, and residents and
employees in high-risk congregate
settings (e.g., correctional facilities,
7 February 2017
nursing homes, homeless shelters,
and hospitals) (25, 26).
Immunocompetent children
younger than 5 years should be
started on “window prophylaxis,”
regardless of baseline TST/IGRA
status, and this therapy should be
stopped only if TST/IGRA results are
negative 8–10 weeks after the last
contact with a contagious case (27).
The CDC endorses 4 LTBI treatment regimens: 9 or 6 months of
isoniazid (INH), 3 months of INH
plus rifapentine (RPT), or 4
months of rifampin (RIF) (Table
2). The newest, the “12-dose regimen,” is a combination of INH
and RPT given weekly for 3
months; treatment completion
was 82% among patients receiving the 12-dose regimen compared with 69% among those
receiving 9 months of INH in the
TB Trials Consortium Prevent TB
study (P < 0.001) (28). Directly
observed therapy (DOT) for this
regimen is currently recommended because the impact of
missed doses is unknown, but at
least 1 CDC-sponsored study
suggests that self-administration
does not lead to inferior adherence in the United States (29).
DOT also provides the opportunity to screen patients for adverse effects and to stop therapy
if they occur. A meta-analysis reports that the weekly INH–RPT
regimen had higher treatment
completion and less hepatotoxicity but more frequent treatmentlimiting adverse events compared with 9 months of daily
treatment with INH (30). The 12dose regimen is an option for
otherwise-healthy persons aged
12 years or older. It is not recommended for children younger
than 12 years, HIV-infected persons receiving antiretroviral medicines (due to drug interactions),
pregnant women or women who
expect to become pregnant during treatment, persons infected
with drug-resistant strains (31),
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In the Clinic
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11. Ringshausen FC,
Schablon A, Nienhaus A.
Interferon-gamma release assays for the tuberculosis serial testing
of health care workers: a
systematic review. J
Occup Med Toxicol.
2012;7:6. [PMID:
22537915]
12. Bunnet D, Kerleguer A,
Kim P, Pean P, Phuong
V, Heng N, et al. Necrotic
tuberculin skin (Mantoux) test reaction: a case
report and an estimation
of frequency. Chest.
2015;148:e1-4. [PMID:
26149555]
13. Johnson DF, Malone LL,
Zalwango S, Mukisa
Oketcho J, Chervenak
KA, Thiel B, et al; Tuberculosis Research Unit.
Tuberculin skin test reversion following isoniazid preventive therapy
reflects diversity of immune response to primary Mycobacterium
tuberculosis infection.
PLoS One. 2014;9:
e96613. [PMID:
24796677]
14. Zwerling A, Benedetti A,
Cojocariu M, McIntosh F,
Pietrangelo F, Behr MA,
et al. Repeat IGRA testing
in Canadian health workers: conversions or unexplained variability? PLoS
One. 2013;8:e54748.
[PMID: 23382955]
15. Slater ML, Welland G, Pai
M, Parsonnet J, Banaei
N. Challenges with
QuantiFERON-TB Gold
assay for large-scale,
routine screening of U.S.
healthcare workers. Am J
Respir Crit Care Med.
2013;188:1005-10.
[PMID: 23978270]
16. Dorman SE, Belknap R,
Graviss EA, Reves R,
Schluger N, Weinfurter
P, et al; Tuberculosis
Epidemiologic Studies
Consortium. Interferon-␥
release assays and tuberculin skin testing for
diagnosis of latent tuberculosis infection in
healthcare workers in the
United States. Am J
Respir Crit Care Med.
2014;189:77-87. [PMID:
24299555]
17. Andrews JR, Hatherill M,
Mahomed H, Hanekom
WA, Campo M, Hawn TR,
et al. The dynamics of
QuantiFERON-TB gold
in-tube conversion and
reversion in a cohort of
South African adolescents. Am J Respir Crit
Care Med. 2015;191:
584-91. [PMID:
25562578]
18. Pai M, Denkinger CM,
Kik SV, Rangaka MX,
Zwerling A, Oxlade O,
et al. Gamma interferon
release assays for detection of Mycobacterium
tuberculosis infection.
Clin Microbiol Rev.
2014;27:3-20. [PMID:
24396134]
姝 2017 American College of Physicians
Table 2. Treatment Regimens for Latent TB*
Drugs
Duration
Interval
Comments
INH
9 mo
Daily
Preferred treatment for:
• Persons with HIV
• Children aged 2–11 y
• Pregnant women (with pyridoxine/vitamin B6 supplements)‡
Preferred treatment for pregnant women (with pyridoxine/vitamin
B6 supplements)‡
Not indicated for HIV-infected persons, persons with fibrotic lesions
on chest radiographs, or children
Twice weekly§
INH
6 mo
Daily
INH + RPT
3 mo
Twice weekly§
Once weekly§
RIF
4 mo
Daily
Rating
(evidence)†
Treatment for persons ≥12 y
Not recommended for persons:
• <2 y
• Receiving antiretroviral treatment
• Presumed to be infected with INH- or RIF-resistant
Mycoplasma tuberculosis
• Who are pregnant or expect to become pregnant
Not recommended for persons:
• Receiving medications that interact with rifamycins
• Who wear contact lenses
• Who are pregnant or expect to become pregnant
HIV–
HIV+
A2
A2
B2
B2
B1
C1
B2
A1
C1
A兩兩1
B2
B3
INH = isoniazid; RIF = rifampin; RPT = rifapentine; TB = tuberculosis.
* Adapted from Centers for Disease Control and Prevention. Treatment Regimens for Latent TB Infection (LTBI) [Internet]. 2016.
Available from www.cdc.gov/tb/topic/treatment/ltbi.htm.
† A = preferred; B = acceptable alternative; C = offer if A or B are not available; 1 = randomized, clinical trial; 2 = data from
clinical trials that were not randomized or were conducted in other populations; 3 = expert opinion.
‡ May be delayed until after delivery and cessation of breastfeeding except in cases of increased risk for placental infection or
progression to active TB.
§ Using directly observed therapy.
兩兩 In otherwise-healthy HIV patients not receiving antiretroviral medication.
19. Rouillon A, Perdrizet S,
Parrot R. Transmission of
tubercle bacilli: the effects of chemotherapy.
Tubercle. 1976;57:27599. [PMID: 827837]
Accessed at http://dx.doi
.org/10.1016/S0041
-3879(76)80006-2 on 20
December 2016.
20. Riley RL, Mills CC,
O’Grady F, Sultan LU,
Wittstadt F, Shivpuri DN.
Infectiousness of air from
a tuberculosis ward.
Ultraviolet irradiation of
infected air: comparative
infectiousness of different patients. Am Rev
Respir Dis. 1962;85:51125. [PMID: 14492300]
21. Dharmadhikari AS,
Mphahlele M, Venter K,
Stoltz A, Mathebula R,
Masotla T, et al. Rapid
impact of effective treatment on transmission of
multidrug-resistant tuberculosis. Int J Tuberc
Lung Dis. 2014;18:
1019-25. [PMID:
25189547]
22. Jensen PA, Lambert LA,
Iademarco MF, Ridzon R.
Guidelines for preventing the transmission of
Mycobacterium tuberculosis in health-care settings, 2005. MMWR
Recomm Rep. 2005;54:
1-141. [PMID:
16382216]
姝 2017 American College of Physicians
and those receiving medications
that interact with rifamycins.
In pregnant women, a 6- to
9-month course of INH may be
delayed until after delivery and
cessation of breastfeeding, except when risk for placental infection or progression to active TB is
increased (i.e., immunocompromising conditions, such as HIV
co-infection or recent M tuberculosis infection) (32). For those
exceptions, treatment with INH
plus pyridoxine/vitamin B6 (plus
B6 to the newborn) should be
initiated during pregnancy or
breastfeeding with close monitoring for INH hepatotoxicity,
which is more common in
women during pregnancy.
Treatment of LTBI in contacts of
patients with drug-resistant TB is
not well-studied. Current guidelines recommend considering an
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In the Clinic
alternative multidrug prophylaxis
regimen if a person is at high risk
for progression to active disease
(i.e., HIV-positive) and the susceptibility of the infecting organism is
known (33). Such patients should
be referred to an experienced
specialist.
How can patients with active
TB protect household members
and other contacts from infection?
Patients who are infected with or are
suspected of being infected with TB
must be educated to cover their
mouth and nose when they cough
or sneeze, not sleep in a room with
other household members, and
refrain from having home visitors
until they are noninfectious.
What are the physician's public
health responsibilities after
diagnosing active TB?
All 50 states require health care
providers to notify the TB pro-
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7 February 2017
gram in their respective departments of health within 24 hours
in cases of suspected or confirmed active TB (34); requirements for further reporting vary
by state. Within 24 hours, a
state's TB program is responsible
for notifying the local board of
health of the patient's residence,
to set up processes to screen potential contacts, and take steps to
avoid further transmission. Providers must report treatment
progress as well as patients who
are nonadherent, leave medical
facilities against medical advice,
or continue to place others at
risk.
Screening and Prevention... Clinicians should screen close contacts of
a person with active pulmonary TB or those who are at high risk for infection or progression to disease once infected. Clinicians should prevent infection by identifying and treating persons with active pulmonary
TB. Patients with evidence of infection but not disease should be offered LTBI therapy. Patients suspected of having TB should be placed
on airborne isolation, and staff who provide care should wear particulate respirators. Clinicians should notify public health authorities about
patients with suspected active TB.
CLINICAL BOTTOM LINE
Diagnosis
What are the signs and
symptoms of active TB?
Table 3 shows some of the main
findings from the history and
physical examination that are associated with active TB. Pulmonary disease is overwhelmingly
the most common presentation
(>80%) (35). Persons with compromised immune systems (e.g.,
HIV co-infected patients) may
present with few classic symptoms and are more likely to present with extrapulmonary TB.
What are the signs and
symptoms of active TB among
HIV co-infected patients?
Signs and symptoms vary by degree of immunodeficiency. Patients with CD4 counts greater
than 350 per cubic millimeter are
more likely to present with classic
constitutional symptoms; those
with CD4 counts less than 200
per cubic millimeter are more
likely to have atypical and asymptomatic presentation and extrapulmonary disease (36, 37).
For this reason, the index of sus-
7 February 2017
picion for active TB should be
high in patients with HIV who
have been exposed to TB. Active
microbiological screening for TB,
regardless of whether symptoms
are present, is important because
disease can be missed when
screening is based on signs and
symptoms alone. Up to 25% of
patients screened before starting
antiretroviral drugs in South Africa were found to have microbiologically confirmed TB (38, 39).
How is active TB diagnosed?
In resource-rich settings, patients
with symptoms, signs, or radiographic findings suggestive of
active TB should receive 3 serial
sputum microscopy and mycobacterial cultures collected at
least 8 hours apart, in addition to
chest radiography. Sputum induction should be done if patients cannot expectorate spontaneously. If there are signs of
extrapulmonary disease, samples
from those areas, such as lymph
nodes or the pleural space,
should also be evaluated. Histopathologic evidence of caseating
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In the Clinic
ITC23
23. Kamat SR, Dawson JJ,
Devadatta S, Fox W,
Janardhanam B, Radhakrishna S, et al. A
controlled study of the
influence of segregation
of tuberculous patients
for one year on the attack
rate of tuberculosis in a
5-year period in close
family contacts in South
India. Bull World Health
Organ. 1966;34:517-32.
[PMID: 5296379]
24. Zwerling A, Behr MA,
Verma A, Brewer TF,
Menzies D, Pai M. The
BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 2011;8:
e1001012. [PMID:
21445325]
25. Centers for Disease Control and Prevention.
Deciding When to Treat
Latent TB Infection.
2016. Accessed at www
.cdc.gov/tb/topic
/treatment/decideltbi
.htm on 20 December
2016.
26. Smieja MJ, Marchetti CA,
Cook DJ, Smaill FM.
Isoniazid for preventing
tuberculosis in non-HIV
infected persons.
Cochrane Database Syst
Rev. 2000:CD001363.
[PMID: 10796642]
27. Loeffler AM. Pediatric
Tuberculosis: An Online
Presentation. 2010.
Accessed at www
.currytbcenter.ucsf.edu
/products/pediatric
-tuberculosis-online
-presentation?productID
=ONL-10 on 20 December 2016.
28. Sterling TR, Villarino ME,
Borisov AS, Shang N,
Gordin F, BlivenSizemore E, et al; TB
Trials Consortium PREVENT TB Study Team.
Three months of rifapentine and isoniazid for
latent tuberculosis infection. N Engl J Med.
2011;365:2155-66.
[PMID: 22150035] www
.ncbi.nlm.nih.gov
/pubmed/22150035 on
20 December 2016.
29. Belknap R, Borisov A,
Holland D, Feng P-J,
Millet J-P, Martinson N,
et al. Adherence to OnceWeekly SelfAdministered INH and
Rifapentine for Latent TB:
iAdhere. In: Conference
on Retroviruses and
Opportunistic Infections.
Seattle; 2017. Accessed
at www.croiconference
.org/sessions/adherence
-once-weekly-self
-administered-inh-and
-rifapentine-latent-tb
-iadhere on 20
December 2016.
姝 2017 American College of Physicians
Table 3. Findings From the History and Physical Examination in Patients With Active TB
History
Notes
TB exposure, infection, disease, or treatment
Patients with recent exposure to TB are more likely to develop disease;
however, known exposure is not necessary to have TB. Clinicians may
contact their local health department to learn whether a patient has received
TB treatment in the past and what regimen was used
HIV infection or other medical conditions, or
demographic factors that may increase the
risk for, or change the presentation of, TB
HIV-infected patients with latent TB infection have >20-fold risk for progression to
active TB than patients without HIV. Signs and symptoms of other concurrent
medical conditions may mask signs and symptoms of TB
Fever
Less likely to be present in elderly persons. Absence of fever does not rule out
TB. Patients may report feeling feverish without having fever
Malaise
Night sweats
A classic symptom of TB but may only be present in disease of long duration
Weight loss
More common in advanced, extrapulmonary, or disseminated disease
Gynecologic symptoms
Pelvic pain, menstrual irregularities, and infertility are the most common
Physical Examination
Systemic signs
Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and
splenomegaly can be present
Throat examination
Hoarseness
Lymph node examination
May be palpable with pulmonary, disseminated disease, or scrofula
Pulmonary examination
Generally not helpful but may include rales, signs of consolidation, or findings
consistent with (often unilateral) pleural effusion (including pleuritic pain)
Pericardial disease
Tachycardia, increased venous pressure, hepatomegaly, pulsus paradoxus,
and friction rub
Abdominal examination
Ascites, “doughy” abdomen, or abdominal mass. Hepatosplenomegaly in
disseminated disease
Genitourinary examination
Recurrent urinary tract infection with no organisms on culture. In men, beaded
vas deferens on palpation, draining scrotal sinus, epididymitis or induration
of prostrate or seminal vesicles
Musculoskeletal examination
Joint swelling, gibbus deformity, or localized pain
Neurologic examination
Abnormal behavior, headache, seizure
TB = tuberculosis.
30. Sharma SK, Sharma A,
Kadhiravan T, Tharyan P.
Rifamycins (rifampicin,
rifabutin and rifapentine)
compared to isoniazid for
preventing tuberculosis
in HIV-negative people at
risk of active TB.
Cochrane Database Syst
Rev. 2013:CD007545.
[PMID: 23828580]
31. Castro KG. New Regimen
Makes Treating Latent
Tuberculosis Infection
Easier. Medscape. 2012.
32. Sackoff JE, Pfeiffer MR,
Driver CR, Streett LS,
Munsiff SS, DeHovitz JA.
Tuberculosis prevention
for non-US-born pregnant women. Am J Obstet Gynecol. 2006;194:
451-6. [PMID:
16458645]
33. Management of persons
exposed to multidrugresistant tuberculosis.
MMWR Recomm Rep.
1992;41:61-71. [PMID:
1640921]
姝 2017 American College of Physicians
granulomas is suggestive of active TB but is not diagnostic; similarly, AFB positivity alone does
not confirm diagnosis.
The gold standard for TB diagnosis is a positive mycobacterial
culture from liquid medium. Negative results on AFB smears occur
in half of patients with active pulmonary TB and in an even higher
percentage of HIV co-infected
persons; therefore, mycobacterial cultures should be routinely
done, even in patients with negative smears. In persons suspected of having disseminated
TB or who are highly immunosuppressed (i.e., advanced AIDS),
blood culture and collection of
first-void urine for mycobacterial
analysis can be done.
ITC24
In the Clinic
Bronchoscopy with either bronchoalveolar lavage or biopsy
should be used for diagnosis in
patients who are suspected of having active disease but have negative sputum samples (40). Symptoms similar to those of TB, such as
weight loss, fever, and cough, can
be caused by nontuberculous mycobacteria, aspiration pneumonia,
lung abscesses, Wegener granulomatosis, actinomycosis, and cancer. Thus, TB infection should be
confirmed on culture whenever
possible. Clinicians should be
aware of other diseases that may
resemble TB on pathologic examination, including nontuberculous
mycobacteria, syphilis, brucellosis,
sarcoidosis, or such fungal diseases as histoplasmosis or coccidiomycosis (41).
Annals of Internal Medicine
7 February 2017
A major operational challenge in
diagnosing TB is the lag time until results from solid media (i.e.,
Löwenstein–Jensen medium) are
available. Liquid medium (e.g.,
Mycobacteria Growth Indicator
Tube) has a shorter median time
to positivity for both smearpositive (7 vs. 14 days) and
smear-negative (14 vs. 25 days)
disease (42). The CDC has endorsed the additional use of nucleic acid amplification (NAA)
testing on sputum specimens
when TB is suspected (43). This
test can provide results in 24 – 48
hours and has a greater positive
predictive value for true M tuberculosis (>95%) compared with
AFB smear-positive specimens in
settings where nontuberculous
mycobacterium are common.
NAA can also rapidly confirm the
presence of M tuberculosis in
50%– 80% of AFB smearnegative, culture-positive specimens. Compared with culture,
results are available weeks earlier
for 80%–90% of patients with suspected pulmonary TB among
those in whom it is ultimately confirmed by culture (44). Thus, although NAA should not replace
culture, it can facilitate earlier decision making regarding whether to
initiate treatment for TB.
The Xpert MTB/RIF assay is an
NAA test that uses a disposable
cartridge in the GeneXpert Instrument System, and results are
available within 2 hours. This assay has been reported to have
specificity of 99% and sensitivity
of 98% in smear-positive and
specificity of 99% and sensitivity
of 67% in smear-negative sputum
specimens (45).
Xpert MTB/RIF testing has been
widely implemented in resourcelimited settings with high TB
prevalence (46). In a large U.S.
study, diagnostic performance of
this test was similar to that in
high–TB burden settings, supporting its use for initial evalua-
7 February 2017
tion of suspected TB in conjunction with other tests (47). Two
negative Xpert MTB/RIF tests
may in the future replace the current standard of 3 sputum smears
to rule out infectious TB, permitting removal of respiratory precautions. A result indicating RIF
susceptibility can also reassure
providers that the patient is unlikely to have multidrug resistance (MDR).
How should drug susceptibility
testing be done, and in which
patients?
If active TB is confirmed, susceptibility testing for first-line drugs
should be done, ideally on the
initial, pretreatment isolate.
Drug-resistant TB was previously
believed to be caused by acquired resistance in initially drugsusceptible disease due to poorquality drugs, poor adherence,
or a weak drug combination.
However, a globally increasing
proportion of drug-resistant
cases is now occurring due to
person-to-person transmission.
Thus, the ability to predict who
has drug-resistant disease has
weakened, making baseline resistance testing even more
important.
Culture remains the standard for
drug susceptibility testing and
should be done at a reference
laboratory. If available, Xpert
MTB/RIF can detect RIF
resistance, allowing for more
rapid triage of samples for additional testing. If RIF resistance is
detected, drug susceptibility testing for both first-line and secondline drugs should be done (see
the CDC TB Web site for details)
and the treatment regimen
should be adjusted accordingly.
Drug-resistant TB refers to M tuberculosis with resistance to any
of the TB drugs. An important
distinction is MDR TB, which is
defined as resistance to INH and
RIF. Patients with this type of
Annals of Internal Medicine
In the Clinic
ITC25
34. Centers for Disease Control and Prevention.
Menu of Suggested
Provisions For State
Tuberculosis Prevention
and Control Laws. 2010.
Accessed at www.cdc.gov
/tb/programs/laws/menu
/caseid.htm on
20 December 2016.
35. Sandgren A, Hollo V, van
der Werf MJ. Extrapulmonary tuberculosis in
the European Union and
European Economic
Area, 2002 to 2011. Euro
Surveill. 2013;18.
[PMID: 23557943]
36. Schutz C, Meintjes G,
Almajid F, Wilkinson RJ,
Pozniak A. Clinical management of tuberculosis
and HIV-1 co-infection.
Eur Respir J. 2010;36:
1460-81. [PMID:
20947678]
37. Mendelson M. Diagnosing tuberculosis in HIVinfected patients: challenges and future
prospects. Br Med Bull.
2007;81-82:149-65.
[PMID: 17470475]
38. Lawn SD, Edwards DJ,
Kranzer K, Vogt M, Bekker LG, Wood R. Urine
lipoarabinomannan
assay for tuberculosis
screening before antiretroviral therapy diagnostic
yield and association
with immune reconstitution disease. AIDS. 2009;
23:1875-80. [PMID:
20108382]
39. Kranzer K, Houben RM,
Glynn JR, Bekker LG,
Wood R, Lawn SD. Yield
of HIV-associated tuberculosis during intensified
case finding in resourcelimited settings: a systematic review and metaanalysis. Lancet Infect
Dis. 2010;10:93-102.
[PMID: 20113978]
40. Malekmohammad M,
Marjani M, Tabarsi P,
Baghaei P, Sadr Z,
Naghan PA, et al. Diagnostic yield of postbronchoscopy sputum
smear in pulmonary
tuberculosis. Scand J
Infect Dis. 2012;44:36973. [PMID: 22497518]
www.ncbi.nlm.nih.gov
/pubmed/22497518 on
20 December 2016.
41. Zumla A, James DG.
Granulomatous infections: etiology and classification. Clin Infect Dis.
1996;23:146-58. [PMID:
8816144]
42. Chihota VN, Grant AD,
Fielding K, Ndibongo B,
van Zyl A, Muirhead D,
et al. Liquid vs. solid
culture for tuberculosis:
performance and cost in
a resource-constrained
setting. Int J Tuberc Lung
Dis. 2010;14:1024-31.
[PMID: 20626948]
姝 2017 American College of Physicians
43. Update: nucleic acid
amplification tests for
tuberculosis. MMWR
Morb Mortal Wkly Rep.
2000;49:593-4. Accessed at https://stacks
.cdc.gov/view/cdc/27233
on 20 December 2016.
44. Updated guidelines for
the use of nucleic acid
amplification tests in the
diagnosis of tuberculosis.
MMWR Morb Mortal
Wkly Rep. 2009;58:7-10.
[PMID: 19145221]
45. Steingart K, Schiller I,
Horne D, Boehme CC,
Dendukuri N. Xpert®
MTB/RIF assay for pulmonary tuberculosis and
rifampicin resistance in
adults. Cochrane Database Syst Rev. 2014;(1):
CD009593. www.ncbi
.nlm.nih.gov/pubmed
/19145221 on 20
December 2016.
46. World Health Organization. Policy statement:
automated real-time
nucleic acid amplification
technology for rapid and
simultaneous detection
of tuberculosis and rifampicin resistance:
Xpert MTB/RIF system.
Geneva: World Health
Organization; 2011.
Accessed at http://apps
.who.int/iris/bitstream
/10665/44586/1
/9789241501545_eng
.pdf on 20 December
2016.
47. Luetkemeyer AF, Firnhaber C, Kendall MA, Wu
X, Mazurek GH, Benator
DA, et al; AIDS Clinical
Trials Group A5295 and
Tuberculosis Trials Consortium Study 34 Teams.
Evaluation of Xpert MTB/
RIF versus AFB smear
and culture to identify
pulmonary tuberculosis
in patients with suspected tuberculosis from
low and higher prevalence settings. Clin Infect
Dis. 2016;62:1081-8.
[PMID: 26839383]
48. Migliori GB, Lange C,
Girardi E, Centis R, Besozzi G, Kliiman K, et al;
SMIRA/TBNET Study
Group. Extensively drugresistant tuberculosis is
worse than multidrugresistant tuberculosis:
different methodology
and settings, same results [Letter]. Clin Infect
Dis. 2008;46:958-9.
[PMID: 18288911]
drug resistance require a change
to a second-line regimen and have
significantly worse outcomes than
those with drug-susceptible TB (1).
Patients with MDR TB and resistance to 2 of the second-line
drugs, a fluoroquinolone and an
injectable aminoglycoside (e.g.,
amikacin, capreomycin, or kanamycin), are considered to have
extensively drug-resistant (XDR) TB
and have extremely poor treatment outcomes, partially due to
the few good drugs left to treat
them (48).
When should clinicians refer
patients with suspected active
TB to an expert?
Providers who rarely care for patients with TB should consult an
expert if the patient has a negative
AFB smear and culture results but
pulmonary TB is still suspected
clinically, if the patient has drugresistant TB, or if the patient has
been treated previously for TB.
Delayed or inappropriate treatment may lead to prolonged transmission of disease and development of drug resistance.
Diagnosis... Patients should be tested for TB if they have prolonged
cough, hemoptysis, chest pain, or systemic symptoms. Clinical suspicion should be higher in patients who are HIV-positive, even if they
have few symptoms and a clear chest radiograph. Patients with negative microbiologic testing but for whom clinical suspicion is still high
should receive empirical treatment with assessment for clinical response after 2 months. Patients should be referred to a TB expert if the
primary physician has little experience with TB, the presentation is not
straightforward, drug resistance is present, or the patient does not respond to therapy.
CLINICAL BOTTOM LINE
Treatment
姝 2017 American College of Physicians
What is the standard drug
treatment for active TB in
cases of drug-susceptible
M tuberculosis infection?
The most recent professional
guidelines for treating drugsusceptible TB were published in
June 2016 (49). The preferred
regimen for treating adults with
TB that is known or believed to
be drug-susceptible consists of
an intensive phase of 4 drugs
(INH, RIF, ethambutol [EMB], and
pyrazinamide [PZA]) for 2
months, followed by a continuation phase consisting of 2 drugs
(INH plus RIF), usually for 4
months. If the M tuberculosis isolate is found to be susceptible to
INH and RIF, EMB can be
stopped early in the intensive
phase. Pyridoxine (vitamin B6)
ITC26
In the Clinic
should be given with INH to all
persons at risk for neuropathy
(i.e., pregnant women; breastfeeding infants; HIV-infected persons; patients with diabetes, alcoholism, malnutrition, or chronic
renal failure; and persons of advanced age). If given correctly
and taken completely, this regimen has a 95% cure rate (50).
The preferred schedule is daily
dosing during both the intensive
and continuation phases with
DOT 5 days per week (49). If
daily DOT is difficult, intermittent
dosing can be done as an alternative in HIV-negative, pulmonary TB cases caused by drugsusceptible organisms without
cavitation, but this should be reviewed with a TB specialist.
Annals of Internal Medicine
7 February 2017
What is the best way to
monitor the results of
treatment and to detect adverse
effects during active TB
therapy?
Table 4 shows recommended
baseline, follow-up, and end-oftreatment evaluations for patients
treated with first-line TB medications (49). The baseline visit
should assess AFB smear and TB
culture status as well as drug susceptibility of the infecting isolate
with rapid molecular diagnostic
and traditional susceptibility testing. A chest radiograph should
be done to assess the extent of
cavitation. Blood should be
drawn to assess general health,
including liver and kidney function. Weight should be recorded,
and baseline symptoms should
be assessed. Patients should be
screened for HIV, hepatitis B and
C viruses, alcoholism, and diabe-
tes—these are common comorbidities among TB patients and
are associated with variable treatment outcomes.
Sputum specimens should be
collected at treatment months 1
and 2 to assess response and,
beyond that point, if treatment
failure or delayed conversion is
suspected. If a patient is culturepositive at treatment month 3,
drug-susceptibility testing should
be repeated to assess for acquired drug resistance.
Medication adverse effects are
common. In a prospective cohort
study of Chinese patients receiving standard first-line treatment,
15% had a documented adverse
drug reaction that led to interruption or discontinuation of therapy; of these, 7.7% resulted in
hospitalization, disability, or
death (51). The most serious ad-
Table 4. Recommended Baseline, Follow-up, and End-of-Treatment
Evaluations for Patients Treated With First-Line TB Medications*
Test
Month of Treatment Completed
Baseline
1
2
3
4
Microbiology
Sputum smears and culture
Drug susceptibility testing
•
•
• • °
°
°
Imaging
Chest radiograph or other imaging
•
•
Clinical Assessment
Weight
Symptom and adherence review
Vision assessment
•
•
•
• • • • • • • •
• • • • • • • •
• • ° ° ° ° ° °
Laboratory Testing
AST, ALT, bilirubin, alkaline phosphate
Platelet count
Creatinine
HIV serology
Hepatitis B and C screen
Diabetes screen
•
•
•
•
°
°
°
°
°
°
°
°
5
6
7
8
End of
treatment
°
°
°
°
°
°
°
°
°
°
°
°
°
°
°
°
°
49. Nahid P, Dorman SE,
Alipanah N, Barry PM,
Brozek JL, Cattamanchi
A, et al. Official American
Thoracic Society/Centers
for Disease Control and
Prevention/Infectious
Diseases Society of America clinical practice guidelines: treatment of drugsusceptible tuberculosis.
Clin Infect Dis. 2016;63:
e147-95. [PMID:
27516382]
50. Zumla A, Raviglione M,
Hafner R, von Reyn CF.
Tuberculosis. N Engl J
Med. 2013;368:745-55.
[PMID: 23425167] www
.ncbi.nlm.nih.gov
/pubmed/23425167 on
20 December 2016.
°
°
°
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TB = tuberculosis.
* Adapted from reference 49.
• = recommended diagnostics or procedures; ° = optional or contingent diagnostics or procedures.
7 February 2017
Annals of Internal Medicine
In the Clinic
ITC27
姝 2017 American College of Physicians
51. Lv X, Tang S, Xia Y, Wang
X, Yuan Y, Hu D, et al.
Adverse reactions due to
directly observed treatment strategy therapy in
Chinese tuberculosis
patients: a prospective
study. PLoS One. 2013;
8:e65037. [PMID:
23750225]
52. Saukkonen JJ, Powell K,
Jereb JA. Monitoring for
tuberculosis drug hepatotoxicity: moving from
opinion to evidence
[Editorial]. Am J Respir
Crit Care Med. 2012;
185:598-9. [PMID:
22422902]
53. Benator D, Bhattacharya
M, Bozeman L, Burman
W, Cantazaro A, Chaisson
R, et al; Tuberculosis
Trials Consortium. Rifapentine and isoniazid
once a week versus rifampicin and isoniazid
twice a week for treatment of drug-susceptible
pulmonary tuberculosis
in HIV-negative patients:
a randomised clinical
trial. Lancet. 2002;360:
528-34. [PMID:
12241657]
54. Jo KW, Yoo JW, Hong Y,
Lee JS, Lee SD, Kim WS,
et al. Risk factors for
1-year relapse of pulmonary tuberculosis treated
with a 6-month daily
regimen. Respir Med.
2014;108:654-9. [PMID:
24518046]
55. Horne DJ, Royce SE,
Gooze L, Narita M,
Hopewell PC, Nahid P,
et al. Sputum monitoring
during tuberculosis treatment for predicting outcome: systematic review
and meta-analysis. Lancet Infect Dis. 2010;10:
387-94. [PMID:
20510279]
56. Chang KC, Leung CC,
Yew WW, Ho SC, Tam
CM. A nested casecontrol study on
treatment-related risk
factors for early relapse
of tuberculosis. Am J
Respir Crit Care Med.
2004;170:1124-30.
[PMID: 15374844]
57. Availability of an assay
for detecting Mycobacterium tuberculosis, including rifampin-resistant
strains, and considerations for its use—United
States, 2013. MMWR
Morb Mortal Wkly Rep.
2013;62:821-7. [PMID:
24141407] Accessed at
www.ncbi.nlm.nih.gov
/pubmed/24141407 on
20 December 2016.
58. Thwaites G, Fisher M,
Hemingway C, Scott G,
Solomon T, Innes J;
British Infection Society.
British Infection Society
guidelines for the diagnosis and treatment of
tuberculosis of the central nervous system in
adults and children. J
Infect. 2009;59:167-87.
[PMID: 19643501]
姝 2017 American College of Physicians
verse effect is often hepatotoxicity, which occurred in 3%–13% of
patients in a review of retrospective studies (52). Patients are encouraged to abstain from alcohol
and avoid acetaminophencontaining products while receiving TB treatment. Persons who
have evidence of hepatotoxicity
at baseline, develop symptoms
of hepatotoxicity, chronically
consume alcohol, have viral hepatitis or a history of liver disease,
or are HIV co-infected should
have liver function tests regularly
throughout treatment. Patients
on an EMB-containing regimen
should have their vision assessed
at baseline and on a monthly basis thereafter with a visual acuity
test (e.g., Snellen test) and a
color discrimination test (e.g.,
Ishihara test).
When and why should the
standard treatment regimen be
modified?
During treatment, a sputum
specimen for AFB and mycobacterial culture should be obtained
monthly until results are negative
for 2 consecutive months. Positive culture results after 2 months
of therapy have been shown to
predict relapse after therapy
completion, although sensitivity
is low (53–55). Cavitation on initial chest radiograph has also
been shown to predict relapse
(53, 56). In patients treated for 6
months, a positive culture at 2
months and cavitation were associated with a relapse rate of almost 20% within 1 year of treatment completion compared with
2% in patients with neither factor
(54). Expert opinion based on
these findings recommends extending the continuation phase
for an additional 3 months (i.e., a
continuation phase of 7 months
leading to a total of 9 months'
treatment) (49).
Because of the complexity,
length, and adverse effects of
treatment, complete adherence
ITC28
In the Clinic
is challenging. Breaks earlier in
treatment and of longer duration
can have more serious effects
and may warrant restarting the
treatment “clock” (49). Specifically, if treatment is interrupted
for 2 weeks or more during the
intensive phase, the patient
should restart this phase from the
beginning. If treatment is interrupted for less than 2 weeks in
the intensive phase, continuation
of therapy until all doses are
completed is acceptable as long
as this occurs within 3 months.
For the continuation phase, if a
patient takes more than 80% of
all doses and AFB smear results
were initially negative, further
therapy may not be necessary. If
the AFB was positive, the patient
should take all doses until completed. If more than 80% of all
doses have been missed but during less than 2 consecutive
months, the patient can continue
therapy until completion. If more
than 2 consecutive months were
missed, the patient should repeat
a full course of therapy from the
beginning (intensive and continuation phases) (57).
How should patients with
extrapulmonary TB be treated?
The principles for treating pulmonary TB apply to extrapulmonary disease. Increasing evidence suggests that 6 –9 months
of INH- and RIF-containing regimens are effective for TB treatment in most extrapulmonary
disease sites, although the robustness of the data for extrapulmonary disease is not as great as
for pulmonary TB (49). The clear
exception is TB meningitis, for
which the ideal treatment regimen is not known but most experts recommend 2 months of
the 4-drug regimen and then 10
months of INH plus RIF (58). A
mortality benefit has also been
shown with the addition of corticosteroids (dexamethasone or
Annals of Internal Medicine
7 February 2017
prednisolone) to this regimen,
tapered over 6 – 8 weeks (59, 60).
No large randomized, controlled
trials or systematic reviews found
differences in mortality, cardiac
tamponade, or constrictive pericarditis among patients with TB
pericarditis who did or did not
receive steroids (49, 61). Regardless, experts recommend that
addition of steroids be considered in patients at highest risk for
inflammatory complications (i.e.,
presence of large pericardial effusions, high levels of inflammatory cells or markers in pericardial fluid, or early signs of
pericardial constriction).
For monitoring treatment response, bacteriologic evaluation
is often limited by difficulty in obtaining follow-up specimens.
Sputum specimens should be
obtained when concurrent pulmonary TB is present; otherwise,
response to therapy is often
judged on clinical and radiographic findings.
What is the approach to
treatment of active TB and HIV
co-infection?
Because patients with HIV infection often have more rapid progression to TB and higher mortality related to delayed treatment
initiation, TB medication should
be started as soon after diagnosis as possible (62). The recommended regimen for drugsusceptible TB is the same for
co-infected patients and HIVuninfected patients. For HIVinfected patients receiving antiretroviral therapy (ART) (which
should be all patients), the standard 6-month daily regimen for
drug-susceptible TB is recommended (49). In rare cases where
an HIV-infected person does not
receive ART during TB treatment,
the continuation phase can be
extended for an additional 3
months (i.e., a total of 9 months'
treatment). As with HIV-
7 February 2017
uninfected patients, regimens
should be extended for the
reasons outlined above. HIVinfected patients should not
receive intermittent dosing regimens, regardless of whether they
are receiving ART, because these
regimens have been associated
with higher rates of relapse and
acquired drug resistance in coinfected persons (53, 63).
Management of patients coinfected with HIV and TB is complicated by the timing of ART initiation, potential drug
interactions between HIV and TB
medications, and paradoxical
reactions (i.e., immune reconstitution inflammatory syndrome
[IRIS] [see below]).
Research now strongly supports
early initiation of ART for patients
with TB. A systematic review
found that the overall reduction
in mortality with ART initiation
during TB treatment was 24%
(relative risk [RR], 0.76 [95% CI,
0.57–1.01]) (49). Overall risk for
HIV disease progression was reduced by 34% by early or immediate ART (RR, 1.88 [CI, 1.31–
2.69]). Based on this review,
patients with a CD4 count less
than 0.050 × 109 cells/L should
be started on ART within 2 weeks
after initiation of TB therapy, and
those with a CD4 count of
0.050 × 109 cells/L or greater
should be started between 8 and
12 weeks after initiation. The important exception is HIV-infected
patients with TB meningitis, in
whom ART should not be initiated during the first 8 weeks of
anti-TB therapy at any CD4 count
to avoid increased morbidity
from IRIS.
The major concern with regard to
drug interactions in co-infected
patients is that between RIF, a
potent inducer of multiple drugmetabolizing enzymes and drug
transporters, and ART. Although
RIF has been shown to decrease
Annals of Internal Medicine
In the Clinic
ITC29
59. Critchley JA, Young F,
Orton L, Garner P. Corticosteroids for prevention
of mortality in people
with tuberculosis: a systematic review and metaanalysis. Lancet Infect
Dis. 2013;13:223-37.
[PMID: 23369413]
60. Thwaites GE, Nguyen DB,
Nguyen HD, Hoang TQ,
Do TTO, Nguyen TCT,
et al. Dexamethasone for
the treatment of tuberculous meningitis in adolescents and adults.
N Engl J Med. 2004 Oct
21;351(17):1741–51.
[PMID: 15496623] Accessed at www.ncbi.nlm
.nih.gov/pubmed
/15496623 on 20
December 2016.
61. Mayosi B, Ntsekhe M,
Smieja M. Immunotherapy for tuberculous pericarditis. N Engl J Med.
2014;371:2532-3.
[PMID: 25539114]
62. Holtz TH, Kabera G, Mthiyane T, Zingoni T, Nadesan S, Ross D, et al. Use
of a WHO-recommended
algorithm to reduce
mortality in seriously ill
patients with HIV infection and smear-negative
pulmonary tuberculosis
in South Africa: an observational cohort study.
Lancet Infect Dis. 2011;
11:533-40. [PMID:
21514234]
63. Vernon A, Burman W,
Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in
patients with HIV-related
tuberculosis treated with
once-weekly rifapentine
and isoniazid. Tuberculosis Trials Consortium.
Lancet. 1999 May 29;
353:1843-7. [PMID:
10359410]
姝 2017 American College of Physicians
drug levels of efavirenz,
efavirenz-based ART with RIFcontaining TB treatment is the
most well-characterized regimen
with the best-documented outcomes for patients and low discontinuation rates; as such, it
remains the preferred drug combination (64). Alternative regimens that include protease inhibitor– based ART paired with a
rifabutin-containing TB regimen
and nevirapine-based ART paired
with a RIF-containing TB regimen
have also been endorsed if a patient cannot take efavirenz. If possible, co-infected patients should be
managed by providers with experience treating the 2 diseases due
to the complexity of the treatment
regimens.
64. Tuberculosis (TB): Managing drug interactions
in the treatment of HIVrelated tuberculosis.
2013. Accessed at www
.cdc.gov/tb/publications
/guidelines/tb_hiv_drugs/table1a.htm
on 21 December 2016.
65. Török ME, Yen NT, Chau
TT, Mai NT, Phu NH, Mai
PP, et al. Timing of initiation of antiretroviral
therapy in human immunodeficiency virus (HIV)—
associated tuberculous
meningitis. Clin Infect
Dis. 2011;52:1374-83.
[PMID: 21596680]
66. Horsburgh CR, Barry CE,
Lange C. Treatment of
tuberculosis. N Engl J
Med. 2015 Nov 26;373:
2149-60. [PMID:
26605929]
67. World Health Organization. WHO treatment
guidelines for drugresistant tuberculosis—
2016 update. Geneva:
World Health Organization; 2016.
姝 2017 American College of Physicians
Co-infected patients are at risk
for paradoxical worsening of TB
symptoms and lesions after beginning TB therapy and ART. This
reaction is a consequence of reconstitution of the immune response brought on by ART and is
referred to as IRIS. IRIS in patients
with TB is reported more commonly in those with CD4 counts
less than 0.050 × 109 cells/L. Before it can be diagnosed, other
reasons for the worsening signs
and symptoms need to be excluded, especially treatment failure due to drug resistance or
other opportunistic diseases.
Patients who start ART within 2
weeks of TB therapy have higher
IRIS rates than those who start
between 8 and 12 weeks; hence,
the recommendation to delay
ART in patients with higher CD4
counts. In patients with a CD4
cell count less than 50 per cubic
millimeter, starting ART within 2
weeks after TB treatment initiation is recommended. Most IRIS
can be managed symptomatically by adding anti-inflammatory
agents, such as ibuprofen or corticosteroids (49). The exception is
central nervous system TB, including TB meningitis: Patients in
ITC30
In the Clinic
whom ART was initiated within
2 weeks of TB therapy had increased rates of adverse events
and higher mortality (65).
What are the indications for
DOT for active TB?
Adherence to TB treatment is challenging but critical for both improved patient outcomes and to
avoid disease transmission; therefore, DOT (in which ingestion of
each dose is witnessed) has been
widely endorsed. DOT remains the
standard of practice in most U.S.
and European TB programs (49)
and is discussed in detail elsewhere (49).
When should patients be
treated for drug-resistant TB,
and what is the basic
approach?
Patients infected with M tuberculosis that is resistant only to INH
(i.e., INH-monoresistant TB) can
receive the 3 other first-line
drugs (RIF, EMB, and PZA) for the
full 6 months of treatment, or a
fluoroquinolone (levofloxacin or
moxifloxacin) could be added to
the 3-drug regimen (66). Patients
with MDR TB (i.e., documented
resistance to both INH and RIF),
or RIF-resistant TB need a greater
adjustment. The WHO has recommended, on the basis of a
large retrospective meta-analysis,
that patients with MDR TB receive 5 drugs to which their isolate is susceptible in the induction phase, which should last 6 to
8 months (67). This regimen ideally should include a fluoroquinolone and an injectable aminoglycoside (amikacin, kanamycin, or
capreomycin). Patients should
then enter a continuation phase
with 4 of those drugs (with removal of the injectable) for an
additional 12–18 months, resulting in a total of 18 –24 months of
treatment. Ideally, these regimens should be tailored to the
susceptibility profile of the specific patient's infection.
Annals of Internal Medicine
7 February 2017
In May 2016, the WHO endorsed
the “shorter” MDR TB regimen,
previously known as the “Bangladesh regimen.” It consists of 7
drugs given for 9 –12 months,
with cure rates of 85%– 89% and
few relapses in specific settings.
Clinical trials in additional settings are under way, but the
WHO encourages use of this reg-
imen in MDR TB patients who
have no evidence of resistance to
any of the 7 drugs, have no history of exposure to second-line
TB medications for more than a
month or intolerance to any of
the medications and low risk for
toxicity, are not pregnant, and do
not have extrapulmonary disease
(68).
68. World Health Organization. The Shorter MDR-TB
Regimen. Geneva: World
Health Organization;
2016. Accessed at www
.who.int/tb/Short_MDR
_regimen_factsheet.pdf
on 20 December 2016.
Treatment... Active TB should be treated with a regimen and for a
length of time tailored to patient characteristics and organism susceptibility. Patients with complications or adverse drug effects that cannot be
managed at home should be hospitalized, but patients should not be
hospitalized solely for isolation. Patients should be monitored at least
monthly for clinical response and adverse drug effects. Sputum of patients whose initial cultures are positive should be cultured monthly until negative. DOT should be considered, especially for patients who do
not respond to therapy, have HIV infection, are receiving intermittent
drug regimens, or have drug-resistant TB. Patients who have HIV coinfection, are drug-resistant, are failing therapy, or have extrapulmonary
disease ideally should be managed in consultation with experts.
CLINICAL BOTTOM LINE
In the Clinic
Tool Kit
Tuberculosis
https://medlineplus.gov/tuberculosis.html
Information on tuberculosis from the National Institutes
of Health MedlinePlus.
www.mayoclinic.org/diseases-conditions/tuberculosis
/home/ovc-20188556
Information on tuberculosis from the Mayo Clinic that is
useful to both patients and medical professionals.
www.cdc.gov/tb/publications/pamphlets/TBgtfctsEng.pdf
Patient handout on tuberculosis from the Centers for
Disease Control and Prevention.
www.cdc.gov/tb/esp/publications/pamphlets/TBgtfctsSpan.PDF
Patient handout in Spanish from the Centers for Disease
Control and Prevention.
Guidelines
www.cdc.gov/tb/publications/guidelines/default.htm
Access guidelines on a variety of specific topics related to
tuberculosis.
www.who.int/publications/guidelines/tuberculosis/en
World Health Organization guidelines on tuberculosis.
Other Information
www.who.int/tb/en
The World Health Organization provides information
about global efforts to eliminate tuberculosis and related programs.
7 February 2017
Annals of Internal Medicine
ITC31
IntheClinic
Patient Information
姝 2017 American College of Physicians
WHAT YOU SHOULD
KNOW ABOUT
TUBERCULOSIS
In the Clinic
Annals of Internal Medicine
What Is Tuberculosis?
Tuberculosis (TB) is a disease caused by bacteria
that attack the lungs. There are 2 kinds of TB:
• Active TB makes a person feel sick and can spread
to others by coughing, sneezing, or speaking.
• Latent TB does not make you feel sick and
does not spread to others. People with latent
TB are infected with the bacteria but do not
have the disease. Some people with latent TB
may progress to active TB later on. People
who are older, have HIV infection or other
immunosuppression, have poor nutrition, or
other health problems are at greater risk.
What Are the Warning Signs?
Latent TB has no symptoms.
How Is It Diagnosed?
There are 2 types of tests for TB infection: a skin
test and a blood test. These tests can check for
both latent and active TB but cannot tell you
which type you have. If either test is positive,
your doctor will test your sputum and order a
chest X-ray. This will help him or her know
whether you have active TB that can spread to
other people. People should be tested for TB
infection if they:
• Have had close contact with someone who has
active TB
• Have certain chronic illnesses, such as HIV
• Have come to the United States in the past 5
years from a country where TB is common
• Work with bacteria in laboratories
• Are health care workers
• Live or work in facilities where many people
congregate, such as jails, nursing homes, and
homeless shelters
• Are smokers or drug users
How Is It Treated?
• Active TB can be treated and usually cured by
taking medicines for 6 or more months.
• Latent TB can be treated with medicine taken
for 3 to 9 months. This medicine will help
prevent you from getting active TB.
• If TB is not treated, it can be deadly.
What Is Drug-Resistant TB?
• Drug-resistant TB happens when the
medicines usually used to treat TB do not
work. The bacteria causing the disease is
“resistant” to the medicines.
• This type of TB is rare in the United States but
is becoming more common in other parts of
the world.
• It is usually treated with more and stronger
medicines for a long period.
Questions for My Doctor
• If I have latent TB, is it safe for me to be
around other people?
• How did I get TB?
• Will I develop active TB?
• Do I need treatment?
• What treatment is best for me?
• How long do I have to stay on treatment?
• What medicines are safe to take with TB
medicines?
• How long will it take to be cured?
• Can I leave my house and go to work?
For More Information
MedlinePlus
https://medlineplus.gov/tuberculosis.html
Centers for Disease Control and Prevention
www.cdc.gov/tb/faqs
Patient Information
Symptoms of active TB in the lungs include the
following:
• A long-lasting cough
• Chest pain
• Coughing up blood or mucus
• Weight loss
• Feeling weak or tired
• Fever and chills
• Night sweats