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Tuberculosis
Karen Doucette
Ryan Cooper
Part 17
Infectious Diseases of the Lungs
Introduction
Tuberculosis (TB) is a severe and contagious disease caused by
infection with members of the Mycobacteria tuberculosis complex
(MTBC). Most often involving the lungs, TB is transmitted by cough,
with an infectious dose of less than 10 bacteria.1 Case fatality rates in
untreated active pulmonary TB approach nearly 60%.2 Major medical advances of the past half-century have brought effective treatment capable of cure in nearly all identified cases.3,4 Despite this TB
causes hundreds of thousands of deaths worldwide every year. The
morbidity and mortality burden of TB is not uniformly distributed
throughout the globe but rather disproportionately affects those
living in poverty and those from resource-limited settings.5
Epidemiology AND MICROBIOLOGY
In this section, aspects of the epidemiology and microbiology of
tuberculosis are presented.
Global burden of TB and Recent Progress
In 1990, the World Health Organization (WHO) declared TB a
global emergency and in response, developed the directly observed
therapy strategy (DOTS), promising to Stop TB by finding and
treating infectious cases in resource-limited settings.6,7 Within a few
years of its design, the World Bank labeled the DOTS strategy the
most cost-effective health-intervention ever deployed and by 2012,
Estimated new
TB cases (all forms)
per 100 000 population
0-24
25-49
50-149
150-299
300
No estimate
Not applicable
Figure 131-1 Estimated TB incidence by Country 2011. (Reproduced with permission from 2012. Global Tuberculosis Report, World Health Organization.)
2012
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189
225
42
424
75
327
258
181
187
288
548
381
118
231
270
97
993
124
193
169
199
603
3.2
61,000
340,000
83,000
61,000
1,000,000
220,000
220,000
2,200,000
450,000
120,000
130,000
180,000
190,000
410,000
260,000
140,000
500,000
86,000
67,000
78,000
180,000
77,000
9951
Source: Data from Global Tuberculosis Report, World Health Organization; 2012.
Afghanistan
Bangladesh
Brazil
Cambodia
China
DR Congo
Ethiopia
India
Indonesia
Kenya
Mozambique
Myanmar
Nigeria
Pakistan
Philippines
Russian Federation
South Africa
Thailand
Uganda
UR Tanzania
Viet Nam
Zimbabwe
United States
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20,000
15,000
10,000
5,000
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
Part 17
Foreign-born
Year
2014
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TABLE 131-3 Key Distinguishing Features of Droplet Nuclei And Respiratory Droplets
Respiratory Droplet Transmission
Source: Reproduced with permission from Garay S, Rom W. Tuberculosis, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
Environmental Factors
Source: Data from Sepkowitz KA. How contagious is tuberculosis? Clin infect Dis.
1996;23(5):954962.
108 bacilli per mL of sputum compared to less than 103 bacilli per mL
of sputum in smear-negative cases.66 About 35% of close contacts of
sputum smearpositive patients will become infected, compared to
less than 10% from sputum smearnegative cases (Fig. 131-4).66,7173
Riley also demonstrated that effective anti-TB treatment could rapidly
render patients noninfectious, usually within a few days of initiation.74
The implications for discontinuing hospital isolation are somewhat controversial.75 As a matter of convention, pulmonary TB patients are usually considered noninfectious after 2 weeks of effective chemotherapy,
provided drug resistance and nonadherence are excluded.76
Particle size
Time for article to settle out of air
Site reached by particle in recipient airway
Number of microbes per particle
UV-light susceptibility
Example pathogens
Conducive Environment
Important environmental factors influencing TB transmission include
ventilation (or room air changes per hour) and ultraviolet light.66,77,78
Proximity and duration of contact with source case are also determinants of TB transmission. Household contacts are several times more
likely to be infected than are casual contacts from the community.66,72
Thus crowded housing with poor ventilation and inadequate natural
lighting such as occurs in prisons, homeless shelters, American
inner-city housing projects, and the large urban slums of the developing world are particularly conducive for TB spread.16,79
Host Susceptibility
Genetic determinants of innate immunity are likely important host
susceptibility factors but are poorly understood.63,80 Some studies
suggest that previous TB infection (as manifested by tuberculin skin
test positivity) may partially protect against reinfection, although
the degree of protection has not been quantified.8183 Vaccination
with attenuated M. bovis Bacille Calmette-Gurin (BCG) strain
probably does not reduce the risk of infection with MTBC, even if
it does reduce the subsequent chance of developing disseminated
active disease once infected.66,80,84
Natural history and pathophysiology
of TB infection
It is estimated that one-third of all humans are infected with TB.85
However, only a small fraction of the individuals within this massive reservoir ever develops active TB; most infections remain latent
without apparent ill effect on the host. Risk factors associated with
progression to active disease once infected are shown in Table 131-5.
From Exposure to Infection and the
Innate immune Response
The natural history of TB infection is outlined in Figure 131-5.
Following exposure to an infectious source case, many contacts do
not become infected, and will not convert their TSTeither because
infectious droplet nuclei did not reach their terminal alveoli or
because any successful invaders were immediately cleared by intrinsic microbicidal activity of macrophages.3
However, in some individuals, invading mycobacteria engulfed
by alveolar macrophages manage to evade intracellular killing.
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40
Close
Casual
Part 17
35
30
25
20
15
10
Smear positive
Smear negative
Primary Disease
About 5% of immune competent individuals do
not control initial mycobacterial replication and
instead progress to primary TB disease, usually
within 18 months. The risk of progression to
primary disease is even higher in those with compromised CMI or other
risk factors. Primary disease may occur at the initial site of lung entry
(typically the mid and lower lung zones where greater airflow directs
droplet nuclei deposition), regional lymph nodes, or rarely at metastatic
sites initially seeded during early occult hematogenous dissemination.
TABLE 131-5 R
isk Factors for Progression to Active TB in Those Latently Infected. Low-Risk Reactor
TST Positive with no Known Risk Factor, Normal Chest Radiograph
Risk Factor
Human immunodeficiency infection
Transplantation, immunosuppressant therapy
Silicosis
End-stage renal disease on hemodialysis
Solid-organ cancer
Hematological malignancy
Recent TB infection, within 2 y
Fibronodular changes on chest radiography
Tumor necrosis factor antagonists
Diabetes mellitus
Corticosteroid therapy
Heavy alcohol use (>40 g/d)
Malnutrition, underweight (BMI <20 kg/m2)
Cigarette smoker (1 pack/d)
Calcified granulomata on chest radiograph
Indoor air pollution
Refugee from TB endemic country, recent arrival
Vitamin D deficiency
Age <5
Low-risk reactor
Relative Risk
5.010
7.4
3.0
2.5
1.4
1.5
0.6
0.4
0.4
0.3
0.3
0.2
3.0
0.20.4
0.1
50100
2074
30
1025
312
40
15
619
24
28
5
34
23
2
2
2
30
1.5
24
1
Reference
Wood (2000), Selwyn (1989)
Torre (2009), Aguado (1997), Singh (2002)
Cowie (1994)
Christanopoulis (2007)
Kamboj (2006)
Kamboj (2006)
Sutherland (1976)
Grzybowski (1975), Cain (2008), Menzies (2008)
Keane (2001), Brassard (2006), Gomez (2007)
Dooley (2009)
Jick (2005), Brassard (2009)
Lonnroth (2008), Olin (1966)
Cigielski (2004)
Bates (2007), Lin (2007)
Menzies (2008)
Lonnroth (2009)
Greenway (2008)
Wilkinson (2000), Nnoham (2008)
Horsburgh (2004), Comstock (1974)
Menzies (2008)
Source: Data from Long R, Hoeppner V, Orr P, et al. Marked disparity in the epidemiology of tuberculosis among Aboriginal peoples on the Canadian prairies: the challenges
and opportunities. Can Respir J. 2013;20(4):223230.
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Exposure to pTB
(close contact)
Unable to reach
terminal alveolar
macrophages
No TST conversion
Macrophage
infection with
immediate clearance
No TST conversion
Infection established
(30% of exposed)
TST conversion
Innate immune
factors
Containment (9095%)
Latent TB Infection
Continued containment
(8590%)
Latent TB Infection
Not infected
(70% of exposed)
Early progression to
active TB within 2
Years (510%)
Primary TB
Figure 131-5 Natural history of TB infection. pTB, pulmonary tuberculosis; TST, tuberculin skin test. (Reproduced with permission from Comstock
GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982;125(3 Pt 2):815).
Reactivation Disease from latent infection
For the individuals who successfully contain the initial infection and
avoid primary disease, mycobacteria lie latent within healed, fibrotic
and/or calcific granulomata. At this stage, mycobacteria cannot be
cultured from host sputum or tissue specimens and symptoms are
not present. It is believed that latent tuberculous infection (LTBI),
with the potential for future reactivation, persists for life of the host.86
In a small minority, granulomas break down, mycobacteria replication increases, and symptomatic disease develops. Such reactivation can occur with age-related immune senescence or in those with
acquired risk factors for active TB. Reactivation most commonly
occurs in the apical-posterior segments of the lungs, where higher
oxygen tension favors bacillary replication, but disease can occur at
any previously seeded site.1 Once reactivated, bacilli can usually be
cultured from sputum and/or tissue samples.
Caseation and Cavitation
Differences in quality of host adaptive immune response determine
clinical presentation.57,80 Some individuals develop a particularly
robust, caseating granulomatous inflammatory response with resultant tissue destruction and lung cavitationthey discharge large
amounts of bacilli into airways and are highly contagious. At the
other end of the spectrum, a severely weak or immature granulomatous response allows hematogenous dissemination of bacilli,
accompanied by widespread inflammatory foci of poorly formed
granulomas. Each focus typically enlarges to about 3 mm in size, or
about the size of millet seed. This severe form of TB (miliary TB) has
a high case-fatality rate.
Clinical Manifestations
TB had had a number of illuminating vernacular names through
history. In ancient Greece, TB was called phthisis meaning to
waste away. And in Rome, tabes was used, indicating wasting and
overall decay. Consumption, a term applied to TB in 19th century
England is particular evocative, referring to the observation that TB
sufferers appear to be gradually consumed by the disease, becoming lighter and less robust over months.87
TABLE 131-6 P
roportion of Reported TB
Cases in the United States, by
Predominant Site of Disease
Site or Type of Disease
Pulmonary
Sputum smearpositive
pulmonary
Sputum smearnegative
pulmonary
Extrapulmonary
Pleural
Peripheral lymph node
Central nervous system
Abdominal
Bone and joint
Genitourinary
Other
Both
Total
Percentage (%)
66.7
40.1
26.6
21.2
3.8
8.2
1.3
1.2
2.3
1.1
4.0
12.1
100
Source: Data from Shah NS, Cavanaugh JS, Pratt R, et al. Epidemiology of
smear-negative pulmonary tuberculosis in the United States, 19932008. Int J
Tuberc Lung Dis. 2012;16(9):12341240 and Frieden T. Reported Tuberculosis in
the United States, 2011, CDC. 2012.
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cough in the case of pulmonary TB, neck mass for cervical lymph
node TB) plus constitutional symptoms that correlate to the production of pyrogenic cytokines such as TNF- (e.g., fevers, night
sweats, anorexia, weight loss). Initially the cough may be dry but
after several months becomes productive. Fever may be absent,
especially in the elderly.90 With advancing disease, hemoptysis,
anorexia, and weight loss can occur.9193 Importantly, some patients
are asymptomatic even with clear TB disease activity demonstrable
on culture or radiographya prospect that frustrates TB control
program efforts at active case finding.3,94
Part 17
Infectious Diseases of the Lungs
Physical Examination
Even when relatively extensive disease is present, pulmonary TB
most often produces no detectable abnormality on physical examination.91,94 It is important to examine for signs of extrapulmonary
disease such as lymphadenopathy, abdominal, or bone and joint
involvement, particularly in HIV-infected individuals. Tachypnea
and hypoxia are relatively rare except with extensive lung destruction or miliary disease.
Chest Radiography in Pulmonary TB
Radiographic findings of TB are well described.9496 Sensitivity for
active TB is 70% to 80%, and even less in patients with HIV or other
severe immune compromise. Further, chest radiography is only
moderately specific and there is generally poor agreement between
chest film readers.9799 Chest radiography alone also cannot reliable
distinguish between active and healed, latent TB.97,98,100
Typical chest Radiograph Patterns
Four radiographic features suggest active TB: (1) Nodular opacities located in the apical-posterior segments of the upper lobes or
superior segment of the lower lobes, (2) associated volume loss
and fibrosis, (3) lung cavitation, and (4) endobronchial spread.
Endobronchial spread to dependent lung segments fills lung acinar
units, resulting in 4- to 5-mm size nodular opacities on plain film
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pneumonia (CAP), and for every few dozen cases of lung cancer,
there is on average one case of TB in the United States.103,104 In
low-incidence settings, many patients diagnosed with TB will have
experienced multiple contacts with the healthcare system before the
diagnosis of TB is considered.105,106
Thus the diagnosis of TB requires a very high-index of suspicion considering epidemiologic risk factors and suggestive clinicalradiographic features (Fig. 131-11). Ultimately, the definitive
diagnosis requires culture confirmation.
mediastinal adenopathy (Fig. 131-9). Intrathoracic TB lymphadenitis is often better appreciated on CT where lymph node enlargement,
rim enhancement, and low central attenuation are characteristic.95
Miliary TB is rare but when present, produces a distinctive,
readily recognizable radiographic pattern: Innumerable, interstitial
nodules uniformly distributed throughout all lung fields, without
reduction in lung volumes (Fig. 131-10).
Diagnosis of TB
Most US clinicians will practice for years without ever encountering a
case of TB. For every 450 ambulatory visits for community-acquired
Specimen Collection
Protocols to ensure proper specimen handling, storage, transport,
and labeling are available.94 Ideally, specimen collection should
occur before initiation of therapy to increase yield.
For the diagnosis of pulmonary TB at least three sputum samples,
each 5 to 10 mL, should be collected at least 1-hour apart. For those
patients unable to expectorate spontaneously, sputum induction
(with nebulized hypertonic saline) or bronchoalveolar lavage (BAL)
is an alternate established method.113 Induced sputum samples produce slightly higher yield than do BAL samples (87% vs. 73%), and
sputum induction is much better tolerated, less invasive, and lower
cost.114,115 If bronchoscopy is performed to evaluate other diagnostic
considerations, then an additional sputum sample collected immediately after bronchoscopy may have particularly high-yield for
mycobacterial identification.113
For diagnostic confirmation of extrapulmonary TB, tissue or
fluid samples should be submitted fresh (or in sterile normal
saline) without addition of preservative (e.g., formalin) because
this will prevent subsequent identification, culture, and DST in the
microbiology laboratory. It is important to notify both the laboratory and clinician before collecting a specimen if extrapulmonary
TB is suspected to allow the laboratory to take appropriate biosafety precautions during specimen handling to prevent laboratory
transmission of TB.
Figure 131-9 This 42-year-old HIV+ man with a CD4 count of 150
cell/mm3 presented with cough. Significant mediastinal and right hilar
adenopathy are present without apparent lung parenchymal disease.
Sputum cultures were smear negative but culture positive for MTBC.
Laboratory Investigations
Anemia is commonly observed in TB, usually due to chronic
inflammatory state or malnutrition.94 Syndrome of inappropriate
ADH can complicate pulmonary or central nervous system TB.107
Historically, disseminated TB was an important cause of adrenal
insufficiency. Hypercalcemia is a relatively frequent complication
of TB.108 Activated macrophages within granulomas upregulate
1-alpha-hydroxylase, which can in turn activate vitamin D and lead
to increase in calcium absorption.109111 Hypercalcemia of TB can
be symptomatic and occasionally leads to nephrocalcinosis, nephrolithiasis, or acute volume depletion. Vitamin D supplementation
during TB therapy may increase the risk of hypercalcemia.112
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Probability
of TB
Part 17
Number of Features
Figure 131-11 Clinical factors increasing index of suspicion for tuberculosis. Increasing probability of TB warrants further investigation, especially collection of respiratory samples for mycobacterial stain and culture.
Mycobacterial Culture
Mycobacterial culture remains the gold standard for the diagnosis of
active TB. About 5000 to 10,000 bacilli per milliliter of specimen are
required for detection by smear microscopy and about 100 bacilli
per millimeter for nucleic acid amplification (NAAT); culture methods can detect as few 10 viable bacilli per millimeter of sample.94 In
addition, biochemical and phenotypic testing of isolated organisms
provides near perfect specificity, distinguishing even between individual members of the MTBC. Of particular importance, isolation
of the infecting organism permits DST and is required to conduct
molecular subtyping (i.e., DNA fingerprinting).
Culture of MTBC from clinical specimens takes, on average,
between 2 to 4 weeks, but as long as 8 weeks in some specimens with
low initial concentration of organism.122 Culture requires a Level III
biosafety laboratory to prevent transmission to laboratory technicians and availability of such facilities is poor in most high-burden,
resource-limited settings.
Nucleic Acid Amplification
NAAT is a useful tool in the diagnosis of TB offering higher sensitivity than microscopy and shorter turn-around-times than culture.100,123,124 Sensitivity of NAAT in AFB smearpositive respiratory
samples is excellent, usually greater than 95%.123 However, in paucibacillary specimen types, such as AFB smearnegative sputum and
extrapulmonary samples, the sensitivity is reduced to 40% to 60%,
with a negative predictive value inadequate to exclude a diagnosis
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TABLE 131-7 D
rug Regimens for Treatment of Active Tuberculosis in Adults, Caused by
Susceptible Organism
Initial Phase (First 2 Mo)
Continuation Phase
Comments
Regimen 1
Regimen 2
4 mo
INH + RIF
Given daily or 3/wkb
7 mo
INH + RIF daily or 3/wk
47 mo
INH + RIF
Given 3/wk
4 mo RPT weekly and INH
900 mg weekly
Regimen 4
Regimen 3
EMB is given pending results of INH susceptibility testingif isolate confirmed fully susceptible than EMB is discontinued.
Rifapentine and INH 900 mg given once-weekly in the continuation phase have been tested in small clinical trials but treatment outcomes were inferior and rifamycin
resistance emerged on treatment in some patients; thus this schedule is probably best avoided.
c
Risk factors for relapse include cavitation on chest radiograph, culture positive after 2 mo of therapy, poorly controlled HIV infection.
d
Risk factors for PZA hepatotoxicity include advanced age or underlying liver disease.
e
Intermittent therapy during the intensive phase is associated with slightly poorer treatment outcomes in patients with extensive disease or HIV coinfection. See text for
adjunctive corticosteroid use recommendations.
Source: Data from Blumberg H, 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(4):603662 and Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med. 2013;368(8):745755.
b
Principles of TB therapy
The aims of TB therapy are to (1) Interrupt transmission by rapidly
rendering patients noninfectious, (2) relieve symptoms and prevent
mortality, (3) prevent the emergence of drug resistance, and (4)
prevent future relapse by providing a definitive cure.
To achieve these aims, treatment regimens must include combination of potent bactericidal drugs which are provided for a minimum
of 6 months. The choice of regimen should be guided by the results
of DST. TB regimens are divided into an initial intensive phase,
designed to quickly reduce large bacillary burden, followed by a
prolonged continuation phase that consolidates antimycobacterial
Thrice-Weekly Dose
Isoniazid (INH)
10 mg/kg (600)
No change
Rifampin (RIF)
No change
Rifapentine (RPT)
No change
Pyrazinamide (PZA)
Ethambutol (EMB)
Moxifloxacin or
Levofloxacin
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Part 17
Infectious Diseases of the Lungs
INH, first introduced in 1952, remains a cornerstone of TB treatment. It has potent bactericidal activity and effects rapid decline
of sputum bacillary load within days of administration and thus
rapidly reduces infectiousness.141 INH is generally well tolerated but
can cause hepatotoxicity, requiring cessation of therapy in a small
subset of patients. Risk factors for severe INH-related hepatotoxicity
include older age and pre-existing liver diseases.142 Peripheral neuropathy can develop in elderly, malnourished, or diabetic patients
taking INH, but this risk is lowered with concomitant administration of pyridoxine (vitamin B6).
RIF revolutionized TB therapy following its introduction in 1968
and has since become a critical component of modern, short-course
TB regimens.141,143,144 Rifampin and other rifamycins appear to have
unique relapse-preventing properties that allow the duration of
chemotherapy to be shortened to 9 months or less. In the absence of
rifampin, relapse rates are unacceptably high, and treatment must be
given more than 18 months.
RIF is very well tolerated in the vast majority of patients. Rarely,
hypersensitivity reactions occur, including thrombocytopenia, flulike syndrome, and neutropenia. Rifampin is a strong inducer of
the cytochrome p450 oxidation system (CYP450) and interacts with
a multitude of other medications.145 Rifampin produces a benign
orange-red discoloration of body fluids (urine, tears, sputum, feces,
sweat) and can permanently stain contact lenses and dentures.
Rifapentine (RPT) is also a rifamycin but with a half-life 5 times
longer than RIF, which allows the drug to be given once-weekly.
The prolonged half-life makes RPT an attractive agent for use in
intermittent treatment regimens in order to facilitate adherence.146
However, use of weekly dosed RPT is associated with relapse and
acquired resistance in those with extensive disease, slow sputum
culture conversion, or HIV coinfection.146148 RPT strongly induces
CYP450 leading to multiple potential drugdrug interactions.
Other rifamycins (e.g., rifabutin) produce lower levels of CYP450
induction. RPT is generally well tolerated but hypersensitivity syndromes including fever, myalgia, and cytopenias occurred in about
3% of patients in a clinical trial of LTBI treatment.149
PZA is bactericidal and when added to treatment regimens containing RIF permits shortening duration to 6 months.150 Arthralgias
are the most frequently reported adverse event and can be alleviated
by the administration of nonsteroidal anti-inflammatories. PZA can
also cause severe hepatotoxicity, especially in the elderly and those
with pre-existing liver disease.
EMB is the weakest first-line agent, contributing little to early
bactericidal activity or to relapse prevention. However, it is effective in preventing the emergence of resistance to isoniazid. It is
generally well tolerated. Optic neuritis, the main adverse drug
event, occurs infrequently with the currently recommended dosages except in the presence of renal impairment. EMB is added
to the initial phase of treatment regimens pending results of susceptibility testing; but absent confirmed drug-resistance, EMB is
discontinued.
Later-generation fluoroquinolones (FQs) are well-tolerated
oral drugs with potent bactericidal activity against MTBC.151155
Based on accumulating clinical evidence, FQs may enter first-line
treatment regimens in the near future.156 However, FQs are currently indicated for intolerance or resistance to other first-line
drugs.157
FQs are not uncommonly prescribed for CAP that later proves
to be pulmonary TB.158 FQ monotherapy can temporarily alleviate
TB symptoms and can reduce the yield of TB sputum cultures, thus
significantly contributing to diagnostic delay.159 Inadvertent monotherapy of TB initially mistaken for CAP also risks the development
of FQ resistance, potentially compromising future TB treatment
options.158 FQs should be used cautiously for suspect CAP in
patients at significant epidemiologic risk for TB.
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TABLE 131-9 H
ierarchy of Second-Line
TB Drugs
Group
Group 1
Group 2
Group 3
Group 5
common resistance pattern observed, does not appear to compromise TB treatment outcomes substantially as long as RIF, EMB, and
PZA can be continued throughout.138,169171 Although definitive data
are lacking, an FQ can probably replace INH in standard treatment
regimens.
Multidrug resistance was demonstrated in less than 1.6% of all
TB cases in the United States in 2012.41 Among patients with a
history of previous TB treatment, MDR-TB prevalence was 8.2%.
The majority (86%) of MDR-TB cases in the United States occur in
foreign-born individuals. Multidrug resistance has a great impact on
treatment outcomes in TB, with success rates ranging from 52% to
77%.172176 Multidrug resistance also adds substantially to the costs
of treatment.32,177 Further, second-line agents used in treatment of
MDR-TB have significant toxicities, high rates of intolerance, highpill burdens, and inconvenient dosing regimens, making adherence
difficult.178 Finally, MDR-TB requires at least 18 to 24 months duration.15,179,180 The management of MDR-TB is complex and referral
to specialized centers that offer experience and expertise is strongly
recommended. Second-line TB agents and important side effects are
listed in Tables 131-9 and 131-10.
Group 4
Drugs
Gl upset
Headache
Nephrotoxicity
Cytopenia
MAO inhibition
Nausea, Gl upset
Nephrotoxicity
Moxifloxacin
Capreomycin
Hypothyroidism
Hepatotoxicity
Neuropathy
Hypothyroidism
Hepatotoxicity
Neurologic and psychiatric impairment
Ototoxicity
Irreversible and reversible
Neuropathy and optic neuritis
Tendinopathy
Ototoxicity, Neuropathy
Source: Data from Drug-resistant Tuberculosis: a Survival Guide for Clinicians. 2nd ed. Curry National Tuberculosis Center; 2008.
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Part 17
Solid-Organ Transplantation
The majority of TB cases in solid-organ transplant recipients arise
from reactivation of latent infection acquired prior to transplantation.192 Donor-derived TB transmitted with organ transplantation
is very rare. Overlapping drug toxicity and significant drugdrug
interactions complicates treatment of TB in transplant recipients.193
Rifampin significantly lowers serum drug concentrations of immunosuppressant medications, which can precipitate organ rejection.
Rifabutin, a rifamycin with less CYP450 activity than either RIF or
RPT, has good activity against MTBC and can be used instead of RIF
in standard TB regimens, albeit with a less robust evidence base.194,195
Liver transplant recipients are particularly prone to INH and PZA
hepatotoxicity and alternative treatment regimens may be required.196
10
15
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TB Vaccination
Laboratory attenuation of M. bovis by repeated sub-cultivations
in bile acids by French researchers Albert Calmette and Camille
Guerin eventually led to the creation of a TB live-attenuated vaccine
BCG in 1928.220,221 This vaccine is rarely used in the United States
today, but worldwide remains one of the most commonly delivered
childhood vaccines with coverage rates approaching 100% in most
resource-limited settings. Despite its wide use, there remains some
controversy as to its actual efficacy, and some concern that ongoing
sub-culture to produce the vaccine is resulting in loss of activity.222
Disseminated infection with BCG has been documented in severely
immune-compromised children and universal vaccination is therefore no longer recommended in low-prevalence settings.223 In the
Unites States, BCG is perhaps more commonly encountered as a
therapeutic agent for management of bladder transitional cell carcinoma. Disseminated TB has been documented in this patient group
but human-to-human transmission is not reported.224,225
Ongoing research is directed toward a vaccine to replace BCG,
ideally with improved efficacy against both infection and progression to TB.226 However, after millennia of coevolution, the
hostpathogen relationship is extremely complex and inadequate
understanding of TB immunity and correlates of protection hamper
progress in vaccine development.
Conclusion
TB has become an uncommon cause of cough in the United States
and a high index of suspicion is required. Diagnostic delay occurs
frequently despite availability of accurate diagnostic technologies. In
settings of chronic medical illness, immunocompromise, and social
depravation, TB can flourish. Treatment is effective and can significantly reduce a high case-fatality rate. Current research is directed to
shortening the duration of therapy to facilitate adherence and treatment completion rates. New drugs are being developed and promise
TABLE 131-12 Acceptable Dosing Regimens for Treatment of Latent Tuberculosis Infection
Regimen
a
Isoniazid
Mode of
Administration
SAT
SAT
SAT
Rifampin
300 mg daily 9 mo
300 mg daily 6 mo
Isoniazid 300 mg and rifampin 600 mg daily
for 3 mo
600 mg daily for 4 mo
Isoniazid Intermittent
Isoniazid and Rifampin
Intermittent
Isoniazid and Rifapentine
Intermittentc
DOT
DOT
SAT
DOT
Evidence Base
Strong evidence, based on several RCTS
(Siamera, 2000); Higher efficacy with 9 mo
Strong evidence (HKCS, 1992 Ena 2005;
Whalen, 1997)
Moderate evidence (HKCS, 1992; Menzies,
2008), 1 Cohort (Villarino, 1997)
Weak evidence (Mwinga, 1998)
Weak evidence (McNab, 2000)
Moderate evidence (Sterling, 2011; CDC/
ATS, 2011)
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MCGH324-Ch131_p2012-2031.indd 2026
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62. Chatterjee D. The mycobacterial cell wall: structure, biosynthesis and sites of drug action. Curr Opin Chem Biol. 1997;1:579
588.
42. Cain KP, Benoit SR, Winston CA, Mac Kenzie WR. Tuberculosis
among foreign-born persons in the United States. JAMA.
2008;300:405412.
44. Hutton MD, Cauthen GM, Bloch AB. Results of a 29-state survey of tuberculosis in nursing homes and correctional facilities.
Public Health Rep. 1993;108:305314.
70.
Fennelly KP. Variability of airborne transmission of
Mycobacterium tuberculosis: implications for control of tuberculosis in the HIV era. Clin Infect Dis. 2007;44:13581360.
71. Morrison J, Pai M, Hopewell PC. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary
tuberculosis in low-income and middle-income countries: a
systematic review and meta-analysis. Lancet Infect Dis. 2008;
8:359368.
72. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active
pulmonary tuberculosis. Bull Int Union Tuberc. 1975;50:90
106.
73. Tostmann A, Kik SV, Kalisvaart NA, et al. Tuberculosis transmission by patients with smear-negative pulmonary tuberculosis in a large cohort in the Netherlands. Clin Infect Dis.
2008;47:11351142.
74. Dharmadhikari AS, Nardell E. Serial acid fast bacilli smear
and culture conversion rates over 26 weeks in a cohort of 93
sputum culturepositive tuberculosis (TB). Clin Infect Dis.
2011;52:554556.
75. Long R, Bochar K, Chomyc S, et al. Relative versus absolute
noncontagiousness of respiratory tuberculosis on treatment.
Infect Control Hosp Epidemiol. 2003;24:831838.
76. Jensen PA, Lambert LA, Iademarco MF, Ridzon R,CDC.
Guidelines for preventing the transmission of Mycobacterium
tuberculosis in health-care settings, 2005. MMWR Recomm
Rep. 2005;54:1141.
77. Nardell EA, Keegan J, Cheney SA, Etkind SC. Airborne infection. Theoretical limits of protection achievable by building
ventilation. Am Rev Respir Dis. 1991;144:302306.
78. Taylor Z, Nolan CM, Blumberg HM. American Thoracic
Society, Centers for Disease Control and Prevention, Infectious
Diseases Society of America. Controlling tuberculosis in the
United States. Recommendations from the American Thoracic
Society, CDC, and the Infectious Diseases Society of America.
MMWR Recomm Rep. 2005;54:181.
79. Daley CL. Molecular epidemiology: a tool for understanding control of tuberculosis transmission. Clin Chest Med.
2005;26:217231.
2027
MCGH324-Ch131_p2012-2031.indd 2027
02/01/15 8:51 PM
80. van Crevel R, Ottenhoff TH, van der Meer JW. Innate
Immunity to Mycobacterium tuberculosis. Clin Microbiol Rev.
2002;15:294309.
81. Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new
tuberculosis. Am J Respir Crit Care Med. 2005;171:14301435.
100. Davies PD, Pai M. The diagnosis and misdiagnosis of tuberculosis. Int J Tuberc Lung Dis. 2008;12:12261234.
Part 17
101. Barnes PF, Verdegem TD, Vachon LA, Leedom JM, Overturf
GD. Chest roentgenogram in pulmonary tuberculosis. New
data on an old test. Chest. 1988;94:316320..
102. Jones BE, Ryu R, Yang Z, et al. Chest radiographic findings in
patients with tuberculosis with recent or remote infection. Am
J Respir Crit Care Med. 1997;156:12701273.
103. U.S. Cancer Statistics Working Group. United States Cancer
Statistics: 19992009 Incidence and Mortality Web-based
Report. Department of Health and Human Services, Center for
Disease Control and Prevention and National Cancer Institute.
http://www.cdc.gov/uscs. March 30, 2013.
104. File T, Marrie T. Burden of community-acquired pneumonia in
North American adults. Postgrad Med. 2010;122:130141.
105. Long R, Zielinski M, Kunimoto D, Manfreda J. The emergency
department is a determinant point of contact of tuberculosis
patients prior to diagnosis. Int J Tuberc Lung Dis. 2002;6:
332339.
106. Sreeramareddy CT, Kishore PV, Menten J, Van den Ende J.
Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature. BMC Infect Dis. 2009;9:91.
107. Lee P. Hyponatremia in pulmonary TBEvidence of ectopic
antidiuretic hormone production. Chest. 2010;137:207208.
108. Rook GA. The role of vitamin D in tuberculosis. Am Rev Respir
Dis. 1988;138:768770.
109. Martineau AR, Honecker FU, Wilkinson RJ, Griffiths CJ.
Vitamin D in the treatment of pulmonary tuberculosis. J
Steroid Biochem Mol Biol. 2007;103:793798.
110. Cadranel JL, Garabdian M, Milleron B, et al. Vitamin D
metabolism by alveolar immune cells in tuberculosis: correlation with calcium metabolism and clinical manifestations. Eur
Respir J. 1994;7:11031110.
111. Sharma OP. Hypercalcemia in granulomatous disorders: a
clinical review. Curr Opin Pulm Med. 2000;6:442447.
112. Martineau AR, Timms PM, Bothamley GH, et al. High-dose
vitamin D3 during intensive-phase antimicrobial treatment of
pulmonary tuberculosis: a double-blind randomised controlled
trial. Lancet. 2011;377:242250.
113. Olsen SR, Long R, Tyrrell G, Kunimoto D. Induced sputum for
the diagnosis of pulmonary tuberculosis: is it useful in clinical
practice? Can Respir J. 2010;17:e81e84.
114. Anderson C, Inhaber N, Menzies D. Comparison of sputum
induction with fiber-optic bronchoscopy in the diagnosis of
tuberculosis. Am J Respir Crit Care Med. 1995;152:15701574.
115. Brown M, Varia H, Bassett P, Davidson RN, Wall R, Pasvol G.
Prospective study of sputum induction, gastric washing, and
bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate. Clin Infect
Dis. 2007;44:14151420.
116. Hooja S, Pal N, Malhotra B, Goyal S, Kumar V, Vyas L.
Comparison of Ziehl Neelsen & Auramine O staining methods on direct and concentrated smears in clinical specimens.
Indian J Tuber. 2011;58:7276.
117. Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams
BG, Nagelkerke NJ D. Natural history of tuberculosis: duration
and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One. 2011;6:e17601.
2028
MCGH324-Ch131_p2012-2031.indd 2028
02/01/15 8:51 PM
121. Grubek-Jaworska H, Walkiewicz R, Safianowska A, et al.
Nontuberculous mycobacterial infections among patients suspected of pulmonary tuberculosis. Eur J Clin Microbiol Infect
Dis. 2009;28:739744.
122. Cruciani M, Scarparo C, Malena M, Bosco O, Serpelloni
G, Mengoli C. Meta-analysis of BACTEC MGIT 960 and
BACTEC 460 TB, with or without solid media, for detection of
mycobacteria. J Clin Microbiol. 2004;42:23212325.
123. Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid
amplification tests for diagnosis of pulmonary tuberculosis
in respiratory specimens: meta-analysis and meta-regression.
PLoS One. 2008;3:e1536.
124. Flores LL, Pai M, Colford JM, Riley LW. In-house nucleic
acid amplification tests for the detection of Mycobacterium
tuberculosis in sputum specimens: meta-analysis and metaregression. BMC Microbiol. 2005;5:55.
125. Daley P, Thomas S, Pai M. Nucleic acid amplification tests
for the diagnosis of tuberculous lymphadenitis: a systematic
review. Int J Tuberc Lung Dis. 2007;11:11661176.
126. Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM
Jr. Diagnostic accuracy of nucleic acid amplification tests for
tuberculous meningitis: a systematic review and meta-analysis.
Lancet Infect Dis. 2003;3:633643.
127. Pai M, Flores LL, Hubbard A, Riley LW, Colford JM Jr. Nucleic
acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis.
2004;4:6.
128. Sarmiento OL, Weigle KA, Alexander J, Weber DJ, Miller WC.
Assessment by Meta-Analysis of PCR for Diagnosis of SmearNegative Pulmonary Tuberculosis. J Clin Microbiol. 2003;41:
32333240.
136. Springett VH. Ten-year results during the introduction of chemotherapy for tuberculosis. Tubercle. 1971;52:7387.
137. Long R. The Canadian Lung Association/Canadian Thoracic
Society and tuberculosis prevention and control. Can Respir J.
2007;14:427431.
138. Blumberg H, 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;167:603662.
139. Blumberg HM, Leonard MK, Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA.
2005;293:27762784..
140. World Health Organization & Initiative ST. The Treatment of
Tuberculosis Guidelines. 2010;1160.
141. Mitchison DA. Role of individual drugs in the chemotherapy of
tuberculosis. Int J Tuberc Lung Dis. 2000;4796806.
142. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An Official ATS
statement: hepatotoxicity of antituberculosis therapy. Am J
Respir Crit Care Med. 2006;174:935952.
143. Connolly LE, Edelstein PH, Ramakrishnan L. Why is long-term
therapy required to cure tuberculosis? Plos Med. 2007;4:e120.
144. Mitchison DA. [Mechanisms of the action of drugs in the shortcourse chemotherapy]. Bull Int Union Tuberc. 1985;60:3640.
145. Budha NR, Lee RE, Meibohm B. Biopharmaceutics, pharmacokinetics and pharmacodynamics of antituberculosis drugs.
Curr med chem. 2008;15:809825.
146. Munsiff SS, Kambili C, Ahuja SD. Rifapentine for the treatment
of pulmonary tuberculosis. Clin Infect Dis. 2006;4314681475.
147. Tam CM, Chan SL, Lam CW, et al. Rifapentine and isoniazid
in the continuation phase of treating pulmonary tuberculosis.
Initial report. Am J Respir Crit Care Med. 1998;15717261733.
148. Vernon A, Burman W, Benator D, Khan A, Bozeman L.
Acquired rifamycin monoresistance in patients with HIVrelated tuberculosis treated with once-weekly rifapentine and
isoniazid. Tuberculosis Trials Consortium. Lancet. 1999;353:
18431847.
149. Sterling TR, Villarino ME, Borisov AS, et al. Three months of
rifapentine and isoniazid for latent tuberculosis infection. N
Engl J Med. 2011;365:21552166.
130. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the
Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet.
2011;377:14951505.
150. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003;7:621.
151. Takiff H, Guerrero E. Current Prospects for the fluoroquinolones as first-line tuberculosis therapy. Antimicrob Agents
Chemother. 2011;55:54215429.
152. Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst. 2008;161.
120. Kendall BA, Varley CD, Choi D, et al. Distinguishing tuberculosis from nontuberculous mycobacteria lung disease, oregon,
USA. Emerg Infect Dis. 2011;17:506509.
135. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using Interferon Gamma Release Assays to detect
Mycobacterium tuberculosis infection - United States, 2010.
MMWR Recomm Rep. 2010;59:125.
2029
MCGH324-Ch131_p2012-2031.indd 2029
02/01/15 8:51 PM
Part 17
174. Mitnick C, Bayona J, Palacios E, et al. 030109 Communitybased therapy for multidrug-resistant tuberculosis. N Engl
J Med. 2003;348:119128.
175. Palacios E, Dallman R, Muoz M, et al. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in
Lima, Peru. Clin Infect Dis. 2009;48:14131419.
176. Goble M, Iseman MD, Madsen LA, et al. Treatment of 171
patients with pulmonary tuberculosis resistant to isoniazid and
rifampin. N Engl J Med. 1993;328:527532.
177. Centers for Disease Control and Prevention (CDC). Plan to
combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force. MMWR Recomm
Rep. 2009;58:143.
178. Franke MF, Appleton SC, Bayona J, et al. Risk factors and
mortality associated with default from multidrug-resistant
tuberculosis treatment. Clin Infect Dis. 2008;46:18441851.
179. Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis.
N Engl J Med. 2013;368:745755.
180. Francis J. Drug-Resistant Tuberculosis: a Survival Guide for
Clinicians. 2nd ed. Curry National Tuberculosis Center; 2008:
1284.
181. Nuermberger EL, Spigelman MK, Yew WW. Current development and future prospects in chemotherapy of tuberculosis.
Respirology. 2010;15:764778.
182. Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline
TMC207 for multidrug-resistant tuberculosis. N Engl J Med.
2009;360:23972405.
183. Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of
eight weeks of bedaquiline (TMC207) treatment for multidrugresistant tuberculosis: long-term outcome, tolerability, and
effect on emergence of drug resistance. Antimicrob Agents
Chemother. 2012;56:32713276.
184. Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid
for multidrug-resistant pulmonary tuberculosis. N Engl J Med.
2012;366:21512160.
185. Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al.
14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.
Lancet. 2012;380:986993.
168. Mitchison DA, Dickinson JM. Laboratory aspects of intermittent drug therapy. Postgrad Med J. 1971;47:737741.
169. Menzies D, Benedetti A, Paydar A, et al. Standardized treatment of active tuberculosis in patients with previous treatment
and/or with mono-resistance to isoniazid: a systematic review
and meta-analysis. PLoS Med. 2009;6:e1000150.
170. Bang D, Andersen PH, Andersen AB, Thomsen V. Isoniazidresistant tuberculosis in Denmark: mutations, transmission
and treatment outcome. J Infect. 2010;60:452457.
188. Chideya S, Winston CA, Peloquin CA, et al. Isoniazid,
rifampin, ethambutol, and pyrazinamide pharmacokinetics
and treatment outcomes among a predominantly HIV-infected
cohort of adults with tuberculosis from Botswana. Clin Infect
Dis. 2009;48:16851694.
171. Five-year follow-up of a controlled trial of five 6-month
regimens of chemotherapy for pulmonary tuberculosis. Hong
Kong Chest Service/British Medical Research Council. Am Rev
Respir Dis. 1987;136:13391342.
172. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome
analysis of 205 patients with multidrug-resistant tuberculosis.
Am J Respir Crit Care Med. 2004;169:11031109.
173. Chiang CY, Schaaf HS. Management of drug-resistant tuberculosis. [State of the art series. Drug-resistant tuberculosis. Edited
by CY. Chiang. Number 6 in the series]. Int J Tuberc Lung Dis.
2010;14:672682.
189. Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized
placebo-controlled trial of prednisone for paradoxical
tuberculosis-associated immune reconstitution inflammatory
syndrome. AIDS. 2010;24:23812390 .
190. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of
antiretroviral therapy with tuberculosis treatment. N Engl
J Med. 2011;365:14921501.
191. Trk ME, Farrar JJ. When to start antiretroviral therapy in HIVassociated tuberculosis. N Engl J Med. 2011;365:15381540.
2030
MCGH324-Ch131_p2012-2031.indd 2030
02/01/15 8:51 PM
192. Bumbacea D, Arend SM, Eyuboglu F, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40:9901013.
193. Morris MI, Daly JS, Blumberg E, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant. 2012;12:
22882300.
195. Gonzalez-Montaner LJ, Natal S, Yongchaiyud P, Olliaro P.
Rifabutin for the treatment of newly-diagnosed pulmonary
tuberculosis: a multinational, randomized, comparative study
versus Rifampicin. Rifabutin Study Group. Tuber Lung Dis.
1994;75:341347.
211. Richeldi L. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2006;174:736742.
212. Simpson T, Fox J, Crouse K, Field K. Quantitative and qualitative QuantiFERON-TB Gold In-Tube results among groups
with varying risks of exposure to tuberculosis. Heart Lung.
2012;41:553561.
213. van Zyl-Smit RN, Zwerling A, Dheda K, Pai M. Within-subject
variability of interferon-g assay results for tuberculosis and
boosting effect of tuberculin skin testing: a systematic review.
PLoS One. 2009;4e8517.
196. Subramanian AK, Morris MI, AST Infectious Diseases
Community of Practice.. Mycobacterium tuberculosis infections
in solid organ transplantation. Am J Transplant. 2013;13:6876.
197. Lincoln EM. The effect of antimicrobial therapy on the prognosis of primary tuberculosis in children. Am Rev Tuberc.
1954;69:682689.
215. van Zyl-Smit RN, Pai M, Peprah K, et al. Within-subject variability and boosting of T-cell interferon- responses after tuberculin skin testing. Am J Respir Crit Care Med. 2009;180:4958.
216. Menzies D, Gardiner G, Farhat M, Greenaway C, Pai M.
Thinking in three dimensions: a web-based algorithm to aid
the interpretation of tuberculin skin test results. Int J Tuberc
Lung Dis. 2008;12:498505.
199. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc. 1970;26:28106.
200. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid
for preventing tuberculosis in non-HIV infected persons.
Cochrane Database Syst Rev. 2000;CD001363.
201. Bennett DE, Courval JM, Onorato I, et al. Prevalence of tuberculosis infection in the United States population: the national
health and nutrition examination survey, 1999-2000. Am J
Respir Crit Care Med. 2008;177:348355.
202. Mancuso JD, Tribble D, Mazurek GH, et al. Impact of targeted
testing for latent tuberculosis infection using commercially
available diagnostics. Clin Infect Dis. 2011;53:234244.
203. Maddrey WC, Boitnott JK. Isoniazid hepatitis. Ann Intern Med.
1973;79:112.
204. Cohn DL, OBrien RJ, Geiter LJ, Gordin FM, Hershfield E,
Horsburgh CR. Targeted tuberculin testing and treatment of
latent tuberculosis infection. MMWR Morb Mortal Wkly Rep.
2000;49:154.
205. Markel H. The medical detectives. N Engl J Med. 2005;353:
24262428.
206. Holden M, Dubin MR, Diamond PH. Frequency of negative
intermediate-strength tuberculin sensitivity in patients with
active tuberculosis. N Engl J Med. 1971;285:15061509.
207. Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based
assays for the diagnosis of latent tuberculosis infection: an
update. Ann Intern Med. 2008;149:177184.
208. 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;146:340354.
209. Smith R, Cattamanchi A, Steingart KR, et al. Interferongamma release assays for diagnosis of latent tuberculosis infection: evidence in immune-mediated inflammatory disorders.
Curr Opin Rheumatol. 2011;23:377384.
194. Davies GR, Cerri S, Richeldi L. Rifabutin for Treating
Pulmonary Tuberculosis. John Wiley & Sons, Ltd; 1996.
doi:10.1002/14651858.CD005159.pub2
210. Cattamanchi A, Smith R, Steingart KR, et al. Interferongamma release assays for the diagnosis of latent tuberculosis
infection in HIV-infected individuals: a systematic review and
meta-analysis. J Acquir Immune Defic Syndr. 2011;56:230238.
2031
MCGH324-Ch131_p2012-2031.indd 2031
02/01/15 8:51 PM