TB Fishman

C H A P T E R 131
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,
an estimated 51 million people had been treated and an estimated

20 million lives saved.810 Since 2004, TB incidence is falling in all
WHO regions and in each of the 22 highest burden countries.
Although global TB incidence is falling, TB remains a leading
cause of global infectious mortality, second only to HIV infection.11,12 There were 8.7 million new cases of TB and 1.4 million
deaths globally in 2011. Moreover, many TB deaths occur in young,
previously healthy adults, and as such, TB is a top 10 cause of lost
disease adjusted life years (DALYs).7
Broadly speaking, there are three major threats to global TB
control: (1) Poor social conditions including inadequate housing
and nutrition,5 (2) Immune compromise related to the HIV pandemic,2,13 and (3) Emergence of drug-resistant TB.14,15
Poverty and TB
Globally, TB distribution correlates closely with poverty and human
development indices.1619 Population health factors such as water
sanitation, childhood immunization rates, and life expectancy also
independently predict TB incidence.20,21 A corollary of these relationships is that only 1% of the global TB burden occurs in the industrially developed countries of North America and Europe while more
than 90% arises in Asia and Africa (Fig. 131-1) (Table 131-1).10
HIV and TB: Co-pandemics
HIV-induced immune suppression increases the risk of progression to active TB nearly 100-fold.2226 Worldwide, TB is the most
common opportunistic illness and a leading cause of death in
patients with AIDS.27 HIV coinfection complicates 13% of all TB
cases worldwide.10 As both a potent and common risk factor, HIV
contributes substantially to TB incidence, especially in Sub-Saharan
Africa.2,13
Drug-resistant TB
In 2011, there were over 600,000 prevalent cases of multidrugresistant (MDR) TB, defined by resistance to the two most
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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TABLE 131-1 T B Incidence and Incidence Rate

in 2011 for the 22-High TB Burden
Countries and the United States
Country
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.
TB epidemiology in the United States:

Historical perspective
In the first half of the 20th century TB was a leading cause of morbidity and mortality in the United States. In 1920 pulmonary TB
accounted for nearly 1 in 13 of all deaths, outranking cancer.6,35,36
Improvements in social conditions and population health during
the early 20th century led to significant reductions in TB incidence
and, with the introduction of effective chemotherapy in the 1950s,
incidence declined even further.4 By the 1970s, TB incidence in
the United States had reached historical lows, less than 10 cases
per 100,000 people and TB seemed on the brink of elimination.
Unfortunately, public health funding for TB control was then
greatly reduced and by the mid-1980s a nationwide resurgence
ensued, particularly in the major urban centers.6,3739 It is estimated
that during the 1980s and early 1990s, when TB funding in the
United States was nearly eliminated, 64,000 excess cases occurred.37,40
Current US trends in TB epidemiology
With renewal of Government investment in the mid-1990s TB control was reestablished and TB rates have since declined every consecutive year in the United States (Fig. 131-2).41 By 2012, there were
less than 10,000 total reported cases of TB in the United States, or
just 3.2 cases per 100,000 people, the lowest rate ever reported.41
TB remains a concern within specific demographic groups. The foreign born, especially newly arrived immigrants, account for an increasing proportion of TB cases in the United States, representing nearly
two-thirds of all US cases in 2012 (Fig. 131-3).41 Mexico (22%) and the
Philippines (12%) are the most common countries of origin of imported
TB.42,43 In foreign-born US residents, TB usually represents reactivation
of infection remotely acquired in TB-endemic countries prior to arrival
rather than new infection resulting from local transmission.43
Among the US born, TB burden is concentrated in indigenous
peoples, incarcerated populations, and the unstably housed.40,4346 In
these groups, mini outbreaks of TB resulting from recent transmission occur with some regularity, especially in major urban centers.
Several authors have shown that race, substance abuse, malnutrition,
and socioeconomic status are each independently correlated with TB
incidence in the United States.18,4751
Childhood TB incidence reflects ongoing TB transmission and as
such, is important indicator of TB control within a community. In
Chapter 131 Tuberculosis
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
TB Incidence (per 100,000 Number of New

population) in 2011
TB Cases in 2011
Newer threats to global TB control

Diabetes, smoking, and malnutrition can also impair immunologic
containment of TB infection. Their prevalence continues to increase
globally and the cumulative impact may well threaten global TB
control in the future.8,17,34
TB incidence, per 100,000
important first-line antimicrobials, isoniazid and rifampin.10,28,29

MDR-TB accounted for approximately 3.7% of newly diagnosed TB
cases and 20% of relapsed cases globally. Reliable global estimates
of MDR-TB are difficult to obtain since rigorous drug-susceptibility testing (DST) is not available in most resource-limited settings
endemic for TB.28,30 Eastern European countries have particularly
high rates of MDR-TB; a phenomenon considered linked to the
underinvestment in national TB programs and the social disruption that occurred following the collapse of
the Soviet Union in the 1990s.31 MDR-TB
40.0
is 100 times more costly to manage than is
35.0
drug-susceptible TB, requiring prolonged
30.0
courses of expensive and difficult to procure second-line drugs.32 In South Africa,
25.0
MDR-TB prevalence is 3.2% but associ20.0
ated treatment costs account for one-third
32
15.0
of the entire national TB program budget.
Treatment outcomes are substantially worse
10.0
in MDR-TB.29 Extensively drug resistant TB,
5.0
or TB resistant to all currently available bac0.0
tericidal agents, has been reported in nearly
29,30
93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
60 countries.
The increasing prevalence of
19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20
MDR-TB is particularly chastening because
U.S. overall
U.S.-born
Foreign-born
it is entirely a man-made phenomena.31,33
Year
With better management of TB programs, the
emergence of resistance can be prevented and
Figure 131-2 TB Case Rates in US-born versus Foreign-born persons, United States, 1993 to 2011.
prevalence of MDR-TB can be reduced.14,15
(Reproduced with permission from Frieden T. Reported Tuberculosis in the United States, 2011. CDC; 2012).
2013
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Number of reported cases
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
M. tuberculosis causes the vast majority

of TB today. In the early 20th century, M.
bovis accounted for up to 20% of all cases
of human TB but with modern surveillance
of animal herds and widespread use of milk
pasteurization, M. bovis now causes less
than 1% of reported TB cases in the United
States.59,60 Sporadic outbreaks of M. bovis
infection still occur in the United States, and
ongoing surveillance is important for foodchain safety. Human-to-human transmission
of M. bovis has been demonstrated.61
Mycolic acid and the

Mycobacterium Genus
The MTBC are members of the diverse
Figure 131-3 Number of TB cases in US-born versus Foreign-born persons United States,
Mycobacterium genus. The outstanding fea1993 to 2011. (Reproduced with permission from Frieden T. Reported Tuberculosis in the United
ture of the mycobacteria is their lipid-rich
States, 2011. CDC; 2012).
cell wall containing very high concentrations of mycolic acids.53,54,56,62 This cell wall
prevents reliable uptake of Gram stain. With phenol additive mycothe United States, 80% of childhood TB occurs in US-born children,
bacteria can eventually be stained to facilitate light microscopy.
and mostly those from racial and ethnic minority groups.43
Once stained, removal of dye is extremely difficult, resisting even
Microbiology of Tuberculosis
acid alcohol wash (hence acid-fast bacilli [AFB]). Lipids in the
Mycobacterium tuberculosis as the causal agent of TB was first conmycobacterial cell wall also help resistance to drying, a property
clusively demonstrated in 1882 by Robert Koch and acknowledged
that allows MTBC to retain infectiousness even within dried dropwith a Nobel Prize in 1905.52
let nuclei. The metabolic investment required to produce mycolic
M. tuberculosis is a slender, slightly curved, rod-shaped bacterium
acids significantly slows growth rate56and prolongs the time to
(or bacillus) averaging 3 by 0.3 in size and visible by light microsdetection in incubated clinical specimens submitted to laboratory.53
copy. It is nonmotile, nonencapsulated, and nonspore forming. M.
The mycolic acid containing cell wall of mycobacteria is also a
tuberculosis is strictly aerobic.53,54 Traditionally, mycobacteria are
major virulence factor, helping mycobacteria avoid innate immune
grown on solid, enriched media where rough, pigmented colonies
defenses and intracellular killing by nonactivated host phagocytes.63
generally appear 4 to 6 weeks after inoculation. MTBC can also be
Comparison to other mycobacteria
cultivated in specialized liquid media where characteristic cords visible by light microscopy are formed. Rapid liquid culture systems (e.g.,
The nontuberculous mycobacteria (NTM) are free-living saproBACTEC) have been adapted for use with mycobacteria and shorten
phytic bacteria, commensal inhabitants of the soil and/or aquatic
time to detection of growth to a little as 9 to 16 days, depending on the
environments (see Chapter 132). The NTM are nontransmissible
initial concentration of the bacteria in the specimen tested.55,56
under ordinary conditions, and only rarely infect humans as opporMTBC: Eight closely related mycobacterial species capable of caustunists. In contrast, MTBC are transmissible, obligate primary
ing human TB have been identified and together they comprise the
pathogens without an environmental reservoir.55
MTBC: M. tuberculosis (Koch bacillus), M. bovis (the agent of bovine
Transmission
TB), M. caprae (bovine TB), M. africanum (a not infrequent cause
of human TB in West Africa), M. microti (agent of rodent TB), M.
Important considerations in the transmission of tuberculosis are
pinnipedii (agent of TB in seals and a rare zoonotic disease in marine
discussed below.
biologists attending to them), and M. canettii (an ancient bacillus and
Droplet Nuclei
rare cause of human TB in East Africa) (Table 131-2).55,57,58
In the late 1930s, William Wells, sanitation engineer at Harvard
University first conceived of droplet nuclei for airborne transmission of infectious diseases.64 He found that forceful expiratory
TABLE 131-2 Members of the Mycobacterium
efforts such as coughing and sneezing, discharge minute respiratory
droplets of sputum containing viable bacilli that, when increasingly
Tuberculosis Complex (MTBC)a
reduced in size by evaporation, become infectious droplet nuclei,
Species
Primary Reservoir Host Geography
each measuring less than 5 .65 Certain healthcare procedures, for
example, bronchoscopy, sputum induction, autopsy, and even irrigaM. tuberculosis Humans
Worldwide
tion of abscesses, also produce infectious droplet nuclei.66
M. bovis
Cattle, deer, elk, bison,
Worldwide
Due to small size, droplet nuclei have an extremely slow settling
badger, opossum
rate
in air (0.5 mm/s or less). This permits their transport by air
M. bovis BCG
Human
Worldwide
currents for significant distances. Larger respiratory droplets, on the
M. caprae
Goats
Worldwide
other hand, settle out of the air quickly, and travel only a few feet
M. africanum
Human
West, Central Africa
from the source case. The microbes suspended within droplet nuclei
M. microti
Vole, rodents
are highly susceptible to germicidal levels of ultraviolet light.2,67 The
M. pinnipedii
Seal, sea lion
small size of droplet nuclei also facilitates penetration of the bronchial defenses allowing access to terminal alveolar macrophages.
M. canettii
Human
East Africa
The fairly tortuous and branched path of the pharynx and bronchial
a
While all members of the MTBC can infect humans, some are zoonotic diseases.
tree ensures that larger respiratory droplets are instead deposited
U.S.-born
Foreign-born
Year
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TABLE 131-3 Key Distinguishing Features of Droplet Nuclei And Respiratory Droplets
Respiratory Droplet Transmission
15-m-diameter particles (dried residua of larger particles)

Suspended indefinitely
Alveolar deposition
Contain few microbes
Susceptible
Measles, TB, Varicella
>100 uM-diameter particles

Settle within seconds, 1 m from source
Upper airway deposition
Contain many microbes
Resistant
RSV, influenza, staphylococcus
Source: Reproduced with permission from Garay S, Rom W. Tuberculosis, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
on the mucosal lining of the airway or trapped in the mucociliary

elevator and expelled (Table 131-3).65
Airborne Transmission of TB
In the 1950s, Richard Riley, a medical student working with Wells, elegantly demonstrated that TB is near exclusively transmitted by droplet
nuclei. Riley commandeered a TB ward of six rooms for his study. The
air from each individual room was ventilated to an upper chamber,
where caged guinea pigs were kept, sometimes passing through an
adjustable UV light source.68 Guinea pigs are considered uniquely susceptible to infection with M. tuberculosis, even by dilute aerosols, and
their use allowed quantification of degree of patient infectiousness.
Relatively few respiratory diseases are preferentially transmitted
via the airborne route; these include TB, measles, varicella, and
smallpox. Most infectious respiratory diseases (including, e.g., pertussis, influenza, the common cold, and pneumococcal pneumonia)
are instead transmitted by direct contact with larger respiratory
droplets leading to colonization of the host nasopharynx before
subsequent lung invasion.
Risk Factors for TB Transmission
The risk of TB infection is a function of exposure to the tubercle
bacilli. In turn, this depends on the interaction of three factors:
infectiousness of the source case, environmental conditions that
impact droplet nuclei concentration per volume of air, and duration
of contact with the source (Table 131-4).
Source Case Infectiousness
An important finding from Rileys studies was the extreme variability
in infectiousness of TB patients.69,70 The dominant predictors of infectiousness in source cases are the presence of cough, lung cavitation
on chest radiograph, and acid-fast bacilli visible in sputum by smear
microscopy. Sputum-smear microscopy positive cases excrete about
TABLE 131-4 F actors Associated with Number

of Infectious Droplet Nuclei per
Volume of Air and TB Transmission
Characteristics of Source Case
Environmental Factors
Sputum-smear positivity for AFB

Cough strength and frequency
Presence of lung cavitation
Effective treatment
Delayed diagnosis
Laryngeal tuberculosis
Air circulation, ventilation

Room volume
Humidity
UV light
Proximity to the source case
Duration of contact with
infected air
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
Droplet Nuclei Transmission
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
Percentage of contacts infected
35
The Adaptive Immune Response and

Containment Of Mycobacterial
Infection
The main effectors of the adaptive, cellmediated immune (CMI) response to mycobacteria are the CD4-positive subset of T
lymphocytes.80 Once stimulated, T lymphocytes release their own battery of cytokines
(including interferon-gamma [IFN-]) that
serve to reciprocally activate infected macrophages and trigger-enhanced intracellular
mycobacteria killing. This is the basis for the
tuberculin skin test and IFN- release assays,
which become positive with the development
of a host CMI response. Over the next few
weeks, the CMI directs necrotizing granuloma formation, which usually contains bacillary replication.
30
25
20
15
10
Smear positive
to sites of infection, setting the stage for the

adaptive cellular immune response.80
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.
Figure 131-4 Infectiousness of tuberculosis by bacteriologic status of and proximity to

source case. (Reproduced with permission from Grzybowski S, Barnett GD, Styblo K. Contacts of
cases of active pulmonary tuberculosis. Bull Int Union Tuberc. 1975;50(1):90106).
Mycobacteria bypass innate immune mechanisms and replicate
without limitation, spreading to regional lymph nodes, and silently
disseminate hematogenously.1,57,80 After a few weeks, dendritic cells
are activated and produce cytokines such as tumor necrosis factor
alpha (TNF-) that recruit blood-borne monocytes and lymphocytes
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
Annual Risk of Infection
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
Cavitation, sputum smear status of source

Ventilation, UV-light in environment
Duration and intimacy of contact
Previous infection
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
Adaptive immune dysfunction

Nutritional condition
Substance use
Vitamin D status
Age at infection
Acquired adaptive immune dysfunction

Nutritional condition
Late progressionComorbid disease

reactivation TB after
Substance use
2 years (5%) Post Primary Vitamin D status
Age-related immune senescence
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
Site of Disease and Clinical Presentation

TB is predominantly a respiratory disease, affecting the lungs in
about 80% of cases (Table 131-6).43,88 About 30% of TB cases involve
an extrapulmonary site, occurring either with or without concomitant lung involvement. TB can affect virtually any organ, although
peripheral lymph nodes and pleural space are the most common
extrapulmonary sites.89
Classically TB presents insidiously over weeks, with persistent
local symptoms correlating to granulomatous inflammation (e.g.,
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
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
Figure 131-6 This 32-year-old male refugee recently arrived from

Eritrea. He presented with persistent cough and fevers despite completing two courses of antimicrobial therapy directed against bacterial
communityacquired pneumonia. Sputum sample was both smear
positive and culture positive for MTBC.
Figure 131-7 This 36-year-old man Aboriginal man with history of

homelessness. This radiograph demonstrates typical manifestations of
reactivation TB: upper lobe nodular opacities, cavitation, acinar shadowing from endobronchial spread, and fibrosis.
(acinar shadows) and a tree-and-bud pattern on computed tomography (CT) (Figs. 131-6 and 131-7).95,98,101
Atypical Chest Radiograph Patterns
Atypical radiographic patterns are seen in children, the elderly,
the immunocompromised, and those with primary disease.96,100,102
Atypical features include lower lung zone infiltrates without cavitation, unilateral pleural effusion (Fig. 131-8), and ipsilateral hilar or
Figure 131-8 This 22-year-old man identified as a close household

contact of a smear-positive case of pulmonary tuberculosis. Seven
weeks later he developed fevers and cough. This radiograph demonstrates unilateral pleural effusion with compressive atelectasis.
Diagnostic thoracocentesis revealed a transudate with cellular infiltrate, predominantly lymphocytic. Sputum was culture negative for
mycobacteria but pleural specimen eventually grew MTBC.
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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
Figure 131-10 This 36-year-old HIV+ man presented with fevers.

Chest radiograph identified right upper lobe infiltrate and a background miliary pattern consisting of innumerable noncalcified nodules
measuring 2 to 3 mm, randomly distributed.
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
Direct Microscopy for AFB

Sputum-smear microscopy is more than 110 years old but remains
the most widely used investigation for active TB today.52 Two
methods are commonly used for acid-fast staining of mycobacteria:
carbolfuchsin (e.g., ZiehlNeelsen [ZN]) and fluorochrome-based
procedures (e.g., auraminerhodamine dye). Fluorescent methods slightly improve sensitivity over ZN and also allow the use of
lower microscopic magnification during inspection of the slide,
significantly shortening the time required to examine an entire
specimen.116
Sputum microscopy is widely available and low cost. It is performed directly on clinical specimens allowing rapid turn-aroundtime, thus facilitating prompt recognition, isolation, and treatment
of infectious TB cases. Microscopy also provides prognostic information: Smear-positive TB cases are more infectious and have much
higher case-fatality rates if untreated than do sputum smearnegative cases.72,117,118
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Collect sputum sample

for AFB and isolate
pending investigations
Probability
of TB
Anemia of chronic disease, minor

or no blood leukocytosis
Persists after course of antimicrobials? Partial
improvement with fluoroquinolone?
Part 17
Relative absence of dyspnea?

High-risk medical condition (see Table 131-5)?
Upper lung zone infiltrate on radiograph +/ cavitation, volume loss,
endobronchial spread?
More than 2 weeks of symptoms?

Pulmonary and constitutional symptoms?
Epidemiologic riskincluding birth in a TB endemic setting, unstable housing, substance use,
low socioeconomic status, aboriginality?
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.
For hospitalized patients, or those in congregate living settings, increasing

suspicion warrants prompt isolation pending results of investigations.
(Used with permission of Richard Long, unpublished observations).
However, sputum-smear microscopy has well-known limitations.

Sensitivity for pulmonary TB is only about 60% to 70%, and even
lower in extrapulmonary specimens and in those with HIV coinfection. That NTM also stain acid-fast lowers the specificity of smear
microscopy.119121 In low TB prevalence settings, NTM are recovered
from about 30% to 50% of AFB smearpositive sputum samples.
of TB.125129 Specificity of NAAT methods is very high, ranging

between 90% and 100% for all specimen types.
Performance of traditional NAAT requires sophisticated laboratory facilities. Recently, an automated in-cartridge assay (Xpert/
MTB-RIF [Cepheid, Sunnyvale, California]) was developed to allow
NAAT directly from unprocessed clinical specimens, without the
need for centralized reference laboratory, even in resource-limited
settings.130132 The Xpert/MTB-RIF simultaneously detects mutations within the mycobacterial RNA-polymerase gene that correlate
with rifampin-drug resistance, thus identifying MDR cases several
weeks before culture-based testing. The WHO has signaled its
intent to deploy this tool in high-burden, resource-limited settings
throughout the world.132
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
Testing for Latent TB infection

There are two main tests for the identification of LTBI: (1) Tuberculin
skin test (TST) and (2) IFN- release assays (IGRAs). Both are indirect, in that they evaluate the presence of host cellmediated immunity rather than detect actual mycobacterial organisms or antigens.133
As such, neither can distinguish active disease from latent infection.
Both tests have very poor sensitivity and predictive value for active
TB and use in this context is discouraged.134,135 These tests are better
used to assess candidates for LTBI treatment (discussed below).
Management of active TB
Prior to the availability of chemotherapy, prevailing wisdom prescribed fresh air, nutrition, sunlight, and rest for treatment of TB.
In 1947, clinical outcomes of smear-positive pulmonary TB patients
treated at a sanatorium in the United Kingdom were recorded:
within 4 years of entry, 55% died, 20% remained chronically
affected, and 25% experienced remission.136 With the discovery of
chemotherapy for TB, mortality dropped orders of magnitude and
within a decade TB sanatoria were shuttered.6,137
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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
INH + RIF + PZA + EMBa

Given daily or 5/wk
Extend continuation phase to 7 mo if risk of relapse

presentc
Regimen 2
INH + RIF + EMBa

Given daily or 5/wk
INH + RIF + PZA+EMBa
Given 5/wk for first 2 wk then wk
for next 6 wke
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
INH + RIF + PZA + EMBa

Given daily or 5/wk
Regimen 3
This PZA-free regimen can be used if risk factors for

hepatotoxicityd or in pregnancy
Intermittent therapy should always be provide as DOTe
Not eligible for this regimen if cavitary disease, positive

sputum cultures at 2 mo, or if HIV+
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
killing while allowing intermittent dosing and lower pill-burden.

A high level of adherence is required to prevent relapse and emergence of resistance. Rifamycins have a critical role in preventing
relapse and whenever possible should be provided throughout the
treatment. Several randomized clinical trials have established standardized treatment regimens as outlined in Table 131-7. Reported
success rates with these regimens approach 95%.138140
First-line TB drugs
Current first-line TB drugs include isoniazid (INH), rifampin (RIF),
pyrazinamide (PZA), and ethambutol (EMB) (see Table 131-8).
TABLE 131-8 TB Drug Dosing and Important Adverse Reactions

Druga
Daily Dose (Maximum Dose)
Thrice-Weekly Dose
Renal Dose: for IHD or

eGFR <30 mL/min
Isoniazid (INH)
5 mg/kg (300 mg)
10 mg/kg (600)
No change
Rifampin (RIF)
10 mg/kg (600 mg)b
10 mg/kg (600 mg)b
No change
Rifapentine (RPT)
No change
Pyrazinamide (PZA)
2025 mg/kg (2000 mg)
10 mg/kg (600 mg), given

once-weekly
3040 mg/kg (4000 mg)
2535 mg/kg 3/wk
Ethambutol (EMB)
Moxifloxacin or
Levofloxacin
1520 mg (1600 mg)

400 mg
7501000 mg
2535 mg/kg (2400 mg)

NS
1525 mg/kg 3/wk

No change; 750 mg 3/wk
Selected Adverse Events

Hepatotoxicity
Peripheral neuropathy
Thrombocytopenia
Drugdrug interactionsc
Drugdrug interactions
Hepatotoxicity
Hyperuricemia
Arthralgia
Optic neuritis
Gl upset
QT prolongation
Insomnia
Tendinopathy
NS, not yet studied; IHD, intermittent hemodialysis.

a
All drugs are provided orally; however, INH, RIF, and the flouroquinolones are available as intravenous formulations.
b
Higher doses of rifampin are well tolerated and perhaps more efficacious; ongoing trials are examining higher dosing schedules.
c
Drugdrug interactions mediated mostly through cytochrome p4503a4 enzyme induction.
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 World Health Organization & Initiative, S.T., 2010. The treatment of tuberculosis guidelines. 4 ed. Geneva.
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Part 17
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.
Adjunctive corticosteroid use

Treatment of TB is occasionally complicated by paradoxical treatment responses whereby clinical deterioration develops a few weeks
into an otherwise effective treatment.160,161 The response is characterized by a robust inflammatory reaction, typically at the site of
initial disease, without apparent microbiologic failure or bacillary
replication. The paradoxical response is most commonly observed
in extrapulmonary disease.162 Paradoxical responses are typically
self-limited, even when TB treatment is continued. Symptomatic
benefit is sometimes observed following a brief course of corticosteroid treatment.161 Important differential diagnostic considerations
of paradoxical responses that should be excluded prior to treatment
with corticosteroids include treatment nonadherence, inadequate
dosing, drug malabsorption, or drug-resistant TB.
For disease of the pericardium and the CNS, the consequences
of a paradoxical response are potentially life threatening including increased intracranial pressure and constrictive pericarditis,
respectively. Meta-analyses have suggested an appreciable benefit to
simultaneous initiation of corticosteroids along with TB treatment
for these forms of TB.163165 The regimens tested in the clinical trials
varied but 40 to 80 mg of prednisone per day for 6 to 12 weeks is a
common prescription.
Direct Observation of Therapy
Direct observation of therapy (DOT) ensures adherence, thus
improving treatment outcomes and preventing emergence of resistance.166 Because physicians are poor at predicting which patients
will adhere to therapy, DOT is recommended for all patients.138
Intermittent dosing
Direct supervision of therapy by healthcare workers is facilitated by
intermittent treatment regimens (e.g., 5 days per week, or Monday
WednesdayFriday or even twice-weekly). Intermittent dosing schedules take advantage of the slow growth of MTBC and the postantibiotic effect of TB drugs.167,168 However, acquired drug resistance has
been documented with intermittent dosing schedules, especially in
patients with extensive disease or poorly controlled HIV coinfection.
Treatment monitoring
Bacteriologic monitoring (e.g., monthly sputum cultures until
negative) is the preferred method of follow-up for pulmonary TB
cases. A persistently positive sputum culture 2 months after starting
effective treatment is a marker for relapse and treatment extension
is suggested. Culture positivity at 3 months is highly suggestive of
treatment failure and patients must be carefully evaluated to identify potential causes (e.g., nonadherence, malabsorption, acquired
resistance, drugdrug interactions). Treatment failure is defined as
persistently positive cultures 4 months into treatment.
Adverse effects
Severe side effects necessitating drug discontinuation are rare with
standard TB treatment regimens. A commonly encountered adverse
event is drug-related hepatotoxicity.138,142 Transient, mild elevation
in liver enzymes early in the course of therapy occurs in about 20%
of patients and is usually inconsequential, usually resolving without
intervention and without treatment interruption. However, for
patients with symptomatic and/or marked elevation of transaminases (above 35 the upper limit of normal) treatment should be
immediately discontinued and drugs cautiously reintroduced one at
a time under close monitoring once the liver enzymes and function
has returned to normal.
Drug-Resistant TB
Drug resistance to any of the first-line TB drugs occurs in about 8%
of TB cases in the United States.41 Mono-resistance to INH, the most
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TABLE 131-9 H
ierarchy of Second-Line
TB Drugs
Group
Group 1
Group 2
Group 3
Group 5
First-line oralbacteriocidal PZA, Ethambutol, Rifabutin

Injectable agent
Amikacin, Kanamycin,
Capreomycin
Fluoroquinolones
Moxifloxacin, Levofloxacin,
Gatifloxacin, Ofloxacin
Second-line oral
Ethionamide, PAS,
(BD-TID)bacteriostatic
Cycloserine
Agents with unclear
Linezolid, Clofazimine,
efficacy
Clarithromycin, INH 900
TIW, Amoxicillin-clavulanate,
ImipenemCilistatin
TIW, three times weekly.

Treatment regimens for MDR-TB should be guided by drug-susceptibility testing.
Typically use between 4 and 6 agents with predicted activity. Wherever possible a fluoroquinolone and injectable agent should be used initially. The lower the group number,
the more preferred are the drugs on the basis of efficacy and anticipated tolerability.
Source: Data from Drug-resistant Tuberculosis: a Survival Guide for Clinicians, 2nd
ed. Curry National Tuberculosis Center; 2008.
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.
Treatment issues in Special Populations

Treatment considerations in two special patient populationsthose
coinfected with HIV and solid organ transplant recipientsare
discussed below.
HIV Coinfection
Standard regimens used for the treatment of TB in HIV-uninfected
individuals have similar efficacy in HIV-infected individuals, provided these patients are also effectively treated with antiretroviral
therapy (ART).187 However, the addition of ART to TB treatment
can result in overlapping drug toxicity and intolerances including
peripheral neuropathy, hepatotoxicity, and Gl upset. Potent bidirectional drugdrug interactions between rifampin and several
classes of antiretroviral drugs can amplify toxicity and undermine
HIV virologic control. A number of studies have also found reduced
serum concentrations of TB drugs in patients coinfected with HIV,
thought to be due to decreased gastrointestinal absorption.188 In
turn, low serum drug concentrations may increase the risk of treatment relapse or acquired rifamycin resistance. Intermittent RPT
in the continuation phase is associated with higher relapse rates in
HIV-infected individuals and should be avoided.146
Successful HIV treatment with ART leads to immune reconstitution and, in patients with concurrent active TB, restores the host
inflammatory response to TB infection. This can clinically present
as transient worsening of TB disease a few weeks following initiation
of ART (a phenomenon known as immune reconstitution inflammatory syndrome or TB-IRIS). TB-IRIS can occur following ART
initiation in patients already on treatment for TB (paradoxical type)
or in patients with previously undiagnosed TB (unmasking type).
TB-IRIS produces significant morbidity, occasionally requiring
glucocorticoid therapy for symptom control.189 However, in patients
diagnosed simultaneously with HIV and TB, treatment outcomes,
relapse rates, and overall mortality are greatly improved when ART
is added early, within a few weeks of initiating TB treatment, even if
this strategy noticeably increases risk of TB-IRIS.190,191
Group 4
Drugs
Several promising new drugs with novel mechanisms of action are in

clinical development.181 Bedaquiline and delamanid have each proven
efficacious in phase 2b trials but demonstration of safety is pending
larger trials.182184 PA-824, SQ-109, and sutezolid have also shown efficacy in small clinical studies and appear ready for further clinical development.179,185 Linezolid, an oxazolidinone commonly used in treatment
of resistant gram-positive infections, has been shown to be effective for
the treatment of MDR-TB in controlled trials but treatment-limiting
toxicities are common with prolonged durations.186
TABLE 131-10 Second-Line TB Drugs and Selected Toxicities

Agent
Common and/or Important AEs
Ethionamide (take with B6)
Gl upset
PAS (p-aminosalicylic acid)
Gl upset (less with PASER formulation)
Cycloserine (take with B6)

Amikacin
Linezolid
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
Targeted Testing and Treatment

of Latent TB Infection
The use of anti-TB drugs in latently infected patients to prevent
subsequent progression to active disease was first reported in the
early 1950s.197 Dozens of controlled clinical trials subsequently
confirmed that isoniazid reduced the risk of TB in those with positive TST by 60% to 90%, depending on the level of adherence.198200
An estimated 4% of the US population is latently infected201 but
currently available tests do not reliably predict which infected individuals will eventually develop active disease.202 Furthermore, up to
5% of those treated for latent infection will experience an adverse
event, rarely this can be severe hepatotoxicity and fulminant hepatic
failure.142,203,204 Thus, the decision to treat LTBI must be individualized, balancing the risk of developing active TB against the potential
for adverse events.
Diagnosis of LTBI
The diagnosis of latent TB infection hinges on a positive TST and/
or IGRA (discussed above). Once infected with MTBC, it is believed
that the potential for reactivation persists for the lifespan of the host.
Tuberculin Skin Test
The TST is more than 100 years old.205 The most commonly used
method for administering the TST is the Mantoux technique: Here,
5 tuberculin units of purified protein derivative (PPD) from M.
tuberculosis are injected intradermally on the inner surface of the
left forearm. In those individuals with cell-mediated immunity to
PPD, a delayed type hypersensitivity (DTH) response will occur,
manifest as a circular indurated skin reaction arising at the site of
injection 48 to 72 hours later.
Several factors can undermine the predictive value of the TST for
latent TB infection.133 Potential causes of false-negative reactions
include immune compromise, malnutrition, chronic renal failure,
improper administration, and expiration of tuberculin.204,206 TB disease itself reduces test sensitivity, with up to 25% of TB cases TST
negative. The TST is also prone to false-positive reactions. PPD is
a relatively crude extract of mycobacterial antigens, many of which
are conserved between mycobacterial species. Sensitization to PPD
can develop after routine exposure to environmental NTM or following previous vaccination with BCG.133
Although technically simple, significant training and expertise is
required for reliable test performance and interpretation. Roughly
speaking, the larger the reaction size, the more likely latent TB infection. The predictive value of the test varies by prevalence of LTBI
and immunocompetence and different reaction size criteria are used
to define positivity in different populations204 (see Table 131-11).
Interferon- release assays
IGRAs are in vitro blood tests of CMI response; they measure T-cell
release of IFN- following stimulation by synthetic peptide antigens
specific to M. tuberculosis.
TABLE 131-11 Interpretation of Tuberculin

Skin Test
TSTReaction
Size (mm)
04
10
15
Situation Where This Reaction is Considered

Positive (i.e., Indication for Treatment
of LTBI)
LTBI treatment not generally indicated
Children <5 y who are recent close contacts
should start INH pending repeat TST
performed 8 wk from last contact
HIV infection
Recent close contact of infectious case
Fibrotic changes on chest X-ray consistent
with old TB (but not previously treated)
Organ transplantation
Other immunosuppressed patients (TNF-,
chemotherapy, glucocorticoidsa)
Other high-risk conditionssilicosis,
diabetes, malignancy,b underweight, CKD
requiring dialysis
Children less than 4 y of age
Recent immigrants from TB endemic countries (>125 per 100,000 incident TB cases
per year) within past 5 y
Healthy, low-risk reactorc
CKD, chronic kidney disease.

a
Glucocorticoids at doses >15 mg/d prednisone equivalent for at least 1 month.
b
Lymphoproliferative disease, head and neck and lung neoplasm.
c
Healthy low-risk reactors may not require LTBI treatment as risk of treatment
related toxicities may outweigh clinical benefit.
Source: Data from Horsburgh CR, Rubin EJ. Clinical practice. Latent tuberculosis
infection in the United States. N Engl J Med. 2011;364(15):14411448.
Replacing the mixture of antigens contained in PPD with specific

synthetic peptides greatly improves the specificity of IGRAs compared to TST, especially in populations previously vaccinated with
BCG.207,208 The sensitivity of the IGRA is comparable to the TST,
even in immunocompromised hosts, although the absence of a gold
standard makes precise estimation difficult.209211
IGRA appear less reproducible on repeated testing than is TST,
especially when values of IFN- release are near the quantitative threshold for reporting positive (i.e., borderline positive).212
This can result in spontaneous conversions and reversion on
serial testing of the same individual, with uncertain clinical
implications.213
There are two currently approved IGRA tests available in the
United States: the QuantiFERON-TB Gold In-Tube assay (Cellestis
Limited, Australia) and the T-SPOT.TB assay (Oxford Immunotec,
United Kingdom).
Which test to use in LTBI
Either the TST or the IGRA are acceptable for the diagnosis of
LTBI.135 The improved specificity of IGRAs, and the need for a
single patient visit, make this test attractive. IGRAs are associated
with high testing costs and require laboratory infrastructure and
significant technical expertise. The improved specificity of the
IGRA might reduce the number of candidates for LTBI treatment
but whether this translates to cost-effectiveness is controversial.214
TST is preferred for serial testing, for example of healthcare workers repeatedly exposed to infectious TB, a setting where the IGRA
performance has not been defined. Use of both tests simultaneously,
where a positive result on either the TST or the IGRA signals latent
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infection, may help improve sensitivity of LTBI screening in those

with compromised immunity.214,215
Treatment for LTBI

The best studied treatment of LTBI is self-administered INH taken
daily for 9 months.200,219 Other acceptable regimens are shown in
Table 131-12. Shorter treatment regimens for LTBI typically result
in improved completion rates. Intermittently dosed regimens have
less supporting efficacy data but might be used in settings where
adherence to unsupervised treatment is expected to be poor.
Contacts of INH-monoresistant cases can be offered 4 months of
RIF daily. Contacts of MDR-TB can be offered therapy with an FQ
daily for 9 months although data are limited.
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.
Decision to Treat LTBI

The first step in deciding whether to treat for LTBI is to assess the
likelihood that a positive TST or IGRA represents true TB infection. Both tests perform poorly in low-prevalence populations and
a true positive result is much more likely in those exposed to active
TB or from high-risk epidemiologic groups such as foreign-born,
travelers to TB endemic countries, homeless, and incarcerated
populations.
The second step is to estimate likelihood of progression to active
TB if actually infected211 (see Table 131-2). The third step is to
evaluate potential risks for adverse reactions to treatment. The main
adverse effect of LTBI treatment is INH-related hepatotoxicity. The
strongest predictor of hepatotoxicity is age. Those younger than 20
years old have less than a 0.1% chance of hepatotoxicity during LTBI
treatment, whereas those over 65 years are exposed to a risk around
2% to 5%. An internet-based calculator is available to assist in
balancing these probabilities and informing treatment decisions.216
Treatment of LTBI has only been demonstrated to be effective in
those with a positive TST or IGRA. Several clinical trials have failed
to demonstrate a benefit of treatment in immunocompromised
individuals at risk but with a negative TST or IGRA.217,218
Before the treatment of LTBI is started, active disease must be
excluded carefully by means of history, physical examination, chest
radiography, and sputum culture, in order to avoid inadvertent
monotherapy of active TB that could lead to resistance.
Patients receiving LTBI treatment should be monitored at least

monthly for clinical symptoms of hepatitis. They should also be
educated about the symptoms of hepatitis and instructed to stop the
medication immediately and seek prompt evaluation to reduce risk
for progression to severe disease.
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
Adult Dosing (Oral)
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
900 mg 2/wk 69 mob

Isoniazid 600 mg and rifampin 600 mg
twice-weekly for 3 mo
Isoniazid 900 mg and rifapentine 900 mg each
weekly for 12 wk, each dose directly observed
DOT
DOT
Isoniazid plus rifampin
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)
SAT, self-administered treatment; DOT, directly observed treatment.

a
Pyridoxine supplementation (2550 mg daily) often provided to prevent INH-associated peripheral neuropathy, especially if risk factors including alcohol use disorder,
diabetes, malnutrition, uremia, and HIV infection.
b
Twice-weekly regimens should be provided under direct observation.
c
This regimen not tested in children or pregnant women or those infected with HIV; the only trial of this regimen provided as DOP.
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 Horsburgh CR, Rubin EJ. Clinical practice. Latent tuberculosis infection in the
United States. N Engl J Med. 2011;364(15):14411448.
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to improve outcomes in MDR disease. Ongoing national surveillance

and funding of TB control programs is required to maintain low TB
incidence in the United States. However, given that an increasing
proportion of TB is imported, further reduction in TB incidence
will ultimately require investment in TB control globally. Even in the
wealthy countries of the West, TB is not conquered but continues to
smolder, threatening reemergence where social injustice prevails and
where the vigilance of TB control programs is relaxed.
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C H A P T E R 131

an estimated 51 million people had been treated and an estimated

TABLE 131-1 T B Incidence and Incidence Rate

TB epidemiology in the United States:

Chapter 131 Tuberculosis

TB Incidence (per 100,000 Number of New

Newer threats to global TB control

TB incidence, per 100,000

important first-line antimicrobials, isoniazid and rifampin.10,28,29

Number of reported cases

M. tuberculosis causes the vast majority

Infectious Diseases of the Lungs

Mycolic acid and the

15-m-diameter particles (dried residua of larger particles)

>100 uM-diameter particles

on the mucosal lining of the airway or trapped in the mucociliary

TABLE 131-4 F actors Associated with Number

Sputum-smear positivity for AFB

Air circulation, ventilation

Chapter 131 Tuberculosis

Droplet Nuclei Transmission

Percentage of contacts infected

Infectious Diseases of the Lungs

The Adaptive Immune Response and

to sites of infection, setting the stage for the

Figure 131-4 Infectiousness of tuberculosis by bacteriologic status of and proximity to

Annual Risk of Infection

Cavitation, sputum smear status of source

Chapter 131 Tuberculosis

Adaptive immune dysfunction

Acquired adaptive immune dysfunction

Late progressionComorbid disease

Age-related immune senescence

Site of Disease and Clinical Presentation

Figure 131-6 This 32-year-old male refugee recently arrived from

Figure 131-7 This 36-year-old man Aboriginal man with history of

Figure 131-8 This 22-year-old man identified as a close household

Figure 131-10 This 36-year-old HIV+ man presented with fevers.

Chapter 131 Tuberculosis

Direct Microscopy for AFB

Collect sputum sample

Anemia of chronic disease, minor

Relative absence of dyspnea?

Infectious Diseases of the Lungs

More than 2 weeks of symptoms?

For hospitalized patients, or those in congregate living settings, increasing

However, sputum-smear microscopy has well-known limitations.

of TB.125129 Specificity of NAAT methods is very high, ranging

Testing for Latent TB infection

INH + RIF + PZA + EMBa

Extend continuation phase to 7 mo if risk of relapse

INH + RIF + EMBa

INH + RIF + PZA + EMBa

Chapter 131 Tuberculosis

This PZA-free regimen can be used if risk factors for

Not eligible for this regimen if cavitary disease, positive

killing while allowing intermittent dosing and lower pill-burden.

TABLE 131-8 TB Drug Dosing and Important Adverse Reactions

Daily Dose (Maximum Dose)

Renal Dose: for IHD or

5 mg/kg (300 mg)

10 mg/kg (600 mg)b

10 mg/kg (600 mg)b

TABLE 131-1 T B Incidence and Incidence Rate

TABLE 131-4 F actors Associated with Number

TABLE 131-8 TB Drug Dosing and Important Adverse Reactions

TABLE 131-10 Second-Line TB Drugs and Selected Toxicities

TABLE 131-11 Interpretation of Tuberculin