Tuberculosis PDF

35 TUBERCULOSIS
PHILIP C. HOPEWELL, MD • MIDORI KATO-MAEDA, MD • JOEL D. ERNST, MD
INTRODUCTION Phylogenetic Lineage- and Strain- Physical Examination

CHARACTERISTICS OF THE Dependent Variation in Pathogenesis Radiographic Features
MYCOBACTERIUM TUBERCULOSIS Latency/Dormancy and Reactivation Bacteriologic Evaluation
COMPLEX ORGANISMS IMMUNITY PLEURAL TUBERCULOSIS
DESCRIPTIVE EPIDEMIOLOGY OF Innate Immunity to Mycobacterium DISSEMINATED TUBERCULOSIS
TUBERCULOSIS tuberculosis TREATMENT
TRANSMISSION OF MYCOBACTERIUM Adaptive Immunity to Mycobacterium
TUBERCULOSIS Current Standard Regimens
tuberculosis
Source Case EXTRAPULMONARY TUBERCULOSIS
Contributions of Immune Responses to
Environmental Factors Tuberculosis Pathology Lymphatic Tuberculosis
Circumstances of Exposure Exogenous Versus Endogenous Infection TREATMENT OF LATENT
TUBERCULOUS INFECTION
Host Factors RISK FACTORS FOR DISEASE
Indications for Treatment
PATHOGENESIS DIAGNOSIS OF LATENT
TUBERCULOSIS INFECTION Current Treatment Regimens
Intracellular Trafficking of Mycobacterium
tuberculosis Tuberculin Skin Test Management of Exposure to Drug-
Resistant Organisms
ESX-1 Protein Secretion System Interferon-γ Release Assays
IMMUNIZATION WITH BACILLE
Induction of Type I Interferons DIAGNOSIS OF PULMONARY CALMETTE-GUÉRIN
Biologically Active Mycobacterial Lipids TUBERCULOSIS
TACKLING CURRENT PROBLEMS
Granulomas Diagnostic Evaluation
Modulation of Apoptosis Patient History
INTRODUCTION must be viewed as a global problem, one that is not con-

tained by national boundaries and whose effects are felt in
Mycobacteria have played an extremely important role in all countries regardless of their state of development.3 In
influencing society throughout history. Tuberculosis and addition to human immunodeficiency virus (HIV) infection,
Hansen disease (leprosy), the two most prominent myco- drug resistance is providing increasing challenges to tuber-
bacterial diseases, have been recognized as scourges of culosis control efforts.4 Both multidrug-resistant (MDR)
humanity since antiquity. Whereas leprosy was most tuberculosis (caused by organisms resistant to at least iso-
apparent as a metaphor for the destitute, disabled, and dis- niazid and rifampin) and extensively drug-resistant (XDR)
figured, tuberculosis was the “captain of all these men of tuberculosis (caused by MDR organisms that are also resis-
death,” according to John Bunyan—a plague that carried tant to one of the fluoroquinolones and to at least one
away the young and talented members of society. Cur- injectable second-line agent) pose significant difficulties for
rently, although the resurgence of tuberculosis in indus- tuberculosis control programs in most of the world.
trialized countries that began in the mid-1980s has
subsided, the disease continues to ravage much of the
developing world and to kill or disable many young, pro- CHARACTERISTICS OF THE
ductive members of society.1,2
Because pulmonary and extrapulmonary tuberculosis MYCOBACTERIUM TUBERCULOSIS
commonly appear together, and because the general mani- COMPLEX ORGANISMS
festations and microbiologic features are the same with all
sites of disease, this chapter addresses both pulmonary and The main phenotypic characteristic that defines the genus
extrapulmonary tuberculosis. Mycobacterium is the property of “acid-fastness,” the ability
Some forms of extrapulmonary tuberculosis, such as to withstand decolorization with an acid-alcohol mixture
genitourinary, bone and joint, central nervous system, after coloration with such stains as carbol fuchsin or aura-
abdominal, and pericardial tuberculosis are covered in the mine O (Fig. 35-1).5 In addition to being acid fast, the myco-
online version of this chapter, which can be found at bacteria are primarily intracellular pathogens, are obligate
ExpertConsult. aerobes, and, in the presence of a normal immune response,
Because tuberculous infection is so prevalent throughout induce a granulomatous response in tissue. Most members
much of the developing world, the conflicts and upheavals of the genus that cause disease in immunocompetent
that result in immigration from low-income to developed humans are phylogenetically close and possess genes that
countries will have a continuing influence on the incidence encode the virulence factors ESAT-6 and CFP-10 (see
of tuberculosis everywhere. For this reason, tuberculosis “ESX-1 Protein Secretion System” later).6
593
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35 • Tuberculosis 593.e1
Genitourinary Tuberculosis
Bone and Joint Tuberculosis
Central Nervous System Tuberculosis
Abdominal Tuberculosis
Pericardial Tuberculosis
APPENDIX: ESSENTIALS OF CHEMOTHERAPY
594 PART 3 • Clinical Respiratory Medicine
A B C
Figure 35-1 Diagnostic imaging of M. tuberculosis. A and B, Kinyoun-stained smears of sputum showing acid-fast bacilli (Mycobacterium tuberculosis
confirmed by culture). (Original magnification A: ×400; B: ×960.) C, Auramine fluorochrome stain of sputum smear (M. tuberculosis confirmed by culture)
(Original magnification, ×400.) (Samples and photomicrographs courtesy Dr. Maria Aguero-Rosenfeld and Dr. Ludovic Desvignes, Bellevue Hospital and New
York University Medical Center (A and B), and Dr. Niaz Banaei, Stanford University Medical Center (C).
Tuberculosis is caused by any one of three mycobacterial pathogen) were surprisingly highly conserved, in contrast
pathogens that are part of the M. tuberculosis complex: to the situation with other pathogens in which antigens
M. tuberculosis, Mycobacterium bovis, and Mycobacterium undergo a high frequency of variation.14 These results indi-
africanum. The other members of the M. tuberculosis complex cate that M. tuberculosis does not use antigenic variation as
are: Mycobacterium microti, Mycobacterium pinnipedii, and a major mechanism of immune evasion, and the results
Mycobacterium caprae, which only rarely cause disease in may help guide vaccine development.
humans. Mycobacterium mungi7 and Mycobacterium orygi8 In addition to providing information about the biology of
have not been reported to cause disease in humans. M. M. tuberculosis, the analysis and comparison of whole
africanum causes disease that is clinically indistinguishable genome sequences have provided phylogenetically robust
from that of M. tuberculosis, but it is restricted to specific markers that enable assessment of the evolution and clas-
regions of Africa or people from those regions. Mycobacte- sification of clinical isolates of M. tuberculosis, as well as
rium canettii is not part of the M. tuberculosis complex, but provide tools to examine the impact of genetic diversity on
it has been identified as a cause of tuberculosis in a small the epidemiology and clinical features of tuberculosis.15
number of patients from or with connection to East Africa.9 The M. tuberculosis phylogenetic tree has a geographic
This strain diverged from the common ancestor of all tuber- structure from which the initial M. tuberculosis major
cle bacilli much earlier than the M. tuberculosis complex. lineage names were derived: Indo-Oceanic (lineage 1), East-
Since the publication of the first complete genome of Asian (lineage 2), Indian and East-African (lineage 3),
M. tuberculosis H37Rv laboratory strain,10 multiple clinical Euro-American (lineage 4), West-African 1 (lineage 5), and
isolates have been sequenced and are publicly available West-African 2 (lineage 6). These last two lineages are also
in GenBank11 and the Tuberculosis Database (TBDB; known as M. africanum.15 This classification has been con-
www.tbdb.org). The sequence of H37Rv genome is anno- firmed using large-sequence polymorphisms (insertions
tated and frequently revised and updated (http://tuberculist. and deletions), multilocus sequence analysis, and genome
epfl.ch/). The most recent version of the H37Rv annotation sequencing, which is now the gold standard for phylogeny
(R27-March 2013) included 4018 protein coding genes, studies.16 Several studies have suggested that different lin-
of which 88% have a defined or possible function and eages of M. tuberculosis may be associated with different
the rest are annotated as conserved hypothetical proteins degrees of pathogenicity.17-21 In The Gambia, the rate of
without known function.12 The genome of M. tuberculosis transmission (measured by skin test conversion) of M.
differs from other bacterial genomes in that 6% of the genes tuberculosis to household contacts was similar among differ-
are predicted or known to be involved in lipid biosynthesis ent lineages. However, the proportion of contacts develop-
and degradation.11 Nearly 400 of its putative proteins share ing active tuberculosis within the 2-year follow-up period
no homology with known proteins and, thus, could be varied: 1% for those exposed to strains of M. africanum, 6%
unique to M. tuberculosis.13 The genetic makeup of the for those exposed to strains from lineage 2, and 1% to 4%
organism indicates that it has the potential to survive in a for strains from lineage 4.20 In San Francisco, strains from
variety of environments, including those with low oxygen sublineage 207, a sublineage of lineage 2, were more likely
tension. to be associated with genotypic clustering (a measurement
The potential for developing new drugs, vaccines, and of the ability of a strain to cause secondary cases) and were
diagnostic tests on the basis of the knowledge of the com- more virulent in guinea pigs when compared with the other
plete array of genes in M. tuberculosis is enormous and is lineage 2 sublineages.22,23 Similarly, strains from sublineage
only beginning to be realized. For example, the analysis of 183, within lineage 4, caused more secondary cases com-
the whole genome sequence of 21 M. tuberculosis clinical pared with other lineage 4 sublineages.24 In California,
isolates representative of the global bacterial population MDR M. tuberculosis caused by lineage 2 organisms was
showed that human T-cell epitopes (peptide fragments in M. associated with genotypic clustering, whereas lineage 1
tuberculosis used by T-cell lymphocytes to recognize the strains produced no secondary (clustered) cases.25
35 • Tuberculosis 595
Reported TB Cases, United States

DESCRIPTIVE EPIDEMIOLOGY 1953–2013
OF TUBERCULOSIS 100,000
For most of recorded history, tuberculosis has been a 80,000

problem of enormous dimensions worldwide—and it still is.
Reported cases
The World Health Organization (WHO) estimates that nearly
60,000
one third (1.9 billion people) of all the people in the world
are infected with M. tuberculosis. According to the latest
(2013) WHO Global report, in 2012 there were an esti- 40,000
mated 8.6 million new cases, of which only 6.1 million
were reported to national tuberculosis programs, leaving an 20,000
estimated 2.5 million unaccounted for.2 This gap is likely
related to limitations in the global surveillance and report- 0
ing systems and because a large amount of care is delivered
57
62
67
72
77
82
87
92
97
02
07
12
by the private sector with no reporting. The total number
19
19
19
19
19
19
19
19
19
20
20
20
of prevalent cases (new and existing) in the world was esti- Year
mated to be 12 million, from which there were an estimated
Figure 35-2 Cases of tuberculosis reported per year in the United States,
1.26 million deaths, making tuberculosis the eighth most 1953–2013. (From Centers for Disease Control and Prevention: Reported
common cause of death in low-income countries.26 Most of tuberculosis in the United States, 2013. Atlanta, 2014.)
the persons with tuberculosis (>95%) and nearly all of
those who die from it (98%) reside in low- and middle-
income countries.
Since 1990, there has been a progressive decrease in the countries in the world where the prevalence of tuberculous
incidence of tuberculosis in all nine WHO regions of the infection was high.
world, although the rates of decline in Eastern Europe and Whereas the incidence of tuberculosis decreased overall
Africa lag behind other regions.2 Globally the rate of decline by 81% from 1993 to 2012, the incidence decreased dispro-
in incidence is about 2% per year, although this rate varies portionately among the U.S.-born population.27 There was
from region to region. Also, in 2012, it was estimated that a 53% reduction in incidence among the foreign born
there were 1.1 million new cases and 300,000 deaths from during the same time period; however, the rate remains
tuberculosis in persons with HIV infection. The distribution relatively high at 15.9/100,000. Among foreign-born
of persons with coexisting HIV and tuberculosis varies con- persons, rates of tuberculosis are the highest during the
siderably around the world, but most (79%) live in sub- first 2 years after entry into the country, regardless of age,
Saharan Africa. with annual rates especially high (>250/100,000 persons)
In spite of the staggering impact of tuberculosis in among immigrants from sub-Saharan Africa and Southeast
developing countries, it was believed that the disease was Asia.3 By contrast, in the United States and other low-
well on its way to being eliminated in most of the high- incidence countries, tuberculosis case rates in persons born
income, low-incidence countries, including the United in these countries tend to be higher in older individuals,
States. In these high-income countries, from at least the because the older a person is, the more likely he or she
beginning of the 20th century, tuberculosis death rates is to have acquired tuberculous infection, having lived
were steadily decreasing, a decline that was accelerated during a time when the disease was more prevalent than it
by the introduction of antituberculosis chemotherapy in is today.
the late 1940s. In the United States following the intro-
duction of effective chemotherapy, rates of new cases of
tuberculosis decreased steadily at an average annual rate
of approximately 5%. However, between 1984 to 1992,
TRANSMISSION OF
the number of tuberculosis cases increased by 20%. With MYCOBACTERIUM TUBERCULOSIS
renewed effort and considerably increased funding, case
rates once again began to decline in 1993, as shown in Knowledge of the factors that govern transmission of M.
Figure 35-2. tuberculosis from a source case and of the sequence by
In 2012 in the United States, 9945 cases of tuberculosis which the disease develops in a potential new host is vital
(3.2 cases per 100,000 population) were reported, the for devising strategies for tuberculosis control and for evalu-
lowest number since systematic national reporting began in ating the risk of a person becoming infected after exposure
1953, and a 5.4% decline from 2011.27 The reasons for the to a patient with tuberculosis.30
resurgence of tuberculosis in the late 1980s and early Transmission of M. tuberculosis is influenced by features
1990s in the United States, as well as in Western Europe, of the source case, particularly the bacillary load, by the
are complex but revolve largely around two major factors: closeness of the potential recipient of the organism to
the epidemic of infection with HIV and the deterioration of the source, and by the condition of the environmental air
public health systems.28,29 Interacting with and amplifying they share. A possible additional factor is the infectivity of
these two major factors were two additional circumstances: the organism—the degree to which M. tuberculosis has the
(1) socioeconomic conditions, particularly homelessness ability to establish itself within the lung or other sites in the
that led to crowding; and (2) immigration of persons from new host. However, even taking these factors into account,
there is substantial unexplained variability in the degree to variability in infectiousness. Jones-Lopez and colleagues37
which persons with untreated tuberculosis transmit the used an air-sampling device to capture M. tuberculosis in
infection to persons to whom they are exposed. exhaled (coughed) air and showed that infectiousness was
associated with the presence of cultivable organisms in the
sampled air. The finding of organisms in the exhaled air was
SOURCE CASE
quite variable from patient to patient and did not correlate
Transmission of M. tuberculosis is a classic example of an with sputum smear results.
airborne infection.31 In nearly all instances, tuberculous Simple maneuvers, such as covering the mouth while
infection is acquired by inhalation of one or more tubercle coughing, can reduce formation of droplet nuclei by deflect-
bacilli contained in an airborne particle small enough (1 to ing droplets from the air stream. Similarly, a mask worn by
5 µm) to reach an alveolus. For a person with tuberculosis the patient is effective because particles are trapped while
to be infectious, the organisms must have access to environ- they are still large, before the water content has evaporated.
mental air and be aerosolized. By and large, this means that Masks (disposable particulate respirators) worn by persons
only patients with pulmonary tuberculosis can be regarded exposed to an infectious source are less effective than are
as infectious. However, respirable particles containing M. masks worn by patients, because most airborne droplet
tuberculosis may rarely be generated from other sources nuclei are much smaller than their parent droplets.
(e.g., irrigation of a tuberculous abscess).32 After aerosol- However, properly constructed, well-fitting masks are very
ized respiratory secretions are expelled from the nose or efficient in removing respirable particles of 1 to 5 µm38 (see
mouth, their water content evaporates rapidly, leaving only also Chapter 11).
a small residue of solid matter—the droplet nucleus—which A second factor of the source case to be considered in
may include tubercle bacilli and which may remain sus- determining infectiousness is the number of organisms
pended in the air for several hours.33 A single bacillus in a contained in the lungs. This can be inferred from the extent
tiny droplet nucleus is more hazardous than several bacilli and morphology of the disease, as determined by the chest
in larger airborne particles, which when inhaled deposit in radiograph and more directly estimated by microscopic
airways rather than alveoli and which then are quickly examination of sputum. Canetti demonstrated that the bac-
removed by mucociliary clearance or killed. illary population of tuberculous lesions varies greatly,
Coughing is the most effective mechanism for generating depending on the morphology of the lesion.39 The number
aerosols that create droplet nuclei, but it is not the only of bacilli in solid nodular lesions ranges from 102 to 104
mechanism. Forced expiratory maneuvers other than organisms, whereas in cavitary lesions, populations are on
coughing—such as sneezing, yelling, singing, and loud the order of 107 to 109 bacilli. Loudon and Spohn,40 among
talking—all involve, to a greater or lesser extent, the sudden others, demonstrated that the prevalence of tuberculin
acceleration of air required to disrupt a liquid surface or reactors among young contacts of patients with newly dis-
mucous strands, thereby aerosolizing particles. Thin, covered tuberculosis increased as the radiographic extent of
watery secretions are more easily fragmented into small involvement increased. Thus, in tuberculosis control, the
respirable droplets than is more viscous mucus. In general, contacts of persons with more extensive tuberculosis should
the greater the volume of respiratory secretions, the greater be accorded a higher priority for evaluation than the con-
the number of potentially infectious droplets. Riley and tacts of persons with less severe disease.
coworkers34 demonstrated marked variability in the infec- The most direct means of estimating bacillary population
tious potential of tuberculosis patients that, in part, could is microscopic examination of properly stained sputum
be related to the severity of coughing. One patient with smears. An average viable bacillary population of 5000 to
exceptionally infectious tuberculosis not only had severe 10,000 organisms per milliliter of sputum is required for
pulmonary tuberculosis but tuberculous laryngitis as well. the organisms to be seen in an acid-fast-stained sputum
It was calculated that this patient was as contagious as a smear.41 The contacts of patients who have organisms
child with measles is to other susceptible children. Similar present in sputum smears have a much higher prevalence
studies by Escombe and coworkers,35 which described the of infection than do contacts of patients with negative
infectiousness of HIV-infected patients with tuberculosis, smears and either positive or negative cultures.42 However,
reported that infectiousness was very heterogeneous. Of 97 the contacts of sputum smear-negative patients may still
patients (118 admissions) hospitalized in an HIV- acquire tuberculous infection and develop tuberculosis.
tuberculosis ward, 10 caused 90% of the infections in Transmission from smear-negative patients was estimated
guinea pigs exposed to air exhausted from the ward. Of the to be the cause of approximately 17% of newly diagnosed
10 infectious patients, 6 had MDR tuberculosis that was cases in San Francisco.43
inadequately treated; in addition to having MDR tuberculo- A third important factor in determining the infectious-
sis, being sputum smear positive and being on suboptimal ness of a source case is the use of chemotherapy. In studies
treatment both contributed to the degree of infectiousness. designed to identify and quantify factors influencing trans-
Likewise, in a study of household contacts of tuberculosis missibility of M. tuberculosis, Sultan and associates44 and
patients, the likelihood of transmission was lower if the Riley and coworkers34 noted that patients who had positive
source case was HIV infected and had a CD4 T-cell count sputum smears but who were receiving antituberculosis
lower than 250/µL.36 In that study, the effect of HIV and drugs were much less infectious for guinea pigs than were
immunodeficiency was larger than could be explained by untreated patients. By their calculations, the relative infec-
differences in smear status, delayed treatment, or the pres- tiousness of untreated patients in comparison with treated
ence of cavitary lesions. Even when the bacillary load is patients was 50 : 1. Escombe and coworkers,35 as already
taken into account, there is substantial unexplained noted, came to a similar conclusion. Consistent with these
experimental observations, a substantial body of clinical persons,49 although immunocompetent persons have also
data has accumulated that indicates that, once treatment been involved.
to which the organisms are susceptible is begun, transmis- The operational implications of these assumptions con-
sion of M. tuberculosis decreases quickly. The quantification cerning infectiousness should be modified in accordance
of the infectiousness of cough-generated aerosols has with the patient’s living and working circumstances. The
shown the same result—that the major factor associated general principles of infection control entail an assessment
with persistent culture-positive aerosols was lack of effec- of the vulnerability to tuberculous infection of persons who
tive treatment during the previous week.37 The most will potentially be exposed and the consequences should
important mechanism by which chemotherapy reduces those who are exposed become infected.
infectiousness is the direct effect of the drug on the bacillary
population in the lungs. Hobby and associates41 found that, ENVIRONMENTAL FACTORS
after an average of 15.6 days of multidrug chemotherapy,
there was a reduction in the number of tubercle bacilli per The physical laws that apply to aerosolized particles,
milliliter of sputum of at least 2 logs, from approximately described in detail in Chapter 11 dictate that droplet nuclei
106 to approximately 104, or a 99% decrease. These data essentially become part of the environmental air; thus, envi-
are similar to those reported by Jindani and coworkers, who ronmental factors are of extreme importance in influencing
demonstrated a reduction in colony counts of nearly 2 logs transmission of tubercle bacilli. Studies by Loudon and asso-
per milliliter of sputum in the first 2 days of treatment and ciates50 showed that, under standard conditions of tempera-
a further reduction of 1 log during the next 12 days.45 Thus, ture and humidity indoors, 60% to 71% of aerosolized
in the initial 2 weeks of treatment, there was a decrease M. tuberculosis organisms survived for 3 hours, 48% to 56%
from approximately 107 to 104 organisms per milliliter of for 6 hours, and 28% to 32% for 9 hours. Apart from the
sputum, or a reduction of 99.9%. However, even with this natural death rate, the only factors influencing the infec-
profound reduction in the bacillary population, the remain- tiousness of organisms in a droplet nucleus under ordinary
ing number of organisms (10,000 per milliliter of sputum) circumstances are its removal by venting or filtering and the
would still be sufficient to produce a positive acid-fast death of the organisms from exposure to ultraviolet light.
sputum smear. In addition to reducing the number of viable Environmental factors may be manipulated to decrease the
bacilli, chemotherapy also promptly decreases coughing. concentration of tubercle bacilli, mainly removing them by
Loudon and Spohn40 noted that coughing was reduced by effective filtration, killing them with ultraviolet light, or
40% after 1 week of treatment and by 65% after 2 weeks. both.51 The influence of the concentration of organisms in
The sum of these effects is that, once a patient with tuber- environmental air in transmission of M. tuberculosis has
culosis is placed on effective therapy, transmission of tuber- been well illustrated in several microepidemics in which
cle bacilli ceases to be a concern. The decline in infectiousness recirculation of air played an important role. The most dra-
is caused mainly by the rapid reduction in bacillary popula- matic example happened on board a U.S. Navy vessel that
tion in the lungs as a result of antituberculosis chemother- had a closed, recirculating ventilation system.52 The index
apy, particularly isoniazid. Drug regimens that do not case had a positive sputum smear and a brisk cough. As a
include isoniazid probably should not be expected to render result of this one case, 53 of 60 persons (88%) in his berth
the patient noninfectious as rapidly as do those containing compartment acquired tuberculous infections and 6 devel-
isoniazid. Likewise, the prompt reduction in infectiousness oped tuberculosis. In a second compartment connected to
cannot be assumed in patients harboring organisms that the same ventilation system, 43 of 81 persons (53%) became
are resistant to isoniazid. infected and 1 developed tuberculosis. Smaller epidemics,
Different strains have different infectiousness. For one caused by a patient who underwent bronchoscopy in
example, strains of M. tuberculosis resistant to isoniazid may an intensive care unit, have been described.53
be less pathogenic than fully susceptible organisms.46,47 Since early in the 20th century, it has been known that
Molecular epidemiologic studies suggest that the mutation exposure to ultraviolet radiation kills tubercle bacilli. Riley
conferring resistance may have a role in the pathogenicity and coworkers,34 in their classic studies of infectiousness in
of M. tuberculosis, especially mutations associated with iso- a series of patients, demonstrated that ultraviolet irradia-
niazid resistance.48 Isolates harboring the most common tion of air passing through an air-conditioning duct com-
mutation, katG S315T and the inhA promoter 15c-t, were pletely eliminated transmission of M. tuberculosis to guinea
able to cause secondary cases of tuberculosis (defined as pigs housed beyond the ultraviolet lights. The major useful-
genotypic clustering of strains in a population). In contrast, ness of ultraviolet lights is for providing UV irradiation of
mutations in katG other than the common S315T muta- room air, using appropriately shielded lamps on the upper
tion did not cause secondary cases. Although more walls in hospital areas or clinics where patients with
information is necessary to confirm this association, this untreated tuberculosis are likely to be encountered. This is
finding may explain the different results regarding the especially important in open areas such as waiting rooms,
pathogenicity of some drug-resistant strains. It is also clear where ventilation may not be adequate to remove infectious
that the lesser pathogenicity can easily be offset by a pro- particles, and within ventilation systems.51
longed period of infectiousness, as might be expected with
ineffective treatment, as suggested by Escombe and associ- CIRCUMSTANCES OF EXPOSURE
ates,35 or with exposure of an immunocompromised host.
Outbreaks of tuberculosis caused by MDR and XDR strains The conditions of exposure have a major influence on the
of tubercle bacilli have taken place in hospitals or correc- number of infectious particles inhaled. If the exposure is of
tional facilities and disproportionately involve HIV-infected long duration and takes place under conditions that would
be associated with a high concentration of droplet nuclei in quantitative, not absolute, and can be overcome by suffi-
the air inhaled by the contact, there is obviously a greater cient exposure to especially virulent strains of bacteria.
likelihood of transmission. This is simply a restatement of There have been few efforts to identify the determinants
what has been known for many years: Crowding and inti- of resistance to acquisition of infection, although a recent
macy of contact are important determinants of transmis- study in a high-prevalence community in South Africa pre-
sion of M. tuberculosis.54 This is reflected in data from the sented evidence for at least one host genetic determinant
United States showing that rates of both clinical tuberculo- that influences the likelihood of acquisition of infection in
sis and tuberculin reactivity are much higher among close children. Genomewide linkage analysis of TST-unreactive
(generally household) than among nonclose (generally out- (zero-mm induration) and TST-reactive (greater than zero;
of-household) contacts. In general, the rate of tuberculosis median, 11.2-mm induration) children revealed evidence
is in the range of 15 per 1000 close contacts and 3 per of a major locus that maps to chromosome region 11p14.58
1000 nonclose contacts. Of close contacts, approximately The identity of the gene(s) at that locus, together with anal-
50% are infected, in comparison with approximately 15% ysis of the cellular distribution and regulation of expression
of nonclose contacts.55 Because the risk of tuberculosis is and the functions of the gene products, may reveal impor-
higher among close contacts, they should also be consid- tant mechanistic information on human resistance to
ered high-priority candidates for isoniazid preventive acquisition of infection with M. tuberculosis.
therapy. However, a number of studies using molecular epi- It is currently unclear whether HIV infection, which has
demiology to track transmission dynamics have shown that a major effect on progression to active tuberculosis, also
substantial transmission may take place outside the house- affects susceptibility to acquisition of infection.59
hold, particularly in social gathering places such as bars or
informal places where alcohol is consumed.56
PATHOGENESIS
HOST FACTORS
The genesis of the pathologic reactions in tuberculosis is
There is substantial evidence that susceptibility to acquisi- inextricably linked with the response of the host to the
tion of infection with M. tuberculosis is highly variable. Most invading tubercle bacillus. In most individuals infected with
descriptions of contact investigations report that 40% to M. tuberculosis, the host response—innate and adaptive—
60% of close contacts of an index case become infected, as restricts the growth of the pathogen, thereby containing
reflected by conversion of the tuberculin skin test (TST) or the infection.60 Paradoxically, however, the immunologic
interferon (IFN)-γ release assay from negative to positive. response to M. tuberculosis is likely responsible for the char-
Although variations in the intensity of exposure contribute acteristic presentation of tuberculosis.61 In contrast, the
to the likelihood of becoming infected, variations in host near absence of cell-mediated adaptive immunity in patients
susceptibility are also likely to contribute. Strong evidence with advanced HIV infection is assumed to be responsible
for variable susceptibility to acquisition of infection with M. for the atypical presentations of tuberculosis in HIV-infected
tuberculosis was provided by a prospective study of student patients. Such patients tend to have multisystem involve-
nurses in a tuberculosis hospital in Philadelphia in the pre- ment and tend not to have cavitary lung lesions.62 Although
chemotherapy era.57 In that study, in which student nurses the lack of immune response minimizes tissue damage, the
were assigned to rotations on the same tuberculosis wards, organism is not met with an effective protective response,
30% remained uninfected (TST unreactive) after 2 years of thus facilitating proliferation and dissemination of the
nursing school, indicating that despite repeated exposure, bacilli.
some of the student nurses were less susceptible to acquisi- Figure 35-3 describes schematically the events and out-
tion of infection than others. However, by the end of the comes that result from human exposure to M. tuberculosis.
third year of nursing school, 100% of the students had There are two phases: the acquisition of infection and the
become infected, indicating that resistance to infection is subsequent development of tuberculosis. Tuberculosis may
Continued
No infection (70%) containment (90%)
Adequate Adequate
Exposure to
infectious Innate immunity Containment (95%) Adaptive (T-cell)
particles immunity
Adequate
Inadequate
Inadequate
Infection (30%) Adaptive (T-cell)
immunity Late progression (5%)
Inadequate
Early progression (5%)
Figure 35-3 Consequences of exposure to an infectious source case of tuberculosis depending on the status of immunity. Exposure to a patient
with infectious tuberculosis causes tuberculous infection in approximately 30% of those exposed. Of those who are infected, 3% to 10% develop tuber-
culosis within 1 year of their becoming infected. Beyond 1 year, an additional 3% to 5% develop tuberculosis during the remainder of their lifetimes.
develop as direct progression from infection to disease (3% system to be discovered and is essential for virulence of M.
to 10% probability within 1 year of infection) or from late tuberculosis. This was first indicated by the discovery that all
progression many years after infection (up to 5% probability strains of BCG, the attenuated strain of M. bovis used as a
for the lifetime of an infected person after the first year of vaccine for tuberculosis, lack a functional ESX-1 system.73-75
infection).63 In HIV-infected populations, the rate of devel- Of the proteins secreted by the M. tuberculosis ESX-1 system,
oping disease is considerably higher.62 ESAT-6 and culture filtrate protein of 10 kD (CFP-10) are the
Although M. tuberculosis possesses many features in best characterized. These proteins are not present in BCG
common with other bacteria, unique characteristics that and, thus, confer specificity to IFN-γ release assays in the
are restricted to M. tuberculosis and its close phylogenetic diagnosis of latent tuberculous infection.
relatives are responsible for the distinct pathogenesis of Although multiple properties have been attributed to
tuberculosis. These unique features, principally consisting ESX-1–secreted proteins, the best characterized are their
of specific secreted proteins and biologically active complex effects on host membrane integrity. ESX-1–deficient bacte-
lipids, have been characterized by a combination of in vitro ria do not escape the phagosome72 and do not stimulate
studies, studies in experimental animals, and studies in host signaling pathways whose sensing mechanisms are in
humans. Together, these unique features account for much the cytoplasm,70 indicating that one target of the ESX-1
of the cellular, subcellular, and molecular pathogenesis of proteins is the phagosome membrane. ESX-1–deficient
tuberculosis. mycobacteria are also defective in cell-to-cell spread, most
likely because they are less able to cause host cell necrosis;
INTRACELLULAR TRAFFICKING OF with cell necrosis, bacteria are released to the extracellular
space, where they can access adjacent cells that support
MYCOBACTERIUM TUBERCULOSIS
subsequent rounds of bacterial replication.73,74,76,77 Studies
Seminal studies by Armstrong and D’Arcy-Hart and col- of the purified protein have directly implicated ESAT-6
leagues64,65 revealed that pathogenic mycobacteria survive in membrane perturbation. ESAT-6 has also been impli-
and replicate in host phagocytes, including macrophages, cated in stimulating epithelial cells to express matrix
by perturbing the normal pathway of phagosome matura- metalloproteinase-9, which promotes migration of unin-
tion that eventuates in fusion with lysosomes and killing fected macrophages to the region adjacent to dying infected
and digestion of other pathogens. Subsequent studies in macrophages when they release viable bacteria, thus sus-
basic cell biology have revealed that phagolysosome forma- taining the infection cycle.78
tion follows an ordered series of interactions between M. tuberculosis possesses five type VII secretion systems,
phagosome membrane proteins and phospholipids, relying of which ESX-1 is the best characterized. Of the remainder,
on proteins that regulate intracellular traffic. One of these ESX-3 is essential for survival of M. tuberculosis79 and con-
regulatory proteins, a low-molecular-weight GTPase termed tributes to pathogenesis; it is responsible for secretion of the
Rab7, is essential for the late step of phagosome acquisition protein, EsxH (also known as Tb10.4), which interferes
of lysosomal constituents; M. tuberculosis disrupts recruit- with the host ESCRT pathway68 and is also a frequent target
ment of Rab7 to the phagosome membrane.66 Normal traf- for recognition by T cells of people infected with M.
ficking also requires conversion of phagosome membrane tuberculosis.
phosphatidylinositol to phosphatidylinositol-3-phosphate;
virulent mycobacteria also interfere with this essential step INDUCTION OF TYPE I INTERFERONS
by mechanisms that remain incompletely defined. Together,
these mechanisms allow M. tuberculosis to survive and rep- An important aspect of tuberculosis pathogenesis is the
licate intracellularly. Recent studies have revealed an addi- induction of type I IFN (IFN-α and/or IFN-β) secretion.
tional requirement for the ESCRT (Endosomal Sorting Whole blood transcriptome analysis to discover human
Complex Required for Transport) pathway of intracellular genes that are differentially expressed in tuberculosis
vesicle trafficking in phagosome maturation,67 and there is revealed a transcriptional signature dominated by IFN-
strong evidence that EsxH, a protein secreted by M. tuber- responsive genes,80 and this finding has been replicated
culosis, disrupts the ESCRT pathway.68 In addition, the in additional patient cohorts.81-83 The strength of the IFN
autophagy system, originally characterized for its role in transcriptional signature correlates with the extent of
degradation of endogenous cellular proteins and organ- disease, and the transcriptional signature is rapidly reversed
elles, has received considerable attention for its role in with effective chemotherapy.84 Whether type I IFN plays a
restricting growth of intracellular mycobacteria,69 espe- pathogenic role or is a secondary effect of active tuberculosis
cially after stimulation of cells by the cytokine, IFN-γ. in humans remains to be defined. However, in mice, there
However, M. tuberculosis employs mechanisms to evade is evidence that type I IFNs play a pathogenic role in M.
autophagy, including disruption of the phagosome mem- tuberculosis infection,85 at least partially by enhancing
brane, giving the bacteria access to the host cell recruitment of mononuclear cells that support intracellular
cytoplasm.70-72 Thus, M. tuberculosis can occupy several dis- bacterial replication.86,87 In addition, type I IFNs limit
tinct intracellular niches: immature phagosomes, autopha- expression of interleukin (IL)-1-β, a cytokine that is essen-
gosomes, and the cytoplasm. tial for control of M. tuberculosis.88,89 A link between viru-
lence and induction of a host-detrimental type I IFN
response has been established by the observation that intact
ESX-1 PROTEIN SECRETION SYSTEM
ESX-1 secretion and phagosome permeabilization are
The early secreted antigen 6 kilodaltons (ESAT-6) secretion required for M. tuberculosis induction of type I IFN expres-
system 1 (ESX-1) was the first bacterial type VII secretion sion.70,71 Despite the growing evidence for a detrimental role
of type I IFNs in tuberculosis, therapeutic administration of the bacterial population.76 In addition, intravital micros-
type I IFN for multiple sclerosis or hepatitis C has not been copy has revealed that macrophages and lymphocytes in
accompanied by a striking increase in the frequency of granulomas are dynamic, with lymphocytes freely migrat-
active tuberculosis. ing between the apparently closely apposed macrophages.99
Together, these studies and others indicate that granulomas
are dynamic structures that may benefit either the patho-
BIOLOGICALLY ACTIVE MYCOBACTERIAL LIPIDS
gen or the host, depending on the stage of infection.
M. tuberculosis has long been known to be rich in lipids,
including mycolic acids that possess acyl chains containing MODULATION OF APOPTOSIS
up to 90 carbons. However, rather than being a mere “waxy
coat” that acts as a barrier to drugs and other polar mole- As a facultative intracellular pathogen, M. tuberculosis
cules, mycobacterial lipids interact directly with the host to shapes its environment to optimize its survival and growth.
contribute to pathogenesis. One mechanism is to inhibit apoptosis (programmed cell
Trehalose dimycolate (TDM), an abundant cell wall lipid death) and prolong the life of infected cells, allowing
traditionally known as mycobacterial “cord factor,” modu- the bacteria to grow to a larger population size in each
lates innate immune and inflammatory responses to M. infected cell before spreading to adjacent cells.100 There
tuberculosis and is sufficient to induce transient granuloma are other benefits to M. tuberculosis from inhibiting apop-
formation when injected into experimental animals. Defi- tosis. Because uptake of apoptotic cell fragments by naive
ciency of TDM decreases pathogenicity of a mutant strain macrophages results in killing of the bacteria formerly
of M. tuberculosis experimental animals,90 indicating that residing in an apoptotic cell, inhibition of apoptosis allows
the responses induced by TDM favor the bacteria. TDM is M. tuberculosis to evade this mode of death.101 Because
recognized by two related C-type lectin receptors, termed bacterial antigens associated with apoptotic cell fragments
Mincle (also termed Clec4e)91 and MCL (also termed are subject to uptake and “cross-presentation” to CD8 T
Clec4d),92 expressed on macrophages and dendritic cells, cells, inhibition of apoptosis of the infected cells minimizes
which transduce signals that result in proinflammatory the frequency of CD8 T-cell activation.102 Evidence that
cytokine production. inhibition of apoptosis is a virulence mechanism in animal
Other complex mycobacterial lipids contribute to patho- models of tuberculosis is provided by the findings that
genesis by mechanisms that remain under investigation. proapoptotic mutants of M. tuberculosis are less pathogenic
Phthiocerol dimycocerosate (PDIM) is present in all clinical in vivo.103
isolates examined, despite its frequent loss during serial
passage of M. tuberculosis in liquid culture; the persistence PHYLOGENETIC LINEAGE- AND STRAIN-
of PDIM in clinical isolates implies that it is essential for
DEPENDENT VARIATION IN PATHOGENESIS
pathogenesis but dispensable in culture.93 PDIM-deficient
mutants are less pathogenic than PDIM-replete bacteria in As noted earlier, use of high-resolution genotyping methods
mice94,95; PDIM masks the molecules recognized by Toll-like has recently revealed genetic diversity in the M. tuberculosis
receptors and dampens initial inflammatory responses.96 complex. This has provided a basis for comparative studies
The structurally related lipoglycans, phosphatidylinositol to understand the phenotypic consequences of genetic
mannans (PIMs) and lipoarabinomannan (LAM), are impli- diversity. For example, M. africanum, which represents a dis-
cated in specific interactions with the host. PIMs can stimu- tinct genetic lineage of the M. tuberculosis complex and is
late innate immune and inflammatory responses by serving endemic in West Africa, compared with strains of other
as agonists for Toll-like receptor-2 (TLR2),97 and studies with lineages, is less pathogenic at specific steps in the infection
LAM-coated beads have indicated a potential role for LAM cycle. It is transmitted as readily as members of other lin-
in altering phagosome maturation.98 eages, but the progression to disease is less frequent than
other lineages.20 Yet once active tuberculosis develops with
M. africanum, it is clinically indistinguishable from tubercu-
GRANULOMAS
losis due to other lineages. Evidence that these findings are
Granulomas, consisting of aggregates of macrophages, not strictly attributable to host population differences is pro-
often including multinucleated giant cells and “epithelioid” vided by finding that M. africanum is also less pathogenic in
macrophages together with variable numbers of lympho- inbred mice.104 As another example, a subfamily of the
cytes, are a pathologic hallmark of tuberculosis. Granulo- Beijing family has been found to be more readily transmit-
mas can also contain variable numbers of necrotic cells and ted than other strains in the same community and causes
microscopic and macroscopic necrotic centers; some also more severe disease in experimentally infected guinea
exhibit caseating necrosis (characterized by complete loss of pigs.22,23 These examples provide evidence for intrinsic
tissue structure and a texture resembling soft cheese) and differences in strains of M. tuberculosis and indicate that
may become calcified. Granulomas have been traditionally studies linking epidemiology and pathogenesis (using
considered to be host-protective structures, thought to animal models) can provide complementary information.
“wall off ” bacteria and keep them from disseminating.
Whereas this view may apply in later stages of fibrotic and LATENCY/DORMANCY AND REACTIVATION
calcified granulomas, early granuloma formation actually
promotes infection by facilitating cell-to-cell spread within One of the most important characteristics of tuberculosis
the macrophage aggregates, thus optimizing expansion of is the state of latent infection, which develops in the
majority of infected humans, with the ability to reactivate

and cause active, transmissible disease. Although host Innate Immune Cells in Tuberculosis
factors (described later) contribute to establishing and M. tuberculosis interacts with diverse cell types. Macro-
maintaining the latent state, the bacteria also possess highly phages have been the longstanding target of attention, ever
evolved mechanisms that are involved in latency and reac- since the studies of Florence Sabin and colleagues112,113 in
tivation. A considerable amount of recent work has focused the 1920s revealed that tubercle bacilli dwell in mononu-
on certain M. tuberculosis genes in which expression is clear cells. Although alveolar macrophages are widely
induced by hypoxia, and which are believed to be involved believed to be the initial cells to encounter M. tuberculosis
in latency (modeled as bacterial dormancy, wherein most of after inhalation of small droplet nuclei, the inflammatory
the bacterial population is not actively dividing). One group macrophages recruited to the site of infection from the
of genes whose expression is controlled by the transcription blood are likely to be the major reservoirs of the bacteria.
factor, dosR, is induced transiently by hypoxia, while other In addition, neutrophils114-116 are increasingly recognized
genes, collectively termed the Enduring Hypoxic Response, as having important roles as cellular sites of infection and
are under alternative regulation.105,106 Together with evi- contributors to innate immune responses in tuberculosis.
dence that reoxygenation reverses the changes in gene In close contacts of pulmonary tuberculosis cases, a lower
expression, these findings provide a paradigm for under- neutrophil count was associated with a higher likelihood of
standing how M. tuberculosis can reversibly adapt to its acquiring infection, and neutrophils contributed to killing
environment and alter its metabolic and growth state. Evi- of M. tuberculosis in an in vitro whole blood assay.116 Den-
dence that such mechanisms operate during latent tuber- dritic cells have also been shown to contain M. tuberculosis
culosis infection in humans is provided by the finding that both in humans and experimentally infected mice117,118;
T-cell responses to proteins encoded by these “dormancy” these cells serve as the dominant source of the cytokine
genes are more common in individuals with latent infection IL-12, and they transport tubercle bacilli from the lungs to
than in those with active tuberculosis.107,108 the local draining lymph nodes, where antigen-specific
The contributions of bacterial determinants to reactiva- T-cell responses are initiated.119 Mononuclear phagocytes,
tion of latent infection are less well understood than are especially dendritic cells and cytokine-activated macro-
those associated with latency. However, the M. tuberculosis phages, are also specialized to present mycobacterial anti-
genome encodes 5 proteins with homology to a family of gens for recognition by CD4+ T cells.
“resuscitation promoting factors” (RPFs) characterized in M. tuberculosis enters macrophages, dendritic cells, and
other bacteria for their ability to stimulate growth of bacte- neutrophils by undergoing phagocytosis, using any of mul-
ria from stagnant cultures. Although RPFs in other bacteria tiple distinct receptors that recognize ligands expressed on
may act in interbacterial communication, the M. tuberculo- the bacteria.120 In addition to phagocytic receptors, specific
sis RPFs characterized to date are peptidoglycan glycosi- components of the bacteria are recognized by pattern-
dases and appear to be involved in remodeling of the cell recognition receptors including TLR 2, 4, and 9; NOD2;
wall. Mutant strains of M. tuberculosis in which the genes DC-SIGN; Dectin-1; Mincle; and MCL.121 These receptors
encoding RPFs have been deleted are defective for reactiva- do not mediate phagocytosis but initiate signaling that
tion in animal models,109-111 suggesting that RPFs may con- results in secretion of specific proinflammatory and anti-
tribute to progression from latent to active tuberculosis in inflammatory cytokines, as well as cell activation and
humans. differentiation.
In addition to mononuclear and polymorphonuclear
phagocytes, certain innate lymphocytes, including natural
IMMUNITY killer T (NKT) cells and at least two subsets of innate T
lymphocytes, respond to M. tuberculosis infection122 and
Countering the highly evolved pathogenetic mechanisms of are believed to be a source of cytokines early after infec-
M. tuberculosis are the host responses that limit progression tion, before adaptive immune responses are activated. NKT
from infection to disease. Although the mechanisms that cells recognize host molecules expressed on stressed cells
determine whether an exposed individual will become while invariant NKT cells recognize complex host and
infected or not (see Fig. 35-3) have not yet been identified, foreign lipids bound to the HLA class I–related molecule,
the mechanisms that determine the outcome after infection CD1d. In vitro studies indicate that invariant NKT cells
are increasingly well understood. can be activated to secrete IFN-γ and granulysin and
restrict growth of intracellular M. tuberculosis.123 Invariant
INNATE IMMUNITY TO NKT cells are depleted from the blood in patients with
active tuberculosis, indicating that they are involved in
the response to M. tuberculosis in vivo.124,125 Mucosal-
Innate immunity includes cellular and humoral defenses Associated Invariant T cells (MAITs) recognize bacterial
that do not depend on clonal rearrangement of antigen metabolites of B vitamins, bound to an HLA class I–like
receptor genes, the defining feature of acquired immunity molecule termed MR1, and are activated by cells infected
as carried out by B and T lymphocytes. Although innate with M. tuberculosis or certain other bacteria.126,127 Their
immune responses play an important role in tuberculosis, abundance and location suggest that MAITs may be
evidence from studies in individuals with HIV and in animal involved in clearance of M. tuberculosis inhaled in droplet
models have established that innate immunity is insufficient nuclei that are too large to reach the alveoli. MAITs are
for control of M. tuberculosis infection. depleted from blood in people infected with HIV, most likely
through an indirect effect, and are not fully reconstituted replication through induction of the antibacterial peptide,
with antiretroviral therapy.128,129 cathelicidin.147,148 Additional studies have revealed that
vitamin D is essential for the antimycobacterial action of
Molecular Mediators of Innate Immunity IFN-γ on human macrophages, acting through induction of
in Tuberculosis cathelicidin and activation of autophagy.139 So far, attempts
Macrophages and dendritic cells respond to M. tuberculosis to augment the effects of chemotherapy for tuberculosis by
by secreting cytokines with distinct activities that contrib- the addition of vitamin D have had limited effects on micro-
ute to control of infection and regulate specific aspects of biological end points145 but clearly accelerate the resolution
immunity. Of the cytokines induced by M. tuberculosis, of inflammation.149
tumor necrosis factor (TNF) is especially well characterized
as essential for immunity to tuberculosis in humans. ADAPTIVE IMMUNITY TO
Patients with rheumatoid arthritis and other conditions
that are treated with agents that block TNF activity have up
to a 25-fold higher risk of tuberculosis than in control pop- Early studies of the mechanisms of immunity to mycobac-
ulations130 and are more likely to have disseminated infec- teria found that adoptive transfer of cells, but not serum,
tion.131 The risk of tuberculosis is higher in patients treated conferred cutaneous hypersensitivity to tuberculin on the
with neutralizing antibodies to TNF than with soluble recipients.150 This initial observation was followed by studies
receptor analogues.130 TNF contributes to immunity to that revealed that cell transfer also improved the ability to
tuberculosis by activating microbicidal activities of macro- control mycobacteria151-153 and that the responsible cells
phages132 and by modulating death of infected cells.132-134 were T lymphocytes.154 Thus, the focus of immunology
In addition, one of the antibodies to TNF, infliximab, when studies in tuberculosis has been on T cells rather than
administered to patients with rheumatoid arthritis, depletes antibodies.
a specific subset of CD8+ T cells that contain membrane-
bound TNF and contribute to killing intracellular M. tuber- CD4+ T Cells
culosis in an in vitro assay.135 CD4+ T cells are essential for immunity to tuberculosis. In
IFN-γ plays an essential role in immune control of tuber- mice, depleting CD4+ cells or impairing their development
culosis. IFN-γ-deficient136,137 or IFN-γ receptor-deficient87 (by deleting MHC class II molecules, which bind antigenic
mice succumb to rapidly progressive M. tuberculosis infec- peptides and are essential for development of CD4+ T cells)
tion and, in patients with IFN-γ receptor mutations, tuber- markedly accelerates the lethal course of infection.155 In
culosis is especially clinically severe (disseminated and/or humans coinfected with HIV, the progressive depletion of
recurrent).138 IFN-γ is believed to contribute to immune CD4+ cells increases the risk of tuberculosis and reconstitu-
control of tuberculosis through activating the microbicidal tion of CD4+ T cells by antiretroviral therapy reduces the
activities of macrophages, including through autoph- risk of tuberculosis.62 In addition to increased risk of tuber-
agy,139,140 and by modulating inflammation at the site of culosis per se, profound depletion of CD4+ T cells by HIV
infection.87,141 Although multiple cell types can be sources alters the clinical manifestations, with a higher frequency
of IFN-γ, the principal cellular sources are lymphocytes, of extrapulmonary disease and a lower frequency of cavi-
including innate T cells, as well as adaptive CD4+ and CD8+ tary lung lesions.62
T cells. Although the principal function of CD4+ T cells is to
Interleukin-12 (IL-12) is another essential innate cyto- secrete cytokines such as IFN-γ, TNF, IL-2, IL-4, IL-17, or
kine for immunity to tuberculosis. The best-characterized IL-22, some CD4+ T cells also possess cytolytic activity and
role of IL-12 is in directing differentiation of CD4 T cells can kill M. tuberculosis–infected cells.156 Several studies
into type 1 T helper (Th1) cells that secrete IFN-γ and con- have revealed that multifunctional CD4+ T cells (which
tribute to control of tuberculosis (see later). Evidence that produce multiple distinct cytokines per cell) are more
IL-12 is essential for control of tuberculosis is provided by common in subjects with latent TB infection, while mono-
experiments in IL-12-deficient mice142,143 and by observa- functional CD4+ T cells (which produce only one cytokine,
tions that children with mutations in the IL-12 receptor usually TNF) are more common in those with active tuber-
beta-1 chain are susceptible to tuberculosis and other culosis.157,158 Together, these findings indicate that multi-
mycobacterial infections.144 functional T cells may be especially important in preventing
Finally, vitamin D has been shown by increasingly strong progression from latent to active tuberculosis.
evidence to contribute to human immunity to tuberculosis.
Vitamin D and tuberculosis share a long history; indeed, CD8+ T Cells
some believe that if there was a benefit of sanatoria, it may Patients also develop antigen-specific CD8+ T-cell responses
be attributable in part to “heliotherapy,” exposure to sun- in tuberculosis. Although the functional contribution of
light, causing activation of vitamin D. More pertinent is CD8+ T cells in human tuberculosis is not well defined, CD8+
that multiple studies have found low serum vitamin D levels T cells contribute to control of M. tuberculosis in experimen-
in patients with tuberculosis (reviewed in Martineau145). tally infected cattle and mice.159 Evidence for a functional
Moreover, a prospective study found that household con- role of human CD8+ T cells in tuberculosis is provided by
tacts of persons with infectious tuberculosis were more the discovery that treatment of patients with rheumatoid
likely to progress to active disease if they were vitamin D arthritis with the anti-TNF antibody, infliximab, increases
deficient at baseline.146 In vitro studies have demonstrated the risk of tuberculosis and depletes a specific subset of
that vitamin D treatment of M. tuberculosis–infected human CD8+ T cells that contribute to killing of M. tuberculosis in
macrophages leads to restriction of intracellular bacterial vitro.135 M. tuberculosis antigen-specific CD8+ T cells are
detected more frequently in active tuberculosis than during the antigenic targets in other pathogens), implying an evo-
latent infection,160 suggesting that CD8+ T cells principally lutionary benefit to the bacteria from T-cell recognition.14
respond when the bacterial burden is especially high.161 These results suggest that T-cell responses to M. tuberculosis,
which provide a benefit to infected people, can also benefit
Mycobacterium Tuberculosis Antigens Recognized the bacteria by promoting pathology in a fraction of infected
by Human T Cells people, resulting in enhanced transmission. This finding
Classical T cells recognize peptide fragments of proteins may guide tuberculosis vaccine antigen selection and
(including from bacteria), bound to MHC (HLA in humans) emphasizes the need to evaluate the potential adverse
class II (CD4+ T cells) or class I (CD8+ T cells) molecules on effects of new tuberculosis vaccines.
dendritic cells and macrophages. Although most studies
have focused on a restricted number of secreted M. tubercu- EXOGENOUS VERSUS ENDOGENOUS INFECTION
losis antigens, emerging evidence indicates that a broad
range of mycobacterial proteins can provide peptide frag- One of the historical controversies in tuberculosis has been
ments (epitopes) that bind HLA class II molecules and are the extent to which tuberculosis can be attributed to new
recognized by CD4+ T cells of people infected with M. infection by recently inhaled exogenous organisms (i.e.,
tuberculosis.162 from the environment) as opposed to a reactivation of viable
In addition to providing protection against active disease, bacilli that have been maintained for many years in a
T-cell responses to M. tuberculosis antigens are the basis dormant or growth-restricted state within the body.171
for TST and for IFN-γ release assays (IGRA, such as This concept is important in that current tuberculosis
Quantiferon-TB and T-SPOT.TB). As noted in a separate control efforts are based largely on the idea that most tuber-
section, the enhanced specificity of IGRAs over TSTs for culosis in low-incidence areas is the result of endogenous
M. tuberculosis infection is due to the use of two antigens reactivation. Thus, prevention entails identification of
(ESAT-6 and CFP-10) that are present in all strains of infected persons and giving them preventive therapy with
M. tuberculosis and uniformly absent from BCG vaccines. isoniazid.
Insight into another potential basis for discordant results Since the early 1990s, genotyping of M. tuberculosis has
between TSTs and IGRAs is provided by the identification been successfully used to determine if tuberculosis is due to
of antigens present in the purified protein derivative (PPD) exogenous or endogenous infection. M. tuberculosis DNA
used for TSTs. PPD is dominated by the presence of M. tuber- fingerprinting derived from different genotyping markers
culosis chaperone proteins (termed GroES, GroEL2, HspX, and methods has been used to track specific isolates of M.
and DnaK), and contains little ESAT-6 or CFP-10.163 There- tuberculosis in a community.172 For example, isolates of
fore, these diagnostic tests, in addition to depending on dif- tubercle bacilli from HIV-positive individuals, in health care
ferent procedures, measure responses to different bacterial facilities or correctional institutions, frequently show iden-
antigens. tical genotypes (Fig. 35-4), indicating that these individuals
CONTRIBUTIONS OF IMMUNE RESPONSES TO

M. intracellulare
M. bovis BCG
TUBERCULOSIS PATHOLOGY
Tuberculosis is a prime example of an infection in which
immune responses clearly contribute to the pathology of Patient number
the disease, suggesting that the balance between protection 1 2 3 4 5 6 7 9 10 11 12 13 14 kb
and pathology requires tight regulation. For example, treat- –23
ment with immunosuppressive corticosteroids predisposes
to tuberculosis,164 can mask the symptoms and reduce the –9.4
radiographic manifestations of pulmonary tuberculosis,165 –6.6
and prevents mortality in some patients with tuberculous
–4.4
meningitis.166,167
Analogous to autoimmune diseases such as type 1 diabe-
tes mellitus and multiple sclerosis, T-cell responses can con-
–2.3
tribute to tissue destruction in tuberculosis. In mice –2.0
selectively lacking PD-1, a molecule that transmits inhibi-
tory signals in T cells, M. tuberculosis infection is rapidly –1.3
lethal, due to excessive CD4+ T-cell activation and very high –1.1
levels of proinflammatory cytokines.168 In humans coin- –0.8
fected with HIV, the frequency of cavitary lesions on chest
radiographs is directly correlated with the CD4+ T-cell count
Figure 35-4 Gel electrophoresis of DNA extracted from organisms iso-
at the time of diagnosis of tuberculosis.62 Since cavitary lated from patients in an outbreak of tuberculosis in San Francisco.
tuberculosis causes more secondary cases than noncavi- Cases 3 through 14 were linked epidemiologically, whereas cases 1 and 2
tary tuberculosis,169,170 mycobacterial induction of detri- were not. This is an example of the use of restriction fragment length poly-
mental T-cell responses may benefit the bacteria by morphism analysis to track strains of Mycobacterium tuberculosis. (From
Daley CL, Small PM, Schecter GF, et al: An outbreak of tuberculosis with accel-
promoting transmission. Examination of the human T-cell erated progression among persons infected with the human immunodefi-
epitopes in diverse strains of M. tuberculosis revealed a high ciency virus: an analysis using restriction fragment length polymorphisms. N
level of sequence conservation (rather than variation, as in Engl J Med 326:231–235, 1992.)
were probably infected by the same source within the facil- remaining bacterial population has shifted to a state of per-
ity.59,173 In such situations, tuberculosis can be assumed to sistence and slow replication. Understanding how this
be due to a recent exogenous infection with rapid progres- latent infection can shift to disease is critical in controlling
sion to active tuberculosis. In contrast, patients with a tuberculosis.
unique DNA fingerprint are considered to have tuberculosis Age is one risk factor. Among persons with tuberculous
due to reactivation of latent infection acquired previously. infection, case rates vary markedly with age. Rates are con-
Genotyping methods can similarly be used to differentiate siderably increased in infants and relatively increased in
relapse from reinfection in a patient with recurrent tuber- adolescents and young adults.190 The reasons for the varia-
culosis: a patient with relapse will have a similar M. tuber- tions are not fully understood but are likely to relate to age-
culosis DNA fingerprint in both episodes while a patient with dependent influences on the effectiveness of the immune
reinfection will have different strains.174-177 Since the early response.191
1990s, these markers have also enabled tuberculosis control HIV infection is by far the most potent risk factor world-
programs, mainly in high-income settings, to track specific wide. In the era before effective antiviral therapy, Selwyn
isolates of M. tuberculosis in a community172 to determine and coworkers192 found that 8 of 212 HIV-infected intrave-
population-level risk factors for transmission, establish tai- nous drug users developed tuberculosis in a 2-year period
lored public health strategies, and gauge the success of of observation, a case rate of 8 per 100 person-years of
control measures.178 observation. Of these, 7 cases developed within a subset of
The genetic markers used to track strains in the commu- 49 persons who were known to be TST positive. Thus, the
nity are sufficiently polymorphic to distinguish among case rate for persons who were dually infected with both
unrelated isolates yet stable enough to recognize isolates HIV and M. tuberculosis was 7.9 per 100 person-years,
that are part of the chain of transmission. These markers which exceeds the rate in a population with tuberculous
include (1) the insertion element (IS) 6110,179 (2) the poly- infection without HIV infection. It also appears that the risk
morphic GC-rich repetitive sequences (PGRS), (3) polymor- of rapid progression of tuberculosis among persons who
phisms in the clustered regularly interspaced short palindromic are infected with HIV and who then become infected with
repeats (CRISPRs),180 and (4) the mycobacterial interspersed M. tuberculosis is tremendously increased, as has been dem-
repetitive unit (MIRU)–variable number tandem repeats onstrated in descriptions of two such outbreaks.59,193 The
(VNTRs).181 The genotypes using CRISPR (also known as reported rates of tuberculosis in cohorts of persons with
spoligotypes) and MIRU-VNTR (MIRU-type) are currently HIV infection vary widely and depend on the prevalence of
widely used to track a strain in the community. For both tuberculosis in the environment, particularly the presence
methods, there are online databases in which researchers of infectious cases; the frequency with which treatment for
can compare (and submit) their genotypes.182,183 Most latent tuberculous infection is used; the severity of immune
recently, the availability of high-throughput technology compromise within the HIV-infected group; and whether
and the dramatic decrease in costs have allowed for the use dually infected persons are receiving antiretroviral therapy,
of whole genome sequencing to identify mutations as which substantially reduces the risk.194,195
markers to study transmission of M. tuberculosis in a The only study conducted to address the incidence of
community.184-189 Compared with the other genetic tuberculosis prospectively in a broad-based group of persons
markers, whole genome sequencing allows the identifica- with HIV infection in the United States—before the wide-
tion of microevolutionary events (i.e., single nucleotide spread use of combined antiretroviral therapy—was the
polymorphisms) within a chain of transmission, identifies Pulmonary Complications of HIV Infection study.196 In this
epidemiologic links, and determines the directionality of cohort, drawn from six centers across the country, the rate
the transmission events. of tuberculosis was 0.71 per 100 person-years of observa-
tion. In multivariate analyses, the factors that were associ-
ated with increased rates were residence in New York City
RISK FACTORS FOR DISEASE or Newark (the two East Coast centers), being TST-positive
(reaction > 5 mm), and having a CD4+ cell count below 200
After acquiring an infection, not all persons are at equal risk cells/µL.
of developing disease. Many conditions increase the likeli- Antiretroviral treatment of HIV markedly reduces the
hood of tuberculosis and serve as markers of increased risk. incidence of tuberculosis, although the effect is not com-
As noted previously, in healthy populations, the risk of plete. A meta-analysis that included 11 published studies
developing tuberculosis is highest during the first year after revealed that antiretroviral treatment and reconstitution of
infection; between 3% and 10% of newly infected persons CD4+ T-cell counts reduces the incidence of tuberculosis as
develop tuberculosis during this period. The three factors much as sixfold.197 However, despite immune reconstitution
presumably involved are the pathogenicity of the bacterial to CD4 T-cell counts greater than 700 cells/µL, the inci-
strain, the dose of bacilli implanted in the lungs, and the dence of tuberculosis in antiretroviral-treated HIV-infected
adequacy of the host response in countering the invasion. people remains 4.4-fold higher than in HIV-uninfected
The “inoculum effect” (in which the likelihood of infection people in the same community.198
is directly related to the dose of bacteria) has not been In persons with both HIV and tuberculous infections,
clearly demonstrated in humans but is strongly suggested antiretroviral therapy and preventive treatment with iso-
by results of animal experiments.34 It is currently assumed niazid substantially decrease the incidence of tuberculosis.
that beyond the first year after infection has taken place, In a retrospective analysis of the incidence of tuberculosis
the immune response has fully developed, the number of among persons with HIV infection in Rio de Janeiro,
organisms present has been substantially reduced, and the Brazil, among patients who received neither antiretroviral
treatment nor isoniazid preventive therapy, the incidence of persons who have had a gastrectomy or an intestinal bypass
tuberculosis was 4/100 person-years.199 Among patients procedure for weight control.209 Body build has also been
who received antiretroviral therapy, the incidence was related to the risk of disease among infected persons. In U.S.
1.9/100 person-years (95% confidence interval [CI], 1.7 to Navy personnel, rates of tuberculosis were nearly three
2.2), and those treated with isoniazid had a rate of 1.3/100 times greater among men who were thin for their height;
person-years (95% CI, 0.4 to 3.0). However, the incidence the increased incidence of tuberculosis did not appear to be
among patients who received both antiretroviral therapy related to nutritional status in that group.207
and isoniazid was only 0.8/100 person-years (95% CI, 0.3 Vitamin D deficiency has also been linked to tuberculosis.
to 1.5). Thus, there was a 76% reduction in tuberculosis Studies on several continents have documented a higher
risk among patients receiving both antiretroviral treatment frequency of vitamin D deficiency in patients with active
and isoniazid. (Isoniazid preventive therapy is discussed in tuberculosis than in control subjects. Moreover, a study
a later section.) in South Africa revealed reciprocal seasonal variations
Inhibition of TNF is the other well-characterized risk in serum vitamin D levels and tuberculosis notification
factor for tuberculosis. TNF can be antagonized by treat- rates: during the winter, vitamin D levels were lowest
ment with a biologic agent, either with a monoclonal anti- and tuberculosis notifications were greatest, whereas
body to TNF itself or soluble receptor analogues that block the converse was true in the summer.210 Because in vitro
the interaction of TNF with its receptor. As mentioned, TNF studies have revealed a role for vitamin D in regulating mac-
contributes to immunity to tuberculosis by activating rophage expression of antimicrobial peptides that restrict
microbicidal activities of macrophages132 and by modulat- intracellular growth of M. tuberculosis, it is likely that
ing apoptosis.132,133 Patients treated with TNF antagonists vitamin D deficiency increases the risk of tuberculosis,
have up to a 25-fold higher risk of tuberculosis than in rather than for vitamin D deficiency to be a consequence of
control populations.130 Neutralizing antibodies to TNF tuberculosis.
increase the risk several fold more and induce tuberculosis Despite the number of risk factors for tuberculosis that
sooner than the soluble receptor analogues.200 This may be have been identified, the majority of cases have no identified
in part because antibodies to TNF also deplete a subset of immunological or physiological abnormality.
CD8+ memory T cells that contribute to killing intracellular
M. tuberculosis in an in vitro assay.135 Screening patients by
TST, followed by treatment of latent tuberculosis infection
before initiation of TNF antagonists, reduces the risk of DIAGNOSIS OF LATENT
active tuberculosis in these patient populations.201 TUBERCULOSIS INFECTION
Other conditions or therapies that interfere with cell-
mediated immunity also increase the risk of tuberculosis. As indicated previously, infection does not necessarily follow
These relationships, although well described and generally exposure to M. tuberculosis, but when infection develops, it
accepted, are poorly quantified. Examples of these disor- causes a cell-mediated immune response that can be identi-
ders include hematologic malignancies and cancer chemo- fied by a positive response to an intradermal test (TST) with
therapy. In addition, conditions such as diabetes mellitus202 purified protein derivative or a whole blood IFN-γ release
and uremia are thought to fit into this general category of assay (IGRA). Until recently the TST was the only test avail-
risk-enhancing diseases, although the basis for this effect is able to identify tuberculous infection. Although the TST
not established. The risk of tuberculosis is also increased continues to be used, IGRAs are widely used in high-
considerably in persons with silicosis,203 presumably owing resource settings.211-213
to the effect of silica on the function of pulmonary
macrophages. TUBERCULIN SKIN TEST
Genetic risk factors had been suggested by twin studies in
which there was a greater concordance of disease in mono- Tuberculin was first prepared by Robert Koch in 1890 and
zygotic than in dizygotic twins.204 However, it is difficult to was touted by him as being therapeutic for tuberculosis.
separate them from linked environmental factors. Case Shortly thereafter, the diagnostic capabilities of the mate-
rates among persons infected with M. tuberculosis living in rial were recognized through its use in animals. In 1934,
Denmark in the 1950s were only 28 per 100,000 per Seibert and Glenn214 prepared the first batch of a much
year.205 This contrasts strikingly with annual rates of 1500 more purified preparation, which they termed purified
to 1800 per 100,000 in Eskimo populations in Alaska and protein derivative (PPD). The most prevalent antigenic pro-
Greenland.206 Genetic differences are also suggested by the teins in PPD are now known to be the bacterial heat shock
pattern of tuberculosis noted among Filipinos in the U.S. proteins (or chaperonins) GroES, GroEL2, HspX, and
Navy, whose rate of disease increased with duration of DnaK.163 The antigen is prepared in liquid form containing
enlistment, in contrast to the decrease observed in blacks the detergent Tween 80 to decrease adsorption of protein
and whites.207 to the glass of the vial. The standard intermediate tubercu-
Undernutrition is known to interfere with cell-mediated lin test consists of the intracutaneous injection (Mantoux
responses and thus is thought to account for the increased method) of 0.1 mL of material, which contains 5 tuberculin
frequency of tuberculosis in malnourished persons.208 In units (TU). The site usually chosen is the volar surface of the
addition to overt malnutrition, other factors related to spe- forearm, but any accessible area can be used. A short-
cific but poorly defined nutritional deficiencies may also beveled 26- or 27-gauge needle should be used with a 1-mL
be associated with an increased risk of tuberculosis. For graduated syringe. A properly placed intracutaneous injec-
example, observations suggest that risk is increased in tion should cause a well-demarcated wheal 6 to 10 mm in
diameter in which the hair follicles form dimples. Conven- There are several reasons why the tuberculin reaction
tionally, the reading is done 48 to 72 hours after the injec- may be interpreted as negative in the presence of tubercu-
tion, but it may be delayed for up to 1 week.215 lous infection. These include errors in application or reading
In persons such as hospital employees, who are likely of the test result, usually related to the inexperience of the
to be tested repeatedly—if tuberculin negative at the tester/reader, and should be easily correctable with proper
outset—a two-step testing procedure is recommended to training. Problems with the antigen are infrequent unless it
avoid confusing a boosted reaction with a true conver- has been improperly handled. Many disease states, espe-
sion.216 The phenomenon of boosting can happen in a cially HIV infection, interfere with cell-mediated immune
person who is infected but loses skin test reactivity after responses. Lymphoreticular malignancies such as Hodgkin
several years. In this situation, a single tuberculin test disease are potent suppressors of cell-mediated immunity.
can be falsely negative, but the test itself can recall (i.e., Corticosteroids and immunosuppressive drugs decrease
boost) the waned reactivity. A subsequent test can then tuberculin reactivity if the patient is on a sufficient dose for
elicit a positive reaction. A positive reaction following a a sufficient period of time; for corticosteroids, the minimum
negative one may cause the person tested to be classified dose is 15 to 20 mg of prednisone or the equivalent of
as a tuberculin converter. To elicit any potential boosted another preparation, given daily for 2 to 3 weeks.219 As
response and to categorize the person more accurately as stated previously, advancing age is associated with loss of
infected or not infected, a second 5-TU tuberculin test is tuberculin reactivity, although it may be recalled.215 Malnu-
applied within 1 to 2 weeks of the first test. If the second trition also may cause defects in cell-mediated immunity
test shows a positive reaction, it is interpreted as a boosted with consequent diminished tuberculin reactivity. Finally,
response indicative of prior infection; if the reaction pleural tuberculosis and overwhelming tuberculosis itself
remains negative, it is assumed to be truly negative. may cause diminished or absent tuberculin responsiveness.
The reaction to the test should be read by inspecting and Even when the test is applied and the result is read with
palpating the area where the tuberculin was injected. The particular care in patients with proven tuberculosis and no
reaction size is determined by measuring the diameter of apparent immunosuppression at the time they are admitted
any induration with a ruler. The amount of erythema to a hospital, only 80% to 85% have reactions of 10 mm or
should not be taken into account; only the extent of indura- more to 5-TU PPD.220 Thus, a negative tuberculin test result
tion is important. Readings must be recorded accurately in cannot be used to exclude tuberculosis as a diagnostic
millimeters. possibility.
The interpretation of tuberculin tests requires clinical The interpretation of the TST in persons with HIV infec-
judgment, as well as an understanding of the test. In a tion is a particular problem because of the progressive
population in which the only mycobacterial species causing immunosuppression in HIV disease. Individuals infected
infection is M. tuberculosis, the curve describing the distri- with HIV are less likely to have a positive tuberculin reac-
bution of reaction sizes in otherwise healthy infected tion. In a cross-sectional study of persons with HIV infec-
persons given 5-TU PPD would be bell shaped, having a tion and a wide range of CD4+ lymphocyte counts,
mode of 17 to 18 mm, with very few reactions less than anergy—defined as lack of any reaction to tuberculin (5
10 mm. Thus, defining the minimum reaction size indica- TU) plus mumps and Candida antigens—was more common
tive of tuberculous infection would be simple.217 However, when the CD4+ count was less than 400 cells/µL.221
in many parts of the world, a portion of the population is
infected with nontuberculous mycobacteria, which induce INTERFERON-γ RELEASE ASSAYS
some degree of sensitization to tuberculin; inoculation with
BCG, for many years the world’s most commonly used IFN-γ release assays (IGRAs) are used for the diagnosis of
vaccination, has the same enhancing effect on tuberculin latent tuberculous infection (LTBI); these assays cannot dis-
reactivity. Although these reactions are on the whole tinguish LTBI from active tuberculosis. Two IGRAs are cur-
smaller than those caused by M. tuberculosis, they blur the rently approved in the United States, the QuantiFERON-TB
distinction between reactions in persons infected with M. test and the T-SPOT.TB test. The QuantiFERON-TB (Qiagen,
tuberculosis and those not infected. On the basis of a large Alameda, CA) tests, specifically QuantiFERON-TB Gold and
amount of epidemiologic data and skin testing with anti- QuantiFERON-TB Gold In-tube (QFT-GIT), measure the
gens prepared from nontuberculous mycobacteria, the best amount of IFN-γ released from sensitized lymphocytes in
compromise between false-positive and false-negative read- whole blood incubated overnight with mixtures of M. tuber-
ings to 5-TU PPD tuberculin tests is 10 mm. Thus, under culosis antigens, ESAT-6 and CFP-10.222 A newer-generation
most circumstances, a reading of 10 mm or more is consid- test includes an additional antigen, Tb7.7. The other
ered indicative of infection with M. tuberculosis. However, approved test, the T-SPOT.TB, utilizes an ELISPOT format
in some situations, smaller reactions should be taken to to quantify the number of cells in peripheral blood that
indicate tuberculous infection. For example, a reaction of secrete IFN-γ when stimulated with ESAT-6 and CFP-10
5 mm in a child who is a contact of a person with smear- (Oxford Immunotec, Abingdon, United Kingdom).223
positive tuberculosis probably indicates tuberculous infec- Neither the TST nor IGRAs have value for the diagnosis
tion and is considered positive. Likewise, a 5-mm reaction of active tuberculosis in adults. A systematic review and
in a person with known HIV infection should be considered meta-analysis showed that the sensitivity to diagnose tuber-
positive. In the United States, the history of BCG admin- culosis in low- and middle-income countries was 76% for
istration is generally ignored in interpreting the results of T-SPOT.TB and 60% for QFT-GIT. The specificity was 61%
the TST.218 and 52%, respectively.224
Compared with the TST, the IGRAs have several advan-

tages: The tests can be performed in one patient visit, they
DIAGNOSIS OF PULMONARY
are more specific in the presence of BCG vaccination or TUBERCULOSIS
infection with nontuberculous mycobacteria, they are not
subject to reader variability, and they do not stimulate Currently, in the United States, 69% of new cases of tuber-
waned immunity (the booster reaction, described earlier).223 culosis involve the lungs only, 21% involve extrapulmonary
A systematic review showed that IGRAs have excellent sites only, and 10% involve both locations.27 Although both
specificity and are not affected by BCG vaccination (due to miliary (disseminated) tuberculosis and pleural tuberculo-
the absence of ESAT-6 and CFP-10 from all strains of sis involve the lungs and/or pleural space, they are consid-
BCG).225 The sensitivity to diagnose infection (using culture- ered extrapulmonary forms of the disease.
positive M. tuberculosis cases as the reference) was variable
in the different studies, but T-SPOT.TB appeared to be more DIAGNOSTIC EVALUATION
sensitive than QuantiFERON-TB Gold and QFT-GIT and the
TST.225,226 In patients with HIV infection, the responses to Clinicians must recognize that, in evaluating persons who
TST and QFT-GIT correlate with the degree of immunode- may have tuberculosis, they are assuming an essential
ficiency, whereas results of the T-SPOT.TB are independent public health function and providing care to an individual
of the level of CD4 T-cell depletion,227 which may explain patient. Early and accurate diagnosis is critical to tubercu-
the variable results of the different IFN-γ-release assays and losis care and control.234 Despite dramatically improved
TST among patients with HIV infection.228 access to high-quality tuberculosis services worldwide
IGRAs have a few disadvantages: The tests require during the past 2 decades, there is substantial evidence that
drawing blood and processing it within a specific time, and failure to identify cases early is a major weakness in efforts
they are less well known than the TST and, therefore, have to ensure optimal outcomes for the patient and to control
much less evidence to characterize their performance for the disease. Diagnostic delays result in ongoing transmis-
diagnosing latent tuberculous infection and for epidemio- sion in the community and more severe, progressive disease
logic studies. For example, risk factors for conversion (from in the affected person.
negative to positive) and reversion (from positive to nega- Globally there are three main reasons for delays in diag-
tive) were different for T-SPOT.TB compared with the TST.229 nosing tuberculosis: the affected person not seeking or not
The authors attributed these findings to a lack of under- having access to care; the provider not suspecting the
standing of the dynamics of the IFN-γ response to ESAT-6 disease; and the lack of sensitivity of the most commonly
and CFP-10. Also, because there is no knowledge about the available diagnostic test, sputum (or other specimen) smear
time required for the IFN-γ release assays to become positive microscopy.235,236 Approaches to reducing these delays are,
after the onset of infection, the interpretation of a negative obviously, quite different. Reducing delays on the part of the
IFN-γ release assay requires caution. affected person entails providing accessible health care
Other authors, who also found a substantial proportion facilities, enhancing community and individual awareness,
of reversions, attributed their findings to the decrease of the and active case finding in high-risk populations. Reducing
bacterial load due to treatment and to the natural resolution provider delay is best approached by increasing provider
of the infection.230 In a study in the United Kingdom, awareness of the risks for and symptoms of tuberculosis
Wilkinson and colleagues,231 using T-SPOT.TB, showed an and of the appropriate and available diagnostic tests. Rapid
early rise in spot-forming counts in patients given isoniazid molecular tests that increase both the speed and the sensi-
and rifampin, then a reduction at month 3. No changes tivity for identifying Mycobacterium tuberculosis are increas-
were observed in those without treatment. In India, Pai and ingly available and, in some situations, are recommended
colleagues232 followed 216 nursing and medical students by the WHO as the initial diagnostic test.
and observed that 9 (24%) of the 38 individuals with an
initial positive QFT-GIT test had reversion, which was asso- PATIENT HISTORY
ciated with a negative TST result. Interestingly, those with
skin test conversion also had an increase in levels of IFN-γ. There must be a clinical suspicion of tuberculosis before
Taken together, these data underscore the uncertainty proper diagnostic tests are ordered. Clinical suspicion is
regarding the interpretation of the IFN-γ release assays in prompted largely by the presence of symptoms and by
providing information about the outcome of infection with awareness of comorbidities and epidemiologic circum-
M. tuberculosis, both treated and untreated. stances that increase the risk of tuberculosis in an individ-
Currently, the U.S. Centers for Disease Control and Preven- ual patient. These risks are summarized in the WHO
tion (CDC) recommends using the QuantiFERON-TB Gold guidelines for screening for tuberculosis.237 The most com-
test for the same indications as the TST: for evaluating monly reported symptom of pulmonary tuberculosis is per-
persons suspected of having tuberculosis and for screen- sistent cough that generally, but not always, is productive of
ing, including contacts of an infectious case of tuberculo- mucus and sometimes blood. In persons with tuberculosis,
sis, children younger than 17 years of age, pregnant the cough is often accompanied by systemic symptoms,
women, and persons at increased risk of tuberculosis, par- such as fever, night sweats, and weight loss. In addition,
ticularly those with HIV infection, recent immigrants who findings such as lymphadenopathy, consistent with concur-
have had BCG vaccination, and health care workers. The rent extrapulmonary tuberculosis, may be noted, especially
QuantiFERON-TB Gold test usually can be used in place in patients with HIV infection. However, chronic cough
of—and not in addition to—the TST.233 with sputum production is not always present, even among
A B
C D E
Figure 35-5 Aspergilloma developing in an old tuberculosis cavity. A, Front chest radiograph in a patient with tuberculosis shows bilateral upper lobe
fibronodular changes with a right apical cavity (arrow). B, Frontal chest radiograph several years after (A) when the patient complained of hemoptysis
shows development of an opacity within the right apical cavity (arrowheads) representing aspergilloma. C-E, Focused axial chest CT confirms the presence
of aspergilloma. (Courtesy Michael Gotway, MD.)
persons with sputum smears showing acid-fast bacilli. Data Hemoptysis is usually seen with more extensive involve-
from several tuberculosis prevalence surveys in countries ment but does not necessarily indicate an active tubercu-
with a high incidence of the disease show that an important lous process. Hemoptysis may also result from bronchiectasis
proportion of persons with active tuberculosis do not have left as a residual of healed tuberculosis; from rupture of a
cough of 2 or more weeks, a criterion that, conventionally, dilated vessel in the wall of an old cavity (Rasmussen aneu-
has been used to define suspected tuberculosis.238,239 In rysm); from bacterial or fungal infection (especially in the
these studies, 10% to 25% of patients with bacteriologically form of a fungus ball [aspergilloma or mycetoma]) in an old
confirmed tuberculosis do not report cough. These data residual cavity (Fig. 35-5); or from erosion of calcified
suggest that evaluation for tuberculosis, using a symptom lesions into the lumen of an airway (broncholithiasis).
review that includes cough of any duration, fever, night The systemic features of tuberculosis include fever in
sweats or weight loss, may be indicated in selected risk approximately 35% to 80%, malaise, and weight loss; there
groups, especially in areas where there is a high prevalence may be a variety of hematologic abnormalities, especially
of the disease and in high-risk populations and individuals leukocytosis and anemia.241-243
with increased susceptibility, such as persons with HIV
infection. Use of this broadened set of questions in a popula- PHYSICAL EXAMINATION
tion of persons with HIV infection was found to have a
negative predictive value of 97.7% for tuberculosis.240 The In most cases, physical findings are not particularly helpful.
presence of any one of the symptoms should be viewed as Crackles may be heard in the area of involvement, along
an indication for an evaluation for tuberculosis in high-risk with bronchial breath sounds, when lung consolidation is
groups or in high-incidence areas. close to the chest wall. Amphoric breath sounds (like the
Figure 35-6 Primary tuberculosis. Frontal chest radiograph in a young

adult shows superior segment right lower lobe consolidation associated
with right hilar lymphadenopathy (arrow) due to primary Mycobacterium
tuberculosis infection. Mild right paratracheal lymph node enlargement
(arrowhead) is also visible. (Courtesy Michael Gotway, MD.)
low sound of blowing across the top of an open bottle) may

be indicative of a cavity. Findings such as lymph node
enlargement, suggestive of extrapulmonary tuberculosis,
may also indicate concurrent pulmonary involvement.
Figure 35-7 Cavitary tuberculosis. Frontal chest radiograph in a patient
RADIOGRAPHIC FEATURES with tuberculosis shows extensive right upper lobe cavitation. (Courtesy
Michael Gotway, MD.)
Radiographic examination of the chest is commonly the
first diagnostic study undertaken, after the history and
physical examination.244,245 However, in resource-limited
settings, a chest radiograph is not necessarily included as
part of the routine evaluation because of cost, complexity,
and nonspecificity of the findings.
Pulmonary tuberculosis nearly always causes detectable
abnormalities on the chest radiograph, although in patients
with HIV infection, a chest radiograph may be normal in up
to 11% of patients with positive sputum cultures.196 In
primary tuberculosis, resulting from recent infection, the
process is generally seen as a middle or lower lung zone
opacity, often associated with ipsilateral hilar adenopathy
(Fig. 35-6). Atelectasis may result from compression of
airways by enlarged lymph nodes. If the primary process
persists beyond the time when specific cell-mediated immu-
nity develops, cavities may form (so-called progressive
primary tuberculosis).
Tuberculosis that develops at a time remote from the
original infection (endogenous reactivation) usually
involves the upper lobes of one or both lungs. Cavitation is Figure 35-8 Disseminated tuberculosis. Frontal chest radiograph in a
common in this form of tuberculosis. The most frequent patient with disseminated tuberculosis shows numerous small, randomly
distributed nodules bilaterally, representing the miliary pattern. (Courtesy
sites are the apical and posterior segments of the right Michael Gotway, MD.)
upper lobe (Fig. 35-7) and the apical-posterior segment of
the left upper lobe. Healing of the tuberculous lesions
usually results in development of a fibrotic scar with shrink- (i.e., “bronchogenic” spread) into the lower portions of the
age of the lung parenchyma and, often, calcification. involved lung or to the other lung. Erosion of a parenchy-
Involvement of the anterior segments alone is unusual. In mal focus of tuberculosis into a blood or lymph vessel may
the immunocompetent adult with tuberculosis, intratho- result in dissemination of the organism and a miliary
racic adenopathy is uncommon. When the disease pro- pattern on the chest imaging (Fig. 35-8, see Fig. 18-25).
gresses, infected material may be spread via the airways Radiographic findings in HIV-infected patients are affected
culture or by identification of specific nucleic acid sequences.

When the lung is involved, sputum is the initial specimen
of choice. Two sputum specimens should be collected,
which can be obtained the same day because the sensitivity
of tests using same-day specimens is similar to tests using
specimens collected on different days.248 The collection of
the sputum in 1 day allows results to be available the same
day, thereby increasing the efficiency of sputum smear
microscopy.248 The strategies for same-day microscopy
include the preparation of 2 or 3 slides from sputum samples
obtained the first day the patient is assessed. Collecting
more than two sputum specimens increases the yield only
slightly.249
There are several options for obtaining specimens from
patients who are not producing sputum. The first and most
useful in terms of yield and avoidance of patient discomfort
is inducing sputum production by the inhalation of a hyper-
Figure 35-9 Tuberculosis in an HIV patient. Frontal chest radiograph in tonic (3% to 5%) saline mist generated by an ultrasonic
a patient with tuberculosis shows bilateral hilar lymph node enlargement
(arrows) associated with poorly defined parenchymal nodular opacities
nebulizer. Sputum induced by this technique is clear and
(arrowheads) and nodular areas of consolidation (double arrowheads). resembles saliva; thus, it must be properly labeled or it may
(Courtesy Michael Gotway, MD.) be discarded by the laboratory. This is a benign and well-
tolerated procedure, although bronchospasm may be pre-
cipitated in asthmatic patients.
by the degree of immunosuppression. As further explained Sampling of gastric contents via a nasogastric tube has a
and illustrated in Chapter 90, tuberculosis relatively early lower yield than sputum induction and is more complicated
in the course of HIV infection tends to produce typical and uncomfortable for the patient. However, in children
radiographic findings with predominantly upper lobe infil- and some adults, gastric contents may be the only specimen
tration and cavitation.246 With more advanced HIV disease, that can be obtained. Gastric lavage should be performed
the radiographic findings become more “atypical”: cavita- early in the morning before the patient has gotten out of
tion is uncommon, and lower lung zone or diffuse opacities bed, eaten, or performed dental hygiene. Once the specimen
and intrathoracic adenopathy are frequent (Fig. 35-9). Sur- is obtained, the specimen should be sent to the laboratory
prisingly, a substantial number of HIV-infected patients and processed the same day. To prolong the viability of the
with pulmonary tuberculosis had normal radiographs at bacteria, neutralization of gastric acid with an equal volume
the end of their course of treatment.247 of sterile 1% sodium bicarbonate is recommended when the
The activity of a presumed tuberculous process cannot specimen is not processed inmediately.250,251
be determined simply from a single radiographic examina- Depending on the clinical circumstances, if the sputum
tion of the chest. A cavity might be a sterile residual of an is negative or cannot be obtained, the next diagnostic step
old infection, whereas a fibrotic-appearing lesion may be is usually fiberoptic bronchoscopy with bronchoalveolar
active. Conversely, not all radiographic worsening of the lavage, and in some instances transbronchial lung biopsy.
residua of prior tuberculous lesions can be ascribed to reac- The yield of bronchoscopy is high in miliary tuberculosis
tivation of the disease, although such worsening should and in focal disease as well. Bronchoscopic procedures have
always be of concern. Superimposed infections with other been especially helpful in the diagnostic evaluations of
organisms or bleeding from bronchiectasis or from residual patients with HIV infection with negative sputum smear
cavities may cause new infiltrations to appear. In addition, microscopy.252 Needle aspiration biopsy may also provide
carcinomas may arise from within the area of scarring specimens from which mycobacteria are isolated, but
(so-called scar carcinomas) and be the cause of radio- the technique is especially suited to the evaluation of
graphic changes. peripheral nodular lesions for which there is a suspicion of
From this discussion, it should be obvious that the chest malignancy.
radiograph, although extremely valuable, cannot provide a In some situations, a therapeutic trial of antituberculosis
definitive diagnosis of tuberculosis. Because of the radio- chemotherapy may be indicated before more invasive
graphic similarities among the other disorders in the dif- studies are undertaken. For example, a radiographic abnor-
ferential diagnosis, and because of the uncertainties in mality consistent with tuberculosis in a person who is
assessing disease activity and in determining the reasons for younger than 40, is a nonsmoker, and comes from a country
progressive radiographic changes, careful microbiologic where there is a high prevalence of tuberculosis, either
evaluation is always indicated. A nondiagnostic microbio- current or past tuberculosis is much more likely than a
logic evaluation should prompt a careful assessment for neoplasm, even in the presence of negative smears and cul-
other causes of the radiographic abnormality. tures of sputum. In such a patient, improvement in the
chest radiograph concomitant with antituberculosis treat-
ment would be sufficient reason for making a diagnosis of
BACTERIOLOGIC EVALUATION
tuberculosis and continuing with a full course of therapy.
As noted previously, a definitive diagnosis of tuberculosis A response should be seen within 2 months of starting
can be established only by isolation of tubercle bacilli in treatment. If no improvement is noted, the abnormality
Initial cultures negative

No change in CXR 4 months RIF +/– INH
Low 9 months INH

suspicion
ent
atm 2 months RIF/PZA
tre
At-risk patient No
Abnormal CXR
Smears negative Initial cultures negative
No other diagnosis Clinical/CXR improved
Positive
tuberculin test INH
/RI 2 months INH/RIF
F/E
MB
High /PZ
A
suspicion
Treatment complete
Initial cultures negative
No change in CXR or Sx
Initial Repeat
evaluation evaluation
0 1 2 3 4 6 11
Time (mo)
Figure 35-10 Treatment algorithm for active, culture-negative pulmonary tuberculosis and inactive tuberculosis. The decision to begin treatment
for a patient with sputum smears that are negative depends on the degree of suspicion that the patient has tuberculosis. If the clinical suspicion is high
(lower portion of figure), then multidrug therapy should be initiated before acid-fast smear/culture results are known. If the diagnosis is confirmed by a
positive culture (see Fig. 35-11), treatment can be continued to complete a standard course of therapy. If initial cultures remain negative and treatment
has been with multiple drugs for 2 months, then there are two options depending on repeat evaluation at 2 months (lower portion of figure). In option
1, if the patient demonstrates symptomatic or radiographic improvement without another apparent diagnosis, then a diagnosis of culture-negative
tuberculosis can be inferred. Treatment should be continued with isoniazid and rifampin for an additional 2 months. In option 2, if the patient demonstrates
neither symptomatic nor radiographic improvement, then tuberculosis is unlikely and treatment can be stopped. In low-suspicion patients not initially
on treatment (upper portion of figure), if cultures remain negative, the patient has no symptoms, and the chest radiograph is unchanged at 2 to 3 months,
there are three treatment options: (1) isoniazid for 9 months; (2) rifampin with or without isoniazid for 4 months; or (3) rifampin and pyrazinamide for 2
months. (See later discussion of latent tuberculous infection.) CXR, chest radiograph; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin;
Sx, symptoms. (From Blumberg HM, Burman WJ, Chaisson RE, et al, for the American Thoracic Society/Centers for Disease Control and Prevention/Infectious
Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 167:603–662, 2003.)
must be the result of either old tuberculosis or another can also be increased by about 10% using a fluorochrome
process. An algorithm illustrating this approach is shown staining procedure with auramine O, a fluorescent stain254
in Figure 35-10. (see Fig. 35-1). This procedure requires use of a fluorescent
Because of the potentially disastrous consequences of microscope, which requires an excitation light source.
delays in diagnosis of tuberculosis, it is essential that tests There are two types of light sources. The first one is the
for M. tuberculosis be performed rapidly and the results be short-arc mercury vapor lamp (MVP) which has a limited
reported promptly. Waiting days for the results of micro- lifespan (200 to 300 hours), is costly, requires high main-
scopic examinations, weeks for culture results, and months tenance, and is potentially toxic due to its mercury content.
for speciation and susceptibility studies is not acceptable. The second is the light-emitting diode (LED) that has a life
span of more than 50,000 hours, is less expensive, and has
Acid-Fast Staining a performance similar to the MVP-based microscopy.255
The first step in the diagnostic sequence is nearly always Fluorochrome-based procedures are faster than acid-fast
staining and examining readily available specimens for staining because the intensity and contrast of the fluores-
AFB. (See below for recommendations for use of rapid cent signal on a dark background enables slides to be
molecular tests in the initial evaluation). Finding AFB is scanned at lower magnification (see Fig. 35-1).
generally specific for mycobacteria but provides no informa- Smears are generally interpreted as negative or, if posi-
tion about species. However, the sensitivity of microscopic tive, are reported as rare (3 to 9 organisms per slide), few
examination is relatively low; the level of detection is (10 or more per slide), or numerous (1 or more per high-
approximately 10,000 bacilli per milliliter of secretions if power oil immersion field). In most situations in which acid-
100 oil immersion microscopic fields are examined. The fast organisms are detected by microscopy, they should be
sensitivity of sputum smear microscopy can be increased by assumed to be M. tuberculosis until proven otherwise.
concentrating the sample either by centrifugation or sedi- Assuming the patient has tuberculosis will trigger the
mentation preceded by chemical processing.253 Sensitivity appropriate prompt responses from the physicians
responsible for treatment and from public health agencies. presence of rough, cauliflower-like, and colorless colonies;
In practice, the sensitivity of sputum smears varies widely: and the presence of organisms that are tangled and form
20% to 80% of patients with M. tuberculosis isolated in corded masses when observed using a microscope.
culture have positive smears.253 The microscopic observation of drug susceptibility (MODS)
assay is a culture-based method that discriminates between
Mycobacterial Culture M. tuberculosis complex and nontuberculous mycobacteria
Culture in liquid media is considered the current diagnos- and determines the drug susceptibility to rifampin and iso-
tic gold standard and can detect as few as 10 to 1000 viable niazid at the same time. MODS incorporates the antituber-
mycobacteria/mL. Culture is an essential step for diagnosis culosis drugs in the culture media at the beginning of the
and is necessary for phenotypic drug susceptibility testing. assay. The method uses a sealed 24-well tissue-culture plate
Culturing mycobacteria from clinical specimens requires a with liquid culture media containing different antibiotics
higher level of technical capability than that needed for and controls that are examined periodically under an
microscopy. The need for biosafety conditions, constant- inverted light microscope. M. tuberculosis can be identified
temperature incubators, and a constant power supply by the observation of a tangled or a corded mass of organ-
restricts the use of culture in many low-resource settings. isms and by a time to detection (including susceptibility
Culture of sputum usually involves digestion, decontamina- test), typically less than 2 weeks. When compared with tra-
tion, and concentration of the specimen before inoculation ditional solid or liquid culture, the overall pooled sensitivity
of media. This process decreases bacterial overgrowth and, of MODS to detect M. tuberculosis growth was 92% and the
when solid media are used, enables more uniform plating specificity was 96% compared with conventional culture.
of the specimen. For specimens other than sputum, diges- The mean time from receipt of specimen to results was 9.2
tion and decontamination are not required. At a minimum, days, and contamination was present in 7%.258 There is
laboratories performing culture should be able to identify currently a MODS kit commercially available.
M. tuberculosis. Isolates that are not M. tuberculosis or are MOLECULAR-BASED IDENTIFICATION METHODS. Several
of questionable identity should then be sent to a more spe- molecular methods are available to identify M. tuberculosis
cialized laboratory for definitive speciation. directly on the specimen or in mycobacterial culture. They
Culture can be performed in solid or liquid media. Solid are based on nucleic acid amplification technologies (NAATs)
media are usually less expensive and allow the morphologic in which as few as 1 to 10 copies of DNA or ribonucleic acid
examination of the colonies to be used for presumptive specific to M. tuberculosis complex are amplified to detect-
species identification. However, results on solid media are able levels. Other targets include proteins specific to M.
delayed due to the slow growth of mycobacteria and, in tuberculosis. All these tests identify the presence of M. tuber-
some settings, the delayed culture results may have limited culosis complex and can rule out the presence of nontuber-
or no impact on patient management.256 The solid media culosis mycobacteria. Importantly, some of these methods
can be based on egg such as Lowenstein-Jensen (LJ) media identify drug resistance–associated mutations in the same
or on agar such as Middlebrook 7H10 or 7H11 media. M. test. There are several commercial technologies, although
tuberculosis colonies appear in 2 to 8 weeks, and cultures only one, the GenProbe Amplified M. tuberculosis Direct test
without growth at 8 weeks are reported as negative, (AMTD), is available in the United States. The current rec-
although they are generally kept for another 2 to 4 weeks ommendation by the CDC is to use an NAAT on at least one
before being discarded, as some strains grow more slowly specimen, preferably the first diagnostic specimen from
than the average. each patient in whom a TB diagnosis is being considered.259
Liquid media are more sensitive and increase the yield by The recommended interpretation algorithm includes the
10%. They enable M. tuberculosis growth to be detected in use of clinical judgment when the nucleic acid amplifica-
10 to 14 days. However, liquid media also have a higher rate tion test is negative. This limitation has been applied because
of contamination with other bacteria or with nonmycobac- it has been found that the sensitivity of the tests is not suf-
teria.257 The growth of M. tuberculosis in liquid media pro- ficiently high to exclude M. tuberculosis.259,260
duces fluorimetric or colorimetric reactions, which are A major breakthrough in NAAT has been the develop-
detected using manual or automated systems. The auto- ment of an automated, self-contained, real-time polymerase
mated systems permit a higher throughput and should be chain reaction (PCR) assay to detect M. tuberculosis complex
used in settings with high workloads, especially for drug and rifampin resistance–associated mutations directly in
susceptibility testing. The manual systems are less expen- clinical specimens (Xpert MTB/RIF).261 This system is based
sive and are used in areas with limited resources. on the amplification of a sequence of the rpoB gene specific
to members of the M. tuberculosis complex and the rifampin
M. tuberculosis Identification. The methods to identify resistance–determining region. It can be used directly on
M. tuberculosis can be classified as (1) phenotype methods clinical specimens or specimens that have been digested and
that include biochemical tests and specific cell and colony decontaminated.262 It requires minimal biosafety mea-
characteristics and (2) molecular-based methods that target sures263 and minimal hands-on technical time.264 It consists
M. tuberculosis complex–specific nucleic acids or proteins. of two main components: (1) a disposable cartridge that
PHENOTYPE-BASED IDENTIFICATION METHODS. The classical contains sample processing and the M. tuberculosis–specific
phenotype-based methods to identify M. tuberculosis real-time PCR reagents and (2) an instrument that controls
complex require a positive culture for mycobacteria. These the fluidics in the cartridge and performs the PCR analy-
tests include niacin production, nitrate reduction, and inac- sis.261 The operational challenges are related to the specific
tivation of catalase at 68° C. The tests also use the time to needs of the components: Cartridges require a temperature
growth, which is usually 12 to 42 days in solid media; the below 28° C and have a 12-month shelf-life, and the
instrument requires a stable electrical power supply and an for the performance of the MTBDRsl was as follows: for
ambient temperature below 30° C.264 A meta-analysis fluoroquinolone sensitivity—87.4%, specificity—97.1%;
showed that, as an initial test replacing smear microscopy, amikacin sensitivity—82.6%, specificity—99.5%; capreo-
Xpert MTB/RIF pooled sensitivity was 89% and pooled spec- mycin sensitivity—82%, specificity—97.3%; kanamycin
ificity 99%.265 As an add-on test following a negative smear sensitivity—44.4%, specificity—99.3%; and ethambutol
microscopy result, Xpert MTB/RIF pooled sensitivity was sensitivity—67.9%, specificity—79.9%.272 In 2008, WHO
67% and specificity 99%. For smear-positive, culture- endorsed the line-probe assays for the rapid detection of
positive TB, Xpert MTB/RIF pooled sensitivity was 98%. For first-line drug resistance in low- and middle-income
people with HIV infection, Xpert MTB/RIF pooled sensitiv- settings.273
ity was 79% and, for people without HIV infection, it was
86%. The pooled sensitivity to detect rifampin resistance Serologic Tests
was 95%, and the pooled specificity was 98%.265 This assay Several antigens, including highly purified and recombi-
has a median time to detection of M. tuberculosis of hours nant antigens specific for M. tuberculosis complex, have
compared with 1 day for microscopy, 16 days for culture in been used in serologic antibody tests with variable results.
liquid media, and 30 days for culture on solid media. The A systematic review found that the results of serologic tests
median time to detection of rifampin resistance with the are highly variable and not better than sputum smear
automated and self-contained real-time PCR assay was 1 microscopy.274 On the basis of these results, WHO has
day compared with 106 days for phenotypic tests.266 More strongly recommended against the use of serologic tests
importantly, Xpert MTB/RIF reduced the median time to for the diagnosis of pulmonary and extrapulmonary
treatment of patients with sputum smear-negative tubercu- tuberculosis.275
losis from 56 days to 5 days.266 On the basis of its diagnostic
accuracy, WHO endorsed the Xpert MTB/RIF for the diag- Drug Susceptibility Testing
nosis of tuberculosis in 2010.267,268 WHO is recommending Determination of susceptibility to antimicrobial agents is
that, for all patients (including children) who are suspected of considerable clinical importance. Because of concerns
of having pulmonary tuberculosis and are capable of pro- regarding tuberculosis caused by drug-resistant organisms,
ducing sputum, a single specimen submitted for Xpert drug susceptibility testing is recommended for all initial
MTB/RIF testing can be used as the initial test in place of M. tuberculosis isolates. Unfortunately, due to lack of
two specimens submitted for smear microscopy. In addition, resources, drug susceptibility testing is not done in most
WHO recommends that Xpert MTB/RIF should be used as high-burden areas or is limited to M. tuberculosis strains
the preferred initial test for patients who are at risk for drug isolated from patients at high risk of having drug-resistant
resistance, who have HIV risks, or who are seriously ill; tuberculosis (see Table 35-3). There are two general
because of the speed of diagnosis, the test is also preferred methods for determining resistance: phenotypic and geno-
for use with cerebrospinal fluid in patients suspected of typic.276 Some of the methods are designed to identify M.
having tuberculous meningitis. tuberculosis and determine the drug susceptibility in the
Other commercially available molecular methods can be same test, such as MODS, Xpert MTB/RIF and line probe
used directly on clinical samples or mycobacterial cultures assays, all of which were reviewed in the previous section
for identification of the M. tuberculosis complex and drug on M. tuberculosis identification.
resistance-associated mutations on the same day the speci- The phenotypic methods are based on culture of M. tuber-
men is received.269 However, these technologies require culosis. There are two methods: absolute and proportional.
more technical expertise and a more complex laboratory These can be done in liquid or solid media. The reference
infrastructure. The line probe assay uses a DNA strip test standard is the proportion method, and it is recommended
that allows the simultaneous identification of M. tuberculo- in liquid media. The proportional methods involve inoculat-
sis and common genetic mutations causing resistance to ing one or more dilutions of cultured mycobacteria on
isoniazid and rifampin from smear-positive sputum samples drug-free media and on media containing appropriate con-
or from positive cultures. Currently, three line probe assays centrations of antituberculosis drugs. Resistance is gener-
exist: the INNO-LiPARif.TB assay (Fujirubio, Europe, ally considered to be present when the growth on the
N.V.),270 which is available for research use only for the drug-containing medium is 1% or more of the control
detection of M. tuberculosis and rifampin resistance, and growth on the drug-free media.
two versions of the GenoTypeMTBDR assay (Hain Life- There are several approaches to detect mycobacterial
Science GmbH, Nehren, Germany). The GenoTypeMTBDR growth.277 The colorimetric method is based on the reduc-
plus detects M. tuberculosis and rifampin and isoniazid tion of an oxidation-reduction indicator (i.e., Alamar Blue,
resistance,271 and the GenoTypeMTBDRsl detects the most resazurin, or tetrazolium) added to the culture media after
common mutations in the gyrA gene for fluoroquinolone the cells of M. tuberculosis are exposed to the antibiotic.
resistance; in the rrs gene for amikacin, capreomycin, and Resistance to antibiotics is identified by the presence of a
kanamycin resistance; and in the embB gene for ethambutol change in color in the media due to the oxidation/reduction
resistance.272 The sensitivity of the INNO-LiPARif.TB for process by viable mycobacteria. This method is highly sensi-
detecting rifampin resistance in culture isolates was greater tive and specific for the detection of rifampin and isoniazid
than 95%, and the specificity was 100%.270 A meta-analysis resistance (98% and 97% sensitive, respectively; 99% and
for the performance of the GenoTypeMTBDR showed 98% specific, respectively) when compared with conven-
a pooled sensitivity of 98.1% and specificity of 98.7% tional culture-based drug susceptibility methods.276,278 The
for rifampicin resistance and a lower sensitivity of 84.3% nitrate reductase assay is based on the ability of M. tubercu-
and specificity of 99.5% for isoniazid.271 Meta-analysis losis to reduce nitrate to nitrite, which is also detected by a
color reaction. The sensitivity of the test was 97%, and the the tests can now be used in clinics in resource-poor areas.
specificity was 100% for the detection of rifampin resis- Currently, the pipeline for such extremely rapid and simple
tance and 97% and 99%, respectively, for detection of iso- tuberculosis diagnostics includes genotypic-based methods
niazid resistance.276,278 that could potentially be used at the patient’s bedside. One
Testing for susceptibility to isoniazid and rifampin is group of assays is based on isothermal amplification tech-
accurate,278 and resistance to rifampin has been used as an nology that requires uniform incubation temperature
indicator for multidrug-resistant tuberculosis.279 Testing for (unlike PCR, which depends on a cyclical incubation tem-
susceptibility to streptomycin, ethambutol, and pyrazin- perature and requires complex equipment) utilizing simple
amide is less reliable and reproducible.278 Testing for second- technology that potentially could be used in peripheral
line drugs is generally performed in reference laboratories laboratories where smear microscopy is performed. Loop-
and is recommended mainly for MDR strains. Testing for mediated isothermal amplification, where amplification
resistance to aminoglycosides, capreomycin, and fluoro- products can be seen via fluorescence under ultraviolet
quinolones is relatively accurate and reproducible, and light, is an example of this technology.288 Preliminary data
the recommendation is to use the automated liquid showed that the loop-mediated isothermal amplification TB
culture systems.278,280 Testing for resistance to the other assay had comparable performance with other commer-
second-line drugs (ethionamide, prothionamide, cycloser- cially available PCR-based assays used to identify M. tuber-
ine, terizidone, para-aminosalicylic acid, clofazimine, culosis288 and could potentially also identify drug-resistance
amoxicillin-clavulanate, clarithromycin, linezolid) is not mutations in the same reactions. Other point-of-care tests
standardized and not currently recommended.279 are based on the identification of M. tuberculosis–specific
The genotypic methods to identify drug resistance are inte- antigens such as lipoarabinomannan (LAM) using lateral
grated with the M. tuberculosis identification methods; flow immunochromatographic assays or strip tests to assay
therefore, these methods are faster than culture-based tests. unprocessed urine. Unfortunately, its performance is low
The genotypic methods are based on the detection of drug and its use is not recommended except for patients with
resistance–associated mutations: mutations in the rpoB advanced immunodeficiency due to HIV.289
rifampin resistance–determining region are present in 96%
of rifampin-resistant strains,281 mutations in katG or inhA
in 65% to 75% of isoniazid-resistant strains,281 and muta-
tions in gyrA and gyrB in 42% to 85% of quinolone-resistant PLEURAL TUBERCULOSIS
strains.281,282 (see Chapter 80)
A common limitation of all genotypic methods is the
inability to detect drug-resistant strains that do not harbor Although the pleural space is within the thorax, for report-
the common mutations. Therefore, it is essential to use con- ing purposes it is considered an extrapulmonary site of
ventional phenotypic methods to exclude drug-resistant tuberculosis. Tuberculous pleuritis accounts for 17% of the
tuberculosis. extrapulmonary cases in the United States.27 The epidemiol-
There are several noncommercial genotypic methods. ogy of pleural tuberculosis parallels that of the overall
Melting temperature (Tm)-based assays utilize fully comple- pattern for tuberculosis, being more common among men
mentary strands of DNA that have higher melting tempera- and increasing in incidence with increasing age between 5
tures than DNA with one or more nucleotide mismatches. and 45 years. As noted previously, this epidemiologic
This assay has been used together with “sloppy” molecular pattern is modified by the presence of HIV infection,
beacons to detect mutations in the rifampin resistance- although pleural involvement seems less frequent among
determining region in a closed system minimizing cross- HIV-infected persons.
contamination.283 Other genotypic methods are based on There are two mechanisms by which the pleural space
sequencing genes or fragments of genes known to harbor becomes involved in tuberculosis. The difference in patho-
drug resistance–associated mutations. Pyrosequencing, a genesis results in different clinical presentations, approaches
rapid real-time method for sequencing small segments of to diagnosis, treatment, and sequelae. The first mechanism
genomic DNA, was successfully used to detect mutations in manifests early in the course of a tuberculous infection—a
strains resistant to first- and second-line drugs.284 few tubercle bacilli may gain access to the pleural space
Another category of noncommercial methods is the and, in the presence of cell-mediated immunity, can cause
bacteriophage-based assays, in which recombinant myco- a hypersensitivity response.290,291 This form of tuberculous
bacteriophage causes emission of light in the presence of pleuritis commonly goes unnoticed, and the process resolves
live, but not dead (i.e., drug-killed), mycobacteria. These are spontaneously; those with resolved tuberculous pleuritis
promising, but several technical issues limit their use.285 have a high likelihood of developing active tuberculosis in
The phage-amplified biologic assay (PhaB) can be used in the next 2 years,292 so tuberculous pleuritis should be con-
sputum or mycobacterial culture to identify M. tuberculosis sidered and treated if found. However, in some patients, the
and drug-resistance mutations.286 The assays are relatively tuberculous involvement of the pleura is manifested as an
simple to use, they do not require extensive materials, and acute illness with fever and pleuritic pain.293 If the effusion
the results are available within 48 hours of processing. A is large enough, it may cause dyspnea, although the effu-
meta-analysis demonstrated that, although these assays sions are generally rather small and rarely bilateral.
had good sensitivity, specificity was low and contamination The diagnosis of pleural tuberculosis is generally estab-
was also a concern.285,287 lished by analysis of pleural fluid and by a pleural biopsy. In
In spite of recent advances, none of the diagnostic a patient with a pleural effusion that might be tuberculous,
methods is yet a point-of-care test, meaning that none of a diagnostic thoracentesis should be performed. Sufficient
fluid should be obtained for cell count, cytologic examina- often necessary and may be required for a prolonged period
tion, biochemical analysis, and microbiologic evaluation of time. In selected patients who need ongoing drainage,
(all described in detail in Chapter 79 and 80), but enough creation of an Eloesser flap, in which a small portion of rib
fluid should be left to allow a needle biopsy to be performed overlying the empyema space is resected and the skin is
if the original specimen proves to be exudative and no diag- sutured to the pleura, is the procedure of choice.302
nosis is evident. The fluid is nearly always straw colored,
although it may be slightly bloody. Leukocyte counts are
usually in the range of 100 to 5000 cells/µL.294 Early in the DISSEMINATED TUBERCULOSIS
course of the process, polymorphonuclear leukocytes may
predominate, but mononuclear cells soon become the Miliary tuberculosis, although it nearly always involves the
majority. The fluid is exudative, with a protein concentra- lungs, is considered among the extrapulmonary forms of
tion greater than 50% of the serum protein concentration, the disease because of the multiplicity of organs affected.
and the glucose level may be normal to low. The term miliary is derived from the similarity of the lesions
Adenosine deaminase has been shown to have high sen- to millet seeds. Grossly, these lesions are 1- to 2-mm yellow-
sitivity, except in HIV-infected patients, but variable specific- ish nodules that on histologic examination are granulomas.
ity, for diagnosing tuberculous pleural effusion.295 IFN-γ has In the past, miliary tuberculosis was mainly seen in young
been reported to have both high sensitivity (0.99) and high children, as an early consequence of initial infection and
specificity (0.98) and to be equally reliable in HIV-infected bacillemia; currently, however, except among HIV-infected
and HIV-uninfected patients.296,297 Further studies are nec- persons, it is more common among older persons, as a
essary to define the diagnostic role of this potentially useful result of endogenous reactivation and bloodstream inva-
test. Because few organisms are present in the pleural space, sion. The shift in age-specific incidence presumably has
acid-fast smears of pleural fluid are rarely positive, and M. been caused at least in part by the paucity of new infections
tuberculosis is isolated by culture in only 20% to 40% of in relation to the number of endogenous reactivations in
patients with proven tuberculous pleuritis.293,298 A single the United States. The incidences in both sexes are nearly
closed-needle biopsy of the pleura with a Cope or an Abrams equal except in the HIV-infected population, in which the
needle, with collection of three or four specimens for histo- disease predominates among men.
logic examination, acid-fast staining, and culture of the Because of the multisystem involvement in disseminated
tissue, confirms the diagnosis in approximately 65% to 75% tuberculosis, the clinical manifestations are protean. Initial
of patients in whom tuberculous pleuritis is ultimately diag- screening laboratory studies are not particularly helpful.
nosed. A second set of specimens in patients whose initial The chest radiograph, however, is abnormal in most but
biopsy is negative increases the yield to 80% to 90%.298 The not all patients with disseminated tuberculosis: the fre-
results of thoracoscopy are nearly always diagnostic, but quency of a classic military pattern has ranged from 50%
the procedure is invasive, costly, and not always available. to 90%. Overall, it appears that, at the time of diagnosis,
In a patient with an exudative mononuclear pleural effu- approximately 85% of patients have the diffuse tiny nodules
sion that remains undiagnosed after a full evaluation, characteristic of miliary tuberculosis. Other abnormalities
including pleural biopsy, and who has a positive tuberculin may be present as well. These include upper lobe opacities
reaction or IGRA result, antituberculosis treatment should with or without cavitation, pleural effusion, and pericardial
be initiated. effusion. As noted previously, HIV-infected patients may not
Treatment of the hypersensitivity variety of tuberculous be able to form granulomas; thus, instead of discrete indi-
pleural effusion consists of standard antituberculosis drug vidual lesions, a diffuse uniform pattern of infiltration may
regimens.299 Drainage via tube thoracostomy is rarely nec- be seen.
essary, although repeat thoracenteses may be required to Autopsy series have shown the liver, lungs, bone marrow,
relieve symptoms. The use of corticosteroids may increase kidneys, adrenal glands, and spleen to be the organs most
the rate of resolution and decrease the residual fluid, but frequently involved in miliary tuberculosis, but any organ
such treatment is rarely indicated.300 can be the site of disease.303 Because of the multiplicity of
The second variety of tuberculous involvement of the sites involved, there are many potential sources of material
pleura, which is much less common than tuberculous pleu- to provide a diagnosis. Acid-fast smears of sputum are posi-
risy with effusion, is a true empyema that follows the spill- tive in 20% to 25% of patients (even when the patient is not
ing into the pleural space of a large number of organisms, spontaneously coughing), and cultures of sputum are posi-
usually from rupture of a cavity or an adjacent parenchy- tive in 30% to 65%.304-306 In a patient with an abnormal
mal focus via a bronchopleural fistula.301 Tuberculous chest radiograph and negative sputum examinations, bron-
empyema is usually associated with evident pulmonary choscopy should be the next step. Combinations of bron-
parenchymal disease on chest films. In this situation the choalveolar lavage and transbronchial biopsy would be
fluid generally is thick and cloudy and may contain choles- expected to have a high yield.307 Other potential sites for
terol, which causes the fluid to look like chyle (pseudochy- biopsy include liver and bone marrow, each of which has a
lous effusion). The fluid is exudative and usually has high likelihood of showing granulomas (70% to 80%), but
a relatively high white blood cell count, nearly all of only a 25% to 40% chance of providing bacteriologic con-
which are lymphocytes. Acid-fast smears and mycobacte- firmation; urine cultures may be positive in up to 25% of
rial cultures are usually positive, making pleural biopsy patients.305,306 Selection of other potential sources of diag-
unnecessary. nostic material should be guided by specific findings.
In addition to standard antituberculosis chemotherapy, The role of rapid nucleic acid amplification tests for
surgical drainage with an ordinary thoracostomy tube is identification of M. tuberculosis in patients with miliary
tuberculosis has not been defined, and neither of the two has been reviewed.317,318 These reviews suggest that anti-
tests licensed by the U.S. Food and Drug Administration is tuberculosis treatment may be given intermittently three
approved for nonrespiratory specimens, although Xpert times a week throughout the full course of therapy or twice
MTB/RIF is recommended for use with specimens from weekly in the continuation phase without apparent loss of
extrapulmonary sites by WHO.308 The reported data are dif- effectiveness except among individuals with advanced HIV
ficult to interpret because, often, the results of specimens infection.317,319-321 However, the WHO does not recommend
from different sites are combined, patients are selected by a the use of twice-weekly intermittent regimens because
variety of criteria, and test performance varies.309-311 In of the potentially greater consequences of missing one of
contrast, several studies have shown that Xpert MTB/RIF the two doses; the recently revised (2016) ATS/IDSA/CDC
can provide rapid molecular diagnostic assessment when Guidelines are in agreement with this recommendation.316
extrapulmonary tuberculosis is suspected. The growing Several caveats apply to these recommendations for treat-
body of literature, including two large studies, demon- ment to be successful. First, the organisms must be suscep-
strated a sensitivity of 81% and specificity of 99%.312-314 tible to the drugs used. Because of concerns with drug
Before the era of chemotherapy, disseminated tuberculo- resistance, initial isolates from patients with tuberculosis
sis was uniformly fatal. With treatment, however, the should have drug susceptibility tests performed and the
reported case-fatality rates range from 29% to 64%.306 results should be used to guide treatment. Second, patients
Meningeal involvement increases mortality and, when it is must take all or nearly all of the prescribed treatment.
present, the duration of standard chemotherapy should be Third, success should be documented by bacteriologic eval-
extended from 6 to 9 or 12 months, and corticosteroids may uation; that is, sputum cultures should be negative by the
be useful to reduce mortality.315 end of 3 months of treatment. If the sputum still contains
M. tuberculosis after 3 months of therapy, the patient should
be reassessed carefully to determine whether a change in
TREATMENT treatment is necessary. The assessment should include a
review of adherence, and evaluation for any comorbidities
Further information about the introduction and develop- that might interfere with response. After 3 months of che-
ment of chemotherapy for pulmonary tuberculosis is pro- motherapy, more than 90% of patients taking regimens
vided in the Appendix for this chapter, which can be found containing isoniazid and rifampin should have negative
online. sputum cultures. Failure of the sputum to become negative
The Appendix also provides details about the mecha- generally means that either the organisms are resistant to
nisms of action, genetic basis of resistance, and chief the agents being used or the patient is not taking the drugs.
adverse effects of each of the main first- and second-line Patients who continue to have M. tuberculosis in their
antituberculosis agents that are currently in use; also sputum after 3 months of treatment should be started on
included is Table 35A-1, which lists the available prepara- directly observed therapy, if not already being supervised,
tions and their recommended doses. and should have drug susceptibility testing performed by
phenotypic methods or a rapid molecular test. If resistance
CURRENT STANDARD REGIMENS is found, the regimen should be modified accordingly. If
sputum samples are still positive after 4 months of therapy,
The treatment regimens that are currently recommended the regimen should be considered a failure and a new
by the American Thoracic Society, the CDC, and the Infec- regimen should be begun, ideally based on recent drug sus-
tious Diseases Society of America and also by the WHO are ceptibility test results. A list of possible regimens for
shown in Table 35-1.316 The recommended basic treatment non-MDR drug resistant tuberculosis (strains resistant to
regimen for previously untreated patients with pulmonary one or more drugs, excluding those with combined isonia-
tuberculosis consists of an initial (or intensive) phase of iso- zid and rifampin resistance) is shown in Table 35-2.
niazid, rifampin, pyrazinamide, and ethambutol given for The recommendation of a four-drug intensive phase is
2 months, followed by a 4-month continuation phase of iso- based, in part, on findings of the British Medical Research
niazid and rifampin. The initial phase rapidly reduces the Council that revealed the need for a regimen that would be
bacterial burden, by killing the actively growing bacteria, effective in the presence of isoniazid resistance; the inclu-
while the continuation phase is protracted and intended to sion of ethambutol during the intensive phase lessens the
eliminate the subpopulation of bacteria that are replicating likelihood of selecting for rifampin resistance in strains with
more slowly. The latter population is sometimes termed drug primary isoniazid resistance.322-324 Several factors have
tolerant, meaning that the bacteria are not efficiently killed been found to be predictive of a poor therapeutic outcome,
by drugs but have not acquired resistance mutations. As including extensive tuberculosis and a large population of
shown in Table 35-1, there are several variations in the fre- bacilli, the rapidity or slowness with which sputum becomes
quency of drug administration that are largely designed to negative after treatment is begun, and several factors asso-
enable health care personnel (or their surrogates) to provide ciated with adherence.299,320,325,326 In U.S. Public Health
closer supervision of treatment and produce acceptable Service Study 22, the presence of cavitation on the initial
results.316 Intermittent administration of antituberculosis chest film and sputum culture positivity at the end of the
drugs enables supervision to be provided more efficiently 2-month intensive phase of treatment were highly predic-
and economically with no reduction in efficacy, although tive of an adverse outcome—either treatment failure or
daily administration provides a greater margin of safety. relapse.320 For this reason, in patients with cavitation on
The evidence on effectiveness of intermittent regimens the initial chest film and who have positive sputum cultures
Further information about the introduction and develop-

ment of chemotherapy for pulmonary tuberculosis is pro-
vided in the Appendix for this chapter.
Table 35-1 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms
INTENSIVE PHASE CONTINUATION PHASE
Range of
b
Interval and Dose Interval and Doseb,c Total Effectiveness
a
Regimen Drug (Minimum Duration) Drugs (Minimum Duration) Doses Commentsc,d of Regimen
1 INH 7 d/wk for 56 doses (8 wk), INH 7 d/wk for 126 doses 182–130 Preferred regimen Greater
RIF or 5 d/wk for 40 doses (8 wk) RIF (18 wk), or 5 d/wk for 90
PZA doses (18 wk)
EMB
2 INH 7 d/wk for 56 doses (8 wk), INH 3 times weekly for 54 doses 110–94 Preferred alternative
RIF or 5 d/wk for 40 doses (8 wk) RIF (18 wk) regimen in situations in
PZA which more frequent DOT
EMB during continuation phase
is difficult to achieve.
3 INH 3 times weekly for 24 doses INH 3 times weekly for 54 doses 78 Avoid or use with caution in
RIF (8 wk) RIF (18 wk) patients with HIV and/or
PZA cavitary disease. Missed
EMB doses can lead to treatment
failure, relapse, and
acquired drug resistance.
4 INH 7 d/wk for 14 doses then INH Twice weekly for 36 doses 62 Do not use twice-weekly
RIF twice weekly for 12 dosese RIF (18 wk) regimens in HIV-infected
PZA patients or patients with
EMB smear-positive and/or
cavitary disease. If doses are
missed, then therapy is
equivalent to once weekly,
which is inferior. Lesser
a
Other combinations may be appropriate in certain circumstances; consult Official American Thoracic Society/Centers for Disease Control and Prevention/
Infectious Diseases Society of America Clinical Practice Guidelines on Treatment of Drug-Susceptible Tuberculosis316 for details.
b
When DOT is used, drugs may be given 5 days per week and the number of doses adjusted accordingly. Although there are no studies that compare 5 with
7 daily doses, extensive experience indicates this would be an effective practice. DOT should be used when drugs are administered <7 days per week.
c
Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week)
continuation phase.
d
Pyridoxine (vitamin B6), 25–50 mg/day, is given with INH to all persons at risk of neuropathy (eg, pregnant women; breastfeeding infants; persons with HIV;
patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or patients with advanced age). For patients with peripheral neuropathy, experts
recommend increasing pyridoxine dose to 100 mg/day.
e
Some U.S. tuberculosis control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12
doses.460
Adapted from Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases
Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016 Aug 10. [Epub ahead of print] PubMed
PMID: 27516382.
at the end of the initial phase of treatment, prolongation of HIV Infection

the continuation phase to 7 months, making a total of 9 The recommended treatment regimen for HIV-infected
months of treatment, is recommended. Factors that have patients with tuberculosis consists of the same 6-month
been associated with poor clinic attendance and, therefore, regimen as described for non–HIV-infected persons, but
with less chance of favorable response, include use of there are several important areas in which therapy may
alcohol, younger age (but older than 18), and unmarried differ. Although, in general, rates of relapse are not
status. Patients with any of these characteristics should be increased among HIV-infected patients who take a standard
monitored especially carefully. Although directly observed 6-month regimen in the United States, there is an associa-
therapy (DOT) is labor intensive, the improved outcomes tion with acquiring rifampin resistance.327-329 In sub-
shown in retrospective analyses justify its use in preventing Saharan Africa, however, the likelihood of death, especially
treatment failure and relapse, both of which have striking during the first 2 months of therapy, and of relapse follow-
cost and public health consequences. ing apparently successful treatment is higher in HIV-infected
The algorithm shown in Figure 35-11 presents the than in non–HIV-infected patients.330
approach to treatment of pulmonary tuberculosis in The cause of rifampin monoresistance is not clear but
patients with M. tuberculosis isolated from sputum, and has been associated with the use of once- or twice-weekly
Figure 35-10 shows a treatment algorithm for patients with drug administration in the continuation phase and prior
radiographic evidence of tuberculosis but negative bacte- use of rifabutin as prophylaxis for Mycobacterium avium
riologic examinations. In the absence of bacteriologic con- complex infections.321,327 For this reason, the rifapentine
firmation, treatment depends first on the degree of suspicion once-weekly regimen is contraindicated for all patients
of active disease, and second on whether or not initial treat- with HIV infection, and a twice-weekly regimen is not
ment causes clinical or radiographic improvement. recommended for HIV-infected patients with CD4+ counts
Table 35-2 Selected Treatment Regimens for Non–Multidrug-Resistant Tuberculosis*

Resistance to Treatment Regimen Duration of Therapy Comments
Isoniazid (± streptomycin) Rifampin 6-9 mo A fluoroquinolone may strengthen the
Ethambutol regimen for patients with extensive
Pyrazinamide disease.
Isoniazid and pyrazinamide Rifampin 9-12 mo A longer duration of treatment should be
Ethambutol used for patients with extensive
Fluoroquinolone† disease.
Isoniazid and ethambutol Rifampin 9-12 mo A longer duration of treatment should be
Pyrazinamide used for patients with extensive
Fluoroquinolone disease.
Rifampin Isoniazid 12-18 mo An injectable drug may strengthen the
Ethambutol regimen for patients with extensive
Fluoroquinolone plus at least 2 mo of disease.
pyrazinamide
Rifampin and ethambutol Isoniazid, pyrazinamide 18 mo A longer course (6 mo) of the injectable
(± streptomycin) Fluoroquinolone plus injectable drug‡ may strengthen the regimen for
for at least the first 2-3 mo patients with extensive disease.
Rifampin and pyrazinamide Isoniazid 18 mo A longer course (6 mo) of the injectable
(± streptomycin) Ethambutol may strengthen the regimen for
Fluoroquinolone plus injectable drug patients with extensive disease.
for at least the first 2-3 mo
Isoniazid, ethambutol Rifampin 18 mo A longer course (6 mo) of the injectable
pyrazinamide Fluoroquinolone plus an oral may strengthen the regimen for
(± streptomycin) second-line agent,§ plus injectable patients with extensive disease.
drug for at least the first 2-3 mo
Pyrazinamide Isoniazid, rifampin plus at least 2 mo 9 mo Most commonly seen in M. bovis
of ethambutol infection.
*Strains resistant to one or more drugs, excluding combined isoniazid and rifampin resistance.
†
Fluoroquinolones: levofloxacin or moxifloxacin.
‡
Injectable drugs: streptomycin, amikacin, kanamycin, or capreomycin.
§
Oral second-line drugs: ethionamide, cycloserine, or p-aminosalicylic acid.
From the Curry National Tuberculosis Center and California Department of Public Health, Drug-Resistant Tuberculosis: A survival guide for clinicians, ed 2.
Sacramento, CA, 2008, California Department of Public Health, pp 34–35.
less than 100 cells/µL.299 An important concern in treating reducing mortality in patients with tuberculosis and HIV
tuberculosis in patients with HIV infection is the potential infection is realized in those having CD4+ counts less than
for interactions with other drugs, especially antiretrovi- 200 cells/µL. For patients with higher CD4+ counts, the
ral agents, as discussed in detail in Chapter 90. Detailed, mortality benefit is less clear.334-336
regularly updated recommendations for managing drug Another feature of the treatment of tuberculosis, as well
interactions during treatment of tuberculosis and HIV as of other opportunistic infections, is the paradoxical wors-
are available online (http://www.cdc.gov/tb/publications/ ening that may be seen in HIV-infected persons who are also
guidelines/TB_HIV_Drugs/default.htm). The most practi- receiving antiretroviral therapy, a clinical phenomenon
cal means of minimizing the effects of interactions is to known as the immune reconstitution inflammatory syndrome
use a regimen consisting of two nucleoside reverse tran- (IRIS). The frequency of tuberculosis-related IRIS varies,
scriptase inhibitors plus efavirenz or, in pregnant women, depending on the case definitions used.333,337 Two main syn-
nevirapine in the HIV treatment regimen, and rifabutin in dromes or forms of IRIS are associated with tuberculosis
place of rifampin in the antituberculosis regimen. Monitor- in persons with HIV infection.338 The more common syn-
ing of serum drug concentrations may be useful in avoiding drome is the paradoxical tuberculosis-associated IRIS that
the adverse consequences of the interactions. Current rec- arises within the first weeks or months after the start of
ommendations are that in persons with HIV infection and antiretroviral therapy in patients already being treated for
tuberculosis who have profound immunosuppression (CD4 tuberculosis. The second IRIS syndrome, known as anti
counts < 50 cells/mm3), ART should be initiated within retroviral therapy–associated tuberculosis, arises when tuber-
2 weeks of beginning treatment for tuberculosis unless culosis (or some other lurking undiagnosed HIV-linked
tuberculous meningitis is present. For all other patients with complication) is “unmasked” and flares up not long after
HIV and tuberculosis, regardless of CD4 counts, antiretrovi- beginning antiretroviral therapy. Characteristic features of
ral therapy should be initiated within 8 weeks of beginning both forms include new or exacerbated symptoms or signs
treatment for tuberculosis. In part, the recommendation of tuberculosis including worsening of pulmonary opaci-
for antiretroviral treatment regardless of CD4 cell counts ties, increasing pleural effusions, or increasing lymphade-
is because of the effect in reducing transmission of HIV.332 nopathy (Fig. 35-12). Usually, the syndrome is self-limiting,
The exception to this recommendation is in patients with with a median duration of 2 months. Risk factors for the
tuberculous meningitis in whom immune reconstitution development of this form of IRIS include advanced HIV
may have serious consequences.333 The greatest benefit for disease, disseminated and extrapulmonary tuberculosis, a
INH, RIF
A
2 month culture negative
INH, RIF
Cavitation
INH, RIF
2 month culture positive B
INH, RIF, EMB*, PZA No cavitation INH, RIF
Tuberculosis strongly
C
suspected or proven
Cavitation
No cavitation
INH, RIF
D
HIV negative or positive
INH, RPT
E
HIV negative 2 month culture positive
2 month culture negative
0 2 3 4 6 9
Months
Figure 35-11 Treatment algorithm for patients with confirmed or strongly suspected tuberculosis. For patients in whom tuberculosis is confirmed
or strongly suspected, the intensive phase of treatment should consist of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months. The choice of
regimen for the continuation phase depends on 3 factors: 1) the presence or absence of cavitation on the initial chest radiograph, 2) the culture status at
the completion of the intensive phase of treatment (month 2), and 3) the presence or absence of advanced HIV infection. In patients without advanced
HIV infection, if there is cavitation on the initial chest radiograph and the 2-month culture is positive, the continuation phase of treatment should consist
of isoniazid and rifampin daily or three times weekly for 7 months to complete a total of 9 months of treatment. (Arm C) Otherwise the continuation
phase should consist of isoniazid and rifampin daily or three times weekly (preferably to twice weekly, which is acceptable) for 4 months to complete a
total of 6 months of treatment. (Arms A, B, & D) No longer recommended316 (hence the shading) is a regimen consisting of isoniazid and rifapentine given
once weekly, which was ONLY for patients without advanced HIV infection, who do not have cavitation on the initial radiograph and who have negative
sputum smears at month 2. (Arm E) In this arm, if the 2-month culture becomes positive, the treatment is extended by an additional 3 months for a total
of 9 months (dashed line). In patients with advanced HIV infection (CD4 counts of less than 100 cells/µl), the continuation phase should follow the same
recommendations as above except that drug administration should be daily or three times weekly. Due to lack of efficacy, patients with advanced HIV
should not have either twice weekly drug administration or the once weekly isoniazid-rifapentine regimen. *EMB may be discontinued when results of
drug susceptibility testing indicate no drug resistance. †PZA may be discontinued after it has been taken for 2 months (56 doses). ‡RPT should not be
used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. §Therapy should be extended to 9 months if 2-month
culture is positive. CXR, chest radiograph; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine. (Modified from Blumberg HM,
Burman WJ, Chaisson RE, et al, for the American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment
of tuberculosis. Am J Respir Crit Care Med 167:603–662, 2003.)
short interval between starting antituberculosis and anti-

retroviral treatments, and a response to antiretroviral
therapy as reflected by a decreased viral load.
Drug Resistance
The fourth Global Drug Resistance Surveillance Project
conducted between 2002 and 2007 by the WHO and the
International Union Against Tuberculosis and Lung Disease
included more than 90,000 patients from 81 countries,
representing 35% of the global notified new smear-positive
cases.339 Drug resistance was found in all countries sur-
veyed, with the exception of Iceland, with a weighted mean
of 17% of new cases having resistance to at least one anti-
tuberculosis drug and 2.9% having MDR (resistance to at
Figure 35-12 Tuberculous lymphadenitis in a patient with immune least isoniazid and rifampin). According to the most recent
reconstitution inflammatory syndrome (IRIS) after initiation of
antiretroviral therapy. With development of IRIS, there was swelling of WHO estimates, in 2012, approximately 450,000 new
an anterior cervical node and onset of purulent drainage from the node. cases of MDR tuberculosis were identified worldwide. This
(Courtesy Dr. Henry M. Blumberg, Emory University.) estimate includes 3.6% of all new, never-treated patients
and 20.2% of all previously treated patients.2 The drug-
resistance surveillance report found areas of the world in
which rates of MDR are truly alarming, such as Baku, Azer- Transmission of drug-resistant strains of M. tuberculosis
baijan, where 56.3% of new cases were resistant to any has been well described in health care facilities, in congre-
drug and 22.3% were MDR, a considerable worsening since gate settings, and in susceptible populations, notably HIV-
the previous report.339 infected persons.173,344-347 However, MDR M. tuberculosis
In 2006, XDR tuberculosis—defined as tuberculosis may spread in the population at large, as was shown in data
caused by M. tuberculosis that is not only MDR but also from a number of countries, including China, the Baltic
resistant to any one of the fluoroquinolones and to at States, and countries of the former Soviet Union.339,348-350
least one of three injectable second-line drugs (amikacin, The strongest factor associated with drug resistance is
capreomycin, or kanamycin)—was identified and rapidly previous antituberculosis treatment.339 In previously
recognized as a serious emerging threat to global public treated patients, the odds of any resistance are at least
health.49,340 Subsequent reports have identified XDR tuber- 4-fold higher, and that of MDR at least 10-fold higher, than
culosis in all regions of the world, with countries from in new (untreated) patients.351 Patients with chronic tuber-
the former Soviet Union reporting as high as 24% XDR culosis (sputum-positive after retreatment) and those who
tuberculosis among the MDR cases.2 The two strongest fail treatment are at highest risk of having MDR tuberculo-
risk factors for XDR tuberculosis are failure of a tubercu- sis, especially if rifampin was used throughout the course
losis treatment regimen that contains second-line drugs, of treatment. Persons who are in close contact with con-
including an injectable agent and a fluoroquinolone, and firmed MDR tuberculosis patients, especially children and
close contact with an individual with documented XDR HIV-infected individuals, also are at high risk of being
tuberculosis or with an individual for whom treatment infected with MDR strains. In some closed settings, prison-
with a regimen including second-line drugs is failing or ers, persons staying in homeless shelters, and certain cat-
has failed. egories of immigrants and migrants are at increased risk of
Drug resistance is largely man-made; a consequence of MDR tuberculosis. These factors are summarized and pre-
suboptimal regimens and treatment interruptions.341 Clini- sented in descending order of level of risk in Table 35-3.
cal errors that commonly lead to the emergence of drug Given the importance of drug resistance, both for the
resistance include failure to provide effective treatment individual and for the community, all patients for whom
support and assurance of adherence; inadequate drug regi- treatment is being initiated should be assessed for their
mens; adding a single new drug to a failing regimen; and risk of having tuberculosis caused by drug-resistant organ-
failure to recognize existing drug resistance. In addition, isms. The assessment should be based on history of prior
comorbid conditions associated with reduced serum levels treatment, exposure to a possible source case having
of antituberculosis drugs (e.g., malabsorption, rapid transit drug-resistant organisms, and the community prevalence
diarrhea, use of antifungal agents) and interruptions of drug resistance (if known). Whenever possible, the
caused by adverse drug reactions may also lead to the assessment should also include history of fluoroquinolone
acquisition of drug resistance.342 An additional potential use in the period preceding diagnosis of tuberculosis
source of drug resistance is substandard drugs, which may because monotherapy with fluoroquinolones for as little as
exist due to poor manufacturing or deterioration due to 10 days increases the incidence of fluoroquinolone-resistant
improper storage.343 M. tuberculosis.352-354 Although drug susceptibility testing
Table 35-3 Assessing Risk for Drug Resistance

Risk Factors for Resistance Comments
Failure of retreatment regimen (a second course of Patients who are still sputum smear positive at the end of a retreatment regimen have
treatment after failure, relapse, or default) perhaps the highest drug-resistance rates of any group, often exceeding 80%.
Close contact with a known drug-resistant case Tuberculosis in close contacts of drug-resistant TB patients is likely to be drug-resistant
TB.
Failure of the initial treatment regimen Patients who fail to become sputum smear negative while on treatment are likely to
have drug-resistant organisms. However, the likelihood depends on a number of
factors, including whether rifampicin was used in the continuation phase and whether
DOT was used throughout treatment. Thus, a detailed history of drugs used is
essential. This is especially true for patients treated by private providers, often with
nonstandard regimens.
Relapse after apparently successful treatment Most patients who relapse have fully susceptible organisms. However, under program
conditions, an apparent relapse, especially an early relapse, may, in fact, be an
unrecognized treatment failure and thus have a higher likelihood of drug resistance.
Return after default without recent treatment failure The likelihood of drug resistant TB varies substantially in this group, depending in part
on the duration of treatment and the degree of adherence before default.
Exposure in institutions that have drug-resistant TB Patients who frequently stay in homeless shelters, prisoners in many countries, and
outbreaks or a high drug-resistant TB prevalence health care workers in clinics, laboratories, and hospitals can have high rates of
drug-resistant TB.
Residence in areas with high prevalence of Drug-resistant TB rates in many areas of the world can be high enough to justify
drug-resistant TB routine drug sensitivity testing in all new cases.
Modified from World Health Organization: Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2008.402.
www.who.int/tb/publications/2008/en/. Accessed July 8, 2014.
should be performed at the start of therapy for all patients, or partial cross-resistance and similar toxicities within
those who are at increased risk of drug resistance should be the groups. Group 4 consists of less potent oral agents:
prioritized and a rapid molecular test (if available) should ethionamide, prothionamide, cycloserine, terizidone, and
be performed. In addition, patients who remain sputum p-aminosalicylic acid. Group 5 is composed of drugs for
culture positive at completion of 3 months of treatment, which antituberculosis action has not been documented in
patients in whom treatment has failed, and patients who clinical trials (except for thiacetazone): clofazimine, line-
have been lost to follow-up, or relapsed following one or zolid, amoxicillin/clavulanate, thioacetazone, imipenem/
more courses of treatment, should always be assessed for cilastatin, high-dose isoniazid, and clarithromycin. A drug
drug resistance. that has been used within a failing regimen should never be
Because of difficulties in the design of randomized con- counted in the total of four drugs for retreatment, even if
trolled treatment trials for MDR/XDR tuberculosis using susceptibility is shown in the laboratory. The doses and
multidrug regimens, none has been conducted to evaluate adverse effects of second-line drugs are described in detail
currently available approaches to treatment. In the absence in the ATS/CDC/IDSA recommendations for treatment of
of clinical trial data, current recommendations for treating tuberculosis.299
MDR/XDR tuberculosis are based on observational studies, Two new second-line drugs, delamanid and bedaquiline,
general microbiologic and therapeutic principles, extrapo- have been introduced, although as of this writing only
lation from available evidence from pilot MDR tuberculosis bedaquiline has been approved by the U.S. Food and Drug
treatment projects, and expert opinion.351-362 Administration.365-368 Given the paucity of data describing
More systematic guidance has been obtained from a care- outcomes and adverse events, the WHO recommends that
fully conducted individual patient meta-analysis that exam- bedaquiline may be added to a WHO-recommended regimen
ined the outcomes of treatment for MDR tuberculosis and in adult patients with pulmonary tuberculosis caused by
concluded that treatment success, compared with failure/ MDR organisms. The recommendations also specify fairly
relapse or death, was associated with use of later-generation rigid conditions under which the drug should be used.
fluoroquinolones, as well as ofloxacin, ethionamide or pro- Thus, informed consent should be obtained from the patient
thionamide, use of four or more likely effective drugs in the and there should be careful monitoring for adverse drug
initial intensive phase, and three or more likely effective effects.
drugs in the continuation phase.363 In addition, not surpris- Empiric treatment regimens are commonly used while
ingly, outcomes in patients with XDR tuberculosis are worse the drug susceptibility results are pending. Empiric regi-
when there was resistance to additional drugs beyond those mens are strongly recommended to avoid clinical deteriora-
that comprise the definition of XDR.364 tion and to prevent transmission of MDR strains of M.
On the basis of available information, there are three tuberculosis to contacts while awaiting the drug susceptibil-
treatment options for MDR/XDR tuberculosis: standard- ity results. Once the results of drug susceptibilities are
ized, empiric, and individualized regimens. The approach is known, an individualized regimen can be started. Individu-
dependent on having an accurate history of prior treat- alized treatment regimens (based on susceptibility profiles
ment, reliable drug susceptibility testing results for indi- and drug history of individual patients, or on local patterns
vidual patients, and/or population data on the prevalent of drug utilization) have the advantage of avoiding toxic
resistance patterns. In general, in areas where drug suscep- and expensive drugs to which the MDR strain is resistant.
tibility is widely available, individualized treatment regi- However, an individualized approach requires access to
mens are used. substantial human, financial, and technical (laboratory)
Current global recommendations are that patients with capacity. Drug susceptibility tests for second-line drugs are
confirmed MDR tuberculosis should be treated with a notoriously difficult to perform, largely because of drug
regimen consisting of an intensive phase of 6 to 8 months instability and the fact that critical concentrations for defin-
containing at least five drugs: pyrazinamide and four drugs ing drug resistance are close to the minimal inhibitory con-
to which the organisms are known or presumed to be sus- centration (MIC) of individual drugs.369
ceptible, including an injectable agent. The continuation A shorter-course standardized regimen used in Bangla-
phase should contain at least three drugs to which the desh has been described with good results reported in a
organisms are known or presumed to be susceptible. The small observational study.370 Although promising, at this
total treatment duration should be at least 18 to 24 months point there is insufficient evidence to recommend the use of
beyond culture conversion.351 Patient-centered measures, this regimen for treating MDR tuberculosis. A clinical trial
including observation of treatment, are required to ensure is under way that should provide substantial new informa-
adherence. Consultation with a specialist experienced in tion on which to base recommendations. Current advice
treatment of patients with MDR/XDR tuberculosis should from WHO is that a short regimen for MDR tuberculosis
be obtained. should be used only under research conditions.371
On the basis of their activity, efficacy, route of administra- The outcomes of treatment for patients with MDR or
tion, tolerance, availability, and costs, antituberculosis XDR tuberculosis have been assessed in two systematic
drugs can be classified in five groups.357 Group 1 consists of reviews. In the review by Johnson and colleagues372 an esti-
first-line drugs: isoniazid, rifampin, ethambutol, pyrazin- mated 62% of patients had successful outcomes, 13%
amide, and rifabutin. Any of these drugs should be used defaulted, and 11% died. Factors associated with worse
if it is thought that susceptibility remains. Only one drug outcome included male gender, alcohol abuse, smear posi-
should be selected from Group 2 (injectable agents— tivity at diagnosis, fluoroquinolone resistance, and an XDR
kanamycin, amikacin, capreomycin, streptomycin) and resistance pattern. Factors associated with successful
Group 3 (fluoroquinolones) because of documented total outcome were surgical intervention, no previous treatment,
and inclusion of a fluoroquinolone in the regimen (when reason, drug susceptibility or resistance often must be
the isolate is susceptible). inferred from the pattern of the presumed source case or
Orenstein and associates373 noted that studies combining community data rather than being determined in the
both at least an 18-month treatment duration and directly laboratory.
observed treatment had significantly higher estimated The management of children with drug-resistant tuber-
success—69%, compared with other studies of treatment culosis is especially difficult because of the lack of culture
outcomes wherein the estimated success was 58%. More- and susceptibility testing to guide treatment. Consequently
over, individualized regimens had an estimated success of there is limited evidence to guide optimal treatment and
64%, compared with standardized regimens in which the follow-up in children. However, the basic principles and
estimated success was 54%, although the difference was approaches described for drug-resistant tuberculosis,
not statistically significant. including MDR and XDR tuberculosis, apply in both chil-
More limited experience with treatment of XDR tubercu- dren and adults.382
losis suggests a substantially worse outcome. In a meta-
analysis of outcomes in 560 patients, Jacobson and Pregnancy and Breast-feeding. Active untreated tuber-
colleagues374 reported a successful outcome in an estimated culosis poses a far greater hazard to a pregnant woman and
44%. Their analysis also suggested that the use of a later- her fetus than does treatment for the disease.383 Pregnant
generation fluoroquinolone was associated with a better women or mothers of young infants, therefore, should be
outcome. Substantial treatment support is commonly nec- started on treatment with isoniazid, rifampin, and etham-
essary to enable patients to complete a second-line regimen. butol. Pyrazinamide is included in recommendations for
MDR/XDR tuberculosis treatment is a complex health inter- treating tuberculosis in pregnant women by the WHO, but
vention: consultation with a specialist experienced in the it has not been included in recommendations in the United
management of these patients is strongly advised. Often States because of insufficient information about possible
second-line drugs are the last best hope for patients with harm to the fetus. Streptomycin, which interferes with
drug-resistant tuberculosis, and it is crucial that such treat- development of the ear and may cause congenital deafness,
ment be designed for maximal effectiveness with the active is the only antituberculosis drug documented to have
participation of the patient to overcome the challenges harmful effects on the fetus.384 This potential is presumably
faced by both provider and patient with MDR/XDR shared by amikacin, kanamycin, and capreomycin; however,
tuberculosis.375 there is little or no information about the effects of these
Of great concern, tuberculosis caused by organisms resis- drugs on the fetus, or about the potential hazards of cyclo-
tant to all drugs tested has been described in India but likely serine, ethionamide, and pyrazinamide. Although several
exists elsewhere as well.376,377 However, because of uncer- antituberculosis drugs are present in breast milk, their con-
tainties about the connection between second-line drug centrations and the total amounts that could possibly be
susceptibility test results and patient outcomes, it is not ingested by a nursing infant are such that adverse effects
clear that there are no treatment options. Nevertheless, at would be unlikely. Thus, no modifications of treatment regi-
least at this time, there are no specific recommended treat- mens are recommended for nursing mothers.299
ment options for such patients and symptomatic or pallia-
tive care may be required. Although the number of such Associated Conditions. Tuberculosis commonly devel-
cases is likely to be small, providers should be attuned to the ops in association with other conditions, either because an
possibility of such situations and be prepared to provide underlying disease or its treatment alters immune respon-
appropriate palliative management to relieve suffering siveness, thereby predisposing to tuberculosis (e.g., HIV
caused by the disease. infection, hematologic or reticuloendothelial malignancies,
chronic renal disease or diabetes mellitus, use of tumor
Treatment in Other Patient Groups necrosis factor inhibitors), or because the accompanying
Children. The basic principles that apply in the manage- condition is common in the same social and cultural milieu
ment of adults with pulmonary tuberculosis are equally as tuberculosis, particularly alcoholism and all its compli-
applicable in children. Although children have been cations and other forms of substance abuse.385-387 Because
excluded from nearly all clinical trials of short durations of all of these conditions may affect the response to and
chemotherapy, there are several reports documenting the outcome of treatment, therapeutic decisions must be made
usefulness of 6- and 9-month regimens in children.378,379 on an individualized basis and, when possible, steps must
The most frequent difference between treating children and be taken to correct the immunosuppression.
adults is the more limited use of ethambutol. Because chil- In patients with impaired renal function, streptomycin,
dren tend to have forms of tuberculosis that are associated kanamycin, amikacin, and capreomycin should be avoided
with lower bacillary populations, the likelihood of drug if at all possible or given two to three times per week in the
resistance is less. Moreover, young children generally usual dose. If there is severe impairment of renal function,
cannot have visual acuity testing performed accurately and reduction in frequency of administration of ethambutol
thus cannot be monitored for toxicity. However, if etham- and pyrazinamide to two to three times per week may be
butol is used, the dose should be increased to 20 mg/kg necessary.299 Liver disease, particularly alcoholic hepatitis
because of differences in pharmacokinetics between adults and cirrhosis, is commonly associated with tuberculosis. In
and children.380 At least in younger children, sputum general, the complications of potentially hepatotoxic anti-
specimens for bacteriologic evaluations cannot usually tuberculosis drugs have not been greater in patients with
be obtained.381 Consequently, the response to treatment is liver disease.388 However, detecting any such adverse effects
assessed by clinical and radiographic criteria. For this same may be difficult because of the preexisting disorder of
hepatic function. Moreover, a drug that would cause minor therapeutic indications for surgery, tuberculosis is some-
hepatotoxicity in a person with normal liver function could times diagnosed by examination of a pulmonary mass or
have major consequences in a patient with severe liver nodule that was resected owing to suspicion of malignancy.
disease. Options in treating patients with severe liver disease In any situation involving possible lung surgery in
include treatment without isoniazid by using rifampin, eth- patients with or suspected of having tuberculosis, including
ambutol, and pyrazinamide for 6 months; treatment the resection of a solitary nodule in a patient with a positive
without pyrazinamide for a total duration of 9 months; tuberculin reaction, it is desirable for the patient to have
treatment with only one potentially hepatotoxic drug, been receiving adequate antituberculosis chemotherapy
usually retaining rifampin and adding ethambutol and a before the operation. This will minimize the possibility of
fluoroquinolone for a total of 12 to 18 months; or treat- spread of tuberculosis within the lung and of bronchial
ment with a regimen that contains no hepatotoxic drugs, stump infection and empyema. The optimum amount of
such as streptomycin, ethambutol, a fluoroquinolone, and time before operation that treatment should be given is not
perhaps another second-line drug for 18 to 24 months.299 clear, but in emergencies, such as massive hemoptysis, at
In patients with severe liver disease, routine testing of liver least single doses of the drugs should be given, whereas
function should be performed at baseline and frequently with elective procedures, it is desirable to wait at least until
during treatment. Finally, in patients with psychiatric dis- the sputum smear is negative. If the sputum smear is nega-
orders, close supervision of treatment with directly observed tive to begin with, 2 weeks of treatment is reasonable.
therapy of all medications is essential.
Corticosteroids. The use of corticosteroids in pulmonary
Adjunctive Therapy tuberculosis has been and remains controversial. In view
Currently, the adjunctive therapies for pulmonary tubercu- of the well-known effects of corticosteroids in decreasing
losis include surgery and corticosteroid treatment. Although cell-mediated immune responses, it seems counterintuitive
surgery was once a mainstay of treatment for pulmonary that these same agents could be beneficial. Nevertheless,
tuberculosis, since the advent of chemotherapy, it has corticosteroids, by interfering with the tissue-damaging
rarely been indicated. Artificial pneumothorax, pneumo- immune response, may minimize the adverse effects of the
peritoneum, phrenic nerve interruption, plombage, and inflammatory reaction. For this reason, corticosteroids may
thoracoplasty—procedures designed to collapse portions of under certain conditions be of benefit in patients with pul-
the lung and close cavities—were common interventions monary tuberculosis who are receiving adequate chemo-
until the 1960s but then rendered obsolete by the effective- therapy. These conditions were defined by a controlled trial
ness of chemotherapy.389 Rarely, even now, patients with reported by Johnson and colleagues391 in which all patients
MDR pulmonary tuberculosis are treated with either pneu- were treated with effective antituberculosis chemotherapy
moperitoneum or thoracoplasty. (although rifampin was not yet available) and were assigned
Currently, surgical resection is the most commonly per- at random to receive either methylprednisolone or placebo.
formed surgical procedure and may be indicated in several This study demonstrated that corticosteroid treatment most
situations. In patients with tuberculosis caused by MDR or benefited the seriously ill patient (defined by low serum
XDR organisms anatomically limited within the lung and albumin concentration, low body weight, and severe weight
who are otherwise deemed to be surgical candidates, resec- loss) who had extensive tuberculosis. This benefit was evi-
tion may be an effective therapeutic option. A systematic denced mainly by an increase in the rate of radiographic
review and meta-analysis suggested that the outcomes clearing; there was no adverse effect on the bacteriologic
were improved in patients who underwent surgery in addi- response. In less severely ill patients, methylprednisolone
tion to medical therapy.390 The outcome assessed at 12 was either of no benefit or actually decreased the speed of
months postprocedure was estimated as successful in 87% sputum conversion. These data suggest that the major role
of patients who underwent surgery for MDR tuberculosis. of corticosteroid treatment is in patients with severe tuber-
All-cause mortality was 6%. The results for patients with culosis and severe systemic effects. Although not considered
XDR tuberculosis were estimated to be 69% successful with in the study by Johnson and colleagues, steroids may also
an all-cause mortality of 4%. However, the literature is dif- be of benefit in patients with marked abnormalities of gas
ficult to interpret because of differences in case selection for exchange and respiratory failure.392 A more recent system-
surgical procedures, differences in the procedures per- atic review examined the results of clinical trials of cortico-
formed (which often are not stated in meta-analyses), varia- steroids as adjunctive therapy for pulmonary tuberculosis
tions in extent of the tuberculous process, differing drug and came to essentially the same conclusions.393 Dexameth-
regimens, and finally the fact that controlled clinical trials asone is also recommended in tuberculous meningitis166
have not been done (and would be difficult to design). and, although the evidence is less persuasive, corticoste-
Ideally, before surgery the bacillary population should be roids are often given in tuberculous pericarditis.
reduced as much as possible with drugs to which the organ-
ism is susceptible. However, the timing of surgery can be
difficult, in that the effectiveness of a limited second-line
drug regimen cannot always be predicted. Resection may EXTRAPULMONARY
also be necessary because of massive hemoptysis associated TUBERCULOSIS
with current or old tuberculosis, because of residual lung
damage (e.g., bronchiectasis) exacerbated by recurrent bac- Extrapulmonary tuberculosis presents more of a diagnostic
terial infections, or because of a bronchopleural fistula and therapeutic problem than does pulmonary tuberculosis.
usually with a tuberculous empyema. In addition to these In part this relates to its being less common and therefore
less familiar to most clinicians.394,395 In addition, extrapul- culture of the material. Smears show acid-fast organisms in
monary tuberculosis involves relatively inaccessible sites, approximately 25% to 50% of biopsy specimens, and M.
and often, because of the vulnerability of the areas involved, tuberculosis is isolated in approximately 70% of instances in
much greater damage can be caused by fewer bacilli. The which the final diagnosis is considered to be tuberculosis.398
combination of small numbers of bacilli in inaccessible sites Caseating granulomas are seen in nearly all biopsy speci-
makes bacteriologic confirmation of a diagnosis more dif- mens from immunocompetent patients. In immunodefi-
ficult, and invasive procedures are frequently necessary to ciency states, granulomas may be poorly formed or
establish a diagnosis. In addition to the need for invasive absent.399
diagnostic procedures, surgery may be an important com- The rate of response of tuberculous lymphadenitis to the
ponent of management. standard 6-month regimen is much slower than that of
In 2012 in the United States, 21% of newly reported pulmonary tuberculosis. Nodes may enlarge, new nodes
cases of tuberculosis involved extrapulmonary sites only may appear, and fistulas may develop during treatment that
and an additional 10% involved both pulmonary and extra- ultimately proves effective, but true bacteriologic relapse
pulmonary sites.27 The proportion of patients with extra- after completion of therapy is unusual.400
pulmonary involvement is greater among patients with HIV Corticosteroid treatment has been used to shrink intra-
infection. In one large retrospective study of tuberculosis in thoracic nodes and relieve bronchial obstruction, primarily
patients with HIV infection, approximately one third of the in children. In a controlled study, Nemir and coworkers401
patients had only extrapulmonary sites of involvement, one demonstrated that corticosteroids increase the rate of reso-
third had both pulmonary and extrapulmonary disease, lution of radiographic changes thought to be due to bron-
and one third had only pulmonary involvement.396 Because chial narrowing by lymph nodes or endobronchial lesions
of the frequency of extrapulmonary tuberculosis among in children with primary tuberculosis. Apart from this indi-
HIV-infected patients, diagnostic specimens from any sus- cation, there is no clear role for corticosteroids in lymphatic
pected site of disease should be cultured for mycobacteria, tuberculosis.
including blood and bone marrow from any febrile patient Surgical intervention may be necessary to make a diag-
who does not have an obvious localized site of disease. nosis of tuberculous lymphadenitis and, on occasion, surgi-
cal incision and drainage are needed to prevent spontaneous
drainage and fistula formation. Surgical excision of involved
LYMPHATIC TUBERCULOSIS
nodes, strictly as an adjunct to chemotherapy, is associated
Lymphatic tuberculosis accounts for approximately 42% of with perhaps a slightly worse outcome than medical treat-
the cases of extrapulmonary tuberculosis in the United ment with aspiration of the node or medical treatment
States.27 Although the basic descriptive epidemiology of alone.402
tuberculosis applies to lymphatic tuberculosis, there are a Various other forms of extrapulmonary tuberculosis,
few differences. This form of tuberculosis is more common including genitourinary, bone and joint, central nervous
among children than among adults. In addition, lymphatic system, abdominal, and pericardial tuberculosis are dis-
tuberculosis differs from the overall pattern in that it cussed in the online version of this chapter.
happens more frequently in women. It also appears to be
more common among Asians and Pacific Islanders than
among blacks and whites. Among HIV-infected persons, the
incidence of tuberculous lymphadenitis increases as the TREATMENT OF LATENT
level of CD4+ T cells decreases.397 TUBERCULOUS INFECTION
Tuberculous lymphadenitis usually presents as painless
swelling of one or more lymph nodes. The nodes most com- The observations on which treatment of LTBI are based
monly involved are those of the posterior or anterior cervi- were made in the 1950s. In these experimental studies, it
cal chain or those in the supraclavicular fossa. Frequently was found that animals given isoniazid before being chal-
the process is bilateral, and other noncontiguous groups of lenged by M. tuberculosis had a much lower frequency of
nodes can be involved. At least initially, the nodes are dis- tuberculosis.431 Subsequently, it was found that isoniazid
crete and the overlying skin is normal. With ongoing given to children with primary tuberculosis nearly elimi-
disease, the nodes may become matted and the overlying nated extrapulmonary spread of the disease.432 These
skin inflamed. Rupture of the node can result in formation results provided the rationale for several large U.S. Public
of a sinus tract, which may persist for years. Intrathoracic Health Service studies of the effectiveness of isoniazid in
adenopathy may compress bronchi, causing atelectasis, preventing tuberculosis. These studies were double-blind,
thereby leading to lung infection and perhaps bronchiecta- placebo-controlled clinical trials that involved approxi-
sis. Although rare, upper airway obstruction may result mately 70,000 participants who were in a number of dif-
from cervical node enlargement. Both chylous pleural effu- ferent settings and who had a variety of different risk factors
sion and ascites have resulted from intrathoracic or abdom- for tuberculosis. The design and results of these studies
inal node involvement with obstruction of retroperitoneal are described in detail by Ferebee.433 The findings were
lymphatics or the thoracic duct. Tuberculous lymphadeni- remarkably similar in all groups studied; participants given
tis may also appear or worsen as a manifestation of IRIS (see isoniazid had a reduction of approximately 80% in the
Fig. 35-12). incidence of tuberculosis during the year the medication
The diagnosis of tuberculous lymphadenopathy is estab- was given, in comparison with those given placebo. The
lished by lymph node biopsy or aspiration with histologic protective effect decreased during subsequent years, but
examination, including stains for acid-fast organisms and the treated groups still showed approximately 50% less
tuberculosis than did the control groups each year after the culosis incidence country, perhaps by reducing reinfection
medication year through 10 to 12 years of observation. with M. tuberculosis.439 However, this regimen is not recom-
Overall, isoniazid reduced the incidence of tuberculosis by mended by WHO at this time.
approximately 60%. Likewise, although there are data showing efficacy of the
The effectiveness of antituberculosis drugs in preventing 12-dose isoniazid-rifapentine regimen in adults with HIV
tuberculosis is presumably a result of the reduction of the infection, it is not yet recommended by WHO.440 Although
viable population of sequestered bacilli in inactive or radio- antiretroviral therapy has a substantial effect in reducing
graphically invisible lesions in the lungs and elsewhere. the risk of tuberculosis, there is additive benefit from isonia-
However, on occasion, treatment may be given to persons zid preventive treatment.197,199,441
who have been exposed to tuberculosis but do not have a
positive TST or IGRA. In this situation, treatment is assumed Close Contacts of New Cases
to prevent the establishment of a tuberculous infection, an Two percent to 4% of persons in close contact with a person
example of “primary prophylaxis.” However, the effective- with infectious tuberculosis develop tuberculosis in the year
ness of antituberculous drugs in preventing tuberculosis is after exposure.442-444 In young children and adolescents, the
limited in high-prevalence populations: a recent large trial risk is perhaps twice that in adults. Because the TST or
in South African gold miners found only a temporary benefit IGRA result may be negative if infection is recent, all close
of isoniazid preventive treatment, most likely because of contacts should be treated. Those with a TST of 5 mm or
frequent re-exposure to tuberculosis after the end of the more should be considered to be infected and should receive
treatment.433a a full course of preventive therapy. Close contacts who have
negative TST should be retested 2 to 3 months after the
index case has ceased being infectious or after contact has
INDICATIONS FOR TREATMENT
been broken. If the TST at that time is less than 5 mm or
The recommendations for testing for and treatment of LTBI if the IGRA has not converted, isoniazid can be discontin-
reflect the concept that only persons who are at increased ued; if the reaction is 5 mm or more or an IGRA has con-
risk of tuberculosis should be tested for latent infection; verted from negative or indeterminate to positive, the drug
thus, any person who is tested and is found to have a posi- should be continued for a full course. Contacts known to be
tive test should be considered for treatment.434,435 The two HIV-infected should be treated even if the TST result is
broad categories of persons in whom the risk of tuberculo- negative.434
sis is substantially higher than that of the general popula-
tion of the United States are persons who are either known Persons with Recent Infection
or presumed to have been recently infected with M. tuber- As discussed in the section describing the pathogenesis of
culosis and persons who have clinical conditions that tuberculosis, the risk of developing tuberculosis is greatest
increase the risk of progressing from latent infection to during the initial 1 to 2 years after acquisition of the infec-
active tuberculosis. The specific groups in which treatment tion. Any person who is documented to have had a conver-
is indicated are as follows (in order of decreasing degree of sion of the TST or an IGRA from negative to positive should
risk for developing tuberculosis). be considered newly infected and receive treatment. A skin
test conversion is defined as an increase in reaction size of
Persons with HIV Infection 10 mm or more within a 2-year period for persons younger
A number of studies have shown that the rates of tuber- than 35 and a 15-mm or more increase for persons older
culosis among persons who are infected with both M. than 35. TST reactors younger than 5 years of age should
tuberculosis and HIV are extremely high, ranging from 3% be accorded a high priority for preventive therapy, both
to 10% per year.436,437 The effectiveness of preventive because they obviously have been infected relatively recently
therapy among persons with HIV infection has been exam- and because of the potential for severe disease in this age
ined in a Cochrane review that included data through group. There is no consensus on the change in the IGRA
April 2008.438 Preventive therapy (with any anti-TB drug) result to define a conversion.
versus placebo was associated with a lower incidence of
active tuberculosis with a relative risk (RR) of 0.68. The Persons with Stable Radiographic Findings
benefit was greater in individuals with a positive TST (RR Consistent with Previous Tuberculosis
0.38) than in those who had a negative test (RR 0.89). This group includes persons with a history of tuberculosis
The efficacy was similar for all regimens, regardless of who never received chemotherapy or were not treated ade-
drug type, frequency, or duration of treatment. However, quately and persons with no known history of the disease.
compared with isoniazid monotherapy, short-course mul- The rate at which new episodes of tuberculosis develop in
tidrug regimens were much more likely to require discon- these groups ranges from approximately 0.4% to 3.5% per
tinuation of treatment due to adverse effects. Although year.445-447 The risk is lowest in persons with small lesions
there was reduction in mortality with isoniazid mono- that have been stable for a long period. In persons with
therapy, there was no evidence that preventive therapy radiographic abnormalities, it is essential that current
reduced all-cause mortality. tuberculosis be excluded by a careful clinical and bacterio-
Currently WHO recommends isoniazid given for at least logic evaluation. Because exclusion of active tuberculosis
6 months to persons with HIV infection at risk of tubercu- might not be feasible or possible at the initiation of therapy,
losis regardless of the TST result. Some data suggest that a an alternative approach is to begin therapy with multiple
36-month treatment duration further reduces the risk of drugs: isoniazid, rifampin, and pyrazinamide, sometimes
tuberculosis in persons with HIV infection in a high tuber- with ethambutol. If disease is determined to be active by a
GENITOURINARY TUBERCULOSIS Positive urine cultures may manifest in the absence of

any clinical, laboratory, or radiographic findings, which
The epidemiologic pattern of genitourinary tuberculosis suggests concomitant genitourinary tuberculosis in patients
parallels that of tuberculosis in general, with the exception with other forms of tuberculosis. Bentz and coworkers408
of HIV-infected patients. The pathogenesis is thought to be found unanticipated positive urine cultures in 21% of
due to seeding of the kidney at the time of the initial infec- patients with other extrapulmonary forms of tuberculosis
tion and bacillemia. This mechanism is supported by the and in 5% of those with pulmonary tuberculosis alone.
finding that, with careful study, tuberculous lesions can be Renal tuberculosis, at least as indicated by a positive
found in both kidneys in 90% of patients with renal tuber- urine culture, may develop in patients with HIV infection.
culosis, even though the disease is clinically evident in only In one series, positive urine cultures were found in 12 (71%)
one kidney.403 Lower genitourinary tract involvement is of 17 cultures submitted in patients with tuberculosis and
thought to represent spread from the kidneys, but it may advanced HIV infection, although this was not a systematic
also represent spread by hematogenous seeding. Genital sampling.396
lesions were reported by Medlar and coworkers404 in 13% There are several treatment considerations for genitouri-
of men with disseminated renal lesions, 52% of those with nary tuberculosis apart from standard chemotherapy.
caseating lesions, and 100% of those with cavitary lesions Nephrectomy, formerly a mainstay of therapy for renal
in the kidney. Genital involvement without renal involve- tuberculosis, now is seldom indicated; however, in patients
ment was reported in 11%. who have tuberculosis caused by MDR organisms and who
In patients with genitourinary tuberculosis, local symp- can tolerate removal of a kidney, nephrectomy may be indi-
toms predominate and systemic symptoms are less cated. Nephrectomy may also be indicated for patients who
common.405,406 Dysuria, hematuria, and frequent urination have recurrent pyogenic bacterial infections in a kidney
are common, and flank pain may also be noted. However, destroyed by tuberculosis, for patients with persistent pain,
in general the symptoms are subtle, and often there is and for those with massive hematuria. Surgical or endo-
advanced destruction of the kidneys by the time a diagnosis scopic procedures may also be necessary to correct ureteral
is established.407 In women, genital involvement is more strictures and to augment the capacity of a contracted
common without renal tuberculosis than in men and may bladder.
cause pelvic pain, menstrual irregularities, and infertility
as presenting complaints.406 In men, a painless or only BONE AND JOINT TUBERCULOSIS
slightly painful scrotal mass is probably the most common
presenting symptom of genital involvement, but symptoms The incidence of tuberculosis involving the joints and bones
of prostatitis, orchitis, or epididymitis may also exist.405 A increases with increasing age and is equally frequent among
substantial number of patients with any form of genitouri- men and women. In comparison with blacks and whites,
nary tuberculosis are asymptomatic, and the disease is other racial groups are less likely to have skeletal involve-
detected because of an evaluation for an abnormal urinaly- ment. Skeletal tuberculosis does not appear to be more fre-
sis. In patients with renal or genital tuberculosis, urinalyses quent in persons with HIV infection.
are abnormal in more than 90%; the main findings are It is presumed that most osteoarticular tuberculosis
pyuria, hematuria, or mixed pyuria and hematuria. Pyuria results from endogenous reactivation of foci of infection
in an acidic urine with no organisms isolated from a routine seeded during the initial bacillemia, although spread from
urine culture should prompt an evaluation for tuberculosis. paravertebral lymph nodes has been postulated to account
Occasionally, when there is an isolated genital focus of for the common localization of spinal tuberculosis to the
disease or when a tuberculous kidney is blocked by a ure- lower thoracic and upper lumbar vertebrae. It is also postu-
teral stricture, the urinalysis may be normal and cultures lated that the predilection for tuberculosis to localize in
may be sterile. the metaphyses of long bones is due to the relatively rich
The suspicion of genitourinary tuberculosis should be blood supply and scarcity of phagocytic cells in this portion
heightened by the presence of abnormalities on the chest of the bone.409 After beginning in the subchondral region
film. In most series, 50% to 75% of patients have chest of the bone, the infection spreads to involve the cartilage,
radiographic abnormalities, although many of these may synovium, and joint space. This produces the typical find-
be the result of previous, not current, tuberculosis.405,406 ings of metaphyseal erosion and cysts and loss of cartilage
When genitourinary tuberculosis is suspected, at least with narrowing of the joint space. Typically, in the spine
three first-voided early morning urine specimens should be these changes involve two adjacent vertebrae and the inter-
collected and stained for AFB and cultured for mycobacte- vertebral disc (eFig. 35-1). An “atypical” form of spondylitis
ria. In men, saprophytic Mycobacterium smegmatis may without evidence of disc involvement may be seen and may
cause a positive smear. However, in the presence of abnor- account for more than half of the patients.410-412 Paraverte-
malities suggesting tuberculosis, the finding of a positive bral or other para-articular abscesses may develop with
smear should be interpreted as confirming the diagnosis of occasional formation of sinus tracts. Although weight-
genitourinary tuberculosis until the results of cultures are bearing joints are the most common sites for skeletal tuber-
known. M. tuberculosis is isolated from the urine in 80% to culosis, any bone or joint may be involved.409 In most series
95% of cases of genitourinary tuberculosis.405,406 Diagnosis of osteoarticular tuberculosis, tuberculosis of the spine
of isolated genital lesions usually requires biopsy because (Pott disease) makes up 50% to 70% of the cases reported.
the differential diagnosis often includes neoplasia, as well as In adults the lower thoracic and upper lumbar vertebrae are
other infectious processes. most commonly involved, whereas in children the upper
625.e2 PART 3 • Clinical Respiratory Medicine
thoracic spine is the most frequent site. The hip or knee is in adults, meningitis accounts for only approximately 6%
involved in 15% to 20% of cases, and shoulders, elbows, of all cases of extrapulmonary tuberculosis, which are
ankles, wrists, and other bones or joints also make up 15% equally divided between males and females.27
to 20%. Usually only one bone or joint is involved, but occa- Central nervous system tuberculosis, especially tubercu-
sionally the process may be multifocal. Evidence of either lomas, seems to develop with greater frequency among HIV-
previous or current pulmonary tuberculosis is found in infected persons. Central nervous system tuberculomas
approximately half the reported patients, and other extra- have been reported even in patients who are receiving what
pulmonary sites may be involved as well. should be adequate chemotherapy.415 Because tuberculo-
The first diagnostic test undertaken is usually a radio- mas may be indistinguishable on CT scan from the lesions
graph of the involved area. Early in the process, the only of toxoplasmosis, specific diagnosis is necessary.
abnormality noted may be soft-tissue swelling. Computed Meningitis presumably can result from direct meningeal
tomography (CT) scans and magnetic resonance imaging of seeding and proliferation during a tuberculous bacillemia
the spine are considerably more sensitive than routine films either at the time of initial infection or reactivation of an
and should be obtained when there is a high index of sus- old pulmonary focus, or it can also result from reactivation
picion of an infectious process. Radionuclide bone scanning of an old parameningeal focus with rupture into the sub-
with technetium-99m can demonstrate occult skeletal arachnoid space.416 The consequences of the subarachnoid
involvement in patients with normal radiographs. Likewise, space contamination include diffuse meningitis, a localized
gallium-67 scanning may define unsuspected sites, espe- arteritis, encephalitis, and myelitis. The symptoms depend
cially soft-tissue involvement not seen on the bone scan. primarily on which of these processes predominates. With
Confirmation of the diagnosis is obtained by aspiration meningitis, the process is primarily located at the base of
of joint fluid or periarticular abscesses or by biopsy of bone the brain.417 Symptoms therefore include those related to
or synovium with histologic and microbiologic evaluation cranial nerve involvement in addition to headache,
of the material obtained. Acid-fast stains are positive in decreased level of consciousness, and neck stiffness. The
20% to 25% of samples of joint fluid, and M. tuberculosis is duration of illness before diagnosis is variable and related
isolated in approximately 60% to 80% of them.409 Biopsy partly to the presence or absence of other sites of involve-
specimens of synovium or bone have a higher yield and ment. In a large series of patients, the average duration of
enable histologic examination as well. Evidence of granulo- illness was 12 days.418 In most series, more than 50% of
matous inflammation even in the absence of bacteriologic patients with meningitis have abnormalities on chest film
proof of the diagnosis is sufficient evidence of tuberculosis that are consistent with an old or current tuberculous
to begin therapy unless another cause is found. process, often miliary tuberculosis. At autopsy, dissemi-
Standard chemotherapy of 6 to 9 months’ duration is nated disease is found in a high percentage of patients with
highly successful in skeletal tuberculosis, but surgery is meningitis. In patients with tuberculous meningitis, sputum
occasionally a necessary adjunct.410 The longer duration of cultures have been positive in 40% to 50%; thus, a substan-
treatment has been suggested because of the difficulties in tial number of patients have pulmonary and systemic
assessing response. Several controlled studies have docu- symptoms in addition to those referable to the central
mented that chemotherapy conducted largely on an ambu- nervous system. Patients in whom arteritis is the predomi-
latory basis is effective in curing spinal tuberculosis without nant manifestation of meningitis can present with a variety
the need for immobilization.411 The role of emergency spinal of focal central nervous system ischemic syndromes in
cord decompression in patients with Pott disease and early addition to the symptoms already described.
neurologic findings is not clear, and, if paraplegia is already In tuberculous meningitis, the lumbar puncture usually
present, the benefit of surgical intervention is even less shows increased opening pressure, and the cerebrospinal
clear. Moreover, there is no well-defined surgical procedure fluid (CSF) usually contains between 100 and 1000
of choice. An “all-or-none” approach has been advocated cells/µL.394,418 In approximately 65% to 75% of patients,
by several surgeons,412-414 which means that surgery is not lymphocytes predominate, whereas polymorphonuclear
performed except in patients with progressive neurologic leukocytes predominate in the remainder, generally early in
deterioration unresponsive to chemotherapy—in whom all the course of the illness. The CSF protein concentration is
affected bone is removed and an anterior spinal fusion is elevated in nearly all patients. Very high (>3300 mg/dL)
performed; there is no role for simple debridement other protein concentrations have been associated with a poor
than for diagnosis. Surgery may be indicated in other forms prognosis; the glucose concentration in CSF is usually low,
of articular tuberculosis when there is extensive destruc- but not as low as that often found in pyogenic bacterial
tion of the joint or surrounding soft tissues, in which case meningitis.418 Acid-fast organisms are seen on smears of
synovectomy and joint fusions may be necessary. CSF in only 10% to 20% of patients, and the rate of culture
positivity varies from 25% to 80% but is generally in the
CENTRAL NERVOUS SYSTEM TUBERCULOSIS lower end of the range.418 In a substantial number of
patients, M. tuberculosis is isolated from other sources,
Meningitis is the most frequent form of central nervous which, in the presence of compatible CSF findings, is suffi-
system tuberculosis; solitary or multiple tuberculomas cient to diagnose tuberculous meningitis. In view of the
ensue less commonly. The epidemiologic pattern of central severity of tuberculous meningitis, a presumptive diagnosis
nervous system tuberculosis is quite different from that of justifies empirical treatment if no other diagnosis can be
either pulmonary or other forms of extrapulmonary tuber- established promptly. Because of the difficulty with estab-
culosis, in that the peak incidence is in infants and children lishing a diagnosis of tuberculous meningitis by bacterio-
up to age 4. Although an appreciable number of cases exist logic methods, Thwaites and associates418 developed and
validated a clinical scoring system by which tuberculous patients with advanced pulmonary tuberculosis, presum-
meningitis could be separated from pyogenic bacterial men- ably being caused by swallowed bacilli from the lungs. In a
ingitis. Younger age (<36 years), lower peripheral white prospective study conducted between 1924 and 1949,
blood cell count (<15,000/mm3), longer duration of illness intestinal abnormalities compatible with tuberculous enter-
(>6 days), lower CSF white blood cell count (<900/µL), and itis were found by contrast radiography in 1%, 4.5%, and
lower percentage (<75%) of neutrophils in the CSF were 24.7% of patients with minimal, moderately advanced, and
associated with a greater likelihood of a tuberculous far advanced pulmonary tuberculosis, respectively.421
etiology. The clinical manifestations of abdominal tuberculosis
A meta-analysis of 14 studies of nucleic acid amplifica- depend on the areas of involvement. In the gut itself, tuber-
tion tests for the diagnosis of tuberculous meningitis found culosis may be in any location from the mouth to the anus,
a combined sensitivity of 56% and a specificity of 98%.309 although lesions proximal to the terminal ileum are
Thus, when a nucleic acid amplification test is positive, one unusual. The most common sites of involvement are the
can assume that the etiology is tuberculous, but a negative terminal ileum and cecum; other portions of the colon and
result does not exclude the diagnosis. the rectum are involved less frequently.422 In the terminal
If there are no epidemiologic indicators of possible ileum or cecum, the most common manifestations are pain
resistance, a treatment regimen of isoniazid, rifampin, (which may lead to a misdiagnosis of appendicitis) and
pyrazinamide, and ethambutol should be effective. The intestinal obstruction. A palpable mass may be noted that,
recommended length of the continuation phase is at least together with its radiographic appearance, can easily be
7 months, for a total treatment duration of 9 to 12 months, mistaken as a carcinoma. Rectal lesions usually present as
although there are no clinical trials that serve to define the anal fissures or fistulas or perirectal abscesses. In addition
optimum treatment duration. to carcinoma, the differential diagnosis of these findings
Corticosteroid treatment has a beneficial effect in patients includes inflammatory bowel disease. Because of the
with tuberculous meningitis and cerebral edema,315 and it concern regarding carcinoma, the diagnosis often is made
decreases the frequency of adverse sequelae in children through surgery.423
with less advanced disease.419 Given the poor prognosis of Tuberculous peritonitis commonly causes pain as its pre-
tuberculous meningitis, the reasonably good data support- senting manifestation, often accompanied by abdominal
ing corticosteroid use in more severe forms of the disease, swelling. Fever, weight loss, and anorexia are also common.
and the paucity of information in patients with less Active pulmonary tuberculosis is uncommon in patients
advanced disease, corticosteroid treatment, specifically with tuberculous peritonitis. Because the process frequently
with dexamethasone, is recommended for all patients315 at coexists with other disorders, especially cirrhosis with
a dosage of 12–16 mg/day for 3 weeks, then decreased ascites, the symptoms of tuberculosis may be obscured. The
gradually during the next 3 to 5 weeks. Even with effective combination of fever and abdominal tenderness in a person
chemotherapy and corticosteroids, however, both the mor- with ascites should always prompt an evaluation for intra-
tality rate and rate of residual neurologic abnormalities abdominal infection, and paracentesis should be performed.
from tuberculous meningitis remain high. Ascitic fluid in tuberculous peritonitis is exudative and con-
The other major central nervous system form of tuber- tains between 50 and 10,000 leukocytes per microliter, the
culosis, the tuberculoma, presents a more subtle clinical majority of which are lymphocytes, although polymorpho-
picture than does tuberculous meningitis.420 The usual pre- nuclear leukocytes occasionally predominate.424 Acid-fast
sentation is that of a slowly growing focal lesion, although organisms are rarely seen on smears of the fluid, and cul-
a few patients have increased intracranial pressure and no tures are positive in only approximately 50%, although the
focal findings. The CSF is usually normal, and the diagnosis yield increases if a large volume of fluid is submitted for
is established by CT scanning or magnetic resonance culture. Because of the generally low yield from culture of
imaging and subsequent resection, biopsy, or aspiration of the fluid, laparoscopic biopsy is often necessary to confirm
any ring-enhancing lesion. The response to antituberculo- the diagnosis.
sis chemotherapy is good, and corticosteroids are indicated Standard chemotherapy is effective in abdominal tuber-
only if there is an increase in intracranial pressure. culosis. Corticosteroids have been advocated in tuberculous
peritonitis to reduce the risk of adhesions causing intestinal
ABDOMINAL TUBERCULOSIS obstructions, but this recommendation is controversial
because of the low frequency of obstruction. As discussed
Tuberculosis can involve any intra-abdominal organ and previously, surgery is often necessary to establish a diagno-
peritoneum. The age distribution of abdominal tuberculosis sis and, in addition, may be necessary to relieve intestinal
shows a higher incidence in young adults and a second obstruction.
peak in older persons. Men and women have similar inci-
dences. The abdomen is a common site of disease in HIV- PERICARDIAL TUBERCULOSIS
infected persons.
Abdominal tuberculosis presumably results from seeding The descriptive epidemiology of pericardial tuberculosis is
at the time of initial infection and then either direct or late not well defined, but in general it tends to afflict older
progression to clinical disease. Peritonitis can also be caused persons, particularly nonwhites and men. The pericardium
by rupture of tuberculous lymph nodes within the abdomen, may become involved during the initial bacillemia, with
and intestinal tuberculosis may result from direct implanta- early progression to clinically evident disease or recrudes-
tion in the gut of ingested tubercle bacilli. Before the advent cence after a quiescent period. Hematogenous seeding
of chemotherapy, tuberculous enteritis was common in may also be present during the course of endogenous
reactivation. Alternatively, there may be direct extension of The fibrotic reaction progresses to complete fusion of vis-
an adjacent focus of disease from the lung parenchyma, ceral and parietal pericardium and encasement of the heart
pleura, or tracheobronchial lymph nodes into the pericar- in a rigid scar that often becomes calcified. Impairment of
dium. Like the pleura, the pericardium is a serosal surface coronary circulation is common. At this point the histologic
capable of exuding large amounts of fluid in response to pattern is usually nonspecific; thus, confirmation of a
inflammation. As presumably happens in tuberculous pleu- tuberculous etiology is infrequent.
ritis with effusion, it is likely that hypersensitivity plays a The definitive diagnosis of tuberculous pericarditis
role in producing the intense inflammatory response and requires identification of tubercle bacilli in pericardial fluid
abundant effusion in the pericardium. This would account or tissue. Although not conclusive, demonstration of case-
for the relative infrequency of isolation of tubercle bacilli ating granulomata in the pericardium and consistent
from pericardial fluid, the nonpurulent nature of the fluid, clinical circumstances provide convincing evidence of a
and the generally prompt response to antituberculosis che- tuberculous etiology. Less conclusive but still persuasive
motherapy in most instances. Conversely, rupture of a evidence is the finding of another form of tuberculosis
caseous lymph node into the pericardium may cause con- in a patient with pericarditis of undetermined cause.
tamination with a much greater number of organisms; a Approximately 25% to 50% of patients with tuberculous
greater inflammatory response with thicker, more purulent pericarditis have evidence of other organ involvement,
fluid; and a greater likelihood of either early or late hemo- particularly pleuritis, at the time pericarditis is diag-
dynamic effects. nosed.427 Still less direct and more circumstantial evidence
The most common form or stage of tuberculous pericar- of a tuberculous etiology is the combination of a positive
ditis is characterized by pericardial effusion with little peri- intermediate-strength TST or IGRA reaction and pericar-
cardial thickening or epicardial involvement. Because in ditis of unproved cause.
most instances the fluid accumulates slowly, the pericar- Because of the potentially life-threatening nature of peri-
dium can expand to accommodate large volumes (2 to 4 L) cardial tuberculosis, treatment with antituberculosis agents
with little apparent hemodynamic compromise. Symptoms should be instituted promptly once the diagnosis is made or
of cardiopulmonary origin tend to manifest later and strongly suspected. It appears that the likelihood of con-
include cough, dyspnea, orthopnea, ankle swelling, and striction is greater in patients who have had symptoms
chest pain. The chest pain may occasionally mimic angina longer; thus, early therapy may reduce the incidence of this
but usually is described as being dull, aching, and often complication. Several studies have suggested that cortico-
affected by position and inspiration. steroids have a beneficial effect in treating both tuberculous
The fluid itself is usually serosanguineous or occasionally pericarditis with effusion and constrictive pericarditis.428-430
grossly bloody, is exudative, and has a white blood cell count However, a meta-analysis of studies examining the effects
ranging from 500 to 50,000 cells/µL, with an average of of corticosteroids in tuberculous pericarditis concluded
5000 to 7000 cells/µL.425 The cells are predominantly that, although steroids could have an important effect, the
mononuclear, although polymorphonuclear leukocytes studies were too small to be conclusive.428 Nevertheless,
occasionally predominate. Tubercle bacilli have been identi- patients with proven tuberculous pericarditis who are
fied in pericardial fluid in approximately 25% to 30% of receiving adequate antituberculosis therapy and who have
cases (smear and culture combined).425 Biopsy of the peri- no major contraindications should receive corticosteroids.
cardium with both histologic and bacteriologic evaluation The optimum regimen is not known, but daily prednisone,
is much more likely to provide a diagnosis, although a non- 60 mg/day for 4 weeks, followed by 30 mg/day for 4 weeks,
specific histologic pattern and failure to recover the organ- 15 mg/day for 2 weeks, and 5 mg/day for 1 week, is the
isms do not exclude a tuberculous cause. recommended regimen.299 Corticosteroid therapy should
Although not well documented, it appears that, if the not be used if there is a strong suspicion that the infection
patient survives the subacute phase without treatment, is caused by a drug-resistant organism unless adequate
chronic fibrotic pericarditis nearly always follows. Before antituberculosis chemotherapy can be ensured.
the advent of antituberculosis therapy, 88% of one series of In the setting of hemodynamic compromise, pericardiec-
patients who had tuberculous pericarditis developed evi- tomy is necessary. Although pericardiocentesis generally
dence of chronic constriction.426 Constriction has also been improves the circulatory status, the improvement is usually
observed to develop during the course of antituberculosis temporary. Pericardial windows with drainage into the left
chemotherapy, although this appears to be uncommon in pleural space also generally provide only temporary relief.
patients who have had symptoms for less than 3 months; it The criteria for selecting patients for pericardiectomy are
is frequent in patients who have had symptoms for more not clear, apart from those patients who have refractory
than 6 months. hemodynamic compromise.
positive culture or by radiographic improvement, therapy Treatment of LTBI with isoniazid or rifampin should not
should be continued for 6 months. If there is no suggestion be undertaken in persons who have active, unstable liver
of active disease, therapy can be stopped after 4 months and disease. Stable chronic liver disease is not a contraindica-
the course of treatment will be sufficient for preventive tion, but such patients deserve careful consideration regard-
purposes.434 ing the indications and need close attention during the
course of treatment. Other persons who should be moni-
Persons with Other Conditions That Increase the tored especially closely during the administration of pre-
Risk of Tuberculosis ventive therapy include persons older than 35; those taking
Although the risk of tuberculosis is not always quantifiable, other medications with which there may be interactions
there is sufficient evidence to warrant preventive therapy in (such as phenytoin, disulfiram, or antiretroviral drugs); and
certain situations: prolonged therapy with corticosteroids persons with other disorders such as alcoholism, diabetes
(usually 15 to 20 mg or more of prednisone daily, or its mellitus, or renal insufficiency that may increase the risk
equivalent, for more than 2 to 3 weeks); immunosuppres- of adverse reactions, mainly hepatitis and peripheral
sive therapy; hematologic or reticuloendothelial malignan- neuropathy.
cies, and perhaps certain solid tumors; end-stage renal Pregnancy is not a contraindication to isoniazid; however,
disease; clinical conditions associated with rapid weight loss in view of the concern with elective administration of any
(including intestinal bypass for obesity and inadequate drug during the course of pregnancy, it is generally prudent
nutritional intake); after gastrectomy; and before treatment to wait until after delivery to give isoniazid. The exceptions
with anti-TNF agents; silicosis or coal workers’ pneumoco- to this general approach are women who have a docu-
niosis.434,448 In addition, even in the absence of any of these mented TST conversion during pregnancy or who are HIV
risk factors, persons in the following circumstances who infected and have a positive TST.
have TST readings of 10 mm or more should be considered
for preventive therapy: foreign-born persons from areas of MANAGEMENT OF EXPOSURE TO
high tuberculosis prevalence; medically underserved, low-
DRUG-RESISTANT ORGANISMS
income populations, including high-risk racial and ethnic
groups; residents of long-term care facilities (e.g., correc- Contacts of persons with drug resistant tuberculosis have a
tional institutions and nursing homes); and other groups substantial risk of being infected and having active tuber-
that, on the basis of local epidemiologic patterns, have been culosis.451 Providing preventive therapy for persons exposed
shown to have a high incidence of tuberculosis (e.g., to MDR or XDR organisms is especially problematic because
migrant workers, homeless persons).434 there are no regimens with proven efficacy. The options that
are available include observation only or administration of
two drugs to which the source case isolate was shown to be
CURRENT TREATMENT REGIMENS
susceptible (e.g., a 6-month regimen of ethambutol and
For many years, the only regimen available for treating pyrazinamide or of pyrazinamide and a fluoroquinolone). It
latent infection was isoniazid given for 6, 9, or 12 months. should be noted that there are no data to guide the choice
Subsequently, rifampin alone given for 4 months was shown of an option. In such situations expert consultation should
to be effective.434 More recently a once-weekly combination be obtained. Regardless of the approach that is chosen, if
of isoniazid and rifapentine given under direct observation evidence suggesting tuberculosis arises, the patient should
for 12 doses was demonstrated to be noninferior to isoniazid be treated promptly with a multidrug regimen to which the
alone given for 9 months.449 The CDC subsequently has organism would be predicted to be susceptible on the basis
published recommendations for the use of the 12-dose of the susceptibility testing of the index case isolate.
regimen, indicating that it should be used under direct
observation in adults without HIV infection.450 The regimen
that is supported most strongly is isoniazid given daily for 9
months. A 6-month regimen has also been shown to IMMUNIZATION WITH BACILLE
produce considerable protection and may provide the best CALMETTE-GUÉRIN
balance between cost and benefit. Both the 6-month and
the 9-month isoniazid regimens may be given twice weekly Administration of BCG vaccine has been the major preven-
under direct observation. The second option is rifampin tive technique used for many years throughout much of the
given daily for 4 months, although the supporting data are world, yet no vaccine has been the subject of greater con-
less strong. troversy.452 BCG is an attenuated tubercle bacillus (Myco-
Isoniazid is given in a single daily dose of 300 mg for bacterium bovis) that was created beginning in 1908 by
adults and 5 to 10 mg/kg body weight (up to 300 mg/day) Calmette and Guérin in France and that was found to
for children. The drug may also be given in doses of 15 mg/ protect a variety of animal species against tuberculosis. It
kg twice a week, which may facilitate direct observation of was first used in humans in 1921 and has since become the
treatment. The minimum duration of treatment is 6 most widely used vaccine in the world: up to 80% of infants
months; 9 months of treatment is considered optimum. in developing countries receive BCG immunizations. In chil-
Rifampin is given in a single dose of approximately 10 mg/ dren, BCG has been demonstrated to prevent disseminated
kg body weight for both adults and children, up to a total and miliary tuberculosis and tuberculosis meningitis.453 In
daily dose of 600 mg. The same dose is used when the drug adults, the results of BCG vaccination are less clear; of eight
is given twice weekly. If rifabutin is substituted for rifampin, controlled clinical trials of BCG against pulmonary tuber-
the dose is 5 mg/kg/day or 300 mg/day. culosis in adults, protection has ranged from 0 to 70%.452
Interestingly, when two different vaccines were used in a there are new diagnostic methods, all of them are either an
Medical Research Council Trial in the United Kingdom, one improvement of the old techniques or based on the detec-
of which produced only poor TST reactivity, equal degrees tion of nucleic acids; none fulfill the urgent need for point-
of protection were seen. Conversely, no protection was seen of-care diagnostic tests.
in the South Indian Trial of more than 200,000 people New drugs and mechanisms to reduce resistance to new
monitored for 15 years, although all patients who devel- drugs are a vital need, as underscored by the increase of
oped tuberculosis had been converted to TST positivity by drug-resistant tuberculosis and the detection of XDR
the vaccine.454 It is unclear why BCG appears to be effective cases.456 Also high on the list of needs is a test for the rapid
in some parts of the world and not in others (a finding that detection of drug resistance suitable for point-of-care use.
is also evident in protection against leprosy). Clearly, there The current technology has identified drug targets and
is a great deal yet to learn about the nature of protective enabled testing of new compounds with high-throughput
host immune responses, host genetic factors, variations in screening methods. Several drugs for active tuberculosis
pathogenicity of tubercle bacilli, and the role of exposure to are now being tested in clinical trials.456,457 Some of them
environmental nontuberculous mycobacteria that may are candidates for first-line drugs that can reduce the
provide resistance or enhance susceptibility. treatment time, while other drugs have fewer drug interac-
There are many variables that potentially could account tions, with the potential benefit of being used with antiret-
for the discordant results. These include variations in roviral drugs. Other drugs have novel targets. However,
potency of the strains of BCG used, technique of adminis- we are still far from having a truly short treatment
tration, handling of the vaccine, and prevalence of infec- (currently the term short course is used for the 6-month
tion with nontuberculous mycobacteria, which may in regimen).
themselves confer some degree of protection.455 Partly Effective vaccines will require a better understanding of
because of these factors, it is now generally accepted that the protective immune response to M. tuberculosis and of
BCG is not a tool that can be used to decrease the overall the pathogenesis of the disease. The availability of whole
incidence of tuberculosis in a population. However, it genomic sequences of thousands of clinical isolates of M.
appears that BCG reduces the likelihood of the more severe tuberculosis, and the recent evidence of the importance of
forms of the disease in children, and it is with this goal in the coevolution of the host and organism458 should assist
mind that it continues to be a component of WHO immu- the design of different vaccination approaches.459 A recent
nization recommendations for developing countries. Due to clinical trial demonstrated that a novel tuberculosis vaccine
the widespread acceptance and use of BCG and its benefits termed MVA85A induced the expected immune responses
to young children, it is not likely that new vaccines for but failed to protect against tuberculosis when used to boost
tuberculosis will immediately replace BCG. Instead, they BCG vaccine in infants458a; such results again demonstrate
will likely be used initially to boost responses after an initial that improved understanding of tuberculosis pathogenesis
dose of BCG, in an effort to induce responses that reliably and protective immunity are needed to inform development
protect adults against pulmonary tuberculosis. of efficacious vaccines. We are still far from understanding
In the United States, BCG has limited applicability. It is why the natural immune system (which prevents 90% of
recommended only for TST-negative persons who are persons infected from developing active tuberculosis) fails
repeatedly exposed to potentially infectious patients who in 10% of those infected and why the adaptive immune
are being ineffectively treated. In general, the recommenda- response in tuberculosis does not protect us from repeated
tion is limited to children. As a live vaccine, BCG should not infections. In spite of these gaps in knowledge, several addi-
be given to immunocompromised persons, including those tional vaccine candidates are now being tested (http://
with symptomatic HIV infection, or to pregnant women. www.aeras.org/candidates/ and http://www.tbvi.eu/).
Although important scientific advances have been made
recently, major gaps in understanding the basic biology of
TACKLING CURRENT PROBLEMS the organism and the human response to infection with M.
tuberculosis remain. The rapidly emerging new challenges
Tuberculosis is becoming a more complicated disease glob- to the care and control of tuberculosis, such as HIV, MDR
ally because of the appearance of MDR and XDR organisms tuberculosis, and more recently XDR tuberculosis, may out-
and the increasing frequency of comorbidities, particularly strip the advances and threaten our ability to control the
HIV infection but also other risk-enhancing factors such as disease.
diabetes, renal insufficiency, immunosuppressive drugs,
and tobacco and other substance addiction. Clearly, new
diagnostic tools and therapeutic options are urgently Key Points
needed. Currently, the most extensively used diagnostic ■ Although tuberculosis cases and case rates are consis-
methods around the world, both for active tuberculosis tently declining in high- and most middle-income
(sputum smear microscopy) and for latent tuberculosis countries, the disease continues to be highly prevalent
(TST), were invented at the end of the 19th century. Simi- in low- and some middle-income countries.
larly, BCG vaccine, despite its wide use, does not provide the ■ The epidemic of HIV infection, especially in sub-
needed protection. Today’s standard treatment with four Saharan Africa, is leading to extremely high tubercu-
drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) losis case rates.
has remained unchanged for more than 30 years, must be ■ Both HIV infection and resistance to antituberculosis
taken for a minimum of 6 months, and is insufficient to drugs, especially multidrug resistance and extensive
treat patients with MDR or XDR tuberculosis. Although
Centers for Disease Control: Recommendations for use of an isoniazid-

drug resistance, present major problems in worldwide rifapentine regimen with direct observation to treat latent Mycobacte-
tuberculosis control. rium tuberculosis infection. MMWR Morb Mortal Wkly Rep 60(48):
■ Adequate treatment for tuberculosis, both drug 1650–1653, 2011.
Centers for Disease Control: Provisional CDC guidelines for the use and
susceptible and drug resistant, is the major interven- safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of
tion for decreasing transmission of Mycobacterium multidrug-resistant tuberculosis. MMWR Recomm Rep 62(RR–09):
tuberculosis. Treatment consists of an initial intensive 1–12, 2013.
phase to eliminate actively replicating bacteria quickly Coussens AK, Wilkinson RJ, Hanifa Y, et al: Vitamin D accelerates resolu-
followed by a continuation phase to eliminate drug- tion of inflammatory responses during tuberculosis treatment. Proc Natl
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■ Assuming an adequate regimen is prescribed, patient dissemination of early tuberculous infection. Cell 136(1):37–49, 2009.
adherence is the critical factor that determines the de Jong BC, Hill PC, Aiken A, et al: Progression to active tuberculosis, but
success of treatment. not transmission, varies by Mycobacterium tuberculosis lineage in the
■ The treatment of extrapulmonary tuberculosis is
Gambia. J Infect Dis 198(7):1037–1043, 2008.
Huang CC, Tchetgen ET, Becerra MC, et al: The effect of HIV-related immu-
largely the same as the treatment of pulmonary tuber- nosuppression on the risk of tuberculosis transmission to household
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tuberculosis and tuberculosis involving bones and Kato-Maeda M, Ho C, Passarelli B, et al: Use of whole genome sequencing
joints, in which treatment of longer duration is to determine the microevolution of Mycobacterium tuberculosis during
an outbreak. PLoS ONE 8(3):e58235, 2013.
recommended. Lienhardt C, Glaziou P, Uplekar M, et al: Global tuberculosis control:
■ Treating latent tuberculous infection in persons at lessons learnt and future prospects. Nat Rev Microbiol 10(6):407–416,
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nificantly reduces the risk of disease. Such increased Philips JA, Ernst JD: Tuberculosis pathogenesis and immunity. Annu Rev
Pathol 7:353–384, 2012.
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eFIGURE IMAGE GALLERY
C D
A B F G H
eFigure 35-1 Tuberculosis involving the spine. A, Frontal and B, lateral chest radiographs show left inferior paraspinous line displacement (arrow, A)
consistent with a posterior mediastinal mass. The lateral chest radiograph shows loss of height of a thoracic vertebral body (arrowhead) at this level, but
the adjacent intervertebral disc spaces are maintained. Contrast-enhanced axial chest CT displayed in bone (C and D) and soft tissue (E) windows shows
lytic vertebral body destruction (long arrow, D) at the level of vertebral body loss of height seen on the lateral chest radiograph (B). Osseous lytic foci are
also present in the sternum (short arrow, C) and posterior ribs (short arrows, C and D). A paraspinous fluid collection with peripheral enhancement, consist-
ent with an abscess (arrowheads, E) is seen anterior to the involved thoracic vertebral body. Sagittal T2-weighted (F) and contrast-enhanced T1-weighted
(G) and axial T2-weighted (H) MR images show the anterior paraspinous abscesses (arrowheads), typical of subligamentous spread. Note the extensive
high signal within the vertebral bodies (arrows, F) representing bone marrow edema. The clear vertebral body enhancement (arrows, G) indicates the
presence of osteomyelitis. Note the relative sparing of the intervertebral disc spaces, typical of granulomatous infections and distinct from the common
appearance of other causes of bacterial osteomyelitis. Extensive fluid collections are seen in the left erector spinae muscle (*) and involve the adjacent
right posterior rib as well. These findings were all the result of tuberculosis. (Courtesy Michael Gotway, MD.)
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APPENDIX: ESSENTIALS OF CHEMOTHERAPY
INTRODUCTION define the major bacteriologic principle on which successful

chemotherapy for tuberculosis depends: bacillary popula-
The development of successful chemotherapy for tubercu- tions are not uniform in their susceptibility to antitubercu-
losis must rank as one of the greatest achievements of losis agents; hence, it is always necessary to treat active
medical science. Beginning in the late 1940s, chemother- disease with more than one drug to which the organisms
apy began to slow down—little by little—the centuries’ long are susceptible.
and ever-growing toll from the incurable “captain of all The concept of multiple-drug chemotherapy was first
these men of death,” John Bunyan’s name for the plague validated in 1950 by a British Medical Research Council
that has killed an estimated 2 billion human beings: more, study in which streptomycin was partnered with para-
by far, than any other disease. Notable victims included aminosalicylic acid, better known as PAS. Long-lasting
kings and princes, cardinals, famous poets, writers, musi- success was achieved because PAS prevented organisms
cians, and artists, and, of course, countless anonymous from becoming resistant to streptomycin and vice versa,
poor people. Finding a cure for this scourge did not happen and two drugs have more bacteriologic and clinical effect
easily, quickly, or by serendipity. It was the cumulative work than only one.11 Since that time, treatment with more than
over decades by many men and women dedicated to that one drug has been standard in the management of patients
single purpose, and—keep this in mind—these efforts are with tuberculosis. Although the combination of streptomy-
ongoing. The history of the initial taming of tuberculosis cin and PAS was effective, neither agent was well tolerated
and why the task remains unfinished makes fascinating and clinical improvement was slow and hampered by side
reading, especially in the accounts of Dubos and Dubos,1 effects. The long-sought solution to antituberculosis che-
Ryan,2 and Daniel.3 motherapy arrived in 1952 with the introduction of isonia-
Even though effective treatment has been available for zid, a powerful drug that was not only highly effective, but
more than 50 years, tuberculosis continues to plague vul- well tolerated and inexpensive.12 However, once again it
nerable regions of the world. More and more strains of was learned that single-drug treatment with isoniazid was
disease-producing Mycobacterium tuberculosis are resistant inadequate because resistance to the agent developed
to standard antituberculosis regimens: some strains are quickly. The solution was clear: combine isoniazid with
resistant to nearly all available agents. The most recent sta- both streptomycin and PAS. This triple therapy became the
tistics report an estimated 8.6 million new cases and 1.26 standard treatment for tuberculosis until 1967, when a
million deaths.4 Globally, 4% of new cases and 20% of pre- new antituberculosis agent, ethambutol, an easily tolerated
viously treated cases are estimated to have multidrug- and minimally toxic drug, was welcomed as a substitute
resistant tuberculosis (MDR, resistant at least to isoniazid for PAS.13
and rifampin).5 It is estimated that 9.6% of MDR cases are Subsequent experiments have shown that, in any wild
XDR (MDR to at least one fluoroquinolone and one second- type strain of M. tuberculosis, there are subpopulations with
line–injectable drug [amikacin, kanamycin, or capreomy- spontaneous mutations in genes that confer drug resis-
cin]) with 96 countries having reported at least one case of tance. The frequency of drug-resistant mutants is 1 in 3.5
XDR.5 The overall frequency of pre-XDR (MDR to either × 106 for isoniazid, 1 in 3.8 × 106 for streptomycin, 1 in 3.1
fluoroquinolone or second-line–injectable drug) is not × 108 for rifampin, and 1 in 0.5 × 104 for ethambutol.14
known, but studies in convenience samples report between Thus, a bacillary population of more than 1012 organisms
15%6 and 42%7,8 of MDR isolates are pre-XDR. would be required before one would expect to find (statisti-
cally) a single bacillus resistant to both isoniazid and
streptomycin.
BEGINNINGS Once optimum doses of each component were estab-
lished, wide use of triple therapy revolutionized the care of
To understand where we currently stand and to appreciate patients with tuberculosis. Springett15 reviewed death rates
the enormity of the task ahead, this appendix provides a from tuberculosis for cohorts of patients in Birmingham,
brief chronology of the use of chemotherapy for treating England, for the years 1947, 1950, 1953, 1956, and 1959.
tuberculosis, starting with streptomycin, the original break- With increasing use of antituberculosis chemotherapy,
through agent, which was first injected into a desperately deaths decreased dramatically during the 10 years after
ill young woman in November 1944. To everyone’s aston- diagnosis, and nearly all of the reduction was accounted for
ishment and relief, she did not die but slowly began to by improvements in survival during the first year after diag-
recover. Then, seemingly miraculously, so did others.9 nosis. In addition, not only were survivors more numerous,
But within a few years, after many more patients with but among survivors, far fewer than in the prechemother-
tuberculosis had been treated with streptomycin, it became apy era continued to be potential sources of new infections.
apparent that the striking clinical and radiographic In the Springett study,15 both the decrease in mortality rate
improvement observed initially did not always last; after and the reduction in the prevalence of chronically infec-
several months of treatment, patients began to worsen and tious patients reached their maximum in 1956, with no
the reason was immediately obvious: their tubercle bacilli further improvement in 1959.
had become resistant to streptomycin.10 The findings of The next major advance in chemotherapy for pulmonary
clinical failure and emergence of drug resistance served to tuberculosis resulted from the discovery of rifampin (or
rifampicin, as it is known in many parts of the world) and FIRST-LINE DRUGS

the demonstration that the combination of isoniazid and
rifampin, generally with ethambutol or streptomycin, could Isoniazid is very effective, specific for certain mycobacteria,
dramatically shorten the necessary duration of treatment.16 relatively nontoxic, easily administered, and inexpensive. It
In a series of important studies from East Africa during the is highly active against M. tuberculosis: most strains are
1970s, the British Medical Research Council established inhibited by concentrations of 0.05 to 0.20 µg/mL, and it
that a 6-month regimen consisting of isoniazid, streptomy- has profound early bactericidal activity. The drug is readily
cin, and rifampin was as effective as the standard regimen absorbed from the gastrointestinal tract; blood concentra-
used at the time in developing countries (18 months of tions of approximately 5 µg/ mL peak 1 to 2 hours after
isoniazid and thiacetazone, plus streptomycin given during administration of 3 to 5 mg/ kg of body weight. The serum
the first 2 months).17 half-life varies depending on whether a person is a rapid or
A critical factor influencing the effectiveness of chemo- slow acetylator: half-lives are 2 to 4 hours in slow acetyl-
therapy was, and continues to be, the adherence (or lack ators and 0.5 to 1.5 hours in rapid acetylators.29 The drug
thereof) of patients to the prescribed regimen, a fact well penetrates well into all body fluids and cavities, producing
documented both in the United States and in developing concentrations similar to those found in serum.
countries.18-20 In spite of initial high rates of success else- Isoniazid is a pro-drug and is activated by bacterial KatG,
where, the results of a U.S. Public Health Service multi- a catalase/peroxidase enzyme.30 Once it is activated, isonia-
center cooperative trial indicated that a 6-month regimen zid inhibits NADH-dependent enoyl-ACP reductase encoded
of isoniazid and rifampin did not have an acceptable rate of by inhA. This process ultimately results in the inhibition of
favorable outcome.21 Positive cultures were found in 6.1% synthesis of essential mycolic acids.31 The most common
of the patients between 3 and 6 months after treatment cause of resistance to isoniazid is deletion of or mutations
began. Of greater importance was that 9.2% experienced in KatG that result in loss of catalase/peroxidase activity. A
relapse after completion of treatment. Strikingly, 16.8% of mutation in katG that results in substitution of threonine
the patients were withdrawn from the study because they for serine in codon 315 (S315T) is the most common muta-
had been delinquent about clinic visits during the 6 months tion found in isoniazid-resistant clinical isolates.32,33
of treatment. This outcome was a setback for efforts to Mutations in the promoter of inhA cause resistance to
shorten the duration of treatment to 6 months, which— isoniazid and the second-line drug ethionamide.32 These
assuming equal effectiveness and tolerance—would have mutations are less frequent than those in katG. In a study
considerable clinical and logistical advantages over 18- to of clinical isolates collected by the CDC, 82% of the M.
24-month regimens. tuberculosis isolates resistant to isoniazid had a mutation in
Studies of chemotherapy then began to focus on the pos- katG only, 6% had mutations in inhA only, and 11% had
sible benefits of pyrazinamide.22 Dickinson and coworkers23 mutations in both.34 Other mutations reported to be associ-
demonstrated that streptomycin, rifampin, and isoniazid ated with isoniazid resistance are mutations in the furA-
are quickly bactericidal for rapidly growing M. tuberculosis katG intergenic region, as well as in the oxyR-ahpC region.33
in vitro. The in vitro conditions could be likened to the con- When isoniazid is used alone, a population of organisms
ditions under which the extracellular organisms in tuber- resistant to the drug emerges rapidly. This was demon-
culous lesions are living. Although both rifampin and strated in an early clinical trial in which 11%, 52%, and
isoniazid are rapidly bactericidal, Mitchison and Dickin- 71% of patients to whom isoniazid alone was given devel-
son24 demonstrated that rifampin is more effective in killing oped resistant strains after 1, 2, and 3 months of treatment,
organisms that grow in spurts rather than continuously. respectively.35
Although both isoniazid and rifampin are effective in killing Hepatitis is the major toxic effect of isoniazid.28,36,37
intracellular organisms, pyrazinamide is especially effective Asymptomatic elevations of aminotransferase—up to five
for this purpose, suggesting that the addition of pyrazin- times the upper limit of normal—are seen in 10% to 20%
amide would strengthen the isoniazid-rifampin combina- of persons receiving isoniazid alone for the treatment of
tion. Subsequently, two studies substantiated the fact that latent tuberculous infection.38 The enzyme levels usually
the addition of pyrazinamide for 2 months to a regimen of return to normal even with continued administration of the
isoniazid and rifampin does indeed improve the effective- drug. In 11,141 patients managed in an urban tuberculosis
ness of a 6-month regimen.25,26 Thus, a 6-month regimen control program who were receiving isoniazid alone as
of isoniazid and rifampin supplemented by pyrazinamide treatment for latent tuberculous infection, hepatitis devel-
and ethambutol for the initial 2 months is now recom- oped in 0.1% to 0.15%.39 A meta-analysis of six studies
mended as standard treatment for most patients with newly estimated the rate of clinical hepatitis in patients given iso-
diagnosed pulmonary tuberculosis.27,28 niazid to be 0.6%.40 The rate of clinical hepatitis was 1.6%
when isoniazid was given with other agents, not including
rifampin.40 When isoniazid was given in combination with
rifampin, the rate of clinical hepatitis averaged 2.7% in 19
DRUGS IN CURRENT USE reports. For isoniazid alone, the risk increases with increas-
ing age; it is uncommon in persons younger than 20 years
As shown in Table 35A-1, 11 drugs currently are approved old but is nearly 2% in persons ages 50 to 64 years.41 The
by the FDA for treating tuberculosis, and 6 other drugs are risk may also be increased in persons with underlying liver
effective but not approved for this indication. The table lists disease, in those with a history of heavy alcohol consump-
both first- and second-line drugs, the available preparation, and in the postpartum period, particularly among His-
tions, and the doses currently used to treat tuberculosis. panic women.41,42 A large survey estimated the rate of fatal
Table 35A-1 Doses* of Antituberculosis Drugs for Adults and Children†

WEEKLY
Adults/
Drug Preparation Children Daily 1× 2× 3×
FIRST-LINE DRUGS
Isoniazid Tablets (50 mg, Adults (max.) 5 mg/kg (300 mg) 15 mg/kg 15 mg/kg 15 mg/kg
100 mg, 300 mg); (900 mg) (900 mg) (900 mg)
elixir (50 mg/5 mL); Children (max.) 10-15 mg/kg — 20-30 mg/kg —
aqueous solution (300 mg) (900 mg)
(100 mg/mL) for IV
or IM injection
Rifampin Capsule (150 mg, Adults‡ (max.) 10 mg/kg (600 mg) — 10 mg/kg 10 mg/kg
300 mg). Powder (600 mg) (600 mg)
may be suspended Children (max.) 10-20 mg/kg — 10-20 mg/kg —
for oral (600 mg) (600 mg)
administration.
Aqueous solution
for IV injection
Rifabutin Capsule (150 mg) Adults‡ (max.) 5 mg/kg (300 mg) — 5 mg/kg (300 mg) 5 mg/kg (300 mg)
Children Appropriate dosing for children is unknown
Rifapentine Tablet (150 mg film Adults — 10 mg/kg — —
coated) (continuation
phase)
(600 mg)
Children The drug is not approved for use in children
Pyrazinamide Tablet (500 mg Adults 20-30 mg/kg (2 g) — 40-50 mg/kg (4 g) 30-45 mg/kg (3 g)
scored) Children (max.) 15-30 mg/kg (2 g) — 50 mg/kg (4 g) —
Ethambutol Tablet (100 mg, Adults 15-20 mg/kg (1.6 g) — 40-50 mg/kg 25-35 mg/kg
400 mg) (2.4 g) (2.4 g)
Children (max.) 20 mg/kg daily (1 g) — 50 mg/kg (4 g) —
SECOND-LINE DRUGS
Cycloserine Capsule (250 mg) Adults (max.) 10-15 mg/kg/day There are no data to support intermittent administration
(1 g in two doses),
usually
500-750 mg/day
in 2 doses§
Children (max.) 10-15 mg/kg/day
(1 g/day)
Ethionamide Tablet (250 mg) Adults (max.) 15-20 mg/kg/day There are no data to support intermittent administration
(1 g/day), usually
500-750 mg/day
in a single daily
dose or two
divided dosesǁ
Children (max.) 15-20 mg/kg/day
(1 g/day)
Streptomycin Aqueous solution Adults (max.) 15 mg/kg/day (1 g) and 10 mg/kg in persons > 59 years (750 mg). Usual dose
(1-g vials) for IM or 750 mg-1 g IM or IV typically given as a single dose 5-7 days a wk and reduced
IV administration to 2-3 times a wk after first 2-4 mo or after culture conversion, depending on
the efficacy of the other drugs in the regimen
Children (max.) 20-40 mg/kg/day — 20 mg/kg —
(1 g)
Amikacin/ Aqueous solution Adults (max.) 15 mg/kg/day (1 g), and 10 mg/kg in persons > 59 (750 mg). Usual dose
Kanamycin (500-mg and 1-g 750 mg-1 g IM or IV typically given as a single dose 5-7 days a week and
vials) for IM or IV reduced to 2-3 times a week after first 2-4 mo or after culture conversion,
administration depending on the efficacy of the other drugs in the regimen
Children (max.) 15-30 mg/kg/day — 15-30 mg/kg —
(1 g) IM or IV as a
single daily dose
Capreomycin Aqueous solution Adults (max.) 15 mg/kg/day (1 g), and 10 mg/kg in persons > 59 (750 mg). Usual dose
(1-g vials) for IM or 750 mg-1 g IM or IV typically given as a single dose 5-7 days a week and
IV administration reduced to 2-3 times a week after first 2-4 mo or after culture conversion,
depending on the efficacy of the other drugs in the regimen
Children (max.) 15-30 mg/kg/day — 15-30 mg/kg —
(1 g) as a single
daily dose
Table 35A-1 Doses* of Antituberculosis Drugs for Adults and Children (Continued)
WEEKLY
Adults/
Drug Preparation Children Daily 1× 2× 3×
para- Granules (4-g Adults 8-12 g/day in 2 or 3 There are no data to support intermittent administration
Aminosalicylic packets) can be doses
Acid (PAS) mixed with food. Children 200-300 mg/kg/day      
Tablets (500 mg) in 2-4 divided
are still available in doses (10 g)
some countries
but not in the
United States. A
solution for IV
administration is
available in Europe
Levofloxacin Tablets (250 mg, Adults 500-1000 mg daily There are no data to support intermittent administration
500 mg, 750 mg); Children The long-term (>several weeks) use of levofloxacin in children and adolescents
aqueous solution has not been approved because of concerns about effects on bone and
(500-mg vials) for cartilage growth. However, most experts agree that the drug should be
IV injection considered for children with tuberculosis caused by organisms resistant to
both isoniazid and rifampin. The optimal dose is not known.
Moxifloxacin Tablets (400 mg); Adults 400 mg daily There are no data to support intermittent administration
aqueous solution Children The long-term (>several weeks) use of moxifloxacin in children and adolescents
(400 mg/250 mL) has not been approved because of concerns about effects on bone and
for IV injection. cartilage growth. The optimal dose is not known.
Gatifloxacin Tablets (400 mg); Adults 400 mg daily There are no data to support intermittent administration
aqueous solution Children The long-term (>several wk) use of gatifloxacin in children and adolescents has
(200 mg/20 mL; not been approved because of concerns about effects on bone and cartilage
400 mg/40 mL) for growth. The optimal dose is not known.
IV injection
Bedaquiline 100-mg tablets Adults 400 mg administered orally once daily
fumarate¶ for 2 wk, followed by 200 mg
administered orally 3 times weekly,
for an entire treatment duration of
24 wk
Drugs in bold are approved by the U.S. Food and Drug Administration for treatment of tuberculosis.
*Dose per weight is based on ideal body weight. Children weighing more than 40 kg should be dosed as adults.
†
For purposes of this document, adult dosing begins at age 15.
‡
Dose may need to be adjusted when there is concomitant use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
§
It should be noted that, although this is the dose recommended generally, most clinicians with experience using cycloserine indicate that it is unusual for
patients to be able to tolerate this amount. Serum concentration measurements are often useful in determining the optimum dose for a given patient.
‖
The single daily dose can be given at bedtime or with the main meal.
¶
From Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis.
MMWR Recomm Rep 62(RR-09):1–12, 2013.
Modified from Blumberg HM, Burman WJ, Chaisson RE, et al: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases
Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 167:604–662, 2003; and Francis J, for the Curry National Tuberculosis Center and
California Department of Public Health, Drug-Resistant Tuberculosis: A survival guide for clinicians, ed 2. Sacramento, CA, 2008, California Department of
Public Health..
hepatitis to be 0.023%,43 but more recent studies suggest taking the drug for several weeks.44 The half- time increases
the rate is substantially lower.39 The risk may be higher in with increasing doses of the drug. For sensitive strains of
women. Death has been associated with continued admin- M. tuberculosis, the minimum inhibitory concentration of
istration of isoniazid well after the onset of symptoms of rifampin is approximately 0.5 µg/ mL, although there is
hepatitis. variation among strains.45 Approximately 75% of the drug
Peripheral neuropathy, the second most frequent adverse is protein bound, but it penetrates well into tissues and cells.
reaction associated with isoniazid administration, arises Penetration through noninflamed meninges is poor;
especially in persons with other disorders that may cause however, therapeutic concentrations are achieved in cere-
neuropathy (HIV infection, diabetes mellitus, uremia, and brospinal fluid when the meninges are inflamed.46
alcoholism). The neuropathy can be prevented or reversed Among susceptible strains of M. tuberculosis, the rate of
by administration of pyridoxine 25 mg/day. mutation seems to be less for rifampin than for isoniazid.
Rifampin is also rapidly bactericidal for M. tuberculosis. David14 reported the rate of mutation to rifampin resistance
The drug is easily administered and is relatively nontoxic. It to be approximately 10 × 1010 per generation. In spite of
is quickly absorbed from the gastrointestinal tract; serum this rather low rate of in vitro mutation, resistance rapidly
concentrations of 6 to 7 µg/mL are reached 1.5 to 2 hours develops when rifampin is used alone in vivo.47 Resistance
after ingestion. The half-time in blood is 3 to 3.5 hours, to rifampin unaccompanied by resistance to other antitu-
although this may be decreased in persons who have been berculosis drugs has been reported to be much more
common among patients with HIV infection, particularly once weekly in the continuation phase of treatment for pul-
among patients being treated with once- or twice-weekly monary tuberculosis.53 However, it should be emphasized
intermittent regimens containing rifamycins.48-50 that this regimen is not to be used for patients with HIV
Rifampin exerts its effect by binding to the β-subunit of infection, patients who have cavitary lesions on chest film,
RNA polymerase.32 For this reason, it has activity against or patients who have positive sputum smears at the end of
many bacteria other than M. tuberculosis. Resistance to the 2-month initial phase of treatment. The toxicity profile
rifampin results from mutations in the rpoB gene, the is similar to that of rifampin. Rifapentine, given weekly with
product of which is the β-subunit of RNA polymerase. high-dose isoniazid for a total of 12 doses, is also effective
Although many different mutations may be involved, alter- treatment of latent tuberculosis infection.54
ations in rpoB, specifically in a “hot spot” of 81 base pairs Ethambutol in usual doses of 15 mg/kg of body weight is
(the rifamycin resistance-determining region; RRDR), generally considered to have a static effect on M. tuberculo-
account for approximately 96% of the rifampin-resistant sis. The drug is easily administered and has a low frequency
strains isolated from patients in many different parts of the of adverse reactions. Its main effect is to reduce the risk of
world.27,33,34 The mechanism for resistance in the remain- rifampin resistance in patients with tuberculosis caused by
ing 4% is not known. strains that have primary resistance to isoniazid. Peak
Adverse reactions to daily rifampin include rashes, hepa- plasma concentrations are recorded 2 to 4 hours after inges-
titis, gastrointestinal upset, and, rarely, thrombocytopenia. tion. With doses of 15 mg/kg, the peak concentration is
The rates of these reactions have been variable, but in approximately 4 µg/mL.55 The concentration increases pro-
general are quite low.28 Hepatitis was a complication in portionally with increasing doses. In persons with normal
3.1% of the patients in the U.S. Public Health Service study renal function, the half-time in blood is approximately 4
of 6-month isoniazid-rifampin treatment.21 Intermittent hours. Minimum inhibitory concentrations of the drug for
(twice-weekly) administration of higher doses of rifampin M. tuberculosis range from 1 to 5 µg/mL. Protein binding is
is associated with several immunologically mediated reac- minimal, but penetration into cells is thought to be poor.
tions, including thrombocytopenia, an influenza-like syn- Cerebrospinal fluid concentrations of ethambutol, even in
drome, hemolytic anemia, and acute renal failure.51 the presence of meningeal inflammation, are low, averaging
Drug-drug interactions due to rifampin induction of 1 to 2 µg/mL after a dose of 25 mg/kg.49 Ethambutol
cytochrome P450 (CYP) enzymes, especially CYPs 1A2, appears to exert its effect by interfering with cell wall arabi-
2C9, 2C19, and 3A4, are common and apply to a broad nogalactan biosynthesis. Mutations in the embB gene that
range of drugs. In the case of tuberculosis, these interac- codes for arabinosyltransferases are found in approximately
tions are especially relevant in patients with HIV infection. 70% of ethambutol-resistant strains.32-34
The rifamycins—rifampin, rifabutin, and rifapentine—have Retrobulbar neuritis is the main adverse effect of etham-
marked effects on the protease inhibitor and non-nucleoside butol. Symptoms include blurred vision, central scotomata,
reverse transcriptase inhibitor classes of antiretroviral and red-green color blindness. This complication is dose
agents.28 The interaction of these classes of drugs is bidirec- related, being in 15% of patients given 50 mg/kg, 1% to 5%
tional: protease inhibitors decrease clearance of rifamycins, of those given 25 mg/kg, and less than 1% in those given
and rifamycins accelerate metabolism of protease inhibitors 15 mg/kg.28 The frequency of ocular effects is increased in
by inducing CYP3A4.52 Of the rifamycins, rifabutin has the patients with renal failure, presumably owing to increased
least effect on the concentration of antiretroviral agents. serum concentrations of the drug.
The practical implications of these interactions on treat- Streptomycin is rapidly bactericidal, although its effective-
ment regimens are discussed in Chapter 90. Rifampin ness is inhibited by an acid pH.28 Because the drug is not
induces the metabolism of a number of other drugs, includ- absorbed from the gut, it must be given parenterally. Peak
ing methadone, warfarin, oral contraceptives, digoxin, serum concentrations take place approximately 1 hour
macrolide antibiotics, and others.28 Doses of these drugs after an intramuscular dose. With a dose of 15 mg/kg, the
need to be adjusted when rifampin is given. Fluconazole peak concentration is in the range of 40 µg/mL. The half-
interferes with absorption of rifampin, thereby decreasing time in blood is approximately 5 hours. Sensitive strains of
its serum concentration. M. tuberculosis are inhibited by streptomycin in a concentra-
Rifabutin, although not approved by the U.S. Food and tion of 8 µg/mL. The drug has good tissue penetration;
Drug Administration for the treatment of tuberculosis, may however, it enters the cerebrospinal fluid only in the pres-
be used as a substitute for rifampin in most treatment regi- ence of meningeal inflammation. Streptomycin and etham-
mens.28 Because of its lesser propensity to induce cyto- butol have been found to be of approximately equal
chrome P-450 enzymes, rifabutin is generally reserved for effectiveness in combination regimens; however, because of
patients who are taking any medication for which there are a high prevalence of resistance to streptomycin, particu-
unacceptable interactions with rifampin. It may also be larly in patients from developing countries, its usefulness is
used for patients who are intolerant of rifampin. There is limited. For this reason and because it requires parenteral
extensive cross-resistance among the rifamycins for M. administration, streptomycin is no longer considered a first-
tuberculosis. The toxicity profile of rifabutin is similar to that line agent in treating tuberculosis.28
of rifampin except that, in some studies with HIV-infected Streptomycin exerts its effect by interfering with ribo-
patients, neutropenia has been reported and uveitis has somal protein synthesis. This effect is mediated by binding
been described when the drug is given with a macrolide of the drug to 16S ribosomal RNA (rRNA), thereby inhibit-
antibiotic that reduces rifabutin clearance.28 ing initiation of translation. Mutations in the genes that
Rifapentine, which has the longest serum half-life of the code for 16S rRNA (rrs and rpsL) have been found in 65%
rifamycins, is effective in combination with isoniazid given to 77% of resistant strains. Mutations in rpsL have been
associated with high-level streptomycin resistance, whereas The drug may also cause nausea and vomiting and skin
low-level resistance has been associated with rrs muta- rashes, especially photosensitive dermatitis.
tions.32 More recently, mutations in the gene gidB were
found to be associated with low-level streptomycin resis- SECOND-LINE DRUGS
tance.33 This gene encodes a methyltransferase specific for
the 16S rRNA. The available data indicate that gidB muta- Five additional agents approved for treating tuberculosis are
tions emerge spontaneously at a high frequency of 10−6.33 available in the United States: PAS, ethionamide, cycloser-
The most serious adverse effect of streptomycin is ototox- ine, capreomycin, and bedaquiline. In addition, the fluoro-
icity.28 This usually results in vertigo, but hearing loss is also quinolones, amikacin, kanamycin, and linezolid have
possible. The risk of ototoxicity is related to cumulative antituberculosis effects and have been used to a greater or
dosage and to peak serum concentrations. In general, peak lesser extent, generally in treating patients with tuberculo-
concentrations of greater than 40 to 50 µg/mL should be sis caused by drug-resistant organisms. All these second-
avoided, and the total dose should not exceed 100 to line drugs have important limitations—effectiveness,
120 g.28 Because of its effect on fetal auditory system devel- toxicity, and cost—that interfere with their general applica-
opment, streptomycin is contraindicated in pregnancy. bility in treating tuberculosis.28
Streptomycin should be used with caution in patients with Of the second-line drugs, the fluoroquinolones, levofloxa-
renal insufficiency, in whom dosing frequency should be cin and moxifloxacin, are the most widely used because both
reduced to two to three times a week because of increased agents possess good in vitro bactericidal activity and moxi-
risk of nephrotoxicity and ototoxicity.28 floxacin has good in vivo bactericidal activity against M.
Pyrazinamide is active against M. tuberculosis at an acid tuberculosis.60,61 The fluoroquinolones are currently not con-
pH, which suggests that the drug is activated under these sidered as first-line agents but should be reserved either for
conditions.56 The drug is particularly active against dormant patients with drug-resistant organisms or those who cannot
or semidormant M. tuberculosis in macrophages or in the tolerate first-line drugs.28 Fluoroquinolones are the most
acidic environment within areas of caseation and is rapidly important second-line drugs available to treat MDR TB.62
bacteriostatic but only slowly bactericidal. Absorption from Although earlier studies indicated that moxifloxacin substi-
the gastrointestinal tract is nearly complete; peak serum tution for isoniazid or ethambutol resulted in earlier conver-
concentrations take place approximately 2 hours after sion to negative sputum cultures, a recent large phase 3 trial,
ingestion. Concentrations generally range from 30 to 50 in which moxifloxacin was substituted for isoniazid
µg/mL with doses of 20 to 25 mg/kg. The serum half-life is or ethambutol in a 4 month regimen for drug-susceptible
9 to 10 hours. At a pH of 5.5, the minimal inhibitory con- tuberculosis, revealed a higher relapse rate in patients
centration of pyrazinamide for M. tuberculosis is 20 µg/mL. receiving the moxifloxacin-containing 4 month regimens
Penetration of the drug into cells and tissues seems to be than in those receiving the standard 6 month regimen.62a
fairly good, although data with regard to tissue concentra- The target of the fluoroquinolones is DNA gyrase, an
tions are limited. enzyme that operates to increase coiling of DNA. Resistance
Recent results indicate that pyrazinamide, after activa- to these agents is mediated by mutations in the gyrA and
tion by pyrazinamidase to pyrazinoic acid, binds to ribo- gyrB genes that encode for DNA gyrase.32,33 In a review of
somal protein S1 (encoded by rpsA) and inhibits 42 studies, 64% of 1220 fluoroquinolone-resistant M.
trans-translation, a mechanism for rescuing protein syn- tuberculosis isolates had mutations in gyrA and 3% had gyrB
thesis on stalled ribosomes.57 The genetic mechanism of mutations.63
mycobacterial resistance to pyrazinamide is predominantly The quinolones are generally well tolerated. The most
due to any of a large number of mutations in the pncA gene, frequent adverse effects include nausea, vomiting, dizziness,
which encodes the enzyme pyrazinamidase. This enzyme is anxiety, and other central nervous system effects. With
necessary for the intracellular conversion of pyrazinamide certain agents, hypoglycemia and hyperglycemia have been
to its active form, pyrazinoic acid. Mutations in the pncA observed and some are associated with prolonged QT inter-
gene are found in approximately 70% to 85% of val, which can be associated with cardiac arrhythmias.
pyrazinamide-resistant strains.32,34,58 Photosensitivity and arthropathy may also manifest.
The most important adverse reaction to pyrazinamide is Although there are multiple small clinical studies of the
liver injury. This appears to be dose related. In a large U.S. usefulness of quinolones in multiple-drug regimens, and
Public Health Service study in which pyrazinamide was their oral administration and moderate cost make them
given in a dose of 25 mg/kg daily for 6 months, hepatotoxic- attractive agents, their roles in regimens for MDR tubercu-
ity developed in 2% to 3% of patients.59 At a dose of 40 mg/ losis remain to be established.
kg per day, also given for 6 months, 6% of patients developed Kanamycin, amikacin, and capreomycin are known as
hepatitis. All patients were also receiving isoniazid and PAS the second-line–injectable (SLI) drugs. According to current
in addition to pyrazinamide. An increased frequency of hep- WHO MDR-TB treatment guidelines,64 at least one SLI is
atotoxicity has been reported in studies of pyrazinamide essential in the 6-month intensive phase of treatment.
combined with rifampin in a 2-month treatment regimen for These drugs are not absorbed from the gastrointestinal tract
latent tuberculous infection in persons without HIV infec- and thus must be administered parenterally. All three drugs
tion; accordingly, the indications for this regimen are limited. may cause hearing loss related to both peak concentrations
Because pyrazinamide impairs renal urate clearance, and cumulative doses and, in addition, may impair renal
hyperuricemia is reported in nearly all patients taking the function.
drug. Clinical gout is not common, but diffuse arthralgias, Bedaquiline was approved by the FDA in 2012 as part of
apparently unrelated to the hyperuricemia, are common. combination therapy (minimum four drugs) administered
by direct observation to adults 18 years old or older with the same time, effective national tuberculosis control pro-
MDR tuberculosis, when an effective treatment regimen grams were introduced into resource-poor countries by the
cannot otherwise be provided (i.e., no other drug to which International Union Against Tuberculosis and Lung
M. tuberculosis is susceptible, or drug intolerance).65 Beda- Disease72; much later, the concepts that made these pro-
quiline is a diarylquinoline and uses adenosine 5′-triphos- grams so efficacious were adopted, updated, and promoted
phate (ATP) synthase inhibition as its mechanism of by the WHO under the rubric Directly Observed Treatment
action.66 It has in vitro activity against both replicating and Short-course, more familiarly known as DOTS.
nonreplicating bacilli and has bactericidal and sterilizing Not surprisingly, the lessons from all these activities were
activity in the murine model of tuberculosis infection. No similar. Among them, the most important programmatic
cross-resistance was found between bedaquiline and isonia- principle is the obligation of the health care system or treat-
zid, rifampin, ethambutol, pyrazinamide, streptomycin, ing physician to provide effective supervision of therapy
amikacin, or moxifloxacin. Resistance has been observed from beginning to end. Because of inadequacies both in the
during clinical studies; bedaquiline has a bacteriostatic provision of tuberculosis control services and in private
effect at low serum levels (0.3 µg/mL) that might predispose physician supervision of treatment, completion of therapy
to acquired resistance.65 Drug-drug interactions exist with is often problematic.73 As an extreme, at Harlem Hospital in
CYP3A4 inducers (e.g., rifampin), but their clinical signifi- New York during the late 1980s, 89% of patients with
cance is uncertain.65 tuberculosis who had been started on appropriate treat-
All of the other oral agents are difficult to administer ment were lost to follow-up after discharge, in large part
because of adverse effects. It is strongly recommended that owing to cutbacks in funding of outpatient services.74 Obvi-
consultation with an expert be obtained before treatment ously, failure to continue medications precludes successful
with these drugs is undertaken.28 Administration of PAS therapy and promotes the emergence of drug-resistant
causes a high frequency of gastrointestinal upset plus organisms as it did in New York City.
hypersensitivity reactions in 5% to 10% of patients. In addi- Even in well-organized tuberculosis control programs,
tion, the usual dose of 10 to 12 g/day requires ingestion of ensuring patient adherence to therapy often presents a dif-
20 to 24 tablets, although administration has been made ficult problem. The reasons for poor adherence are complex
somewhat easier by the availability of a granular formula- and numerous. Prediction of who will be compliant and
tion. Ethionamide likewise causes a high frequency of gas- who will not is difficult and generally unreliable. To improve
trointestinal side effects, often necessitating discontinuation adherence, a number of modifications in the organization
of the drug. Cycloserine causes behavioral disturbances, of treatment have been tried, with varying degrees of
ranging from irritability and depression to frank psychosis, success.75 These include setting clinic hours to suit the
in a large percentage of patients taking the drug; seizures patient’s schedule; directly observing treatment in the
and peripheral neuropathy are possible, especially with high clinic, the patient’s home, or another location; and offering
doses and when cycloserine and isoniazid are given together. incentives and enablers, such as meals and transportation
In addition to the adverse effects of PAS, ethionamide, and reimbursements.28 Although all of these approaches, as
cycloserine, none of these drugs is particularly potent well as others, have had their successes, it is obvious that
against M. tuberculosis. Other unapproved but possibly compliance will remain a major problem as long as treat-
useful antituberculosis agents include the β-lactam imipe- ment regimens continue to be lengthy and cumbersome. It
nem, the β-lactam/β-lactamase combination amoxicillin- has come to be generally accepted that the best means of
clavulanate, clofazimine, and linezolid.67-69 These agents ensuring completion of therapy is giving the drugs under
have been used in small numbers of patients with tubercu- directly observed therapy (DOT),27,28 which is one of the
losis caused by MDR organisms. However, their role in the essential elements of the WHO’s DOTS global tuberculosis
treatment of tuberculosis has not been precisely deter- control strategy, mentioned earlier.76 The use of the DOTS
mined. The currently available compounds of the macrolide strategy has been associated with improved treatment
class of agents, which are useful against Mycobacterium outcomes in several cohort analyses.20,77,78 However, a
avium complex, do not have antituberculosis effects. Cochrane review of 11 trials with 5609 patients did not
show a significant difference in the cure of patients who
were treated with observed therapy compared with self-
administration.19 These results highlight the fact that
PROGRAMMATIC simply observing medication ingestion does not ensure suc-
CONSIDERATIONS cessful completion of treatment and that the full range of
measures for supporting patients in completion of treat-
The availability of powerful antituberculosis medications ment must be employed.
made it possible to cure around 95% of patients with disease Because of heightened public health concerns regarding
caused by susceptible organisms, but it soon became appar- transmission of M. tuberculosis by noncompliant patients
ent that drugs alone are insufficient: they are but one key and, in particular, concern about MDR organisms, public
element in a comprehensive tuberculosis control program. health statutes that could require DOT or, in some instances,
As far back as 1959, at the landmark Arden House Confer- confinement until treatment is completed were strength-
ence, the basic components of a national public health ened in the early 1990s. A review of the use and usefulness
program were defined with, as a long-range goal, the eradi- of these laws in New York City has shown that they were
cation of tuberculosis in the United States.70 Twenty years not abused and added significantly to the ability of health
later, another conference reviewed and refined the objec- authorities to improve treatment outcome and minimize
tives and proposed new control strategies.71 At practically spread of tuberculous infection.
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35 TUBERCULOSIS

PHILIP C. HOPEWELL, MD • MIDORI KATO-MAEDA, MD • JOEL D. ERNST, MD

INTRODUCTION Phylogenetic Lineage- and Strain- Physical Examination

INTRODUCTION must be viewed as a global problem, one that is not con-

Bone and Joint Tuberculosis

Central Nervous System Tuberculosis

APPENDIX: ESSENTIALS OF CHEMOTHERAPY

Reported TB Cases, United States

For most of recorded history, tuberculosis has been a 80,000

majority of infected humans, with the ability to reactivate

CONTRIBUTIONS OF IMMUNE RESPONSES TO

Compared with the TST, the IGRAs have several advan-

Figure 35-6 Primary tuberculosis. Frontal chest radiograph in a young

low sound of blowing across the top of an open bottle) may

culture or by identification of specific nucleic acid sequences.

Initial cultures negative

Low 9 months INH

Further information about the introduction and develop-

at the end of the initial phase of treatment, prolongation of HIV Infection

Table 35-2 Selected Treatment Regimens for Non–Multidrug-Resistant Tuberculosis*

2 month culture negative

short interval between starting antituberculosis and anti-

Table 35-3 Assessing Risk for Drug Resistance

GENITOURINARY TUBERCULOSIS Positive urine cultures may manifest in the absence of

Centers for Disease Control: Recommendations for use of an isoniazid-

eFIGURE IMAGE GALLERY

APPENDIX: ESSENTIALS OF CHEMOTHERAPY

INTRODUCTION define the major bacteriologic principle on which successful

rifampicin, as it is known in many parts of the world) and FIRST-LINE DRUGS

Table 35A-1 Doses* of Antituberculosis Drugs for Adults and Children†

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Table 35A-1 Doses* of Antituberculosis Drugs for Adults and Children†