vii.
  Mycobacterial Diseases
Mycobacterium tuberculosis
249  Daniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas
Microbiology
• Humans are the only reservoir for
Mycobacterium tuberculosis.
• The organism is an acid-fast, aerobic bacillus
with a high cell wall content of
high-molecular-weight lipids.
• Incomplete necrosis produces cheesy, acellular
material (i.e., caseous necrosis).
• Pulmonary cavities contain huge numbers of
organisms.
Epidemiology
• M. tuberculosis infects one-quarter of the
world’s population, with 10.4 million new
cases reported each year.
• Almost all infections are due to inhalation of
droplet nuclei.
• Key determinants of infection are closeness of
contact and infectiousness of the source.
• The strongest risk factor for progression to
active tuberculosis (TB) is acquired
immunodeficiency syndrome (AIDS).
• The highest case rates are in countries heavily
affected by human immunodeficiency virus
(HIV)/AIDS.
• Drug resistance can be primary or secondary.
• Multidrug-resistant tuberculosis (MDR-TB)
indicates resistance to both isoniazid (INH)
and rifampin (RIF).
• Extensively drug-resistant tuberculosis
(XDR-TB), which indicates resistance to INH,
RIF, a fluoroquinolone, and a second-line
injectable drug, is of immense concern.
Immunology and Pathogenesis
• Infection requires a cellular immune response.
• Airborne droplet nuclei reach the terminal air
spaces, where they are ingested by alveolar
macrophages and then carried by lymphatics
to regional lymph nodes.
• Occult preallergic lymphohematogenous
dissemination occurs to the lung apices and
elsewhere.
• Granulomas form when antigen load is small
and tissue hypersensitivity is high.
• Age influences likelihood and pattern of
disease.
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SHORT VIEW SUMMARY
• TB in advanced AIDS is characterized by
middle or lower lung field location, absence of
cavitation, increased extrapulmonary disease,
and a negative test for M. tuberculosis
infection (e.g., tuberculin skin test or
interferon-γ release assay).
Tuberculin Skin Testing and Interferon-γ
Release Assays
• To detect M. tuberculosis infection, a positive
tuberculin test is defined by induration.
Interpretation depends on the diameter of
induration.
• Interferon-γ release assays may be used
instead of skin testing. They are more specific
for M. tuberculosis than tuberculin skin
testing. Results are positive, negative, or
indeterminate. T-Spot results can also be
borderline.
• Testing for M. tuberculosis latent infection is
recommended for persons at high risk for
developing TB if untreated.
• Test results (particularly the skin test) are
negative in at least 20% of active TB cases.
Diagnosis
• Culture is the gold standard.
• Visible growth takes 3 to 8 weeks on solid
media, and a mean of 10 days for
smear-positive and 20 days for smear-negative
specimens on liquid media.
• An estimated 10,000 organisms per milliliter
are required for sputum smear positivity.
Nucleic acid amplification testing (NAAT; e.g.,
Xpert MTB/RIF and Xpert MTB/RIF Ultra) have
sensitivities and specificities that approach
those of culture and can be completed in
1 day.
• The use of three sputum specimens increases
sensitivity.
• A radiograph showing a patchy or nodular
infiltrate in the lung apices is highly
suggestive, especially if the infiltrate is
cavitary.
• Pulmonary TB can occur in persons with
normal chest radiographs, particularly in
HIV-positive persons with advanced
immunosuppression.
Therapy (see Tables 249.7 and 249.8)
• Multidrug regimens, typically starting with at
least four active drugs, are recommended for
initial treatment.
• At least 6 months of therapy is usually
required.
• INH is the cornerstone of therapy; RIF, the
second major antituberculous agent, causes
many drug-drug interactions; 2 months of
pyrazinamide is essential for 6-month
regimens.
• Adjustment of doses of antiretroviral agents
during treatment of TB with RIF and rifabutin
is shown in Chapter 39, Tables 39.3 and 39.5.
The time to initiate antiretroviral therapy
during TB treatment is shown in Chapter 39,
Table 39.2.
• Directly observed therapy is crucial.
• Susceptibility testing is important to guide
therapy. NAAT and DNA sequencing are
offering more rapid approaches to
susceptibility testing.
• With appropriate chemotherapy, patients
usually become noninfectious within 2 weeks.
• Treatment of XDR-TB is usually associated
with poor outcomes.
• Bedaquiline is an approved drug for MDR-TB.
Therapy for Latent Infection
• Short-course regimens are replacing 9 months
of INH for latent infection, particularly in
low–TB incidence settings.
• Twelve weeks of directly observed,
once-weekly INH plus rifapentine, and 4
months of daily rifampin, are as effective as 9
months of INH.
Prevention
• Case finding and treatment comprise the most
effective method of control of TB.
• Hospitalized HIV-positive patients with
respiratory symptoms should be admitted to
negative-pressure isolation rooms. N95 masks
are used for health care workers.
• Childhood bacillus Calmette-Guérin
vaccination in high-burden countries decreases
incident TB. Other vaccines are in clinical trial.
2985
 2985.e1
Revised March 31, 2020

Chapter 249  Mycobacterium tuberculosis

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 2986
The term tuberculosis describes a broad range of clinical illnesses caused
by Mycobacterium tuberculosis (or, less commonly, Mycobacterium bovis).
Tuberculosis (TB) is the leading cause of death due to a single infectious
agent worldwide, and ranks ninth among all causes of death. In 2014
Part III  Infectious Diseases and Their Etiologic Agents
the World Health Assembly embraced a resolution to reduce deaths
from TB by 95% by the year 2035. In 2016 there were an estimated 10.4
million new cases of TB and 1.7 million deaths from TB worldwide.1
TB can affect virtually every organ, most importantly the lungs, and is
typically associated with granuloma formation.
HISTORY
There is evidence of spinal TB in Neolithic, pre-Columbian, and early
Egyptian remains. However, TB did not become a major problem until
the Industrial Revolution, when crowded living conditions favored its
spread. In the 17th and 18th centuries, TB caused one-fourth of all
adult deaths in Europe. Before antimicrobial agents became available,
the cornerstone of treatment was rest in the open air in specialized
sanatoria. Sanatorium regimens probably benefited some patients who
were diagnosed before cavitation but had little impact on cavitary disease.
When it became clear that cavitation was the pivotal event in progressive
pulmonary TB, most special therapies focused on cavity closure.
The modern era of TB began in 1946 with demonstration of the
efficacy of streptomycin (STM). In 1952, the availability of isoniazid
(INH) made TB curable in most patients, and the addition of rifampin
(RIF) in 1970 allowed for even more effective combination therapy.
With drug coverage, it became possible to successfully resect tuberculous
tissue, but with drug treatment, resection was rarely necessary. Bed rest
and collapse therapy added nothing to chemotherapy; treated patients
rapidly became noninfectious; and specialized sanatoria ultimately
disappeared. The duration of chemotherapy progressively decreased
from approximately 2 years before the availability of RIF, to 9 months
with INH plus RIF, and to 6 months with multidrug therapy including
INH, RIF, and pyrazinamide (PZA). With INH it also became practical
to treat asymptomatic people believed to harbor tubercle bacilli based
on positive tuberculin test results.
In the United States, reported cases of TB had declined nearly every
year since accurate statistics became available. However, in 1985, case
rates began increasing, driven largely by human immunodeficiency
virus (HIV) infection. TB-control programs in some large cities were
not equipped to manage this emerging problem. The often-interrelated
factors of illicit drug use, homelessness, and HIV infection predispose
to reactivation of remote TB, to the acquisition and spread of new
disease, and, because of irregular adherence to drug therapy, to the
development and spread of drug-resistant strains. Epidemics involving
strains that were resistant to at least INH and RIF (i.e., multidrug-resistant
[MDR] strains) emerged in these populations and spread to HIV-negative
persons, including health care workers. Many outbreaks were caused
by the Beijing strain, with “strain W” dominating in New York City.
Estimates based on data from 2006 through 2008 suggest that 80% of
cases in the United States are due to reactivation.2
Treatment programs failed because of drug resistance, medication
nonadherence, and nosocomial transmission of M. tuberculosis. Since
1992, however, TB incidence rates in the United States have progressively
declined and in 2016 reached the lowest in history.3 This attests to the
success that can be achieved with intensified diagnostic, treatment, and
prevention efforts, and with control of HIV-induced immunocompromise
by means of antiretroviral therapy (ART).
The global situation has, unfortunately, not been as successful. The
HIV pandemic fueled increased TB case rates in resource-limited coun-
tries worldwide, especially in sub-Saharan Africa. Scant resources and
fragile infrastructure, together with a high prevalence of HIV infection
and acquired immunodeficiency syndrome (AIDS), have driven the global
burden of TB. As in the United States, multidrug-resistant tuberculosis
(MDR-TB) emerged and spread. In response, the World Health Organiza-
tion (WHO) has worked diligently to expand TB treatment services,
including directly observed therapy, short-course (DOTS) programs. In
parallel, second-line medications, including fluoroquinolones, were made
increasingly available worldwide. Since 2011, WHO has recommended
that MDR-TB be treated using mainly ambulatory care, which appears
to be more effective than hospitalization.4
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With widespread use of second-line agents, selection for M. tuber-
culosis resistant to both first- and second-line drugs was inevitable.
Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance
to at least INH, RIF, a fluoroquinolone, and a second-line injectable
drug (kanamycin, capreomycin, amikacin), first occurred as early as
2001 in KwaZulu-Natal, South Africa,5,6 and by 2016 it had been reported
in at least 121 countries worldwide.1 Although application of established
TB public health principles, supported by ample funding, may ultimately
control this dire situation,7 the immensity of this challenge is daunting.
There are added challenges in reaching vulnerable populations, including
those who experience inequality, prejudice, marginalization, and limits
on their social, economic, cultural, and other rights.8
MICROBIOLOGY
The M. tuberculosis complex comprises at least nine species in the genus
Mycobacterium, family Mycobacteriaceae, and order Actinomycetales
that are causes of human TB and zoonotic disease. The M. tuberculosis
complex species share 99.9% sequence identity and likely evolved from
a single clonal ancestor.9 The species M. tuberculosis sensu stricto causes
the vast majority of human TB worldwide. Mycobacterium africanum
causes human TB in West Africa, where it accounts for up to 50% of
cases.10 Mycobacterium canettii is an extremely rare cause of human TB
in the Horn of Eastern Africa. M. bovis causes disease in cattle and
spreads to humans through animal contact and consumption of
unpasteurized milk. An investigation of six TB cases in the United
Kingdom demonstrated that M. bovis can be transmitted by aerosol
from patients with pulmonary lesions.11 Mycobacterium caprae, another
cattle pathogen, Mycobacterium microti, a pathogen for rodents, and
Mycobacterium pinnipedii, a pathogen for seals, have been reported to
cause zoonotic TB in humans. Mycobacterium orygis (antelope) and
Mycobacterium mungi (mongoose) have been described in animals but
have not been reported in humans.
Advances in genetic analysis, including whole-genome sequencing
(WGS), have shed new light on the phylogenetics of the M. tuberculosis
complex.12,13 These studies show that M. tuberculosis sensu stricto and
M. africanum, the predominant causes of human disease, can be further
divided into seven phylogenetic lineages, L1 to L7. This is a rapidly
changing field of study, with multiple nomenclatures in use. For example,
the L2 lineage is also called the East Asian lineage or the Beijing strain.
There is some evidence that different lineages vary in virulence, host
adaptation, transmissibility, or ability to acquire drug resistance, but
further research is needed to clarify the clinical importance of such
differences.
Humans are the only reservoir for the species M. tuberculosis, although
many animals are susceptible to infection.14 Some have postulated that
an ancient ancestor of M. tuberculosis infected hominids in East Africa
3 million years ago and has since coevolved with its human host.15 M.
tuberculosis is an aerobic, non–spore-forming, nonmotile bacillus with
a high cell wall content of high-molecular-weight lipids. Growth is slow,
the generation time being 15 to 20 hours, compared with much less
than 1 hour for most common bacterial pathogens, and visible growth
takes from 3 to 8 weeks on solid media. The organism tends to grow
in parallel groups, producing the colony characteristic of serpentine
cording. In radical contrast to other bacteria, a very large portion of
M. tuberculosis genes encode enzymes involved in lipogenesis and
lipolysis.
A wide spectrum of laboratory techniques has been developed to
diagnose active TB. No single test is perfect, and, unfortunately, some
diagnostics on which clinicians still rely were developed over 100 years
ago. Advantages and limitations of various methods are presented in
Table 249.1.
Acid-Fast Staining
The term acid-fast bacilli (AFB) is practically synonymous with myco-
bacteria, although Nocardia and some other organisms are variably acid
fast. In the Ziehl-Neelsen stain, a fixed smear covered with carbol-fuchsin
is heated, rinsed, decolorized with acid-alcohol, and counterstained
with methylene blue. The Kinyoun stain is modified to make heating
unnecessary. The organisms appear as slightly bent, beaded rods 2 to
4 µm long and 0.2 to 5 µm wide. In sputum they often lie parallel, or

TABLE 249.1  Comparison of Assays Used in the Diagnosis of Active Tuberculosis
CLINICAL LABORATORY
QUESTION
Are mycobacteria present in a
clinical specimen?
Is a mycobacterium isolated
from a clinical specimen a
member of M. tuberculosis
complex? (M. tuberculosis,
Mycobacterium bovis, M.
bovis–BCG, Mycobacterium
africanum, Mycobacterium
microti, or Mycobacterium
canettii)
To which species of M.
tuberculosis complex does a
clinical isolate belong?
Do different M. tuberculosis
isolates represent the same
strain?
Is an M. tuberculosis isolate
drug resistant?
AIDS, Acquired immunodeficiency syndrome; BCG, bacillus Calmette-Guérin; CDC, Centers for Disease Control and Prevention; CFU, colony-forming unit; ELISA, enzyme-
linked immunosorbent assay; FDA, US Food and Drug Administration; LAM, lipopolysaccharide lipoarabinomannan; PCR, polymerase chain reaction.
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DIAGNOSTIC ASSAY
Culture on solid media (Löwenstein-
Jensen egg-based or Middlebrook
agar-based media)
Culture in liquid broth
Acid-fast stain (Ziehl-Neelsen,
Kinyoun, auramine rhodamine)
Nucleic acid amplification (e.g., PCR)
Nucleic acid amplification with
GeneXpert MTB/RIF and Xpert
MTB/RIF Ultra
Urinary antigen detection (e.g., ELISA
for LAM)
Nucleic acid amplification
Nucleic acid probes
BACTEC p-nitroacetyl-
aminohydroxypropiophenone assay
(NAP)
High-performance liquid
chromatography (HPLC)
Colony morphology and biochemical
assays (e.g., niacin test, heat-
sensitive catalase, nitrate reduction,
pyrazinamide monodrug resistance)
PCR genomic analysis
Genotyping by restriction fragment
length polymorphism analysis,
spoligotyping, mycobacterial
interspersed repetitive unit analysis,
and whole-genome sequencing
Agar proportion method
Liquid BACTEC method
Molecular line probe assays and
whole-genome sequencing for
chromosomal mutations associated
with drug resistance (see above for
GeneXpert MTB/RIF)
2987
ADVANTAGES LIMITATIONS
Chapter 249  Mycobacterium tuberculosis
Gold standard for isolating Visible growth takes 3–8 wk
Mycobacterium tuberculosis; detects
10–100 organisms/mL; shows colony
morphology, detects mixed infection,
allows quantification of growth;
provides organisms for speciation,
strain identification, susceptibility
testing
Sensitivity and specificity similar to Does not show colony morphology,
solid media; automated systems detect mixed cultures, or quantify
decrease workload; provides growth
organisms for speciation, strain
identification, and susceptibility
testing; turn positive in a mean of
10 days for smear-positive and 20
days for smear-negative specimens
Same-day results; simple technology; Less sensitive than culture, requiring
inexpensive light microscope; 10,000 organisms/mL; cannot
fluorescence microscope required for distinguish M. tuberculosis from
auramine-rhodamine stain other mycobacteria
Same-day results; sensitivity Requires advanced laboratory
intermediate between acid-fast stain techniques; cannot distinguish dead
and culture; identifies organisms as from viable organisms; culture still
members of M. tuberculosis complex needed for speciation, strain
identification, and susceptibility
testing
Sensitivity of Xpert MTB/RIF roughly Expensive equipment; detects dead
100 CFUs/mL, requires 100 min, bacilli; culture needed for other
detects rifampin resistance mutations susceptibility testing
with sensitivity of 95% and
specificity of 98%
Xpert MTB/RIF Ultra is more sensitive
than Xpert MTB/RIF but with slightly
less specificity
Point-of-care testing; relatively high Sensitivity very low in situations other
sensitivity in advanced untreated than advanced AIDS
AIDS (<50 CD4 T cells/mm3)
(See above) (See above)
Results available in 2 h; sensitivity and Requires at least 105 organisms; most
specificity approach 100%; does not useful for pure culture, not directly
require amplification on clinical specimen; cannot
distinguish among members of M.
tuberculosis complex
Provides preliminary identification of Need for paired cultures increases cost
M. tuberculosis complex (NAP (growth with and without NAP)
susceptible)
Same-day results; sensitivity and Requires HPLC technology; only useful
specificity approach 100%; can with pure culture
distinguish M. bovis BCG from other
members of M. tuberculosis complex
Classic approach for speciation of Time-consuming and labor-intensive
M. tuberculosis
May rapidly distinguish among M. Not yet commercially available for this
tuberculosis complex species purpose
The CDC offers free strain typing Sophisticated assay available only at
through the National Tuberculosis specialized centers
Genotyping and Surveillance
Network
Quantifies the proportion of organisms Requires as long as 8 wk
resistant to a drug
Results within 5–14 days Does not quantify proportion of
resistance
Allow same-day determination of drug Need to be validated in multiple
resistance; line probe assay can be clinical settings and not yet FDA
performed directly on smear positive approved
sputum samples or culture isolates;
can detect resistance to isoniazid,
rifampin, quinolones, and second
line injectibles
 2988
two organisms adhere at one end to form a V. An estimated 10,000
organisms per milliliter of sputum are required for smear positivity,
and detection of at least 10 organisms on a slide is optimal; a single
organism on a slide is highly suggestive. The sensitivity of sputum
Part III  Infectious Diseases and Their Etiologic Agents
acid-fast bacillus smear when compared with culture is approximately
60%.16 Sensitivity is significantly lower with noncavitary disease and
HIV infection. Sensitivity increases by approximately 10% with the
collection of a second sputum sample, and 2% with a third.17 Sputum
processing with bleach and concentration before acid-fast staining also
increases sensitivity.18 Most laboratories in the United States now use
a fluorochrome stain with phenolic auramine or auramine-rhodamine,
a slightly modified acid-alcohol decolorization step, and potassium
permanganate counterstaining. Because the mycobacteria are easily seen
with a 20× or 40× low-magnification objective, fluorescence microscopy
requires less technician time and may increase the sensitivity over
conventional acid-fast bacillus smears.19 Advances in ultrabright light-
emitting diode (LED) microscopes make the technology more robust
for use in resource-poor settings.20 WHO recommends that LED
microscopy replace conventional fluorescence microscopy and that it
be phased in as an alternative for conventional Ziehl-Neelsen microscopy.21
As with all laboratory procedures, strict quality control is needed for
acid fast staining, or rates of false positives and negatives quickly rise.22
Any biologic fluid or material can be examined directly (e.g., pleural
fluid, cerebrospinal fluid [CSF], urine, gastric lavage fluid), although
thin fluids are best examined after sedimentation by centrifugation.
Positive smears from concentrated gastric aspiration material are usually
due to M. tuberculosis and are especially important in young children
from whom sputum collection may not be possible.
Culture Methods for Mycobacterium
tuberculosis
Culture is the gold standard for detecting mycobacteria in clinical
specimens. Samples of sputum or tissue require initial decontamination
to remove fast-growing nonmycobacterial organisms and liquefaction
to allow access of decontaminants to nonmycobacterial organisms and
media nutrients to surviving mycobacteria. Decontamination-liquefaction
is most commonly done using N-acetyl-l-cysteine as a mucolytic in
1% sodium hydroxide solution. Mycobacteria are relatively protected
during this procedure by a fatty acid–rich cell wall. However, normally
sterile tissues or fluids such as CSF or pleural fluid should not be
decontaminated, because some loss of mycobacterial viability does occur.
The sample is then neutralized and centrifuged, and the sediment is
inoculated onto media.
Three types of media may be used for culture of mycobacteria: solid
egg-based media (e.g., Löwenstein-Jensen), solid agar-based media (e.g.,
Middlebrook 7H11), and liquid broth (e.g., Middlebrook 7H12). Media
are made selective for mycobacteria by adding antibiotics. Nonselective
media, on which growth is more rapid, are available. Growth is more
rapid in 5% to 10% carbon dioxide. Liquid broth cultures require a
mean of 10 days of incubation for smear-positive and 20 days for
smear-negative specimens for detection of organisms, as compared with
solid media, which require 3 to 8 weeks. However, solid media allow
examination of colony morphology, detection of mixed cultures, and
quantification of growth. Furthermore, occasional strains of mycobacteria
may grow only on solid media. For these reasons, experts suggest using
liquid and solid media in conjunction, with inoculation of at least one
solid medium culture.23
Commercial automated liquid broth systems greatly facilitate
mycobacterial culture. They monitor mycobacterial growth through
detection of CO2 production or O2 consumption with radiometric,
fluorometric, or colorimetric indicators. The BACTEC mycobacterial
growth indicator tube (MGIT) system (Becton Dickinson Microbiology
Systems, Sparks, MD), which detects growth in 1 to 3 weeks by means
of a fluorometric method, is widely used.24,25
A noncommercial liquid broth assay was developed in which
mycobacteria are cultured in liquid media on a multiwell plate and
then examined microscopically for characteristic serpentine cording.
The addition of antimicrobial agents to the media allows drug susceptibil-
ity testing to be performed simultaneously. This microscopic-observation
drug-susceptibility (MODS) assay yields results in 7 to 10 days, with
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sensitivity and specificity similar to those of commercially available
liquid broth systems.26 Sensitivity is diminished (65.4%) when the source
of diagnostic material is not sputum (lymph node sampling).27 An
automated MODS (Auto-MODS) has been compared with conventional
culture in Thailand. With 95.5% sensitivity and 97.1% specificity and
a time to culture positivity of 10 days (interquartile range, 8–13 days),
this test appears to be effective and attractive in resource-limited settings.28
In addition, a commercial kit (the Hardy TB MODS Kit; Hardy Diag-
nostics, Santa Maria, CA) now provides results comparable to those of
the conventional MODS, with the ability to detect INH and RIF resistance
in a Biosafety Level 2 setting and 97.9% concordance with indirect
proportion susceptibility testing.29
Nucleic Acid Amplification
Nucleic acid amplification testing (NAAT) offers another technique for
the direct detection of M. tuberculosis in clinical specimens. The Xpert
MTB/RIF assay (Cepheid, Sunnyvale, CA) is a US Food and Drug
Administration (FDA)–approved automated molecular test for detection
of M. tuberculosis with sensitivity and specificity that approach those
of culture.30 The test is simple to perform and gives results in 100 minutes.
It uses real-time polymerase chain reaction (PCR) amplification of an
M. tuberculosis gene for detection. GeneXpert MTB/RIF assay had an
overall sensitivity of 89% and specificity of 99% for detection of
M. tuberculosis in sputum samples compared with gold standard culture
testing. Sensitivity was 98% for smear- and culture-positive cases and
67% for smear-negative culture-positive cases.31 Analysis of three sputum
samples further increases sensitivity.32 These initial reports continue to
be modified under the influence of factors such as prevalence of disease,
prevalence of HIV coinfection, and variable performance on smear-
positive and smear-negative samples.33,34 The GeneXpert MTB/RIF
simultaneously detects RIF resistance (see “Drug Susceptibility Testing”
later).
The Xpert MTB/RIF assay has also been used on nonrespiratory
samples (e.g., pleural fluid, CSF, peritoneal fluid, urine, fine-needle
aspirates), but the performance in nonrespiratory specimens varies by
population, TB prevalence, and type of fluid sampled. Detection in
pleural fluid in a report from India revealed a sensitivity of only 54.8%.35
The assay has been endorsed by WHO and is rapidly being deployed
to countries with high rates of endemic TB. A pooled testing strategy,
which might ameliorate some of the cost burden, has been reported
with encouraging results.36 With increased use, the examination of the
clinical utility now extends to the test’s impact on mortality, and in
South Africa no reduction associated with the use of the Xpert MTB/
RIF was found compared with microscopy.37 FDA approval has been
extended to an indication for use of the test in removing patients from
airborne isolation after one or two negative test results.38 A single-
institution analysis of 207 airborne-isolation cases found that the
efficiency (time to result and sensitivity) was greatest with a two-test
strategy, and a one-test strategy missed one case.39 A multisite (Burkino
Faso, Cambodia, Cameroon, and Vietnam) assessment comparing Xpert
MTB/RIF testing of nasopharyngeal aspirates and stool versus culture
in HIV-infected children younger than 13 years yielded a sensitivity
on all samples of 79.3% and 75.8%, respectively, on the alternative
sources.40
The confounding issue of detection of residual DNA not representative
of replication-competent bacteria has been addressed in South Africa,
where patients with re-treatment cases were significantly more likely
to have false-positive results (14%) than those with newly diagnosed
cases.41
A new version, the Xpert MTB/RIF Ultra assay (Cepheid, Sunnyvale,
CA) has been developed. Initial studies suggest that it improves sensitivity
by approximately 15% in smear negative-culture positive pulmonary
TB; however, there is a small decrease in specificity from 99% to 98%.42,43
The newer Xpert MTB/RIF Ultra assay may also improve sensitivity in
nonrespiratory samples. In a study in Uganda of 129 HIV-infected
patients with suspected meningitis, the Xpert MTB/RIF Ultra had a
sensitivity of 70% versus a clinical case definition of tuberculous
meningitis compared with a sensitivity of 43% for BACTEC culture
and 43% for the older Xpert MTB/RIF.44 WHO has recommended that
the Xpert Ultra assay be adopted in settings with high rates of HIV and

TB such as sub-Saharan Africa. Given the lower specificity, there may
be more false-positive results in low-HIV and low-TB settings.45
Another commercially available and FDA-approved NAAT assay
that can be used directly on respiratory samples is the Amplified M.
tuberculosis Direct (MTD) test (Hologic, San Diego, CA). The sensitivity
is intermediate between acid-fast staining and culture. For smear-positive
specimens, the sensitivity is 98% and the specificity is 99%. For smear-
negative cases, sensitivity ranges from 60% to 80% and the specificity
remains 99%.46–48
A number of other NAAT tests use novel technologies but are not FDA
approved.49 The COBAS TaqMan MTB assay (Roche Molecular Diagnostics,
Pleasanton, CA) is a real-time PCR test that targets M. tuberculosis ribo-
somal RNA. The loop-mediated isothermal amplification assay (TB-LAMP;
Eiken Chemical Company, Tokyo, Japan) does not require a thermal cycler
or other sophisticated laboratory equipment. It can be performed manually
in less than 1 hour, with results read with the naked eye.
Nucleic acid amplification testing complements but does not replace
clinical judgment, acid-fast smear, and culture in the diagnosis of TB.50
In sputum acid-fast smear-positive individuals, positive nucleic acid
amplification indicates the presence of M. tuberculosis complex and
confirms active TB. When there is a high clinical index of suspicion
for pulmonary TB but with a negative acid-fast smear, a positive NAAT
result is highly predictive of TB and allows early initiation of therapy.
NAAT assays perform less well when the clinical index of suspicion for
TB is low, in which case the frequency of false-positive tests may approach
that of true positives.51
Detection of Mycobacterial
Antigens in Urine
Detection of M. tuberculosis antigens in urine may have some usefulness
in diagnosing TB in patients with advanced AIDS, particularly in
countries where coinfection is highly prevalent. The Alere Determine
lateral flow urine lipoarabinomannan (LF-LAM) assay (Abbott, Abbott
Park, IL) is a commercially available point-of-care test for the diagnosis
of active TB.52 In a review of 12 studies of the LF-LAM test for TB
diagnosis in HIV-infected patients, the pooled sensitivity was 45% and
the specificity was 92%.53 The combination of microscopy and urinary
LAM testing provides incremental diagnostic sensitivity in HIV-infected
adults. Sensitivity for TB in HIV-uninfected persons is less than 25%.
Speciation of Mycobacteria
Once mycobacteria have been identified in a clinical specimen, speciation
is necessary for clinical diagnosis and epidemiologic investigation. For
example, speciation may be important in immunocompromised patients
at risk for nontuberculous mycobacterial infection, in localities where
M. bovis transmission from animals to humans is possible, or in bladder
cancer patients receiving bacillus Calmette-Guérin (BCG) immune
stimulatory therapy. Speciation generally involves two steps: First,
mycobacteria are identified as members of the M. tuberculosis complex
(e.g., M. tuberculosis, M. bovis, M. africanum) or as Mycobacterium
species other than tuberculosis (MOTT). Subsequently, if necessary,
mycobacteria can be speciated within the M. tuberculosis complex. NAAT
assays, growth in selective antibiotic media, nucleic acid probes, and
high-performance liquid chromatography are all used to place myco-
bacteria within the M. tuberculosis complex.54 Each has advantages and
limitations that are detailed in Table 249.1. Identifying individual species
within the M. tuberculosis complex is more challenging. M. tuberculosis
grows slowly, lacks pigment, produces niacin, reduces nitrates, has weak
catalase activity that is lost by heating to 68°C at pH 7.0, does not
demonstrate monodrug resistance to PZA, is resistant to thiophen-
2-carboxylic acid hydrazide, and prefers aerophilic conditions. Other
members of the complex show different patterns with these tests.
Next-generation sequencing technology is rapidly making WGS of
clinical isolates routine and also enables identification of species within
the M. tuberculosis complex.55
Genotyping of Mycobacterium
tuberculosis
Characterizing the particular strain of M. tuberculosis is important for
epidemiologic purposes, such as tracing transmission from person to
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2989
person, distinguishing exogenous reinfection from endogenous reactiva-
tion in cases of recurrent TB, and identifying laboratory cross-
contamination of cultures. The Centers for Disease Control and
Prevention (CDC) offers free strain typing through the National
Chapter 249  Mycobacterium tuberculosis
Tuberculosis Genotyping Service based on four typing methods: restric-
tion fragment length polymorphism (RFLP) analysis, spacer oligonucle-
otide typing (spoligotyping), mycobacterial interspersed repetitive unit
(MIRU) analysis, and WGS.56 In RFLP analysis, DNA cleavage fragments
generated using pvuII are separated by means of electrophoresis and
visualized with use of a probe to a repetitive DNA sequence, insertion
sequence (IS) 6110. Because numerous copies of IS6110 are present at
variable chromosomal locations in most M. tuberculosis isolates, identical
RFLP patterns represent the same strain. Spoligotyping detects variability
in the direct repeat (DR) region in M. tuberculosis genome. There are
direct repeats of a conserved 36-bp sequence, separated by multiple
spacer sequences. Different M. tuberculosis strains are distinguished by
the presence or absence of 43 unique spacers. Each possible combination
of spacers is designated by a unique numeric code that identifies a
unique spoligotype strain. In MIRU analysis, 12 different DNA sequences,
each of which can be tandemly repeated in the M. tuberculosis genome,
are analyzed. The number of tandem repeats for each of the 12 sequences
(or loci) is determined by means of PCR to create a 12-number code.
Each code corresponds to a unique MIRU strain.
WGS of clinical isolates is rapidly supplanting prior typing technology.
In the United States, many state public health laboratories and the
National TB Molecular Surveillance Center routinely perform WGS on
isolates from every TB case. Many other countries are developing similar
systems. WGS provides data on species, strain type, and drug susceptibil-
ity (see later). The WGS bioinformatics pipeline and reporting system
are being standardized, and clinicians should anticipate WGS reports
on every culture-positive TB case in the near future.57
Drug Susceptibility Testing
Testing of M. tuberculosis isolates for drug susceptibility is important
to guide therapy. There are two broad methods to test an M. tuberculosis
isolate’s drug susceptibility: phenotypic testing, which relies on culturing
M. tuberculosis in media with varying concentrations of antibiotics,
and genotypic testing, which correlates specific mutations in the isolate’s
genome with known drug susceptibility patterns.
In the United States, the agar proportion method is most commonly
used to determine phenotypic drug resistance. The absolute concentration
method and resistance ratio method are used less commonly. The agar
proportion method compares growth of appropriately diluted inocula
on drug-containing media versus growth on drug-free media and is
reported as proportion resistant. For most drugs, resistance is significant
when growth on drug-containing media exceeds 1% of control; 6% to
10% resistance or more indicates that the drug will add nothing to
multidrug therapy. Liquid broth systems, such as BACTEC, can also
be used and provide results in 5 to 14 days, but they do not give the
proportion of resistant organisms.58,59
As noted earlier, the MODS method shows promise as an inexpensive
and rapid method for culture and drug susceptibility testing.26
Molecular testing to detect M. tuberculosis chromosomal mutations
associated with mycobacterial drug resistance is an exciting develop-
ment.32,60–63 Most commonly used are tests for RIF resistance, which
predicts poor treatment outcomes and is a surrogate marker for MDR-TB.
Assays detect mutations in the 81-base-pair rpoB gene, which encodes
the β-subunit of RNA polymerase and correlates with greater than 96%
of RIF resistance. Resistance to INH is more complex and is encoded
by multiple genes, including the catalase peroxidase gene katG, the
inhA gene involved in fatty acid biosynthesis, the ahpC gene, the oxyR
gene, and the kasA gene.64 Mutations associated with resistance to PZA,
ethambutol (EMB), second-line injectable drugs, and fluoroquinolones
have also been identified.
The GeneXpert MTB/RIF assay detects mutations in the rpoB gene
and has a sensitivity of 95% and specificity of 98% for detection of RIF
resistance in respiratory samples that are RIF resistant with culture
techniques. However, use of the test in populations with high rates of
HIV infection and drug resistance, such as in Swaziland, revealed that
the test failed to detect a high-prevalence rpoBI491F outbreak strain.
 2990
This RIF-resistance–conferring mutation was present in 30% of MDR
strains.65 The drug-resistance assay is performed on sputum simultane-
ously with detection of organisms, and results are available within 2
hours. Three line probe assays are also commercially available: the
Part III  Infectious Diseases and Their Etiologic Agents
INNO-LiPA Rif. TB kit (Innogenetics, Zwijndrecht, Belgium), which
detects resistance to RIF in culture isolates; the Genotype MTBDRplus
assay (version 2.0) (Hain Lifescience, Nehren, Germany), which detects
resistance to INH and RIF in culture isolates and smear-positive sputum
samples, and thereby can enable identification of MDR-TB; and the
Genotype MTBDRsl assay (Hain Lifescience), which detects resistance
to fluoroquinolones and second-line injectable drugs in culture isolates
and smear-positive sputum samples and thereby can be used to identify
XDR-TB.66–69 WHO has recommended widespread use of these molecular
assays.70 The clinical impact of rapid diagnosis and drug-resistance
detection has been reported from Tbilisi, Georgia, where the MTBDRplus
assay was associated with selection of drug regimens that provided
higher and more rapid rates of culture conversion at 24 weeks.71
WGS is also becoming a powerful tool for the detection of drug-
resistance mutations in the M. tuberculosis genome.72,73 Currently it can
be performed only on culture isolates, and the bioinformatics pipelines,
databases cataloguing drug-resistance mutations, and reporting systems
are being standardized for routine clinical use.
EPIDEMIOLOGY
General Considerations
M. tuberculosis infects 1.7 billion people or approximately one-quarter
of the world’s population and caused 10.4 million new cases of TB and
approximately 1.7 million deaths in 2016.1,74,75 TB is the leading cause
of death worldwide resulting from a single infectious agent, ranking
above HIV since 2014.76 Immunocompromise due to HIV infection is
a risk factor for TB, and 374,000 TB deaths are in HIV-infected individu-
als. Drug-resistant TB is emerging globally, with approximately 490,000
new MDR-TB cases in 2016. Two factors essential for the rapid spread
of M. tuberculosis are crowded living conditions and a population with
little native resistance. In the 19th century, TB caused more than one-
fourth of all adult deaths in Europe, eliminating those with the least
native resistance. A downward trend had been established before the
turn of the 20th century. Epidemiologists once believed the disease
would eventually disappear based on the assumptions that 1 in 20
infections result in active cavitary disease of the lung (i.e., become
contagious). Thus, each cavitary case would have to infect 20 persons
for case rates to be maintained.77 In Holland in the early 1900s, one
infectious case produced only 13 new infections.77 The annual decrement
in mortality and morbidity from TB was approximately 5% in developed
countries owing to progressively higher natural residual resistance in
those who survived infection and to living conditions less conducive
to airborne spread. This rate of decline approximately doubled after
chemotherapy became widespread.
In the 1980s and 1990s, the high incidence of TB in Africa, Asia,
Eastern Europe, and South America, the HIV coepidemic, and burgeoning
MDR-TB demonstrated that predictions of the disappearance of TB
were premature, and WHO declared TB a global public health emergency.
Since then, tremendous gains have been made in reducing the number
of new TB cases, now in decline for the past several years. The integration
of multiple modalities, such as genotyping combined with a series of
spatial analysis tools, might improve the efficiency of targeted transmis-
sion control.78
Recent Morbidity and Mortality Trends
In the United States, the incidence of TB has decreased steadily over
the past 25 years, from 10.5 reported cases per 100,000 population in
1992 to 2.8 cases per 100,000 population in 2017, the lowest in recorded
history.2,79 Recent estimates of latent infection in the United States suggest
a prevalence of latent infection in 2011–12 of 4.4% by the tuberculin
skin test (TST) and 4.8% by the QuantiFERON-TB Gold In-Tube test
(QFT-GIT; Cellestis Limited, Carnegie, Victoria, Australia).80 In the
United States the TB rate in foreign-born persons is 15 times higher
than in US-born persons, and foreign-born persons now account for
almost 70% of reported cases in the United States (Fig. 249.1).79 This
reflects increased immigration from high-prevalence countries, especially
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40
35
Rate of Tuberculosis Cases
(per 100,000 population)
30
25 Foreign-born persons
20
15
Overall
10
5
US-born persons
0
93
95
97
99
01
03
05
07
09
11
13
15
19
19
19
19
20
20
20
20
20
20
20
20
FIG. 249.1  Rates of tuberculosis cases among US-born versus
foreign-born persons, United States, 1993–2015. (Modified from
Tuberculosis in the United States: National Tuberculosis Surveillance System
highlights from 2015. Slide 17. https://www.cdc.gov/tb/statistics/surv/
surv2015/default.htm.)
Mexico, the Philippines, India, Vietnam, and China, from which
immigrants account for more than half of the TB cases in foreign-born
individuals.81 Strain genotyping suggests that TB among foreign-born
persons is from reactivation of latent infection acquired before arrival
in the United States. Furthermore, the risk declines with duration of
residency, also suggesting that most infections were acquired before
immigration.82 Screening of immigrants to the United States with a
culture-based, rather than a smear-based, algorithm is justified by the
high rate (54.4%) of smear-negative and culture-positive cases.83
TB has also become concentrated in certain ethnic and racial minori-
ties and medically underserved populations, often occurring in contact-
based microepidemics. In 2017, rates among US-born blacks was seven
times higher than in non-Hispanic US-born whites; the rate in Native
Americans was nine times higher than in whites.79 A number of outbreaks
have affected the urban poor, alcoholics, injection drug users, the
homeless, migrant farm workers, and prison inmates.
The age distribution of TB reflects the degree of ongoing transmission
in a given population. Disease in the elderly is generally due to reactiva-
tion of infection acquired in the remote past, whereas TB in young
children indicates ongoing active transmission in the community. In
this regard, 75% of childhood cases in the United States occurred in
patients who had TB exposure through foreign-born parents or prior
residence outside the United States.84,85
TB in the United States is most frequent in geographic regions and
demographic groups where AIDS is prevalent, notably in urban blacks
and Hispanics between 25 and 45 years of age.86 Persons with active
TB are more frequently HIV positive than is the general population.
Approximately 8% of all TB cases in the United States occur in HIV-
infected persons.3
Despite a predominantly urban epidemiology, large TB outbreaks
have also affected small communities.87,88 One well-characterized outbreak
began in 1988 in a coastal Maine village where TB had not been reported
in the previous 3 years.88 A shipyard worker with cavitary TB was the
source of 21 subsequent active cases and 697 new tuberculous infections.
In retrospect, the source patient had repeatedly sought medical attention
for cough, sore throat, and hoarseness during 8 months before TB was
diagnosed and treated. This report highlights the need for vigilance
regarding all segments of the population, not just those known to have
high TB case rates.
The prevalence of positive TST results in US Navy recruits offers
insights into trends of latent tuberculosis infection (LTBI) over time
and risk factors for infection. From 1958 through 1969, more than
1 million US Navy recruits underwent TSTs, and in 5.2% the results
were positive. In the 1980s and 1990s, the rate of tuberculin reactivity
dropped to approximately 1.5% of new Navy recruits. The prevalence
was greater in blacks (5%), Hispanics (5%), and Asian/Pacific Island-
ers (26%) than in whites (0.8%). Tuberculin positivity was more than
10-fold more prevalent among foreign-born recruits.89–91 In a survey
 2991

TABLE 249.2  Reported Tuberculosis Case Rates in TABLE 249.3  Estimated Incidence of Tuberculosis
Immigrants According to Country of Birth: Cases in Countries That Accounted for 75% of
Stratified by Time Since Entry Into the United Cases Worldwide, 2016

Chapter 249  Mycobacterium tuberculosis

States
RATE PER 100,000
CRUDE RATE (PER 100,000 COUNTRY CASES POPULATION
PERSON-YEARS)a India 2,790,000 211
US ENTRY US ENTRY Indonesia 1,020,000 391
COUNTRY ≤2 YEARS >2 YEARS
China 895,000 64
Somalia 889 179
Philippines 573,000 554
Ethiopia and Eritrea 562 82
Pakistan 518,000 268
Vietnam 319 47
South Africa 438,000 781
Cambodia 307 65
Democratic Republic of Congo 425,000 323
Philippines 283 38
Nigeria 407,000 219
Ecuador 194 31
Bangladesh 360,000 221
Haiti 189 40
Myanmar 191,000 361
Honduras 177 28
Ethiopia 182,000 177
Peru 159 32
Modified from World Health Organization. Global Tuberculosis Report 2017. http://
Guatemala 111 21 www.who.int/tb/publications/global_report/gtbr2017_annex4.pdf.
India 106 33
China 74 26
Africa, where the incidence of TB has risen in parallel with the incidence
El Salvador 73 11 of HIV infection. Between 1990 and 2005, the incidence of TB more
Mexico 52 14 than doubled, from 149 to 343 per 100,000 population. TB is the leading
Korea 40 19
cause of death in HIV-infected people, and in 2016, 22% of the 1.7
million TB deaths were in HIV-coinfected people. Seventy-five percent
All foreign-born individuals 75 16 of the world’s HIV-positive TB deaths occurred in Africa.1 The continued
a
Data provided for the 15 most commonly reported countries of birth. scale-up and integration of HIV and TB programs are necessary to
Modified from Cain KP, Benoit SR, Winston CA, et al. Tuberculosis among foreign decrease the deaths in these populations.
born persons in the United States. JAMA. 2008;300;405–412.
Drug-Resistant Tuberculosis
Drug-resistant TB poses an immense challenge for TB control. Resistance
of noninstitutionalized civilians in the United States, the prevalence of to antituberculous agents can be either primary, that is, present before
tuberculin reactivity among persons 25 to 74 years of age decreased initiation of therapy and due to transmission of a drug-resistant M.
from 14.4% in 1972 to 5.6% in 2000 and to 4.4% in 2011.80,92 tuberculosis strain, or secondary, indicating emergence of resistance after
Immigrants for the most part retain the tuberculin positivity and antituberculosis therapy. Risk factors for infection with drug-resistant
TB rates of their country of origin (Table 249.2).93,94 Other groups, such TB are listed in Table 249.4. Strains resistant to at least INH and RIF
as injection drug users, patients with end-stage renal disease or diabetes, are defined as MDR-TB. Strains resistant to at least INH, RIF, a fluo-
health care workers in endemic countries, residents of institutions for roquinolone, and second-line injectable drugs are defined as XDR-TB.112
the homeless, and, to a lesser degree, nursing home residents, demonstrate WHO has regularly reported global drug-resistance rates since
morbidity rates greatly in excess of the general population.95–103 1994.113–116 In the United States, the rate of primary resistance to any
On a global scale, TB has a devastating impact in lower- and middle- antituberculosis drug has remained stable at about 12%, with that of
income nations, with 10 countries accounting for nearly 70% of all MDR-TB at about 1%.115 Globally, 3.3% of new TB cases and 20.1% of
prevalent cases (Table 249.3).104 In 1993, WHO declared TB a global previously treated TB cases are MDR.116 In 2016, there were an estimated
public health emergency and intensified major initiatives to address 490,000 new cases of MDR-TB worldwide. Parts of Eastern Europe and
the problem. An important aspect of this strategy is supervised treatment, central Asia, including Belarus, Estonia, Latvia, the Russian oblasts of
which may include DOTS.105 WHO subsequently reported decreasing Ivanovo and Tomsk, and Henan Province in China, have rates of MDR
incidence rates of TB in all six regions of the world, including Southeast in newly diagnosed patients with TB that exceed 18%.114–118
Asia, the Western Pacific, and Africa. In China, access to DOT was Prior antituberculosis treatment is the most important risk factor
rapidly expanded from 31% of TB cases in 2001 to 80% in 2005, and for drug-resistant TB. Additional historical clues that increase the
from 1990 to 2010 the prevalence of smear-positive disease decreased likelihood of drug resistance include infection acquired in regions where
from 170 to 59 cases per 100,000, in a population of greater than 1.3 resistance is prevalent and known contact with a drug-resistant case.
billion.106,107 Similar progress has also been made in India, the country One study from southern California recorded resistance in 71% of
with the greatest number of TB cases.108,109 Challenges remain; molecular patients with TB who had been previously treated and had cavitary
epidemiologic data from China from 2009 through 2012 indicate that disease.119 Of immense concern is transmission of XDR-TB.112 Cases
recent transmission still accounts for a substantial proportion of new of XDR-TB have been reported in 105 countries worldwide, and it is
cases and that sputum smear–negative cases may be responsible for estimated that 9.7% of MDR-TB is XDR-TB.116
30% of secondary cases.110 In 2014 WHO launched its End TB Strategy
with the goal of reducing global TB deaths by 90% and TB incidence Mode of Spread
by 80% by 2030. Major expansions of current activities and new preven- Almost all infections with M. tuberculosis are due to inhalation of droplet
tion and treatment strategies will be needed to achieve this goal.1 nuclei—infectious particles from a person with pulmonary TB aerosolized
Over 35 million persons worldwide are now living with HIV/AIDS.111 by coughing, sneezing, or talking—which dry while airborne, remain
The potential for continued interaction between HIV and TB is therefore suspended for long periods, and reach the terminal air passages. A
immense. In some developing countries where most persons harbor cough can produce 3000 infectious droplet nuclei, talking for 5 minutes
tubercle bacilli before adulthood, the prevalence of HIV infection becomes an equal number, and sneezing many more than that. Accordingly, the
the only determinant of coinfection. The situation is worst in sub-Saharan air in a room occupied by a person with pulmonary TB may remain

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 2992
TABLE 249.4  Epidemiologic Circumstances in
Which an Exposed Person Is at Increased Risk for
Infection With Drug-Resistant Mycobacterium
Part III  Infectious Diseases and Their Etiologic Agents
tuberculosisa
• Exposure to a person who has known drug-resistant tuberculosis
• Exposure to a person with active tuberculosis who has had prior treatment
for tuberculosis (treatment failure or relapse) and whose susceptibility test
results are not known
• Exposure to persons with active tuberculosis from areas in which there is a
high prevalence of drug resistance
• Exposure to persons who continue to have positive sputum smears after
2 months of combination chemotherapy
• Travel in an area of high prevalence of drug resistance
a
This information is to be used in deciding whether to add a fourth drug (usually
ethambutol) for children with active tuberculosis, not to infer the empirical need
for a second-line treatment regimen.
From Centers for Disease Control and Prevention. Treatment of tuberculosis.
American Thoracic Society, CDC and Infectious Diseases Society of America.
MMWR Recomm Rep. 2003;52(RR–11):1–88.
infectious for approximately 30 minutes even after his or her absence.
Although in theory one droplet nucleus may be sufficient to establish
infection, prolonged exposure and multiple aerosol inocula are usually
required. Strains may vary widely in their transmissibility,87 but infection
does not generally occur outdoors because M. tuberculosis is killed by
ultraviolet light. Although homes are the focus of TB contact investiga-
tions, evidence is mounting that in high-TB settings, approximately
85% of transmission occurs in other social spaces including medical
facilities, public transportation vehicles, workplaces, schools, churches,
bars, and other areas where people congregate.120
Large drops of respiratory secretions and fomites are unimportant
in transmission, and special housekeeping measures for dishes and bed
linens are unnecessary. Other modes of transmission are rare. Infection
with M. bovis from ingestion of contaminated milk was once com-
monplace. Skin inoculation of M. tuberculosis from contamination of
an abrasion occurs in pathologists and laboratory personnel (prosector’s
wart), and venereal transmission has been recorded. Although the source
is pulmonary in the vast majority of cases, aerosolization of organisms
during irrigation of cutaneous lesions or at autopsy has caused spread
to health care workers.121,122 The special case of organ-donor–transmitted
infection should be noted because transplant recipients have a higher
frequency of TB than the general population, and high mortality.123
Because donor-derived disease develops late (>90 days) in the majority
of cases, and many donors have identifiable risk factors for tuberculous
infection, it has been proposed that screening protocols using donor
histories that would heighten surveillance of recipients, in addition
to cultures and smears, and testing for latent TB in donors should be
undertaken.124
Risk for Infection
The most important determinants of infection of tuberculin-negative
persons are closeness of contact and infectiousness of the source. From
2002 to 2011, 26 outbreaks in the United States were associated with
index cases with a substantial burden of substance abuse, incarceration,
and homelessness.125 Cases with positive smears are highly infectious;
those positive only on culture are less so. The degree of sputum positivity
and pattern of coughing are important. Compared with measles, one
case of which will infect 80% of susceptible casual contacts, TB is only
moderately infectious in most circumstances. In the United Kingdom,
a study of 111 cases with 825 contacts found that a shorter interval to
liquid culture positivity identified patients at high risk of transmitting
infection and was also superior to detection by means of smear.126
TB morbidity in a population is determined both by the risk for
infection and the risk for acquiring active disease once infected. In
Holland in the 1970s, 50% of newborn to 14-year-old household contacts
of individuals with smear-positive cases became tuberculin positive,
but only 5% did so when the contact case was culture positive but smear
negative.77 In the United States, approximately 27% of household contacts
of individuals with smear-positive cases become infected, although rates
as high as 80% occur in closed environments.127 A large epidemiologic
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investigation in San Francisco from 1991 to 1996 estimated that
17% of new active TB cases arose from smear-negative, culture-positive
index cases.
Persons coinfected with HIV do not appear to be more infectious
than HIV-negative source cases and because they are more likely to be
smear negative than are HIV-negative patients, they may be less infectious.
In one large study from the Democratic Republic of Congo, household
contacts of HIV-positive patients with pulmonary TB were no more
likely to become infected with M. tuberculosis than were household
contacts of HIV-negative TB patients.128 A study in Uganda demonstrated
that transmission from an HIV-infected index case to contacts was
dependent on the index patient’s sputum smear positivity and presence
of a cavity on chest radiograph.129 A meta-analysis of six studies involving
exposed health care workers supports this finding, as does a study of
household contacts in Peru.130,131
Influence of Chemotherapy on
Spread of Infection
Patients receiving appropriate chemotherapy promptly become noninfec-
tious as cough subsides and the concentration of organisms in sputum
decreases. The time required to become noninfectious depends on the
patient’s burden of organisms, but there is indirect evidence that this
occurs within 2 weeks in patients with drug-sensitive TB.132 Thus, case
finding and treatment comprise the most effective method of TB control.
Risk for Progression From Infection to
Active Disease
In general, 3% to 4% of infected individuals acquire active TB during
the first year after tuberculin conversion and an additional 5% do so
thereafter, although the uniformity of these rates has been challenged
in a study from Victoria, Australia, in which the cumulative hazard for
progression to disease after infection was 14.5%, with most risk occurring
within the first 5 months and greater risk in children younger than 5
years (50.6%).133,134 These estimates are based on heavy exposures during
disease-prone periods of life. Persons infected with small inocula or
during disease-resistant periods probably have a much smaller risk,135
whereas the risk for progression in immunocompromised persons is
greater. In one study of 12,876 unvaccinated adolescents, 10.4% of those
who converted their tuberculin tests acquired clinical TB, 54% of these
within 1 year and 78% within 2 years.77 The three periods of life during
which infection is most likely to produce disease are infancy, ages 15
to 25 years, and old age. (The effect of age on disease progression is
discussed in “Influence of Age on Tuberculous Infection.”)
The likelihood of active disease developing varies with the intensity
and duration of exposure. Persons with intense exposures are most at
risk not only for infection but also for disease.127 The degree of tuberculin
positivity has some predictive value. Malnutrition, renal failure, and
immunosuppression all favor progression of infection to active disease,
but by far the strongest risk factor is HIV infection. Among tuberculin-
positive, HIV-positive injection drug users in one methadone clinic
population, 8% per year acquired active TB.136
Institutional Spread of Tuberculosis
Hospitals
TB has long been a recognized risk to health care workers and hospitalized
patients. In the 1980s, numerous explosive outbreaks of TB occurred
among HIV-infected patients in specialized wards and hospices in the
United States and Europe.137–141 In the first reported outbreak on an
HIV ward, the index patient had fever, cough, a normal chest radiograph,
and negative acid-fast smears, but a positive sputum culture for M.
tuberculosis.138 On the same ward, 39% of other HIV-positive patients
acquired active TB within 60 days. Major factors contributing to these
outbreaks included (1) delays in diagnosis, especially in HIV-infected
patients with atypical chest radiographs; (2) inadequate negative-pressure
ventilation inpatient rooms; (3) use of aerosol-generating procedures
such as bronchoscopy and sputum induction; (4) rapid progression to
active TB in HIV-positive patients; and (5) in the case of MDR-TB,
prolonged infectivity despite antituberculous chemotherapy.142 In high-
income countries, decreased numbers of AIDS hospitalizations, decreased
TB incidence, low rates of MDR, and improved hospital infection-control

programs have generally diminished these outbreaks. In middle- and
lower-income countries, with higher rates of HIV- and TB-related hospital
admissions and less resources for infection control, nosocomial transmis-
sion remains a major public health problem. An investigation of 404
cases of XDR-TB in South Africa demonstrated the continued importance
of nosocomial transmission.143,144
In reaction to outbreaks of MDR-TB, the CDC in 1994 established
very stringent criteria for removing from respiratory isolation patients
who were suspected to have pulmonary TB and had not begun empirical
treatment. These criteria now include three consecutive negative sputum
smears on good-quality specimens obtained at least 8 hours apart.145
Studies have demonstrated that two negative sputum Xpert MTB/RIF
tests improve sensitivity and specificity for identifying patients who
will be found to be culture and smear negative. Use of the Xpert MTB/
RIF will decrease time in isolation and will be more cost-effective than
use of three AFB smears.146,147
Shelters for the Homeless
Approximately 1% of the US population experiences homelessness in
a given year, and these people account for a disproportionately high
percentage (6%) of all the TB cases in the country annually. Poor
nutrition, injection drug use, alcoholism, lack of access to TB screening
and treatment, and crowding increase the risk for both endogenous
reactivation of remote infection and acquisition of new (exogenous)
infection in homeless shelter clients.96 A review of cases between 1994
and 2003 showed that 6% of TB cases in the United States occurred in
homeless individuals, of whom 87% were men and 34% were HIV
positive and in whom alcohol and drug abuse was common.148 A 2015
CDC-sponsored workshop with homeless shelter staff and public health
officials from across the country defined key measures to prevent TB
transmission in shelters including strict infection-control procedures,
active case finding, screening for latent TB, cooperation between shelters
and public health authorities, education of shelter staff and clients, data
sharing, and prevention of stigma so that clients with symptoms will
freely come forward.149
Correctional Facilities
The incidence of TB is markedly higher in incarcerated persons than
in the general population.150 In the United States, high-risk populations—
including young black and Hispanic men, injection drug users, and
HIV-infected persons—are overrepresented in prison populations.151
Although most prison cases are due to reactivation of old infections,
outbreaks of MDR-TB have shown that transmission of new (exogenous)
infection also occurs. Although difficult for obvious reasons, preventive
and curative services in correctional facilities are a high public health
priority for everyone.151,152 Transmission in prisons and jails may serve
as an amplifier for spread to the community. In a study in a medium-size
city in Brazil between 2009 and 2013, 25% of TB cases occurred among
prisoners, who represented <1% of the city’s population, and an additional
25% of the TB cases in the city were in ex-prisoners who had recently
been released into the community. The remaining 50% occurred in
community members. M. tuberculosis strain typing demonstrated clear
clonal links between the prison cases, cases in ex-prisoners, and com-
munity cases.153
Controlling Nosocomial Spread
Spread of TB in the health care setting has raised justifiable concern.
Tuberculin conversion rates as high as 50% among health care workers
on HIV wards were reported early in the AIDS epidemic.139 Delays in
diagnosis and initiation of therapy are critical for both outcome and
infectiousness to others.142,154 Accordingly, TB must be considered in
any HIV-positive patient with subacute or chronic pulmonary symptoms
or symptoms compatible with extrapulmonary TB. Screening with NAAT
tests such as Xpert MTB/RIF may expedite diagnosis.
Hospitalized HIV-positive patients with respiratory symptoms or
people with suspected TB should be admitted to negative-pressure
isolation rooms (so that air flows from the corridor into the room and
is safely exhausted to the outside) with six air changes per hour. Pro-
cedures that stimulate coughing, such as sputum induction or bron-
choscopy, should be carried out in negative-pressure rooms or special
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2993
booths. The use of particulate respirator masks (N95), with appropriate
training and fitting, further reduces risk and is recommended by the
CDC. Ultraviolet irradiation of the air— either with the air pulled by
a fan through a radiation chamber or with the ultraviolet beam directed
Chapter 249  Mycobacterium tuberculosis
into the uppermost parts of the room so as to avoid direct irradiation
of personnel—is also advised. The CDC has published extensive guidelines
for control of transmission of TB in diverse health care settings.155 Further
evidence from a guinea pig model, in which the animals breathed
untreated air from a TB ward, supports the use of air disinfection based
on ultraviolet treatment.156 WHO has also published TB infection-control
guidelines for health care facilities with strategies that may be attainable
for low- and middle-income countries.157
IMMUNOLOGY
TB is the prototype of infections that require a cellular immune response
for their control (see Chapter 6). An effective immune response against
M. tuberculosis infection relies on CD4+ T cells and the cytokines
interleukin (IL)-12, interferon-γ, and tumor necrosis factor (TNF).158
Conversely, M. tuberculosis has adapted to host immunity and likely
depends on the cellular immune response to facilitate tissue damage,
formation of pulmonary cavities, and its own aerosol transmission.
WGS of M. tuberculosis shows that the 491 major human T-cell epitopes
expressed by the mycobacterial genome are highly conserved, suggesting
that M. tuberculosis is no longer evolving to evade the human immune
response but rather has reached an equilibrium with it.159
After initial inhalation, droplet nuclei with M. tuberculosis must
bypass mechanical barriers, ciliated respiratory epithelial cells, and
mucins in the upper airways to arrive in the alveolar spaces.160 In the
alveoli, M. tuberculosis is phagocytized by the alveolar macrophage.
Entry into macrophages involves interactions with complement receptors,
mannose receptors, and Fc receptors. Various M. tuberculosis molecules
are recognized by multiple pattern recognition receptors (PRRs) at the
cell surface, in the phagosome, or in the cytosol of the macrophage.
Other immune cells that participate in the initial host response include
neutrophils, dendritic cells, λδ T cells, mucosal-associated invariant T
(MAIT) cells, CD1-restricted T cells, and natural killer (NK) cells.161
The alveolar macrophage may successfully kill the mycobacteria
through phagosome maturation, fusion with the lysosome, or autophagy.
Alternatively the mycobacteria may release virulence factors that delay
phagosome maturation or result in phagosome rupture. M. tuberculosis
uses several strategies to survive within macrophage phagosomes while
delaying or preventing effective immune responses. Mycobacterial urease
helps prevent acidification of the phagosome, thus limiting the effective-
ness of bactericidal enzymes. In addition, by remaining within the
phagosome, the organism does not initially elicit T-cell responses via
the proteosomal pathway of antigen presentation. The organism also
secretes abundant superoxide dismutase, catalase, thioredoxin, and other
antioxidants that detoxify reactive oxygen species generated by phago-
cytes. Microbial antioxidants not only provide direct protection against
host-generated oxidants but also suppress early oxidant-mediated immune
responses needed for efficient antigen presentation, including the
activation and apoptosis of macrophages.162 This both ensures the
organism’s continued survival within its host cell and delays the develop-
ment of strong adaptive T-cell responses. The recent elucidation of such
pathogenic mechanisms has fostered rational strategies toward vaccine
development (see “Vaccination”).
If the initial infection is successful, unrestrained replication proceeds
for weeks, both in the initial focus and in lymphohematogenous metastatic
foci. The development of adaptive cellular immunity is delayed and
takes approximately 4 to 8 weeks and ultimately supervenes. Tissue
hypersensitivity is florid in comparison with other intracellular infections,
perhaps fueled by the adjuvant activity of mycobacterial lipids.
CD4+ Th1 cells, which secrete interferon-γ, are central to the
protective immune response against M. tuberculosis. M. tuberculosis
antigen-specific CD4+ Th1 cells are activated by dendritic cells via the
IL-12 pathway in the lymphatic tissue, clonally expand, and then migrate
to the site of infection. CD4+ T-cell production of interferon-γ activates
macrophages at the site of antigen. Activated macrophages accumulate
high concentrations of lytic enzymes and reactive metabolites that greatly
increase their mycobactericidal competence, causing a decrease in the
 2994
mycobacterial load. Activated macrophages also secrete regulatory
molecules (e.g., TNF-α and transforming growth factor-β), which in
concert with lymphocyte secretory proteins (e.g., interferon-γ, migration-
inhibitory factor) determine the character of the pathologic and clinical
Part III  Infectious Diseases and Their Etiologic Agents
response. Epithelioid cells, characteristic of the tuberculous granuloma,
are highly stimulated macrophages. The Langhans giant cell consists
of fused macrophages oriented around TB antigen with the multiple
nuclei in a peripheral position, representing the most successful type of
host-tissue response. Cytotoxic CD8+ T cells are also generated during
infection and may directly lyse infected mononuclear phagocytes.
When the population of activated lymphocytes reaches a certain
size, cutaneous delayed reactivity to tuberculin manifests, generally
within 3 to 9 weeks after initial infection. At the same time, enhanced
macrophage microbicidal activity appears. The pathologic features of
TB are the result of the degree of hypersensitivity and the local concentra-
tion of antigen. When the antigen load is small and tissue hypersensitivity
is high, organization of lymphocytes, macrophages, Langhans giant
cells, fibroblasts, and capillaries results in granuloma formation. Foci
characterized by the resulting hard tubercles are said to be proliferative
or productive and constitute a successful tissue reaction with containment
of infection, healing with eventual fibrosis, encapsulation, and scar
formation. When both antigen load and hypersensitivity are high,
epithelioid cells and giant cells are sparse or entirely lacking; lymphocytes,
macrophages, and granulocytes are present in a less organized fashion;
and tissue necrosis may be present, a tissue reaction that has been called
exudative. In the absence of necrosis, exudative lesions may heal
completely or tissue necrosis may occur. Necrosis in TB tends to be
incomplete, resulting in solid or semisolid acellular material referred
to as caseous because of its cheesy consistency. The chemical environment
and oxygen tension in solid caseous material tend to inhibit microbial
multiplication. However, caseous necrosis is unstable, especially in the
lungs, where it tends to liquefy and discharge through the bronchial
tree, producing a tuberculous cavity and providing conditions in which
bacterial populations reach very high titers. Cavities may contain 107
to 109 organisms compared with only 102 to 104 in areas of caseous
necrosis.163 Infectious material sloughed from a cavity creates new
exudative foci in other parts of the lung (bronchogenic spread). A cross
section of a pulmonary cavity demonstrates all these pathologic reactions,
from the least to the most successful in terms of containment of infection.
The central cavity, which contains myriad bacilli, is surrounded by a
layer of caseous material with fewer organisms, a more peripheral layer
of macrophages and lymphocytes with little organization and still fewer
organisms, an area that is even more peripheral with epithelioid cells
and giant cells in which the bacterial content is quite low, and, most
peripherally, a bacillus-free layer of encapsulating fibrosis.
When the degree of hypersensitivity is very low, the tissue reaction
may be nonspecific, consisting of polymorphonuclear leukocytes and
mononuclear cells with huge numbers of tubercle bacilli, so-called
nonreactive tuberculosis.164 The immunologic spectrum from florid
hypersensitivity to little or no specific tissue reaction is similar to that
seen in leprosy and is recapitulated in HIV-infected persons as the
CD4+ T-cell count declines.165
Epidemiologic studies suggest that in a very small subgroup of
individuals exposed to M. tuberculosis, the initial innate immune response
may be able to prevent M. tuberculosis infection. These individuals have
been termed “resistors” and likely represent <10% of the population.166
Of those who become infected with M. tuberculosis and develop a cellular
CD4+ T-cell response, the adaptive immune response will be successful
in containing the infection and preventing TB disease 90% to 95% of
the time.158 Active disease from M. tuberculosis does not generate a
durable immunity against the occurrence of a second TB disease episode.
To the contrary, a first episode of active TB is a significant risk factor
for a second episode of TB.167–169 Immune correlates of these successful
and unsuccessful immune responses are not fully known and are an
area of intense investigation.
Testing for Latent Tuberculosis Infection
Individuals infected with M. tuberculosis with no clinical evidence of
disease have LTBI. They have been infected with M. tuberculosis but
do not have TB disease. To test for LTBI, a skin or blood test is performed
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to detect a cellular immune response to tuberculous antigens, indicating
prior infection. The CDC suggests testing people who are at increased
likelihood for infection and progressing to active TB, and who would
therefore benefit from preventive therapy. The CDC also recommends
stratifying patients’ risk of developing TB when interpreting TST results.
The TST is the classic test, but blood interferon-γ release assays are
increasingly recommended by expert panels.170
TUBERCULIN SKIN TEST
The TST is used to determine whether an individual is infected with
M. tuberculosis. Koch’s tuberculin (old tuberculin) was an extract of a
boiled culture of tubercle bacilli. In 1934, Siebert made a simple protein
precipitate (purified protein derivative [PPD]) of old tuberculin, which
became the preferred reagent in most areas. In 1941, a large single lot
was adopted as the biologic standard (PPD-S) to which other preparations
are now standardized. A 5-tuberculin unit (TU) dose of PPD is equivalent
to 0.0001 mg of PPD-S protein in 0.1 mL of solution.171
DOSAGE
The sensitivity and specificity of the 5-TU dose were derived in popula-
tions in which the incidence of TB was accurately known. A 5-TU dose
of tuberculin clearly separated groups with 100% infection, such as
sanatorium patients, from groups with a very low incidence of TB, such
as infants from noninfectious environments. In the former, tuberculin
reactions peaked at 16 to 17 mm; in the latter, 0- to 5-mm reactions
were elicited.
Technical Aspects
The TST is performed by means of intradermal injection of 5 TU of
PPD in 0.1 mL of solution, usually on the volar aspect of the forearm.
The injection is made with a short, beveled 26- or 27-gauge needle with
the bevel facing upward (Mantoux test). Correct injection produces a
raised, blanched, 6- to 10-mm wheal. Deeper injections may be washed
out by vascular flow, resulting in false-negative results. The loss of potency
that occurs when PPD adsorbs to glass surfaces is prevented by the
addition of the detergent polysorbate 80 (Tween 80). Tween-stabilized
tuberculin in solution is light sensitive and must be refrigerated. The
skin reaction is usually read in 48 to 72 hours. A positive test result is
defined by the diameter of induration, not erythema, in response to 5
TU. The diameter should be read across the forearm and can be measured
by viewing the reaction tangentially against a light background. An
alternative is to use a medium-point ballpoint pen to draw a line starting
1 to 2 cm away from the skin reaction and moving toward its center.
The pen is lifted when resistance is felt, the procedure repeated from
the opposite direction, and the distance between opposing line ends
measured.
Targeted Tuberculin Testing
The American Thoracic Society (ATS), Infectious Diseases Society of
America (IDSA), and CDC guidelines for LTBI testing recommend
targeted testing of persons at increased likelihood of infection and/or
at high risk for developing TB and with the intent for treatment of LTBI
if the test is positive.170,172 This includes persons at high risk of infection
(e.g., recent immigrants, household TB contacts) and persons with
clinical conditions that increase the risk for TB disease (e.g., those with
HIV/AIDS, organ transplant recipients, patients taking TNF inhibitors).
Testing of persons at lower risk of infection and disease progression is
discouraged. Initial testing is also recommended for persons whose
activities place them at increased risk for exposure, such as employees
at medical and correctional facilities.
Interpretation
Based on sensitivity and specificity of tuberculin skin testing, three
cutoff levels have been recommended for defining positive reactions:
5 mm, 10 mm, and 15 mm (see “Treatment of Latent Tuberculous
Infection”).170,172 The 5-mm cutoff is used for close contacts, children
younger than 5 years, people who have HIV infection, those who
are undergoing immunosuppressive therapy, those with an abnormal
chest radiograph consistent with prior TB, and patients with silicosis.
The 10-mm cutoff is used for people who are likely to be infected

but at are low-to-intermediate risk of disease progression. The 15-mm
cutoff is for people at low risk, although current guidelines for targeted
testing suggest that low-risk persons not be tested. Ninety percent
of persons with 10 mm of induration and virtually all with greater
than 15 mm of induration to 5 TU are infected with M. tuberculosis.
Induration of less than 10 mm may reflect cross reactions caused
by infection with other mycobacterial species or prior BCG vaccina-
tion. However, even 5- to 10-mm reactions are suggestive of
tuberculous infection in geographic areas substantially free of other
mycobacteria, such as the northeastern United States, and in persons
with immune suppression, such as HIV-infected persons.173,174 Because
of the potential for false-positive TST results in people who have
received BCG vaccine, the ATS, IDSA, and CDC recommend an
interferon-γ release assay rather than the TST for people from
countries that vaccinate with BCG.170,175
Booster Effect
Although tuberculin cannot sensitize an uninfected person, it can
restimulate remote hypersensitivity that has deteriorated. This booster
effect (a positive tuberculin test result after a negative one) develops
within several days after a first injection and may be persistent. This
causes interpretative problems, because a negative test result followed
by a positive test result approximately 10 weeks later may be a product
of either a recent infection or a booster effect. This problem is circum-
vented by retesting nonreactors 1 to 3 weeks after the initial test. If the
second test result is positive, this indicates boosting rather than recent
tuberculin conversion. In early rheumatoid arthritis patients, with baseline
increased risk of TB compounded by the use of TNF-α inhibitor therapy,
the use of a booster PPD skin test increased LTBI detection from 31.3%
to 46.5% in early rheumatoid arthritis and 21.7% to 28.8% in late
rheumatoid arthritis patients.176
False-Positive and False-Negative
Reactions
False-positive reactions represent nontuberculous mycobacterial
infection. False-negative reactions occur in at least 20% of all persons
with known active TB. In one study, 25% of 200 patients with active
TB were nonreactive to 5 TU and 10% were also nonreactive to 250
TU.177 Most false-negative test results in patients with TB are attributed
to general illness and become positive 2 to 3 weeks after effective
treatment is initiated. Protein malnutrition diminishes all cutaneous
delayed hypersensitivity reactions. Sarcoidosis may cause false-negative
TST results. Intercurrent viral infections (including HIV-1 infection
with <200 CD4+ T cells/mm3), vaccination with live-virus vaccines
(measles, smallpox), reticuloendothelial disease, and corticosteroid
therapy may cause false-negative tuberculin reactions. Attempts to
correlate negative tuberculin test results with generalized anergy (e.g.,
negative skin test responses to mumps, Candida, and tetanus toxoid)
have not been illuminating, and such “anergy testing” is therefore
not recommended (see “Tuberculin Skin Testing and HIV Infection”).178
Intraobserver reliability in reading reactivity may vary by as much
as 3 mm, causing some classification uncertainty if induration is close
to the cutoff value.179 TST results are negative during the first 3 to 9
weeks of initial infection.
Variant (“Delayed”) Tuberculin Reactivity
An unusual form of tuberculin response (so-called delayed reactivity)
has been described among Indochinese immigrants. This involves
induration of less than 10 mm at 48 to 72 hours, which increases to
greater than 10 mm when the skin test is read again at 6 days.
Loss of Tuberculin Reactivity
Earlier in the 20th century, lifelong tuberculin positivity was maintained
by frequent reexposure to tubercle bacilli or continued active disease.
However, a positive tuberculin test will revert to negative unless
restimulated by new aerosol inocula or persisting infection. In one
tuberculin survey, 8.1% of positive reactors reverted to true negative
when retested 1 year later (Table 249.5).180 Persons with a history of a
positive skin test result can be safely retested. Two negative tests a week
apart (to exclude boosting) indicate true negativity.
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2995
TABLE 249.5  Annual Tuberculin Conversion Rates
(Positive to Negative) According to Age Groups,
Victoria County, Canada, 1959–1962
Chapter 249  Mycobacterium tuberculosis
POSITIVE
REACTORS NO. OF
AGE RETESTED REVERSIONS REVERSION
GROUPS AFTER 1 YEAR TO NEGATIVE RATE (%)
0–19 99 22 22.2
20–39 200 16 8.0
40–59 525 25 4.8
60 and older 377 34 9.0
Total 1201 97 8.1
From Grzybowski S, Allen EA. The challenge of tuberculosis in decline: a study
based on the epidemiology of tuberculosis in Ontario, Canada. Am Rev Respir Dis.
1964;90:707–720.
Tuberculin Skin Testing and HIV Infection
During HIV infection, tuberculin reactivity decreases as the CD4 cell
count falls. One study of patients with active TB demonstrated 10 mm
or greater induration in response to 5 TU in only 60% of persons with
HIV infection and in 35% of those with AIDS.181 Induration of 5 mm
in persons with HIV infection is sufficient to warrant treatment of LTBI
(see “Treating Latent Tuberculous Infection in Persons With HIV
Infection”).182 Testing simultaneously for cutaneous anergy with
ubiquitous antigens such as mumps, tetanus toxoid, and Candida is not
recommended. Because of lack of standardization and reproducibility,
and variable risk for TB among anergic persons, cutaneous anergy does
not predict M. tuberculosis infection, and responsiveness to control
antigens but not PPD does not exclude tuberculous infection (see
“Treatment of Latent Tuberculous Infection”).
Interferon-γ Release Assays for Latent
M. tuberculosis Infection
Three interferon-γ release assays are FDA approved to detect latent
M. tuberculosis infection. These tests measure host cellular immune
response to M. tuberculosis antigens in whole-blood samples. These
tests overcome several limitations of the TST, including false-positive
results from environmental mycobacterial exposure or BCG vaccina-
tion, operator-dependent variability in test placement and reading,
and the need for a follow-up visit to examine skin induration. Unlike
the TST, blood tests do not require a follow-up visit for determination
of results. The CDC recommends that these tests be used preferentially
for most populations rather than the TST to detect LTBI.170,183 In a
patient population at increased risk for tuberculous disease, such as
candidates for organ transplantation, serial testing with interferon-γ
release assays before transplant has revealed conversion and reversion
rates of reactivity that undermine the ability to determine true-positive
rates.184 These conversion and reversion rates have also been studied
in South African adolescents. Concordance with the development of
disease was good for conversion but not reversion, and incident TB
was eightfold higher in reverters than in those with consistently
negative results.185 In a study in 17 European centers, TST, QFT-GIT
test, and T-SPOT.TB test (Oxford Immunotec, Abingdon, United
Kingdom) (see later) were compared for their performance and
comparability in immunocompromised patients (HIV infection,
chronic renal failure, rheumatoid arthritis, solid-organ and hemato-
poietic stem cell transplant patients) versus immunocompetent
controls. TB incidence was low but higher in HIV-infected persons
with a positive TST result than with either interferon-γ release assay.
Treatment was effective in preventing disease.186
The QFT-GIT test quantifies release of interferon-γ from lymphocytes
in whole blood incubated overnight with three M. tuberculosis antigens:
the early secretory antigen target-6 (ESAT-6), culture filtrate protein-10
(CFP10), and TB7.7. These three proteins are absent from BCG and
from most other nontuberculous mycobacterial species. Blood must be
tested within 12 hours of collection. The FDA has approved the QFT-GIT
test, and the CDC has established guidelines for its use to detect latent
 2996
TB.183 According to the CDC, the QTF-GIT may be used in all circum-
stances in which TST is used and is often the preferred test.
The next-generation QuantiFERON-TB Gold Plus (QFTPlus) test
has been FDA approved and is starting to be rolled out in the United
Part III  Infectious Diseases and Their Etiologic Agents
States and Europe. QTFPlus contains a fourth tube with short peptides
from CFP-10, which are designed to elicit increased CD8+ T-cell produc-
tion of interferon-γ. Furthermore, the next generation assay does not
use the TB7.7 antigen. Four milliliters of blood are divided into four
tubes. After incubation, if either antigen tube produces more interferon-γ
than the nil (no antigen) tube, the result is positive. If the mitogen tube
does not produce more interferon-γ than the nil tube, the result is
indeterminate. There are only a few studies comparing the QFT-GIT
and QTFPlus, and these suggest comparable results or perhaps slightly
improved sensitivity of the QTFPlus in elderly or immunocompromised
populations.187–189 Larger studies in diverse populations are needed.
Another assay, the T-SPOT.TB (Oxford Immunotec, Abingdon,
United Kingdom) is an ELISPOT assay that also detects T-cell responses
to M. tuberculosis antigens ESAT-6 and CFP10.190 It has been approved
for use by the FDA in the United States. In an investigation of a large
school outbreak of TB in the United Kingdom, the ELISPOT had 89%
agreement with the TST and correlated more closely with exposure to
the index case than the TST. Its performance for health care worker
screening in US hospitals demonstrates high concordance among serial
tests and high test completion rates.191
Data on the performance of the interferon-γ release assays in children
are limited, and guidelines differ on the optimal test. The ATS/IDSA/
CDC guidelines recommend use of the same criteria as in adults for
children aged 5 years and older. For children younger than 5 years,
these guidelines recommend the TST, recognizing the limited data. Of
note, 5 mL of blood is required for the interferon-γ release assay, which
may be excessive for small children.183 The American Academy of
Pediatrics states that the TST is recommended for children younger
than 2 years. Either the TST or an interferon-γ release assay is acceptable
for children aged 2 years and older, but for BCG-vaccinated children
aged 2 years and older the γ release assay is preferred.192 Of note, a
negative TST or γ release assay does not exclude active disease, and
children are at high risk of rapid progression to TB disease.
PATHOGENESIS
Airborne droplet nuclei containing tubercle bacilli reach the terminal
air spaces where multiplication begins. The initial focus is usually
subpleural and in the midlung zone (the lower parts of the upper lobes
and the upper parts of the lower and middle lobes), where greater
airflow favors deposition of bacilli. (Very rarely, nonpulmonary initial
foci will involve abraded skin, the intestine, the oropharynx, or the
genitalia, all associated with foci in regional lymph nodes.)
The initial pulmonary focus is typically single, although multiple
foci are present in about one-fourth of cases. The bacteria are ingested
by alveolar macrophages, which may be able to eliminate small numbers
of bacilli. However, bacterial multiplication tends to be mostly unim-
peded, destroying the macrophage. Bloodborne lymphocytes and
monocytes are attracted to this focus, the latter differentiating into
macrophages, which ingest bacilli released from degenerating cells, and
pneumonitis slowly develops. Infected macrophages are carried by
lymphatics to regional (hilar, mediastinal, and sometimes supraclavicular
or retroperitoneal) lymph nodes, but in the nonimmune host may spread
hematogenously throughout the body. During this occult preallergic
lymphohematogenous dissemination, some tissues favor retention and
bacillary multiplication. These include the lymph nodes, kidneys,
epiphyses of the long bones, vertebral bodies, and juxtaependymal
meningeal areas adjacent to the subarachnoid space, but, most important,
the apical-posterior areas of the lungs. Before the development of
hypersensitivity (tuberculin reactivity), microbial growth is uninhibited,
both in the initial focus and in metastatic foci, providing a nidus for
subsequent progressive disease in the lung apices and in extrapulmonary
sites, either promptly or after a variable period of latency.
Evolution of the Primary Infection
Tuberculin positivity appears 3 to 9 weeks after infection and marks
the development of cellular immunity and tissue hypersensitivity. In
most instances the infection is controlled, with the only evidence of
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infection being a positive skin test result. In a minority of cases, antigen
concentration in the primary complex, consisting of the initial pulmonary
focus (the Ghon focus) and the draining regional nodes, will have reached
sufficient size that hypersensitivity results in necrosis and radiographically
visible calcification, producing the Ranke complex (parenchymal and
mediastinal calcific foci). Much less commonly, pulmonary apical and
subapical metastatic foci contain sufficient bacilli that necrosis ensues
with the onset of hypersensitivity, producing tiny calcific deposits (Simon
foci) in which viable bacilli may persist.
The onset of tuberculin hypersensitivity may be associated with
erythema nodosum or phlyctenular keratoconjunctivitis (a severe
unilateral inflammation of the eye), although these manifestations are
unusual in the United States. The primary complex may progress. In
children, large hilar or mediastinal lymph nodes may produce bronchial
collapse with distal atelectasis or may erode into a bronchus and spread
infection distally. Also, typically in children but also in those infected
in advanced age97 and HIV-infected patients,193 the primary focus may
become an area of advancing pneumonia, so-called progressive primary
disease, which may cavitate and spread via the bronchi. Again, typically
in the very young, preallergic lymphohematogenous dissemination may
progress directly to hyperacute miliary TB as a result of caseous material
directly reaching the bloodstream, either from the primary complex or
from a caseating metastatic focus in the wall of a pulmonary vein (Weigert
focus). Hematogenous dissemination in the very young is often followed
within weeks by tuberculous meningitis. In adolescents and young adults,
the subpleural primary focus may rupture, delivering bacilli and antigen
into the pleural space to produce serofibrinous pleurisy with effusion.
Overwhelmingly, the most important consequence of preallergic
lymphohematogenous dissemination is seeding of the apical-posterior
areas of the lung, where disease may progress without interruption or
after a latent period of months or years, resulting in pulmonary TB of
the adult or reactivation-type TB (endogenous reinfection).
Primary (Childhood) and Reinfection
(Adult) Tuberculosis
The traditional terms primary or childhood pulmonary tuberculosis and
reinfection or adult pulmonary tuberculosis followed radiographic
observations early in the 20th century when initial (primary) infection
in childhood was believed to be universal.194 Children’s radiographs
characteristically demonstrated large mediastinal or hilar lymph nodes
with inconspicuous pneumonitis in the lower or middle lung field,
whereas in adolescents and adults, apical or subapical infiltrates, often
with cavitation and no hilar adenopathy, were the rule. These clinical
and radiographic differences are due to age-related immunologic factors.
Although many primary infections in adolescents and adults resemble
primary infection in childhood, in others in this age group, an apical-
posterior, metastatic pulmonary focus progresses within weeks to
“adult”-type pulmonary disease, whereas the initial focus in the lower
lung field and hilar nodes involutes undetected.
CHRONIC PULMONARY
TUBERCULOSIS
Apical Localization
In adults, apical localization of pulmonary TB has often been attributed
to the hyperoxic environment of the apices and the aerobic nature of
the organism. A more plausible theory attributes it to deficient lymphatic
flow at the lung apices, especially the posterior apices, where the pumping
effect of respiratory motion is minimal. Deficient lymph traffic would
favor retention of bacillary antigen and, when hypersensitivity ensues,
tissue necrosis. Apical-posterior localization with a tendency to cavitation
and progression is characteristic of pulmonary TB in adolescents and
adults. In contrast, infection acquired by the elderly often causes
nondescript lower lobe pneumonia similar to progressive primary
infection of childhood.97
Endogenous Versus Exogenous
Reinfection
In countries where the level of contagion is low, most cases of active
TB reflect reactivation of latent foci.194 However, when contagion is
high, exogenous reinfection may be more common.77,195 The temporal
dynamics of relapse versus reinfection in high-prevalence settings suggest
 2997
that most relapse occurs early after completion of therapy, but reinfection
becomes predominant 1 year after completion of therapy, accounting
in total for at least half of recurrence.196 In a large study in Malawi, 85%
of recurrent TB cases in HIV-infected people were due to reinfections

Chapter 249  Mycobacterium tuberculosis

with a new M. tuberculosis strain, and HIV-infected adults were 20
times more likely to develop disease from reinfection than HIV-negative
people.197 Airflow in the apical-posterior areas of the lung is low, but
when inhaled droplet nuclei reach that location, as is more likely with
high levels of contagion, bacillary multiplication will be favored by the
same local factors that enhance multiplication of bloodborne organisms.
Support for this comes from a study from India that showed that disease
in household contacts of active cases was most common in the middle-
aged and elderly, who were certain to have been previously infected,198
and from molecular epidemiology data.96 Repeated inhalational exposures
to tubercle bacilli maintain tissue hypersensitivity and cellular immunity,
making superinfection more difficult; however, when the airborne
inoculum is large, or in immunocompromised hosts, superinfection
may occur.

Influence of Age on
Tuberculous Infection
Many of the best clinical descriptions of TB come from the preantimi-
crobial era, when infection occurred early in life and cellular immunity
was maintained by frequent exposure to tubercle bacilli. However, in
industrialized countries, infection more often occurs later in life and FIG. 249.2  Chest radiograph showing marked right hilar lymph-
cellular immunity may wane in the absence of restimulation. Accordingly, adenopathy and lower lobe opacity in a 58-year-old woman with
clinical patterns have changed. At one time, most patients were ado- primary tuberculosis.
lescents and young adults with apical cavitary disease. In developed
countries, the incidence of TB (cases per 100,000) is now greatest in
older persons, in whom hypersensitivity is less marked and in whom
the clinical manifestations may be different and more subtle. Hyper- 22 reporting states
30
sensitivity and cellular immunity likely become less vigorous with age
(see “Epidemiology”). 13 reporting cities
>250,000 population
Infection in Infancy and Childhood 20
Infection in infants often results in disease with local progression and %
dissemination (miliary-meningeal disease). The younger the patient,
the greater the risk for progressive disease until the age of 5 years. From 10
age 5 until puberty is a time of relative resistance to progressive disease,
although not to infection. When disease occurs, it is usually the childhood
type of pulmonary TB. Involvement of lymph nodes, bones, and, less 0
0-4 5-14 15-24 25-44 45-64 65+
commonly, other progressive extrapulmonary foci may develop, but Age
TB confined to the lung in this age group usually heals spontaneously.
The short-term prognosis in these individuals is good even if untreated, FIG. 249.3  Percentage of positive tuberculin reactors by age, selected
but there is a high frequency of relapse with chronic cavitary TB areas, United States, 1979. (From Centers for Disease Control and Preven-
tion [CDC], Tuberculosis Control Division. Tuberculosis in the United States,
when the more disease-prone periods of adolescence and young 1979. Atlanta, GA: CDC; 1981:4–31.)
adulthood arrive.199

Infection in Adolescence and

Young Adulthood
Clinical disease developing after infection in adolescence or young
adulthood may resemble childhood infection (lower lung field pneu-
monitis, hilar adenitis) but with less parenchymal and hilar calcification
(Fig. 249.2). This is particularly the case in immunocompromised patients,
including those living with HIV.194 Rarely, the radiographic picture may
be mixed, with features of childhood disease subsiding while chronic
upper lobe (adult) disease progresses. However, disease in this age group
frequently first appears as chronic upper lobe TB with no clinical
manifestations of childhood disease. The tendency toward apical cavita-
tion soon after the initial infection appears soon after puberty and is
marked in young adults.172 Evidence suggests that adolescents (and
adults) may have a subclinical tuberculous pneumonia for months prior
to the onset of overt disease.200,201 Because most young people in
industrialized countries are tuberculin negative (Fig. 249.3), most
pulmonary TB in adolescents and young adults is due to recent initial
infection rather than to late progression of childhood infection.
Infection in Midadulthood
Infection acquired during the middle years has a much better immediate
and probably long-term prognosis than infection acquired in the teens
and early 20s, presumably because of a reduced tendency to tissue
necrosis.199,202 One study demonstrated progression from infection to
cavitary TB in 23% of patients infected from 15 to 19 years of age, 13%
of those infected from 20 to 24 years of age, 4% of those infected from
25 to 29 years of age, and only 2% of those infected after 30 years of
age. Progression occurred in 3 months in many and within 1 year in
most.203 (Elderly individuals were not included in the study.)
Infection in Old Age
In the elderly, infection acquired years earlier can progress as age
compromises immunity, producing typical apical-posterior disease.
Studies of TB in nursing homes, however, have demonstrated that elderly
patients are often tuberculin negative, either because they had never
been infected or because remote past infection had been completely
cleared, with a loss of tissue hypersensitivity. Such tuberculin-negative
persons are susceptible to new infection; and if this occurs, they acquire
active disease with a frequency similar to that of adolescents. This is
typically a nondescript, poorly resolving pneumonitis in the lower or
middle lobes or anterior segments of the upper lobes, sometimes with
pleural effusion and resembling primary infection in children except
with much less hilar-mediastinal lymphadenopathy.97 Even with prompt
diagnosis and treatment, TB after age 65 appears to be more frequently
associated with death.

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 2998
Late Hematogenous Tuberculosis
Chronic TB is probably always associated with recurrent abortive episodes
of hematogenous spread. However, when aging or other factors com-
promise cellular immunity, such episodes may become progressively
Part III  Infectious Diseases and Their Etiologic Agents
pneumonia results in progressive primary disease, which may spread
via the bronchial tree or the bloodstream. However, most infections
during the relatively disease-resistant period of childhood (ages 5–12
years) are usually nonprogressive, with healing by involution and

more frequent, producing the subtle and often fatal syndrome of late
hematogenous or progressive generalized TB.
Intercurrent Events
General stress, poor health, and malnutrition favor progression of infec-
tion. Therapy with corticosteroids or other immunosuppressive agents
compromises host defenses, as do hematopoietic-reticuloendothelial
diseases, particularly malignancies. TB in complicating myeloprolif-
erative disorders may cause confusion because disseminated TB can
cause aplastic anemia, thrombocytopenia, leukopenia, and leukemoid
reactions that may mimic leukemia. However, most patients with
TB and hematologic findings that suggest leukemia will have both
diseases. Inflammatory diseases such as rheumatoid arthritis and
systemic sclerosis are often accompanied by immunologic derange-
ments that may decrease immunocompetence even prior to the use
of immunosuppressive therapies. Patients with systemic sclerosis in
Taiwan had a significantly higher risk for TB and pulmonary TB,
independent of systemic sclerosis treatment, compared with matched
control subjects drawn from the National Health Insurance database
(incidence rate ratios, 2.81 and 2.53, respectively).204 Biologic TNF-α
inhibitors (e.g., infliximab, etanercept, and adalimumab) that are
prescribed for rheumatoid arthritis and other inflammatory diseases
increase the likelihood of reactivation TB, including extrapulmonary
and disseminated disease.205–209
The postgastrectomy state, jejunal-ileal bypass surgery, and end-stage
renal disease are all risk factors for progression (see “Treatment of
Latent Tuberculous Infection”). Viral illnesses, particularly in children,
may predispose to progression of infection. Destructive local pulmonary
processes such as lung abscess, carcinoma, cavitary histoplasmosis, and
pulmonary resection occasionally are followed by activation of previously
quiescent pulmonary foci. The development of bone and joint TB after
physical injury and late generalized hematogenous TB after major trauma
both illustrate that the balance between host and infection can be altered
by both systemic factors and local physical disturbance.
Tuberculosis in People With HIV Infection
The earliest descriptions of TB with AIDS emphasized the very great
risk for reactivation of remote infection as a result of progressively
compromised cellular immunity. Among Haitians, all of whom were
likely infected with M. tuberculosis in childhood, HIV infection was
associated with development of active TB in 60%.103 Subsequent studies
of HIV-positive and tuberculin-positive methadone clinic patients in
New York City showed that active TB developed in 8% yearly.136
TB remains the leading cause of death in HIV infection in reports
from highly endemic areas, despite the introduction of ART.210 As
discussed in “Epidemiology,” HIV-infected patients are predisposed not
only to reactivation of remote infection but also to rapid progression
of recently acquired infection.137,138 It is unclear whether AIDS increases
susceptibility to acquisition of new infection. Provision of ART restores
immune function and decreases risk for TB, although not to levels seen
among HIV-negative individuals.211
encapsulation.199 Progression, if any, occurs in extrapulmonary metastatic
foci or with the development of apical-posterior pulmonary TB, usually
when the patient reaches puberty or young adulthood.
Postprimary (Adult-Type)
Pulmonary Tuberculosis
Primary infection in adolescents and adults (1) may occur without
symptoms and signs, (2) may produce a typical primary complex, or
(3) may result in typical chronic pulmonary TB without a demonstrable
primary complex. Any pneumonic infiltrate, especially if associated
with a hilar or mediastinal node, may represent primary infection.
These lesions may undergo caseation, liquefaction, and bronchogenic
spread just as with classic chronic pulmonary TB.
Postprimary pulmonary TB in adults is usually asymmetrical and
characterized by caseation, fibrosis, and frequently cavity formation. It
begins as a patch of pneumonitis in the subapical-posterior aspect of
an upper lobe, usually just below the clavicle or first rib (Fig. 249.4). A
less frequent location is the apex of the lower lobe, where it may be
obscured by the heart and hilum on a chest radiograph but readily
visible on a chest CT image. The inflammatory response in the sensitized
host produces a fibrin-rich alveolar exudate containing a mixture of
inflammatory cells. Serial radiographs may demonstrate waxing and
waning and sometimes complete regression. If the process accelerates,
however, an area of caseous necrosis surrounded by epithelioid cells,
granulation tissue, and eventually fibrosis develops. This may arrest by
inspissation of the caseous area, fibrous encapsulation, and healing.
Caseation, however, tends to liquefy and drain into the bronchial tree,
spreading bacillary contents by coughing. The cavity is prevented from
collapsing by the fibrous capsule and the inelasticity of the surrounding
lung. The pulmonary cavity favors bacillary multiplication to enormous
titers, 5 to 6 logs greater than in noncavitary lesions. The progressive
nature of pulmonary TB is due to (1) the tendency of apical caseous
foci to liquefy, (2) the enormous concentrations of organisms in the
resulting pulmonary cavities, and (3) spread of this bacilli-rich material
through the bronchial tree. Progression from minimal infiltrate to
far-advanced cavitary disease can occur within a few months (Fig. 249.5).

PULMONARY TUBERCULOSIS
Primary Tuberculosis in Childhood
The initial focus of pulmonary TB in children occurs most frequently
in the midlung zones but may develop anywhere. At the time of tuberculin
conversion, fever and lassitude and rarely erythema nodosum or
phlyctenular keratoconjunctivitis may be present briefly. Clinical
manifestations of the initial infection depend on the age of the patient.
It is most often symptomatic in childhood because of an age-related
tendency to extensive regional lymphadenitis. This may compress central
bronchi, causing a brassy cough or atelectasis of a segment or lobe, or
may rupture into a bronchus, seeding infection distally and causing
pneumonia. In the very young, there is a tendency to progressive
lymphohematogenous dissemination with miliary-meningeal disease. FIG. 249.4  Chest radiograph showing a right apical infiltrate in a
Uncommonly, again more in infants, local progression of the initial patient with moderately advanced postprimary tuberculosis.

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FIG. 249.5  Chest radiograph showing far-advanced bilateral apical
cavitary pulmonary tuberculosis in a 32-year-old woman from
Ethiopia.
Coughing aerosolizes infectious cavity secretions that may distribute
widely throughout the lung (bronchogenic spread). New foci eventually
develop that, in turn, may undergo caseation, fibrosis, and healing or
slough, resulting in new cavities. The segment or lobe containing the
initial cavity is typically involved first with scattered patchy disease, but
the contralateral apex is often secondarily involved with progressive
disease. Bronchogenic spread may establish foci of infection in the
lower lobe and anterior portions of the upper lobe, producing a poly-
morphous mottling on a chest radiograph, but these are usually non-
progressive and heal with fibrosis. Although hematogenous spread from
an established pulmonary focus can occur, it is usually limited by
hypersensitivity-induced thrombosis.
The highly infectious secretions from a cavity always cause some
degree of endobronchial inflammation and ulceration, which may be
extensive. Ulcerative tuberculous laryngitis is an extension of this process,
as is local disease throughout the upper airways, mouth, middle ear,
and gastrointestinal tract.
Mechanisms of healing are the same whether spontaneous or under
the influence of chemotherapy. Without drug therapy, solid caseous
foci surrounded by contracting fibrous tissue occasionally arrest. However,
viable bacilli almost always persist in such lesions and can later reactivate.
Before drug therapy, healing of persisting cavities never occurred, and
some large, thick-walled cavities in shrunken fibrotic lobes could persist
for years with minimal symptoms while remaining highly infectious
(chronic fibroid TB). With drug therapy, cavities may resolve or they
may heal but remain open, sometimes with complete reepithelialization.
The major risk for such persistent cavities is superinfection with organ-
isms such as Aspergillus or nontuberculous mycobacteria.
Lower Lobe and Endobronchial
Tuberculosis
These terms lower lobe tuberculosis and endobronchial tuberculosis are not
appropriate for chronic pulmonary TB of the ordinary kind that happens
to involve the apex of the lower lobes. In adults, lower lung field tuberculosis
describes three different but often associated processes: (1) progressive
lower lobe pneumonia in recently infected older individuals; (2)
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2999
endobronchial TB, often with parenchymal consolidation-collapse; and
(3) TB complicating AIDS. These three processes differ from postprimary
TB radiographically, and the former two have a low bacterial content.
Chapter 249  Mycobacterium tuberculosis
Progressive Lower Lobe Disease
in Older Persons
TB in an older individual frequently causes a nonspecific, non-resolving
pneumonitis in the lower or middle lobes or anterior segments of the
upper lobes, similar to primary infection in childhood, except with less
hilar and mediastinal adenopathy.127 TB should be considered in any
slowly or non-resolving pneumonitis in an older patient.
Endobronchial Tuberculosis
In the past, superficial endobronchial lesions resulting from infectious
secretions were common, sometimes spreading to the larynx and beyond
or causing obstructive atelectasis with collapse. These superficial lesions
responded quickly to chemotherapy. Now endobronchial disease is most
frequently caused by rupture of an adjacent node into the bronchial
tree, or less frequently by direct spread from parenchymal TB.212 The
chest radiograph typically reveals collapse-consolidation but may be
normal in as many as 20% of cases, although a chest computed tomog-
raphy (CT) scan may be abnormal. Sputum smear results are usually
negative, but the bronchial lavage result is frequently positive.212
The usual bronchoscopic findings are mucosal edema, ulceration,
and narrowing, but in 30% of cases, bulky granulation tissue may resemble
bronchogenic carcinoma. Endobronchial involvement is usual in lower
lung field TB,213 and endobronchial ulcers occasionally produce positive
sputum smears with normal chest radiographs. Large parenchymal
cavities may be present, at times associated with an air-fluid level resulting
from intermittent obstruction and poor drainage. Bronchial perforation
by tuberculous nodes with endobronchial mass formation and lower
lobe consolidation has been observed in patients with AIDS.
Calcified nodes can erode into the bronchial tree and cause hemop-
tysis, expectoration of calcific material (lithoptysis), or spread of previ-
ously quiescent bacilli. The atelectatic pneumonitis, which may result
with or without new active disease, is most frequently seen in the anterior
segment of the upper lobe and medial segment of the middle lobe.
Pulmonary Tuberculosis in AIDS
TB as first described in persons with advanced AIDS was characterized
by middle or lower lung field location, absence of cavitation, a greatly
increased incidence of extrapulmonary disease, and usually a negative
TST.214,215 It resembled childhood TB except for a negative TST and less
prominent hilar and mediastinal lymphadenopathy. A later study of TB
in a much less ill population of persons in TB clinics unaware of their
HIV infection found a clinical picture no different from ordinary
reactivation TB in HIV-negative patients, with apical, often cavitary,
disease and tuberculin positivity being the rule. The clinical picture of
TB during HIV infection is determined by the degree of immunocom-
promise (Table 249.6). Although HIV-positive persons may have
symptoms similar to those seen in HIV-uninfected persons, presentations
can also be atypical or patients can be asymptomatic.216
HIV-positive persons may also acquire new infection from others
in their environment, a risk that was first observed among patients with
advanced AIDS living in HIV wards and domiciles. The clinical picture
in these patients can include diffuse, rapidly progressive, noncavitary
disease that is often fatal.137,138 It is unclear whether HIV-infected persons
are more likely to become infected after exposure to M. tuberculosis
than HIV-uninfected persons, but once infected, they are more likely
to progress to active disease. HIV-infected persons do not appear to
be more likely to transmit M. tuberculosis than HIV-uninfected persons,130
but TB disease, and therefore M. tuberculosis transmission, can occur
even when the source patient has a normal chest radiograph or a negative
acid-fast sputum stain.217,218 The Cepheid GeneXpert MTB/RIF or the
more recent Ultra version should assist in rapid detection of M. tuber-
culosis in sputum of such patients.
It is important to consider TB in HIV-positive individuals with respira-
tory failure in the intensive care unit. Patients may have adult respiratory
distress or sepsis syndrome with multiple organ system failure. The diagnosis
can be made readily by stain and culture of sputum or blood or both.
 3000
TABLE 249.6  Clinical Manifestations of Active
Tuberculosis in Early Versus Late HIV Infectiona
EARLY HIV LATE HIV
Part III  Infectious Diseases and Their Etiologic Agents
INFECTION INFECTION
Tuberculin test result Usually positive Usually negative
Adenopathy Common Unusual
Pulmonary distribution Upper lobe Lower and middle lobe
Cavitation Often present Typically absent
Extrapulmonary disease 10%–15% of cases 50% of cases
a
For practical purposes, “early” and “late” may be defined as CD4+ cell counts
greater than 300 cells/mm3 and less than 200 cells/mm3, respectively.
HIV, Human immunodeficiency virus.
Tuberculomas
Asymptomatic rounded lesions may develop as the parenchymal
residua of the initial infection or as an upper lobe caseous lesion
encapsulates (Fig. 249.6). These are ordinarily static, but larger ones
may cavitate to produce new spread of disease. In some persons,
excessive fibrosis occurs with small caseous or granulomatous residua
becoming surrounded by concentric layers of fibrous tissue, at times
with central or concentric calcification resembling histoplasmomas.
Most such lesions are stable, but important in that they can be
confused with cancer.
Symptoms
Initial infection with M. tuberculosis is usually asymptomatic, although
some persons may have a relatively brief period of symptoms.219,220 Early
pulmonary TB is asymptomatic and may be discovered by chance on a
chest radiograph. As the bacillary population grows, however, nonspecific
constitutional symptoms such as anorexia, fatigue, weight loss, chills,
fever, and night sweats may ensue. A productive cough is usually present.
Coughing to clear cavitary secretions is usually mild and well tolerated
but may become bothersome when bronchial involvement is extensive.
The mucopurulent sputum is nonspecific, and both cough and sputum
may be ignored by patients with chronic bronchitis. Hemoptysis resulting
from caseous sloughing or endobronchial erosion is usually minor but
connotes advanced disease. Sudden massive hemoptysis resulting from
erosion of a pulmonary or bronchial artery by an advancing cavity
(Rasmussen aneurysm) was an occasional terminal event in the predrug
era but is now seldom seen. In inactive disease, brisk hemoptysis may
be due to Aspergillus superinfection of residual cavities (aspergilloma).
Chest pain is usually due to extension of inflammation to the parietal
pleura. Pleural involvement adjacent to an established cavity tends to
cause visceral-parietal pleural symphysis without effusion (dry pleurisy).
Serofibrinous pleurisy with effusion is often an early postprimary event
but may also complicate chronic pulmonary TB. Rarely, chest pain leads
to discovery of tuberculous empyema. Symptoms often pertain to site
of disease, such as painful pharyngeal ulcers; indolent and nonhealing
ulcers of the mouth or tongue; hoarseness and dysphagia that are due
to laryngeal involvement; tuberculous otitis media; gastrointestinal
symptoms that are due to enteric ulceration, perforation, or mass
formation; or anal pain that is due to tuberculous perirectal abscess
and fistula formation. Lower lobe TB resulting from bronchial lymph
node perforation may be associated with lithoptysis (stone spitting) and
characteristically produces symptoms of severe endobronchial disease
with serious cough and often hemoptysis.
Physical Examination
Physical findings are not specific, and in general do not reflect the
extent of the illness and may be absent in spite of extensive disease.
Dullness with decreased fremitus may indicate pleural thickening or
fluid. Crackles may be appreciated only when the patient breathes in
after a short cough (posttussive rales) and may persist long after healing,
owing to permanent distortion of small airways. With large lesions,
signs of consolidation with open bronchi (whispered pectoriloquy,
tubular breath sounds) can be heard. Distant hollow breath sounds
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FIG. 249.6  Chest radiograph demonstrating multiple bilateral
pulmonary tuberculomas in an asymptomatic 35-year-old man from
Poland.
heard over cavities are called amphoric, like the sound made by blowing
across the mouth of a jar (amphora).
Radiographic Findings
The chest radiograph is central to diagnosis, determination of the extent
and character of disease, and evaluation of the response to therapy.
Chest CT is a valuable adjunct to routine chest radiography. Certain
patterns are highly suggestive, although not diagnostic, of TB. A patchy
or nodular infiltrate in the apical- or subapical-posterior areas of the
upper lobes or the superior segment of a lower lobe is highly suggestive
of early chronic TB, especially if bilateral or associated with cavity
formation (see Fig. 249.4). Cavities may be more apparent with CT or
magnetic resonance imaging (MRI). On routine chest radiography,
cavitation in the apical segment of the lower lobe may be obscured by
the heart shadow and, in the lateral view, by the dorsal spine. Air-fluid
levels are uncommon in upper lobe TB (less than 10%) but occur more
frequently in lower lobe cavities. Fresh bronchogenic spread from recent
spillage of infectious cavity contents appears as multiple, discrete, soft,
fluffy infiltrates, or a confluent infiltrate adjacent to a cavity, or in the
middle or lower lung field on the same or opposite side. These latter
types of spread are seldom progressive and heal by rounding up into
more discrete lesions with regular borders.
Both chronicity and histopathologic features can be estimated based
on the chest radiograph. Granulomatous lesions tend to be small, nodular,
and sharply defined, indicating few organisms and a good host response.
Exudative lesions (pneumonic) tend to have soft, indistinct borders
and are more unstable. Fibrotic scars have sharp margins and tend to
contract. Caseation causes increased density. Healing exudative lesions
first become smaller and less dense and then, as scarring develops,
become more sharply defined. Lower lobe TB is nonspecific radiographi-
cally. Other patterns include poorly resolving pneumonia, atelectasis,
mass lesions, and large cavities with air-fluid levels; initial misdiagnosis
is the rule. Pneumonia associated with hilar adenopathy should always
suggest primary TB, regardless of the lung fields involved and patient
age. Pulmonary TB can also occur in persons with a normal chest
radiograph; up to 6% of HIV-seronegative and 22% of HIV-seropositive
persons with pulmonary TB have a normal chest radiograph.217,221–223
Laboratory Findings
Normocytic, normochromic anemia, hypoalbuminemia, and hypergam-
maglobulinemia are characteristic of advanced disease. The white blood
cell count is usually normal but may be between 10,000 and 15,000

cells/mm3. Many HIV-negative patients with active TB have CD4+ T-cell
counts much lower than 500 cells/L, which return toward normal with
treatment.224 Monocytosis is seen in less than 10% of cases. Hematuria
or sterile pyuria should suggest coexisting renal TB. Hyponatremia
with features of inappropriate secretion of antidiuretic hormone is
characteristic of tuberculous meningitis but also occurs with isolated
pulmonary involvement. Hyponatremia should also suggest associated
Addison disease due to adrenal TB. Hypercalcemia is also seen during
pulmonary TB, usually in the first weeks of therapy.
Diagnosis
A strong presumptive diagnosis can often be made based on the
radiographic pattern. A positive sputum smear, usual in extensive
disease, provides additional evidence in support of a diagnosis. However,
an intercurrent cancer or lung abscess, particularly in the apices, may
erode a quiescent focus of TB and cause brief shedding of tubercle
bacilli without causing active disease. The best diagnostic sputum
specimen is an early morning sample. Although two sputum specimens
are sufficient in some settings, three specimens are recommended
because of greater sensitivity.225 Aspiration of gastric contents, obtained
early in the morning to sample sputum swallowed during sleep, is an
alternative when sputum is not produced. The specificity of gastric
aspiration is diminished by the presence of nontuberculous mycobacteria
but may be higher in children than adults. Sputum induction by
hypertonic saline aerosols is also an effective substitute in ambulatory
patients; the yield is comparable to that of fiberoptic bronchoscopy.226
Pulmonary TB in patients with AIDS is often noncavitary and therefore
may have a lower bacillary burden than in HIV-seronegative persons.
The high prevalence of smear-negative TB in HIV-infected persons
underscores the importance of obtaining sputum culture, even in
resource-poor settings.227 Positive sputum smears are much more likely
to indicate M. tuberculosis than Mycobacterium avium complex, even
in areas where both diseases are common.228 NAAT, described previ-
ously, can provide a rapid distinction between the two infections in
smear-positive respiratory secretions. (Additional diagnostic assays,
including NAAT and testing for M. tuberculosis antigens in urine, are
discussed under “Microbiology.”)
A negative tuberculin reaction or interferon-γ release assay does
not exclude TB; skin test anergy and negative assays can occur in the
setting of active disease.177,229,230 The TST and interferon-γ release assays
are insensitive in immunocompromised persons, such as HIV-infected
persons with less than 100 CD4+ T cells/mm3.230,231 Granuloma formation
at histologic examination, even with AFB, is still only strong presump-
tive evidence, because similar findings may be produced by MOTT.
Granulomas in the absence of AFB can be seen with other infectious
diseases (e.g., histoplasmosis) and noninfectious causes (e.g., sarcoidosis,
autoimmune disease). Definitive diagnosis requires culture and speciation.
Fiberoptic Bronchoscopy
Diagnostic fiberoptic bronchoscopy with transbronchial biopsy and
bronchoalveolar lavage should be considered when sputum tests are
inconclusive and the suspicion of TB remains high. In AIDS patients
with pulmonary TB but negative smears, bronchoscopy yields a rapid
diagnosis (based on smears and histologic features) in only one-third
of cases.232–234 Thus, a negative acid-fast stain at bronchoscopy does not
exclude TB, although such cases are certainly less contagious.
Tuberculosis Diagnosed at Autopsy
From 1985 through 1988, 5.1% of all reported TB cases in the United
States were diagnosed at death.235 Usually, the patient was elderly and
had underlying diseases. Both nonresolving pulmonary processes and
extrapulmonary TB, particularly chronic miliary and meningeal disease,
are often present in such patients. The usual reason for failure to diagnose
TB in such patients is failure to look for it; delays in TB diagnosis, as
can occur when persons receive fluoroquinolones, can also contribute.236
Tuberculosis and Cancer
It has been estimated that 1% to 5% of TB patients also have cancer, most
being male smokers. It is possible that cancer can arise in tuberculous
scars, and it is certain that cancer can erode old quiescent tuberculous
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3001
foci, causing active disease. However, in many patients the diseases
will be anatomically remote. No one cancer cell type predominates.
When TB and cancer occur together, diagnosis of the latter is often
difficult but should be kept in mind in older men with TB who smoke,
Chapter 249  Mycobacterium tuberculosis
and sputum cytologic studies should be performed. There are certain
radiographic findings that suggest concomitant cancer, such as progression
of one area while the remainder of the lesion is regressing, a large (>3 cm)
mass lesion admixed with infiltrative disease, the presence of hilar nodes
in adult chronic pulmonary TB, and postobstructive atelectasis.237
THERAPY
Before effective drugs were available, 50% of patients with active pul-
monary TB died within 2 years and only 25% were cured.238 With the
advent of chemotherapy, successful treatment became a reasonable goal
in all adults. In practice, failures occur because of drug resistance or
an inappropriate regimen, or, most important, because of nonadherence
to therapy. For this reason the responsibility for adequate treatment
has been shifted from the patient to the prescribing physician and to
the health department, emphasizing the importance of directly observed
therapy (DOT).239
Antituberculous Drugs
Additional information on dosage, adverse effects, drug-drug interactions,
and other aspects of the pharmacology of antituberculous drugs is
provided in Chapter 39.
Isoniazid
INH is the cornerstone of therapy and should be included in all regimens
unless the M. tuberculosis strain is INH resistant. Occasionally, when
the M. tuberculosis strain is resistant to low-level INH but susceptible
to higher INH levels, and there is resistance to other antituberculosis
drugs, INH is included in the regimen (although not considered to
have full activity). The most important adverse effect of INH is hepatitis,
the risk for which increases with age and underlying liver disease.
Although rare, this complication can be fatal.240 INH continues to be
a cause of significant drug-induced liver injury, which may be associated
with a lack of adherence to guidelines that recommend cessation of
therapy based on symptoms (nausea, abdominal pain, jaundice, or
unexplained fatigue) or alanine aminotransferase levels. In one study,
70% of patients who died or underwent liver transplantation continued
INH for more than 7 days after meeting stopping criteria.241
Rifampin
RIF is the second major antituberculous agent. The most important
complication of RIF is hepatitis, which is usually cholestatic. Although
the risk for hepatitis is lower with RIF than INH,242,243 hepatitis occurs
more frequently in regimens containing both INH and RIF than in
those containing INH alone.244
Of special concern is that RIF, by inducing hepatic P-450 cytochrome
oxidases, causes many drug-drug interactions. Examples of drugs whose
levels are reduced in the presence of RIF include warfarin, hormonal
contraceptives, azole antifungal agents, methadone, corticosteroids,
cyclosporine, tacrolimus, nonnucleoside reverse transcriptase inhibitors,
and HIV-1 protease inhibitors. This can result in subtherapeutic levels
of these drugs, necessitating either increases in their dosage or use of
an antituberculosis drug other than RIF. The interaction between RIF
and HIV-1 protease inhibitors can lead to substantially lower HIV-1
protease inhibitor levels, inadequate control of viral replication, and
emergence of drug-resistant virus. In this setting, RIF may be replaced
by rifabutin, which has comparable antituberculous activity but is a
weaker enzyme inducer.245 Adjustment of antiretroviral drugs with
treatment of TB is shown in Tables 39.3 and 39.5.
Rifapentine
Rifapentine is a rifamycin antibiotic with a longer half-life than RIF or
rifabutin, which allows once-weekly administration.239,246 Once-weekly
therapy, together with INH or moxifloxacin, may be considered in
HIV-seronegative persons in the continuation phase of TB treatment
of noncavitary pulmonary disease239,247; however, the rifapentine-INH
regimen is not generally recommended in the recent ATS/CDC/IDSA
 3002
guidelines.239 Once-weekly rifapentine should not be used to treat
HIV-infected persons with active TB owing to the high risk for acquired
rifamycin resistance.248
Part III  Infectious Diseases and Their Etiologic Agents
Pyrazinamide
PZA is an essential component of 6-month regimens. Early studies of
PZA using high doses recorded such serious hepatotoxicity that it was
largely abandoned. At currently recommended doses, PZA is associated
with higher rates of hepatotoxicity and rash than other first-line drugs.249
Cohort and case-control analyses found that adding PZA to INH and
RIF increased the risk for hepatotoxicity appreciably.250 In addition,
severe hepatic injury and deaths have been reported among predomi-
nantly HIV-negative adults receiving short-course RIF plus PZA for
LTBI.251 The beneficial effect of PZA is limited to the first 2 months
in regimens containing both INH and RIF.252 Additional side effects
include hyperuricemia, mild nongouty polyarthralgias that respond to
nonsteroidal antiinflammatory agents, and gout. M. bovis is uniformly
resistant to PZA.253
Ethambutol
EMB is included in initial treatment regimens until drug susceptibility
results are returned and resistance to the other first-line drugs has been
excluded, at which time it can be discontinued. It is given at a daily
dose of 15 to 20 mg/kg. At 15 mg/kg the risk for ocular toxicity is low,
but assessment of visual acuity and color discrimination should be
performed at baseline and monthly while the patient is on therapy.
Streptomycin
STM, the first major antituberculous drug, was promptly replaced by
INH as the cornerstone of therapy. Its activity is similar to that of EMB
when either drug is given with INH, RIF, and PZA. Its use is limited
by relatively high rates of resistance (particularly in high-incidence
countries), parenteral administration, nephrotoxicity, and ototoxicity.
Fluoroquinolones
In vitro activity and some favorable trial results suggest that fluoroqui-
nolones, particularly later-generation agents such as levofloxacin and
moxifloxacin, are effective antituberculosis drugs.254–256 However, fluo-
roquinolones should not be used as first-line therapy but rather should
be reserved for patients who are intolerant of first-line drugs or who
have drug-resistant TB, as part of a well-designed multidrug regimen.
In the treatment of INH-resistant infection, a retrospective cohort study
found more frequent favorable outcomes with regimens that contained
a fluoroquinolone, without regard to the other components of standard
TB therapy.257 In countries where fluoroquinolones are easily available,
use of quinolones by persons with undiagnosed TB is likely contributing
to increased resistance in M. tuberculosis. In a high-prevalence country
such as India, rates of quinolone resistance are already high both in
new and previously treated cases.258 The potential role of fluoroquinolones
as first-line antituberculosis therapy is currently under evaluation in
clinical trials. A 6-month regimen in South Africa, Zimbabwe, Botswana,
and Zambia using daily (2 months) and then weekly moxifloxacin in
place of INH and weekly rifapentine was as effective as a control
regimen.247 A dose of moxifloxacin 10 mg/kg/day may be insufficient
for children 7 to 15 years of age being treated for MDR-TB.259
Unfortunately, multiple phase III trials have not supported the use
of fluoroquinolones in regimens meant to shorten the duration of therapy
to 4 months. In sub-Saharan Africa, a 4-month gatifloxacin-containing
regimen was inferior to standard therapy.260 The previously referenced
trial in South Africa, Zimbabwe, Botswana, and Zambia contained an
arm based on 4-month therapy that was inferior to standard therapy,
and a trial in nine countries on three continents also found that a
4-month regimen replacing EMB or INH with moxifloxacin was inferior
to standard 6-month therapy.247,261
Bedaquiline
Bedaquiline (Sirturo) is a diarylquinoline; its mechanism of action is
adenosine triphosphate synthase inhibition. It has potent activity against
M. tuberculosis. In persons with MDR-TB, there were improved 2-month
sputum culture conversion rates among those who received bedaquiline
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plus optimal background therapy, compared with optimal background
therapy alone (48% vs. 9%, respectively).262 Potential toxicities include
nausea and QT interval prolongation. The terminal elimination half-life
is 164 days; in one study almost all patients had detectable plasma levels
96 weeks after the last dose.263 In December 2012, bedaquiline was
approved by the FDA for treatment of MDR-TB, but with a black box
warning because of a greater number of deaths in the bedaquiline arm
compared with those who received optimal background therapy only.
Safety will be monitored closely in future trials. A report of 35 French
patients who received bedaquiline for at least 1 month did not encounter
drug-associated deaths.264 With data now reported in the follow-up of
patients through 120 weeks from baseline, the addition of bedaquiline
led to faster culture conversion and more conversions at the end of
observation. There were 10 deaths in the 79-patient bedaquiline group
compared with 2 in the 81-patient placebo group, although FDA analysis
of these differences noted that both deaths in the placebo group and 5
in the bedaquiline group were due to progression of disease.265,266
A large retrospective observational study among 428 MDR-TB patients
treated with bedaquiline noted good safety and tolerability, and only
one death.267 The recommended dosage for bedaquiline is 400 mg once
daily orally for 2 weeks, followed by 200 mg three times a week for 22
weeks taken orally with food to maximize absorption. Pharmacokinetic
analysis suggests that penetration into the CSF is poor.268 High cost
may be a significant barrier to use of bedaquiline. Drug interactions
will require further study; phase I data indicate that RIF and rifapentine
increase bedaquiline clearance (4.78- and 3.96-fold, respectively).269
Interactions with HIV therapy that includes the potent CYP3A4 inhibitor
ritonavir suggest that concomitant administration with bedaquiline
might require dose adjustment.270 A provisional guideline for use of
bedaquiline has been published.271
Second-Line Agents
Second-line agents are less efficacious or more toxic, or both, than first-line
drugs. These include ethionamide, cycloserine, terizidone (available
overseas), amikacin, kanamycin, capreomycin, thiacetazone, para-
aminosalicylic acid (PAS), and other agents discussed in Chapter 39.
Third-Line Agents
Third-line agents have even less activity against M. tuberculosis than
second-line agents and are usually given only as adjunctive therapy to
persons with XDR-TB. These drugs have generally not been evaluated
in a systematic manner for the treatment of TB. Such drugs include
amoxicillin-clavulanate, clarithromycin, and linezolid (see “Treatment
of Multidrug-Resistant Tuberculosis” and “Therapy for Extensively
Drug-Resistant Tuberculosis”). Clofazimine is also in this group, but
is now being evaluated as a more prominent treatment option given its
important role in shortening treatment of MDR-TB.272,273
Agents Under Development
There are several new drugs that are currently under investigation for
potential use in MDR-TB. These include the oxazolidinones (e.g., sutezolid
[Sequella] and LCB01-0371 [LegoChem Biosciences]), nitroimidiazoles
(e.g., delamanid [Otsuka] and pretomanid [Global Alliance for TB Drug
Development]), and diamines (e.g., SQ-109 [Sequella]).274 Delamanid,
when given with optimal background therapy for MDR-TB, was associated
with significantly higher rates of 2-month sputum culture conversion.275
However, it did not improve cure and survival compared with optimal
background therapy in a phase III trial, so WHO has recommended
that it be used when other, more effective drugs, cannot be used.276 Of
note, delamanid significantly prolongs the QT interval.277 Pretomanid
(PA-824) is a prodrug, as is delamanid, and in phase II trials seems to
have had its greatest efficacy in combinations containing PZA.277,278 A
phase IIb trial in drug-susceptible and drug-resistant TB of a regimen
of moxifloxacin, pretomanid, and PZA had an acceptable safety profile.
Bactericidal activity was superior at the 8-week assessment, although
the predictive utility of that end point remains controversial.279
Selecting a Drug Regimen
Before RIF was available, excellent results in drug-sensitive infections
were obtained with INH plus either PAS or EMB given for 18 to 24

months, “reinforced” in extensive disease by STM for the first 6 to 12
weeks. Relapse rates were unacceptably high with shorter courses.
However, demonstration that RIF was equal to INH in efficacy led to
studies of shorter treatment regimens. In definitive studies, drug-sensitive
3003
Several well-studied regimens are presented in Tables 249.7 and 249.8.239
As an alternative in persons with drug-susceptible disease, INH and
RIF can be given daily during the first 2 months, followed by 7 months
of either daily or intermittent therapy, with no less than thrice-weekly

Chapter 249  Mycobacterium tuberculosis

TB responded as effectively to 9 months of INH and RIF as to 18- to
24-month regimens not containing RIF.280,281 It was subsequently
demonstrated that 6-month regimens based on an initial 2-month
intensive “bactericidal phase” of INH, RIF, PZA, and either STM or
EMB, followed by a “continuation phase” of INH and RIF for 4 more
months, performed as well.282–284 Next it was shown that neither STM
nor EMB improved results over a three-drug regimen (INH, RIF, and
PZA) during the first 2 months of intensive therapy when the isolate
was fully susceptible.282 This 6-month three-drug regimen is acceptable
for drug-sensitive disease. However, given concerns about resistance,
EMB should be included until susceptibility testing results are known.
A 6-month continuation phase of INH and EMB is inferior to a 4-month
continuation phase of INH and RIF.285
Standard Regimens Based on Isoniazid
and Rifampin
The combination of INH (5 mg/kg; maximum 300 mg), RIF (10 mg/kg;
maximum 600 mg), PZA (25 mg/kg, maximum 2 g), and EMB (15 mg/
kg), all given once daily by mouth, should be initiated in persons suspected
of having TB.239,286,287 Therapy should be given daily throughout the entire
course of treatment.239 If intermittent therapy is considered, it should be
no less frequent than three times per week, and given only in persons at
low relapse risk.239 Intermittent therapy should be provided under direct
observation. These four drugs should be continued for 2 months; EMB
can be discontinued when susceptibility results are received, noting that
the infecting organism is susceptible to the other three drugs.
At the end of 2 months, PZA and EMB can be discontinued and
INH and RIF continued to complete a 6-month course. Several treatment
regimens have been endorsed by the CDC, ATS, IDSA,239 and WHO.288
administration preferred.239,289 When given thrice or twice weekly, the
RIF dose remains the same and the INH dose is increased to 15 mg/
kg (900 mg maximum). In persons with a cavity on initial chest
radiograph and positive sputum cultures after 2 months of therapy, TB
relapse risk is high290; INH and RIF should be continued for an additional
3 months (9-month total course) to decrease the relapse risk.239
In persons with resistance to or intolerance of INH, a 6-month
regimen of RIF, PZA, and EMB can be used. Results of all 6-month
regimens in patients with initial resistance to RIF are poor, and such
cases probably require 18- to 24-month courses, as was the case before
RIF was available.291
When hepatitis (defined as aminotransferase levels greater than five
times the upper limit of normal regardless of symptoms or greater than
three times the upper limit of normal in persons with symptoms of
hepatitis) occurs in patients receiving INH, RIF, and/or PZA, all drugs
should be discontinued until hepatic aminotransferase levels normalize
and symptoms resolve. Drugs may then be cautiously reintroduced in
a stepwise fashion while serum aminotransferase levels are monitored.
If persons are intolerant of INH, a regimen of RIF, PZA, and EMB can
be given to complete a 6-month course. If persons are intolerant of RIF,
a more prolonged (18- to 24-month) regimen based on INH and at
least one companion drug (e.g., EMB and possibly a fluoroquinolone)
can be continued.
Directly Observed Treatment
Poor adherence to antituberculosis therapy over the entire course of
treatment, with resultant development of drug-resistant TB and low
rates of TB cure and treatment completion, has led to the recommen-
dation to use DOT whenever feasible.239 Important to note, DOT is

TABLE 249.7  Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by

Drug-Susceptible Organisms
INITIAL PHASE CONTINUATION PHASE
RANGE OF TOTAL
INTERVAL AND DOSESe INTERVAL AND DOSESe,f DOSES (MINIMAL
a,b,c d d
REGIMEN DRUGS (MINIMAL DURATION) REGIMEN DRUGS (MINIMAL DURATION) DURATION)
1 INH 7 days/wk for 56 doses (8 wk) 1 INH/RIF 7 days/wk for 126 doses (18 wk) or 182–130 (26 wk)
RIF or 5 days/wk for 40 doses 5 days/wk for 90 doses (18 wk)g
PZA (8 wk)g
EMB
2 INH 7 days/wk for 56 doses (8 wk), 2 INH/RIF 3 times/wk for 54 doses (18 wk) 110–94 (26 wk)
RIF or 5 days/wk for 40 doses
PZA (8 wk)g
EMB
3 INH 3 times/wk for 24 doses 3 INH/RIF 3 times/wk for 54 doses (18 wk) 78 (26 wk)
RIF (8 wk)
PZA
EMB
4 INH 7 days/wk for 14 doses (2 wk), 4 INH/RIF 2 times/wk for 36 doses (18 wk) 62 (26 wk)
RIF then 2 times/wk for 12
PZA EMB doses (6 wk)
a
Regimen effectiveness is greatest for Regimen 1 to least for Regimen 4. Regimen 1 is preferred for newly diagnosed pulmonary tuberculosis. Regimen 2 is a preferred
alternative regimen when more frequent DOT during the continuation phase is difficult to achieve. Regimen 3 should be used with caution in patients with HIV and/or
cavitary disease; missed doses can lead to treatment failure, relapse, and acquired drug resistance. Regarding Regimen 4, twice-weekly regimens should be avoided in
HIV-positive patients and patients with smear-positive and/or cavitary disease; if doses are missed, therapy is equivalent to once weekly, which is inferior.
b
If the patient’s isolate is susceptible to both INH and RIF, EMB is not necessary, and the intensive phase can consist of INH, RIF, and PZA only.
c
Variations of the preferred regimen may be acceptable in certain clinical and/or public health situations, as described elsewhere.239
d
Pyridoxine (vitamin B6), 25–50 mg/day, is given with INH to all persons at risk of neuropathy (e.g., 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
When directly observed therapy is used, drugs may be given 5 days/wk and the necessary number of doses adjusted accordingly. Although there are no studies that
compare five with seven daily doses, extensive experience indicates this would be an effective practice.
f
Patients with cavitation on an initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase.
g
Five-day-a-week administration is always given by DOT.
DOT, Directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.
Modified from Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, 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; 63:e147–e195.

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For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 3004
TABLE 249.8  First-Line Tuberculosis Medicationsa
DRUG DOSE
(MAXIMUM)
Part III  Infectious Diseases and Their Etiologic Agents
Isoniazida (INH)
Daily
C: 10–15 mg/kg (300 mg)
A: 5 mg/kg (300 mg)
Once weekly
C: Not recommended
A: 15 mg/kg (900 mg)
Twice weekly
C: 20–30 mg/kg (900 mg)
A: 15 mg/kg (900 mg)
Three times weekly
C: Not recommended
A: 15 mg/kg (900 mg)
Rifampina (RIF)
Daily
C: 10–20 mg/kg (600 mg)
A: 10 mg/kg (600 mg)
Once weekly
C: Not recommended
A: Not recommended
Twice weekly
C: 10–20 mg/kg (600 mg)
A: 10 mg/kg (600 mg)
Three times weekly
C: Not recommended
A: 10 mg/kg (600 mg)
Pyrazinamide (PZA)
Daily
C: 15–30 mg/kg (2 g)
A: 15–30 mg/kg (2 g)
Once weekly
C: Not recommended
A: Not recommended
Twice weekly
C: 50 mg/kg (2 g)
A: 50–70 mg/kg (4 g)
Three times weekly
C: Not recommended
A: 50–70 mg/kg (3 g)
Ethambutolb (EMB)
Daily
C: 15–20 mg/kg (1000 mg)
A: 15–25 mg/kg (1600 mg)
Once weekly
C: Not recommended
A: Not recommended
Twice weekly
C: 50 mg/kg (2.5 g)
A: 50 mg/kg (4 g)
Three times weekly
C: Not recommended
A: 25–30 mg/kg (2400 mg)
Rifabutin (RBT)
Daily
C: Not recommended
A: 5 mg/kg (300 mg)
Once weekly
C: Not recommended
A: Not recommended
Twice weekly
C: Not recommended
A: 5 mg/kg (300 mg)
Three times weekly
C: Not recommended
A: 5 mg/kg (300 mg)
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MAJOR ADVERSE
REACTIONS
Hepatic enzyme elevation,
peripheral neuropathy,
hepatitis, rash, CNS effects,
increased phenytoin,
(Dilantin), and disulfiram
(Antabuse) levels
Hepatitis, fever,
thrombocytopenia, flulike
syndrome, rash,
gastrointestinal upset, renal
failure
Reduces levels of many drugs,
including methadone,
warfarin (Coumadin), birth
control pills, theophylline,
dapsone, ketoconazole, PIs,
and some NNRTIs
Orange discoloration of
secretions (sputum, urine,
sweat, tears) and may
permanently stain soft
contact lenses
Gastrointestinal upset,
hepatotoxicity,
hyperuricemia, arthralgias,
rash, gout (rare)
Decreased red-green color
discrimination, decreased
visual acuity (optic neuritis),
rash
Hepatitis fever,
thrombocytopenia,
neutropenia, leukopenia,
flulike symptoms,
hyperuricemia Orange
discoloration of secretions
(sputum, urine, sweat,
tears) and may permanently
stain soft contact lenses
Reduces levels of many drugs,
including methadone,
warfarin (Coumadin), birth
control pills, theophylline,
dapsone, ketoconazole, PIs,
and NNRTIs
With increased rifabutin
levels, severe arthralgias,
uveitis, leukopenia occur
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
RECOMMENDED
MONITORING
Baseline hepatic enzymes
Repeat monthly if baseline
abnormal, risk factors for
hepatitis, or symptoms of
adverse reactions
CDC no longer recommends
routine monitoring tests;
however, many clinicians
continue to order baseline
CBC, platelets, hepatic
enzymes
Repeat if baseline abnormal,
risk factors for hepatitis, or
symptoms of adverse
reactions
Baseline tests of visual acuity
and color vision
Monthly testing for patients
taking >15–25 mg/kg, for
those taking EMB for >2 mo,
and for patients with renal
insufficiency
Baseline hepatic enzymes
Repeat if baseline values
abnormal, risk factors for
hepatitis, or symptoms of
adverse reactions
DOSAGE FORMS
Scored tablets: 50 mg,
100 mg, and 300 mg
Syrup: 50 mg/5 mL
Aqueous solution (IV/IM):
Scarce and may not be
available
Capsules: 150 mg and
300 mg
Syrup: can be formulated
from capsules by pharmacy
Aqueous solution (IV/IM):
Scarce and may not be
available
Scored tablets: 500 mg
Tablets: 100 mg and 400 mg
Capsules: 150 mg
COMMENTS
Hepatitis risk increases with
age and alcohol
consumption. Overdose may
be fatal. Aluminum-
containing antacids reduce
absorption. Pyridoxine
(vitamin B6) may decrease
peripheral neuritis and CNS
effects.
Patients on methadone will
need an increased dose of
methadone (average 50%) to
avoid opiate withdrawal.
Interaction with many drugs
leads to decreased levels of
one or both. May make
glucose control more difficult
in diabetics. Contraindicated
for patients taking PIs and
some NNRTIs. Women on
birth control pills need a
barrier method while on
rifampin.
May complicate management
of diabetes mellitus. Treat
increased uric acid only if
symptomatic. Most common
reason for TB patients
experiencing GI upset.
Optic neuritis may be
unilateral; check each eye
separately. Not recommended
for children too young for
monitoring of vision unless
drug resistant. Use lowest
possible dose in range
(except for drug-resistant
patients). EMB should be
discontinued immediately
and permanently if any signs
of visual toxicity occur.
Patients on methadone may
need an increased dose to
avoid opiate withdrawal.
Interaction with many drugs
leads to decreased levels of
one or both. May make
glucose control more difficult
in diabetics. Women on birth
control pills need to use a
barrier method while on
rifabutin.
In combination with NNRTIs or
PIs, dosages change
significantly.
 3005

TABLE 249.8  First-Line Tuberculosis Medicationsa—cont’d

DRUG DOSE MAJOR ADVERSE RECOMMENDED
(MAXIMUM) REACTIONS MONITORING DOSAGE FORMS COMMENTS

Chapter 249  Mycobacterium tuberculosis

Rifapentine (RPT)
Once weekly only Hepatitis, thrombocytopenia, Baseline hepatic enzymes, Tablets (film-coated): 150 mg See drug interactions with
C: Not approved for use in neutropenia, leukopenia, CBC, and platelets. Repeat if Indications: Pulmonary TB rifampin.
children hyperuricemia, flulike baseline values are abnormal, patients who are HIV
A: 10 mg/kg (600 mg) syndrome risk factors for hepatitis are negative, noncavitary, not
(Data indicate that 900 mg Reduces levels of many drugs, present, or there are pregnant, with organisms
of RPT is well tolerated including methadone, symptoms of adverse pan-sensitive and culture
and CDC is warfarin (Coumadin), birth reactions negative at 2 months (two
recommending this control pills, theophylline, consecutive negative
higher dose for latent dapsone, ketoconazole, PIs, cultures) Administered once
tuberculosis when given and NNRTIs weekly with INH during the
once weekly with INH.) Orange discoloration of continuation phase of
secretions (sputum, urine, treatment.
sweat, tears) and may
permanently stain soft
contact lenses
a
Combination drugs are recommended in the rare instance in which a patient is placed on self-administered therapy: IsonaRif contains INH, 150 mg, RIF, 300 mg; Rifamate
contains INH, 150 mg, RIF, 300 mg; Rifater contains INH, 50 mg, RIF, 120 mg, and PZA, 300 mg.
b
In 2003, the CDC recommended dosing based on weight ranges for PZA and EMB. After reviewing available data, the Maryland TB Expert panel recommended that the
previously recommended dosage ranges be used, advising use of the lowest possible dose in the dose range.
A, Adult; C, child; CBC, complete blood cell count; CDC, Centers for Disease Control and Prevention, CNS, central nervous system; GI, gastrointestinal; HIV, human
immunodeficiency virus; NNRTIs, nonnucleoside reverse-transcriptase inhibitors; PIs, protease inhibitors.
Modified from the 2007 Maryland Guidelines for Prevention and Treatment of Tuberculosis. http://phpa.dhmh.maryland.gov/OIDPCS/CTBCP/CTBCPDocuments/
tbguidelines.pdf.

cost-effective, especially when considering the cost of MDR-TB cases
that are prevented.292 Because all doses are observed, compliance is
improved and the likelihood of emergence of resistance minimized. The
ability of mandatory DOT to control drug resistance in a community
is well established.293,294 In some cases, recalcitrant patients must be
detained for completion of therapy.
Regimens of Less Than 6 Months for
Minimal Disease
Extent of disease can be quantified by the mycobacterial content of
sputum, with smear- and culture-positive sputum representing most
severe disease, smear-negative and culture-positive sputum representing
intermediate disease, and smear- and culture-negative sputum represent-
ing the least amount of disease. The possibility that the early bactericidal
activity of moxifloxacin or gatifloxacin in combinations might permit
4-month regimens in smear-positive, culture-positive cases has, to date,
not been confirmed (see “Fluoroquinolones”).247,257,260 Good results have
been obtained with as little as 4 months of therapy in patients with less
extensive TB.295 A 4-month course of treatment (2 months of INH, RIF,
PZA, and EMB followed by 2 months of INH and RIF) is recommended
for HIV-seronegative persons with smear-negative, culture-negative
pulmonary TB.239 In HIV-seropositive persons with culture-negative
TB, a 6-month regimen is recommended.
Fixed-Dose Combination Tablets
Fixed-dose preparations are available; these contain 150 mg of INH
and 300 mg of RIF (Rifamate); INH 50 mg, RIF 120 mg, and PZA
300 mg (Rifater); or INH 75 mg, RIF 150 mg, PZA 400 mg, and EMB
275 mg (Rifafour). These prevent the patient from omitting drugs and
taking monotherapy and therefore decrease the risk for resistance.
Fixed-dose combinations are particularly useful when DOT cannot be
provided.
Treatment of Multidrug-Resistant
Tuberculosis
Surprisingly, studies of four-drug, 6-month chemotherapy demonstrated
that initial INH or STM resistance did not compromise outcome, but
results were very poor (>50% lack of conversion or relapse) when initial
RIF resistance was present.291 In a meta-analysis, treatment failure and
relapse were substantially higher in the presence of initial drug resis-
tance.296 A critical component in combatting the development of
extensively resistant strains in patients with MDR-TB is access to effective
second-line agents, with increased sputum culture, susceptibility testing,
and genotypic data. In 832 patients with MDR disease followed by the
Green Light Committee (GLC), the mandate of which is to facilitate
increased access to these interventions in middle- and low-income
countries, 8.9% without baseline resistance to second-line agents still
acquired XDR disease, and as baseline drug resistance increased, the
risk of new cases with acquired XDR TB increased also. There was less
resistance acquired during treatment in GLC-approved sites.297 Additional
data from the United States support the need for increased monitoring
for treatment failure associated with the acquisition of resistance to
second-line drugs, with mortality significantly higher (26.5% vs. 10.0%)
in patients with acquisition of resistance versus control patients.298
Acquisition of resistance may impart greater risk than baseline resistance
to the same drugs.299 It is important to note retrospective results from
the Russian Federation, where an “aggressive” regimen of at least five
likely effective drugs was associated with a decreased risk of death and
failure during MDR-TB treatment.300
For therapy for TB that is resistant to both INH and RIF, susceptibility
testing for second-line drugs should be performed and treatment
individualized according to the susceptibility test results. Support for
this recommendation has been provided in a meta-analysis of studies
including almost 9000 patients, in whom susceptibility testing for EMB,
PZA, and second-line agents was associated with higher odds of treatment
success.301 In some settings, standardized second-line regimens are used.
If a suboptimal regimen is prescribed, resistance to additional drugs
may emerge and the opportunity for success may be lost. In a study
from Denver, Colorado, only one-half of 171 HIV-negative patients
with MDR-TB ever converted sputum cultures to negative despite
prolonged administration of carefully selected regimens (not including
fluoroquinolones).302 In a follow-up study from the same institution,
the long-term success rate was 75%.303 In a study from Latvia, 66% of
MDR-TB patients completed therapy or were cured.304 In contrast, two
smaller studies among HIV-seronegative patients from New York City
and San Francisco noted remission in virtually all evaluable HIV-negative
patients treated for MDR-TB.305,306 A study from Bangladesh found that
at least 9 months of gatifloxacin, clofazimine, EMB, and PZA, supple-
mented with prothionamide, kanamycin, and high-dose INH during
an initial intensive phase of at least 4 months, resulted in an 88%
relapse-free cure rate.272 Recent preliminary results of the STREAM
trial, in which the “Bangladesh” regimen was compared with standard
therapy, demonstrated similar effectiveness of the 9-month regimen,
although noninferiority was not demonstrated.307 A randomized trial
of the addition of clofazimine to “individual-based” drug regimens in
China found a significant increase in treatment success in the clofazimine

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 3005.e1
Update: Six-Month Treatment of Drug-Resistant Tuberculosis

Chapter 249  Mycobacterium tuberculosis

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 3006
group versus the control group (74% vs. 54%; P = .035).308 In a CDC
report, 38% of MDR isolates were resistant to PZA, so the role of PZA
may be limited in MDR-TB.309 For TB that is INH and RIF resistant
but fluoroquinolone susceptible, a fluoroquinolone should always be
Part III  Infectious Diseases and Their Etiologic Agents
administered along with other drugs to which the organism is susceptible.
In this setting, 2-month sputum culture conversion rates are improved
by adding bedaquiline.262 The risk for treatment failure is increased if
the M. tuberculosis isolate is also resistant to fluoroquinolones.310,311
Levofloxacin may be preferred over ofloxacin, but moxifloxacin has the
greatest in vitro activity against M. tuberculosis. Companion drugs may
include aminoglycosides (STM, kanamycin, or amikacin) or capreomycin,
ethionamide, and cycloserine.305,312–315 The injectable agents are particu-
larly important for good outcomes, although nephrotoxicity and ototoxic-
ity are concerns. The uncertain efficacy of newer therapies is underlined
by the report of the development of resistance to bedaquiline and
delamanid during treatment of MDR-TB.316 In a small observational
study of imipenem/clavulanate added to an optimized background
regimen, either indifferent or worse outcomes were noted, suggesting
that adding imipenem-clavulanate in the setting of treatment failure
was not likely to improve outcome.317
Therapy for Extensively
Drug-Resistant Tuberculosis
Therapy for XDR-TB, which is defined as resistance to INH, RIF, any
fluoroquinolone, and at least one of three injectable second-line drugs
(amikacin, kanamycin, or capreomycin),112 is difficult and usually
associated with poor outcomes. The risk for treatment failure and death
has been higher than in patients with MDR-TB in some series,318,319 but
not all.320 Cure rate in a report from South Africa was 5%, and mortality
was 78% at 60 months.321 Treatment with at least five drugs to which
the organism is susceptible is recommended. In a study of 41 patients
with treatment-refractory XDR-TB, linezolid was associated with sputum
culture conversion, but 82% of patients had clinically significant adverse
events attributable to linezolid.322 The cure rate 1 year after the end of
treatment was 78%.323 A similar trial in China also found a significantly
higher cure rate (70% vs. 34% in the control group), but again with an
adverse event rate in the linezolid group of 82%.324 A retrospective
report in a predominantly HIV-infected South African population noted
improved culture conversion with clofazimine (40% vs. 29% in the
comparator group), with only minor adverse effects.325
Course of Therapy and
Duration of Observation
At least three sputum samples should be submitted for smear and culture
before beginning treatment. If available, specimens for GeneXpert should
also be obtained. In patients with presumed TB, treatment should be
initiated immediately; a few days of antituberculous treatment will not
interfere with bacteriologic diagnosis. If cultures are negative and there
are no alternative diagnoses, clinical and radiographic response to therapy
after 2 months of treatment is consistent with a diagnosis of TB. Beginning
1 month after initiation of therapy, three sputum cultures should be
obtained monthly to monitor conversion to negative or, if sputum cultures
remain positive, to detect treatment failure and the possible emergence
of drug resistance. Sputum cultures should convert to negative within
2 months. In a minority of patients, sputum smears remain positive
after cultures turn negative. Sporadic positive smears for long periods
presumably represent inactive bacilli released from caseous foci. When
cultures remain positive after 4 months of treatment, it is considered
treatment failure. Causes of treatment failure include drug resistance,
noncompliance with therapy, and malabsorption of antituberculosis
drugs. Sensitivity testing should be performed and consideration given
to adding at least two new drugs to which the organism was sensitive
at the outset of treatment, at least until sensitivities are known. Addition
of only one drug risks development of resistance to the added drug.
Adherence to therapy should be ensured and serum drug levels considered
to assess absorption.
Patients receiving INH, RIF, and PZA should be asked monthly
about symptoms of hepatitis, and hepatic aminotransferase levels should
be checked in symptomatic persons. In persons with abnormal hepatic
aminotransferase levels at baseline, such laboratory findings should be
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monitored regularly, particularly early in the course of therapy. Patients
receiving EMB should be regularly questioned regarding visual symptoms;
their visual acuity should be measured (Snellen chart) and red-green
color discrimination assessed monthly. Patients receiving STM should
be examined for balance and high-frequency hearing loss, and their
renal function should be monitored closely.
Relapse after adequate treatment of drug-sensitive infections is
infrequent (2%–5%). Prolonged follow-up of appropriately treated patients
is not necessary except in the case of unusually extensive disease, slow
bacteriologic response to treatment, suspicion of poor compliance,
drug-resistant disease, or high-risk patients with intercurrent diseases.
In high-incidence settings, an additional 12 months of INH after
completion of a 6-month RIF-containing regimen reduces the TB
recurrence rate among HIV-infected adults.326,327 However, such a practice
is often not performed owing to logistical constraints.
Retreatment
Recurrent TB may be due to either relapse (same M. tuberculosis strain
as the original episode) or reinfection (different M. tuberculosis strain).
Genotyping (RFLP, MIRU, and spoligotyping) or WGS may be used to
distinguish M. tuberculosis isolates. Clinical judgment based on experience
is critical in re-treatment cases, and testing of susceptibility to first- and
second-line drugs is required.239 Some generalizations concerning re-
treatment can be made:
1. In a patient with drug-susceptible TB who receives
rifamycin-based DOT, relapse is likely due to a drug-susceptible
organism. Such patients usually respond again to the initial
regimen.
2. If compliance has been irregular, particularly if the patient has not
received DOT, resistant organisms will probably be present.
3. When drug resistance is suspected, the treatment regimen should
include INH, RIF, PZA, EMB, a fluoroquinolone, and an
injectable agent (e.g., capreomycin), pending susceptibility results.
4. Capreomycin or amikacin can replace STM. Kanamycin is less
effective and more toxic and is used as a last resort. There is
usually no cross-resistance between capreomycin and STM,
amikacin, or kanamycin, but amikacin and kanamycin are usually
cross-resistant.
5. TB resistant to INH and RIF (i.e., MDR-TB) should be treated
with a fluoroquinolone, ethionamide (or protionamide), PZA, and
probably an injectable agent plus either cycloserine or PAS. The
intensive phase of treatment is for 8 months, and the total
treatment duration is 20 months.314,315,328 For those who meet the
criteria, the 9-month short-course regimen should be
considered.315
6. TB resistant to INH, RIF, an injectable agent, and a
fluoroquinolone (i.e., XDR-TB) should be treated with at least
four second-line antituberculosis drugs likely to be effective, in
addition to PZA during the intensive phase of treatment.315,320
Surgical resection may be required. A prolonged course of
treatment is necessary, but the optimal duration is unknown.
Other Forms of Treatment
Bed rest does not influence outcome when effective chemotherapy is
given. Resection still has a role in the salvage of patients in whom
treatment fails and who have localized, resectable disease, and extensive
drug resistance.
Corticosteroids
Corticosteroids in conjunction with antituberculosis therapy improve
neurologic outcome and mortality in persons with tuberculous meningitis.
Use of corticosteroids is therefore recommended in this situation. For
all other clinical manifestations of TB, however, there is no definite
long-term benefit of adjunctive corticosteroids and therefore no thera-
peutic role.329
Treatment of Tuberculosis in
HIV-Infected Patients
The treatment of HIV-related TB is complicated by major drug-drug
interactions between antituberculosis drugs and ART. These interactions

affect the choice of therapy (and appropriate doses) for both diseases.
Invaluable websites that provide extensive advice and information
regarding treatment options for HIV-related TB, including managing
and avoiding drug-drug interactions, are maintained by the Department
of Health and Human Services245 and the CDC.330 These websites are
updated regularly and should be consulted routinely because new
antiretroviral agents and interactions are being discovered. Chapter 39
includes tables from the CDC website about use of antiretroviral agents
together with RIF or rifabutin.
The rifamycins interact with many HIV-1 protease inhibitors, non-
nucleoside reverse transcriptase inhibitors, and integrase strand transfer
inhibitors.245 Among the rifamycins, RIF has the most interactions;
rifapentine appears to have a similar effect,331 but rifabutin has less
profound interactions. RIF is contraindicated for use with HIV-1 protease
inhibitors (e.g., saquinavir, indinavir, nelfinavir, fosamprenavir, atazanavir,
darunavir, tipranavir) and the nonnucleoside reverse-transcriptase
inhibitors etravirine and rilpivirine. RIF also lowers nevirapine levels,
so there are concerns that these two drugs should not be given in
combination.245 Maraviroc can be used with RIF if the maraviroc
dose is increased to 600 mg twice daily. The RIF pharmacokinetic
interaction with saquinavir-ritonavir and lopinavir-ritonavir may be
overcome with increased protease inhibitor dosages.332,333 However,
several healthy volunteer studies were prematurely terminated when
individuals receiving RIF promptly developed marked hepatotoxicity with
addition of ritonavir-boosted lopinavir,332 saquinavir,333 or atazanavir.334
Accordingly, these combinations are generally not used. Rifabutin may
be used in combination with protease inhibitors, with appropriate dose
modification.245 Unfortunately, rifabutin is not presently available in
most resource-limited countries.
RIF modestly lowers plasma levels of efavirenz and, to a greater
extent, nevirapine. However, among patients receiving multidrug
regimens for TB, RIF has been shown to paradoxically increase
plasma levels of efavirenz, particularly among CYP2B6 slow metabo-
lizers335; NAT2 slow metabolizers of INH may also contribute to
increased efavirenz levels.336 RIF does not appear to affect the antiviral
efficacy of efavirenz, and they can be administered concomitantly
with the efavirenz dose maintained at 600 mg daily, particularly in
persons <60 kg. There are greater concerns about concomitant
administration of RIF and nevirapine. Several small studies have
demonstrated favorable clinical and virologic responses, but toxicity
is greater than when RIF is given with efavirenz.337 In persons with
concurrent TB at the start of ART, failure to achieve virologic
suppression was more common in persons who received nevirapine
than efavirenz (both given with RIF).338 RIF lowers raltegravir levels
by 40%; the raltegravir dose should be increased to 800 mg twice
daily and virologic response followed closely. No dosage adjustments
are needed when raltegravir is given with rifabutin. RIF lowers
maraviroc levels by 64%. Although it is preferred to not coadminister
these drugs, if it is done, the dose of maraviroc should be increased
to 600 mg twice daily. Additional interactions and drug dose adjust-
ments are given in Chapter 39.
Despite this extensive list of interactions, it is not recommended
that treatment of TB be delayed or that highly active ART be avoided.
Because antimycobacterial drugs other than the rifamycins do not have
substantial interactions, an alternative regimen with INH, STM, PZA,
and EMB can be considered. However, in HIV-infected persons, regimens
that are not rifamycin based may be less effective than rifamycin-based
regimens.
Acquired rifamycin resistance in the setting of TB relapse is seen
almost exclusively in patients with advanced AIDS who receive highly
intermittent antituberculosis therapy, such as once-weekly INH plus
rifapentine or twice-weekly INH plus rifabutin.248,339 Additional data
suggest that the risk of acquired RIF resistance is also increased in
HIV-infected persons treated with thrice-weekly therapy.340 It is therefore
now recommended that HIV-infected persons should receive daily
antituberculosis therapy in both the intensive and continuation phase
of TB treatment.239
Patients with HIV-related enteropathy may not respond to chemo-
therapy because of inadequate absorption of oral agents, and, in some
cases, pharmacokinetic monitoring may be necessary.341
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3007
Immune Reconstitution
Inflammatory Syndrome
Immune reconstitution inflammatory syndrome (IRIS) results from
rapid restoration of immune responses to opportunistic pathogens, most
Chapter 249  Mycobacterium tuberculosis
importantly M. tuberculosis. This has most often been described in
patients receiving ART. It has additionally been seen in other immu-
nodeficiencies, as in a report of a severe inflammatory reaction that
occurred during therapy of disseminated TB in a Thai woman who had
anti–interferon-γ antibodies.342 Characteristic features include initiation
of virologically effective ART within the previous 3 weeks (the period
of most rapid immune recovery), clinical deterioration with exaggerated
inflammation, and absence of an alternative explanation such as drug
resistance, drug hypersensitivity, other infections, or lymphoma. TB-
associated IRIS comprises two main categories: (1) onset in patients
who are already being treated for TB (termed paradoxical IRIS) and
(2) onset in patients with previously unrecognized, untreated TB (termed
unmasking IRIS). During paradoxical IRIS, patients have typically been
responding to TB therapy but develop recurrent, new, or worsening
manifestations, such as fever, cough, lymph node enlargement, or
radiographic abnormalities after starting antiretroviral agents.343,344 Such
patients demonstrate robust peripheral blood T-cell responses to PPD
and increased proinflammatory cytokines.345 Paradoxical IRIS is most
likely to occur in patients with more advanced AIDS, disseminated and
extrapulmonary TB, and a good immunologic and virologic response
to antiretroviral agents and in those who initiate antiretroviral agents
soon after starting antituberculous drugs.346,347 Reported frequencies
range from 8% to 43%.346 Although symptoms of paradoxical IRIS are
usually self-limited and last a median of 2 months,348,349 morbidity can
be substantial and mortality can occur but is rare. A 4-week course of
prednisone improved symptoms and decreased the need for hospitaliza-
tion in one clinical trial.350 Paradoxical reactions such as lymph node
enlargement or cerebral tuberculomas infrequently affect HIV-negative
individuals or HIV-positive individuals not receiving antiretroviral
agents. In one study, paradoxical reactions affected 36% of HIV-infected
patients receiving therapy for both TB and HIV but only 2% of HIV-
negative patients and 7% of HIV-infected patients not on ART.343 Para-
doxical reactions after the initiation of ART tend to be more severe and
more likely to involve multiple organs. Paradoxical reactions in previously
healthy patients can be confused with uncontrolled infection.
Less is understood about unmasking IRIS. In resource-limited settings,
TB is frequently diagnosed during the initial months of ART, but
underlying mechanisms vary.351 Some represent new or progressive TB
due to persistent immunodeficiency, some reflect active TB that was
present but undiagnosed before ART was started, and others reflect
subclinical TB that was truly unmasked by restoration of robust immune
responses to M. tuberculosis. Consensus case definitions have been
published to facilitate research into TB-associated IRIS in resource-limited
settings.346
The optimal timing of ART initiation in HIV-infected persons with
TB has been evaluated in three clinical trials.352–354 Among persons with
fewer than 50 CD4+ T cells/mm3, initiation of ART within 2 to 4 weeks
of starting antituberculosis therapy was associated with improved
AIDS-free survival compared with delayed initiation of ART. Among
persons with more than 50 CD4+ T cells/mm3, initiation of ART 8 to
12 weeks after initiation of antituberculosis therapy was associated with
a lower risk for IRIS and adverse events without increasing the risk for
AIDS or death.353,354 The most recent TB treatment guidelines recommend
the timing of ART initiation in these patient groups according to these
findings.239,288
Duration of Therapy
The duration of antituberculosis therapy is determined by relapse risk.
Several observational studies noted comparable relapse rates in HIV-
infected and HIV-uninfected persons after 6 months of rifamycin-based
antituberculosis therapy. Based on these data, the current recommendation
is to treat for the same duration regardless of HIV status, particularly if
the HIV-positive patient is receiving ART.239,286,288 However, some obser-
vational studies have noted higher recurrence rates in HIV-infected than
HIV-uninfected persons who receive 6 months of treatment.355,356 A recent
meta-analysis found that ART decreased the risk for TB relapse;
 3008
rifamycin-based therapy for 8 months or more and daily administration TABLE 249.9  Criteria for Tuberculin Positivity by
in the intensive phase were also associated with improved treatment Risk Group
outcomes.357 In the only clinical trial of 6 versus 9 months of antituber-
culosis treatment in HIV-infected persons, TB recurrence risk was lower REACTION ≥5 MM REACTION ≥10 MM REACTION ≥15 MM
Part III  Infectious Diseases and Their Etiologic Agents

in those who received treatment for 9 months, but mortality rate did not OF INDURATION OF INDURATION OF INDURATION
differ; all persons received antituberculosis treatment three times a week, HIV-positive persons Recent immigrants Persons with no risk
and none received ART.358 The most recent ATS/CDC/IDSA guidelines (within 5 yr) from factors for
recommend extending the duration of antituberculosis treatment to 9 high-prevalence tuberculosis
countries
months in HIV-positive persons who do not receive concomitant ART.239
Recent contacts of Injection drug users
Other Special Treatment Circumstances tuberculosis case
patients
Childhood
Pulmonary TB in childhood should be treated with INH, RIF, and PZA Fibrotic changes on Residents and employees
for 2 months, followed by INH and RIF for 4 months. The inability to chest radiograph of high-risk congregate
consistent with prior settings (prisons and
monitor visual acuity limits the use of EMB in very young children, tuberculosis jails, nursing homes,
although it can be given if the bacillary burden is high, drug resistance hospitals and other
is suspected, or both.239 health care facilities,
residential facilities for
patients with AIDS,
Pregnancy and homeless shelters)
Treatment should not be deferred during pregnancy. For drug-sensitive
TB, INH, RIF, and EMB comprise the regimen of choice. STM should Patients with organ Children <4 yr of age, or
transplants and other infants, children, and
not be used during pregnancy because of potential eighth nerve toxicity immunosuppressed adolescents exposed to
in the fetus. Although PZA is routinely recommended by international patients (receiving adults at high risk
organizations, use has not been uniformly recommended in the United equivalent of
States because of inadequate teratogenicity data; its use should be ≥15 mg/day of
prednisone for at
considered on a case-by-case basis.239 least 1 mo)
AIDS, Acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.
Uremia and End-Stage Renal Disease Modified from centers for disease control and prevention. Targeted tuberculin
Dosages of INH and RIF need not be adjusted for renal failure but testing and treatment of latent tuberculosis infection. American thoracic society.
should be administered after dialysis, and pyridoxine supplementation MMWR Morb Mortal Wkly Rep. 2000;49(Rr-6):1–51.
should be routine. In patients with creatinine clearance less than 30 mL/
min and those on hemodialysis, EMB should be administered at 20 to
25 mg/kg, and PZA at 25 to 35 mg/kg, both given three times per week treatment of LTBI. The current strategy in the United States is to test
(after dialysis for those on hemodialysis). Biochemical monitoring of for M. tuberculosis infection using the TST or an interferon-γ release
hepatotoxicity during renal failure may be complicated by abnormally assay in persons who are at high risk for progressing to active TB, and
low aminotransferase levels in uremia. then to treat all persons with a positive test result regardless of age.
Criteria for TST positivity and groups for whom treatment of LTBI is
Liver Disease indicated are listed in Table 249.9.172,359
The selection and dosage of antituberculous agents do not need to be
modified in most patients with underlying liver disease, but hepatic Drug Regimens
aminotransferase and bilirubin levels must be followed closely. In persons Nine months of INH, up to 300 mg daily, is a recommended regimen
intolerant of INH owing to hepatotoxicity, a 6-month regimen of RIF, for treatment of LTBI in adults and children, regardless of HIV status.172,360
PZA, and EMB can be used. If PZA cannot be tolerated, a regimen of Although 90% efficacious, its effectiveness is limited by low treatment
INH, RIF, and EMB for 2 months, followed by 7 months of INH and completion rates. When necessary, supervised intermittent treatment
RIF, should be given.239 For persons with extensive TB and severe hepatitis of LTBI with INH, 15 mg/kg (up to 900 mg) twice weekly, can be used.
who should not have a prolonged treatment interruption, “bridging” Pyridoxine supplementation, 10 to 50 mg daily, is recommended to
regimens that include EMB, fluoroquinolone, and STM could be prevent peripheral neuropathy in persons older than 65 years; pregnant
considered until a more standard regimen can be instituted.239 Preexisting and breastfeeding women; persons with diabetes mellitus, chronic renal
liver disease (e.g., hepatitis C virus infection) may complicate the failure, or alcoholism; persons undergoing treatment with anticonvulsants;
detection of drug-related hepatotoxicity; accordingly, clinical and and persons who are malnourished. A 3-month regimen of once-weekly
biochemical supervision should be assiduous. INH plus rifapentine given to adults and children under direct observa-
tion is as effective as 9 months of INH.361,362 Implementation of this
Patients Receiving 3-month regimen led to a 31% increase in completion of preventive
Immunosuppressive Drugs therapy in New York City health clinics.363 The weekly dose of both
TB that develops during immunosuppressive treatment of another disease drugs for adults weighing more than 50 kg is 900 mg. This regimen is
should be treated with the same regimens used to treat immunocompetent an equal alternative to 9 months of INH for persons 12 years of age
hosts. Immunosuppressive therapy need not be discontinued. Given and older who are at increased risk for progressing from latent infection
the increased predisposition to TB among persons receiving a TNF-α to active TB; this includes HIV-infected persons who are not receiving
inhibitor (e.g., etanercept, infliximab, adalimumab), discussion between ART.364–366 It is important to exclude active TB in HIV-infected patients
all of the patient’s medical providers (e.g., rheumatologist, gastroenterolo- on this regimen. Permanent drug discontinuation due to an adverse
gist, pulmonologist, and infectious disease specialist) may be helpful event was more common with the 3-month regimen than with 9 months
to determine a rational treatment strategy. of INH alone (4.9% vs. 3.7%, respectively). The most common side
effect was a flulike syndrome that has been seen before with intermittent
Treatment of Latent RIF therapy, and with INH.367 Another option is 4 months of RIF (10 mg/
Tuberculous Infection kg; 600 mg maximum).172 This regimen is effective and well toler-
Soon after INH became available, it became widely used in the United ated.242,243,368 A 3-month regimen of daily INH and RIF is also effective.
States to treat not only persons with active disease (as part of combination Although there have been limited head-to-head comparisons, a recent
therapy) but also M. tuberculosis infection, to prevent progression to network meta-analysis demonstrated similar safety and effectiveness
active TB. In contrast, many other countries have used a TB-prevention of 3 months of weekly INH plus rifapentine, 3 months of daily INH
strategy based primarily on BCG vaccination at birth rather than plus RIF, and 4 months of daily RIF.369

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A 2-month regimen of daily RIF-PZA is as effective as a 12-month
daily regimen of INH in HIV-infected adults.370 Unfortunately, initial
enthusiasm for this 2-month regimen waned after numerous reports
of severe liver injury and death, primarily in HIV-negative individuals.251
3009
release assay results before exposure should be assembled. Persons with
a negative test result should be retested 8 weeks after the exposure to
allow time for TST or interferon-γ release assay conversion. However,
if exposure is particularly heavy, or in HIV-positive health care workers,

Chapter 249  Mycobacterium tuberculosis

This regimen is no longer recommended.371 preventive therapy should be started even before retesting. Treatment
Optimal treatment of LTBI when resistance to both INH and RIF can later be discontinued in HIV-negative persons if they remain TST
(i.e., MDR-TB) is likely is not known. Regimens of PZA plus either or interferon-γ release assay negative.155
EMB or a fluoroquinolone for 6 to 12 months have been recommended,
but such regimens are poorly tolerated and their effectiveness has never Treatment of Quiescent, Previously
been studied.172 Untreated Pulmonary Tuberculosis
Tuberculin-positive patients with fibrotic upper lobe lesions and patients
Risk for Isoniazid Hepatotoxicity During who had active TB before drugs were available are at increased risk for
Treatment of Latent Tuberculous Infection developing TB.378 Treatment is the same as for LTBI (see earlier
Use of INH is associated with an increased risk for hepatotoxicity; discussion). The longer the lesion has been stable, the lower is the risk
the risk in a recent clinical trial of 9 months of INH was 2.7%.361 A for relapse.
US Public Health Service survey found that the incidence of probable
INH-associated hepatitis increased with age: Rates per 1000 persons Treatment of Individuals
were 0 for those younger than age 20, 3 for ages 20 to 34, 12 for ages 35 With Recent Infection
to 49, 23 for ages 50 to 64, and 8 for age older than 64.240 The incidence The first 2 years after M. tuberculosis infection is the period of greatest
in daily drinkers of alcohol was also high (26.5 per 1000). The number risk for development of active disease. Most authorities recommend
in the elderly was probably falsely low because of a small sample size. A treatment of LTBI for any person known to have become infected within
much larger experience recorded hepatitis in 4.6% of patients older than 2 years, regardless of age. This is documented by conversion of the
65.372 A large European study reported a hepatitis incidence of 520 per TST or interferon-γ release assay result from negative to positive within
100,000 population; the figure was 280 per 100,000 for those younger 2 years.
than 35 years and 770 per 100,000 for those older than 54 years. Most
hepatitis develops within the first 3 months, and the risk for death, once Treating Latent Tuberculous Infection in
clinical hepatitis develops, is substantial.240,373 Biochemical monitoring Persons With HIV Infection
will likely prevent some deaths, because there is a subclinical phase of In the era before highly active ART, TST- and HIV-positive injection
at least several weeks. Byrd and colleagues recorded increased serum drug users had an annual risk for active TB of approximately 8% per
aminotransferase levels in 18.3% of patients taking INH but no deaths year.136 As indicated in Table 249.10, the CDC recommends that a
in a biochemically monitored population. Many patients with severe TST showing greater than 5 mm induration or a positive interferon-γ
biochemical hepatitis would not have been detected with monitoring release assay result is an indication for treating LTBI in persons with
of symptoms only.374 In contrast, one public health clinic reported only known or suspected HIV infection in whom active TB has been ruled
11 cases of clinical hepatotoxicity and no deaths among more than out.172 WHO recommends treating LTBI in HIV-positive persons with
11,000 persons receiving INH over a 7-year period.375 Based on this a positive or unknown TST; treatment options include 6 to 9 months
and other considerations, emphasis is now placed on clinic monitoring of INH, 3 months of INH plus rifapentine, 3 to 4 months of INH plus
for signs and symptoms of adverse effects, with prompt evaluation if RIF, or 3 to 4 months of RIF.381 Due to concerns regarding reinfection,
these develop. Current recommendations advocate routine baseline and WHO recommends at least 36 months of INH in HIV-positive persons
follow-up laboratory monitoring only for persons with HIV infection, living in TB-endemic countries.381 In Côte d’Ivoire, both immediate
pregnant and early postpartum women, and persons with chronic liver initiation of ART and completion of 6 months of INH preventive
disease or who use alcohol regularly.172 therapy demonstrated independent decreases in the risk of death or
Snider and Caras analyzed 177 cases of fatal hepatitis from various
sources376 and estimated a case rate of 14 per 100,000 of those starting
and 23 per 100,000 of those completing therapy. Sixty-nine percent
were female, with clustering around pregnancy. TABLE 249.10  Miliary Tuberculosis
STUDY
Treatment of Contacts of Active Cases
The US Public Health Service contact study showed that treatment of FACTOR OR MAARTENS KIM ET
FINDING BIEHL400 MUNT401 ET AL.402 AL.403
LTBI decreased the incidence of subsequent TB among contacts of
active cases from 1550 to 610 cases per 100,000, a 61% reduction over No. of cases 69 68 109 38%a
10 years.377 In those who were tuberculin negative when first surveyed, Mean age 51 50 — 60%a
the figures (per 100,000) were 510 without and 150 with chemopro-
Nonwhite race 85% 87% 94% 79%a
phylaxis, a 59% reduction. Estimates of the risk to contacts in some
smaller studies are much higher. One year of INH therapy is about 70% Predisposing factors 15% 31% 42% 66%a
effective in preventing disease, with failures most often caused by Weeks of symptoms 2-16 3-24 1-52 —
nonadherence.378 INH prophylaxis may also fail in drug-resistant infec-
Meningitis 17% 19% 22% —
tions. It appears unlikely that prophylactic INH monotherapy taken
reliably by contacts results in subsequent INH resistance.360,379 Tuberculin positive 61% 84% 43% 28%
Treatment of LTBI is indicated for persons found to be interferon-γ Miliary radiograph 93% 97% — 91%a
release assay or TST positive (5 mm of induration for the latter) after
contact with an active case. In children younger than 5 who are close Other foci of 32% 23% — —
tuberculosis
contacts of an active case, the TST is preferred over the interferon-γ
release assay380; if the TST result is negative, preventive therapy should Positive sputum — 39% 33% (21/64) 36% (12/33)
smear
be initiated and the test repeated after 3 months. If the result of the
second test is positive, a preventive therapy course should be completed; Marrow diagnosticb — 20% 41% (9/22) 9% (2/22)
if it is negative, treatment can be discontinued. Transbronchial biopsy — — 76% (39/51) 63% (5/8)
To address the risk to health care workers inadvertently exposed to diagnosticc
TB, Stead reviewed 33 previously investigated hospital and nursing a
This percentage includes interstitial and diffuse alveolar patterns.
home outbreaks.174 In this setting, on discovering that exposures have b
Marrow diagnostic if caseating granuloma or acid-fast bacilli are seen.
occurred, a list of all exposed personnel and their TST or interferon-γ c
Transbronchial biopsy diagnostic if any granuloma or acid-fast bacilli are seen.

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 3010
severe HIV-related disease among HIV-positive persons with >500
CD4+ lymphocytes/mm3.382
Anergy testing in immunocompromised persons is unreliable, and
treatment of latent TB in anergic HIV-infected persons with latent TB
Part III  Infectious Diseases and Their Etiologic Agents
does not decrease the risk of reactivation. Therefore, since 1997 the
CDC has recommended against routine anergy testing for HIV-positive
persons at risk for TB (see “Tuberculin Skin Testing and HIV Infec-
tion”).383 The failure of predictive tests in high TB incidence areas is
underlined by experience in Khayelitsha, South Africa, where there was
no association between the benefit of INH preventive therapy and TST
or interferon-γ release assay result, leading to the recommendation that
all patients receiving ART in moderate- to high-incidence areas should
receive INH preventive therapy.384
Mycobacterium tuberculosis Infection in
Persons With Additional Risk Factors
Treatment of LTBI is advised for persons with M. tuberculosis infection
who are from groups with a known high incidence of TB, including
immigrants from developing countries, injection drug users, the homeless,
prisoners, and residents of long-term care facilities.172 An argument
has been made for treating latent tuberculous infection in patients
after gastrectomy and jejunoileal bypass surgery for obesity. There is a
greatly increased incidence of TB in patients undergoing chronic renal
dialysis100 and in renal transplant patients. Treatment of LTBI is also
recommended for infected persons with silicosis,and for those those with
myeloproliferative disorders and hematologic malignancies, especially
when corticosteroids are given. Prolonged treatment with high doses
of corticosteroids undoubtedly predisposes to activation of latent TB.
Latently infected individuals who are to receive anti–TNF-α monoclonal
antibodies (e.g., infliximab, etanercept, or adalimumab) should receive
treatment of latent tuberculous infection.205 As much treatment as pos-
sible should be received before the patient starts immunosuppressive
therapy; ideally a treatment course would be completed, and this may
be facilitated by short-course regimens.
Hepatotoxicity of INH has made preventive therapy difficult in
patients with severe liver disease or after liver transplant. Fluoroqui-
nolones have been considered as an option, with recognition of issues
such as tendon rupture, although data to support this use are sparse.385,386
Pregnant Women
Because INH treatment for latent tuberculous infection may be associated
with a slightly increased risk for maternal hepatitis, added caution with
respect to INH-induced hepatotoxicity is indicated. There are insufficient
safety data for the other preventive therapy regimens in pregnancy.
The Nursing Home Problem
A major analysis by Stead and colleagues showed that 3.8% of men and
2.3% of women who were tuberculin positive at admission to nursing
homes acquired active disease and that this could be decreased 10-fold
with treatment of latent tuberculous infection.372 Treatment of latent
tuberculous infection was clearly beneficial in patients who tuberculin
converted after admission, with 11.6% of men and 7.6% of women
acquiring active disease without treatment of latent tuberculous infection,
but only 0.2% with treatment.
Vaccination
BCG, a live-attenuated vaccine derived from a strain of M. bovis, is
used in young children throughout much of the world. Vaccination
of children results in a 60% to 80% decrease in the incidence of TB,387
but efficacy has varied widely. Its use is reasonable in high-prevalence
situations, greater than those that now exist in the United States and
most industrialized nations. It should be administered only to
tuberculin-negative persons. Although BCG vaccine does not prevent
infection, it usually prevents progression to clinical disease and
effectively prevents disseminated disease in young children. The risk
for disseminated BCG infection after vaccination in infants born to
HIV-positive mothers is small. BCG should not be given to persons
known to be infected with HIV. Prior BCG vaccination does not alter
guidelines for TST interpretation, particularly if at least 10 years have
passed since vaccination.
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The effect of BCG vaccination on tuberculin reactivity depends on
the age at vaccination and interval before skin testing. In a study in
Montreal, children vaccinated once with BCG before the age of 1 year
had a 7.9% prevalence of positive TST results 10 to 25 years later,
comparable to those who never received BCG.388 Prevalence of positive
TST results was 18% among those vaccinated between 1 and 5 years
of age and 25.4% among those vaccinated after age 5. Although tuberculin
reactivity wanes after infant BCG vaccination, later skin testing can
cause a booster effect, a potential source of confusion. Interesting to
note, there is no relationship between tuberculin reactivity after BCG
vaccination and protection against development of active TB.175
Intravesicular BCG, used to treat bladder cancer, is a rare cause of
miliary granuloma in the liver or lung, psoas abscess, or osteomyelitis.389–391
This mycobacteriosis responds to treatment with INH and RIF.
The development of a better vaccine for TB is a high priority.392
Some candidates are subunit vaccines wherein immunodominant antigens
are expressed by viral vectors or formulated with adjuvant. Live-attenuated
vaccines have the potential advantage of inducing responses to a broader
array of antigens, and the current vaccine against TB—BCG—has been
modified to produce greater amounts of immunodominant antigens.
The Aeras Foundation is a not-for-profit organization based in
Rockville, Maryland, dedicated to the development and testing of new
TB vaccine candidates. Candidate vaccines furthest along in the Aeras
Foundation pipeline for testing in clinical trials include the following:
M72/AS01E (a fusion protein derived from M. tuberculosis antigens
MTB32A and MTB39A plus adjuvant AS01E); H4:IC31 (a fusion protein
derived from antigens 85B and TB10.4 plus adjuvant IC31); H56:IC31
(a fusion protein derived from antigens 85B, ESAT-6, and Rv2660c plus
adjuvant IC31); and MTBVAC (a live-attenuated vaccine based on a
human M. tuberculosis isolate); MVA85A (Ag85A expressed by modified
Vaccinia Ankara virus); Aeras-402 (adenovirus expressing Ag85B and
TB10.4); M72F (a fusion of Rv1196 and Rv0125 delivered in AS01
adjuvant); H56 (a fusion of Ag85B, ESAT-6, and Rv2660 delivered in
IC31 adjuvant); ID93 (a fusion of Rv1813, Rv2608, Rv3619, and Rv3620
delivered in GLA-SE adjuvant); and Hybrid-4 (a fusion of Ag85B and
TB10.4 delivered in IC31 adjuvant).
In the first infant efficacy trial of any TB vaccine for nearly a half
century, more than 2700 infants (given BCG as neonates) were enrolled,
with 1399 infants given a boosting inoculation with MVA85A within
6 months after receiving BCG. Although MVA85A was well tolerated
and induced modest cell-mediated immune responses, it unfortunately
did not provide significant protection against the development of TB.393
In contrast, a trial of M72/AS01E in HIV-negative adults with latent
TB in Kenya provided 54% protection against reactivation.394
An improved understanding of host pathways for presenting
antigens of intracellular pathogens and mechanisms by which M.
tuberculosis suppresses antigen presentation may foster novel and
effective live-attenuated vaccine candidates. The Stop TB Partner-
ship regularly updates an online document describing new vaccine
candidates.395
EXTRAPULMONARY TUBERCULOSIS
Extrapulmonary TB can be divided into three groups based on patho-
genesis. The first comprises superficial mucosal foci resulting from the
spread of infectious pulmonary secretions via the respiratory and
gastrointestinal tracts. Such lesions were once almost inevitable complica-
tions of extensive cavitary pulmonary disease but are now rare. The
second group comprises foci established by contiguous spread, such as
from a subpleural focus into the pleural space. The third group comprises
foci established by lymphohematogenous dissemination, either at the
time of primary infection or, less commonly, from established chronic
pulmonary or extrapulmonary foci.
AIDS and Extrapulmonary Tuberculosis
Before 1985, cases of pulmonary TB in the United States decreased
each year, whereas the number of extrapulmonary cases remained stable
at about 4000 per year. The percentage of cases caused by extrapulmonary
disease subsequently increased, largely as a result of coinfection with
HIV. Unlike in non-AIDS patients, concomitant pulmonary and
extrapulmonary disease is very common in AIDS patients with TB.
 3011
Cases of HIV-associated pulmonary and extrapulmonary TB have
declined in the United States since 1992.396 There are certain distinguish-
ing features of AIDS-associated extrapulmonary TB. The frequency of
disseminated disease (more than one focus or progressive hematogenous

Chapter 249  Mycobacterium tuberculosis

disease) is high—38% in one series—and rapidly progressive forms
with diffuse pulmonary infiltrates, acute respiratory failure, and dis-
seminated intravascular coagulation have been observed. TB pleuritis,
when it occurs, is often bilateral and part of a disseminated process.
Visceral lymphadenopathy, both mediastinal and abdominal, is frequent,
and a contrast-enhanced CT scan showing nodes with central low
attenuation suggests the diagnosis. Abscesses of the liver, pancreas,
prostate, spleen, chest, abdominal wall, and other soft tissues have also
been described. Among 320 cases of extrapulmonary TB from 1995 to
2007 managed at Grady Memorial Hospital in Atlanta, HIV coinfection
was associated with a decreased likelihood of the pleural space as a site
of extrapulmonary disease; among HIV-infected patients with extra-
pulmonary TB, those with fewer than 100 CD4+ T cells/mm3 were more
likely to have central nervous system (CNS), meningeal, and/or dis-
seminated TB.397 Extrapulmonary TB appears to be predictive of an
increased risk for developing paradoxical IRIS when ART is initiated
(see “Immune Reconstitution Inflammatory Syndrome”).346

General Comments on Treatment of

Extrapulmonary Tuberculosis
Extrapulmonary foci usually respond to treatment more rapidly than does
cavitary pulmonary TB, owing to the lower burden of organisms in the
former. Therapy with four-drug regimens (INH, RIF, PZA, and EMB)
for 2 months, followed by INH and RIF for 4 months, is advised in most
cases caused by drug-sensitive organisms. The exceptions include bone
and joint disease (6–9 months) and tuberculous meningitis (9–12 months,
although optimal duration is unknown).239 Adjunctive corticosteroids
are recommended for persons with pericardial or CNS TB.
Diagnostic difficulty and delay can have a devastating impact on
survival in critically ill patients. In a study from Uganda, a highly endemic
country, empirical therapy for TB, despite negative sputum smears, led
to improved survival in patients presenting with “danger signs,” including
fever greater than 39°C, tachycardia greater than 120 beats/min, or
tachypnea greater than 30 breaths/min.398 However, among HIV-positive
persons with <50 CD4+ lymphocytes/mm3 starting ART, empirical
four-drug therapy did not improve survival compared with INH preven-
tive therapy alone.399
Miliary Tuberculosis
The term miliary tuberculosis, first used to describe its pathologic
resemblance to millet seeds, now describes any progressive disseminated
hematogenous TB. Miliary TB can be roughly divided into three groups:
(1) acute miliary TB associated with a brisk and histologically typical
tissue reaction; (2) cryptic miliary TB, a more prolonged illness with
subtle clinical findings and an attenuated histologic response; and (3)
nonreactive TB characterized by huge numbers of organisms, little
organized tissue response, and often a septic or typhoidal clinical
picture.164
Usual (Acute) Miliary Tuberculosis
In the prechemotherapy era, miliary TB occurred either soon after
primary infection in children or young adults or as a terminal event in
untreated chronic organ TB. In children, the illness is acute or subacute,
with high intermittent fevers, night sweats, and occasional rigors. Pleural
effusion, peritonitis, or meningitis occurs in as many as two-thirds of
affected persons. The illness in young adults is usually more chronic
and initially less severe. However, miliary TB is now more frequently
observed in older individuals, often with underlying illnesses or condi-
tions that may confuse diagnosis.
Four large series in the chemotherapy era400–403 have emphasized the
frequency of miliary TB in minority racial groups and the importance
of underlying conditions such as alcoholism, cirrhosis, neoplasm,
pregnancy, rheumatologic disease, and treatment with immunosup-
pressive agents (see Table 249.10).400–403 There is usually no prior history
of TB, and the onset is often subtle. Generalized symptoms of fever,
anorexia, weakness, and weight loss are nonspecific. Headache may
FIG. 249.7  Detail of a chest radiograph (left midlung zone) showing
countless 0.5- to 1.0-mm nodules typical of miliary tuberculosis.
indicate meningitis; abdominal pain may be due to peritonitis; and
pleural pain may result from pleuritis. Physical findings are likewise
usually nonspecific, but a careful search for cutaneous eruptions, sinus
tracts, scrotal masses, and lymphadenopathy may yield a prompt biopsy
diagnosis. A miliary infiltrate on a chest radiograph is the most helpful
finding and the usual reason miliary TB is suspected (Fig. 249.7).
Unfortunately, many patients, particularly the elderly, succumb to miliary
TB before the chest radiograph becomes abnormal.404 The white blood
cell count is usually normal, and anemia is the rule. Hyponatremia with
the laboratory features of inappropriate secretion of antidiuretic hormone
is frequent, particularly with meningitis.401 Addison disease should be
considered as a cause of hyponatremia. Increased levels of alkaline
phosphatase and aminotransferases are common, as are hypoxemia,
hypocapnia, and impairment of pulmonary diffusion capacity. Cultures
of sputum, gastric contents, urine, and CSF are positive in some combina-
tion in most cases, but smears of sputum and pulmonary secretions
alone are positive in fewer than one-third. Immediate diagnosis often
results from examination of tissue (lymph nodes, scrotal masses when
present, liver biopsy, or bone marrow specimens). Mycobacterial blood
cultures may also be positive. Transbronchial biopsy is an excellent way
to obtain tissue and should be performed promptly when the diagnosis
is suspected.405 The finding of caseating granulomas or AFB is virtually
diagnostic.
Rapid diagnosis is mandatory. However, treatment should be initiated
immediately based on strong clinical suspicion, because mortality from
miliary TB is most often due to delays in treatment. Response may be
prompt or may take several weeks. Fulminant miliary TB may be
associated with severe refractory hypoxemia and disseminated intra-
vascular coagulation.
Cryptic Miliary Tuberculosis and Late
Generalized (Chronic Hematogenous)
Tuberculosis
Chronic organ TB is probably always associated with intermittent,
nonprogressive seeding of the bloodstream. In some individuals,
however, especially as age or other factors compromise immunity,
this becomes continuous and produces progressive hematogenous TB
long after the primary infection.406 The term cryptic miliary tuberculosis
usually describes older patients with miliary TB in whom the diagnosis
is obscure because of normal chest radiographs, negative TST results,
and often confounding underlying illnesses to which symptoms are

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 3012
mistakenly attributed407; this term has also been applied to miliary
TB diagnosed at autopsy.404
The foci responsible for late generalized TB are often clinically
silent—for example, renal, genitourinary, osseous, or visceral lymph
Part III  Infectious Diseases and Their Etiologic Agents
nodes.406 Chronic pulmonary foci are at times involved but are rarely
the only source. The clinical picture is frequently fever of unknown
origin, often with a normal chest radiograph and a negative TST result.
Fever may be absent, and in one series antemortem diagnosis was made
in only 15% of cases.406 Late generalized TB may be associated with
major hematologic abnormalities.
Nonreactive Tuberculosis
The histologic appearance in this rare form of disseminated hema-
togenous TB shows nonspecific necrosis containing disintegrating
neutrophils and enormous numbers of tubercle bacilli.190 In the typical
case, granulomas and epithelioid cells are lacking, although intermedi-
ate cases have areas more typical for TB. The gross pathologic findings
are soft abscesses from minute to 1 cm, which always involve the
liver and spleen, usually the marrow, commonly the lungs and
kidneys, but never the meninges. The clinical picture may be over-
whelming sepsis, with splenomegaly and often an inconspicuous
diffuse mottling on the chest radiograph. Major hematologic abnor-
malities are common (see “Miliary Tuberculosis and Hematologic
Abnormalities”).
Miliary Tuberculosis and Hematologic
Abnormalities
Some patients with late generalized TB and most with nonreactive TB
have serious hematologic abnormalities, including leukopenia, throm-
bocytopenia, anemia, leukemoid reactions, myelofibrosis, and polycy-
themia.408 Leukemoid reactions may suggest acute leukemia, although
most patients in whom hematogenous TB coexists with the clinical
picture of leukemia have both diseases. Disseminated TB should be
considered when pancytopenia is associated with fever and weight loss
or as a cause of other obscure hematologic disorders.
Primary Hepatic Tuberculosis
Rarely, miliary TB may mimic cholangitis, with fever, liver function
test abnormalities suggestive of obstructive disease, and little evidence
of hepatocellular disease. Diagnosis is made through liver biopsy.
Miliary Tuberculosis in AIDS
In AIDS patients, 10% with TB and 38% with extrapulmonary TB
have miliary disease.232,409 Major constitutional symptoms and hectic
fevers are characteristic. The chest radiograph is abnormal in 80%
and may include typical miliary mottling. Only 10% of patients are
tuberculin positive.232 The sputum smear is positive in only 25%,409
but cultures of many materials will be positive, including blood in
50% to 60%. Biopsy specimens during life show typical tuberculous
histologic appearance but with more stainable organisms than in
non-HIV miliary TB. In fatal cases, in contrast, the histologic picture
is often nonreactive TB.232
Abscesses of various soft tissue and visceral organs have been
described in patients with AIDS and TB, usually with other evidence
of disseminated disease. Locations include the liver, spleen, pancreas,
psoas muscle with or without spinal involvement, mediastinum, neck,
chest wall, abdominal wall, and prostate.232,409,410 Diagnosis is usually
made by means of CT or ultrasonography and confirmed with needle
or catheter aspiration. Clinical response to chemotherapy and drainage
is usually good. An abscess may appear or reappear during therapy and
respond to repeated aspiration.
Central Nervous System Tuberculosis:
Tuberculous Meningitis
This condition is usually caused by rupture of a subependymal tubercle
into the subarachnoid space rather than direct hematogenous seeding.
Meningitis complicating miliary disease usually develops several weeks
into the illness. In childhood, meningitis is an early postprimary event,
and three-fourths of these persons have a concurrently active primary
complex, pleural effusion, or miliary TB. Subependymal foci may remain
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quiescent indefinitely before rupturing. This may follow head trauma
or be associated with general depression of host immunity as a result
of alcohol abuse or other factors.
Pathologic Features
Meningeal involvement is most pronounced at the base of the brain.
In long-standing cases, a gelatinous mass may extend from the pons
to the optic nerves, being most prominent adjacent to the optic chiasm.
In more chronic cases, fibrous tissue may encase cranial nerves. Vasculitis
of local arteries and veins may lead to aneurysm, thrombosis, and focal
hemorrhagic infarction. Perforating vessels to the basal ganglia and
pons are most often involved, producing movement disorders or lacunar
infarcts; involvement of branches of the middle cerebral artery may
cause hemiparesis.
Clinical Manifestations
The usual illness begins with a prodrome of malaise, intermittent
headache, and low-grade fever, followed within 2 to 3 weeks by protracted
headache, vomiting, confusion, meningismus, and focal neurologic signs.
The clinical spectrum is broad, ranging from chronic headache or subtle
mental status changes to sudden, severe meningitis progressing to coma.
Fever may be absent, and the peripheral white blood cell count is usually
normal. Mild anemia is usual, and hyponatremia resulting from inap-
propriate antidiuretic hormone secretion is common. Evidence of
concomitant extrameningeal TB is present in roughly three-fourths of
cases,411 with miliary shadowing on the chest radiograph being most
suggestive. In many cases, however, there are no clinical or historical
clues to suggest TB.
The cornerstone of diagnosis is examination of the CSF. The cell
count generally ranges from 0 to 1500/mm3, the protein level is increased,
and the CSF glucose is characteristically low. A lymphocytic predomi-
nance is usual, although one-fourth of cases have a polymorphonuclear
pleocytosis, usually early in the course. Identifying bacilli often requires
examination of large volumes of fluid from repeated lumbar punctures.
In one study, stains of sediment revealed AFB in 37% of cases on initial
examination but in 90% when fluids from four large-volume lumbar
punctures were examined.411 Initial atypical findings such as neutrophilic
pleocytosis, a normal glucose concentration, or even entirely normal
CSF indices evolve to more typical mononuclear cell predominance
with hypoglycorrhachia over time. Commercial kits for detecting M.
tuberculosis in respiratory specimens by means of amplification technol-
ogy (see Table 249.1) can also be used on CSF. Overall, the sensitivity
of PCR assay for examination of the CSF is low. The CSF is often culture
negative for M. tuberculosis, but the CSF PCR assay has been reported
to be positive in roughly 60% to 90% of CSF samples that eventually
are culture positive.412,413 Results of testing CSF with the Xpert MTB/
RIF Ultra assay were positive in 16 of 23 cases of proven or probable
tuberculous meningitis, making this the preferred rapid test for this
infection.414
In patients with meningitis, CT or MRI may reveal rounded lesions
presumed to be tuberculomas, basilar arachnoiditis, cerebral infarction,
or hydrocephalus (Fig. 249.8). Contrast-enhanced MRI frequently reveals
concomitant spinal cord and radicular involvement (transverse and
longitudinal myelitis, spinal tuberculoma, or abscess and other manifesta-
tions), which may lead to disabling complications.415
Prognosis is influenced by age, duration of symptoms, and neu-
rologic deficits. Mortality is greatest in patients younger than age 5
(20%), in those older than age 50 (60%), or in those in whom illness
has been present for more than 2 months (80%).411 Patients without
neurocognitive impairment, focal neurologic signs, or hydrocephalus
at the start of therapy are likely to recover, whereas approximately
half of patients who are stuporous or have dense paraplegia or
hemiplegia die or recover with severe residual neurologic defects.411
A prognostic score derived from cases in 43 centers in 14 countries
found that altered consciousness, diabetes mellitus, immunosuppression,
neurologic deficits, hydrocephalus, and vasculitis predicted an unfavor-
able outcome in culture-proven tuberculous meningitis.416 Concomitant
HIV infection does not appear to alter the clinical and laboratory
manifestations or the prognosis of tuberculous meningitis, except that
CNS mass lesions are more likely.417

FIG. 249.8  Multiple cerebral cortical densities on computed
tomography scan of a patient with tuberculous meningitis.
Therapy
In the presence of meningeal inflammation, both INH and PZA
reach concentrations in the CSF equaling those in blood. RIF pen-
etrates the blood-brain barrier less well but still adequately. In some
cases, PZA is given beyond the first 2 months of treatment because
of its excellent CNS penetration, although its activity after 2 months
of treatment is unclear. The RIF dose is sometimes increased owing
to its poor CNS penetration, particularly with concomitant admin-
istration of corticosteroids. Otherwise, the dosages are as for pul-
monary TB. A recent study demonstrated that higher-dose RIF
(13 mg/kg IV vs. the standard 10 mg/kg oral), together with INH,
PZA, and corticosteroids, was associated with improved 6-month
survival and neurologic recovery.418 However, a trial of intensification
with high-dose RIF (15 mg/kg/day) and levofloxacin for the first 8
weeks, added to a standard 9-month regimen, in Vietnam failed to
improve survival.419
Most authorities recommend adjunctive corticosteroids in TB
meningitis, particularly stage 2 (objective neurologic findings) and
stage 3 (stupor-coma) patients, beginning prednisone at 60 to 80 mg
daily. This may be gradually reduced after 1 to 2 weeks and discon-
tinued by 6 to 8 weeks, as guided by symptoms. Symptoms and CSF
abnormalities may rebound transiently as corticosteroids are tapered.
Ventricular shunting may be beneficial if symptomatic hydrocephalus
supervenes.
Tuberculomas
Intracranial tuberculomas are space-occupying lesions that may manifest
as seizures. They are most frequently multiple, appearing on imaging
studies as avascular masses with surrounding edema. Corticosteroids
reduce edema and decrease symptoms, and chemotherapy prevents
spread of infection in cases diagnosed at operation.
Tuberculous Spinal Meningitis
Infrequently, TB causes spinal meningitis with or without intracranial
involvement. In advanced cases, the cord may be completely encased
in a gelatinous exudate. An intramedullary tuberculoma or an
extradural granulomatous mass can cause symptoms without men-
ingeal involvement. Nerve root or cord compression causes pain,
bladder or rectal sphincter weakness, hypesthesia, anesthesia, pares-
thesias in the distribution of a nerve root, or paralysis. Subarachnoid
block may cause CSF protein concentrations to be extremely high,
with or without cells.
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3013
Tuberculous Pleurisy (Serofibrinous
Pleurisy With Effusion)
Types of Tuberculous Pleurisy
Early Postprimary Pleurisy With Effusion
Chapter 249  Mycobacterium tuberculosis
When infection occurs early in life, tuberculous pleurisy with effusion
follows the primary infection within weeks or months. The pathogenesis
is rupture of a large subpleural component of the primary infection
and delivery of infectious, antigenic material into the pleural space,
with inflammation and seeding of foci over the visceral and parietal
pleura. In the past, this affected mostly adolescents and young adults
and, rarely, older adults. Immediate prognosis was excellent, with resolu-
tion of the effusion within several months in as many as 90% of cases.
However, studies of soldiers during World War II (before chemotherapy)
demonstrated that 65% relapsed with chronic organ TB within 5 years.420
Early postprimary serofibrinous pleurisy with effusion identifies
quantitatively large primary infections with a relatively poor long-term
prognosis.
Pleurisy With Effusion Complicating Chronic
Pulmonary Tuberculosis
In contrast to early studies,420 an increased proportion of pleurisy with
effusion since the early 1980s occurs in older individuals with chronic
pulmonary TB, often with complicating illnesses such as cirrhosis or
congestive heart failure to which the effusion is mistakenly attributed.
In one study, one half of pleurisy cases occurred in the setting of
established chronic pulmonary TB.421
Pleurisy With Effusion Complicating
Miliary Tuberculosis
Pleural effusions occur in 10% to 30% of cases of miliary TB.400,402 These
may be associated with other progressive extrapulmonary foci and
involvement of other serous membranes. Cases with coexistent pleural
(at times bilateral), peritoneal, and pericardial TB have been referred
to as tuberculous polyserositis.
Clinical Manifestations and Diagnosis
The clinical presentation may be low grade and subtle or abrupt and
severe, easily confused with acute bacterial pneumonia. Cough and
pleuritic chest pain are usual, and fever may be high. The effusion is
usually less than massive and almost always unilateral except when
associated with miliary TB. The pleural fluid typically contains 500 to
2500 white blood cells/mm3, with more than 90% lymphocytes in
two-thirds of cases. However, 38% of cases in one series had predomi-
nantly neutrophils and 15% had more than 90% neutrophils on the
first tap.422 Repeated taps demonstrate a shift to lymphocytic predomi-
nance. Mesothelial cells, characteristic of neoplastic effusions, are sparse
or absent, eosinophils are rarely present, and less than 10% of effusions
are serosanguineous. The pleural fluid protein level usually exceeds
2.5 g/dL, the glucose concentration is usually moderately low compared
with serum values but rarely less than 20 mg/dL, and the pH is almost
always 7.3 or lower and may be as low as 7.0. Increased pleural fluid
adenosine deaminase levels have been suggested to be highly sensitive
and specific for tuberculous pleuritis.423,424 High pleural fluid adenosine
deaminase levels with other conditions (e.g., neoplasia) limit its diagnostic
utility in countries with a low prevalence of TB,425 although levels with
such conditions infrequently exceed the suggested cutoff for TB.426,427
A significant negative association of age and pleural fluid adenosine
deaminase suggests the need for a lower cutoff in patients older than
45 years, to decrease false-negative results.428 Bloody pleural fluid suggests
either TB or malignancy. In the usual case of early postprimary pleurisy
with effusion, the acid-fast stain of the fluid sediment is seldom positive,
the culture is positive in 25% to 30%, pleural needle biopsy yields
granulomas in 75%, and culture of a needle biopsy specimen may be
positive even in the 25% of cases with nonspecific pleuritis on histologic
examination. Cases complicating chronic pulmonary TB more often
have positive pleural acid-fast smears (50%) and positive cultures (60%)
but are less likely (25%) to demonstrate granulomas on pleural biopsy.
Repeat pleural biopsy may be necessary to establish the diagnosis, and
a small open pleural biopsy or thoracoscopy is diagnostic in virtually
all cases. Smears of sputum or gastric fluid are rarely positive in early
 3014
postprimary cases, and cultures are positive in 25% to 33%. In contrast,
sputum smear is positive in 50% and the culture is positive in 60% of
“reactivation” cases.421 TB is often not considered as the cause of a
pleural effusion in an older person with complicating illnesses such as
Part III  Infectious Diseases and Their Etiologic Agents
cirrhosis or congestive heart failure.422 When pleural effusion complicates
miliary TB, findings associated with the latter condition usually dominate
the clinical picture.
Therapy
Early postprimary pleural effusions spontaneously resolve in 2 to 4
months. Chemotherapy does not hasten resolution but prevents active
disease elsewhere in the body, which will otherwise occur in 65% of
cases.420 Therapy is as described for pulmonary TB. Multiple thora-
centeses are not necessary once the diagnosis is established and
treatment initiated. A small minority heals with pleural fibrosis.
Corticosteroid therapy hastens symptomatic improvement and fluid
resorption, but no long-term benefit has been shown and therefore it
is not recommended.
Tuberculous Empyema and
Bronchopleural Fistula
Tuberculous empyema occurs when a major cavity ruptures into
the pleural space. This often catastrophic illness is usually associated
with bronchopleural fistula formation and frank pus. Before anti-
tuberculous drugs were available, tuberculous empyema was almost
always rapidly fatal. It virtually never occurs in patients being treated
with chemotherapy.
Tuberculous Pericarditis
Tuberculous pericarditis is most often caused by extension from a
contiguous focus of infection, usually mediastinal or hilar nodes but
also the lung, spine, or sternum. Less commonly, it occurs during miliary
TB. It sometimes develops during the course of otherwise effective drug
therapy. In the United States, tuberculous pericarditis is an uncommon
complication of AIDS; but in two series from sub-Saharan Africa, the
vast majority of effusive pericarditis cases were tuberculous and almost
all patients were HIV positive.429,430
Clinical Manifestations and Diagnosis
The onset may be abrupt, resembling acute idiopathic pericarditis, or
insidious, resembling congestive heart failure. Symptoms of infection
or cardiovascular compromise may be present. Individual cases may
manifest as chronic constrictive pericarditis and may be mistaken for
cirrhosis with ascites. As many as 39% of patients also have a pleural
effusion, providing a convenient source for diagnostic fluid and
tissue.431,432 Echocardiography demonstrates effusion when present and
may reveal multiple loculations suggestive of TB.
Pericarditis with effusion is usually quickly diagnosed based on
physical findings and radiologic examination, but establishing that it
is tuberculous in nature is often difficult. The TST result may be negative,
and evidence of extrapericardial TB lacking. In areas of high endemicity,
a presumptive diagnosis is often correctly made.431,432 In the United
States, however, many cases are initially misdiagnosed as idiopathic,
uremic, or rheumatoid pericarditis.433
Pericardiocentesis (ideally performed in a cardiac catheterization
laboratory) is indicated for hemodynamic compromise. However,
because pericardiocentesis carries risk, and because 90% of acute
pericarditis in the United States is idiopathic (presumed viral) and
subsides spontaneously in 2 to 3 weeks, some authorities advise
against early pericardiocentesis. If improvement has not occurred
by that time, a subxiphoid pericardial window can be performed.
This provides both fluid and tissue for diagnosis, although in some
cases the biopsy demonstrates only nonspecific inflammation.431,432
Tuberculous pericardial fluid demonstrates many of the characteristics
of tuberculous pleural fluid, with acid-fast smears being rarely positive
and cultures being positive in approximately 50% of cases. Bloody
fluid suggests either TB or malignancy. The usefulness of adenosine
deaminase determinations on pericardial fluid is not certain,
but PCR assay for M. tuberculosis may be diagnostic, although
sensitivity is low.
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Therapy
Antibiotic treatment is the same as for pulmonary TB. In a large study
from South Africa from the 1980s, treatment with corticosteroids (60 mg/
day for 4 weeks, 30 mg/day for 4 weeks, and 15 mg/day for 2 weeks)
decreased mortality from 11% in controls to 4% in treated patients.
Pericardiectomies were also less frequently necessary in patients given
corticosteroids (30% in controls vs. 11% in corticosteroid-treated
patients). However, a larger comparative trial of immunotherapy with
either Mycobacterium indicus pranii (1250 patients) or prednisolone
(1400 patients), for definite or probable tuberculous pericarditis, failed
to demonstrate a significant effect on a composite score of death, cardiac
tamponade requiring pericardiocentesis, or constrictive pericarditis.434
The incidence of constrictive pericarditis and hospitalization was
decreased in prednisolone-treated patients, and rates of adverse events,
especially cancer, were elevated in HIV-infected patients. Because the
size of this study was much larger than that in previous reports, current
recommendations for the use of adjunctive corticosteroids in the
management of tuberculous pericarditis have been revised: They should
not be routinely used.239 However, selective use of corticosteroids in
persons at the highest risk of inflammatory complications should be
considered. Surgical drainage via a subxiphoid pericardial window at
the outset did not decrease either mortality or the eventual need for
pericardiectomy, although it provided diagnostic tissue and obviated
the need for recurrent pericardiocenteses. However, 2% surgical mortality
was associated with the procedure.431,435
When hemodynamic compromise persists for 6 to 8 weeks, peri-
cardiectomy is usually indicated, and this should probably be performed
earlier rather than later. Approximately two-thirds of patients, however,
do well without surgery.
Skeletal Tuberculosis: Pott Disease
(Tuberculous Spondylitis)
One-third of cases of skeletal TB involve the spine, as a result of past
hematogenous foci, contiguous disease, or lymphatic spread from pleural
disease. The earliest focus is the anterior superior or inferior angle of
the vertebral body. This usually spreads to the intervertebral disk and
adjacent vertebra, producing the classic radiographic picture of anterior
wedging of two adjacent vertebral bodies with destruction of the
intervening disk and the physical finding of a tender spine prominence
or gibbus. The lower thoracic spine is involved most frequently, followed
by the lumbar spine (Fig. 249.9).
In endemic countries, Pott disease usually occurs in older children
and young adults, but in developed countries it has become a disease
of older persons.436 In a country such as Denmark, with large immigrant
populations from endemic areas, spinal TB accounted for more than
half of bone and joint disease and was mainly seen in younger immi-
grants.437 Evidence of other foci of TB and systemic symptoms are often
absent, early complaints may be back pain or stiffness with an initially
normal radiograph, and diagnosis may be delayed until signs of advanced
disease such as paralysis, deformity, or sinus formation develop. Bacilli
are sparse, and smear and culture of pus or tissue are positive in only
one-half of cases. Histologic studies reveal granulomas with or without
caseation in three-fourths of cases.
Clinical Manifestations
Abscess and Sinus Formation
Paraspinal cold abscesses develop in 50% or more, in some cases
appearing after treatment has been initiated, and in some cases visible
only with CT or MRI. The pus, confined by tight ligamentous investments,
can dissect along tissue planes for long distances to present as a mass
or a draining sinus in the supraclavicular space, above the posterior
iliac crest in the Petit triangle, or in the groin, the buttock, or even the
popliteal fossa. The abscess can spread infection to distant vertebral
bodies, sometimes without affecting the intervening vertebrae. Epidural
or psoas abscess can also complicate tuberculous spondylitis.
Spinal Tuberculosis Without Bony Involvement on
Plain Films
In high TB/HIV prevalence settings, radiculomyelitis may be a common
manifestation of spinal TB, and often manifests as a paradoxical reaction.
 3015

TABLE 249.11  Clinical Manifestations of Renal

Tuberculosis in Two Series of Patients
STUDY

Chapter 249  Mycobacterium tuberculosis

SIMON
FACTOR OR FINDING ET AL.445 CHRISTENSEN446
No. of patients 102 78
Primarily genitourinary symptoms 61% 71%
Back and flank pain 27% 10%
Dysuria, frequency 31% 34%
Constitutional symptoms 33% 14%
Abnormal urine, no symptoms 5% 20%
Abnormal urinalysis 66% 93%
Abnormal intravenous pyelogram 68% 93%
Tuberculin positive 88% 95%
Abnormal chest radiograph 75% 66%
Active pulmonary tuberculosis 38% 7%
Other old or active 5% 20%
extrapulmonary disease
Urine culture positive
FIG. 249.9  Magnetic resonance image showing extensive destruction
of L1 and L2 vertebral bodies and the intervening disk with posterior   For tuberculosis 80% 90%
extension in a Pakistani man with Pott disease.   For routine pathogens 45% 12%
Epididymitis, orchitis 19% 17%
Among 274 mostly HIV-positive South African patients who were Chronic prostatitis 6% 6%
referred to a center for patients with spinal disease but without bony
involvement on plain films, MRI imaging revealed radiculomyelitis in
76%, spondylitis in 39%, subdural abscess in 15%, and intramedullary
tuberculoma in 12%.438 thickening, and eventually destruction of cartilage and bone. Cold
abscesses and draining sinuses often develop in chronic cases.
Pott Paraplegia In the absence of coexistent extraarticular TB, diagnosis almost
In approximately half of cases, weakness or paralysis of the lower always requires biopsy. Histologic features compatible with TB warrant
extremities is present or develops after treatment has begun, perhaps chemotherapy, although other chronic infections (fungi, nontuberculous
owing to arachnoiditis and vasculitis.436 Less frequently, it will be due mycobacteria) can cause identical clinical and histologic pictures. For
to compression of the cord by an inflammatory mass or rarely pressure early cases, prolonged chemotherapy results in complete resolution.
in the abscess producing ischemic changes in the subjacent cord. Surgery is necessary only when serious joint instability requires fusion,
Inflammatory thrombosis of the anterior spinal artery can occur, and and then only after chemotherapy has failed.
sudden cord compression may result from marked spinal instability. Tuberculous osteomyelitis can affect any bone, including the ribs,
skull, phalanx, pelvis, and long bones.443 Other causes of osteomyelitis
Therapy of the rib are rare, and TB is the most common infectious cause of
A 6- to 9-month course of therapy that contains INH and RIF is at least single or multiple osteomyelitic rib lesions. Tuberculous osteomyelitis
as effective as 18-month regimens that include INH plus PAS and outside the vertebral body manifests as a cold abscess, with swelling
EMB.439,440 Adjunctive surgical débridement or resection of the involved and only modest erythema or pain.
bone plus bone grafting did not improve outcome compared with
antituberculosis therapy alone. Thus, current recommendations are to Genitourinary Tuberculosis:
treat spinal TB with a 6- to 9-month regimen that includes INH and Renal Tuberculosis
RIF, with PZA and EMB for the first 2 months.239 Surgical intervention Asymptomatic renal cortical foci may occur during all forms of TB.
may be necessary in patients who do not respond to therapy or those An autopsy study of pulmonary TB revealed unsuspected renal foci in
with cord compression with neurologic deficits or spine instability. 73% of cases, usually bilateral; in 25% of miliary cases, patients have
positive urine cultures.444 Cortical foci tend to be stable unless they
Peripheral Osteoarticular Tuberculosis penetrate to the medulla, where local factors favor accelerated infection.
Older reports described peripheral tuberculous arthritis as a chronic, Most patients have evidence of concomitant extragenitourinary disease,
slowly progressive monoarthritis in 90% of cases,441 often without systemic usually pulmonary and most frequently inactive. In normal hosts, the
symptoms or extraskeletal TB, and most frequently in the hip or knee. interval between infection and active renal disease is usually years and
A history of trauma was common, followed weeks or months later by sometimes decades. Local symptoms predominate, and advanced tissue
indolent progressive inflammation. More recent reports suggest a shift destruction may occur long before the diagnosis is made.
to an older population with a different clinical picture, including more The clinical manifestations in two large series of cases are presented
systemic symptoms, multiple joint involvement, and periarticular abscess in Table 249.11.445,446 Although sterile pyuria is typical of renal TB,
formation.442 Tenosynovitis of the hand, arthritis of the wrist, and carpal positive cultures for routine bacterial pathogens may lead to misdiagnosis,
tunnel syndrome can be caused by TB. Clinical confusion occurs when sometimes for years. The contrast-enhanced abdominal CT is usually
TB superinfects joints previously involved with other arthritides. abnormal. Early findings are nonspecific, but later changes may be more
The earliest manifestation of tuberculous arthritis is pain, which suggestive, including papillary necrosis, ureteral strictures, “pipestem”
may precede signs of inflammation and radiographic changes by weeks changes, “corkscrewing,” “beading,” hydronephrosis, gross parenchymal
or months. Radiographs initially may show soft tissue swelling but later cavitation, and autonephrectomy. Focal calcification is particularly
demonstrate osteopenia, periarticular bony destruction, periosteal suggestive. The clinical disease is usually unilateral, although microscopic

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 3016
changes are probably always bilateral. Culture of three morning urine
specimens for mycobacteria establishes the diagnosis in 80% to 90% of
cases. When a renal abnormality is present but urine cultures are negative,
cytologic studies and culture of material obtained by fine-needle biopsy
Part III  Infectious Diseases and Their Etiologic Agents
may be diagnostic. Ureteral cicatrization and obstruction may occur
after otherwise effective chemotherapy, but surgery is rarely required.
Hypertension is not a feature of renal TB, and renal function is
usually preserved. However, a rare condition called tuberculous interstitial
nephritis may cause renal failure.447 It is characterized by interstitial
granulomas and normal-sized kidneys, usually in the presence of active
extrarenal TB. AFB have been seen but not cultured from renal biopsy
specimens, and renal dysfunction responds to corticosteroid therapy
but not antituberculous chemotherapy alone. It is unclear that tuberculous
interstitial nephritis is actually caused by tuberculous infection.
Male Genital Tuberculosis
Eighty percent of male genital TB is associated with coexistent renal
disease, and most advanced renal TB is associated with some male
genital focus.448 Spread of infection from renal foci involves the prostate,
seminal vesicles, epididymis, and testis, in that order. The usual clinical
finding is a scrotal mass that may be tender or associated with a draining
sinus. Calcified foci may form within the prostate during treatment of
prostatic TB. Genital foci not associated with renal disease can be
established by lymphohematogenous spread and usually present as a
painful testicular or scrotal mass. Diagnosis may be suggested by the
presence of epididymal or prostatic calcification, although the latter
also occurs with nontuberculous chronic prostatitis. The diagnosis is
usually established by biopsy, and response to chemotherapy is
excellent.
Genitourinary Tuberculosis in AIDS
In a study of 79 HIV-positive patients with TB, 77% had positive urine
cultures, usually as an incidental finding. Only two had male genital
involvement, none had symptoms of renal disease, and in only 4% was
the genitourinary tract the only apparent site of TB.409
Female Genital Tuberculosis
Female genital TB begins with a hematogenous focus in the endosalpinx,
from which it may spread to the endometrium (50%), ovaries (30%),
cervix (10%), and vagina (1%).449 In the cervix, a granulomatous ulcerat-
ing mass may resemble carcinoma. Common complaints are infertility
or local symptoms consisting of menstrual disorders and abdominal
pain. The clinical picture may suggest pelvic inflammatory disease that
is unresponsive to therapy. Spread to the peritoneum may also occur.
Systemic symptoms are uncommon, and evidence of old TB need not
be present. Pregnancies that occur in the presence of pelvic TB are
often ectopic. Although cultures of menstrual blood or endometrial
scrapings may be positive, the diagnosis is usually made by examination
of tissue removed at operation. Response to chemotherapy is excellent,
and surgery is needed only for residual large tubo-ovarian abscesses.
Gastrointestinal Tuberculosis
Before effective chemotherapy was available, 70% of patients with
advanced pulmonary disease acquired gastrointestinal TB from swal-
lowing infectious secretions and usually developed diarrhea and
abdominal pain. Although most cases at present are likely due to
swallowed respiratory secretions, radiographic evidence of pulmonary
TB is less frequent, the diagnosis being made unexpectedly with surgery
or endoscopy.450
Any location from mouth to anus can be involved. Nonhealing ulcers
of the tongue or oropharynx and nonhealing sockets after tooth extraction
may be due to TB. Esophageal disease is most frequently caused by an
adjacent caseous node, which leads to stricture with obstruction or
tracheoesophageal fistula formation and rarely to fatal hematemesis
from an aortoesophageal fistula. Stomach involvement may be ulcerative
or hyperplastic and may cause gastric outlet obstruction. Isolated
duodenal disease can produce symptoms of peptic ulcer or obstruction.
Small bowel involvement may lead to perforation, obstruction, entero-
enteric and enterocutaneous fistulas, massive hemorrhage, and severe
malabsorption. Small bowel lesions are frequently multiple. The ileocecal
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area is the most typical site of enteric TB, producing pain, anorexia,
diarrhea, obstruction, hemorrhage that may be severe, and often a
palpable mass. Clinical, radiographic, endoscopic, and even operative
findings may suggest carcinoma. A successful diagnosis is usually made
by means of colonoscopy. In a study of 50 cases, ileocecal involvement
with or without involvement of other areas was found in 35 cases,
isolated segmental colonic disease was found in 13 cases, and pancolitis
was initially misdiagnosed as ulcerative colitis in 2 cases. Evidence of
pulmonary TB was present in only 18 cases.451 The response of
gastrointestinal TB to chemotherapy is excellent. Once the diagnosis
is established, surgery should be deferred if possible until the results
of chemotherapy have been assessed.
Pancreatic TB may manifest as an abscess or as a mass involving
local nodes and resembling carcinoma. The biliary tract may be obstructed
by tuberculous nodes, and tuberculous ascending cholangitis has been
described. TB is a frequent cause of granulomatous hepatitis. This is
usually asymptomatic but may be associated with an increased alkaline
phosphatase level that is out of proportion to bilirubin levels with normal
aminotransferase levels. Very rarely, tuberculous granulomatous hepatitis
causes jaundice without evidence of extrahepatic TB. This is called
primary tuberculosis of the liver. Focal hepatic tuberculosis describes
single or multiple tuberculous abscesses. These appear to occur most
frequently in racial groups with little natural immunity to TB and in
children.452
Gastrointestinal Tuberculosis in AIDS
Bowel involvement is not a common feature of extrapulmonary TB in
AIDS patients. One series reported bowel fistulas in less than 4% of
such cases,409 another reported CT evidence of gastrointestinal abnormali-
ties in 4 of 23 cases,453 and a third study noted positive stool cultures
for M. tuberculosis in 4 of 10 cases.454 Tuberculous visceral abscesses,
including hepatic, splenic, and pancreatic, may occur in AIDS patients.
Pain and fever are usually present. Diagnosis is often made by means
of CT or ultrasonographically guided drainage procedures. Chemotherapy
alone has not been effective in all cases.410
Tuberculous Peritonitis
Tuberculous peritonitis results either from spread of adjacent tuberculous
disease such as an abdominal lymph node, intestinal focus, or fallopian
tube, or during miliary TB. In a summary of 11 series, evidence of
associated pleuropulmonary TB was present in 25% to 83% of cases
and the TST result was positive in 30% to 100% of cases.455 Pleural
effusion is the most frequent associated finding, but evidence of TB in
other sites is often present. AIDS patients do not have an increased
frequency of peritonitis.409
The clinical picture has been divided into plastic and serous types.
The less common plastic type is characterized by tender abdominal
masses and a “doughy abdomen.” Serous effusions present as ascites
with or without signs of peritonitis. Symptoms of fever, abdominal pain,
and weight loss are common.455 The onset may be insidious, although
acute presentations resembling bacterial peritonitis also occur. In the
past, diagnosis was often made at surgery for a mass or an acute
abdominal condition. Tuberculous peritonitis often goes undiagnosed
in patients with concomitant cirrhosis with ascites.456 Of 20 patients
with both conditions, the diagnosis of tuberculous peritonitis was
suspected before death in only 11. Tuberculous peritonitis has been
reported in peritoneal dialysis patients with the clinical picture of bacterial
peritonitis unresponsive to routine antibiotics.457
The peritoneal fluid is exudative, usually containing 500 to 2000
cells. Lymphocytes typically predominate, although in some cases
neutrophils are more abundant early in the process. Acid-fast smear of
peritoneal fluid is seldom positive, and culture is positive in only 25%
of cases. An increased adenosine deaminase level in ascitic fluid has
been reported to have high sensitivity and specificity,458 although among
140 patients in India the positive predictive value was only 25%.459
Analysis of peritoneal fluid with PCR, such as the Xpert MTB/RIF
or Xpert MTB/RIF Ultra assay, may provide rapid diagnosis. In the
absence of other foci of TB, peritoneal tissue may need to be obtained
in order to make the diagnosis. Histologic examination of peritoneal
biopsy specimens obtained with a Cope needle were positive in 64%

of cases and those obtained by peritoneoscopy in 85% in one series.460
Fatal hemorrhages after both Cope needle biopsy and peritoneoscopy
have been recorded.455
Treatment is the same as for pulmonary TB. There is some evidence
that adjunctive corticosteroids decrease the likelihood of late intestinal
obstruction,460 but pending definitive studies, the routine use of adjunctive
corticosteroids cannot be recommended.461
Tuberculous Lymphadenitis (Scrofula):
Peripheral Nodes
Lymphadenitis is the most frequent form of extrapulmonary TB. In
HIV-negative persons, it is usually unilateral and cervical in loca-
tion.462 The most common site is along the upper border of the
sternocleidomastoid muscle, where it presents as a painless, red, firm
mass. It is seen most frequently in young adult females of non-
European ancestry, although it can affect any age or race. Children
often have an ongoing primary infection, but in other age groups
evidence of extranodal TB and systemic symptoms are usually absent.
Lymphadenopathy outside the cervical and supraclavicular area
indicates more serious TB, usually with systemic symptoms. The
TST result is almost always positive. Fine-needle aspiration demon-
strates cytologic evidence of granuloma, but smears or cultures are
usually negative.463 Biopsy with culture is often required for diagnosis,
because nodes with a nonspecific histologic appearance have been
positive for M. tuberculosis on culture, and material with typical
histologic features may be due to other mycobacteria or fungi.
Complete excision of involved nodes with no drain left in place is
recommended in order to diminish the possibility of postoperative
fistula formation. Untoward events such as node enlargement with
pain, suppuration, sinus formation, and appearance of new nodes
occur in 25% to 30% of cases, both during and after chemotherapy,
and do not indicate failure of drug treatment. These likely represent
reactions to retained tuberculous antigens rather than uncontrolled
infection; they usually subside spontaneously, and short courses of
corticosteroids may be beneficial when the problem persists.464
Conversely, in individuals with AIDS, peripheral tuberculous
lymphadenitis is almost always multifocal and associated with major
systemic symptoms such as fever, weight loss, and evidence of TB in
the lungs (parenchyma, nodes, or pleura) or elsewhere (Fig. 249.10).463
In an early series from New York City, TB caused 57% of generalized
lymphadenopathy in HIV-positive injection drug users.465 In contrast
to non–HIV-infected persons, material removed with fine-needle
aspiration is positive on acid-fast stain in the great majority of cases—as
frequently as it is with culture. However, both cytologic and histologic
findings are less specific than in HIV-negative persons.466
Mediastinal Tuberculous
Lymphadenopathy
Mediastinal adenopathy during primary infection is often visible
radiographically, especially in children. In African Americans, mediastinal
adenopathy resulting from TB may also be seen in young adults, and
cases in very old persons have been reported.467 Associated systemic
symptoms may or may not be present, causing confusion with other
mediastinal masses such as histoplasmosis, lymphoma, and carcinoma.
The finding of low-density areas in the nodes on CT scan suggests TB,
but diagnosis usually requires mediastinoscopy. In HIV-infected persons
with TB, in contrast, mediastinal lymphadenopathy is frequent. Multiple
nodes are usually involved, coalescing into large mediastinal masses
with low-density centers, peripheral contrast enhancement, and no
calcification.468,469
Fibrosing Mediastinitis
TB can cause fibrosing mediastinitis, although less commonly than
histoplasmosis. Patients present with dyspnea on exertion resulting from
compression of pulmonary veins and arteries or, less commonly, superior
vena cava syndrome. Hilar adenopathy or active pulmonary disease is
rarely found. A perfusion lung scan helps define the extent of pulmonary
vascular compression, but thoracotomy is required for diagnosis.
Mediastinoscopy is either contraindicated because of superior vena cava
syndrome or unsuccessful because of fibrosis.
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3017
Chapter 249  Mycobacterium tuberculosis
FIG. 249.10  Axillary lymphadenitis caused by Mycobacterium
tuberculosis in a patient with acquired immunodeficiency syndrome.
Mesenteric Tuberculous Lymphadenitis
In HIV-negative persons, isolated symptomatic mesenteric lymphadenitis
without bowel disease or peritonitis is rare. It may cause abdominal
pain, fever, a palpable mass, or symptoms of partial small bowel obstruc-
tion. In AIDS patients with TB, abdominal lymphadenopathy is common
and may be massive.469,470 Involvement is more often intraabdominal
than retroperitoneal, and occasionally obstruction of the biliary tract,
ureters, or bowel is observed. As with thoracic disease, the nodes often
are low density or have low-density centers and peripheral enhancement.
Other abnormalities on CT may include abscesses in the liver, spleen,
pancreas, or kidney; local ileal thickening; extraluminal bowel gas
indicating fistula formation; and ascites.
Cutaneous Tuberculosis
In the past, a number of cutaneous conditions were associated with TB
elsewhere in the body, although M. tuberculosis could not be identified
in the lesions. These have been considered allergic reactions to the
infection and termed tuberculids. They include erythema induratum of
Bazin, papulonecrotic tuberculids, and others. This association has been
questioned, and some have attributed tuberculids to other processes,
such as sarcoidosis.471 M. tuberculosis DNA has been detected in erythema
induratum skin lesions with PCR.472 Erythema nodosum has been
attributed to primary TB, although organisms cannot be cultured from
the lesions.
The pathogenesis of cutaneous involvement in TB is varied. Skin
involvement may result from exogenous inoculation (which in the
previously nonsensitized host is associated with regional lymphadenitis).
TB verrucosa cutis, arising from direct inoculation, has also been called
prosector’s wart, referring to inoculation of a hand at time of autopsy
of a patient with TB. Infection may also spread from an adjacent focus
to the overlying skin (as from lymphadenitis, osteomyelitis, or epididy-
mitis), and hematogenous spread from a distant focus or as a part of
the generalized hematogenous dissemination. This last is seen in patients
with AIDS and tuberculous bacteremia.473 The clinical picture of all
cutaneous mycobacterial infections, including TB, is highly variable,
and any unexplained skin lesion, especially if it has nodular or ulcerative
components, may be due to TB, particularly in AIDS patients.
Tuberculous Laryngitis
In the prechemotherapy era, laryngeal TB occurred in more than a
third of patients dying of pulmonary TB, often associated with painful
ulcers of the epiglottis, pharynx, tonsils, and mouth, and with middle
 3018
ear involvement. Laryngeal disease was highly infectious and often
caused terminal widespread bronchogenic dissemination throughout
the lungs. At present, however, more than one-half of laryngeal TB
cases are due to hematogenous seeding. Such cases are still highly
Part III  Infectious Diseases and Their Etiologic Agents
animals may be infected. In developing countries, infection is acquired
from close contact with infected cattle or ingestion of infected dairy
products.481,482 From 2006 to 2013, M. bovis caused approximately
1% of TB cases in the United States, with higher prevalence among

contagious. Lesions vary from erythema to ulceration and exophytic
masses resembling carcinoma.474 Symptoms include cough, wheezing,
hemoptysis, dysphagia, odynophagia, and otalgia.
Tuberculous Otitis
Tuberculous otitis media is rare and frequently misdiagnosed. Half of
the cases have no other evidence of present or past TB. The classic
clinical picture is painless otorrhea with multiple tympanic perforations,
exuberant granulation tissue, early severe hearing loss, and mastoid
bone necrosis. The diagnosis has been missed for years by excellent
otolaryngologists, even when tissue was available. Tuberculous otitis
may be complicated by facial nerve paralysis. Response to drug therapy
is excellent, and surgery is usually not required.475
Miscellaneous Conditions
TB of the aorta with or without aneurysm formation can be caused by
spread from contiguous diseased nodes, pericarditis, spondylitis,
paravertebral abscesses, or empyema. Extensive hematogenous dis-
semination or aortic rupture may occur. TB produces various ocular
syndromes, including choroidal tubercles, uveitis, iritis, and episcleritis
(see Chapter 115). An interesting observation has been made in patients
with uveitis (most suggestive of sarcoidosis) who had positive interferon-γ
release assays to TB. Fifteen of the 20 patients had lived in an area
endemic for TB before moving to the Netherlands. Despite the absence
of documented tuberculous infection elsewhere in the body, antituber-
culosis therapy was associated with remission in 91% of those treated.476
During disseminated TB in areas of high TB prevalence, choroidal TB
(usually without symptoms) may occur in 5% to 20% of patients.477 TB
may also involve the breast, producing abscesses, sclerosing lesions
resembling carcinoma, and multiple nodules. Destructive nasal lesions
resembling Wegener granulomatosis both clinically and histologically
have been caused by TB.478 TB of the adrenal glands may cause adrenal
enlargement with or without calcification, as may histoplasmosis, but
granulomatous adrenal TB may cause Addison disease without either
calcification or adrenal enlargement.479
Mycobacterium bovis and Bacillus
Calmette-Guérin
M. bovis is a member of the M. tuberculosis complex. Isolation requires
that decontamination and culture procedures used for TB be optimized.
Sodium pyruvate is often substituted for glycerol in the culture medium.
M. bovis may be mistaken as M. tuberculosis clinically, but molecular
methods including WGS can distinguish the two. The BCG strain of
M. bovis is used to vaccinate against TB. BCG Tice and BCG Connaught
are the most widely used strains in North America and Europe, but
very many other strains have been used to treat bladder cancer.480
Unlike M. tuberculosis, M. bovis largely infects humans as a zoonosis.
Cattle are the primary reservoir, but a large variety of warm-blooded
infants and children, foreign-born patients, Hispanics, females, and
persons living near the Mexican border.480 M. bovis infection may also
complicate intravesicular BCG administered to treat intraepithelial
bladder cancer.483,484
Intravesicular BCG is given as a series of bladder injections through
a catheter, with each instillation containing as many as 8 × 108 bacilli.
Symptoms of cystitis are common during treatment. Infections within
the genitourinary tract can appear during the following weeks and may
manifest as ulcers, plaques, or nodules in the bladder or urethra.
Epididymo-orchitis or prostatitis may also occur months later. Spread
beyond the urinary tract affects 3% to 7% of recipients.483 A sepsis-like
syndrome after intravesicular BCG manifests as fever, hypotension, and
dyspnea. This can occur in the first few days after injection or appear
with insidious onset of malaise, low-grade fever, weight loss, and dyspnea
many weeks later.485 A miliary pattern may affect the lungs. Granulomas
may be seen in bone marrow, but cultures of blood and bone marrow
are usually negative. Focal lesions can appear weeks or even years after
intravesicular therapy, including thoracolumbar spondylodiscitis,
granulomatous hepatitis, arthritis, uveitis, and mycotic aneurysm.484 In
a series of 20 cases of mycotic aortic aneurysm, the peak incidence was
at 6 weeks after treatment, with declining incidence over 7 years.486 In
another series of mycotic aneurysms after intravesicular BCG, average
time to diagnosis was 19 months.487 Vascular grafts and prosthetic joints
may also become infected. Culture isolation of M. bovis has occurred
in only 41% of reported cases, although PCR may be positive at culture-
negative sites.483 Disruption of mucosal integrity from a recent urologic
procedure or during the bladder treatment is suspected but unproven
as the predisposing factor.483
Treatment largely includes RIF, INH, and EMB for 2 to 3 months,
followed by 6 months of INH and RIF.483,484 Most strains of M. bovis,
including BCG strains, are PZA resistant. Fluoroquinolones have suc-
cessfully replaced INH or RIF in some cases. Results are generally
favorable except with mycotic aneurysm, which has a poor outcome.486,487
Ingestion of M. bovis in unpasteurized dairy products can cause
cervical lymphadenitis.488 Pulmonary M. bovis infection resembles typical
TB and is acquired from exposure to infected animals or, rarely,
humans.489 In North America, reactivation of M. bovis acquired in other
countries may occur. M. bovis accounts for 0.3% of diagnosed pulmonary
TB cases in the Americas.481 Isolates acquired from animals or humans,
and rarely from vaccine, may be resistant to INH or RIF.490
In countries where BCG vaccine is routinely given to children,
unrecognized primary immune deficiencies such as severe combined
immunodeficiency or mutations in the IL-12/interferon-γ axis may
predispose to disseminated M. bovis infection. In this setting, infection
occurs at the injection site, contiguous axillary lymph nodes, and distant
sites including bones. Restoration of immune response by means of
allogeneic hematopoietic stem cell transplantation may be required
for cure.491

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3021
437. Johansen IS, Nielsen SL, Hove M, et al. Characteristics
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476. La Distia Nora R, van Velthoven ME, Ten Dam-van Loon

Chapter 249  Mycobacterium tuberculosis

diagnosis of pleural tuberculosis. Int J Tuberc Lung Dis. 1987;23:1418–1422. NH, et al. Clinical manifestations of patients with
2014;18:1363–1369. 434. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and intraocular inflammation and positive QuantiFERON-TB
431. Strang JIG, Gibson DG, Mitchison DA, et al. Controlled Mycobacterium indicus pranii in tuberculous pericarditis. gold in-tube test in a country nonendemic for
clinical trial of complete open surgical drainage and of N Engl J Med. 2014;371:1121–1130. tuberculosis. Am J Ophthalmol. 2014;157:754–761.

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 3021.e1
UPDATE

Six-Month Treatment of Drug-Resistant Tuberculosis

Chapter 249  Mycobacterium tuberculosis

John E. Bennett, MD neutropenia in 8 and thrombocytopenia in 6. Optic neuritis developed in two
patients. The linezolid dose was reduced or interrupted for up to 35 days in roughly
half the patients because of toxicity. With that intervention, the optic neuritis
March 31, 2020
resolved and peripheral neuropathy improved. Only 37 patients (41%) completed
A three-drug combination treatment (linezolid, bedaquiline, pretomanid) for
26 weeks of linezolid at 1200 mg per day without interruption. Eight patients had
drug-resistant tuberculosis was evaluated in a small open, single group trial of 109
the regimen interrupted for hepatic adverse events, but all resumed and completed
patients in South Africa.1 Fifty-one percent were HIV positive, all receiving antiret-
26 weeks of therapy. How much toxicity was due to pretomanid is unknown.
rovirals during the trial and with an initial CD4 count above 50/mm3. XDR tuberculosis
Despite the absence of any comparison group, this small, controversial study
was diagnosed in 73 patients; 38 had MDR tuberculosis and had failed or could
offers encouragement that XDR and complicated MDR tuberculosis can be treated
not tolerate treatment. A favorable outcome was reported in 89% of the former
for 6 months with an all-oral regimen. The study provided the data the FDA used
and 92% of the latter. Treatment was given for 26 weeks except for two patients
to approve the use of pretomanid in this combination. Ongoing studies will explore
who were given an additional 13 weeks because of positive cultures during treatment.
different doses and duration of linezolid to determine whether the high toxicity
Among the 11 patients who had an unsatisfactory outcome, there were only two
can be reduced and whether the results can be extrapolated beyond South Africa.
relapses during 6 months of follow up. One of the two relapsed patients had
acquired a bedaquiline resistant isolate; the other relapsed patient’s isolate remained
susceptible to all three study drugs. The treatment included a linezolid dose of 600 Reference
mg twice daily or 1200 mg once daily and encountered substantial toxicity. During 1. https://www.ncbi.nlm.nih.gov/pubmed/?term=N+Engl+J+Med.+2020+Mar+5%
treatment, 88 patients (81%) reported peripheral neuropathy and almost half had 3B382(10)%3A893-902.
hematologic toxicity. Anemia was considered treatment related in 38 patients,

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For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 3021.e2
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