Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases

vii.
Mycobacterial Diseases
Mycobacterium tuberculosis
249 Daniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas
SHORT VIEW SUMMARY

Microbiology • TB in advanced AIDS is characterized by Therapy (see Tables 249.7 and 249.8)
• Humans are the only reservoir for middle or lower lung field location, absence of • Multidrug regimens, typically starting with at
Mycobacterium tuberculosis. cavitation, increased extrapulmonary disease, least four active drugs, are recommended for
• The organism is an acid-fast, aerobic bacillus and a negative test for M. tuberculosis initial treatment.
with a high cell wall content of infection (e.g., tuberculin skin test or • At least 6 months of therapy is usually
high-molecular-weight lipids. interferon-γ release assay). required.
• Incomplete necrosis produces cheesy, acellular • INH is the cornerstone of therapy; RIF, the
Tuberculin Skin Testing and Interferon-γ
material (i.e., caseous necrosis). second major antituberculous agent, causes
Release Assays
• Pulmonary cavities contain huge numbers of many drug-drug interactions; 2 months of
• To detect M. tuberculosis infection, a positive
organisms. pyrazinamide is essential for 6-month
tuberculin test is defined by induration.
regimens.
Epidemiology Interpretation depends on the diameter of
• Adjustment of doses of antiretroviral agents
• M. tuberculosis infects one-quarter of the induration.
during treatment of TB with RIF and rifabutin
world’s population, with 10.4 million new • Interferon-γ release assays may be used
is shown in Chapter 39, Tables 39.3 and 39.5.
cases reported each year. instead of skin testing. They are more specific
The time to initiate antiretroviral therapy
• Almost all infections are due to inhalation of for M. tuberculosis than tuberculin skin
during TB treatment is shown in Chapter 39,
droplet nuclei. testing. Results are positive, negative, or
Table 39.2.
• Key determinants of infection are closeness of indeterminate. T-Spot results can also be
• Directly observed therapy is crucial.
contact and infectiousness of the source. borderline.
• Susceptibility testing is important to guide
• The strongest risk factor for progression to • Testing for M. tuberculosis latent infection is
therapy. NAAT and DNA sequencing are
active tuberculosis (TB) is acquired recommended for persons at high risk for
offering more rapid approaches to
immunodeficiency syndrome (AIDS). developing TB if untreated.
susceptibility testing.
• The highest case rates are in countries heavily • Test results (particularly the skin test) are
• With appropriate chemotherapy, patients
affected by human immunodeficiency virus negative in at least 20% of active TB cases.
usually become noninfectious within 2 weeks.
(HIV)/AIDS.
Diagnosis • Treatment of XDR-TB is usually associated
• Drug resistance can be primary or secondary.
• Culture is the gold standard. with poor outcomes.
• Multidrug-resistant tuberculosis (MDR-TB)
• Visible growth takes 3 to 8 weeks on solid • Bedaquiline is an approved drug for MDR-TB.
indicates resistance to both isoniazid (INH)
media, and a mean of 10 days for
and rifampin (RIF). Therapy for Latent Infection
smear-positive and 20 days for smear-negative
• Extensively drug-resistant tuberculosis • Short-course regimens are replacing 9 months
specimens on liquid media.
(XDR-TB), which indicates resistance to INH, of INH for latent infection, particularly in
• An estimated 10,000 organisms per milliliter
RIF, a fluoroquinolone, and a second-line low–TB incidence settings.
are required for sputum smear positivity.
injectable drug, is of immense concern. • Twelve weeks of directly observed,
Nucleic acid amplification testing (NAAT; e.g.,
once-weekly INH plus rifapentine, and 4
Immunology and Pathogenesis Xpert MTB/RIF and Xpert MTB/RIF Ultra) have
months of daily rifampin, are as effective as 9
• Infection requires a cellular immune response. sensitivities and specificities that approach
months of INH.
• Airborne droplet nuclei reach the terminal air those of culture and can be completed in
spaces, where they are ingested by alveolar 1 day. Prevention
macrophages and then carried by lymphatics • The use of three sputum specimens increases • Case finding and treatment comprise the most
to regional lymph nodes. sensitivity. effective method of control of TB.
• Occult preallergic lymphohematogenous • A radiograph showing a patchy or nodular • Hospitalized HIV-positive patients with
dissemination occurs to the lung apices and infiltrate in the lung apices is highly respiratory symptoms should be admitted to
elsewhere. suggestive, especially if the infiltrate is negative-pressure isolation rooms. N95 masks
• Granulomas form when antigen load is small cavitary. are used for health care workers.
and tissue hypersensitivity is high. • Pulmonary TB can occur in persons with • Childhood bacillus Calmette-Guérin
• Age influences likelihood and pattern of normal chest radiographs, particularly in vaccination in high-burden countries decreases
disease. HIV-positive persons with advanced incident TB. Other vaccines are in clinical trial.
immunosuppression.
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2985.e1
Revised March 31, 2020
Chapter 249 Mycobacterium tuberculosis
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The term tuberculosis describes a broad range of clinical illnesses caused With widespread use of second-line agents, selection for M. tuber-
by Mycobacterium tuberculosis (or, less commonly, Mycobacterium bovis). culosis resistant to both first- and second-line drugs was inevitable.
Tuberculosis (TB) is the leading cause of death due to a single infectious Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance
agent worldwide, and ranks ninth among all causes of death. In 2014 to at least INH, RIF, a fluoroquinolone, and a second-line injectable
Part III Infectious Diseases and Their Etiologic Agents
the World Health Assembly embraced a resolution to reduce deaths drug (kanamycin, capreomycin, amikacin), first occurred as early as
from TB by 95% by the year 2035. In 2016 there were an estimated 10.4 2001 in KwaZulu-Natal, South Africa,5,6 and by 2016 it had been reported
million new cases of TB and 1.7 million deaths from TB worldwide.1 in at least 121 countries worldwide.1 Although application of established
TB can affect virtually every organ, most importantly the lungs, and is TB public health principles, supported by ample funding, may ultimately
typically associated with granuloma formation. control this dire situation,7 the immensity of this challenge is daunting.
There are added challenges in reaching vulnerable populations, including
HISTORY those who experience inequality, prejudice, marginalization, and limits
There is evidence of spinal TB in Neolithic, pre-Columbian, and early on their social, economic, cultural, and other rights.8
Egyptian remains. However, TB did not become a major problem until
the Industrial Revolution, when crowded living conditions favored its MICROBIOLOGY
spread. In the 17th and 18th centuries, TB caused one-fourth of all The M. tuberculosis complex comprises at least nine species in the genus
adult deaths in Europe. Before antimicrobial agents became available, Mycobacterium, family Mycobacteriaceae, and order Actinomycetales
the cornerstone of treatment was rest in the open air in specialized that are causes of human TB and zoonotic disease. The M. tuberculosis
sanatoria. Sanatorium regimens probably benefited some patients who complex species share 99.9% sequence identity and likely evolved from
were diagnosed before cavitation but had little impact on cavitary disease. a single clonal ancestor.9 The species M. tuberculosis sensu stricto causes
When it became clear that cavitation was the pivotal event in progressive the vast majority of human TB worldwide. Mycobacterium africanum
pulmonary TB, most special therapies focused on cavity closure. causes human TB in West Africa, where it accounts for up to 50% of
The modern era of TB began in 1946 with demonstration of the cases.10 Mycobacterium canettii is an extremely rare cause of human TB
efficacy of streptomycin (STM). In 1952, the availability of isoniazid in the Horn of Eastern Africa. M. bovis causes disease in cattle and
(INH) made TB curable in most patients, and the addition of rifampin spreads to humans through animal contact and consumption of
(RIF) in 1970 allowed for even more effective combination therapy. unpasteurized milk. An investigation of six TB cases in the United
With drug coverage, it became possible to successfully resect tuberculous Kingdom demonstrated that M. bovis can be transmitted by aerosol
tissue, but with drug treatment, resection was rarely necessary. Bed rest from patients with pulmonary lesions.11 Mycobacterium caprae, another
and collapse therapy added nothing to chemotherapy; treated patients cattle pathogen, Mycobacterium microti, a pathogen for rodents, and
rapidly became noninfectious; and specialized sanatoria ultimately Mycobacterium pinnipedii, a pathogen for seals, have been reported to
disappeared. The duration of chemotherapy progressively decreased cause zoonotic TB in humans. Mycobacterium orygis (antelope) and
from approximately 2 years before the availability of RIF, to 9 months Mycobacterium mungi (mongoose) have been described in animals but
with INH plus RIF, and to 6 months with multidrug therapy including have not been reported in humans.
INH, RIF, and pyrazinamide (PZA). With INH it also became practical Advances in genetic analysis, including whole-genome sequencing
to treat asymptomatic people believed to harbor tubercle bacilli based (WGS), have shed new light on the phylogenetics of the M. tuberculosis
on positive tuberculin test results. complex.12,13 These studies show that M. tuberculosis sensu stricto and
In the United States, reported cases of TB had declined nearly every M. africanum, the predominant causes of human disease, can be further
year since accurate statistics became available. However, in 1985, case divided into seven phylogenetic lineages, L1 to L7. This is a rapidly
rates began increasing, driven largely by human immunodeficiency changing field of study, with multiple nomenclatures in use. For example,
virus (HIV) infection. TB-control programs in some large cities were the L2 lineage is also called the East Asian lineage or the Beijing strain.
not equipped to manage this emerging problem. The often-interrelated There is some evidence that different lineages vary in virulence, host
factors of illicit drug use, homelessness, and HIV infection predispose adaptation, transmissibility, or ability to acquire drug resistance, but
to reactivation of remote TB, to the acquisition and spread of new further research is needed to clarify the clinical importance of such
disease, and, because of irregular adherence to drug therapy, to the differences.
development and spread of drug-resistant strains. Epidemics involving Humans are the only reservoir for the species M. tuberculosis, although
strains that were resistant to at least INH and RIF (i.e., multidrug-resistant many animals are susceptible to infection.14 Some have postulated that
[MDR] strains) emerged in these populations and spread to HIV-negative an ancient ancestor of M. tuberculosis infected hominids in East Africa
persons, including health care workers. Many outbreaks were caused 3 million years ago and has since coevolved with its human host.15 M.
by the Beijing strain, with “strain W” dominating in New York City. tuberculosis is an aerobic, non–spore-forming, nonmotile bacillus with
Estimates based on data from 2006 through 2008 suggest that 80% of a high cell wall content of high-molecular-weight lipids. Growth is slow,
cases in the United States are due to reactivation.2 the generation time being 15 to 20 hours, compared with much less
Treatment programs failed because of drug resistance, medication than 1 hour for most common bacterial pathogens, and visible growth
nonadherence, and nosocomial transmission of M. tuberculosis. Since takes from 3 to 8 weeks on solid media. The organism tends to grow
1992, however, TB incidence rates in the United States have progressively in parallel groups, producing the colony characteristic of serpentine
declined and in 2016 reached the lowest in history.3 This attests to the cording. In radical contrast to other bacteria, a very large portion of
success that can be achieved with intensified diagnostic, treatment, and M. tuberculosis genes encode enzymes involved in lipogenesis and
prevention efforts, and with control of HIV-induced immunocompromise lipolysis.
by means of antiretroviral therapy (ART). A wide spectrum of laboratory techniques has been developed to
The global situation has, unfortunately, not been as successful. The diagnose active TB. No single test is perfect, and, unfortunately, some
HIV pandemic fueled increased TB case rates in resource-limited coun- diagnostics on which clinicians still rely were developed over 100 years
tries worldwide, especially in sub-Saharan Africa. Scant resources and ago. Advantages and limitations of various methods are presented in
fragile infrastructure, together with a high prevalence of HIV infection Table 249.1.
and acquired immunodeficiency syndrome (AIDS), have driven the global
burden of TB. As in the United States, multidrug-resistant tuberculosis Acid-Fast Staining
(MDR-TB) emerged and spread. In response, the World Health Organiza- The term acid-fast bacilli (AFB) is practically synonymous with myco-
tion (WHO) has worked diligently to expand TB treatment services, bacteria, although Nocardia and some other organisms are variably acid
including directly observed therapy, short-course (DOTS) programs. In fast. In the Ziehl-Neelsen stain, a fixed smear covered with carbol-fuchsin
parallel, second-line medications, including fluoroquinolones, were made is heated, rinsed, decolorized with acid-alcohol, and counterstained
increasingly available worldwide. Since 2011, WHO has recommended with methylene blue. The Kinyoun stain is modified to make heating
that MDR-TB be treated using mainly ambulatory care, which appears unnecessary. The organisms appear as slightly bent, beaded rods 2 to
to be more effective than hospitalization.4 4 µm long and 0.2 to 5 µm wide. In sputum they often lie parallel, or
2987
TABLE 249.1 Comparison of Assays Used in the Diagnosis of Active Tuberculosis

CLINICAL LABORATORY
QUESTION DIAGNOSTIC ASSAY ADVANTAGES LIMITATIONS

Are mycobacteria present in a Culture on solid media (Löwenstein- Gold standard for isolating Visible growth takes 3–8 wk
clinical specimen? Jensen egg-based or Middlebrook Mycobacterium tuberculosis; detects
agar-based media) 10–100 organisms/mL; shows colony
morphology, detects mixed infection,
allows quantification of growth;
provides organisms for speciation,
strain identification, susceptibility
testing
Culture in liquid broth 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
Acid-fast stain (Ziehl-Neelsen, Same-day results; simple technology; Less sensitive than culture, requiring
Kinyoun, auramine rhodamine) inexpensive light microscope; 10,000 organisms/mL; cannot
fluorescence microscope required for distinguish M. tuberculosis from
auramine-rhodamine stain other mycobacteria
Nucleic acid amplification (e.g., PCR) 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
Nucleic acid amplification with Sensitivity of Xpert MTB/RIF roughly Expensive equipment; detects dead
GeneXpert MTB/RIF and Xpert 100 CFUs/mL, requires 100 min, bacilli; culture needed for other
MTB/RIF Ultra 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
Urinary antigen detection (e.g., ELISA Point-of-care testing; relatively high Sensitivity very low in situations other
for LAM) sensitivity in advanced untreated than advanced AIDS
AIDS (<50 CD4 T cells/mm3)
Is a mycobacterium isolated Nucleic acid amplification (See above) (See above)
from a clinical specimen a Nucleic acid probes Results available in 2 h; sensitivity and Requires at least 105 organisms; most
member of M. tuberculosis specificity approach 100%; does not useful for pure culture, not directly
complex? (M. tuberculosis, require amplification on clinical specimen; cannot
Mycobacterium bovis, M. distinguish among members of M.
bovis–BCG, Mycobacterium tuberculosis complex
africanum, Mycobacterium BACTEC p-nitroacetyl- Provides preliminary identification of Need for paired cultures increases cost
microti, or Mycobacterium aminohydroxypropiophenone assay M. tuberculosis complex (NAP (growth with and without NAP)
canettii) (NAP) susceptible)
High-performance liquid Same-day results; sensitivity and Requires HPLC technology; only useful
chromatography (HPLC) specificity approach 100%; can with pure culture
distinguish M. bovis BCG from other
members of M. tuberculosis complex
To which species of M. Colony morphology and biochemical Classic approach for speciation of Time-consuming and labor-intensive
tuberculosis complex does a assays (e.g., niacin test, heat- M. tuberculosis
clinical isolate belong? sensitive catalase, nitrate reduction,
pyrazinamide monodrug resistance)
PCR genomic analysis May rapidly distinguish among M. Not yet commercially available for this
tuberculosis complex species purpose
Do different M. tuberculosis Genotyping by restriction fragment The CDC offers free strain typing Sophisticated assay available only at
isolates represent the same length polymorphism analysis, through the National Tuberculosis specialized centers
strain? spoligotyping, mycobacterial Genotyping and Surveillance
interspersed repetitive unit analysis, Network
and whole-genome sequencing
Is an M. tuberculosis isolate Agar proportion method Quantifies the proportion of organisms Requires as long as 8 wk
drug resistant? resistant to a drug
Liquid BACTEC method Results within 5–14 days Does not quantify proportion of
resistance
Molecular line probe assays and Allow same-day determination of drug Need to be validated in multiple
whole-genome sequencing for resistance; line probe assay can be clinical settings and not yet FDA
chromosomal mutations associated performed directly on smear positive approved
with drug resistance (see above for sputum samples or culture isolates;
GeneXpert MTB/RIF) can detect resistance to isoniazid,
rifampin, quinolones, and second
line injectibles
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.
2988
two organisms adhere at one end to form a V. An estimated 10,000 sensitivity and specificity similar to those of commercially available
organisms per milliliter of sputum are required for smear positivity, liquid broth systems.26 Sensitivity is diminished (65.4%) when the source
and detection of at least 10 organisms on a slide is optimal; a single of diagnostic material is not sputum (lymph node sampling).27 An
organism on a slide is highly suggestive. The sensitivity of sputum automated MODS (Auto-MODS) has been compared with conventional
acid-fast bacillus smear when compared with culture is approximately culture in Thailand. With 95.5% sensitivity and 97.1% specificity and
60%.16 Sensitivity is significantly lower with noncavitary disease and a time to culture positivity of 10 days (interquartile range, 8–13 days),
HIV infection. Sensitivity increases by approximately 10% with the this test appears to be effective and attractive in resource-limited settings.28
collection of a second sputum sample, and 2% with a third.17 Sputum In addition, a commercial kit (the Hardy TB MODS Kit; Hardy Diag-
processing with bleach and concentration before acid-fast staining also nostics, Santa Maria, CA) now provides results comparable to those of
increases sensitivity.18 Most laboratories in the United States now use the conventional MODS, with the ability to detect INH and RIF resistance
a fluorochrome stain with phenolic auramine or auramine-rhodamine, in a Biosafety Level 2 setting and 97.9% concordance with indirect
a slightly modified acid-alcohol decolorization step, and potassium proportion susceptibility testing.29
permanganate counterstaining. Because the mycobacteria are easily seen
with a 20× or 40× low-magnification objective, fluorescence microscopy Nucleic Acid Amplification
requires less technician time and may increase the sensitivity over Nucleic acid amplification testing (NAAT) offers another technique for
conventional acid-fast bacillus smears.19 Advances in ultrabright light- the direct detection of M. tuberculosis in clinical specimens. The Xpert
emitting diode (LED) microscopes make the technology more robust MTB/RIF assay (Cepheid, Sunnyvale, CA) is a US Food and Drug
for use in resource-poor settings.20 WHO recommends that LED Administration (FDA)–approved automated molecular test for detection
microscopy replace conventional fluorescence microscopy and that it of M. tuberculosis with sensitivity and specificity that approach those
be phased in as an alternative for conventional Ziehl-Neelsen microscopy.21 of culture.30 The test is simple to perform and gives results in 100 minutes.
As with all laboratory procedures, strict quality control is needed for It uses real-time polymerase chain reaction (PCR) amplification of an
acid fast staining, or rates of false positives and negatives quickly rise.22 M. tuberculosis gene for detection. GeneXpert MTB/RIF assay had an
Any biologic fluid or material can be examined directly (e.g., pleural overall sensitivity of 89% and specificity of 99% for detection of
fluid, cerebrospinal fluid [CSF], urine, gastric lavage fluid), although M. tuberculosis in sputum samples compared with gold standard culture
thin fluids are best examined after sedimentation by centrifugation. testing. Sensitivity was 98% for smear- and culture-positive cases and
Positive smears from concentrated gastric aspiration material are usually 67% for smear-negative culture-positive cases.31 Analysis of three sputum
due to M. tuberculosis and are especially important in young children samples further increases sensitivity.32 These initial reports continue to
from whom sputum collection may not be possible. be modified under the influence of factors such as prevalence of disease,
prevalence of HIV coinfection, and variable performance on smear-
Culture Methods for Mycobacterium positive and smear-negative samples.33,34 The GeneXpert MTB/RIF
tuberculosis simultaneously detects RIF resistance (see “Drug Susceptibility Testing”
Culture is the gold standard for detecting mycobacteria in clinical later).
specimens. Samples of sputum or tissue require initial decontamination The Xpert MTB/RIF assay has also been used on nonrespiratory
to remove fast-growing nonmycobacterial organisms and liquefaction samples (e.g., pleural fluid, CSF, peritoneal fluid, urine, fine-needle
to allow access of decontaminants to nonmycobacterial organisms and aspirates), but the performance in nonrespiratory specimens varies by
media nutrients to surviving mycobacteria. Decontamination-liquefaction population, TB prevalence, and type of fluid sampled. Detection in
is most commonly done using N-acetyl-l-cysteine as a mucolytic in pleural fluid in a report from India revealed a sensitivity of only 54.8%.35
1% sodium hydroxide solution. Mycobacteria are relatively protected The assay has been endorsed by WHO and is rapidly being deployed
during this procedure by a fatty acid–rich cell wall. However, normally to countries with high rates of endemic TB. A pooled testing strategy,
sterile tissues or fluids such as CSF or pleural fluid should not be which might ameliorate some of the cost burden, has been reported
decontaminated, because some loss of mycobacterial viability does occur. with encouraging results.36 With increased use, the examination of the
The sample is then neutralized and centrifuged, and the sediment is clinical utility now extends to the test’s impact on mortality, and in
inoculated onto media. South Africa no reduction associated with the use of the Xpert MTB/
Three types of media may be used for culture of mycobacteria: solid RIF was found compared with microscopy.37 FDA approval has been
egg-based media (e.g., Löwenstein-Jensen), solid agar-based media (e.g., extended to an indication for use of the test in removing patients from
Middlebrook 7H11), and liquid broth (e.g., Middlebrook 7H12). Media airborne isolation after one or two negative test results.38 A single-
are made selective for mycobacteria by adding antibiotics. Nonselective institution analysis of 207 airborne-isolation cases found that the
media, on which growth is more rapid, are available. Growth is more efficiency (time to result and sensitivity) was greatest with a two-test
rapid in 5% to 10% carbon dioxide. Liquid broth cultures require a strategy, and a one-test strategy missed one case.39 A multisite (Burkino
mean of 10 days of incubation for smear-positive and 20 days for Faso, Cambodia, Cameroon, and Vietnam) assessment comparing Xpert
smear-negative specimens for detection of organisms, as compared with MTB/RIF testing of nasopharyngeal aspirates and stool versus culture
solid media, which require 3 to 8 weeks. However, solid media allow in HIV-infected children younger than 13 years yielded a sensitivity
examination of colony morphology, detection of mixed cultures, and on all samples of 79.3% and 75.8%, respectively, on the alternative
quantification of growth. Furthermore, occasional strains of mycobacteria sources.40
may grow only on solid media. For these reasons, experts suggest using The confounding issue of detection of residual DNA not representative
liquid and solid media in conjunction, with inoculation of at least one of replication-competent bacteria has been addressed in South Africa,
solid medium culture.23 where patients with re-treatment cases were significantly more likely
Commercial automated liquid broth systems greatly facilitate to have false-positive results (14%) than those with newly diagnosed
mycobacterial culture. They monitor mycobacterial growth through cases.41
detection of CO2 production or O2 consumption with radiometric, A new version, the Xpert MTB/RIF Ultra assay (Cepheid, Sunnyvale,
fluorometric, or colorimetric indicators. The BACTEC mycobacterial CA) has been developed. Initial studies suggest that it improves sensitivity
growth indicator tube (MGIT) system (Becton Dickinson Microbiology by approximately 15% in smear negative-culture positive pulmonary
Systems, Sparks, MD), which detects growth in 1 to 3 weeks by means TB; however, there is a small decrease in specificity from 99% to 98%.42,43
of a fluorometric method, is widely used.24,25 The newer Xpert MTB/RIF Ultra assay may also improve sensitivity in
A noncommercial liquid broth assay was developed in which nonrespiratory samples. In a study in Uganda of 129 HIV-infected
mycobacteria are cultured in liquid media on a multiwell plate and patients with suspected meningitis, the Xpert MTB/RIF Ultra had a
then examined microscopically for characteristic serpentine cording. sensitivity of 70% versus a clinical case definition of tuberculous
The addition of antimicrobial agents to the media allows drug susceptibil- meningitis compared with a sensitivity of 43% for BACTEC culture
ity testing to be performed simultaneously. This microscopic-observation and 43% for the older Xpert MTB/RIF.44 WHO has recommended that
drug-susceptibility (MODS) assay yields results in 7 to 10 days, with the Xpert Ultra assay be adopted in settings with high rates of HIV and
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TB such as sub-Saharan Africa. Given the lower specificity, there may person, distinguishing exogenous reinfection from endogenous reactiva-
be more false-positive results in low-HIV and low-TB settings.45 tion in cases of recurrent TB, and identifying laboratory cross-
Another commercially available and FDA-approved NAAT assay contamination of cultures. The Centers for Disease Control and
that can be used directly on respiratory samples is the Amplified M. Prevention (CDC) offers free strain typing through the National

tuberculosis Direct (MTD) test (Hologic, San Diego, CA). The sensitivity Tuberculosis Genotyping Service based on four typing methods: restric-
is intermediate between acid-fast staining and culture. For smear-positive tion fragment length polymorphism (RFLP) analysis, spacer oligonucle-
specimens, the sensitivity is 98% and the specificity is 99%. For smear- otide typing (spoligotyping), mycobacterial interspersed repetitive unit
negative cases, sensitivity ranges from 60% to 80% and the specificity (MIRU) analysis, and WGS.56 In RFLP analysis, DNA cleavage fragments
remains 99%.46–48 generated using pvuII are separated by means of electrophoresis and
A number of other NAAT tests use novel technologies but are not FDA visualized with use of a probe to a repetitive DNA sequence, insertion
approved.49 The COBAS TaqMan MTB assay (Roche Molecular Diagnostics, sequence (IS) 6110. Because numerous copies of IS6110 are present at
Pleasanton, CA) is a real-time PCR test that targets M. tuberculosis ribo- variable chromosomal locations in most M. tuberculosis isolates, identical
somal RNA. The loop-mediated isothermal amplification assay (TB-LAMP; RFLP patterns represent the same strain. Spoligotyping detects variability
Eiken Chemical Company, Tokyo, Japan) does not require a thermal cycler in the direct repeat (DR) region in M. tuberculosis genome. There are
or other sophisticated laboratory equipment. It can be performed manually direct repeats of a conserved 36-bp sequence, separated by multiple
in less than 1 hour, with results read with the naked eye. spacer sequences. Different M. tuberculosis strains are distinguished by
Nucleic acid amplification testing complements but does not replace the presence or absence of 43 unique spacers. Each possible combination
clinical judgment, acid-fast smear, and culture in the diagnosis of TB.50 of spacers is designated by a unique numeric code that identifies a
In sputum acid-fast smear-positive individuals, positive nucleic acid unique spoligotype strain. In MIRU analysis, 12 different DNA sequences,
amplification indicates the presence of M. tuberculosis complex and each of which can be tandemly repeated in the M. tuberculosis genome,
confirms active TB. When there is a high clinical index of suspicion are analyzed. The number of tandem repeats for each of the 12 sequences
for pulmonary TB but with a negative acid-fast smear, a positive NAAT (or loci) is determined by means of PCR to create a 12-number code.
result is highly predictive of TB and allows early initiation of therapy. Each code corresponds to a unique MIRU strain.
NAAT assays perform less well when the clinical index of suspicion for WGS of clinical isolates is rapidly supplanting prior typing technology.
TB is low, in which case the frequency of false-positive tests may approach In the United States, many state public health laboratories and the
that of true positives.51 National TB Molecular Surveillance Center routinely perform WGS on
isolates from every TB case. Many other countries are developing similar
Detection of Mycobacterial systems. WGS provides data on species, strain type, and drug susceptibil-
Antigens in Urine ity (see later). The WGS bioinformatics pipeline and reporting system
Detection of M. tuberculosis antigens in urine may have some usefulness are being standardized, and clinicians should anticipate WGS reports
in diagnosing TB in patients with advanced AIDS, particularly in on every culture-positive TB case in the near future.57
countries where coinfection is highly prevalent. The Alere Determine
lateral flow urine lipoarabinomannan (LF-LAM) assay (Abbott, Abbott Drug Susceptibility Testing
Park, IL) is a commercially available point-of-care test for the diagnosis Testing of M. tuberculosis isolates for drug susceptibility is important
of active TB.52 In a review of 12 studies of the LF-LAM test for TB to guide therapy. There are two broad methods to test an M. tuberculosis
diagnosis in HIV-infected patients, the pooled sensitivity was 45% and isolate’s drug susceptibility: phenotypic testing, which relies on culturing
the specificity was 92%.53 The combination of microscopy and urinary M. tuberculosis in media with varying concentrations of antibiotics,
LAM testing provides incremental diagnostic sensitivity in HIV-infected and genotypic testing, which correlates specific mutations in the isolate’s
adults. Sensitivity for TB in HIV-uninfected persons is less than 25%. genome with known drug susceptibility patterns.
In the United States, the agar proportion method is most commonly
Speciation of Mycobacteria used to determine phenotypic drug resistance. The absolute concentration
Once mycobacteria have been identified in a clinical specimen, speciation method and resistance ratio method are used less commonly. The agar
is necessary for clinical diagnosis and epidemiologic investigation. For proportion method compares growth of appropriately diluted inocula
example, speciation may be important in immunocompromised patients on drug-containing media versus growth on drug-free media and is
at risk for nontuberculous mycobacterial infection, in localities where reported as proportion resistant. For most drugs, resistance is significant
M. bovis transmission from animals to humans is possible, or in bladder when growth on drug-containing media exceeds 1% of control; 6% to
cancer patients receiving bacillus Calmette-Guérin (BCG) immune 10% resistance or more indicates that the drug will add nothing to
stimulatory therapy. Speciation generally involves two steps: First, multidrug therapy. Liquid broth systems, such as BACTEC, can also
mycobacteria are identified as members of the M. tuberculosis complex be used and provide results in 5 to 14 days, but they do not give the
(e.g., M. tuberculosis, M. bovis, M. africanum) or as Mycobacterium proportion of resistant organisms.58,59
species other than tuberculosis (MOTT). Subsequently, if necessary, As noted earlier, the MODS method shows promise as an inexpensive
mycobacteria can be speciated within the M. tuberculosis complex. NAAT and rapid method for culture and drug susceptibility testing.26
assays, growth in selective antibiotic media, nucleic acid probes, and Molecular testing to detect M. tuberculosis chromosomal mutations
high-performance liquid chromatography are all used to place myco- associated with mycobacterial drug resistance is an exciting develop-
bacteria within the M. tuberculosis complex.54 Each has advantages and ment.32,60–63 Most commonly used are tests for RIF resistance, which
limitations that are detailed in Table 249.1. Identifying individual species predicts poor treatment outcomes and is a surrogate marker for MDR-TB.
within the M. tuberculosis complex is more challenging. M. tuberculosis Assays detect mutations in the 81-base-pair rpoB gene, which encodes
grows slowly, lacks pigment, produces niacin, reduces nitrates, has weak the β-subunit of RNA polymerase and correlates with greater than 96%
catalase activity that is lost by heating to 68°C at pH 7.0, does not of RIF resistance. Resistance to INH is more complex and is encoded
demonstrate monodrug resistance to PZA, is resistant to thiophen- by multiple genes, including the catalase peroxidase gene katG, the
2-carboxylic acid hydrazide, and prefers aerophilic conditions. Other inhA gene involved in fatty acid biosynthesis, the ahpC gene, the oxyR
members of the complex show different patterns with these tests. gene, and the kasA gene.64 Mutations associated with resistance to PZA,
Next-generation sequencing technology is rapidly making WGS of ethambutol (EMB), second-line injectable drugs, and fluoroquinolones
clinical isolates routine and also enables identification of species within have also been identified.
the M. tuberculosis complex.55 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
Genotyping of Mycobacterium resistance in respiratory samples that are RIF resistant with culture
tuberculosis techniques. However, use of the test in populations with high rates of
Characterizing the particular strain of M. tuberculosis is important for HIV infection and drug resistance, such as in Swaziland, revealed that
epidemiologic purposes, such as tracing transmission from person to the test failed to detect a high-prevalence rpoBI491F outbreak strain.
2990
This RIF-resistance–conferring mutation was present in 30% of MDR
40
strains.65 The drug-resistance assay is performed on sputum simultane-
ously with detection of organisms, and results are available within 2 35
Rate of Tuberculosis Cases

hours. Three line probe assays are also commercially available: the
(per 100,000 population)

30
INNO-LiPA Rif. TB kit (Innogenetics, Zwijndrecht, Belgium), which
detects resistance to RIF in culture isolates; the Genotype MTBDRplus 25 Foreign-born persons
assay (version 2.0) (Hain Lifescience, Nehren, Germany), which detects 20
resistance to INH and RIF in culture isolates and smear-positive sputum 15
samples, and thereby can enable identification of MDR-TB; and the Overall
Genotype MTBDRsl assay (Hain Lifescience), which detects resistance 10
to fluoroquinolones and second-line injectable drugs in culture isolates 5
and smear-positive sputum samples and thereby can be used to identify US-born persons
0
XDR-TB.66–69 WHO has recommended widespread use of these molecular
93
95
97
99
01
03
05
07
09
11
13
15
assays.70 The clinical impact of rapid diagnosis and drug-resistance
19
19
19
19
20
20
20
20
20
20
20
20
detection has been reported from Tbilisi, Georgia, where the MTBDRplus
assay was associated with selection of drug regimens that provided FIG. 249.1 Rates of tuberculosis cases among US-born versus
higher and more rapid rates of culture conversion at 24 weeks.71 foreign-born persons, United States, 1993–2015. (Modified from
WGS is also becoming a powerful tool for the detection of drug- Tuberculosis in the United States: National Tuberculosis Surveillance System
resistance mutations in the M. tuberculosis genome.72,73 Currently it can highlights from 2015. Slide 17. https://www.cdc.gov/tb/statistics/surv/
surv2015/default.htm.)
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.
Mexico, the Philippines, India, Vietnam, and China, from which
EPIDEMIOLOGY immigrants account for more than half of the TB cases in foreign-born
General Considerations individuals.81 Strain genotyping suggests that TB among foreign-born
M. tuberculosis infects 1.7 billion people or approximately one-quarter persons is from reactivation of latent infection acquired before arrival
of the world’s population and caused 10.4 million new cases of TB and in the United States. Furthermore, the risk declines with duration of
approximately 1.7 million deaths in 2016.1,74,75 TB is the leading cause residency, also suggesting that most infections were acquired before
of death worldwide resulting from a single infectious agent, ranking immigration.82 Screening of immigrants to the United States with a
above HIV since 2014.76 Immunocompromise due to HIV infection is culture-based, rather than a smear-based, algorithm is justified by the
a risk factor for TB, and 374,000 TB deaths are in HIV-infected individu- high rate (54.4%) of smear-negative and culture-positive cases.83
als. Drug-resistant TB is emerging globally, with approximately 490,000 TB has also become concentrated in certain ethnic and racial minori-
new MDR-TB cases in 2016. Two factors essential for the rapid spread ties and medically underserved populations, often occurring in contact-
of M. tuberculosis are crowded living conditions and a population with based microepidemics. In 2017, rates among US-born blacks was seven
little native resistance. In the 19th century, TB caused more than one- times higher than in non-Hispanic US-born whites; the rate in Native
fourth of all adult deaths in Europe, eliminating those with the least Americans was nine times higher than in whites.79 A number of outbreaks
native resistance. A downward trend had been established before the have affected the urban poor, alcoholics, injection drug users, the
turn of the 20th century. Epidemiologists once believed the disease homeless, migrant farm workers, and prison inmates.
would eventually disappear based on the assumptions that 1 in 20 The age distribution of TB reflects the degree of ongoing transmission
infections result in active cavitary disease of the lung (i.e., become in a given population. Disease in the elderly is generally due to reactiva-
contagious). Thus, each cavitary case would have to infect 20 persons tion of infection acquired in the remote past, whereas TB in young
for case rates to be maintained.77 In Holland in the early 1900s, one children indicates ongoing active transmission in the community. In
infectious case produced only 13 new infections.77 The annual decrement this regard, 75% of childhood cases in the United States occurred in
in mortality and morbidity from TB was approximately 5% in developed patients who had TB exposure through foreign-born parents or prior
countries owing to progressively higher natural residual resistance in residence outside the United States.84,85
those who survived infection and to living conditions less conducive TB in the United States is most frequent in geographic regions and
to airborne spread. This rate of decline approximately doubled after demographic groups where AIDS is prevalent, notably in urban blacks
chemotherapy became widespread. and Hispanics between 25 and 45 years of age.86 Persons with active
In the 1980s and 1990s, the high incidence of TB in Africa, Asia, TB are more frequently HIV positive than is the general population.
Eastern Europe, and South America, the HIV coepidemic, and burgeoning Approximately 8% of all TB cases in the United States occur in HIV-
MDR-TB demonstrated that predictions of the disappearance of TB infected persons.3
were premature, and WHO declared TB a global public health emergency. Despite a predominantly urban epidemiology, large TB outbreaks
Since then, tremendous gains have been made in reducing the number have also affected small communities.87,88 One well-characterized outbreak
of new TB cases, now in decline for the past several years. The integration began in 1988 in a coastal Maine village where TB had not been reported
of multiple modalities, such as genotyping combined with a series of in the previous 3 years.88 A shipyard worker with cavitary TB was the
spatial analysis tools, might improve the efficiency of targeted transmis- source of 21 subsequent active cases and 697 new tuberculous infections.
sion control.78 In retrospect, the source patient had repeatedly sought medical attention
for cough, sore throat, and hoarseness during 8 months before TB was
Recent Morbidity and Mortality Trends diagnosed and treated. This report highlights the need for vigilance
In the United States, the incidence of TB has decreased steadily over regarding all segments of the population, not just those known to have
the past 25 years, from 10.5 reported cases per 100,000 population in high TB case rates.
1992 to 2.8 cases per 100,000 population in 2017, the lowest in recorded The prevalence of positive TST results in US Navy recruits offers
history.2,79 Recent estimates of latent infection in the United States suggest insights into trends of latent tuberculosis infection (LTBI) over time
a prevalence of latent infection in 2011–12 of 4.4% by the tuberculin and risk factors for infection. From 1958 through 1969, more than
skin test (TST) and 4.8% by the QuantiFERON-TB Gold In-Tube test 1 million US Navy recruits underwent TSTs, and in 5.2% the results
(QFT-GIT; Cellestis Limited, Carnegie, Victoria, Australia).80 In the were positive. In the 1980s and 1990s, the rate of tuberculin reactivity
United States the TB rate in foreign-born persons is 15 times higher dropped to approximately 1.5% of new Navy recruits. The prevalence
than in US-born persons, and foreign-born persons now account for was greater in blacks (5%), Hispanics (5%), and Asian/Pacific Island-
almost 70% of reported cases in the United States (Fig. 249.1).79 This ers (26%) than in whites (0.8%). Tuberculin positivity was more than
reflects increased immigration from high-prevalence countries, especially 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

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
2992
TABLE 249.4 Epidemiologic Circumstances in investigation in San Francisco from 1991 to 1996 estimated that
Which an Exposed Person Is at Increased Risk for 17% of new active TB cases arose from smear-negative, culture-positive
Infection With Drug-Resistant Mycobacterium index cases.
Persons coinfected with HIV do not appear to be more infectious
tuberculosisa
than HIV-negative source cases and because they are more likely to be
• Exposure to a person who has known drug-resistant tuberculosis smear negative than are HIV-negative patients, they may be less infectious.
• Exposure to a person with active tuberculosis who has had prior treatment In one large study from the Democratic Republic of Congo, household
for tuberculosis (treatment failure or relapse) and whose susceptibility test
results are not known contacts of HIV-positive patients with pulmonary TB were no more
• Exposure to persons with active tuberculosis from areas in which there is a likely to become infected with M. tuberculosis than were household
high prevalence of drug resistance contacts of HIV-negative TB patients.128 A study in Uganda demonstrated
• Exposure to persons who continue to have positive sputum smears after that transmission from an HIV-infected index case to contacts was
2 months of combination chemotherapy
• Travel in an area of high prevalence of drug resistance dependent on the index patient’s sputum smear positivity and presence
a
of a cavity on chest radiograph.129 A meta-analysis of six studies involving
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
exposed health care workers supports this finding, as does a study of
for a second-line treatment regimen. household contacts in Peru.130,131
From Centers for Disease Control and Prevention. Treatment of tuberculosis.
American Thoracic Society, CDC and Infectious Diseases Society of America. Influence of Chemotherapy on
MMWR Recomm Rep. 2003;52(RR–11):1–88.
Spread of Infection
Patients receiving appropriate chemotherapy promptly become noninfec-
tious as cough subsides and the concentration of organisms in sputum
infectious for approximately 30 minutes even after his or her absence. decreases. The time required to become noninfectious depends on the
Although in theory one droplet nucleus may be sufficient to establish patient’s burden of organisms, but there is indirect evidence that this
infection, prolonged exposure and multiple aerosol inocula are usually occurs within 2 weeks in patients with drug-sensitive TB.132 Thus, case
required. Strains may vary widely in their transmissibility,87 but infection finding and treatment comprise the most effective method of TB control.
does not generally occur outdoors because M. tuberculosis is killed by
ultraviolet light. Although homes are the focus of TB contact investiga- Risk for Progression From Infection to
tions, evidence is mounting that in high-TB settings, approximately Active Disease
85% of transmission occurs in other social spaces including medical In general, 3% to 4% of infected individuals acquire active TB during
facilities, public transportation vehicles, workplaces, schools, churches, the first year after tuberculin conversion and an additional 5% do so
bars, and other areas where people congregate.120 thereafter, although the uniformity of these rates has been challenged
Large drops of respiratory secretions and fomites are unimportant in a study from Victoria, Australia, in which the cumulative hazard for
in transmission, and special housekeeping measures for dishes and bed progression to disease after infection was 14.5%, with most risk occurring
linens are unnecessary. Other modes of transmission are rare. Infection within the first 5 months and greater risk in children younger than 5
with M. bovis from ingestion of contaminated milk was once com- years (50.6%).133,134 These estimates are based on heavy exposures during
monplace. Skin inoculation of M. tuberculosis from contamination of disease-prone periods of life. Persons infected with small inocula or
an abrasion occurs in pathologists and laboratory personnel (prosector’s during disease-resistant periods probably have a much smaller risk,135
wart), and venereal transmission has been recorded. Although the source whereas the risk for progression in immunocompromised persons is
is pulmonary in the vast majority of cases, aerosolization of organisms greater. In one study of 12,876 unvaccinated adolescents, 10.4% of those
during irrigation of cutaneous lesions or at autopsy has caused spread who converted their tuberculin tests acquired clinical TB, 54% of these
to health care workers.121,122 The special case of organ-donor–transmitted within 1 year and 78% within 2 years.77 The three periods of life during
infection should be noted because transplant recipients have a higher which infection is most likely to produce disease are infancy, ages 15
frequency of TB than the general population, and high mortality.123 to 25 years, and old age. (The effect of age on disease progression is
Because donor-derived disease develops late (>90 days) in the majority discussed in “Influence of Age on Tuberculous Infection.”)
of cases, and many donors have identifiable risk factors for tuberculous The likelihood of active disease developing varies with the intensity
infection, it has been proposed that screening protocols using donor and duration of exposure. Persons with intense exposures are most at
histories that would heighten surveillance of recipients, in addition risk not only for infection but also for disease.127 The degree of tuberculin
to cultures and smears, and testing for latent TB in donors should be positivity has some predictive value. Malnutrition, renal failure, and
undertaken.124 immunosuppression all favor progression of infection to active disease,
but by far the strongest risk factor is HIV infection. Among tuberculin-
Risk for Infection positive, HIV-positive injection drug users in one methadone clinic
The most important determinants of infection of tuberculin-negative population, 8% per year acquired active TB.136
persons are closeness of contact and infectiousness of the source. From
2002 to 2011, 26 outbreaks in the United States were associated with Institutional Spread of Tuberculosis
index cases with a substantial burden of substance abuse, incarceration, Hospitals
and homelessness.125 Cases with positive smears are highly infectious; TB has long been a recognized risk to health care workers and hospitalized
those positive only on culture are less so. The degree of sputum positivity patients. In the 1980s, numerous explosive outbreaks of TB occurred
and pattern of coughing are important. Compared with measles, one among HIV-infected patients in specialized wards and hospices in the
case of which will infect 80% of susceptible casual contacts, TB is only United States and Europe.137–141 In the first reported outbreak on an
moderately infectious in most circumstances. In the United Kingdom, HIV ward, the index patient had fever, cough, a normal chest radiograph,
a study of 111 cases with 825 contacts found that a shorter interval to and negative acid-fast smears, but a positive sputum culture for M.
liquid culture positivity identified patients at high risk of transmitting tuberculosis.138 On the same ward, 39% of other HIV-positive patients
infection and was also superior to detection by means of smear.126 acquired active TB within 60 days. Major factors contributing to these
TB morbidity in a population is determined both by the risk for outbreaks included (1) delays in diagnosis, especially in HIV-infected
infection and the risk for acquiring active disease once infected. In patients with atypical chest radiographs; (2) inadequate negative-pressure
Holland in the 1970s, 50% of newborn to 14-year-old household contacts ventilation inpatient rooms; (3) use of aerosol-generating procedures
of individuals with smear-positive cases became tuberculin positive, such as bronchoscopy and sputum induction; (4) rapid progression to
but only 5% did so when the contact case was culture positive but smear active TB in HIV-positive patients; and (5) in the case of MDR-TB,
negative.77 In the United States, approximately 27% of household contacts prolonged infectivity despite antituberculous chemotherapy.142 In high-
of individuals with smear-positive cases become infected, although rates income countries, decreased numbers of AIDS hospitalizations, decreased
as high as 80% occur in closed environments.127 A large epidemiologic TB incidence, low rates of MDR, and improved hospital infection-control
2993
programs have generally diminished these outbreaks. In middle- and booths. The use of particulate respirator masks (N95), with appropriate
lower-income countries, with higher rates of HIV- and TB-related hospital training and fitting, further reduces risk and is recommended by the
admissions and less resources for infection control, nosocomial transmis- CDC. Ultraviolet irradiation of the air— either with the air pulled by
sion remains a major public health problem. An investigation of 404 a fan through a radiation chamber or with the ultraviolet beam directed

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

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 necrosis.199,202 One study demonstrated progression from infection to
Clinical disease developing after infection in adolescence or young cavitary TB in 23% of patients infected from 15 to 19 years of age, 13%
adulthood may resemble childhood infection (lower lung field pneu- of those infected from 20 to 24 years of age, 4% of those infected from
monitis, hilar adenitis) but with less parenchymal and hilar calcification 25 to 29 years of age, and only 2% of those infected after 30 years of
(Fig. 249.2). This is particularly the case in immunocompromised patients, age. Progression occurred in 3 months in many and within 1 year in
including those living with HIV.194 Rarely, the radiographic picture may most.203 (Elderly individuals were not included in the study.)
be mixed, with features of childhood disease subsiding while chronic
upper lobe (adult) disease progresses. However, disease in this age group Infection in Old Age
frequently first appears as chronic upper lobe TB with no clinical In the elderly, infection acquired years earlier can progress as age
manifestations of childhood disease. The tendency toward apical cavita- compromises immunity, producing typical apical-posterior disease.
tion soon after the initial infection appears soon after puberty and is Studies of TB in nursing homes, however, have demonstrated that elderly
marked in young adults.172 Evidence suggests that adolescents (and patients are often tuberculin negative, either because they had never
adults) may have a subclinical tuberculous pneumonia for months prior been infected or because remote past infection had been completely
to the onset of overt disease.200,201 Because most young people in cleared, with a loss of tissue hypersensitivity. Such tuberculin-negative
industrialized countries are tuberculin negative (Fig. 249.3), most persons are susceptible to new infection; and if this occurs, they acquire
pulmonary TB in adolescents and young adults is due to recent initial active disease with a frequency similar to that of adolescents. This is
infection rather than to late progression of childhood infection. typically a nondescript, poorly resolving pneumonitis in the lower or
middle lobes or anterior segments of the upper lobes, sometimes with
Infection in Midadulthood pleural effusion and resembling primary infection in children except
Infection acquired during the middle years has a much better immediate with much less hilar-mediastinal lymphadenopathy.97 Even with prompt
and probably long-term prognosis than infection acquired in the teens diagnosis and treatment, TB after age 65 appears to be more frequently
and early 20s, presumably because of a reduced tendency to tissue associated with death.
2998
Late Hematogenous Tuberculosis pneumonia results in progressive primary disease, which may spread
Chronic TB is probably always associated with recurrent abortive episodes via the bronchial tree or the bloodstream. However, most infections
of hematogenous spread. However, when aging or other factors com- during the relatively disease-resistant period of childhood (ages 5–12
promise cellular immunity, such episodes may become progressively years) are usually nonprogressive, with healing by involution and
more frequent, producing the subtle and often fatal syndrome of late encapsulation.199 Progression, if any, occurs in extrapulmonary metastatic
hematogenous or progressive generalized TB. foci or with the development of apical-posterior pulmonary TB, usually
when the patient reaches puberty or young adulthood.
Intercurrent Events
General stress, poor health, and malnutrition favor progression of infec- Postprimary (Adult-Type)
tion. Therapy with corticosteroids or other immunosuppressive agents Pulmonary Tuberculosis
compromises host defenses, as do hematopoietic-reticuloendothelial Primary infection in adolescents and adults (1) may occur without
diseases, particularly malignancies. TB in complicating myeloprolif- symptoms and signs, (2) may produce a typical primary complex, or
erative disorders may cause confusion because disseminated TB can (3) may result in typical chronic pulmonary TB without a demonstrable
cause aplastic anemia, thrombocytopenia, leukopenia, and leukemoid primary complex. Any pneumonic infiltrate, especially if associated
reactions that may mimic leukemia. However, most patients with with a hilar or mediastinal node, may represent primary infection.
TB and hematologic findings that suggest leukemia will have both These lesions may undergo caseation, liquefaction, and bronchogenic
diseases. Inflammatory diseases such as rheumatoid arthritis and spread just as with classic chronic pulmonary TB.
systemic sclerosis are often accompanied by immunologic derange- Postprimary pulmonary TB in adults is usually asymmetrical and
ments that may decrease immunocompetence even prior to the use characterized by caseation, fibrosis, and frequently cavity formation. It
of immunosuppressive therapies. Patients with systemic sclerosis in begins as a patch of pneumonitis in the subapical-posterior aspect of
Taiwan had a significantly higher risk for TB and pulmonary TB, an upper lobe, usually just below the clavicle or first rib (Fig. 249.4). A
independent of systemic sclerosis treatment, compared with matched less frequent location is the apex of the lower lobe, where it may be
control subjects drawn from the National Health Insurance database obscured by the heart and hilum on a chest radiograph but readily
(incidence rate ratios, 2.81 and 2.53, respectively).204 Biologic TNF-α visible on a chest CT image. The inflammatory response in the sensitized
inhibitors (e.g., infliximab, etanercept, and adalimumab) that are host produces a fibrin-rich alveolar exudate containing a mixture of
prescribed for rheumatoid arthritis and other inflammatory diseases inflammatory cells. Serial radiographs may demonstrate waxing and
increase the likelihood of reactivation TB, including extrapulmonary waning and sometimes complete regression. If the process accelerates,
and disseminated disease.205–209 however, an area of caseous necrosis surrounded by epithelioid cells,
The postgastrectomy state, jejunal-ileal bypass surgery, and end-stage granulation tissue, and eventually fibrosis develops. This may arrest by
renal disease are all risk factors for progression (see “Treatment of inspissation of the caseous area, fibrous encapsulation, and healing.
Latent Tuberculous Infection”). Viral illnesses, particularly in children, Caseation, however, tends to liquefy and drain into the bronchial tree,
may predispose to progression of infection. Destructive local pulmonary spreading bacillary contents by coughing. The cavity is prevented from
processes such as lung abscess, carcinoma, cavitary histoplasmosis, and collapsing by the fibrous capsule and the inelasticity of the surrounding
pulmonary resection occasionally are followed by activation of previously lung. The pulmonary cavity favors bacillary multiplication to enormous
quiescent pulmonary foci. The development of bone and joint TB after titers, 5 to 6 logs greater than in noncavitary lesions. The progressive
physical injury and late generalized hematogenous TB after major trauma nature of pulmonary TB is due to (1) the tendency of apical caseous
both illustrate that the balance between host and infection can be altered foci to liquefy, (2) the enormous concentrations of organisms in the
by both systemic factors and local physical disturbance. resulting pulmonary cavities, and (3) spread of this bacilli-rich material
through the bronchial tree. Progression from minimal infiltrate to
Tuberculosis in People With HIV Infection far-advanced cavitary disease can occur within a few months (Fig. 249.5).
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
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.
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.

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
FIG. 249.5 Chest radiograph showing far-advanced bilateral apical from intermittent obstruction and poor drainage. Bronchial perforation
cavitary pulmonary tuberculosis in a 32-year-old woman from
Ethiopia.
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-
Coughing aerosolizes infectious cavity secretions that may distribute ously quiescent bacilli. The atelectatic pneumonitis, which may result
widely throughout the lung (bronchogenic spread). New foci eventually with or without new active disease, is most frequently seen in the anterior
develop that, in turn, may undergo caseation, fibrosis, and healing or segment of the upper lobe and medial segment of the middle lobe.
slough, resulting in new cavities. The segment or lobe containing the
initial cavity is typically involved first with scattered patchy disease, but Pulmonary Tuberculosis in AIDS
the contralateral apex is often secondarily involved with progressive TB as first described in persons with advanced AIDS was characterized
disease. Bronchogenic spread may establish foci of infection in the by middle or lower lung field location, absence of cavitation, a greatly
lower lobe and anterior portions of the upper lobe, producing a poly- increased incidence of extrapulmonary disease, and usually a negative
morphous mottling on a chest radiograph, but these are usually non- TST.214,215 It resembled childhood TB except for a negative TST and less
progressive and heal with fibrosis. Although hematogenous spread from prominent hilar and mediastinal lymphadenopathy. A later study of TB
an established pulmonary focus can occur, it is usually limited by in a much less ill population of persons in TB clinics unaware of their
hypersensitivity-induced thrombosis. HIV infection found a clinical picture no different from ordinary
The highly infectious secretions from a cavity always cause some reactivation TB in HIV-negative patients, with apical, often cavitary,
degree of endobronchial inflammation and ulceration, which may be disease and tuberculin positivity being the rule. The clinical picture of
extensive. Ulcerative tuberculous laryngitis is an extension of this process, TB during HIV infection is determined by the degree of immunocom-
as is local disease throughout the upper airways, mouth, middle ear, promise (Table 249.6). Although HIV-positive persons may have
and gastrointestinal tract. symptoms similar to those seen in HIV-uninfected persons, presentations
Mechanisms of healing are the same whether spontaneous or under can also be atypical or patients can be asymptomatic.216
the influence of chemotherapy. Without drug therapy, solid caseous HIV-positive persons may also acquire new infection from others
foci surrounded by contracting fibrous tissue occasionally arrest. However, in their environment, a risk that was first observed among patients with
viable bacilli almost always persist in such lesions and can later reactivate. advanced AIDS living in HIV wards and domiciles. The clinical picture
Before drug therapy, healing of persisting cavities never occurred, and in these patients can include diffuse, rapidly progressive, noncavitary
some large, thick-walled cavities in shrunken fibrotic lobes could persist disease that is often fatal.137,138 It is unclear whether HIV-infected persons
for years with minimal symptoms while remaining highly infectious are more likely to become infected after exposure to M. tuberculosis
(chronic fibroid TB). With drug therapy, cavities may resolve or they than HIV-uninfected persons, but once infected, they are more likely
may heal but remain open, sometimes with complete reepithelialization. to progress to active disease. HIV-infected persons do not appear to
The major risk for such persistent cavities is superinfection with organ- be more likely to transmit M. tuberculosis than HIV-uninfected persons,130
isms such as Aspergillus or nontuberculous mycobacteria. but TB disease, and therefore M. tuberculosis transmission, can occur
even when the source patient has a normal chest radiograph or a negative
Lower Lobe and Endobronchial acid-fast sputum stain.217,218 The Cepheid GeneXpert MTB/RIF or the
Tuberculosis more recent Ultra version should assist in rapid detection of M. tuber-
These terms lower lobe tuberculosis and endobronchial tuberculosis are not culosis in sputum of such patients.
appropriate for chronic pulmonary TB of the ordinary kind that happens It is important to consider TB in HIV-positive individuals with respira-
to involve the apex of the lower lobes. In adults, lower lung field tuberculosis tory failure in the intensive care unit. Patients may have adult respiratory
describes three different but often associated processes: (1) progressive distress or sepsis syndrome with multiple organ system failure. The diagnosis
lower lobe pneumonia in recently infected older individuals; (2) 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
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 FIG. 249.6 Chest radiograph demonstrating multiple bilateral
with central or concentric calcification resembling histoplasmomas. pulmonary tuberculomas in an asymptomatic 35-year-old man from
Most such lesions are stable, but important in that they can be Poland.
confused with cancer.
Symptoms heard over cavities are called amphoric, like the sound made by blowing
Initial infection with M. tuberculosis is usually asymptomatic, although across the mouth of a jar (amphora).
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 Radiographic Findings
chest radiograph. As the bacillary population grows, however, nonspecific The chest radiograph is central to diagnosis, determination of the extent
constitutional symptoms such as anorexia, fatigue, weight loss, chills, and character of disease, and evaluation of the response to therapy.
fever, and night sweats may ensue. A productive cough is usually present. Chest CT is a valuable adjunct to routine chest radiography. Certain
Coughing to clear cavitary secretions is usually mild and well tolerated patterns are highly suggestive, although not diagnostic, of TB. A patchy
but may become bothersome when bronchial involvement is extensive. or nodular infiltrate in the apical- or subapical-posterior areas of the
The mucopurulent sputum is nonspecific, and both cough and sputum upper lobes or the superior segment of a lower lobe is highly suggestive
may be ignored by patients with chronic bronchitis. Hemoptysis resulting of early chronic TB, especially if bilateral or associated with cavity
from caseous sloughing or endobronchial erosion is usually minor but formation (see Fig. 249.4). Cavities may be more apparent with CT or
connotes advanced disease. Sudden massive hemoptysis resulting from magnetic resonance imaging (MRI). On routine chest radiography,
erosion of a pulmonary or bronchial artery by an advancing cavity cavitation in the apical segment of the lower lobe may be obscured by
(Rasmussen aneurysm) was an occasional terminal event in the predrug the heart shadow and, in the lateral view, by the dorsal spine. Air-fluid
era but is now seldom seen. In inactive disease, brisk hemoptysis may levels are uncommon in upper lobe TB (less than 10%) but occur more
be due to Aspergillus superinfection of residual cavities (aspergilloma). frequently in lower lobe cavities. Fresh bronchogenic spread from recent
Chest pain is usually due to extension of inflammation to the parietal spillage of infectious cavity contents appears as multiple, discrete, soft,
pleura. Pleural involvement adjacent to an established cavity tends to fluffy infiltrates, or a confluent infiltrate adjacent to a cavity, or in the
cause visceral-parietal pleural symphysis without effusion (dry pleurisy). middle or lower lung field on the same or opposite side. These latter
Serofibrinous pleurisy with effusion is often an early postprimary event types of spread are seldom progressive and heal by rounding up into
but may also complicate chronic pulmonary TB. Rarely, chest pain leads more discrete lesions with regular borders.
to discovery of tuberculous empyema. Symptoms often pertain to site Both chronicity and histopathologic features can be estimated based
of disease, such as painful pharyngeal ulcers; indolent and nonhealing on the chest radiograph. Granulomatous lesions tend to be small, nodular,
ulcers of the mouth or tongue; hoarseness and dysphagia that are due and sharply defined, indicating few organisms and a good host response.
to laryngeal involvement; tuberculous otitis media; gastrointestinal Exudative lesions (pneumonic) tend to have soft, indistinct borders
symptoms that are due to enteric ulceration, perforation, or mass and are more unstable. Fibrotic scars have sharp margins and tend to
formation; or anal pain that is due to tuberculous perirectal abscess contract. Caseation causes increased density. Healing exudative lesions
and fistula formation. Lower lobe TB resulting from bronchial lymph first become smaller and less dense and then, as scarring develops,
node perforation may be associated with lithoptysis (stone spitting) and become more sharply defined. Lower lobe TB is nonspecific radiographi-
characteristically produces symptoms of severe endobronchial disease cally. Other patterns include poorly resolving pneumonia, atelectasis,
with serious cough and often hemoptysis. mass lesions, and large cavities with air-fluid levels; initial misdiagnosis
is the rule. Pneumonia associated with hilar adenopathy should always
Physical Examination suggest primary TB, regardless of the lung fields involved and patient
Physical findings are not specific, and in general do not reflect the age. Pulmonary TB can also occur in persons with a normal chest
extent of the illness and may be absent in spite of extensive disease. radiograph; up to 6% of HIV-seronegative and 22% of HIV-seropositive
Dullness with decreased fremitus may indicate pleural thickening or persons with pulmonary TB have a normal chest radiograph.217,221–223
fluid. Crackles may be appreciated only when the patient breathes in
after a short cough (posttussive rales) and may persist long after healing, Laboratory Findings
owing to permanent distortion of small airways. With large lesions, Normocytic, normochromic anemia, hypoalbuminemia, and hypergam-
signs of consolidation with open bronchi (whispered pectoriloquy, maglobulinemia are characteristic of advanced disease. The white blood
tubular breath sounds) can be heard. Distant hollow breath sounds cell count is usually normal but may be between 10,000 and 15,000
3001
cells/mm3. Many HIV-negative patients with active TB have CD4+ T-cell foci, causing active disease. However, in many patients the diseases
counts much lower than 500 cells/L, which return toward normal with will be anatomically remote. No one cancer cell type predominates.
treatment.224 Monocytosis is seen in less than 10% of cases. Hematuria When TB and cancer occur together, diagnosis of the latter is often
or sterile pyuria should suggest coexisting renal TB. Hyponatremia difficult but should be kept in mind in older men with TB who smoke,

with features of inappropriate secretion of antidiuretic hormone is and sputum cytologic studies should be performed. There are certain
characteristic of tuberculous meningitis but also occurs with isolated radiographic findings that suggest concomitant cancer, such as progression
pulmonary involvement. Hyponatremia should also suggest associated of one area while the remainder of the lesion is regressing, a large (>3 cm)
Addison disease due to adrenal TB. Hypercalcemia is also seen during mass lesion admixed with infiltrative disease, the presence of hilar nodes
pulmonary TB, usually in the first weeks of therapy. in adult chronic pulmonary TB, and postobstructive atelectasis.237
Diagnosis THERAPY
A strong presumptive diagnosis can often be made based on the Before effective drugs were available, 50% of patients with active pul-
radiographic pattern. A positive sputum smear, usual in extensive monary TB died within 2 years and only 25% were cured.238 With the
disease, provides additional evidence in support of a diagnosis. However, advent of chemotherapy, successful treatment became a reasonable goal
an intercurrent cancer or lung abscess, particularly in the apices, may in all adults. In practice, failures occur because of drug resistance or
erode a quiescent focus of TB and cause brief shedding of tubercle an inappropriate regimen, or, most important, because of nonadherence
bacilli without causing active disease. The best diagnostic sputum to therapy. For this reason the responsibility for adequate treatment
specimen is an early morning sample. Although two sputum specimens has been shifted from the patient to the prescribing physician and to
are sufficient in some settings, three specimens are recommended the health department, emphasizing the importance of directly observed
because of greater sensitivity.225 Aspiration of gastric contents, obtained therapy (DOT).239
early in the morning to sample sputum swallowed during sleep, is an
alternative when sputum is not produced. The specificity of gastric Antituberculous Drugs
aspiration is diminished by the presence of nontuberculous mycobacteria Additional information on dosage, adverse effects, drug-drug interactions,
but may be higher in children than adults. Sputum induction by and other aspects of the pharmacology of antituberculous drugs is
hypertonic saline aerosols is also an effective substitute in ambulatory provided in Chapter 39.
patients; the yield is comparable to that of fiberoptic bronchoscopy.226
Pulmonary TB in patients with AIDS is often noncavitary and therefore Isoniazid
may have a lower bacillary burden than in HIV-seronegative persons. INH is the cornerstone of therapy and should be included in all regimens
The high prevalence of smear-negative TB in HIV-infected persons unless the M. tuberculosis strain is INH resistant. Occasionally, when
underscores the importance of obtaining sputum culture, even in the M. tuberculosis strain is resistant to low-level INH but susceptible
resource-poor settings.227 Positive sputum smears are much more likely to higher INH levels, and there is resistance to other antituberculosis
to indicate M. tuberculosis than Mycobacterium avium complex, even drugs, INH is included in the regimen (although not considered to
in areas where both diseases are common.228 NAAT, described previ- have full activity). The most important adverse effect of INH is hepatitis,
ously, can provide a rapid distinction between the two infections in the risk for which increases with age and underlying liver disease.
smear-positive respiratory secretions. (Additional diagnostic assays, Although rare, this complication can be fatal.240 INH continues to be
including NAAT and testing for M. tuberculosis antigens in urine, are a cause of significant drug-induced liver injury, which may be associated
discussed under “Microbiology.”) with a lack of adherence to guidelines that recommend cessation of
A negative tuberculin reaction or interferon-γ release assay does therapy based on symptoms (nausea, abdominal pain, jaundice, or
not exclude TB; skin test anergy and negative assays can occur in the unexplained fatigue) or alanine aminotransferase levels. In one study,
setting of active disease.177,229,230 The TST and interferon-γ release assays 70% of patients who died or underwent liver transplantation continued
are insensitive in immunocompromised persons, such as HIV-infected INH for more than 7 days after meeting stopping criteria.241
persons with less than 100 CD4+ T cells/mm3.230,231 Granuloma formation
at histologic examination, even with AFB, is still only strong presump- Rifampin
tive evidence, because similar findings may be produced by MOTT. RIF is the second major antituberculous agent. The most important
Granulomas in the absence of AFB can be seen with other infectious complication of RIF is hepatitis, which is usually cholestatic. Although
diseases (e.g., histoplasmosis) and noninfectious causes (e.g., sarcoidosis, the risk for hepatitis is lower with RIF than INH,242,243 hepatitis occurs
autoimmune disease). Definitive diagnosis requires culture and speciation. more frequently in regimens containing both INH and RIF than in
those containing INH alone.244
Fiberoptic Bronchoscopy Of special concern is that RIF, by inducing hepatic P-450 cytochrome
Diagnostic fiberoptic bronchoscopy with transbronchial biopsy and oxidases, causes many drug-drug interactions. Examples of drugs whose
bronchoalveolar lavage should be considered when sputum tests are levels are reduced in the presence of RIF include warfarin, hormonal
inconclusive and the suspicion of TB remains high. In AIDS patients contraceptives, azole antifungal agents, methadone, corticosteroids,
with pulmonary TB but negative smears, bronchoscopy yields a rapid cyclosporine, tacrolimus, nonnucleoside reverse transcriptase inhibitors,
diagnosis (based on smears and histologic features) in only one-third and HIV-1 protease inhibitors. This can result in subtherapeutic levels
of cases.232–234 Thus, a negative acid-fast stain at bronchoscopy does not of these drugs, necessitating either increases in their dosage or use of
exclude TB, although such cases are certainly less contagious. an antituberculosis drug other than RIF. The interaction between RIF
and HIV-1 protease inhibitors can lead to substantially lower HIV-1
Tuberculosis Diagnosed at Autopsy protease inhibitor levels, inadequate control of viral replication, and
From 1985 through 1988, 5.1% of all reported TB cases in the United emergence of drug-resistant virus. In this setting, RIF may be replaced
States were diagnosed at death.235 Usually, the patient was elderly and by rifabutin, which has comparable antituberculous activity but is a
had underlying diseases. Both nonresolving pulmonary processes and weaker enzyme inducer.245 Adjustment of antiretroviral drugs with
extrapulmonary TB, particularly chronic miliary and meningeal disease, treatment of TB is shown in Tables 39.3 and 39.5.
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 Rifapentine
can occur when persons receive fluoroquinolones, can also contribute.236 Rifapentine is a rifamycin antibiotic with a longer half-life than RIF or
rifabutin, which allows once-weekly administration.239,246 Once-weekly
Tuberculosis and Cancer therapy, together with INH or moxifloxacin, may be considered in
It has been estimated that 1% to 5% of TB patients also have cancer, most HIV-seronegative persons in the continuation phase of TB treatment
being male smokers. It is possible that cancer can arise in tuberculous of noncavitary pulmonary disease239,247; however, the rifapentine-INH
scars, and it is certain that cancer can erode old quiescent tuberculous regimen is not generally recommended in the recent ATS/CDC/IDSA
3002
guidelines.239 Once-weekly rifapentine should not be used to treat plus optimal background therapy, compared with optimal background
HIV-infected persons with active TB owing to the high risk for acquired therapy alone (48% vs. 9%, respectively).262 Potential toxicities include
rifamycin resistance.248 nausea and QT interval prolongation. The terminal elimination half-life
is 164 days; in one study almost all patients had detectable plasma levels
Pyrazinamide 96 weeks after the last dose.263 In December 2012, bedaquiline was
PZA is an essential component of 6-month regimens. Early studies of approved by the FDA for treatment of MDR-TB, but with a black box
PZA using high doses recorded such serious hepatotoxicity that it was warning because of a greater number of deaths in the bedaquiline arm
largely abandoned. At currently recommended doses, PZA is associated compared with those who received optimal background therapy only.
with higher rates of hepatotoxicity and rash than other first-line drugs.249 Safety will be monitored closely in future trials. A report of 35 French
Cohort and case-control analyses found that adding PZA to INH and patients who received bedaquiline for at least 1 month did not encounter
RIF increased the risk for hepatotoxicity appreciably.250 In addition, drug-associated deaths.264 With data now reported in the follow-up of
severe hepatic injury and deaths have been reported among predomi- patients through 120 weeks from baseline, the addition of bedaquiline
nantly HIV-negative adults receiving short-course RIF plus PZA for led to faster culture conversion and more conversions at the end of
LTBI.251 The beneficial effect of PZA is limited to the first 2 months observation. There were 10 deaths in the 79-patient bedaquiline group
in regimens containing both INH and RIF.252 Additional side effects compared with 2 in the 81-patient placebo group, although FDA analysis
include hyperuricemia, mild nongouty polyarthralgias that respond to of these differences noted that both deaths in the placebo group and 5
nonsteroidal antiinflammatory agents, and gout. M. bovis is uniformly in the bedaquiline group were due to progression of disease.265,266
resistant to PZA.253 A large retrospective observational study among 428 MDR-TB patients
treated with bedaquiline noted good safety and tolerability, and only
Ethambutol one death.267 The recommended dosage for bedaquiline is 400 mg once
EMB is included in initial treatment regimens until drug susceptibility daily orally for 2 weeks, followed by 200 mg three times a week for 22
results are returned and resistance to the other first-line drugs has been weeks taken orally with food to maximize absorption. Pharmacokinetic
excluded, at which time it can be discontinued. It is given at a daily analysis suggests that penetration into the CSF is poor.268 High cost
dose of 15 to 20 mg/kg. At 15 mg/kg the risk for ocular toxicity is low, may be a significant barrier to use of bedaquiline. Drug interactions
but assessment of visual acuity and color discrimination should be will require further study; phase I data indicate that RIF and rifapentine
performed at baseline and monthly while the patient is on therapy. increase bedaquiline clearance (4.78- and 3.96-fold, respectively).269
Interactions with HIV therapy that includes the potent CYP3A4 inhibitor
Streptomycin ritonavir suggest that concomitant administration with bedaquiline
STM, the first major antituberculous drug, was promptly replaced by might require dose adjustment.270 A provisional guideline for use of
INH as the cornerstone of therapy. Its activity is similar to that of EMB bedaquiline has been published.271
when either drug is given with INH, RIF, and PZA. Its use is limited
by relatively high rates of resistance (particularly in high-incidence Second-Line Agents
countries), parenteral administration, nephrotoxicity, and ototoxicity. Second-line agents are less efficacious or more toxic, or both, than first-line
drugs. These include ethionamide, cycloserine, terizidone (available
Fluoroquinolones overseas), amikacin, kanamycin, capreomycin, thiacetazone, para-
In vitro activity and some favorable trial results suggest that fluoroqui- aminosalicylic acid (PAS), and other agents discussed in Chapter 39.
nolones, particularly later-generation agents such as levofloxacin and
moxifloxacin, are effective antituberculosis drugs.254–256 However, fluo- Third-Line Agents
roquinolones should not be used as first-line therapy but rather should Third-line agents have even less activity against M. tuberculosis than
be reserved for patients who are intolerant of first-line drugs or who second-line agents and are usually given only as adjunctive therapy to
have drug-resistant TB, as part of a well-designed multidrug regimen. persons with XDR-TB. These drugs have generally not been evaluated
In the treatment of INH-resistant infection, a retrospective cohort study in a systematic manner for the treatment of TB. Such drugs include
found more frequent favorable outcomes with regimens that contained amoxicillin-clavulanate, clarithromycin, and linezolid (see “Treatment
a fluoroquinolone, without regard to the other components of standard of Multidrug-Resistant Tuberculosis” and “Therapy for Extensively
TB therapy.257 In countries where fluoroquinolones are easily available, Drug-Resistant Tuberculosis”). Clofazimine is also in this group, but
use of quinolones by persons with undiagnosed TB is likely contributing is now being evaluated as a more prominent treatment option given its
to increased resistance in M. tuberculosis. In a high-prevalence country important role in shortening treatment of MDR-TB.272,273
such as India, rates of quinolone resistance are already high both in
new and previously treated cases.258 The potential role of fluoroquinolones Agents Under Development
as first-line antituberculosis therapy is currently under evaluation in There are several new drugs that are currently under investigation for
clinical trials. A 6-month regimen in South Africa, Zimbabwe, Botswana, potential use in MDR-TB. These include the oxazolidinones (e.g., sutezolid
and Zambia using daily (2 months) and then weekly moxifloxacin in [Sequella] and LCB01-0371 [LegoChem Biosciences]), nitroimidiazoles
place of INH and weekly rifapentine was as effective as a control (e.g., delamanid [Otsuka] and pretomanid [Global Alliance for TB Drug
regimen.247 A dose of moxifloxacin 10 mg/kg/day may be insufficient Development]), and diamines (e.g., SQ-109 [Sequella]).274 Delamanid,
for children 7 to 15 years of age being treated for MDR-TB.259 when given with optimal background therapy for MDR-TB, was associated
Unfortunately, multiple phase III trials have not supported the use with significantly higher rates of 2-month sputum culture conversion.275
of fluoroquinolones in regimens meant to shorten the duration of therapy However, it did not improve cure and survival compared with optimal
to 4 months. In sub-Saharan Africa, a 4-month gatifloxacin-containing background therapy in a phase III trial, so WHO has recommended
regimen was inferior to standard therapy.260 The previously referenced that it be used when other, more effective drugs, cannot be used.276 Of
trial in South Africa, Zimbabwe, Botswana, and Zambia contained an note, delamanid significantly prolongs the QT interval.277 Pretomanid
arm based on 4-month therapy that was inferior to standard therapy, (PA-824) is a prodrug, as is delamanid, and in phase II trials seems to
and a trial in nine countries on three continents also found that a have had its greatest efficacy in combinations containing PZA.277,278 A
4-month regimen replacing EMB or INH with moxifloxacin was inferior phase IIb trial in drug-susceptible and drug-resistant TB of a regimen
to standard 6-month therapy.247,261 of moxifloxacin, pretomanid, and PZA had an acceptable safety profile.
Bactericidal activity was superior at the 8-week assessment, although
Bedaquiline the predictive utility of that end point remains controversial.279
Bedaquiline (Sirturo) is a diarylquinoline; its mechanism of action is
adenosine triphosphate synthase inhibition. It has potent activity against Selecting a Drug Regimen
M. tuberculosis. In persons with MDR-TB, there were improved 2-month Before RIF was available, excellent results in drug-sensitive infections
sputum culture conversion rates among those who received bedaquiline were obtained with INH plus either PAS or EMB given for 18 to 24
3003
months, “reinforced” in extensive disease by STM for the first 6 to 12 Several well-studied regimens are presented in Tables 249.7 and 249.8.239
weeks. Relapse rates were unacceptably high with shorter courses. As an alternative in persons with drug-susceptible disease, INH and
However, demonstration that RIF was equal to INH in efficacy led to RIF can be given daily during the first 2 months, followed by 7 months
studies of shorter treatment regimens. In definitive studies, drug-sensitive of either daily or intermittent therapy, with no less than thrice-weekly

TB responded as effectively to 9 months of INH and RIF as to 18- to administration preferred.239,289 When given thrice or twice weekly, the
24-month regimens not containing RIF.280,281 It was subsequently RIF dose remains the same and the INH dose is increased to 15 mg/
demonstrated that 6-month regimens based on an initial 2-month kg (900 mg maximum). In persons with a cavity on initial chest
intensive “bactericidal phase” of INH, RIF, PZA, and either STM or radiograph and positive sputum cultures after 2 months of therapy, TB
EMB, followed by a “continuation phase” of INH and RIF for 4 more relapse risk is high290; INH and RIF should be continued for an additional
months, performed as well.282–284 Next it was shown that neither STM 3 months (9-month total course) to decrease the relapse risk.239
nor EMB improved results over a three-drug regimen (INH, RIF, and In persons with resistance to or intolerance of INH, a 6-month
PZA) during the first 2 months of intensive therapy when the isolate regimen of RIF, PZA, and EMB can be used. Results of all 6-month
was fully susceptible.282 This 6-month three-drug regimen is acceptable regimens in patients with initial resistance to RIF are poor, and such
for drug-sensitive disease. However, given concerns about resistance, cases probably require 18- to 24-month courses, as was the case before
EMB should be included until susceptibility testing results are known. RIF was available.291
A 6-month continuation phase of INH and EMB is inferior to a 4-month When hepatitis (defined as aminotransferase levels greater than five
continuation phase of INH and RIF.285 times the upper limit of normal regardless of symptoms or greater than
three times the upper limit of normal in persons with symptoms of
Standard Regimens Based on Isoniazid hepatitis) occurs in patients receiving INH, RIF, and/or PZA, all drugs
and Rifampin should be discontinued until hepatic aminotransferase levels normalize
The combination of INH (5 mg/kg; maximum 300 mg), RIF (10 mg/kg; and symptoms resolve. Drugs may then be cautiously reintroduced in
maximum 600 mg), PZA (25 mg/kg, maximum 2 g), and EMB (15 mg/ a stepwise fashion while serum aminotransferase levels are monitored.
kg), all given once daily by mouth, should be initiated in persons suspected If persons are intolerant of INH, a regimen of RIF, PZA, and EMB can
of having TB.239,286,287 Therapy should be given daily throughout the entire be given to complete a 6-month course. If persons are intolerant of RIF,
course of treatment.239 If intermittent therapy is considered, it should be a more prolonged (18- to 24-month) regimen based on INH and at
no less frequent than three times per week, and given only in persons at least one companion drug (e.g., EMB and possibly a fluoroquinolone)
low relapse risk.239 Intermittent therapy should be provided under direct can be continued.
observation. These four drugs should be continued for 2 months; EMB
can be discontinued when susceptibility results are received, noting that Directly Observed Treatment
the infecting organism is susceptible to the other three drugs. Poor adherence to antituberculosis therapy over the entire course of
At the end of 2 months, PZA and EMB can be discontinued and treatment, with resultant development of drug-resistant TB and low
INH and RIF continued to complete a 6-month course. Several treatment rates of TB cure and treatment completion, has led to the recommen-
regimens have been endorsed by the CDC, ATS, IDSA,239 and WHO.288 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.
3004
TABLE 249.8 First-Line Tuberculosis Medicationsa

DRUG DOSE MAJOR ADVERSE RECOMMENDED
(MAXIMUM) REACTIONS MONITORING DOSAGE FORMS COMMENTS
Isoniazida (INH)
Daily Hepatic enzyme elevation, Baseline hepatic enzymes Scored tablets: 50 mg, Hepatitis risk increases with
C: 10–15 mg/kg (300 mg) peripheral neuropathy, Repeat monthly if baseline 100 mg, and 300 mg age and alcohol
A: 5 mg/kg (300 mg) hepatitis, rash, CNS effects, abnormal, risk factors for Syrup: 50 mg/5 mL consumption. Overdose may
Once weekly increased phenytoin, hepatitis, or symptoms of Aqueous solution (IV/IM): be fatal. Aluminum-
C: Not recommended (Dilantin), and disulfiram adverse reactions Scarce and may not be containing antacids reduce
A: 15 mg/kg (900 mg) (Antabuse) levels available absorption. Pyridoxine
Twice weekly (vitamin B6) may decrease
C: 20–30 mg/kg (900 mg) peripheral neuritis and CNS
A: 15 mg/kg (900 mg) effects.
Three times weekly
C: Not recommended
A: 15 mg/kg (900 mg)
Rifampina (RIF)
Daily Hepatitis, fever, CDC no longer recommends Capsules: 150 mg and Patients on methadone will
C: 10–20 mg/kg (600 mg) thrombocytopenia, flulike routine monitoring tests; 300 mg need an increased dose of
A: 10 mg/kg (600 mg) syndrome, rash, however, many clinicians Syrup: can be formulated methadone (average 50%) to
Once weekly gastrointestinal upset, renal continue to order baseline from capsules by pharmacy avoid opiate withdrawal.
C: Not recommended failure CBC, platelets, hepatic Aqueous solution (IV/IM): Interaction with many drugs
A: Not recommended Reduces levels of many drugs, enzymes Scarce and may not be leads to decreased levels of
Twice weekly including methadone, Repeat if baseline abnormal, available one or both. May make
C: 10–20 mg/kg (600 mg) warfarin (Coumadin), birth risk factors for hepatitis, or glucose control more difficult
A: 10 mg/kg (600 mg) control pills, theophylline, symptoms of adverse in diabetics. Contraindicated
Three times weekly dapsone, ketoconazole, PIs, reactions for patients taking PIs and
C: Not recommended and some NNRTIs some NNRTIs. Women on
A: 10 mg/kg (600 mg) Orange discoloration of birth control pills need a
secretions (sputum, urine, barrier method while on
sweat, tears) and may rifampin.
permanently stain soft
contact lenses
Pyrazinamide (PZA)
Daily Gastrointestinal upset, Scored tablets: 500 mg May complicate management
C: 15–30 mg/kg (2 g) hepatotoxicity, of diabetes mellitus. Treat
A: 15–30 mg/kg (2 g) hyperuricemia, arthralgias, increased uric acid only if
Once weekly rash, gout (rare) symptomatic. Most common
C: Not recommended reason for TB patients
A: Not recommended experiencing GI upset.
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 Decreased red-green color Baseline tests of visual acuity Tablets: 100 mg and 400 mg Optic neuritis may be
C: 15–20 mg/kg (1000 mg) discrimination, decreased and color vision unilateral; check each eye
A: 15–25 mg/kg (1600 mg) visual acuity (optic neuritis), Monthly testing for patients separately. Not recommended
Once weekly rash taking >15–25 mg/kg, for for children too young for
C: Not recommended those taking EMB for >2 mo, monitoring of vision unless
A: Not recommended and for patients with renal drug resistant. Use lowest
Twice weekly insufficiency possible dose in range
C: 50 mg/kg (2.5 g) (except for drug-resistant
A: 50 mg/kg (4 g) patients). EMB should be
Three times weekly discontinued immediately
C: Not recommended and permanently if any signs
A: 25–30 mg/kg (2400 mg) of visual toxicity occur.
Rifabutin (RBT)
Daily Hepatitis fever, Baseline hepatic enzymes Capsules: 150 mg Patients on methadone may
C: Not recommended thrombocytopenia, Repeat if baseline values need an increased dose to
A: 5 mg/kg (300 mg) neutropenia, leukopenia, abnormal, risk factors for avoid opiate withdrawal.
Once weekly flulike symptoms, hepatitis, or symptoms of Interaction with many drugs
C: Not recommended hyperuricemia Orange adverse reactions leads to decreased levels of
A: Not recommended discoloration of secretions one or both. May make
Twice weekly (sputum, urine, sweat, glucose control more difficult
C: Not recommended tears) and may permanently in diabetics. Women on birth
A: 5 mg/kg (300 mg) stain soft contact lenses control pills need to use a
Three times weekly Reduces levels of many drugs, barrier method while on
C: Not recommended including methadone, rifabutin.
A: 5 mg/kg (300 mg) warfarin (Coumadin), birth In combination with NNRTIs or
control pills, theophylline, PIs, dosages change
dapsone, ketoconazole, PIs, significantly.
and NNRTIs
With increased rifabutin
levels, severe arthralgias,
uveitis, leukopenia occur
3005
TABLE 249.8 First-Line Tuberculosis Medicationsa—cont’d

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

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 and genotypic data. In 832 patients with MDR disease followed by the
that are prevented.292 Because all doses are observed, compliance is Green Light Committee (GLC), the mandate of which is to facilitate
improved and the likelihood of emergence of resistance minimized. The increased access to these interventions in middle- and low-income
ability of mandatory DOT to control drug resistance in a community countries, 8.9% without baseline resistance to second-line agents still
is well established.293,294 In some cases, recalcitrant patients must be acquired XDR disease, and as baseline drug resistance increased, the
detained for completion of therapy. risk of new cases with acquired XDR TB increased also. There was less
resistance acquired during treatment in GLC-approved sites.297 Additional
Regimens of Less Than 6 Months for data from the United States support the need for increased monitoring
Minimal Disease for treatment failure associated with the acquisition of resistance to
Extent of disease can be quantified by the mycobacterial content of second-line drugs, with mortality significantly higher (26.5% vs. 10.0%)
sputum, with smear- and culture-positive sputum representing most in patients with acquisition of resistance versus control patients.298
severe disease, smear-negative and culture-positive sputum representing Acquisition of resistance may impart greater risk than baseline resistance
intermediate disease, and smear- and culture-negative sputum represent- to the same drugs.299 It is important to note retrospective results from
ing the least amount of disease. The possibility that the early bactericidal the Russian Federation, where an “aggressive” regimen of at least five
activity of moxifloxacin or gatifloxacin in combinations might permit likely effective drugs was associated with a decreased risk of death and
4-month regimens in smear-positive, culture-positive cases has, to date, failure during MDR-TB treatment.300
not been confirmed (see “Fluoroquinolones”).247,257,260 Good results have For therapy for TB that is resistant to both INH and RIF, susceptibility
been obtained with as little as 4 months of therapy in patients with less testing for second-line drugs should be performed and treatment
extensive TB.295 A 4-month course of treatment (2 months of INH, RIF, individualized according to the susceptibility test results. Support for
PZA, and EMB followed by 2 months of INH and RIF) is recommended this recommendation has been provided in a meta-analysis of studies
for HIV-seronegative persons with smear-negative, culture-negative including almost 9000 patients, in whom susceptibility testing for EMB,
pulmonary TB.239 In HIV-seropositive persons with culture-negative PZA, and second-line agents was associated with higher odds of treatment
TB, a 6-month regimen is recommended. success.301 In some settings, standardized second-line regimens are used.
If a suboptimal regimen is prescribed, resistance to additional drugs
Fixed-Dose Combination Tablets may emerge and the opportunity for success may be lost. In a study
Fixed-dose preparations are available; these contain 150 mg of INH from Denver, Colorado, only one-half of 171 HIV-negative patients
and 300 mg of RIF (Rifamate); INH 50 mg, RIF 120 mg, and PZA with MDR-TB ever converted sputum cultures to negative despite
300 mg (Rifater); or INH 75 mg, RIF 150 mg, PZA 400 mg, and EMB prolonged administration of carefully selected regimens (not including
275 mg (Rifafour). These prevent the patient from omitting drugs and fluoroquinolones).302 In a follow-up study from the same institution,
taking monotherapy and therefore decrease the risk for resistance. the long-term success rate was 75%.303 In a study from Latvia, 66% of
Fixed-dose combinations are particularly useful when DOT cannot be MDR-TB patients completed therapy or were cured.304 In contrast, two
provided. smaller studies among HIV-seronegative patients from New York City
and San Francisco noted remission in virtually all evaluable HIV-negative
Treatment of Multidrug-Resistant patients treated for MDR-TB.305,306 A study from Bangladesh found that
Tuberculosis at least 9 months of gatifloxacin, clofazimine, EMB, and PZA, supple-
Surprisingly, studies of four-drug, 6-month chemotherapy demonstrated mented with prothionamide, kanamycin, and high-dose INH during
that initial INH or STM resistance did not compromise outcome, but an initial intensive phase of at least 4 months, resulted in an 88%
results were very poor (>50% lack of conversion or relapse) when initial relapse-free cure rate.272 Recent preliminary results of the STREAM
RIF resistance was present.291 In a meta-analysis, treatment failure and trial, in which the “Bangladesh” regimen was compared with standard
relapse were substantially higher in the presence of initial drug resis- therapy, demonstrated similar effectiveness of the 9-month regimen,
tance.296 A critical component in combatting the development of although noninferiority was not demonstrated.307 A randomized trial
extensively resistant strains in patients with MDR-TB is access to effective of the addition of clofazimine to “individual-based” drug regimens in
second-line agents, with increased sputum culture, susceptibility testing, China found a significant increase in treatment success in the clofazimine
3005.e1
Update: Six-Month Treatment of Drug-Resistant Tuberculosis
3006
group versus the control group (74% vs. 54%; P = .035).308 In a CDC monitored regularly, particularly early in the course of therapy. Patients
report, 38% of MDR isolates were resistant to PZA, so the role of PZA receiving EMB should be regularly questioned regarding visual symptoms;
may be limited in MDR-TB.309 For TB that is INH and RIF resistant their visual acuity should be measured (Snellen chart) and red-green
but fluoroquinolone susceptible, a fluoroquinolone should always be color discrimination assessed monthly. Patients receiving STM should
administered along with other drugs to which the organism is susceptible. be examined for balance and high-frequency hearing loss, and their
In this setting, 2-month sputum culture conversion rates are improved renal function should be monitored closely.
by adding bedaquiline.262 The risk for treatment failure is increased if Relapse after adequate treatment of drug-sensitive infections is
the M. tuberculosis isolate is also resistant to fluoroquinolones.310,311 infrequent (2%–5%). Prolonged follow-up of appropriately treated patients
Levofloxacin may be preferred over ofloxacin, but moxifloxacin has the is not necessary except in the case of unusually extensive disease, slow
greatest in vitro activity against M. tuberculosis. Companion drugs may bacteriologic response to treatment, suspicion of poor compliance,
include aminoglycosides (STM, kanamycin, or amikacin) or capreomycin, drug-resistant disease, or high-risk patients with intercurrent diseases.
ethionamide, and cycloserine.305,312–315 The injectable agents are particu- In high-incidence settings, an additional 12 months of INH after
larly important for good outcomes, although nephrotoxicity and ototoxic- completion of a 6-month RIF-containing regimen reduces the TB
ity are concerns. The uncertain efficacy of newer therapies is underlined recurrence rate among HIV-infected adults.326,327 However, such a practice
by the report of the development of resistance to bedaquiline and is often not performed owing to logistical constraints.
delamanid during treatment of MDR-TB.316 In a small observational
study of imipenem/clavulanate added to an optimized background Retreatment
regimen, either indifferent or worse outcomes were noted, suggesting Recurrent TB may be due to either relapse (same M. tuberculosis strain
that adding imipenem-clavulanate in the setting of treatment failure as the original episode) or reinfection (different M. tuberculosis strain).
was not likely to improve outcome.317 Genotyping (RFLP, MIRU, and spoligotyping) or WGS may be used to
distinguish M. tuberculosis isolates. Clinical judgment based on experience
Therapy for Extensively is critical in re-treatment cases, and testing of susceptibility to first- and
Drug-Resistant Tuberculosis second-line drugs is required.239 Some generalizations concerning re-
Therapy for XDR-TB, which is defined as resistance to INH, RIF, any treatment can be made:
fluoroquinolone, and at least one of three injectable second-line drugs 1. In a patient with drug-susceptible TB who receives
(amikacin, kanamycin, or capreomycin),112 is difficult and usually rifamycin-based DOT, relapse is likely due to a drug-susceptible
associated with poor outcomes. The risk for treatment failure and death organism. Such patients usually respond again to the initial
has been higher than in patients with MDR-TB in some series,318,319 but regimen.
not all.320 Cure rate in a report from South Africa was 5%, and mortality 2. If compliance has been irregular, particularly if the patient has not
was 78% at 60 months.321 Treatment with at least five drugs to which received DOT, resistant organisms will probably be present.
the organism is susceptible is recommended. In a study of 41 patients 3. When drug resistance is suspected, the treatment regimen should
with treatment-refractory XDR-TB, linezolid was associated with sputum include INH, RIF, PZA, EMB, a fluoroquinolone, and an
culture conversion, but 82% of patients had clinically significant adverse injectable agent (e.g., capreomycin), pending susceptibility results.
events attributable to linezolid.322 The cure rate 1 year after the end of 4. Capreomycin or amikacin can replace STM. Kanamycin is less
treatment was 78%.323 A similar trial in China also found a significantly effective and more toxic and is used as a last resort. There is
higher cure rate (70% vs. 34% in the control group), but again with an usually no cross-resistance between capreomycin and STM,
adverse event rate in the linezolid group of 82%.324 A retrospective amikacin, or kanamycin, but amikacin and kanamycin are usually
report in a predominantly HIV-infected South African population noted cross-resistant.
improved culture conversion with clofazimine (40% vs. 29% in the 5. TB resistant to INH and RIF (i.e., MDR-TB) should be treated
comparator group), with only minor adverse effects.325 with a fluoroquinolone, ethionamide (or protionamide), PZA, and
probably an injectable agent plus either cycloserine or PAS. The
Course of Therapy and intensive phase of treatment is for 8 months, and the total
Duration of Observation treatment duration is 20 months.314,315,328 For those who meet the
At least three sputum samples should be submitted for smear and culture criteria, the 9-month short-course regimen should be
before beginning treatment. If available, specimens for GeneXpert should considered.315
also be obtained. In patients with presumed TB, treatment should be 6. TB resistant to INH, RIF, an injectable agent, and a
initiated immediately; a few days of antituberculous treatment will not fluoroquinolone (i.e., XDR-TB) should be treated with at least
interfere with bacteriologic diagnosis. If cultures are negative and there four second-line antituberculosis drugs likely to be effective, in
are no alternative diagnoses, clinical and radiographic response to therapy addition to PZA during the intensive phase of treatment.315,320
after 2 months of treatment is consistent with a diagnosis of TB. Beginning Surgical resection may be required. A prolonged course of
1 month after initiation of therapy, three sputum cultures should be treatment is necessary, but the optimal duration is unknown.
obtained monthly to monitor conversion to negative or, if sputum cultures
remain positive, to detect treatment failure and the possible emergence Other Forms of Treatment
of drug resistance. Sputum cultures should convert to negative within Bed rest does not influence outcome when effective chemotherapy is
2 months. In a minority of patients, sputum smears remain positive given. Resection still has a role in the salvage of patients in whom
after cultures turn negative. Sporadic positive smears for long periods treatment fails and who have localized, resectable disease, and extensive
presumably represent inactive bacilli released from caseous foci. When drug resistance.
cultures remain positive after 4 months of treatment, it is considered
treatment failure. Causes of treatment failure include drug resistance, Corticosteroids
noncompliance with therapy, and malabsorption of antituberculosis Corticosteroids in conjunction with antituberculosis therapy improve
drugs. Sensitivity testing should be performed and consideration given neurologic outcome and mortality in persons with tuberculous meningitis.
to adding at least two new drugs to which the organism was sensitive Use of corticosteroids is therefore recommended in this situation. For
at the outset of treatment, at least until sensitivities are known. Addition all other clinical manifestations of TB, however, there is no definite
of only one drug risks development of resistance to the added drug. long-term benefit of adjunctive corticosteroids and therefore no thera-
Adherence to therapy should be ensured and serum drug levels considered peutic role.329
to assess absorption.
Patients receiving INH, RIF, and PZA should be asked monthly Treatment of Tuberculosis in
about symptoms of hepatitis, and hepatic aminotransferase levels should HIV-Infected Patients
be checked in symptomatic persons. In persons with abnormal hepatic The treatment of HIV-related TB is complicated by major drug-drug
aminotransferase levels at baseline, such laboratory findings should be interactions between antituberculosis drugs and ART. These interactions
3007
affect the choice of therapy (and appropriate doses) for both diseases. Immune Reconstitution
Invaluable websites that provide extensive advice and information Inflammatory Syndrome
regarding treatment options for HIV-related TB, including managing Immune reconstitution inflammatory syndrome (IRIS) results from
and avoiding drug-drug interactions, are maintained by the Department rapid restoration of immune responses to opportunistic pathogens, most

of Health and Human Services245 and the CDC.330 These websites are importantly M. tuberculosis. This has most often been described in
updated regularly and should be consulted routinely because new patients receiving ART. It has additionally been seen in other immu-
antiretroviral agents and interactions are being discovered. Chapter 39 nodeficiencies, as in a report of a severe inflammatory reaction that
includes tables from the CDC website about use of antiretroviral agents occurred during therapy of disseminated TB in a Thai woman who had
together with RIF or rifabutin. anti–interferon-γ antibodies.342 Characteristic features include initiation
The rifamycins interact with many HIV-1 protease inhibitors, non- of virologically effective ART within the previous 3 weeks (the period
nucleoside reverse transcriptase inhibitors, and integrase strand transfer of most rapid immune recovery), clinical deterioration with exaggerated
inhibitors.245 Among the rifamycins, RIF has the most interactions; inflammation, and absence of an alternative explanation such as drug
rifapentine appears to have a similar effect,331 but rifabutin has less resistance, drug hypersensitivity, other infections, or lymphoma. TB-
profound interactions. RIF is contraindicated for use with HIV-1 protease associated IRIS comprises two main categories: (1) onset in patients
inhibitors (e.g., saquinavir, indinavir, nelfinavir, fosamprenavir, atazanavir, who are already being treated for TB (termed paradoxical IRIS) and
darunavir, tipranavir) and the nonnucleoside reverse-transcriptase (2) onset in patients with previously unrecognized, untreated TB (termed
inhibitors etravirine and rilpivirine. RIF also lowers nevirapine levels, unmasking IRIS). During paradoxical IRIS, patients have typically been
so there are concerns that these two drugs should not be given in responding to TB therapy but develop recurrent, new, or worsening
combination.245 Maraviroc can be used with RIF if the maraviroc manifestations, such as fever, cough, lymph node enlargement, or
dose is increased to 600 mg twice daily. The RIF pharmacokinetic radiographic abnormalities after starting antiretroviral agents.343,344 Such
interaction with saquinavir-ritonavir and lopinavir-ritonavir may be patients demonstrate robust peripheral blood T-cell responses to PPD
overcome with increased protease inhibitor dosages.332,333 However, and increased proinflammatory cytokines.345 Paradoxical IRIS is most
several healthy volunteer studies were prematurely terminated when likely to occur in patients with more advanced AIDS, disseminated and
individuals receiving RIF promptly developed marked hepatotoxicity with extrapulmonary TB, and a good immunologic and virologic response
addition of ritonavir-boosted lopinavir,332 saquinavir,333 or atazanavir.334 to antiretroviral agents and in those who initiate antiretroviral agents
Accordingly, these combinations are generally not used. Rifabutin may soon after starting antituberculous drugs.346,347 Reported frequencies
be used in combination with protease inhibitors, with appropriate dose range from 8% to 43%.346 Although symptoms of paradoxical IRIS are
modification.245 Unfortunately, rifabutin is not presently available in usually self-limited and last a median of 2 months,348,349 morbidity can
most resource-limited countries. be substantial and mortality can occur but is rare. A 4-week course of
RIF modestly lowers plasma levels of efavirenz and, to a greater prednisone improved symptoms and decreased the need for hospitaliza-
extent, nevirapine. However, among patients receiving multidrug tion in one clinical trial.350 Paradoxical reactions such as lymph node
regimens for TB, RIF has been shown to paradoxically increase enlargement or cerebral tuberculomas infrequently affect HIV-negative
plasma levels of efavirenz, particularly among CYP2B6 slow metabo- individuals or HIV-positive individuals not receiving antiretroviral
lizers335; NAT2 slow metabolizers of INH may also contribute to agents. In one study, paradoxical reactions affected 36% of HIV-infected
increased efavirenz levels.336 RIF does not appear to affect the antiviral patients receiving therapy for both TB and HIV but only 2% of HIV-
efficacy of efavirenz, and they can be administered concomitantly negative patients and 7% of HIV-infected patients not on ART.343 Para-
with the efavirenz dose maintained at 600 mg daily, particularly in doxical reactions after the initiation of ART tend to be more severe and
persons <60 kg. There are greater concerns about concomitant more likely to involve multiple organs. Paradoxical reactions in previously
administration of RIF and nevirapine. Several small studies have healthy patients can be confused with uncontrolled infection.
demonstrated favorable clinical and virologic responses, but toxicity Less is understood about unmasking IRIS. In resource-limited settings,
is greater than when RIF is given with efavirenz.337 In persons with TB is frequently diagnosed during the initial months of ART, but
concurrent TB at the start of ART, failure to achieve virologic underlying mechanisms vary.351 Some represent new or progressive TB
suppression was more common in persons who received nevirapine due to persistent immunodeficiency, some reflect active TB that was
than efavirenz (both given with RIF).338 RIF lowers raltegravir levels present but undiagnosed before ART was started, and others reflect
by 40%; the raltegravir dose should be increased to 800 mg twice subclinical TB that was truly unmasked by restoration of robust immune
daily and virologic response followed closely. No dosage adjustments responses to M. tuberculosis. Consensus case definitions have been
are needed when raltegravir is given with rifabutin. RIF lowers published to facilitate research into TB-associated IRIS in resource-limited
maraviroc levels by 64%. Although it is preferred to not coadminister settings.346
these drugs, if it is done, the dose of maraviroc should be increased The optimal timing of ART initiation in HIV-infected persons with
to 600 mg twice daily. Additional interactions and drug dose adjust- TB has been evaluated in three clinical trials.352–354 Among persons with
ments are given in Chapter 39. fewer than 50 CD4+ T cells/mm3, initiation of ART within 2 to 4 weeks
Despite this extensive list of interactions, it is not recommended of starting antituberculosis therapy was associated with improved
that treatment of TB be delayed or that highly active ART be avoided. AIDS-free survival compared with delayed initiation of ART. Among
Because antimycobacterial drugs other than the rifamycins do not have persons with more than 50 CD4+ T cells/mm3, initiation of ART 8 to
substantial interactions, an alternative regimen with INH, STM, PZA, 12 weeks after initiation of antituberculosis therapy was associated with
and EMB can be considered. However, in HIV-infected persons, regimens a lower risk for IRIS and adverse events without increasing the risk for
that are not rifamycin based may be less effective than rifamycin-based AIDS or death.353,354 The most recent TB treatment guidelines recommend
regimens. the timing of ART initiation in these patient groups according to these
Acquired rifamycin resistance in the setting of TB relapse is seen findings.239,288
almost exclusively in patients with advanced AIDS who receive highly
intermittent antituberculosis therapy, such as once-weekly INH plus Duration of Therapy
rifapentine or twice-weekly INH plus rifabutin.248,339 Additional data The duration of antituberculosis therapy is determined by relapse risk.
suggest that the risk of acquired RIF resistance is also increased in Several observational studies noted comparable relapse rates in HIV-
HIV-infected persons treated with thrice-weekly therapy.340 It is therefore infected and HIV-uninfected persons after 6 months of rifamycin-based
now recommended that HIV-infected persons should receive daily antituberculosis therapy. Based on these data, the current recommendation
antituberculosis therapy in both the intensive and continuation phase is to treat for the same duration regardless of HIV status, particularly if
of TB treatment.239 the HIV-positive patient is receiving ART.239,286,288 However, some obser-
Patients with HIV-related enteropathy may not respond to chemo- vational studies have noted higher recurrence rates in HIV-infected than
therapy because of inadequate absorption of oral agents, and, in some HIV-uninfected persons who receive 6 months of treatment.355,356 A recent
cases, pharmacokinetic monitoring may be necessary.341 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
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
3009
A 2-month regimen of daily RIF-PZA is as effective as a 12-month release assay results before exposure should be assembled. Persons with
daily regimen of INH in HIV-infected adults.370 Unfortunately, initial a negative test result should be retested 8 weeks after the exposure to
enthusiasm for this 2-month regimen waned after numerous reports allow time for TST or interferon-γ release assay conversion. However,
of severe liver injury and death, primarily in HIV-negative individuals.251 if exposure is particularly heavy, or in HIV-positive health care workers,

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

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 FIG. 249.7 Detail of a chest radiograph (left midlung zone) showing
countless 0.5- to 1.0-mm nodules typical of miliary tuberculosis.
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, indicate meningitis; abdominal pain may be due to peritonitis; and
although optimal duration is unknown).239 Adjunctive corticosteroids pleural pain may result from pleuritis. Physical findings are likewise
are recommended for persons with pericardial or CNS TB. usually nonspecific, but a careful search for cutaneous eruptions, sinus
Diagnostic difficulty and delay can have a devastating impact on tracts, scrotal masses, and lymphadenopathy may yield a prompt biopsy
survival in critically ill patients. In a study from Uganda, a highly endemic diagnosis. A miliary infiltrate on a chest radiograph is the most helpful
country, empirical therapy for TB, despite negative sputum smears, led finding and the usual reason miliary TB is suspected (Fig. 249.7).
to improved survival in patients presenting with “danger signs,” including Unfortunately, many patients, particularly the elderly, succumb to miliary
fever greater than 39°C, tachycardia greater than 120 beats/min, or TB before the chest radiograph becomes abnormal.404 The white blood
tachypnea greater than 30 breaths/min.398 However, among HIV-positive cell count is usually normal, and anemia is the rule. Hyponatremia with
persons with <50 CD4+ lymphocytes/mm3 starting ART, empirical the laboratory features of inappropriate secretion of antidiuretic hormone
four-drug therapy did not improve survival compared with INH preven- is frequent, particularly with meningitis.401 Addison disease should be
tive therapy alone.399 considered as a cause of hyponatremia. Increased levels of alkaline
phosphatase and aminotransferases are common, as are hypoxemia,
Miliary Tuberculosis hypocapnia, and impairment of pulmonary diffusion capacity. Cultures
The term miliary tuberculosis, first used to describe its pathologic of sputum, gastric contents, urine, and CSF are positive in some combina-
resemblance to millet seeds, now describes any progressive disseminated tion in most cases, but smears of sputum and pulmonary secretions
hematogenous TB. Miliary TB can be roughly divided into three groups: alone are positive in fewer than one-third. Immediate diagnosis often
(1) acute miliary TB associated with a brisk and histologically typical results from examination of tissue (lymph nodes, scrotal masses when
tissue reaction; (2) cryptic miliary TB, a more prolonged illness with present, liver biopsy, or bone marrow specimens). Mycobacterial blood
subtle clinical findings and an attenuated histologic response; and (3) cultures may also be positive. Transbronchial biopsy is an excellent way
nonreactive TB characterized by huge numbers of organisms, little to obtain tissue and should be performed promptly when the diagnosis
organized tissue response, and often a septic or typhoidal clinical is suspected.405 The finding of caseating granulomas or AFB is virtually
picture.164 diagnostic.
Rapid diagnosis is mandatory. However, treatment should be initiated
Usual (Acute) Miliary Tuberculosis immediately based on strong clinical suspicion, because mortality from
In the prechemotherapy era, miliary TB occurred either soon after miliary TB is most often due to delays in treatment. Response may be
primary infection in children or young adults or as a terminal event in prompt or may take several weeks. Fulminant miliary TB may be
untreated chronic organ TB. In children, the illness is acute or subacute, associated with severe refractory hypoxemia and disseminated intra-
with high intermittent fevers, night sweats, and occasional rigors. Pleural vascular coagulation.
effusion, peritonitis, or meningitis occurs in as many as two-thirds of
affected persons. The illness in young adults is usually more chronic Cryptic Miliary Tuberculosis and Late
and initially less severe. However, miliary TB is now more frequently Generalized (Chronic Hematogenous)
observed in older individuals, often with underlying illnesses or condi- Tuberculosis
tions that may confuse diagnosis. Chronic organ TB is probably always associated with intermittent,
Four large series in the chemotherapy era400–403 have emphasized the nonprogressive seeding of the bloodstream. In some individuals,
frequency of miliary TB in minority racial groups and the importance however, especially as age or other factors compromise immunity,
of underlying conditions such as alcoholism, cirrhosis, neoplasm, this becomes continuous and produces progressive hematogenous TB
pregnancy, rheumatologic disease, and treatment with immunosup- long after the primary infection.406 The term cryptic miliary tuberculosis
pressive agents (see Table 249.10).400–403 There is usually no prior history usually describes older patients with miliary TB in whom the diagnosis
of TB, and the onset is often subtle. Generalized symptoms of fever, is obscure because of normal chest radiographs, negative TST results,
anorexia, weakness, and weight loss are nonspecific. Headache may and often confounding underlying illnesses to which symptoms are
3012
mistakenly attributed407; this term has also been applied to miliary quiescent indefinitely before rupturing. This may follow head trauma
TB diagnosed at autopsy.404 or be associated with general depression of host immunity as a result
The foci responsible for late generalized TB are often clinically of alcohol abuse or other factors.
silent—for example, renal, genitourinary, osseous, or visceral lymph
nodes.406 Chronic pulmonary foci are at times involved but are rarely Pathologic Features
the only source. The clinical picture is frequently fever of unknown Meningeal involvement is most pronounced at the base of the brain.
origin, often with a normal chest radiograph and a negative TST result. In long-standing cases, a gelatinous mass may extend from the pons
Fever may be absent, and in one series antemortem diagnosis was made to the optic nerves, being most prominent adjacent to the optic chiasm.
in only 15% of cases.406 Late generalized TB may be associated with In more chronic cases, fibrous tissue may encase cranial nerves. Vasculitis
major hematologic abnormalities. of local arteries and veins may lead to aneurysm, thrombosis, and focal
hemorrhagic infarction. Perforating vessels to the basal ganglia and
Nonreactive Tuberculosis pons are most often involved, producing movement disorders or lacunar
The histologic appearance in this rare form of disseminated hema- infarcts; involvement of branches of the middle cerebral artery may
togenous TB shows nonspecific necrosis containing disintegrating cause hemiparesis.
neutrophils and enormous numbers of tubercle bacilli.190 In the typical
case, granulomas and epithelioid cells are lacking, although intermedi- Clinical Manifestations
ate cases have areas more typical for TB. The gross pathologic findings The usual illness begins with a prodrome of malaise, intermittent
are soft abscesses from minute to 1 cm, which always involve the headache, and low-grade fever, followed within 2 to 3 weeks by protracted
liver and spleen, usually the marrow, commonly the lungs and headache, vomiting, confusion, meningismus, and focal neurologic signs.
kidneys, but never the meninges. The clinical picture may be over- The clinical spectrum is broad, ranging from chronic headache or subtle
whelming sepsis, with splenomegaly and often an inconspicuous mental status changes to sudden, severe meningitis progressing to coma.
diffuse mottling on the chest radiograph. Major hematologic abnor- Fever may be absent, and the peripheral white blood cell count is usually
malities are common (see “Miliary Tuberculosis and Hematologic normal. Mild anemia is usual, and hyponatremia resulting from inap-
Abnormalities”). propriate antidiuretic hormone secretion is common. Evidence of
concomitant extrameningeal TB is present in roughly three-fourths of
Miliary Tuberculosis and Hematologic cases,411 with miliary shadowing on the chest radiograph being most
Abnormalities suggestive. In many cases, however, there are no clinical or historical
Some patients with late generalized TB and most with nonreactive TB clues to suggest TB.
have serious hematologic abnormalities, including leukopenia, throm- The cornerstone of diagnosis is examination of the CSF. The cell
bocytopenia, anemia, leukemoid reactions, myelofibrosis, and polycy- count generally ranges from 0 to 1500/mm3, the protein level is increased,
themia.408 Leukemoid reactions may suggest acute leukemia, although and the CSF glucose is characteristically low. A lymphocytic predomi-
most patients in whom hematogenous TB coexists with the clinical nance is usual, although one-fourth of cases have a polymorphonuclear
picture of leukemia have both diseases. Disseminated TB should be pleocytosis, usually early in the course. Identifying bacilli often requires
considered when pancytopenia is associated with fever and weight loss examination of large volumes of fluid from repeated lumbar punctures.
or as a cause of other obscure hematologic disorders. 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
Primary Hepatic Tuberculosis punctures were examined.411 Initial atypical findings such as neutrophilic
Rarely, miliary TB may mimic cholangitis, with fever, liver function pleocytosis, a normal glucose concentration, or even entirely normal
test abnormalities suggestive of obstructive disease, and little evidence CSF indices evolve to more typical mononuclear cell predominance
of hepatocellular disease. Diagnosis is made through liver biopsy. with hypoglycorrhachia over time. Commercial kits for detecting M.
tuberculosis in respiratory specimens by means of amplification technol-
Miliary Tuberculosis in AIDS ogy (see Table 249.1) can also be used on CSF. Overall, the sensitivity
In AIDS patients, 10% with TB and 38% with extrapulmonary TB of PCR assay for examination of the CSF is low. The CSF is often culture
have miliary disease.232,409 Major constitutional symptoms and hectic negative for M. tuberculosis, but the CSF PCR assay has been reported
fevers are characteristic. The chest radiograph is abnormal in 80% to be positive in roughly 60% to 90% of CSF samples that eventually
and may include typical miliary mottling. Only 10% of patients are are culture positive.412,413 Results of testing CSF with the Xpert MTB/
tuberculin positive.232 The sputum smear is positive in only 25%,409 RIF Ultra assay were positive in 16 of 23 cases of proven or probable
but cultures of many materials will be positive, including blood in tuberculous meningitis, making this the preferred rapid test for this
50% to 60%. Biopsy specimens during life show typical tuberculous infection.414
histologic appearance but with more stainable organisms than in In patients with meningitis, CT or MRI may reveal rounded lesions
non-HIV miliary TB. In fatal cases, in contrast, the histologic picture presumed to be tuberculomas, basilar arachnoiditis, cerebral infarction,
is often nonreactive TB.232 or hydrocephalus (Fig. 249.8). Contrast-enhanced MRI frequently reveals
Abscesses of various soft tissue and visceral organs have been concomitant spinal cord and radicular involvement (transverse and
described in patients with AIDS and TB, usually with other evidence longitudinal myelitis, spinal tuberculoma, or abscess and other manifesta-
of disseminated disease. Locations include the liver, spleen, pancreas, tions), which may lead to disabling complications.415
psoas muscle with or without spinal involvement, mediastinum, neck, Prognosis is influenced by age, duration of symptoms, and neu-
chest wall, abdominal wall, and prostate.232,409,410 Diagnosis is usually rologic deficits. Mortality is greatest in patients younger than age 5
made by means of CT or ultrasonography and confirmed with needle (20%), in those older than age 50 (60%), or in those in whom illness
or catheter aspiration. Clinical response to chemotherapy and drainage has been present for more than 2 months (80%).411 Patients without
is usually good. An abscess may appear or reappear during therapy and neurocognitive impairment, focal neurologic signs, or hydrocephalus
respond to repeated aspiration. at the start of therapy are likely to recover, whereas approximately
half of patients who are stuporous or have dense paraplegia or
Central Nervous System Tuberculosis: hemiplegia die or recover with severe residual neurologic defects.411
Tuberculous Meningitis A prognostic score derived from cases in 43 centers in 14 countries
This condition is usually caused by rupture of a subependymal tubercle found that altered consciousness, diabetes mellitus, immunosuppression,
into the subarachnoid space rather than direct hematogenous seeding. neurologic deficits, hydrocephalus, and vasculitis predicted an unfavor-
Meningitis complicating miliary disease usually develops several weeks able outcome in culture-proven tuberculous meningitis.416 Concomitant
into the illness. In childhood, meningitis is an early postprimary event, HIV infection does not appear to alter the clinical and laboratory
and three-fourths of these persons have a concurrently active primary manifestations or the prognosis of tuberculous meningitis, except that
complex, pleural effusion, or miliary TB. Subependymal foci may remain CNS mass lesions are more likely.417
3013
Tuberculous Pleurisy (Serofibrinous
Pleurisy With Effusion)
Types of Tuberculous Pleurisy
Early Postprimary Pleurisy With Effusion

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
FIG. 249.8 Multiple cerebral cortical densities on computed congestive heart failure to which the effusion is mistakenly attributed.
tomography scan of a patient with tuberculous meningitis. In one study, one half of pleurisy cases occurred in the setting of
established chronic pulmonary TB.421
Pleurisy With Effusion Complicating

Therapy Miliary Tuberculosis
In the presence of meningeal inflammation, both INH and PZA Pleural effusions occur in 10% to 30% of cases of miliary TB.400,402 These
reach concentrations in the CSF equaling those in blood. RIF pen- may be associated with other progressive extrapulmonary foci and
etrates the blood-brain barrier less well but still adequately. In some involvement of other serous membranes. Cases with coexistent pleural
cases, PZA is given beyond the first 2 months of treatment because (at times bilateral), peritoneal, and pericardial TB have been referred
of its excellent CNS penetration, although its activity after 2 months to as tuberculous polyserositis.
of treatment is unclear. The RIF dose is sometimes increased owing
to its poor CNS penetration, particularly with concomitant admin- Clinical Manifestations and Diagnosis
istration of corticosteroids. Otherwise, the dosages are as for pul- The clinical presentation may be low grade and subtle or abrupt and
monary TB. A recent study demonstrated that higher-dose RIF severe, easily confused with acute bacterial pneumonia. Cough and
(13 mg/kg IV vs. the standard 10 mg/kg oral), together with INH, pleuritic chest pain are usual, and fever may be high. The effusion is
PZA, and corticosteroids, was associated with improved 6-month usually less than massive and almost always unilateral except when
survival and neurologic recovery.418 However, a trial of intensification associated with miliary TB. The pleural fluid typically contains 500 to
with high-dose RIF (15 mg/kg/day) and levofloxacin for the first 8 2500 white blood cells/mm3, with more than 90% lymphocytes in
weeks, added to a standard 9-month regimen, in Vietnam failed to two-thirds of cases. However, 38% of cases in one series had predomi-
improve survival.419 nantly neutrophils and 15% had more than 90% neutrophils on the
Most authorities recommend adjunctive corticosteroids in TB first tap.422 Repeated taps demonstrate a shift to lymphocytic predomi-
meningitis, particularly stage 2 (objective neurologic findings) and nance. Mesothelial cells, characteristic of neoplastic effusions, are sparse
stage 3 (stupor-coma) patients, beginning prednisone at 60 to 80 mg or absent, eosinophils are rarely present, and less than 10% of effusions
daily. This may be gradually reduced after 1 to 2 weeks and discon- are serosanguineous. The pleural fluid protein level usually exceeds
tinued by 6 to 8 weeks, as guided by symptoms. Symptoms and CSF 2.5 g/dL, the glucose concentration is usually moderately low compared
abnormalities may rebound transiently as corticosteroids are tapered. with serum values but rarely less than 20 mg/dL, and the pH is almost
Ventricular shunting may be beneficial if symptomatic hydrocephalus always 7.3 or lower and may be as low as 7.0. Increased pleural fluid
supervenes. adenosine deaminase levels have been suggested to be highly sensitive
and specific for tuberculous pleuritis.423,424 High pleural fluid adenosine
Tuberculomas deaminase levels with other conditions (e.g., neoplasia) limit its diagnostic
Intracranial tuberculomas are space-occupying lesions that may manifest utility in countries with a low prevalence of TB,425 although levels with
as seizures. They are most frequently multiple, appearing on imaging such conditions infrequently exceed the suggested cutoff for TB.426,427
studies as avascular masses with surrounding edema. Corticosteroids A significant negative association of age and pleural fluid adenosine
reduce edema and decrease symptoms, and chemotherapy prevents deaminase suggests the need for a lower cutoff in patients older than
spread of infection in cases diagnosed at operation. 45 years, to decrease false-negative results.428 Bloody pleural fluid suggests
either TB or malignancy. In the usual case of early postprimary pleurisy
Tuberculous Spinal Meningitis with effusion, the acid-fast stain of the fluid sediment is seldom positive,
Infrequently, TB causes spinal meningitis with or without intracranial the culture is positive in 25% to 30%, pleural needle biopsy yields
involvement. In advanced cases, the cord may be completely encased granulomas in 75%, and culture of a needle biopsy specimen may be
in a gelatinous exudate. An intramedullary tuberculoma or an positive even in the 25% of cases with nonspecific pleuritis on histologic
extradural granulomatous mass can cause symptoms without men- examination. Cases complicating chronic pulmonary TB more often
ingeal involvement. Nerve root or cord compression causes pain, have positive pleural acid-fast smears (50%) and positive cultures (60%)
bladder or rectal sphincter weakness, hypesthesia, anesthesia, pares- but are less likely (25%) to demonstrate granulomas on pleural biopsy.
thesias in the distribution of a nerve root, or paralysis. Subarachnoid Repeat pleural biopsy may be necessary to establish the diagnosis, and
block may cause CSF protein concentrations to be extremely high, a small open pleural biopsy or thoracoscopy is diagnostic in virtually
with or without cells. 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, Therapy
sputum smear is positive in 50% and the culture is positive in 60% of Antibiotic treatment is the same as for pulmonary TB. In a large study
“reactivation” cases.421 TB is often not considered as the cause of a from South Africa from the 1980s, treatment with corticosteroids (60 mg/
pleural effusion in an older person with complicating illnesses such as day for 4 weeks, 30 mg/day for 4 weeks, and 15 mg/day for 2 weeks)
cirrhosis or congestive heart failure.422 When pleural effusion complicates decreased mortality from 11% in controls to 4% in treated patients.
miliary TB, findings associated with the latter condition usually dominate Pericardiectomies were also less frequently necessary in patients given
the clinical picture. corticosteroids (30% in controls vs. 11% in corticosteroid-treated
patients). However, a larger comparative trial of immunotherapy with
Therapy either Mycobacterium indicus pranii (1250 patients) or prednisolone
Early postprimary pleural effusions spontaneously resolve in 2 to 4 (1400 patients), for definite or probable tuberculous pericarditis, failed
months. Chemotherapy does not hasten resolution but prevents active to demonstrate a significant effect on a composite score of death, cardiac
disease elsewhere in the body, which will otherwise occur in 65% of tamponade requiring pericardiocentesis, or constrictive pericarditis.434
cases.420 Therapy is as described for pulmonary TB. Multiple thora- The incidence of constrictive pericarditis and hospitalization was
centeses are not necessary once the diagnosis is established and decreased in prednisolone-treated patients, and rates of adverse events,
treatment initiated. A small minority heals with pleural fibrosis. especially cancer, were elevated in HIV-infected patients. Because the
Corticosteroid therapy hastens symptomatic improvement and fluid size of this study was much larger than that in previous reports, current
resorption, but no long-term benefit has been shown and therefore it recommendations for the use of adjunctive corticosteroids in the
is not recommended. management of tuberculous pericarditis have been revised: They should
not be routinely used.239 However, selective use of corticosteroids in
Tuberculous Empyema and persons at the highest risk of inflammatory complications should be
Bronchopleural Fistula considered. Surgical drainage via a subxiphoid pericardial window at
Tuberculous empyema occurs when a major cavity ruptures into the outset did not decrease either mortality or the eventual need for
the pleural space. This often catastrophic illness is usually associated pericardiectomy, although it provided diagnostic tissue and obviated
with bronchopleural fistula formation and frank pus. Before anti- the need for recurrent pericardiocenteses. However, 2% surgical mortality
tuberculous drugs were available, tuberculous empyema was almost was associated with the procedure.431,435
always rapidly fatal. It virtually never occurs in patients being treated When hemodynamic compromise persists for 6 to 8 weeks, peri-
with chemotherapy. cardiectomy is usually indicated, and this should probably be performed
earlier rather than later. Approximately two-thirds of patients, however,
Tuberculous Pericarditis do well without surgery.
Tuberculous pericarditis is most often caused by extension from a
contiguous focus of infection, usually mediastinal or hilar nodes but Skeletal Tuberculosis: Pott Disease
also the lung, spine, or sternum. Less commonly, it occurs during miliary (Tuberculous Spondylitis)
TB. It sometimes develops during the course of otherwise effective drug One-third of cases of skeletal TB involve the spine, as a result of past
therapy. In the United States, tuberculous pericarditis is an uncommon hematogenous foci, contiguous disease, or lymphatic spread from pleural
complication of AIDS; but in two series from sub-Saharan Africa, the disease. The earliest focus is the anterior superior or inferior angle of
vast majority of effusive pericarditis cases were tuberculous and almost the vertebral body. This usually spreads to the intervertebral disk and
all patients were HIV positive.429,430 adjacent vertebra, producing the classic radiographic picture of anterior
wedging of two adjacent vertebral bodies with destruction of the
Clinical Manifestations and Diagnosis intervening disk and the physical finding of a tender spine prominence
The onset may be abrupt, resembling acute idiopathic pericarditis, or or gibbus. The lower thoracic spine is involved most frequently, followed
insidious, resembling congestive heart failure. Symptoms of infection by the lumbar spine (Fig. 249.9).
or cardiovascular compromise may be present. Individual cases may In endemic countries, Pott disease usually occurs in older children
manifest as chronic constrictive pericarditis and may be mistaken for and young adults, but in developed countries it has become a disease
cirrhosis with ascites. As many as 39% of patients also have a pleural of older persons.436 In a country such as Denmark, with large immigrant
effusion, providing a convenient source for diagnostic fluid and populations from endemic areas, spinal TB accounted for more than
tissue.431,432 Echocardiography demonstrates effusion when present and half of bone and joint disease and was mainly seen in younger immi-
may reveal multiple loculations suggestive of TB. grants.437 Evidence of other foci of TB and systemic symptoms are often
Pericarditis with effusion is usually quickly diagnosed based on absent, early complaints may be back pain or stiffness with an initially
physical findings and radiologic examination, but establishing that it normal radiograph, and diagnosis may be delayed until signs of advanced
is tuberculous in nature is often difficult. The TST result may be negative, disease such as paralysis, deformity, or sinus formation develop. Bacilli
and evidence of extrapericardial TB lacking. In areas of high endemicity, are sparse, and smear and culture of pus or tissue are positive in only
a presumptive diagnosis is often correctly made.431,432 In the United one-half of cases. Histologic studies reveal granulomas with or without
States, however, many cases are initially misdiagnosed as idiopathic, caseation in three-fourths of cases.
uremic, or rheumatoid pericarditis.433
Pericardiocentesis (ideally performed in a cardiac catheterization Clinical Manifestations
laboratory) is indicated for hemodynamic compromise. However, Abscess and Sinus Formation
because pericardiocentesis carries risk, and because 90% of acute Paraspinal cold abscesses develop in 50% or more, in some cases
pericarditis in the United States is idiopathic (presumed viral) and appearing after treatment has been initiated, and in some cases visible
subsides spontaneously in 2 to 3 weeks, some authorities advise only with CT or MRI. The pus, confined by tight ligamentous investments,
against early pericardiocentesis. If improvement has not occurred can dissect along tissue planes for long distances to present as a mass
by that time, a subxiphoid pericardial window can be performed. or a draining sinus in the supraclavicular space, above the posterior
This provides both fluid and tissue for diagnosis, although in some iliac crest in the Petit triangle, or in the groin, the buttock, or even the
cases the biopsy demonstrates only nonspecific inflammation.431,432 popliteal fossa. The abscess can spread infection to distant vertebral
Tuberculous pericardial fluid demonstrates many of the characteristics bodies, sometimes without affecting the intervening vertebrae. Epidural
of tuberculous pleural fluid, with acid-fast smears being rarely positive or psoas abscess can also complicate tuberculous spondylitis.
and cultures being positive in approximately 50% of cases. Bloody
fluid suggests either TB or malignancy. The usefulness of adenosine Spinal Tuberculosis Without Bony Involvement on
deaminase determinations on pericardial fluid is not certain, Plain Films
but PCR assay for M. tuberculosis may be diagnostic, although In high TB/HIV prevalence settings, radiculomyelitis may be a common
sensitivity is low. 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

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
3016
changes are probably always bilateral. Culture of three morning urine area is the most typical site of enteric TB, producing pain, anorexia,
specimens for mycobacteria establishes the diagnosis in 80% to 90% of diarrhea, obstruction, hemorrhage that may be severe, and often a
cases. When a renal abnormality is present but urine cultures are negative, palpable mass. Clinical, radiographic, endoscopic, and even operative
cytologic studies and culture of material obtained by fine-needle biopsy findings may suggest carcinoma. A successful diagnosis is usually made
may be diagnostic. Ureteral cicatrization and obstruction may occur by means of colonoscopy. In a study of 50 cases, ileocecal involvement
after otherwise effective chemotherapy, but surgery is rarely required. with or without involvement of other areas was found in 35 cases,
Hypertension is not a feature of renal TB, and renal function is isolated segmental colonic disease was found in 13 cases, and pancolitis
usually preserved. However, a rare condition called tuberculous interstitial was initially misdiagnosed as ulcerative colitis in 2 cases. Evidence of
nephritis may cause renal failure.447 It is characterized by interstitial pulmonary TB was present in only 18 cases.451 The response of
granulomas and normal-sized kidneys, usually in the presence of active gastrointestinal TB to chemotherapy is excellent. Once the diagnosis
extrarenal TB. AFB have been seen but not cultured from renal biopsy is established, surgery should be deferred if possible until the results
specimens, and renal dysfunction responds to corticosteroid therapy of chemotherapy have been assessed.
but not antituberculous chemotherapy alone. It is unclear that tuberculous Pancreatic TB may manifest as an abscess or as a mass involving
interstitial nephritis is actually caused by tuberculous infection. local nodes and resembling carcinoma. The biliary tract may be obstructed
by tuberculous nodes, and tuberculous ascending cholangitis has been
Male Genital Tuberculosis described. TB is a frequent cause of granulomatous hepatitis. This is
Eighty percent of male genital TB is associated with coexistent renal usually asymptomatic but may be associated with an increased alkaline
disease, and most advanced renal TB is associated with some male phosphatase level that is out of proportion to bilirubin levels with normal
genital focus.448 Spread of infection from renal foci involves the prostate, aminotransferase levels. Very rarely, tuberculous granulomatous hepatitis
seminal vesicles, epididymis, and testis, in that order. The usual clinical causes jaundice without evidence of extrahepatic TB. This is called
finding is a scrotal mass that may be tender or associated with a draining primary tuberculosis of the liver. Focal hepatic tuberculosis describes
sinus. Calcified foci may form within the prostate during treatment of single or multiple tuberculous abscesses. These appear to occur most
prostatic TB. Genital foci not associated with renal disease can be frequently in racial groups with little natural immunity to TB and in
established by lymphohematogenous spread and usually present as a children.452
painful testicular or scrotal mass. Diagnosis may be suggested by the
presence of epididymal or prostatic calcification, although the latter Gastrointestinal Tuberculosis in AIDS
also occurs with nontuberculous chronic prostatitis. The diagnosis is Bowel involvement is not a common feature of extrapulmonary TB in
usually established by biopsy, and response to chemotherapy is AIDS patients. One series reported bowel fistulas in less than 4% of
excellent. 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
Genitourinary Tuberculosis in AIDS for M. tuberculosis in 4 of 10 cases.454 Tuberculous visceral abscesses,
In a study of 79 HIV-positive patients with TB, 77% had positive urine including hepatic, splenic, and pancreatic, may occur in AIDS patients.
cultures, usually as an incidental finding. Only two had male genital Pain and fever are usually present. Diagnosis is often made by means
involvement, none had symptoms of renal disease, and in only 4% was of CT or ultrasonographically guided drainage procedures. Chemotherapy
the genitourinary tract the only apparent site of TB.409 alone has not been effective in all cases.410
Female Genital Tuberculosis Tuberculous Peritonitis

Female genital TB begins with a hematogenous focus in the endosalpinx, Tuberculous peritonitis results either from spread of adjacent tuberculous
from which it may spread to the endometrium (50%), ovaries (30%), disease such as an abdominal lymph node, intestinal focus, or fallopian
cervix (10%), and vagina (1%).449 In the cervix, a granulomatous ulcerat- tube, or during miliary TB. In a summary of 11 series, evidence of
ing mass may resemble carcinoma. Common complaints are infertility associated pleuropulmonary TB was present in 25% to 83% of cases
or local symptoms consisting of menstrual disorders and abdominal and the TST result was positive in 30% to 100% of cases.455 Pleural
pain. The clinical picture may suggest pelvic inflammatory disease that effusion is the most frequent associated finding, but evidence of TB in
is unresponsive to therapy. Spread to the peritoneum may also occur. other sites is often present. AIDS patients do not have an increased
Systemic symptoms are uncommon, and evidence of old TB need not frequency of peritonitis.409
be present. Pregnancies that occur in the presence of pelvic TB are The clinical picture has been divided into plastic and serous types.
often ectopic. Although cultures of menstrual blood or endometrial The less common plastic type is characterized by tender abdominal
scrapings may be positive, the diagnosis is usually made by examination masses and a “doughy abdomen.” Serous effusions present as ascites
of tissue removed at operation. Response to chemotherapy is excellent, with or without signs of peritonitis. Symptoms of fever, abdominal pain,
and surgery is needed only for residual large tubo-ovarian abscesses. and weight loss are common.455 The onset may be insidious, although
acute presentations resembling bacterial peritonitis also occur. In the
Gastrointestinal Tuberculosis past, diagnosis was often made at surgery for a mass or an acute
Before effective chemotherapy was available, 70% of patients with abdominal condition. Tuberculous peritonitis often goes undiagnosed
advanced pulmonary disease acquired gastrointestinal TB from swal- in patients with concomitant cirrhosis with ascites.456 Of 20 patients
lowing infectious secretions and usually developed diarrhea and with both conditions, the diagnosis of tuberculous peritonitis was
abdominal pain. Although most cases at present are likely due to suspected before death in only 11. Tuberculous peritonitis has been
swallowed respiratory secretions, radiographic evidence of pulmonary reported in peritoneal dialysis patients with the clinical picture of bacterial
TB is less frequent, the diagnosis being made unexpectedly with surgery peritonitis unresponsive to routine antibiotics.457
or endoscopy.450 The peritoneal fluid is exudative, usually containing 500 to 2000
Any location from mouth to anus can be involved. Nonhealing ulcers cells. Lymphocytes typically predominate, although in some cases
of the tongue or oropharynx and nonhealing sockets after tooth extraction neutrophils are more abundant early in the process. Acid-fast smear of
may be due to TB. Esophageal disease is most frequently caused by an peritoneal fluid is seldom positive, and culture is positive in only 25%
adjacent caseous node, which leads to stricture with obstruction or of cases. An increased adenosine deaminase level in ascitic fluid has
tracheoesophageal fistula formation and rarely to fatal hematemesis been reported to have high sensitivity and specificity,458 although among
from an aortoesophageal fistula. Stomach involvement may be ulcerative 140 patients in India the positive predictive value was only 25%.459
or hyperplastic and may cause gastric outlet obstruction. Isolated Analysis of peritoneal fluid with PCR, such as the Xpert MTB/RIF
duodenal disease can produce symptoms of peptic ulcer or obstruction. or Xpert MTB/RIF Ultra assay, may provide rapid diagnosis. In the
Small bowel involvement may lead to perforation, obstruction, entero- absence of other foci of TB, peritoneal tissue may need to be obtained
enteric and enterocutaneous fistulas, massive hemorrhage, and severe in order to make the diagnosis. Histologic examination of peritoneal
malabsorption. Small bowel lesions are frequently multiple. The ileocecal biopsy specimens obtained with a Cope needle were positive in 64%
3017
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 FIG. 249.10 Axillary lymphadenitis caused by Mycobacterium
histologic features may be due to other mycobacteria or fungi. tuberculosis in a patient with acquired immunodeficiency syndrome.
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 Mesenteric Tuberculous Lymphadenitis
pain, suppuration, sinus formation, and appearance of new nodes In HIV-negative persons, isolated symptomatic mesenteric lymphadenitis
occur in 25% to 30% of cases, both during and after chemotherapy, without bowel disease or peritonitis is rare. It may cause abdominal
and do not indicate failure of drug treatment. These likely represent pain, fever, a palpable mass, or symptoms of partial small bowel obstruc-
reactions to retained tuberculous antigens rather than uncontrolled tion. In AIDS patients with TB, abdominal lymphadenopathy is common
infection; they usually subside spontaneously, and short courses of and may be massive.469,470 Involvement is more often intraabdominal
corticosteroids may be beneficial when the problem persists.464 than retroperitoneal, and occasionally obstruction of the biliary tract,
Conversely, in individuals with AIDS, peripheral tuberculous ureters, or bowel is observed. As with thoracic disease, the nodes often
lymphadenitis is almost always multifocal and associated with major are low density or have low-density centers and peripheral enhancement.
systemic symptoms such as fever, weight loss, and evidence of TB in Other abnormalities on CT may include abscesses in the liver, spleen,
the lungs (parenchyma, nodes, or pleura) or elsewhere (Fig. 249.10).463 pancreas, or kidney; local ileal thickening; extraluminal bowel gas
In an early series from New York City, TB caused 57% of generalized indicating fistula formation; and ascites.
lymphadenopathy in HIV-positive injection drug users.465 In contrast
to non–HIV-infected persons, material removed with fine-needle Cutaneous Tuberculosis
aspiration is positive on acid-fast stain in the great majority of cases—as In the past, a number of cutaneous conditions were associated with TB
frequently as it is with culture. However, both cytologic and histologic elsewhere in the body, although M. tuberculosis could not be identified
findings are less specific than in HIV-negative persons.466 in the lesions. These have been considered allergic reactions to the
infection and termed tuberculids. They include erythema induratum of
Mediastinal Tuberculous Bazin, papulonecrotic tuberculids, and others. This association has been
Lymphadenopathy questioned, and some have attributed tuberculids to other processes,
Mediastinal adenopathy during primary infection is often visible such as sarcoidosis.471 M. tuberculosis DNA has been detected in erythema
radiographically, especially in children. In African Americans, mediastinal induratum skin lesions with PCR.472 Erythema nodosum has been
adenopathy resulting from TB may also be seen in young adults, and attributed to primary TB, although organisms cannot be cultured from
cases in very old persons have been reported.467 Associated systemic the lesions.
symptoms may or may not be present, causing confusion with other The pathogenesis of cutaneous involvement in TB is varied. Skin
mediastinal masses such as histoplasmosis, lymphoma, and carcinoma. involvement may result from exogenous inoculation (which in the
The finding of low-density areas in the nodes on CT scan suggests TB, previously nonsensitized host is associated with regional lymphadenitis).
but diagnosis usually requires mediastinoscopy. In HIV-infected persons TB verrucosa cutis, arising from direct inoculation, has also been called
with TB, in contrast, mediastinal lymphadenopathy is frequent. Multiple prosector’s wart, referring to inoculation of a hand at time of autopsy
nodes are usually involved, coalescing into large mediastinal masses of a patient with TB. Infection may also spread from an adjacent focus
with low-density centers, peripheral contrast enhancement, and no to the overlying skin (as from lymphadenitis, osteomyelitis, or epididy-
calcification.468,469 mitis), and hematogenous spread from a distant focus or as a part of
the generalized hematogenous dissemination. This last is seen in patients
Fibrosing Mediastinitis with AIDS and tuberculous bacteremia.473 The clinical picture of all
TB can cause fibrosing mediastinitis, although less commonly than cutaneous mycobacterial infections, including TB, is highly variable,
histoplasmosis. Patients present with dyspnea on exertion resulting from and any unexplained skin lesion, especially if it has nodular or ulcerative
compression of pulmonary veins and arteries or, less commonly, superior components, may be due to TB, particularly in AIDS patients.
vena cava syndrome. Hilar adenopathy or active pulmonary disease is
rarely found. A perfusion lung scan helps define the extent of pulmonary Tuberculous Laryngitis
vascular compression, but thoracotomy is required for diagnosis. In the prechemotherapy era, laryngeal TB occurred in more than a
Mediastinoscopy is either contraindicated because of superior vena cava third of patients dying of pulmonary TB, often associated with painful
syndrome or unsuccessful because of fibrosis. ulcers of the epiglottis, pharynx, tonsils, and mouth, and with middle
3018
ear involvement. Laryngeal disease was highly infectious and often animals may be infected. In developing countries, infection is acquired
caused terminal widespread bronchogenic dissemination throughout from close contact with infected cattle or ingestion of infected dairy
the lungs. At present, however, more than one-half of laryngeal TB products.481,482 From 2006 to 2013, M. bovis caused approximately
cases are due to hematogenous seeding. Such cases are still highly 1% of TB cases in the United States, with higher prevalence among
contagious. Lesions vary from erythema to ulceration and exophytic infants and children, foreign-born patients, Hispanics, females, and
masses resembling carcinoma.474 Symptoms include cough, wheezing, persons living near the Mexican border.480 M. bovis infection may also
hemoptysis, dysphagia, odynophagia, and otalgia. complicate intravesicular BCG administered to treat intraepithelial
bladder cancer.483,484
Tuberculous Otitis Intravesicular BCG is given as a series of bladder injections through
Tuberculous otitis media is rare and frequently misdiagnosed. Half of a catheter, with each instillation containing as many as 8 × 108 bacilli.
the cases have no other evidence of present or past TB. The classic Symptoms of cystitis are common during treatment. Infections within
clinical picture is painless otorrhea with multiple tympanic perforations, the genitourinary tract can appear during the following weeks and may
exuberant granulation tissue, early severe hearing loss, and mastoid manifest as ulcers, plaques, or nodules in the bladder or urethra.
bone necrosis. The diagnosis has been missed for years by excellent Epididymo-orchitis or prostatitis may also occur months later. Spread
otolaryngologists, even when tissue was available. Tuberculous otitis beyond the urinary tract affects 3% to 7% of recipients.483 A sepsis-like
may be complicated by facial nerve paralysis. Response to drug therapy syndrome after intravesicular BCG manifests as fever, hypotension, and
is excellent, and surgery is usually not required.475 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
Miscellaneous Conditions many weeks later.485 A miliary pattern may affect the lungs. Granulomas
TB of the aorta with or without aneurysm formation can be caused by may be seen in bone marrow, but cultures of blood and bone marrow
spread from contiguous diseased nodes, pericarditis, spondylitis, are usually negative. Focal lesions can appear weeks or even years after
paravertebral abscesses, or empyema. Extensive hematogenous dis- intravesicular therapy, including thoracolumbar spondylodiscitis,
semination or aortic rupture may occur. TB produces various ocular granulomatous hepatitis, arthritis, uveitis, and mycotic aneurysm.484 In
syndromes, including choroidal tubercles, uveitis, iritis, and episcleritis a series of 20 cases of mycotic aortic aneurysm, the peak incidence was
(see Chapter 115). An interesting observation has been made in patients at 6 weeks after treatment, with declining incidence over 7 years.486 In
with uveitis (most suggestive of sarcoidosis) who had positive interferon-γ another series of mycotic aneurysms after intravesicular BCG, average
release assays to TB. Fifteen of the 20 patients had lived in an area time to diagnosis was 19 months.487 Vascular grafts and prosthetic joints
endemic for TB before moving to the Netherlands. Despite the absence may also become infected. Culture isolation of M. bovis has occurred
of documented tuberculous infection elsewhere in the body, antituber- in only 41% of reported cases, although PCR may be positive at culture-
culosis therapy was associated with remission in 91% of those treated.476 negative sites.483 Disruption of mucosal integrity from a recent urologic
During disseminated TB in areas of high TB prevalence, choroidal TB procedure or during the bladder treatment is suspected but unproven
(usually without symptoms) may occur in 5% to 20% of patients.477 TB as the predisposing factor.483
may also involve the breast, producing abscesses, sclerosing lesions Treatment largely includes RIF, INH, and EMB for 2 to 3 months,
resembling carcinoma, and multiple nodules. Destructive nasal lesions followed by 6 months of INH and RIF.483,484 Most strains of M. bovis,
resembling Wegener granulomatosis both clinically and histologically including BCG strains, are PZA resistant. Fluoroquinolones have suc-
have been caused by TB.478 TB of the adrenal glands may cause adrenal cessfully replaced INH or RIF in some cases. Results are generally
enlargement with or without calcification, as may histoplasmosis, but favorable except with mycotic aneurysm, which has a poor outcome.486,487
granulomatous adrenal TB may cause Addison disease without either Ingestion of M. bovis in unpasteurized dairy products can cause
calcification or adrenal enlargement.479 cervical lymphadenitis.488 Pulmonary M. bovis infection resembles typical
TB and is acquired from exposure to infected animals or, rarely,
Mycobacterium bovis and Bacillus humans.489 In North America, reactivation of M. bovis acquired in other
Calmette-Guérin countries may occur. M. bovis accounts for 0.3% of diagnosed pulmonary
M. bovis is a member of the M. tuberculosis complex. Isolation requires TB cases in the Americas.481 Isolates acquired from animals or humans,
that decontamination and culture procedures used for TB be optimized. and rarely from vaccine, may be resistant to INH or RIF.490
Sodium pyruvate is often substituted for glycerol in the culture medium. In countries where BCG vaccine is routinely given to children,
M. bovis may be mistaken as M. tuberculosis clinically, but molecular unrecognized primary immune deficiencies such as severe combined
methods including WGS can distinguish the two. The BCG strain of immunodeficiency or mutations in the IL-12/interferon-γ axis may
M. bovis is used to vaccinate against TB. BCG Tice and BCG Connaught predispose to disseminated M. bovis infection. In this setting, infection
are the most widely used strains in North America and Europe, but occurs at the injection site, contiguous axillary lymph nodes, and distant
very many other strains have been used to treat bladder cancer.480 sites including bones. Restoration of immune response by means of
Unlike M. tuberculosis, M. bovis largely infects humans as a zoonosis. allogeneic hematopoietic stem cell transplantation may be required
Cattle are the primary reservoir, but a large variety of warm-blooded for cure.491
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3021
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3021.e1
UPDATE
Six-Month Treatment of Drug-Resistant 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,
3021.e2
26. Moore DA, Evans CA, Gilman RH, et al. Microscopic- 49. Eddabra R, Benhassou HA. Rapid molecular assays for
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What are some of the characteristics of Mycobacterium tuberculosis?

What are some of the characteristics of Mycobacterium tuberculosis?

How does M. tuberculosis infect humans?

How does M. tuberculosis infect humans?

vii.

SHORT VIEW SUMMARY

Chapter 249 Mycobacterium tuberculosis

TABLE 249.1 Comparison of Assays Used in the Diagnosis of Active Tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Rate of Tuberculosis Cases

(per 100,000 population)

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Infection in Adolescence and

Chapter 249 Mycobacterium tuberculosis

TABLE 249.6 Clinical Manifestations of Active

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

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

TABLE 249.8 First-Line Tuberculosis Medicationsa

TABLE 249.8 First-Line Tuberculosis Medicationsa—cont’d

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

General Comments on Treatment of

Chapter 249 Mycobacterium tuberculosis

Pleurisy With Effusion Complicating Chronic

Pleurisy With Effusion Complicating

TABLE 249.11 Clinical Manifestations of Renal

Chapter 249 Mycobacterium tuberculosis

Female Genital Tuberculosis Tuberculous Peritonitis

Chapter 249 Mycobacterium tuberculosis

Tuberculous Lymphadenitis (Scrofula):

Key References 9. Ernst JD, Trevejo-Nunez G, Banaiee N. Genomics and

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Six-Month Treatment of Drug-Resistant Tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

Chapter 249 Mycobacterium tuberculosis

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