Mycobacterium tuberculosis

Acid-Fast Staining

The term acid-fast bacilli (AFB) is practically synonymous with mycobacteria, although Nocardia and some other organisms are variably acid fast. In the Ziehl-Neelsen stain, a fixed smear covered with carbol-fuchsin is heated, rinsed, decolorized with acid-alcohol, and counterstained with methylene blue. The Kinyoun stain is modified to make heating unnecessary. The organisms appear as slightly bent, beaded rods 2 to 4 µm long and 0.2 to 5 µm wide. In sputum they often lie parallel, or two organisms adhere at one end to form a V. An estimated 10,000 organisms per milliliter of sputum are required for smear positivity, and detection of at least 10 organisms on a slide is optimal; a single organism on a slide is highly suggestive. The sensitivity of sputum acid-fast bacillus smear when compared with culture is approximately 60%. Sensitivity is significantly lower with noncavitary disease and HIV infection. Sensitivity increases by approximately 10% with the collection of a second sputum sample, and 2% with a third. Sputum processing with bleach and concentration before acid-fast staining also increases sensitivity. Most laboratories in the United States now use a fluorochrome stain with phenolic auramine or auramine-rhodamine, a slightly modified acid-alcohol decolorization step, and potassium permanganate counterstaining. Because the mycobacteria are easily seen with a 20× or 40× low-magnification objective, fluorescence microscopy requires less technician time and may increase the sensitivity over conventional acid-fast bacillus smears. Advances in ultrabright light-emitting diode (LED) microscopes make the technology more robust for use in resource-poor settings. WHO recommends that LED microscopy replace conventional fluorescence microscopy and that it be phased in as an alternative for conventional Ziehl-Neelsen microscopy. As with all laboratory procedures, strict quality control is needed for acid fast staining, or rates of false positives and negatives quickly rise.

Any biologic fluid or material can be examined directly (e.g., pleural fluid, cerebrospinal fluid [CSF], urine, gastric lavage fluid), although thin fluids are best examined after sedimentation by centrifugation. Positive smears from concentrated gastric aspiration material are usually due to M. tuberculosis and are especially important in young children from whom sputum collection may not be possible.

Culture Methods for Mycobacterium tuberculosis

Culture is the gold standard for detecting mycobacteria in clinical specimens. Samples of sputum or tissue require initial decontamination to remove fast-growing nonmycobacterial organisms and liquefaction to allow access of decontaminants to nonmycobacterial organisms and media nutrients to surviving mycobacteria. Decontamination-liquefaction is most commonly done using N -acetyl- l -cysteine as a mucolytic in 1% sodium hydroxide solution. Mycobacteria are relatively protected during this procedure by a fatty acid–rich cell wall. However, normally sterile tissues or fluids such as CSF or pleural fluid should not be decontaminated, because some loss of mycobacterial viability does occur. The sample is then neutralized and centrifuged, and the sediment is inoculated onto media.

Three types of media may be used for culture of mycobacteria: solid egg-based media (e.g., Löwenstein-Jensen), solid agar-based media (e.g., Middlebrook 7H11), and liquid broth (e.g., Middlebrook 7H12). Media are made selective for mycobacteria by adding antibiotics. Nonselective media, on which growth is more rapid, are available. Growth is more rapid in 5% to 10% carbon dioxide. Liquid broth cultures require a mean of 10 days of incubation for smear-positive and 20 days for smear-negative specimens for detection of organisms, as compared with solid media, which require 3 to 8 weeks. However, solid media allow examination of colony morphology, detection of mixed cultures, and quantification of growth. Furthermore, occasional strains of mycobacteria may grow only on solid media. For these reasons, experts suggest using liquid and solid media in conjunction, with inoculation of at least one solid medium culture.

Commercial automated liquid broth systems greatly facilitate mycobacterial culture. They monitor mycobacterial growth through detection of CO ₂ production or O ₂ consumption with radiometric, fluorometric, or colorimetric indicators. The BACTEC mycobacterial growth indicator tube (MGIT) system (Becton Dickinson Microbiology Systems, Sparks, MD), which detects growth in 1 to 3 weeks by means of a fluorometric method, is widely used.

A noncommercial liquid broth assay was developed in which mycobacteria are cultured in liquid media on a multiwell plate and then examined microscopically for characteristic serpentine cording. The addition of antimicrobial agents to the media allows drug susceptibility testing to be performed simultaneously. This microscopic-observation drug-susceptibility (MODS) assay yields results in 7 to 10 days, with sensitivity and specificity similar to those of commercially available liquid broth systems. Sensitivity is diminished (65.4%) when the source of diagnostic material is not sputum (lymph node sampling). An automated MODS (Auto-MODS) has been compared with conventional culture in Thailand. With 95.5% sensitivity and 97.1% specificity and a time to culture positivity of 10 days (interquartile range, 8–13 days), this test appears to be effective and attractive in resource-limited settings. In addition, a commercial kit (the Hardy TB MODS Kit; Hardy Diagnostics, Santa Maria, CA) now provides results comparable to those of the conventional MODS, with the ability to detect INH and RIF resistance in a Biosafety Level 2 setting and 97.9% concordance with indirect proportion susceptibility testing.

Nucleic Acid Amplification

Nucleic acid amplification testing (NAAT) offers another technique for the direct detection of M. tuberculosis in clinical specimens. The Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA) is a US Food and Drug Administration (FDA)–approved automated molecular test for detection of M. tuberculosis with sensitivity and specificity that approach those of culture. The test is simple to perform and gives results in 100 minutes. It uses real-time polymerase chain reaction (PCR) amplification of an M. tuberculosis gene for detection. GeneXpert MTB/RIF assay had an overall sensitivity of 89% and specificity of 99% for detection of M. tuberculosis in sputum samples compared with gold standard culture testing. Sensitivity was 98% for smear- and culture-positive cases and 67% for smear-negative culture-positive cases. Analysis of three sputum samples further increases sensitivity. These initial reports continue to be modified under the influence of factors such as prevalence of disease, prevalence of HIV coinfection, and variable performance on smear-positive and smear-negative samples. The GeneXpert MTB/RIF simultaneously detects RIF resistance (see “ Drug Susceptibility Testing ” later).

The Xpert MTB/RIF assay has also been used on nonrespiratory samples (e.g., pleural fluid, CSF, peritoneal fluid, urine, fine-needle aspirates), but the performance in nonrespiratory specimens varies by population, TB prevalence, and type of fluid sampled. Detection in pleural fluid in a report from India revealed a sensitivity of only 54.8%.

The assay has been endorsed by WHO and is rapidly being deployed to countries with high rates of endemic TB. A pooled testing strategy, which might ameliorate some of the cost burden, has been reported with encouraging results. With increased use, the examination of the clinical utility now extends to the test's impact on mortality, and in South Africa no reduction associated with the use of the Xpert MTB/RIF was found compared with microscopy. FDA approval has been extended to an indication for use of the test in removing patients from airborne isolation after one or two negative test results. A single-institution analysis of 207 airborne-isolation cases found that the efficiency (time to result and sensitivity) was greatest with a two-test strategy, and a one-test strategy missed one case. A multisite (Burkino Faso, Cambodia, Cameroon, and Vietnam) assessment comparing Xpert MTB/RIF testing of nasopharyngeal aspirates and stool versus culture in HIV-infected children younger than 13 years yielded a sensitivity on all samples of 79.3% and 75.8%, respectively, on the alternative sources.

The confounding issue of detection of residual DNA not representative of replication-competent bacteria has been addressed in South Africa, where patients with re-treatment cases were significantly more likely to have false-positive results (14%) than those with newly diagnosed cases.

A new version, the Xpert MTB/RIF Ultra assay (Cepheid, Sunnyvale, CA) has been developed. Initial studies suggest that it improves sensitivity by approximately 15% in smear negative-culture positive pulmonary TB; however, there is a small decrease in specificity from 99% to 98%. The newer Xpert MTB/RIF Ultra assay may also improve sensitivity in nonrespiratory samples. In a study in Uganda of 129 HIV-infected patients with suspected meningitis, the Xpert MTB/RIF Ultra had a sensitivity of 70% versus a clinical case definition of tuberculous meningitis compared with a sensitivity of 43% for BACTEC culture and 43% for the older Xpert MTB/RIF. WHO has recommended that the Xpert Ultra assay be adopted in settings with high rates of HIV and TB such as sub-Saharan Africa. Given the lower specificity, there may be more false-positive results in low-HIV and low-TB settings.

Another commercially available and FDA-approved NAAT assay that can be used directly on respiratory samples is the Amplified M. tuberculosis Direct (MTD) test (Hologic, San Diego, CA). The sensitivity is intermediate between acid-fast staining and culture. For smear-positive specimens, the sensitivity is 98% and the specificity is 99%. For smear-negative cases, sensitivity ranges from 60% to 80% and the specificity remains 99%.

A number of other NAAT tests use novel technologies but are not FDA approved. The COBAS TaqMan MTB assay (Roche Molecular Diagnostics, Pleasanton, CA) is a real-time PCR test that targets M. tuberculosis ribosomal RNA. The loop-mediated isothermal amplification assay (TB-LAMP; Eiken Chemical Company, Tokyo, Japan) does not require a thermal cycler or other sophisticated laboratory equipment. It can be performed manually in less than 1 hour, with results read with the naked eye.

Nucleic acid amplification testing complements but does not replace clinical judgment, acid-fast smear, and culture in the diagnosis of TB. In sputum acid-fast smear-positive individuals, positive nucleic acid amplification indicates the presence of M. tuberculosis complex and confirms active TB. When there is a high clinical index of suspicion for pulmonary TB but with a negative acid-fast smear, a positive NAAT result is highly predictive of TB and allows early initiation of therapy. NAAT assays perform less well when the clinical index of suspicion for TB is low, in which case the frequency of false-positive tests may approach that of true positives.

Detection of Mycobacterial Antigens in Urine

Detection of M. tuberculosis antigens in urine may have some usefulness in diagnosing TB in patients with advanced AIDS, particularly in countries where coinfection is highly prevalent. The Alere Determine lateral flow urine lipoarabinomannan (LF-LAM) assay (Abbott, Abbott Park, IL) is a commercially available point-of-care test for the diagnosis of active TB. In a review of 12 studies of the LF-LAM test for TB diagnosis in HIV-infected patients, the pooled sensitivity was 45% and the specificity was 92%. The combination of microscopy and urinary LAM testing provides incremental diagnostic sensitivity in HIV-infected adults. Sensitivity for TB in HIV-uninfected persons is less than 25%.

Speciation of Mycobacteria

Once mycobacteria have been identified in a clinical specimen, speciation is necessary for clinical diagnosis and epidemiologic investigation. For example, speciation may be important in immunocompromised patients at risk for nontuberculous mycobacterial infection, in localities where M. bovis transmission from animals to humans is possible, or in bladder cancer patients receiving bacillus Calmette-Guérin (BCG) immune stimulatory therapy. Speciation generally involves two steps: First, mycobacteria are identified as members of the M. tuberculosis complex (e.g., M. tuberculosis, M. bovis, M. africanum ) or as Mycobacterium species other than tuberculosis (MOTT). Subsequently, if necessary, mycobacteria can be speciated within the M. tuberculosis complex. NAAT assays, growth in selective antibiotic media, nucleic acid probes, and high-performance liquid chromatography are all used to place mycobacteria within the M. tuberculosis complex. Each has advantages and limitations that are detailed in Table 249.1 . Identifying individual species within the M. tuberculosis complex is more challenging. M. tuberculosis grows slowly, lacks pigment, produces niacin, reduces nitrates, has weak catalase activity that is lost by heating to 68°C at pH 7.0, does not demonstrate monodrug resistance to PZA, is resistant to thiophen-2-carboxylic acid hydrazide, and prefers aerophilic conditions. Other members of the complex show different patterns with these tests. Next-generation sequencing technology is rapidly making WGS of clinical isolates routine and also enables identification of species within the M. tuberculosis complex.

Genotyping of Mycobacterium tuberculosis

Characterizing the particular strain of M. tuberculosis is important for epidemiologic purposes, such as tracing transmission from person to person, distinguishing exogenous reinfection from endogenous reactivation in cases of recurrent TB, and identifying laboratory cross-contamination of cultures. The Centers for Disease Control and Prevention (CDC) offers free strain typing through the National Tuberculosis Genotyping Service based on four typing methods: restriction fragment length polymorphism (RFLP) analysis, spacer oligonucleotide typing (spoligotyping), mycobacterial interspersed repetitive unit (MIRU) analysis, and WGS. In RFLP analysis, DNA cleavage fragments generated using pvuII are separated by means of electrophoresis and visualized with use of a probe to a repetitive DNA sequence, insertion sequence (IS) 6110. Because numerous copies of IS 6110 are present at variable chromosomal locations in most M. tuberculosis isolates, identical RFLP patterns represent the same strain. Spoligotyping detects variability in the direct repeat (DR) region in M. tuberculosis genome. There are direct repeats of a conserved 36-bp sequence, separated by multiple spacer sequences. Different M. tuberculosis strains are distinguished by the presence or absence of 43 unique spacers. Each possible combination of spacers is designated by a unique numeric code that identifies a unique spoligotype strain. In MIRU analysis, 12 different DNA sequences, each of which can be tandemly repeated in the M. tuberculosis genome, are analyzed. The number of tandem repeats for each of the 12 sequences (or loci) is determined by means of PCR to create a 12-number code. Each code corresponds to a unique MIRU strain.

WGS of clinical isolates is rapidly supplanting prior typing technology. In the United States, many state public health laboratories and the National TB Molecular Surveillance Center routinely perform WGS on isolates from every TB case. Many other countries are developing similar systems. WGS provides data on species, strain type, and drug susceptibility (see later). The WGS bioinformatics pipeline and reporting system are being standardized, and clinicians should anticipate WGS reports on every culture-positive TB case in the near future.

Drug Susceptibility Testing

Testing of M. tuberculosis isolates for drug susceptibility is important to guide therapy. There are two broad methods to test an M. tuberculosis isolate's drug susceptibility: phenotypic testing, which relies on culturing M. tuberculosis in media with varying concentrations of antibiotics, and genotypic testing, which correlates specific mutations in the isolate's genome with known drug susceptibility patterns.

In the United States, the agar proportion method is most commonly used to determine phenotypic drug resistance. The absolute concentration method and resistance ratio method are used less commonly. The agar proportion method compares growth of appropriately diluted inocula on drug-containing media versus growth on drug-free media and is reported as proportion resistant. For most drugs, resistance is significant when growth on drug-containing media exceeds 1% of control; 6% to 10% resistance or more indicates that the drug will add nothing to multidrug therapy. Liquid broth systems, such as BACTEC, can also be used and provide results in 5 to 14 days, but they do not give the proportion of resistant organisms.

As noted earlier, the MODS method shows promise as an inexpensive and rapid method for culture and drug susceptibility testing.

Molecular testing to detect M. tuberculosis chromosomal mutations associated with mycobacterial drug resistance is an exciting development. Most commonly used are tests for RIF resistance, which predicts poor treatment outcomes and is a surrogate marker for MDR-TB. Assays detect mutations in the 81-base-pair rpoB gene, which encodes the β-subunit of RNA polymerase and correlates with greater than 96% of RIF resistance. Resistance to INH is more complex and is encoded by multiple genes, including the catalase peroxidase gene katG, the inhA gene involved in fatty acid biosynthesis, the ahpC gene, the oxyR gene, and the kasA gene. Mutations associated with resistance to PZA, ethambutol (EMB), second-line injectable drugs, and fluoroquinolones have also been identified.

The GeneXpert MTB/RIF assay detects mutations in the rpoB gene and has a sensitivity of 95% and specificity of 98% for detection of RIF resistance in respiratory samples that are RIF resistant with culture techniques. However, use of the test in populations with high rates of HIV infection and drug resistance, such as in Swaziland, revealed that the test failed to detect a high-prevalence rpoBI491F outbreak strain. This RIF-resistance–conferring mutation was present in 30% of MDR strains. The drug-resistance assay is performed on sputum simultaneously with detection of organisms, and results are available within 2 hours. Three line probe assays are also commercially available: the INNO-LiPA Rif. TB kit (Innogenetics, Zwijndrecht, Belgium), which detects resistance to RIF in culture isolates; the Genotype MTBDRplus assay (version 2.0) (Hain Lifescience, Nehren, Germany), which detects resistance to INH and RIF in culture isolates and smear-positive sputum samples, and thereby can enable identification of MDR-TB; and the Genotype MTBDRsl assay (Hain Lifescience), which detects resistance to fluoroquinolones and second-line injectable drugs in culture isolates and smear-positive sputum samples and thereby can be used to identify XDR-TB. WHO has recommended widespread use of these molecular assays. The clinical impact of rapid diagnosis and drug-resistance detection has been reported from Tbilisi, Georgia, where the MTBDRplus assay was associated with selection of drug regimens that provided higher and more rapid rates of culture conversion at 24 weeks.

WGS is also becoming a powerful tool for the detection of drug-resistance mutations in the M. tuberculosis genome. Currently it can be performed only on culture isolates, and the bioinformatics pipelines, databases cataloguing drug-resistance mutations, and reporting systems are being standardized for routine clinical use.

General Considerations

M. tuberculosis infects 1.7 billion people or approximately one-quarter of the world's population and caused 10.4 million new cases of TB and approximately 1.7 million deaths in 2016. TB is the leading cause of death worldwide resulting from a single infectious agent, ranking above HIV since 2014. Immunocompromise due to HIV infection is a risk factor for TB, and 374,000 TB deaths are in HIV-infected individuals. Drug-resistant TB is emerging globally, with approximately 490,000 new MDR-TB cases in 2016. Two factors essential for the rapid spread of M. tuberculosis are crowded living conditions and a population with little native resistance. In the 19th century, TB caused more than one-fourth of all adult deaths in Europe, eliminating those with the least native resistance. A downward trend had been established before the turn of the 20th century. Epidemiologists once believed the disease would eventually disappear based on the assumptions that 1 in 20 infections result in active cavitary disease of the lung (i.e., become contagious). Thus, each cavitary case would have to infect 20 persons for case rates to be maintained. In Holland in the early 1900s, one infectious case produced only 13 new infections. The annual decrement in mortality and morbidity from TB was approximately 5% in developed countries owing to progressively higher natural residual resistance in those who survived infection and to living conditions less conducive to airborne spread. This rate of decline approximately doubled after chemotherapy became widespread.

In the 1980s and 1990s, the high incidence of TB in Africa, Asia, Eastern Europe, and South America, the HIV coepidemic, and burgeoning MDR-TB demonstrated that predictions of the disappearance of TB were premature, and WHO declared TB a global public health emergency. Since then, tremendous gains have been made in reducing the number of new TB cases, now in decline for the past several years. The integration of multiple modalities, such as genotyping combined with a series of spatial analysis tools, might improve the efficiency of targeted transmission control.

Recent Morbidity and Mortality Trends

In the United States, the incidence of TB has decreased steadily over the past 25 years, from 10.5 reported cases per 100,000 population in 1992 to 2.8 cases per 100,000 population in 2017, the lowest in recorded history. Recent estimates of latent infection in the United States suggest a prevalence of latent infection in 2011–12 of 4.4% by the tuberculin skin test (TST) and 4.8% by the QuantiFERON-TB Gold In-Tube test (QFT-GIT; Cellestis Limited, Carnegie, Victoria, Australia). In the United States the TB rate in foreign-born persons is 15 times higher than in US-born persons, and foreign-born persons now account for almost 70% of reported cases in the United States ( Fig. 249.1 ). This reflects increased immigration from high-prevalence countries, especially Mexico, the Philippines, India, Vietnam, and China, from which immigrants account for more than half of the TB cases in foreign-born individuals. Strain genotyping suggests that TB among foreign-born persons is from reactivation of latent infection acquired before arrival in the United States. Furthermore, the risk declines with duration of residency, also suggesting that most infections were acquired before immigration. Screening of immigrants to the United States with a culture-based, rather than a smear-based, algorithm is justified by the high rate (54.4%) of smear-negative and culture-positive cases.

TB has also become concentrated in certain ethnic and racial minorities and medically underserved populations, often occurring in contact-based microepidemics. In 2017, rates among US-born blacks was seven times higher than in non-Hispanic US-born whites; the rate in Native Americans was nine times higher than in whites. A number of outbreaks have affected the urban poor, alcoholics, injection drug users, the homeless, migrant farm workers, and prison inmates.

The age distribution of TB reflects the degree of ongoing transmission in a given population. Disease in the elderly is generally due to reactivation of infection acquired in the remote past, whereas TB in young children indicates ongoing active transmission in the community. In this regard, 75% of childhood cases in the United States occurred in patients who had TB exposure through foreign-born parents or prior residence outside the United States.

TB in the United States is most frequent in geographic regions and demographic groups where AIDS is prevalent, notably in urban blacks and Hispanics between 25 and 45 years of age. Persons with active TB are more frequently HIV positive than is the general population. Approximately 8% of all TB cases in the United States occur in HIV-infected persons.

Despite a predominantly urban epidemiology, large TB outbreaks have also affected small communities. One well-characterized outbreak began in 1988 in a coastal Maine village where TB had not been reported in the previous 3 years. A shipyard worker with cavitary TB was the source of 21 subsequent active cases and 697 new tuberculous infections. In retrospect, the source patient had repeatedly sought medical attention for cough, sore throat, and hoarseness during 8 months before TB was diagnosed and treated. This report highlights the need for vigilance regarding all segments of the population, not just those known to have high TB case rates.

The prevalence of positive TST results in US Navy recruits offers insights into trends of latent tuberculosis infection (LTBI) over time and risk factors for infection. From 1958 through 1969, more than 1 million US Navy recruits underwent TSTs, and in 5.2% the results were positive. In the 1980s and 1990s, the rate of tuberculin reactivity dropped to approximately 1.5% of new Navy recruits. The prevalence was greater in blacks (5%), Hispanics (5%), and Asian/Pacific Islanders (26%) than in whites (0.8%). Tuberculin positivity was more than 10-fold more prevalent among foreign-born recruits. In a survey of noninstitutionalized civilians in the United States, the prevalence of tuberculin reactivity among persons 25 to 74 years of age decreased from 14.4% in 1972 to 5.6% in 2000 and to 4.4% in 2011.

Immigrants for the most part retain the tuberculin positivity and TB rates of their country of origin ( Table 249.2 ). Other groups, such as injection drug users, patients with end-stage renal disease or diabetes, health care workers in endemic countries, residents of institutions for the homeless, and, to a lesser degree, nursing home residents, demonstrate morbidity rates greatly in excess of the general population.

On a global scale, TB has a devastating impact in lower- and middle-income nations, with 10 countries accounting for nearly 70% of all prevalent cases ( Table 249.3 ). In 1993, WHO declared TB a global public health emergency and intensified major initiatives to address the problem. An important aspect of this strategy is supervised treatment, which may include DOTS. WHO subsequently reported decreasing incidence rates of TB in all six regions of the world, including Southeast Asia, the Western Pacific, and Africa. In China, access to DOT was rapidly expanded from 31% of TB cases in 2001 to 80% in 2005, and from 1990 to 2010 the prevalence of smear-positive disease decreased from 170 to 59 cases per 100,000, in a population of greater than 1.3 billion. Similar progress has also been made in India, the country with the greatest number of TB cases. Challenges remain; molecular epidemiologic data from China from 2009 through 2012 indicate that recent transmission still accounts for a substantial proportion of new cases and that sputum smear–negative cases may be responsible for 30% of secondary cases. In 2014 WHO launched its End TB Strategy with the goal of reducing global TB deaths by 90% and TB incidence by 80% by 2030. Major expansions of current activities and new prevention and treatment strategies will be needed to achieve this goal.

Over 35 million persons worldwide are now living with HIV/AIDS. The potential for continued interaction between HIV and TB is therefore immense. In some developing countries where most persons harbor tubercle bacilli before adulthood, the prevalence of HIV infection becomes the only determinant of coinfection. The situation is worst in sub-Saharan Africa, where the incidence of TB has risen in parallel with the incidence of HIV infection. Between 1990 and 2005, the incidence of TB more than doubled, from 149 to 343 per 100,000 population. TB is the leading 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 of the world's HIV-positive TB deaths occurred in Africa. The continued scale-up and integration of HIV and TB programs are necessary to decrease the deaths in these populations.

Drug-Resistant Tuberculosis

Drug-resistant TB poses an immense challenge for TB control. Resistance to antituberculous agents can be either primary, that is, present before initiation of therapy and due to transmission of a drug-resistant M. tuberculosis strain, or secondary, indicating emergence of resistance after antituberculosis therapy. Risk factors for infection with drug-resistant TB are listed in Table 249.4 . Strains resistant to at least INH and RIF are defined as MDR-TB. Strains resistant to at least INH, RIF, a fluoroquinolone, and second-line injectable drugs are defined as XDR-TB.

WHO has regularly reported global drug-resistance rates since 1994. In the United States, the rate of primary resistance to any antituberculosis drug has remained stable at about 12%, with that of MDR-TB at about 1%. Globally, 3.3% of new TB cases and 20.1% of previously treated TB cases are MDR. In 2016, there were an estimated 490,000 new cases of MDR-TB worldwide. Parts of Eastern Europe and central Asia, including Belarus, Estonia, Latvia, the Russian oblasts of Ivanovo and Tomsk, and Henan Province in China, have rates of MDR in newly diagnosed patients with TB that exceed 18%.

Prior antituberculosis treatment is the most important risk factor for drug-resistant TB. Additional historical clues that increase the likelihood of drug resistance include infection acquired in regions where resistance is prevalent and known contact with a drug-resistant case. One study from southern California recorded resistance in 71% of patients with TB who had been previously treated and had cavitary disease. Of immense concern is transmission of XDR-TB. Cases of XDR-TB have been reported in 105 countries worldwide, and it is estimated that 9.7% of MDR-TB is XDR-TB.

Mode of Spread

Almost all infections with M. tuberculosis are due to inhalation of droplet nuclei—infectious particles from a person with pulmonary TB aerosolized by coughing, sneezing, or talking—which dry while airborne, remain suspended for long periods, and reach the terminal air passages. A cough can produce 3000 infectious droplet nuclei, talking for 5 minutes an equal number, and sneezing many more than that. Accordingly, the air in a room occupied by a person with pulmonary TB may remain infectious for approximately 30 minutes even after his or her absence. Although in theory one droplet nucleus may be sufficient to establish infection, prolonged exposure and multiple aerosol inocula are usually required. Strains may vary widely in their transmissibility, but infection does not generally occur outdoors because M. tuberculosis is killed by ultraviolet light. Although homes are the focus of TB contact investigations, evidence is mounting that in high-TB settings, approximately 85% of transmission occurs in other social spaces including medical facilities, public transportation vehicles, workplaces, schools, churches, bars, and other areas where people congregate.

Large drops of respiratory secretions and fomites are unimportant in transmission, and special housekeeping measures for dishes and bed linens are unnecessary. Other modes of transmission are rare. Infection with M. bovis from ingestion of contaminated milk was once commonplace. Skin inoculation of M. tuberculosis from contamination of an abrasion occurs in pathologists and laboratory personnel (prosector's wart), and venereal transmission has been recorded. Although the source is pulmonary in the vast majority of cases, aerosolization of organisms during irrigation of cutaneous lesions or at autopsy has caused spread to health care workers. The special case of organ-donor–transmitted infection should be noted because transplant recipients have a higher frequency of TB than the general population, and high mortality. Because donor-derived disease develops late (>90 days) in the majority of cases, and many donors have identifiable risk factors for tuberculous infection, it has been proposed that screening protocols using donor histories that would heighten surveillance of recipients, in addition to cultures and smears, and testing for latent TB in donors should be undertaken.

Risk for Infection

The most important determinants of infection of tuberculin-negative persons are closeness of contact and infectiousness of the source. From 2002 to 2011, 26 outbreaks in the United States were associated with index cases with a substantial burden of substance abuse, incarceration, and homelessness. Cases with positive smears are highly infectious; those positive only on culture are less so. The degree of sputum positivity and pattern of coughing are important. Compared with measles, one case of which will infect 80% of susceptible casual contacts, TB is only moderately infectious in most circumstances. In the United Kingdom, a study of 111 cases with 825 contacts found that a shorter interval to liquid culture positivity identified patients at high risk of transmitting infection and was also superior to detection by means of smear.

TB morbidity in a population is determined both by the risk for infection and the risk for acquiring active disease once infected. In Holland in the 1970s, 50% of newborn to 14-year-old household contacts of individuals with smear-positive cases became tuberculin positive, but only 5% did so when the contact case was culture positive but smear negative. In the United States, approximately 27% of household contacts of individuals with smear-positive cases become infected, although rates as high as 80% occur in closed environments. A large epidemiologic investigation in San Francisco from 1991 to 1996 estimated that 17% of new active TB cases arose from smear-negative, culture-positive index cases.

Persons coinfected with HIV do not appear to be more infectious than HIV-negative source cases and because they are more likely to be smear negative than are HIV-negative patients, they may be less infectious. In one large study from the Democratic Republic of Congo, household contacts of HIV-positive patients with pulmonary TB were no more likely to become infected with M. tuberculosis than were household contacts of HIV-negative TB patients. A study in Uganda demonstrated that transmission from an HIV-infected index case to contacts was dependent on the index patient's sputum smear positivity and presence of a cavity on chest radiograph. A meta-analysis of six studies involving exposed health care workers supports this finding, as does a study of household contacts in Peru.

Influence of Chemotherapy on Spread of Infection

Patients receiving appropriate chemotherapy promptly become noninfectious as cough subsides and the concentration of organisms in sputum decreases. The time required to become noninfectious depends on the patient's burden of organisms, but there is indirect evidence that this occurs within 2 weeks in patients with drug-sensitive TB. Thus, case finding and treatment comprise the most effective method of TB control.

Risk for Progression From Infection to Active Disease

In general, 3% to 4% of infected individuals acquire active TB during the first year after tuberculin conversion and an additional 5% do so thereafter, although the uniformity of these rates has been challenged in a study from Victoria, Australia, in which the cumulative hazard for progression to disease after infection was 14.5%, with most risk occurring within the first 5 months and greater risk in children younger than 5 years (50.6%). These estimates are based on heavy exposures during disease-prone periods of life. Persons infected with small inocula or during disease-resistant periods probably have a much smaller risk, whereas the risk for progression in immunocompromised persons is greater. In one study of 12,876 unvaccinated adolescents, 10.4% of those who converted their tuberculin tests acquired clinical TB, 54% of these within 1 year and 78% within 2 years. The three periods of life during which infection is most likely to produce disease are infancy, ages 15 to 25 years, and old age. (The effect of age on disease progression is discussed in “Influence of Age on Tuberculous Infection.”)

The likelihood of active disease developing varies with the intensity and duration of exposure. Persons with intense exposures are most at risk not only for infection but also for disease. The degree of tuberculin positivity has some predictive value. Malnutrition, renal failure, and immunosuppression all favor progression of infection to active disease, but by far the strongest risk factor is HIV infection. Among tuberculin-positive, HIV-positive injection drug users in one methadone clinic population, 8% per year acquired active TB.

Institutional Spread of Tuberculosis

Controlling Nosocomial Spread

Spread of TB in the health care setting has raised justifiable concern. Tuberculin conversion rates as high as 50% among health care workers on HIV wards were reported early in the AIDS epidemic. Delays in diagnosis and initiation of therapy are critical for both outcome and infectiousness to others. Accordingly, TB must be considered in any HIV-positive patient with subacute or chronic pulmonary symptoms or symptoms compatible with extrapulmonary TB. Screening with NAAT tests such as Xpert MTB/RIF may expedite diagnosis.

Hospitalized HIV-positive patients with respiratory symptoms or people with suspected TB should be admitted to negative-pressure isolation rooms (so that air flows from the corridor into the room and is safely exhausted to the outside) with six air changes per hour. Procedures that stimulate coughing, such as sputum induction or bronchoscopy, should be carried out in negative-pressure rooms or special booths. The use of particulate respirator masks (N95), with appropriate training and fitting, further reduces risk and is recommended by the CDC. Ultraviolet irradiation of the air— either with the air pulled by a fan through a radiation chamber or with the ultraviolet beam directed into the uppermost parts of the room so as to avoid direct irradiation of personnel—is also advised. The CDC has published extensive guidelines for control of transmission of TB in diverse health care settings. Further evidence from a guinea pig model, in which the animals breathed untreated air from a TB ward, supports the use of air disinfection based on ultraviolet treatment. WHO has also published TB infection-control guidelines for health care facilities with strategies that may be attainable for low- and middle-income countries.

Testing for Latent Tuberculosis Infection

Individuals infected with M. tuberculosis with no clinical evidence of disease have LTBI. They have been infected with M. tuberculosis but do not have TB disease. To test for LTBI, a skin or blood test is performed to detect a cellular immune response to tuberculous antigens, indicating prior infection. The CDC suggests testing people who are at increased likelihood for infection and progressing to active TB, and who would therefore benefit from preventive therapy. The CDC also recommends stratifying patients’ risk of developing TB when interpreting TST results. The TST is the classic test, but blood interferon-γ release assays are increasingly recommended by expert panels.

Technical Aspects

The TST is performed by means of intradermal injection of 5 TU of PPD in 0.1 mL of solution, usually on the volar aspect of the forearm. The injection is made with a short, beveled 26- or 27-gauge needle with the bevel facing upward (Mantoux test). Correct injection produces a raised, blanched, 6- to 10-mm wheal. Deeper injections may be washed out by vascular flow, resulting in false-negative results. The loss of potency that occurs when PPD adsorbs to glass surfaces is prevented by the addition of the detergent polysorbate 80 (Tween 80). Tween-stabilized tuberculin in solution is light sensitive and must be refrigerated. The skin reaction is usually read in 48 to 72 hours. A positive test result is defined by the diameter of induration, not erythema, in response to 5 TU. The diameter should be read across the forearm and can be measured by viewing the reaction tangentially against a light background. An alternative is to use a medium-point ballpoint pen to draw a line starting 1 to 2 cm away from the skin reaction and moving toward its center. The pen is lifted when resistance is felt, the procedure repeated from the opposite direction, and the distance between opposing line ends measured.

Targeted Tuberculin Testing

The American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA), and CDC guidelines for LTBI testing recommend targeted testing of persons at increased likelihood of infection and/or at high risk for developing TB and with the intent for treatment of LTBI if the test is positive. This includes persons at high risk of infection (e.g., recent immigrants, household TB contacts) and persons with clinical conditions that increase the risk for TB disease (e.g., those with HIV/AIDS, organ transplant recipients, patients taking TNF inhibitors). Testing of persons at lower risk of infection and disease progression is discouraged. Initial testing is also recommended for persons whose activities place them at increased risk for exposure, such as employees at medical and correctional facilities.

Interpretation

Based on sensitivity and specificity of tuberculin skin testing, three cutoff levels have been recommended for defining positive reactions: 5 mm, 10 mm, and 15 mm (see “ Treatment of Latent Tuberculous Infection ”). The 5-mm cutoff is used for close contacts, children younger than 5 years, people who have HIV infection, those who are undergoing immunosuppressive therapy, those with an abnormal chest radiograph consistent with prior TB, and patients with silicosis. The 10-mm cutoff is used for people who are likely to be infected but at are low-to-intermediate risk of disease progression. The 15-mm cutoff is for people at low risk, although current guidelines for targeted testing suggest that low-risk persons not be tested. Ninety percent of persons with 10 mm of induration and virtually all with greater than 15 mm of induration to 5 TU are infected with M. tuberculosis. Induration of less than 10 mm may reflect cross reactions caused by infection with other mycobacterial species or prior BCG vaccination. However, even 5- to 10-mm reactions are suggestive of tuberculous infection in geographic areas substantially free of other mycobacteria, such as the northeastern United States, and in persons with immune suppression, such as HIV-infected persons. Because of the potential for false-positive TST results in people who have received BCG vaccine, the ATS, IDSA, and CDC recommend an interferon-γ release assay rather than the TST for people from countries that vaccinate with BCG.

Booster Effect

Although tuberculin cannot sensitize an uninfected person, it can restimulate remote hypersensitivity that has deteriorated. This booster effect (a positive tuberculin test result after a negative one) develops within several days after a first injection and may be persistent. This causes interpretative problems, because a negative test result followed by a positive test result approximately 10 weeks later may be a product of either a recent infection or a booster effect. This problem is circumvented by retesting nonreactors 1 to 3 weeks after the initial test. If the second test result is positive, this indicates boosting rather than recent tuberculin conversion. In early rheumatoid arthritis patients, with baseline increased risk of TB compounded by the use of TNF-α inhibitor therapy, the use of a booster PPD skin test increased LTBI detection from 31.3% to 46.5% in early rheumatoid arthritis and 21.7% to 28.8% in late rheumatoid arthritis patients.

False-Positive and False-Negative Reactions

False-positive reactions represent nontuberculous mycobacterial infection. False-negative reactions occur in at least 20% of all persons with known active TB. In one study, 25% of 200 patients with active TB were nonreactive to 5 TU and 10% were also nonreactive to 250 TU. Most false-negative test results in patients with TB are attributed to general illness and become positive 2 to 3 weeks after effective treatment is initiated. Protein malnutrition diminishes all cutaneous delayed hypersensitivity reactions. Sarcoidosis may cause false-negative TST results. Intercurrent viral infections (including HIV-1 infection with <200 CD4 ⁺ T cells/mm ³ ), vaccination with live-virus vaccines (measles, smallpox), reticuloendothelial disease, and corticosteroid therapy may cause false-negative tuberculin reactions. Attempts to correlate negative tuberculin test results with generalized anergy (e.g., negative skin test responses to mumps, Candida, and tetanus toxoid) have not been illuminating, and such “anergy testing” is therefore not recommended (see “ Tuberculin Skin Testing and HIV Infection ”). Intraobserver reliability in reading reactivity may vary by as much as 3 mm, causing some classification uncertainty if induration is close to the cutoff value. TST results are negative during the first 3 to 9 weeks of initial infection.

Variant (“Delayed”) Tuberculin Reactivity

An unusual form of tuberculin response (so-called delayed reactivity) has been described among Indochinese immigrants. This involves induration of less than 10 mm at 48 to 72 hours, which increases to greater than 10 mm when the skin test is read again at 6 days.

Loss of Tuberculin Reactivity

Earlier in the 20th century, lifelong tuberculin positivity was maintained by frequent reexposure to tubercle bacilli or continued active disease. However, a positive tuberculin test will revert to negative unless restimulated by new aerosol inocula or persisting infection. In one tuberculin survey, 8.1% of positive reactors reverted to true negative when retested 1 year later ( Table 249.5 ). Persons with a history of a positive skin test result can be safely retested. Two negative tests a week apart (to exclude boosting) indicate true negativity.

Tuberculin Skin Testing and HIV Infection

During HIV infection, tuberculin reactivity decreases as the CD4 cell count falls. One study of patients with active TB demonstrated 10 mm or greater induration in response to 5 TU in only 60% of persons with HIV infection and in 35% of those with AIDS. Induration of 5 mm in persons with HIV infection is sufficient to warrant treatment of LTBI (see “ Treating Latent Tuberculous Infection in Persons With HIV Infection ”). Testing simultaneously for cutaneous anergy with ubiquitous antigens such as mumps, tetanus toxoid, and Candida is not recommended. Because of lack of standardization and reproducibility, and variable risk for TB among anergic persons, cutaneous anergy does not predict M. tuberculosis infection, and responsiveness to control antigens but not PPD does not exclude tuberculous infection (see “ Treatment of Latent Tuberculous Infection ”).

Interferon-γ Release Assays for Latent M. tuberculosis Infection

Three interferon-γ release assays are FDA approved to detect latent M. tuberculosis infection. These tests measure host cellular immune response to M. tuberculosis antigens in whole-blood samples. These tests overcome several limitations of the TST, including false-positive results from environmental mycobacterial exposure or BCG vaccination, operator-dependent variability in test placement and reading, and the need for a follow-up visit to examine skin induration. Unlike the TST, blood tests do not require a follow-up visit for determination of results. The CDC recommends that these tests be used preferentially for most populations rather than the TST to detect LTBI. In a patient population at increased risk for tuberculous disease, such as candidates for organ transplantation, serial testing with interferon-γ release assays before transplant has revealed conversion and reversion rates of reactivity that undermine the ability to determine true-positive rates. These conversion and reversion rates have also been studied in South African adolescents. Concordance with the development of disease was good for conversion but not reversion, and incident TB was eightfold higher in reverters than in those with consistently negative results. In a study in 17 European centers, TST, QFT-GIT test, and T-SPOT.TB test (Oxford Immunotec, Abingdon, United Kingdom) (see later) were compared for their performance and comparability in immunocompromised patients (HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ and hematopoietic stem cell transplant patients) versus immunocompetent controls. TB incidence was low but higher in HIV-infected persons with a positive TST result than with either interferon-γ release assay. Treatment was effective in preventing disease.

The QFT-GIT test quantifies release of interferon-γ from lymphocytes in whole blood incubated overnight with three M. tuberculosis antigens: the early secretory antigen target-6 (ESAT-6), culture filtrate protein-10 (CFP10), and TB7.7. These three proteins are absent from BCG and from most other nontuberculous mycobacterial species. Blood must be tested within 12 hours of collection. The FDA has approved the QFT-GIT test, and the CDC has established guidelines for its use to detect latent TB. According to the CDC, the QTF-GIT may be used in all circumstances in which TST is used and is often the preferred test.

The next-generation QuantiFERON-TB Gold Plus (QFTPlus) test has been FDA approved and is starting to be rolled out in the United States and Europe. QTFPlus contains a fourth tube with short peptides from CFP-10, which are designed to elicit increased CD8 ⁺ T-cell production of interferon-γ. Furthermore, the next generation assay does not use the TB7.7 antigen. Four milliliters of blood are divided into four tubes. After incubation, if either antigen tube produces more interferon-γ than the nil (no antigen) tube, the result is positive. If the mitogen tube does not produce more interferon-γ than the nil tube, the result is indeterminate. There are only a few studies comparing the QFT-GIT and QTFPlus, and these suggest comparable results or perhaps slightly improved sensitivity of the QTFPlus in elderly or immunocompromised populations. Larger studies in diverse populations are needed.

Another assay, the T-SPOT.TB (Oxford Immunotec, Abingdon, United Kingdom) is an ELISPOT assay that also detects T-cell responses to M. tuberculosis antigens ESAT-6 and CFP10. It has been approved for use by the FDA in the United States. In an investigation of a large school outbreak of TB in the United Kingdom, the ELISPOT had 89% agreement with the TST and correlated more closely with exposure to the index case than the TST. Its performance for health care worker screening in US hospitals demonstrates high concordance among serial tests and high test completion rates.

Data on the performance of the interferon-γ release assays in children are limited, and guidelines differ on the optimal test. The ATS/IDSA/CDC guidelines recommend use of the same criteria as in adults for children aged 5 years and older. For children younger than 5 years, these guidelines recommend the TST, recognizing the limited data. Of note, 5 mL of blood is required for the interferon-γ release assay, which may be excessive for small children. The American Academy of Pediatrics states that the TST is recommended for children younger than 2 years. Either the TST or an interferon-γ release assay is acceptable for children aged 2 years and older, but for BCG-vaccinated children aged 2 years and older the γ release assay is preferred. Of note, a negative TST or γ release assay does not exclude active disease, and children are at high risk of rapid progression to TB disease.

Evolution of the Primary Infection

Tuberculin positivity appears 3 to 9 weeks after infection and marks the development of cellular immunity and tissue hypersensitivity. In most instances the infection is controlled, with the only evidence of infection being a positive skin test result. In a minority of cases, antigen concentration in the primary complex, consisting of the initial pulmonary focus (the Ghon focus) and the draining regional nodes, will have reached sufficient size that hypersensitivity results in necrosis and radiographically visible calcification, producing the Ranke complex (parenchymal and mediastinal calcific foci). Much less commonly, pulmonary apical and subapical metastatic foci contain sufficient bacilli that necrosis ensues with the onset of hypersensitivity, producing tiny calcific deposits (Simon foci) in which viable bacilli may persist.

The onset of tuberculin hypersensitivity may be associated with erythema nodosum or phlyctenular keratoconjunctivitis (a severe unilateral inflammation of the eye), although these manifestations are unusual in the United States. The primary complex may progress. In children, large hilar or mediastinal lymph nodes may produce bronchial collapse with distal atelectasis or may erode into a bronchus and spread infection distally. Also, typically in children but also in those infected in advanced age and HIV-infected patients, the primary focus may become an area of advancing pneumonia, so-called progressive primary disease, which may cavitate and spread via the bronchi. Again, typically in the very young, preallergic lymphohematogenous dissemination may progress directly to hyperacute miliary TB as a result of caseous material directly reaching the bloodstream, either from the primary complex or from a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus). Hematogenous dissemination in the very young is often followed within weeks by tuberculous meningitis. In adolescents and young adults, the subpleural primary focus may rupture, delivering bacilli and antigen into the pleural space to produce serofibrinous pleurisy with effusion. Overwhelmingly, the most important consequence of preallergic lymphohematogenous dissemination is seeding of the apical-posterior areas of the lung, where disease may progress without interruption or after a latent period of months or years, resulting in pulmonary TB of the adult or reactivation-type TB (endogenous reinfection).

Primary (Childhood) and Reinfection (Adult) Tuberculosis

The traditional terms primary or childhood pulmonary tuberculosis and reinfection or adult pulmonary tuberculosis followed radiographic observations early in the 20th century when initial (primary) infection in childhood was believed to be universal. Children's radiographs characteristically demonstrated large mediastinal or hilar lymph nodes with inconspicuous pneumonitis in the lower or middle lung field, whereas in adolescents and adults, apical or subapical infiltrates, often with cavitation and no hilar adenopathy, were the rule. These clinical and radiographic differences are due to age-related immunologic factors. Although many primary infections in adolescents and adults resemble primary infection in childhood, in others in this age group, an apical-posterior, metastatic pulmonary focus progresses within weeks to “adult”-type pulmonary disease, whereas the initial focus in the lower lung field and hilar nodes involutes undetected.

Apical Localization

In adults, apical localization of pulmonary TB has often been attributed to the hyperoxic environment of the apices and the aerobic nature of the organism. A more plausible theory attributes it to deficient lymphatic flow at the lung apices, especially the posterior apices, where the pumping effect of respiratory motion is minimal. Deficient lymph traffic would favor retention of bacillary antigen and, when hypersensitivity ensues, tissue necrosis. Apical-posterior localization with a tendency to cavitation and progression is characteristic of pulmonary TB in adolescents and adults. In contrast, infection acquired by the elderly often causes nondescript lower lobe pneumonia similar to progressive primary infection of childhood.

Endogenous Versus Exogenous Reinfection

In countries where the level of contagion is low, most cases of active TB reflect reactivation of latent foci. However, when contagion is high, exogenous reinfection may be more common. The temporal dynamics of relapse versus reinfection in high-prevalence settings suggest 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. 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. 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, and from molecular epidemiology data. 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 preantimicrobial 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 cellular immunity may wane in the absence of restimulation. Accordingly, clinical patterns have changed. At one time, most patients were adolescents 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. Hypersensitivity and cellular immunity likely become less vigorous with age (see “ Epidemiology ”).

Infection in Infancy and Childhood

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 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 commonly, other progressive extrapulmonary foci may develop, but TB confined to the lung in this age group usually heals spontaneously. The short-term prognosis in these individuals is good even if untreated, but there is a high frequency of relapse with chronic cavitary TB when the more disease-prone periods of adolescence and young adulthood arrive.

Infection in Adolescence and Young Adulthood

Clinical disease developing after infection in adolescence or young adulthood may resemble childhood infection (lower lung field pneumonitis, hilar adenitis) but with less parenchymal and hilar calcification ( Fig. 249.2 ). This is particularly the case in immunocompromised patients, including those living with HIV. Rarely, the radiographic picture may be mixed, with features of childhood disease subsiding while chronic upper lobe (adult) disease progresses. However, disease in this age group frequently first appears as chronic upper lobe TB with no clinical manifestations of childhood disease. The tendency toward apical cavitation soon after the initial infection appears soon after puberty and is marked in young adults. Evidence suggests that adolescents (and adults) may have a subclinical tuberculous pneumonia for months prior to the onset of overt disease. Because most young people in industrialized countries are tuberculin negative ( Fig. 249.3 ), most pulmonary TB in adolescents and young adults is due to recent initial infection rather than to late progression of childhood infection.

Infection in Midadulthood

Infection acquired during the middle years has a much better immediate and probably long-term prognosis than infection acquired in the teens and early 20s, presumably because of a reduced tendency to tissue necrosis. One study demonstrated progression from infection to cavitary TB in 23% of patients infected from 15 to 19 years of age, 13% of those infected from 20 to 24 years of age, 4% of those infected from 25 to 29 years of age, and only 2% of those infected after 30 years of age. Progression occurred in 3 months in many and within 1 year in most. (Elderly individuals were not included in the study.)

Infection in Old Age

In the elderly, infection acquired years earlier can progress as age compromises immunity, producing typical apical-posterior disease. Studies of TB in nursing homes, however, have demonstrated that elderly patients are often tuberculin negative, either because they had never been infected or because remote past infection had been completely cleared, with a loss of tissue hypersensitivity. Such tuberculin-negative persons are susceptible to new infection; and if this occurs, they acquire active disease with a frequency similar to that of adolescents. This is typically a nondescript, poorly resolving pneumonitis in the lower or middle lobes or anterior segments of the upper lobes, sometimes with pleural effusion and resembling primary infection in children except with much less hilar-mediastinal lymphadenopathy. Even with prompt diagnosis and treatment, TB after age 65 appears to be more frequently associated with death.

Late Hematogenous Tuberculosis

Chronic TB is probably always associated with recurrent abortive episodes of hematogenous spread. However, when aging or other factors compromise cellular immunity, such episodes may become progressively more frequent, producing the subtle and often fatal syndrome of late hematogenous or progressive generalized TB.

Intercurrent Events

General stress, poor health, and malnutrition favor progression of infection. Therapy with corticosteroids or other immunosuppressive agents compromises host defenses, as do hematopoietic-reticuloendothelial diseases, particularly malignancies. TB in complicating myeloproliferative disorders may cause confusion because disseminated TB can cause aplastic anemia, thrombocytopenia, leukopenia, and leukemoid reactions that may mimic leukemia. However, most patients with TB and hematologic findings that suggest leukemia will have both diseases. Inflammatory diseases such as rheumatoid arthritis and systemic sclerosis are often accompanied by immunologic derangements that may decrease immunocompetence even prior to the use of immunosuppressive therapies. Patients with systemic sclerosis in Taiwan had a significantly higher risk for TB and pulmonary TB, independent of systemic sclerosis treatment, compared with matched control subjects drawn from the National Health Insurance database (incidence rate ratios, 2.81 and 2.53, respectively). Biologic TNF-α inhibitors (e.g., infliximab, etanercept, and adalimumab) that are prescribed for rheumatoid arthritis and other inflammatory diseases increase the likelihood of reactivation TB, including extrapulmonary and disseminated disease.

The postgastrectomy state, jejunal-ileal bypass surgery, and end-stage renal disease are all risk factors for progression (see “ Treatment of Latent Tuberculous Infection ”). Viral illnesses, particularly in children, may predispose to progression of infection. Destructive local pulmonary processes such as lung abscess, carcinoma, cavitary histoplasmosis, and pulmonary resection occasionally are followed by activation of previously quiescent pulmonary foci. The development of bone and joint TB after physical injury and late generalized hematogenous TB after major trauma both illustrate that the balance between host and infection can be altered by both systemic factors and local physical disturbance.

Tuberculosis in People With HIV Infection

The earliest descriptions of TB with AIDS emphasized the very great risk for reactivation of remote infection as a result of progressively compromised cellular immunity. Among Haitians, all of whom were likely infected with M. tuberculosis in childhood, HIV infection was associated with development of active TB in 60%. Subsequent studies of HIV-positive and tuberculin-positive methadone clinic patients in New York City showed that active TB developed in 8% yearly.

TB remains the leading cause of death in HIV infection in reports from highly endemic areas, despite the introduction of ART. 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. 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.

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. Uncommonly, again more in infants, local progression of the initial pneumonia results in progressive primary disease, which may spread via the bronchial tree or the bloodstream. However, most infections during the relatively disease-resistant period of childhood (ages 5–12 years) are usually nonprogressive, with healing by involution and encapsulation. Progression, if any, occurs in extrapulmonary metastatic foci or with the development of apical-posterior pulmonary TB, usually when the patient reaches puberty or young adulthood.

Postprimary (Adult-Type) Pulmonary Tuberculosis

Primary infection in adolescents and adults (1) may occur without symptoms and signs, (2) may produce a typical primary complex, or (3) may result in typical chronic pulmonary TB without a demonstrable primary complex. Any pneumonic infiltrate, especially if associated with a hilar or mediastinal node, may represent primary infection. These lesions may undergo caseation, liquefaction, and bronchogenic spread just as with classic chronic pulmonary TB.

Postprimary pulmonary TB in adults is usually asymmetrical and characterized by caseation, fibrosis, and frequently cavity formation. It begins as a patch of pneumonitis in the subapical-posterior aspect of an upper lobe, usually just below the clavicle or first rib ( Fig. 249.4 ). A less frequent location is the apex of the lower lobe, where it may be obscured by the heart and hilum on a chest radiograph but readily visible on a chest CT image. The inflammatory response in the sensitized host produces a fibrin-rich alveolar exudate containing a mixture of inflammatory cells. Serial radiographs may demonstrate waxing and waning and sometimes complete regression. If the process accelerates, however, an area of caseous necrosis surrounded by epithelioid cells, granulation tissue, and eventually fibrosis develops. This may arrest by inspissation of the caseous area, fibrous encapsulation, and healing. Caseation, however, tends to liquefy and drain into the bronchial tree, spreading bacillary contents by coughing. The cavity is prevented from collapsing by the fibrous capsule and the inelasticity of the surrounding lung. The pulmonary cavity favors bacillary multiplication to enormous titers, 5 to 6 logs greater than in noncavitary lesions. The progressive nature of pulmonary TB is due to (1) the tendency of apical caseous foci to liquefy, (2) the enormous concentrations of organisms in the resulting pulmonary cavities, and (3) spread of this bacilli-rich material through the bronchial tree. Progression from minimal infiltrate to far-advanced cavitary disease can occur within a few months ( Fig. 249.5 ).

Coughing aerosolizes infectious cavity secretions that may distribute widely throughout the lung (bronchogenic spread). New foci eventually develop that, in turn, may undergo caseation, fibrosis, and healing or slough, resulting in new cavities. The segment or lobe containing the initial cavity is typically involved first with scattered patchy disease, but the contralateral apex is often secondarily involved with progressive disease. Bronchogenic spread may establish foci of infection in the lower lobe and anterior portions of the upper lobe, producing a polymorphous mottling on a chest radiograph, but these are usually nonprogressive and heal with fibrosis. Although hematogenous spread from an established pulmonary focus can occur, it is usually limited by hypersensitivity-induced thrombosis.

The highly infectious secretions from a cavity always cause some degree of endobronchial inflammation and ulceration, which may be extensive. Ulcerative tuberculous laryngitis is an extension of this process, as is local disease throughout the upper airways, mouth, middle ear, and gastrointestinal tract.

Mechanisms of healing are the same whether spontaneous or under the influence of chemotherapy. Without drug therapy, solid caseous foci surrounded by contracting fibrous tissue occasionally arrest. However, viable bacilli almost always persist in such lesions and can later reactivate. Before drug therapy, healing of persisting cavities never occurred, and some large, thick-walled cavities in shrunken fibrotic lobes could persist for years with minimal symptoms while remaining highly infectious (chronic fibroid TB). With drug therapy, cavities may resolve or they may heal but remain open, sometimes with complete reepithelialization. The major risk for such persistent cavities is superinfection with organisms such as Aspergillus or nontuberculous mycobacteria.

Lower Lobe and Endobronchial Tuberculosis

These terms lower lobe tuberculosis and endobronchial tuberculosis are not appropriate for chronic pulmonary TB of the ordinary kind that happens to involve the apex of the lower lobes. In adults, lower lung field tuberculosis describes three different but often associated processes: (1) progressive lower lobe pneumonia in recently infected older individuals; (2) 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.