Man must want to achieve more than he is able to achieve. … If we do not reach for the impossible, we shall never reach far enough to discover the possible. Our wishes should be boundless. Dr. Gerhard Domagk (1947 Nobel Prize in medicine for the discovery of the first antimicrobial drug)

Over the last century, tuberculosis (TB) has killed more than 100 million people and this has continued relatively unchanged over the last 50 years, despite the development of effective antituberculous drugs. This chapter summarizes the current status of the epidemiology, pathogenesis, diagnosis, treatment, and control of pulmonary tuberculosis. We have excluded nontuberculous mycobacterial disorders and the various forms of extrapulmonary disease, except pleural TB.

Historical overview

• Egyptian mummies with severe skeletal deformities suggest that TB has existed since antiquity (Pott’s disease).
• After the plague devastated Europe during the Middle Ages, TB (the “white plague”) began to take its heavy toll.
• TB affected famous kings and political figures (e.g., King Edward VI, King Louis VIII of France, John Calvin, Cardinal Richelieu, Napoleon II).
• TB, also called writer’s or artist’s disease, killed, among others, Nicolo Paganini, Robert Louis Stevenson, Franz Kafka, George Orwell, all five Brontë sisters, Thomas Mann, Albert Camus, and Igor Stravinsky.
• The Nobel Prize for Medicine for TB-related work was given to the following:
• Dr. Robert Koch (fig. 1) for the discovery of TB bacillus (1905)
• Dr. Gerhard Domagk for the discovery of the first antibacterial drug (Prontosil); also pioneered anti-TB drug development (1947)
• Dr. Selman Waksman for the development of streptomycin as an anti-TB drug (1952)
• In 1993, the World Health Organization (WHO) declared TB a global emergency, the only disease ever so designated. In 2003, WHO reported a continued TB pandemic.

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Prevalence and risk factors

Tuberculosis Worldwide

About one third of the world’s population is infected with Mycobacterium tuberculosis. Among the communicable diseases, TB is the second leading cause of death worldwide after HIV-AIDS, killing nearly two million people each year. Approximately 13% of TB patients have coexistent HIV infection. There were an estimated eight million to nine million new cases of TB in 2000, but fewer than one half were actually reported. Most cases (5 million to 6 million) occur in those aged 15 to 49 years, with significant socioeconomic impact. More than 50% of TB cases occur in the largest Asian countries (India, China, Indonesia, Bangladesh, Philippines, and Pakistan). Sub-Saharan Africa has the highest incidence rate (approximately 300/100,000 population/year). Even though TB has declined steadily in western Europe and North America, the global TB burden appears on the rise, especially in the former Soviet Union, Eastern Europe, and Africa. HIV infection accounts for much of the recent increase in the global TB incidence.

Tuberculosis in the United States

In the 1900s, TB was one of the leading causes of death in the United States. Here, the most important risk factors for the development of TB are immigration from or travel to an endemic area, close contact with a TB patient, exposure to untreated cases in crowded living facilities, advanced age, residing in an inner city, and host immunodeficiency. Although the TB incidence was already decreasing in the first half of the 20th century because of better nutrition and housing conditions, the introduction of effective chemotherapy produced a steep decline in mortality and an accelerated drop in incidence, reaching an average of a 5.5% decline per year of TB case rates between 1953 and 1983. Between 1985 and 1992, however, the incidence of TB unexpectedly increased by about 20%. The responsible factors were increased immigration from high-prevalence countries, the emergence of the HIV-AIDS epidemic, an increased number of medically underserved persons (e.g., homeless, drug abusers, low-income persons), emergence of drug-resistant TB cases and, most importantly, deterioration of the public health infrastructure for the control of TB.

In 2005, a total of 14,093 TB cases (4.8 cases/100,000 population) was reported in the United States, representing a 3.8% decline in the rate from 2004. These findings indicated that although the 2005 TB rate was the lowest recorded since national reporting began in 1953, the decline has slowed from an average of 7.1% per year (1993-2000) to an average of 3.8% per year (2001-2005). In 2005, the TB rate in foreign-born persons in the United States was 8.7 times that of U.S.-born persons. Hispanics, African Americans, and Asians had TB rates 7.3, 8.3, and 19.6 times higher than whites, respectively. Moreover, the number of multidrug-resistant (MDR) TB cases in the United States increased by 13.3%, with 128 cases of MDRTB in 2004, the most recent year for which complete drug-susceptibility data are available. Effective TB control and prevention in the United States require adequate resources, sustained collaborative measures with other countries to reduce the incidence of TB worldwide, and interventions targeted to populations with the highest TB rates.¹

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Etiology

Tuberculosis is caused by a group of five closely related species, which form the Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canettii. M. tuberculosis (Koch’s bacillus) is responsible for the vast majority of TB cases in the United States. The main defining characteristic of the genus Mycobacterium is the property called acid-fastness, which is the ability to withstand decolorization with an acid-alcohol mixture after staining with carbolfuchsin or auramine-rhodamine. Mycobacteria are primarily intracellular pathogens, have slow growth rates, are obligate aerobes, and produce a granulomatous reaction in normal hosts. In cultures, M. tuberculosis does not produce significant amounts of pigment, has a buff-colored, smooth surface appearance, and biochemically produces niacin. These characteristics are useful in differentiating M. tuberculosis from nontuberculous mycobacteria. One characteristic but not distinctive morphologic property of M. tuberculosis is the tendency to form cords, or dense clusters of bacilli, aligned in parallel (Fig. 2). The biochemical background of cording is called cord factor (a trehalose dimycolate), and its contribution to bacterial virulence is still unclear.

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Pathophysiology and natural history

TB transmission occurs almost exclusively from human to human; a prerequisite is having contact with a source case. More than 80% of new TB cases result from exposure to sputum smear-positive cases, although smear-negative, culture-positive cases can be responsible for up to 17% of new cases. Tuberculosis is spread by airborne droplet nuclei, which are 1- to 5-µm particles containing 1 to 400 bacilli each. They are expelled in the air by, for example, coughing, sneezing, singing, laughing, or talking, and remain suspended in the air for many hours. They can be inhaled and subsequently entrapped in the distal airways and alveoli. There, bacilli are ingested by local macrophages, multiply within the cells and, within 2 weeks, are transported through the lymphatics to establish secondary sites (lymphohematogenous spread). The development of an immune response, heralded by a delayed-type hypersensitivity reaction over the next 4 weeks, leads to granuloma formation, with a subsequent decrease in the number of bacilli. Some of them remain viable, or dormant, for many years. This stage is called latent TB infection (LTBI), which is generally an asymptomatic, radiologically undetected process in humans. Sometimes, a primary complex (Ghon complex) can be seen radiographically, mostly in the lower and middle lobes, and comprises the primary lesion, hilar lymphadenopathy, with or without a lymphangitic track. Later, the primary lesion tends to become calcified and can be identified on chest radiographs for decades. Most commonly, a positive tuberculin test result remains the only proof of LTBI, and therefore does not signify active disease.

Under certain conditions of immature or disregulated immunity, alveolar macrophages and the subsequent biologic cascade could fail in limiting the mycobacterial proliferation, leading to primary progressive tuberculosis; this is seen mostly in children younger than 5 years or in HIV-positive or profoundly immunosuppressed individuals. Factors known to influence this unfavorable course are patient’s age, nutritional status, host immunity, and bacterial infective load.

Once infected with M. tuberculosis, 3% to 5% of immunocompetent persons develop active disease (i.e., secondary progressive tuberculosis) within 2 years and an additional 3% to 5% later on during their lifetime. Overall, there is a lifetime risk of re-activation of 10%, with one half occurring during the first 2 years after infection—hence, the necessity to treat all tuberculin skin test converters. The lifetime re-activation rate is approximately 20% for most persons with purified protein derivative (PPD) induration of more than 10 mm and either HIV infection or evidence of old, healed tuberculosis; it is between 10% and 20% for recent PPD skin test converters, adults younger than 35 years with an induration of more than 15 mm or on therapy with infliximab (a tumor necrosis factor α [TNF-α] receptor blocker), and children younger than 5 years and a skin induration of more than 10 mm.

Studies performed in New York City and San Francisco using DNA fingerprinting have indicated that recent transmission (exogenous reinfection), especially among HIV patients, could account for up to 40% of new TB cases. This is significantly different from older studies, which have shown that approximately 90% of new TB cases are the result of endogenous re-activation.

After inhalation, the pathogenic bacilli start to replicate slowly and continuously and lead to the development of a cellular immunity in about 4 to 6 weeks. T lymphocytes and local (pulmonary and lymphatic node) macrophages represent key players in limiting further spread of bacilli in the host. This can be seen at the pathologic level, where the bacilli are in the center of necrotizing (caseating) and non-necrotizing (noncaseating) granulomas, surrounded by lymphocytes and macrophages. The infected macrophages release interleukins 12 and 18 (IL-12 and IL-18), which stimulate CD4-positive T lymphocytes to secrete IFN-γ (interferon gamma), which in turn activate the macrophage phagocytosis of M. tuberculosis and the release of TNF-α. TNF-α has an important role in granuloma formation and the control of infection.

Genetic defects are illustrated by different polymorphisms of the NRAMP-1 gene (natural resistance-associated macrophage protein-1); vitamin D receptors, and interleukin-1 have also been shown to be involved in TB pathogenesis. It can be difficult to differentiate between genetic predisposition and overwhelming bacteriologic load, as often seen in countries with a high prevalence of TB.

HIV coinfection is the greatest risk factor for progression to active disease in adults. The relation between HIV and TB has augmented the deadly potential of each disease. Other risk factors include diabetes mellitus, renal failure, coexistent malignancies, malnutrition, silicosis, immunosuppressive therapies (including steroids and anti-TNF drugs), and TNF-α receptor, IFN-γ receptor, or IL-12 β₁ receptor defects.

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Diagnosis

Signs and Symptoms

A high index of suspicion is needed in countries with a high prevalence of infection or in patients with immunosuppression, although bacteriologic confirmation is required whenever possible. Persistent cough for more than 2 to 4 weeks should raise the possibility of pulmonary TB. Other common associated symptoms are hemoptysis, dyspnea, malaise, weight loss, night sweats, and chest pain. The symptoms are less pronounced in children, and any exposure to an active TB patient or a positive tuberculin test should raise more concerns about this disease. Box 1 shows the Centers for Disease Control and Prevention (CDC) recommendations for the clinical and laboratory criteria of TB diagnosis.

Laboratory Tests

One inexpensive and rapid diagnostic test is the sputum smear, done by Ziehl-Neelsen (ZN) carbolfuchsin, Kinyoun carbolfuchsin, or fluorochrome staining methods. ZN stain identifies 50% to 80% of culture-positive TB cases and is a useful diagnostic and epidemiologic tool, because smear-positive TB patients are more infectious than smear-negative patients and have a higher fatality rate. Nevertheless, smear-negative cases may account for up to 20% of M. tuberculosis transmission. In countries with a high prevalence of TB, a positive smear signifies TB in 95% of ases. The lower limit of detection of ZN staining is 5 × 10³ organisms/mL, whereas rhodamine-auramine fluorochrome staining tends to be more sensitive. In children, M. tuberculosis can be recovered from gastric aspirates, with yields varying from 30% to 50% in older children to 70% in infants for three consecutive specimens. The role of induced sputum or bronchoscopy in diagnosing TB is well established in patients unable to provide good-quality sputum specimens.

Culture media most often used for diagnosis include the following:

• Solid culture medium: egg-based Löwenstein-Jensen, or agar-based Middlebrook 7H10 or 7H11 (growth can take up to 6 weeks)
• Liquid culture medium (growth in 1-3 weeks)

The speciation can be done with biochemical tests or DNA probes. The direct specimen polymerase chain reaction assay is rapid (1-2 days), although it can lead to false-positive results and has been disappointing in its practicality.

Imaging Studies

Radiographic findings suggesting TB include upper lobe infiltrates, cavitary lesions, and hilar or paratracheal lymphadenopathy. In many patients with primary progressive disease and in HIV patients, radiographic findings can be subtle and include lower lobe opacities, a miliary pattern, or both. In a study done on HIV-infected pulmonary TB patients, 8% of cases had normal chest radiographs.

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Treatment

Lifestyle Modifications

These include good nutrition, which is of paramount importance, and physical activity, which is strongly encouraged.

Treatment Options

• Drug treatment is an individual and public health measure.
• Regimens must contain multiple drugs to which organisms are susceptible, given for a sufficient period of time.
• Adherence to the drug regimen is critical for success. Directly observed therapy (DOT) is cost effective for patients at high risk for nonadherence, and should be used in all cases.
• Chemotherapy can be successful only within a health system infrastructure that addresses the clinical and social management of patients and their contacts.
• Surgery is indicated for TB abscesses or loculated foci of infection that are unresponsive to medical therapy.

Practice Guidelines

• Use the major antituberculous drugs, isoniazid (INH) and rifampin (RIF) throughout the course, unless there is a resistant organism to one of them.
• Use pyrazinamide (PZA) for the first 2 months. Studies have shown that 6 months of INH and RIF with 2 initial months of PZA are as effective as 9 months of INH and RIF alone, but leads to a higher sputum conversion rate and a smaller chance of secondary resistance.
• If PZA cannot be used in the first 2 months, a reasonable alternative is INH and RIF administered for 9 months.
• Use ethambutol (ETB) or streptomycin (SM) as a fourth drug until susceptibilities are known if the patient comes from a community with a higher than 4% chance of drug resistance (currently, in 41 of 50 states), has undergone prior therapy, or has possible exposure to a drug-resistant case.
• Once susceptibilities are known and M. tuberculosis is susceptible to INH, RIF and PZA, ETB, and SM can be discontinued.
• If cultures are positive after 2 months of therapy, triple-drug therapy continuation is recommended; the treatment should be continued for about 4 months after the cultures become negative.
• The 7 day/week regimens are interchangeable with 5 day/week regimens for the same duration of therapy if M. tuberculosis is susceptible to the respective drugs.
• Corticosteroids have been shown to be of benefit in preventing cardiac constriction from TB pericarditis, decreasing neurologic sequelae in TB meningitis, and (possibly) preventing bronchial stenosis in cases of diffuse endobronchial TB. Once there is absolute assurance that the chemotherapeutic regimen is effective, some have advocated the use of low-dose steroids in the initial phase, especially in malnourished patients, although supporting data are lacking.
• Pregnant women with active TB need to be treated with INH and RIF, which are safe during pregnancy. PZA, although recommended by many, has not been thoroughly studied in pregnancy and should be used at the discretion of the treating physician. ETM has not been recommended, and SM is definitely harmful during the pregnancy.
• Pulmonology or infectious disease consultations, or both, are recommended for guiding expertise in the management of pulmonary TB.
• Public Health Department notification and assistance are essential for the management of TB, and the institution of DOT.

Treatment Regimens

When discussing treatment regimens for TB, the nomenclature used needs to be defined. The expression nHRZS(E)_m refers to n months of isoniazid, H, rifampin, R, pyrazinamide, Z, and streptomycin, S (or ethambutol, E), for m days a week. The first term represents the initial phase and the second term respresents the continuation phase.

For culture-positive pulmonary tuberculosis caused by drug-susceptible organisms, there are four acceptable regimens²:

• 2HRZE(S)₇ + 4HR₇ (preferred)
• 0.5HRZE(S)₇ + 1.5HRZS(E)₂ + 4HR₂
• 2HRSZ(E)₃ + 4HR₃

or

• 2HRE₇ + 7HR₇

For smear-negative, culture-negative TB cases (clinical TB), a 4-month HR regimen (4HR₇ or 4HR₂) is acceptable. The doses used in TB regimens are shown in Table 1.

Drug Resistance Considerations

Antituberculous drug resistance has been increasing worldwide. Treatment of resistant TB, especially MDRTB, is frequently unsuccessful, requiring the use of more toxic, expensive drugs, surgery, or both. Thus, emphasis should be on strategies developed to avoid the emergence of drug resistance. Primary resistance occurs in patients with active TB who have never received antituberculous drugs. Secondary (or acquired) resistance is the occurrence of resistance after a mutant’s selection or facilitation in the presence of various antituberculous drugs. A cavitary TB lesion may contain up to 10⁹ bacilli in a perfect, culture-type, aerobic environment. M. tuberculosis has low rates of spontaneous chromosomal mutations, in the range of 1 : 10⁶ for INH, 1 : 10⁸ for RIF and approximately 1 : 10¹⁴ for both agents. These rates are clinically insignificant, unless suboptimal time intervals or doses of anti-TB drugs facilitate the resistant subpopulation’s growth.

MDRTB is defined as the presence of at least 1% of Mycobacterium strains in a bacterial population or culture that are resistant to at least INH and RIF. The practices associated with the occurrence of MDRTB include failure to predict, identify, or adequately address nonadherence to therapy, use of an inadequate initial regimen, use of INH monotherapy when the patient actually has active disease (not LTBI), and the addition of a single drug to a failing regimen. The most important demographic clues for drug resistance are being a resident of a large urban, coastal, or border community area (in the United States), or from areas with high MDRTB rates (outside the United States, such as Russia), or being HIV-infected (probably reflecting a higher proportion of disease resulting from recent transmission). The most important historical clues are prior therapy for TB, and, less so, cavitary lesions. MDRTB is treated with four drugs, as in the usual therapeutic regimens, plus at least an additional two drugs to which the patient’s infective organism is believed to be susceptible. Patients with culture-confirmed MDRTB should be treated with at least three drugs to which the organism is susceptible for at least 12 months after the sputum conversion. Most experts recommend 18 to 24 months of therapy. INH-resistant cases can be treated with RIF, PZA, and ETB for 6 to 9 months, and patients with RIF-resistant TB are treated with INH, PZA, and ETB for 9 to 12 months after sputum cultures become negative. Consultation with a TB expert and the public health department’s assistance are mandatory when managing an MDRTB case.

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Disease control

Infection control efforts to stem TB outbreaks among inpatients and health care staff are essential, because they represent the proximal contacts for any TB source in that particular setting. Although most patients do not ultimately need hospitalization (e.g., an isolated TB pleurisy), patients suspected of having active TB are kept in isolation until they are no longer infectious, until TB is ruled out, or three negative sputum specimens are obtained. Isolation rooms should have negative-pressure ventilation, with at least six air exchanges per hour. Health care workers who come in contact with these patients should wear N95 masks or powered air-purifying respirators (PAPRs) to avoid inhaling infectious particles while in the room with the patient. The isolation can be discontinued after 10 to 14 days of therapy if the patient responds to therapy. Patients can be removed from isolation and discharged home if they are returning to their previous residence, where the health department has identified no individuals at risk (children younger than 2 years, immunocompromised patients) and the other possibly exposed individuals are being evaluated for LTBI. Outpatient medications should be given using DOT to ensure adherence to treatment. The recent decline in the United States is largely the result of the implementation and use of DOT, which has been shown to improve therapy completion rates and to prevent the emergence of acquired resistance and MDRTB.^3-5

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Special considerations

Latent Tuberculosis Infection

The intradermal administration of tuberculin has been used as a diagnostic test for TB infection since the early 1900s, and the standardized purified protein derivative (PPD-S) since 1939. The diagnosis of TB infection relies on determining the size of the delayed-type hypersensitivity reaction to an injection of 0.1 mL of 5 tuberculin units (TU) after 48 to 72 hours (Mantoux test). The tine test has no role in the evaluation of an individual patient.

Although the PPD is still the best available way to diagnose TB infection, it is not a perfect test because of the following:

• It has low sensitivity in immunosuppressed patients (e.g., HIV-infected patients; the threshold for positivity is 5 mm for these patients), or in the preimmune initial phase of infection.
• It has cross-reactivity with bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria (low specificity). The larger the induration, the greater is the likelihood that the reaction represents a M. tuberculosis infection versus environmental mycobacterial sensitization or reaction from prior BCG vaccination.
• It usually needs a follow-up visit in 48 to 72 hours for reading the results, although e-mail, digital pictures, and other means in this era of telemedicine have become available and are widely used.
• The reading is subjective and requires expertise (low interrater variability).
• There is a booster effect. It is known that delayed-type hypersensitivity reactions from a prior mycobacterial infection or BCG vaccination may wane over time. Although subsequent skin reactions could be still negative for a particular individual, the stimulus of the first test may boost or increase the size of the second test results, generally by less than 5 mm, administered 1 week to 1 year later, suggesting a false conversion. When PPD skin testing is repeated periodically, as in employee health or institutional screening programs, an initial two-step approach can reduce the likelihood that a boosted reaction will be interpreted as a sign of recent infection. If the first PPD skin test is negative, a second 5-TU test should be performed 1 to 3 weeks later; a positive second reaction would indicate boosting of a previous infection or BCG vaccination. The major problem with a booster effect is LTBI overdiagnosis (false-positive result for infection).

The American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) statement on LTBI⁶ has established the thresholds of PPD indurations for different settings and hosts (Box 2). An increase in induration of more than 10 mm within a 2-year period indicates conversion, irrespective of age. In patients at low risk for TB infection, PPD skin testing is not recommended. The ATS-CDC has specifically recommended LTBI screening to be used only for high-risk patients, the concept of targeted LTBI screening. The old term, INH prophylaxis, applied to the treatment of LTBI should be abandoned.

Similar to the principle of the Mantoux reaction, a whole-blood IFN-γ release assay (IGRA) evaluates cell-mediated immunity to tuberculin. Although it seems to be less sensitive and less specific, it can differentiate between infection and prior BCG vaccination. An enzyme-linked immunosorbent spot (ELISPOT) assay has been developed that is relatively sensitive and specific for detecting LTBI by targeting early-secreted antigenic target (ESAT-6), which is expressed only by M. tuberculosis, and not by other Mycobacterium spp. or by BCG. In May 2005, an in vitro test, QuantiFERON-TB Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia), received approval from the U.S. Food and Drug Administration (FDA) as an aid for diagnosing M. tuberculosis infection. The test detects the IFN-γ released in fresh heparinized whole blood from sensitized persons when it is incubated with a mixture of synthetic peptides representing two proteins from M. tuberculosis, ESAT-6 and culture filtrate protein-10 (CFP-10). These antigens have greater specificity than PPD as the TB antigen. In direct comparisons, the sensitivity of QFT-G was statistically similar to that of the tuberculin skin test (TST) for detecting infection in persons with untreated culture-confirmed TB.

In July 2005, the CDC,⁷ after reviewing existing data, recommended that the QFT-G can be used in all cases in which the TST is currently recommended, including contact investigations, evaluation of recent immigrants, and sequential testing surveillance programs for infection control (e.g., those for health care workers). The report provided specific cautions for interpreting negative QFT-G results in persons from select populations. Although approved by the FDA, the cost-effectiveness and practicality of the molecular methods discussed are still unclear.

The recommended approach in LTBI is given in Box 3. The ATS-CDC guidelines⁶ for LTBI treatment recommend isoniazid (INH), 5 mg/kg daily to a maximum of 300 mg, or 15 mg/kg twice weekly to a maximum of 900 mg. The duration of therapy recommended is 9 months for all patients (including children); if this cannot be accomplished, 6 months is acceptable. This represents a change in previous recommendations of 6 months of therapy for adults and 12 months for HIV-positive patients, which was based on studies showing that a 9-month course is superior to a 6-month course and almost as effective as 12 months of therapy. Following concerns about decreased rates of adherence to this length of therapy, studies have shown that RIF in doses of 10 mg/kg/day, up to a total of 600 mg for 4 months, or RIF (alternatively, rifabutin, with less interactions with other drugs) with PZA) daily for 2 months in HIV-infected individuals is an effective alternative to INH for 9 months. However, as a result of reports of severe hepatic injury following RIF-PZA combination administration in HIV-negative patients, the ATS-CDC has revised its recommendations, endorsed by the Infectious Diseases Society of America (IDSA), which state that this combination should no longer be offered to persons with LTBI.⁸ The tuberculin skin testing is safe during pregnancy.

Bacillus Calmette-Guérin Vaccination

BCG, an attenuated strain of M. bovis, was first used as a vaccine in the 1920s. It has become the most widely used vaccine in the world, despite questions regarding its variable efficacy (0%-80%) in preventing TB in adults. Although less than ideal, studies have consistently shown its effectiveness in reducing fatal or severe forms of TB in infants and young children—miliary TB or meningitis. Most countries give only one BCG vaccine, at birth) Only 50% of vaccinated infants ever become PPD-positive, but by 1 to 2 years of age, only 20% are reactors. Of note, there are multiple BCG variants worldwide, with different results and varying rates of PPD conversion, which has greatly confounded their use. The chance of developing a postvaccination positive PPD test increases with the age of the BCG recipient, whereas repeated vaccinations have much higher rates of long-term conversion or booster effects on PPD rechallenge. In BCG recipients, the reactions to PPD are generally smaller than 10 mm, although reactions up to 18 mm have been reported.

In the United States, it is generally accepted that a positive tuberculin reaction in an adult indicates a true infection with M. tuberculosis, especially if that individual is a close contact of a TB case, from a high-prevalence area, or at high risk of exposure. BCG’s lower efficacy in preventing TB compared with INH, as part of LTBI treatment, and interference with tuberculin skin testing has limited its use in the United States.

Tuberculous Pleural Effusion

Tuberculous Pleurisy

Tuberculous pleurisy is the most common form of extrapulmonary TB; it occurs in 10% of PPD converters. It develops when a subpleural TB focus ruptures into the pleural space and elicits a significant immune response. This can happen after the primary phase (up to 6 months after exposure) or during the secondary phase (endogenous reactivation). Clinically, it often manifests with cough, pleuritic chest pain, dyspnea, low-grade fever, and other nonspecific constitutional symptoms. The PPD skin test is generally positive in 90% of cases. Radiographically, it is generally unilateral, small to moderate in size, more frequent on the right side, and sometimes associated with parenchymal disease (ipsilateral infiltrates).

The pleural fluid is serous or serosanguineous (rarely hemorrhagic), exudative, with high protein concentrations (>5 g/dL), low pH (<7.30), moderately depressed glucose levels (<60 mg/dL), and usually lymphocytic (typically >90% cells). Acid-fast bacilli can be isolated in pleural fluid sediment in less than 5% of cases and, in cultures, in up to 70% of cases. Pleural biopsy specimens can increase the diagnostic yield to 20% of the cases, on microscopy, and to 80% of the cases, in cultures. Closed pleural biopsy, with pleural fluid analysis and sputum examination, yield the diagnosis of pleural TB in more than 80% of cases, whereas video-assisted surgical biopsy has an even higher diagnostic yield. The sputum can be positive for TB from 4% in isolated TB pleurisy to 50% of cases in those with extensive parenchymal infiltrates. A pleural fluid adenosine deaminase (ADA) level higher than 60 U/L may support the diagnosis if rheumatoid arthritis or empyema is unlikely, although this test is not routinely recommended.

Even if the pleurisy is not treated, the clinical course is toward spontaneous resolution, with minimal pleural scarring. However, the reactivation rate is higher for cases with coexistent parenchymal foci, more than 65% of cases at 5 years. Pleural TB is treated with a 4- to 6HR₂ regimen._. Steroids may hasten the pleural fluid resorption and resolution of clinical symptom resolution, although they do not seem to prevent scar formation.

Tuberculous Empyema

Less common than TB pleurisy, tuberculous empyema represents a chronic active infection of the pleural space. Its incidence was higher historically in patients who had undergone therapeutic pneumothorax, oleothorax, Lucite ball plombage, or pneumonectomy. It can run its course for decades, with a surprising paucity of clinical symptoms. On the chest computed tomography (CT) scan, the pleural peel is thickened, calcified, and sometimes loculated; the pleural mass may be accompanied by an extrapleural mass, which is diagnostic of empyema necessitans. The pleural fluid is generally thick, purulent in appearance, and positive on microscopic examination for acid-fast bacilli and occasionally other aerobic and anaerobic bacteria, indicating the presence of a bronchopleural fistula. In general, therapy is surgical, with a wide range of possible interventions, from parietal decortication to thoracoplasty, with or without omentopexy or myoplasty. Medical therapy is mandatory in an attempt to sterilize all residual TB foci.

Tuberculosis and HIV Infection⁹

It is estimated that 33% to 50% of the 20 million individuals infected with HIV worldwide are coinfected with M. tuberculosis. In many TB clinics, more than 10% of patients are HIV-seropositive. The AIDS case definition was modified in 1987 to include any form of extrapulmonary TB in an HIV-positive patient. Most cases represent the re-activation of old TB, occurring earlier than other opportunistic infections, because of the virulence of M. tuberculosis. There is also a significantly higher fraction of HIV-infected subjects who develop primary progressive TB, especially at the AIDS stage.

There is no evidence that HIV coinfection makes the patient more likely to transmit the disease, although AIDS patients are more predisposed to develop the progressive disease and can be more difficult to diagnose. The mean CD4 count at TB presentation is 200 to 300 cells/mm³, which is earlier than other opportunistic infections. With a CD4 count higher than 300 cells/mm³, the clinical presentation is similar to that of those who are HIV-negative—that is, isolated pulmonary disease, with focal apical infiltrates, occasionally with cavitation. As immunosuppression worsens, the incidence of diffuse pulmonary disease without cavitation, miliary TB, and extrapulmonary TB increases, up to 70% of AIDS patients.

Patients with HIV infection have a similar response to anti-TB medications as that of HIV-negative patients. However, drug interactions are important issues. Many of the highly active antiretroviral therapy (HAART) drugs interfere with rifampin’s metabolism, which is a potent inducer of the cytochrome P-450 enzyme system. Consequently, the levels of anti-HIV drugs could be suboptimal. Rifabutin, a RIF-derivative, has equivalent efficacy and less effect on hepatic enzymes and therefore is preferred for most HIV-positive patients. Clinical deterioration may occur in patients with active TB started on HAART—for example, worsening infiltrates, severe hypoxemia to full-blown acute respiratory distress syndrome, necrotizing lymphadenitis, enlarging brain tuberculomas, miliary TB, or severe systemic toxicity. This is called immune reconstitution syndrome and is believed to be caused by re-arming of the cellular immune system during the first weeks of HAART. A possible preventive measure is initiating anti-TB treatment 2 weeks before stating HAART.

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Conclusions

Tuberculosis is probably one of the greatest killers of all time, over the centuries taking more than 1 billion lives and up to 2 million people every year (i.e., one life every 15 seconds, as opposed to a life lost in an accident every 50 seconds). Every year, TB infects up to 100 million people worldwide, and up to 8 million develop active disease. If the tuberculosis is not treated, every source case infects, on average, 10 to 15 other persons each year. TB can be considered a social disease, disrupting families emotionally, educationally, and economically. Furthermore, only about 20% of worldwide TB cases are detected and treated successfully.

DOT strategy implemented by the World Heath Organization (WHO) is probably one of the most cost-effective of all health interventions. Achievement of global targets of 70% detection and 85% cure rates would reduce incidence and mortality by 10%. The United States and several other low-incidence countries have embarked on plans to eliminate tuberculosis completely. Important elements in an elimination strategy would be to identify and treat effectively LTBI persons at risk of developing active disease, and to ensure provision of inexpensive and efficacious drugs to countries that cannot afford them. However, even though a constellation of drugs, molecular tools, and public health strategies are on the horizon, newer diagnostic tools, a better vaccine, and novel therapeutic agents are urgently needed to fight this condition more effectively.

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Summary

About one third of the world’s population is infected with Mycobacterium tuberculosis. Once infected with M. tuberculosis, 3% to 5% of immunocompetent individuals will develop active disease.

• Among communicable diseases, tuberculosis is the second leading cause of death worldwide.
• Tuberculosis is caused by the Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canettii.
• TB transmission occurs almost exclusively from human to human, most commonly via airborne droplet nuclei.
• Persistent cough, hemoptysis, dyspnea, malaise, weight loss, night sweats, and chest pain are the common symptoms of tuberculosis.
• Standard anti-TB therapeutic regimens have to be administered after notification of the local public health department, preferably under DOT (directly observed therapy).
• DOT strategy, which is implemented and enforced by the World Heath Organization, is probably one of the most cost effective of all health interventions.

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Suggested Readings

• American Thoracic Society. Centers for Disease Control and Prevention. Infectious Diseases Society of America. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling tuberculosis in the United States. Am J Respir Crit Care Med. 2005, 172: 1169-1227.
• Blumberg HM, Burman WJ, Chaisson RE, et al: American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003, 167: 603-662.
• British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax. 2005, 60: 800-805.
• Centers for Disease Control and Prevention (CDC). American Thoracic Society. Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003, 52: 735-739.
• Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000, 161: 1376-1395.
• Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep. 2005, 54: 1-141.
• Mazurek GH, Jereb J, Lobue P, et al: Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep. 2005, 54: 49-55.
• Mofenson LM, Oleske J, Serchuck L, et al: National Institutes of Health; Infectious Diseases Society of America: Treating opportunistic infections among HIV-exposed and infected children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004, 53: (RR-14): 1-92.
• Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med. 2000, 161: S221-S247.
• American Thoracic Society. Centers for Disease Control and Prevention. Infectious Diseases Society of America. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep. 2005, 54: (RR-12): 1-81.