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Table of Contents

Published
September 2, 2004

Octavian
Ioachimescu, MD

Department of
Pulmonary, Allergy,
& Critical
Care Medicine

J. Walton
Tomford, MD

Print Chapter

Motto: "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

Historical Overview

Epidemiology

Etiology

Pathophysiology

Diagnosis

Treatment

Control

Special Considerations

References

Over the last 100 years, tuberculosis (TB) has killed more than 100 million people¹, and this has continued unaffected over the last half-century, in spite of the existence of effective anti-tuberculous drugs. This chapter summarizes the current status of the epidemiology, pathogenesis, diagnosis, treatment and control of pulmonary tuberculosis. For purpose of this discussion, we have excluded in the present chapter nontuberculous mycobacterial diseases and other forms of extrapulmonary disease, except pleural TB.

• Several Egyptian mummies with severe skeletal deformities suggested that TB existed since antiquity (? Pott's disease).
• After the plague devastated Europe during the Middle Ages, TB ('White Plague') began to take its heavy toll.
• TB affected famous kings and political figures (King Edward VI, King Louis VIII of France, John Calvin, Cardinal Richelieu, Napoleon II, etc).
• TB, also called 'writers' or artists' disease', killed among others F. Schiller, N. Paganini, R.L. Stevenson, F. Kafka, G. Orwell, all five Brontë sisters, T. Mann, A. Camus, I. Stravinsky etc.

• Robert Koch, 1843-1910 (reproduced with permission from College of Physicians of Philadelphia).

  Figure 1

  Nobel Prizes for Medicine ("…awarded to those…who have conferred the greatest benefit on mankind in the field of medicine"), for TB-related work:
  • 1905 Dr. Robert Koch (Figure 1) for the discovery of TB bacillus
  • 1947 Dr. Gerhard Domagk for the discovery of the first antibacterial drug (Prontosil); he also pioneered anti-TB drug development.
  • 1952 Dr. Selman Waksman for the development of streptomycin as an anti-TB drug
• In 1993 World Health Organization (WHO) declared TB "a global emergency", the only disease ever so designated.² In 2003 WHO reported a continued TB pandemic.³

TB Worldwide
About a third of the world's population is infected with Mycobacterium tuberculosis. Among communicable diseases, TB is the second leading cause of death worldwide after HIV/AIDS, killing nearly 2 million people each year. Approximately 13% of TB cases have co-existent HIV infection. There were an estimated 8-9 million new cases of TB in 2000, fewer than half being actually reported. Most cases (5-6 milion) occur in people aged 15-49 years, with significant socio-economic impact. More than a half of TB cases occur in the largest Asian countries (India, China, Indonesia, Bangladesh, Philippines, and Pakistan). Sub-Saharan Africa presents with the highest incidence rate (around 300/100,000 population per 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.

TB in the USA
In the 1900's TB was one of the leading causes of death in the USA. Although the TB incidence was already decreasing in the first half of the 20th century due to 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 5.5% decline per year of TB case rates between 1953 and 1983. Between 1985 and 1992, however, TB unexpectedly increased by about 20%. The responsible factors were: increased immigration from high-prevalence countries, the emergence of HIV epidemic, an increased number of medically underserved persons (eg, homeless, drug abusers, low income individuals), emergence of drug-resistant TB cases, and, most importantly, deterioration of the public health infrastructure for the control of TB. With significant expenditures and subsequent improvements in TB control, the number of cases has decreased significantly over the last 10 years, although TB still remains a significant national public health problem. In 2003, there were a total of 14,871 cases reported, with a historical low rate of 5.1 cases per 100,000 population per year.⁴ However, there is still a disease reservoir of approximately 15 million infected people in the USA.

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 in normal hosts a granulomatous reaction. 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. The biochemical background of cording is called 'cord factor' (a trehalose dimycolate), and its contribution to bacterial virulence is still unclear.

TB transmission occurs almost exclusively from human to human; a pre-requisite 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% new cases.⁵ In the USA the most important risk factors for development of TB are: immigration from or travel to an endemic area, close contact with a TB case, exposure to untreated cases in congregate living facilities, advanced age, inner-city population, and host immunodeficiency.

Tuberculosis is spread by airborne droplet nuclei, which are 1-5 µm particles containing 1 to 400 bacilli each. They are expelled in the air with coughing, sneezing, singing, laughing, talking etc 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 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 plus/minus a lymphangitic track. Later on, the primary lesion tends to become calcified, and can be identified on the chest radiographs for decades. Most commonly, a positive tuberculin test 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 (mostly in children less than 5 years old, HIV positive or profoundly immunosuppressed individuals). Factors known to influence this unfavorable course are: patients' age, nutritional status, host immunity, and bacterial infective load.

Once infected with M. tuberculosis, 3-5% of immunocompetent individuals will develop active disease eg, secondary progressive tuberculosis within 2 years, and an additional 3-5% later on during their lifetime. So, overall, there is a lifetime risk of reactivation of 10%, with half of it occurring during the first 2 years after infection,⁶ hence the necessity to treat all tuberculin skin test converters. A recent analysis⁷ showed that the lifetime reactivation rate is around 20% for most persons with PPD induration more than 10 mm and either HIV infection or evidence of old, healed tuberculosis, and is between 10 and 20% for recent PPD skin test converters, adults younger than 35 years of age with an induration more than 15 mm, or on therapy with Infliximab (a TNFa receptor blocker), and for children younger than 5 years of age and skin induration more than 10 mm.

Studies performed in New York City and San Francisco, utilizing DNA fingerprinting indicate that recent transmission (exogenous re-infection), especially among HIV patients, could account for up to 40% of new TB cases. This is significantly different from older studies, which showed that around 90% of new TB cases are the result of endogenous reactivation.^8,9

After inhalation, the pathogenic bacilli start to replicate slowly and continuously and lead to development of a cellular immunity in about 4-6 weeks. T lymphocytes and local (pulmonary and lymphatic node) macrophages represent key-players in limiting further spread of the bacilli in the host's organism. This can be seen at the pathological level, where the bacilli are in the center of necrotizing (caseating) and non-necrotizing (non-caseating) granulomas, surrounded by lymphocytes and macrophages. The infected macrophages release interleukin 12, and 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 (tumor necrosis factor-alpha). TNF-α has an important role in the granuloma formation, and the control of infection. Genetic defects illustrated by different polymorphisms of the following genes: NRAMP-1 (natural resistance-associated macrophage protein-1), vitamin D receptors, and interleukin-1 have also been shown to be involved in TB pathogenesis.¹⁰ It is often difficult to differentiate between genetic predisposition and overwhelming bacteriological load, as often seen in countries with high prevalence of TB.

HIV co-infection is the greatest risk factor for progression to active disease in adults. The 'partnership' between HIV and TB has augmented the deadly potentials of each disease. Other risk factors are: diabetes mellitus, renal failure, co-existent malignancies, malnutrition, silicosis, immunosuppressive therapies (including steroids and anti-TNF drugs), and TNF-α receptor, TNF-γ receptor, or IL-12 ß1 receptor defects.

A high index of suspicion is needed in countries with high prevalence of infection, though the bacteriological confirmation is required whenever possible. Persistent cough for more than 2-4 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. Table 1 shows the CDC recommendations for clinical and laboratory criteria of TB diagnosis.

One inexpensive and rapid diagnostic test is the sputum smear, done by Ziehl-Neelsen (ZN), Kinyoun, or fluorochrome staining methods. ZN stain identifies 50-80% of culture-positive TB cases, and is a very useful diagnostic and epidemiological tool, since smear-positive TB cases 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 high prevalence of TB, a positive smear signifies TB in 95% of the cases. The lower limit of detection of ZN stain is 5X10³ organisms/mL, while rhodamine-auramine fluorochrome staining tends to be more sensitive. In children, M. tuberculosis can be recovered from gastric aspirates, with yields varying from 30%-50% in older children to 70% in infants for 3 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 are:

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

The speciation can be done with biochemical tests, or DNA probes. Direct specimen polymerase chain reaction is a rapid test (1-2 days), though can lead to false-positive results, and has been disappointing in its practicality. 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 very subtle, and include lower lobe opacities and/or miliary pattern. In a study done on HIV-infected pulmonary TB patients, 8% of cases had normal chest radiographs.¹¹

Major Principles

1. Drug treatment is both an individual and a 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 non-adherence, and should be used in all cases.
2. Chemotherapy can be successful only within an appropriate health system infrastructure which addresses both the clinical and social management of patients and their contacts.

General Recommendations

• Use the major antituberculous drugs: izoniazid (INH, H) and rifampin (RIF, R) throughout the course, unless resistant organism to one of them.
• Use pyrazinamide (PZA, Z) for the first two months. There is data to support that 6 months of INH and RIF with 2 initial months of PZA is 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 either ethambutol (ETB, E) or streptomycin (SM, S) as a 4th drug until susceptibilities are known if the patient comes from a community with >4% chance of drug resistance (currently 41/50 states), underwent prior therapy or 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 days-per-week regimens are interchangeable with 5 days-per-week ones 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, in decreasing neurological sequelae in TB meningitis, and (possibly) in preventing bronchial stenosis in cases of diffuse endobronchial TB. Once there is absolute assurance that the chemotherapeutic regimen is effective, some advocate the use of low-dose steroids in the initial phase, especially in malnourished patients, although the supporting data is lacking.
• Pregnant women with active TB need to be treated with INH and RIF, which are safe during pregnancy; PZA, although recommended by many authorities, has not been thoroughly studied in pregnancy, and should be used at the discretion of the treating physician; ETM has not been recommended, while SM is definitely harmful during the pregnancy.
• Pulmonology and/or Infectious Disease consultations are recommended for guiding expertise in the management of pulmonary TB.
• Public Health Department notification and assistance is essential in the management of TB, and the institution of directly observed therapy (DOT).

Therapeutic Regimens
Nomenclature: nHRZS(E)_m= n months of isoniazid, rifampin, pyrazinamide and streptomycin (or ethambutol) m days a week; the first term represents the initial phase, the second term the continuation phase.

For the culture-positive pulmonary tuberculosis caused by drug-susceptible organisms, there are 4 acceptable regimens:¹²

1. 2HRZE(S)₇ + 4HR₇ (preferred)0.5HRZE(S)₇ + 1.5HRZS(E)₂ + 4HR₂ 2HRSZ(E)₃ + 4HR₃ or
2. 2HRE₇ + 7HR₇

For smear-negative, culture-negative TB cases ('clinical TB') a 4-month HR regimen (4HR_{7 or 2}) is acceptable. The doses used in TB regimens are as shown in Table 2.

Drug Resistance
Anti-tuberculous drug resistance has been increasing worldwide. Treatment of resistant TB, especially multi-drug resistant TB, is frequently unsuccessful, requiring the use of more toxic, expensive drugs, and/or surgery. Thus, emphasis should be on strategies developed to avoid the emergence of drug resistance.

Primary resistance occurs in patients with active TB who never received anti-tuberculous drugs

Secondary (or acquired) resistance is the occurrence of resistance after mutant's selection or facilitation in the presence of various anti-tuberculous 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 chromosomial mutations, in the range of 1:10⁶ for INH, 1:10⁸ for RIF and around 1:10¹⁴ for both agents. These rates are clinically insignificant, unless sub-optimal time intervals or doses of anti-TB drugs facilitate the resistant subpopulations' growth

Multi-drug resistant TB (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 are: failure to predict, identify or adequately address non-adherence 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 USA), or from areas of high MDRTB (outside the USA, eg, Russia), or being HIV-infected (probably reflecting 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 4 drugs as in usual therapeutic regimens, plus at least additional 2 drugs to which the patient's organism is thought to be susceptible. In patients with culture-confirmed MDRTB, treatment with at least 3 drugs the organism is susceptible to, for at least 12 months after the sputum conversion. Most experts recommend 18 to 24 months total duration of therapy. INH-resistant cases can be treated with RIF, PZA and ETB for 6-9 months, while patients with RIF-resistant TB are treated with INH, PZA and ETB for 9-12 months after sputum cultures become negative. Consultation with a TB expert and Public Health Department's assistance are mandatory in managing a MDRTB case.

Infection control efforts to stem TB outbreaks among inpatients and health care staff are essential, since they represent the proximal contacts for any TB source in that particular setting. Although most cases do not need ultimately hospitalization (eg, an isolated TB pleurisy), patients suspected of having active TB are kept in isolation until they are no longer infectious or until TB is ruled out / three negative sputum specimens are obtained. Isolation rooms should have negative-pressure ventilation, with at least 6 air exchanges per hour. Health care workers who come in contact with these patients should wear N95 masks or PAPRs (powered air-purifying respirators) to avoid inhaling infectious particles while in the room with the patients. The isolation can be discontinued after 10-14 days of therapy if they respond to therapy. Patients can be removed from isolation and discharged home if they are returning to their previous non-congregate residence, where the health department identified no individuals at risk (children less than 2 years of age, immunocompromized patients), and the other plausible exposed individuals are being evaluated for LTBI. The outpatient medications should be given using DOT (directly observed therapy) in order to insure adherence to treatment. The recent decline in the USA is largely due to the implementation and utilization of DOT, which has been shown to improve therapy completion rates and to prevent the emergence of acquired resistance and MDRTB.

Latent TB infection (LTBI)
The intradermal administration of tuberculin has been used as a diagnostic test for TB infection since the early 1900's,¹³ 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 48-72 hours (Mantoux test). The tine test has no role in evaluation of an individual patient.

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

• It has low-sensitivity in immunospressed patients (eg, HIV-infected patients; the threshold for positivity is 5 mm for these patients), or in pre-immune, initial phase of infection.
• It has cross-reactivity with bacille Calmette-Guerin (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 form prior BCG.
• It usually needs follow-up visit in 48-72 hours for reading, although email, digital pictures or other means of todays' telemedicine have become available and used.
• The reading is subjective and requires expertise (low inter-rater variability).
• There is a 'booster effect'. It is known that delayed-type hypersensitivity reactions from a prior mycobacterial infection or BCG vaccination could wane in time. Although subsequent skin reactions could be still negative for that particular individual, the stimulus of the first test may boost or increase (generally by less than 5 mm) the size of the second test administered 1 week to 1 year later, suggesting a false-conversion. When a PPD skin testing is repeated periodically, as in employee-health or institutional screening programs, an initial 2-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 applied 1 to 3 weeks later; a positive second reaction would indicate boosting a previous infection or a BCG vaccination. The major problem with booster effect is LTBI over-diagnosis (false-positive for infection).

ATS/CDC recent statement on LTBI¹⁴ establishes the thresholds of PPD indurations for different settings and hosts (Table 3).

An increase in induration of greater than 10 mm within a 2-year period indicates conversion, irrespective of age. In low-risk patients for TB infection PPD skin testing is not recommended. ATS/CDC recommends specifically LTBI screening to be applied only for high-risk patients (the concept of 'targeted LTBI screening'). The old terminology of 'INH prophylaxis' applied for treatment of LTBI should be abandoned.

Similar to the principle of Mantoux reaction, a whole-blood interferon-y release assay (IGRA®) evaluates the cell-mediated immunity to tuberculin. Although it seems to be less sensitive and less specific, it can differentiate between infection and prior BCG vaccination.¹⁵ An enzyme-linked immunospot (ELISPOT®) assay has recently been developed that is relatively sensitive and specific in detecting LTBI, by targeting early-secreted antigenic target (ESAT-6), which is expressed only by M tuberculosis, and not by other Mycobacteria or by BCG.¹⁶ Although approved by FDA, the cost-effectiveness and the practicality of the above molecular methods are still unclear.

The recommended approach to a patient with LTBI is depicted in Table 4. The new ATS/CDC guidelines¹⁴ for LTBI treatment recommend isoniazid (INH) either 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. This 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 showed that rifampin (RIF) in doses of 10 mg/kg/day up to a total of 600 mg for 4 months or RIF (alternative: rifabutin, with less interactions with other drugs) with pyrazinamide (PZA) daily for 2 months in HIV-infected individuals are effective alternatives 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 revised recommendations, endorsed by Infectious Diseases Society of America (IDSA), state that this combination should not be offered to persons with LTBI anymore.¹⁷ The tuberculin skin testing is safe during pregnancy.

BCG Vaccination
Bacillus of Calmette-Guérin (BCG), an attenuated strain of M. bovis, was first used as a vaccine in 1920's. 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, multiple studies consistently showed effectiveness in reducing fatal or severe forms of TB in infants and young children (miliary TB or meningitis). Most countries give only 1 BCG vaccine (at birth). Only 50% of vaccinated infants ever become PPD positive, while by 1-2 years, only 20%. Of note, there are multiple BCG variants worldwide, with different results and variable rates of PPD conversion, which has greatly confounded their use. The chance of developing a positive PPD increases with the age of the BCG recipient, while repeated vaccinations have much higher rates of long-term conversion or booster-effects upon PPD re-challenge. In BCG recipients the reactions to PPD are generally less than 10 mm, although reactions up to 18 mm have been reported.

In USA, 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 to INH (as part of LTBI treatment), and the 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 extrapulmonaryTB ; 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 either after the primary phase (up to 6 months post-exposure), or during the secondary phase (endogenous reactivation).^18,19

Clinically, it often presents with cough, pleuritic chest pain, dyspnea, low-grade fever, and other non-specific constitutional symptoms. 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, 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 (classically >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. The 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, make the diagnosis of pleural TB in more than 80% cases, while video-assisted surgical biopsy has an even higher diagnostic yield. The sputum can be positive for TB between 4% (in isolated TB pleurisy) and 50% cases (in those with extensive parenchymal infiltrates). A pleural fluid adenosin-deaminase (ADA) >60 U/L may support the diagnosis if rheumatoid arthritis or empyema are unlikely, although this test is not routinely recommended. Even if not treated, the clinical course is toward spontaneous resolution, with minimal pleural scarring. Howether, the reactivation rate is higher for cases with co-existent parenchymal foci (>65% of cases at 5 years). The pleural TB is treated with 4-6HR₂ regimens. Steroids may hasten the pleural fluid resorbtion and clinical symptoms' resolution, though they don't seem to prevent scar formation.

• Tuberculous empyema

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

TB and HIV Infection
It is estimated that 33 to 50% of the 20 million individuals infected with HIV worldwide are co-infected 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 extra-pulmonary TB in an HIV-positive individual. Most of the cases are re-activation of old TB, occurring earlier than other opportunistic infections, due to 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 co-infection makes the patient more likely to transmit the disease, although AIDS patients are more predisposed to get the progressive disease, and can be more difficult to diagnose. The mean CD4 count at TB presentation is 200-300 cells/mm³, which is earlier than other opportunistic infections. At CD4 >300 cells/mm³ the clinical presentation is similar to those who are HIV-negative, eg, isolated pulmonary disease, with focal, apical infiltrates, occasionally with cavitation. As immunosuppression worsens, the incidence of diffuse pulmonary disease without cavitation, miliary TB and extra-pulmonary TB increase to up to 70% of AIDS patients. Patients with HIV infection have a similar response to anti-TB medications to that of HIV-negative patients. However, drug interactions are very important issues. Many of the highly active anti-retroviral therapy (HAART) drugs interfere with rifampin's metabolism, which is a potent inducer of P450 enzymatic 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 for this reason is preferred in most HIV-positive patients. Clinical deterioration may occur in patients with active TB started on HAART, eg, worsening infiltrates, severe hypoxemia to full-blown ARDS (acute respiratory distress syndrome), necrotizing lymphadenitis, enlarging brain tuberculomas, milliary TB or severe systemic toxicity. This is called 'immune reconstitution syndrome' and is thought to be due to '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.

TB: To Be
Tuberculosis is probably one of the greatest killers of all times, over the centuries taking more than a billion lives, and up to 2 million people every year (eg, 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 people get active disease. If not treated, every source case infects on average 10-15 other individuals per year. TB is a 'social disease', disrupting families emotionally, educationally, and economically. Furthermore, only about 20% of the TB cases in the world are detected and treated successfully.

TB: Not To Be
DOT strategy implemented by World Heath Organization (WHO) is probably one of the most cost-effective of all health interventions. Achievement of the global targets of 70% detection and 85% cure rates worldwide would reduce both the incidence and the deaths by 10%. USA and several other low-incidence countries have embarked on plans to completely eliminate tuberculosis. Important elements in an elimination strategy would be to identify and treat effectively LTBI persons at risk to develop active disease, and to insure provisions of cheap and efficacious drugs to countries that cannot afford them.

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 needed urgently in order to fight better this condition.

Return to Medicine Index

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