Tuberculosis

Tuberculosis is probably one of the greatest killers of all times, over the centuries taking more than one 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 not treated, every source case infects, on average, 10 to 15 other individuals 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.

Causes

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 1). The biochemical background of cording is called cord factor (a trehalose dimycolate), and its contribution to bacterial virulence is still unclear.

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-mm 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 individuals will 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 a [TNF-a] 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-a. 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.

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.

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 s 5 × 10 ³ 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 to 3 weeks)

The speciation can be done with biochemical tests or DNA probes. The direct specimen polymerase chain reaction assay is rapid (1 to 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.