Development of disease from Mycobacterium tuberculosis (MTB) is the most common global infectious cause of death. Such disease caused by bacteria of the MTB complex preeminently affects the lungs, although other organs are involved in up to one-third of cases. Transmission of TB occurs when a contagious patient cough, sneezes, or otherwise spreads the bacilli through generation of airborne droplet nuclei to individuals in close proximity sharing the same ventilatory space. Of note, M. bovis belonging to the MTB complex is transmitted by ingestion of contaminated, unpasteurized dairy products from infected cattle. M. tuberculosis is a rod shaped, non-spore-forming, nonmotile, thin aerobic bacterium measuring 0.5 μm × 3 μm. Mycobacteria, including M. tuberculosis, are often neutral on Gram stain; however, once stained, the bacilli are not easily decolorized by acid alcohol and hence the classification acid-fast bacilli (AFB) (Fig. 36.1; see also Fig. 34.15).
AFB smear showing M. tuberculosis. See also Fig. 34.15 Courtesy of the CDC, Atlanta.
Other microorganisms may also display some acid fastness, including species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium. With respect to the mycobacteria, the cell wall contains lipids (eg, mycolic acids) that are linked to underlying arabinogalactan and peptidoglycan residues. These collectively confer low permeability characteristics to the cell wall, and so reduce the effectiveness of most antimicrobial drugs.
Pathogenesis and Clinical Manifestations
Tuberculosis is broadly classified as pulmonary or extrapulmonary; pulmonary tuberculosis represents the majority of disease cases. Tubercle bacilli on droplet nuclei are inhaled into the respiratory zone of the host's lungs after exposure to contagious individuals, especially in crowded conditions. MTB bacilli are deposited in the small airways and the alveoli of better-ventilated areas of the lung. This is typically the middle to lower regions (lower lobes) in adults. After phagocytosis by alveolar macrophages, MTB organisms undergo intra-cellular replication. The initial inflammatory response to the MTB infection in the lung is referred to as a primary or Ghon focus. MTB organisms can thereafter spread, during this early stage, via the lymphatics to the draining lymph nodes and result in hilar or mediastinal lymphadenopathy. Alternatively, the bacilli may enter the bloodstream and spread hematogenously to other organs of the body. Disease presenting at this stage is called primary tuberculosis (Fig. 36.2).
The variable clinical course of tuberculosis. Adapted from a sketch provided by Professor R.K. Kumar, Department of Pathology, School of Medical Sciences, the University of New South Wales, Sydney, Australia.
However, more commonly the host develops cell-mediated immune reaction involving alveolar macrophages that phagocytize tubercle bacilli, and CD4+ T lymphocytes, which induce protection through the production of cytokines, mainly interferon-γ (IFN-γ). Coincident with the development of immunity, delayed-type hypersensitivity to M. tuberculosis develops. This stage is referred to as latent TB infection and is the basis of tuberculin skin testing. In most instances, the immune response successfully controls the tuberculosis infection although 3%-5% of infected subjects progress to active disease within 2 years, termed progressive primary TB (Fig. 36.2). Primary tuberculosis is common among at-risk children up to 4 years of age. Furthermore, among infected individuals, the incidence is highest during late adolescence and early adulthood.
Because the healed primary infected lung foci often contain bacilli that are viable for many years, progression to subsequent disease can occur if the immunity wanes, which is referred to as post-primary or reactivation pulmonary tuberculosis. Overall, individuals infected with MTB have a 5%-10% risk of reactivation during their lives, particularly in the setting of several well-defined risk factors culminating in relative degrees of immunosuppression (Table 36.1). In this context, the risk of developing TB disease after infection depends largely on the host's innate susceptibility to the disease and level of function of cell-mediated immune responses. Reactivation disease has a predilection for the upper lobes of the lungs as well as having a propensity for cavitation (Fig. 36.3) without accompanying intrathoracic lymphadenopathy. However, the entire pathogenetic sequence represents a continuum and becomes less distinct in conditions of immune deficiency such as in HIV seropositive individuals. Importantly, the distinction between primary and postprimary tuberculosis has questionable clinical relevance, inasmuch as active tuberculosis should always be treated and pharmacological therapy remains similar.
Table 36.1Risk factors for progression of tuberculosis disease ||Download (.pdf) Table 36.1 Risk factors for progression of tuberculosis disease
|HIV infection ||Underlying cancer ||Silicosis ||Chemotherapy |
|Diabetes mellitus ||Malnutrition ||Leukemia ||Lymphoma |
|Advanced age ||IV drug abuse ||Post-gastrectomy ||Jejunoileal bypass |
|Renal failure ||Hemodialysis || |
|Immunosuppressive drug therapy (eg, steroids, cytotoxic drugs, TNF-α blockers) |
(a) The chest x-ray of a patient diagnosed with reactivation tuberculosis. Note the right upper lobe air-space opacities with suggestion of cavitary process. (b) CT scan of the chest (lung attenuation window) of the same patient with reactivation (post-primary) TB. Note extensive cavitation due to necrosis of the lung parenchyma and the satellite nodules. The patient (a resident of Colombia in South America) presented to the hospital with hemoptysis while visiting the United States on a business trip.
The development of specific immunity results in activation of macrophages and their accumulation in large numbers at the primary site, leading to hallmark pathologic lesion, the necrotizing granuloma. Necrosis results from the tissue damaging effect of delayed-type hypersensitivity. Because the necrotic material resembles soft cheese, it is termed caseous necrosis (Fig. 36.4).
Extrapulmonary tuberculosis can involve lymph nodes (lymphadenitis), pleura (empyema and effusions), genitourinary tract, bones and joints (osteomyelitis), meninges (meningitis), peritoneum (peritonitis), pericardium (pericarditis), gastrointestinal tract, and disseminated disease as a result of hematogenous spread especially in immunocompromised hosts such as those with HIV coinfection.
CLINICAL CORRELATION 36.1
Tuberculosis is an important opportunistic disease among HIV-infected patients. An individual with skin test-documented latent TB infection that acquires concomitant HIV infection has over a 100-fold increased relative risk of progression to active disease, an increased annual risk if developing active TB disease approximating 8% per year, as well as an accelerated natural history of TB and mortality. The clinical and radiographic manifestations of HIV-related tuberculosis depend on the degree of immunosuppression. When the cell-mediated immunity is only partially compromised (eg, a circulating CD4+ T lymphocyte count >200 cell/μL), pulmonary tuberculosis presents as a typical pattern of upper-lobe opacities and cavitation, without significant lymphadenopathy or pleural effusion (post-primary disease). However, as the CD4+ T lymphocyte cell count declines in untreated or advanced HIV infection, the more common manifestation is a primary tuberculosis-like pattern of diffuse interstitial or miliary opacities, airspace opacities with little or no cavitation, and intrathoracic adenopathy. Also of note, extrapulmonary tuberculosis is common among HIV-infected patients, with the most common forms being lymphatic, disseminated, pleural, and pericardial disease, respectively.
Diagnostic Tests for Tuberculosis
A comprehensive medical history should be obtained, exploring TB exposure risks, previous TB infection or disease, and risk factors for progression in an individual with clinical symptoms of productive cough, hemoptysis, or shortness of breath along with systemic symptoms such as fever, chills, night sweats, weight loss, and fatigability. However, objective tests are essential in establishing a secure diagnosis. Culturing M. tuberculosis from sputum or other respiratory specimens confirms diagnosis of pulmonary TB, and from other affected body tissues or fluids for extrapulmonary TB (Chap. 19). On an average, it takes about 2 weeks to culture and identify M. tuberculosis in the laboratory, even with rapid culture techniques. Even so, a preliminary diagnosis can be made when acid-fast bacilli are seen on a sputum smear or from other body tissues or fluids in the appropriate clinical setting. With respect to pulmonary TB, three sputum specimens for smear and culture are necessary if initial specimens are negative; if this is not possible because the patient is not expectorating sputum, invasive sampling of the respiratory tract is usually necessary with sputum induction or fiberoptic bronchoscopy.
Tuberculin Skin Test Reactivity
Delayed-type hypersensitivity to M. tuberculosis develops with the appearance of immunity and is the basis of tuberculin skin testing using an intradermal injection of 0.1 mL of five tuberculin units of purified protein derivative (PPD), with tests read 48-72 hours afterwards based on the size in millimeters of the resulting induration. Different cut-points with respect to the amount of induration have been established for interpretation of positive tuberculin skin test reactivity, based on risk of M. tuberculosis infection and progression to active disease (Table 36.2). The previously sensitized CD4+ T lymphocytes are attracted to the skin-test site and produce cytokines along with cellular proliferation. PPD skin-test positivity, though suggestive of protective immunity, does not assure protection against postprimary disease (reactivation) disease.
Table 36.2Interpretation of tuberculin skin test reactivity indicative of TB infection ||Download (.pdf) Table 36.2 Interpretation of tuberculin skin test reactivity indicative of TB infection
5 mm induration
High probability of infection
Close contacts of active TB patients
Chest radiographic evidence of old TB disease
Organ transplant recipients
10 mm induration
Medical conditions that increase the risk of progression of active TB
Immigrants from endemic regions of TB disease
Residents and staff of institutionalized settings
15 mm induration