Tuberculosis: Clinical Manifestations and Diagnosis of Disease

Philip A. LoBue

TB has a wide array of pulmonary and extrapulmonary clinical manifestations. Inhaled droplet nuclei of Mycobacterium tuberculosis initially lodge in the middle or lower lung zones where regional ventilation is greatest, resulting in a local inflammatory reaction with spread to regional lymph nodes and subsequent hematogenous dissemination. Distant organs, especially the kidneys, bone, CNS, as well as the lung apices, are seeded, but overt clinical disease of these areas does not usually ensue. A low-grade fever and symptoms of an upper respiratory illness also may be present. The chest radiograph may show a small area of pneumonitis and often hilar and paratracheal lymphadenopathy. Prominent hilar adenopathy is frequent in children; it is found less commonly in adults.

This initial infection, termed primary TB, resolves spontaneously in most individuals. Healed lesions appear on chest radiograph as calcified parenchymal nodules and are often associated with calcified hilar lymph nodes. In a small percentage of individuals, the initial infection progresses and can manifest as (1) rupture of subpleural infectious foci into the pleural space resulting in tuberculous pleuritis; (2) extensive caseous pneumonia; (3) enlargement of tuberculous lymph nodes causing bronchial obstruction (collapse–consolidation lesion); (4) rupture of a tuberculous focus into a bronchus leading to extensive endobronchial spread throughout one or both lungs; or (5) rupture of a tuberculous focus into a pulmonary blood vessel with hematogenous spread leading to acute disseminated disease.

TB can reactivate months to years after containment of the primary infection. The factors causing reactivation lesions are poorly understood. Certain conditions increase the likelihood of progression from latent TB infection to disease, including malnutrition, alcoholism, poorly controlled diabetes mellitus, silicosis, immunosuppression (by disease processes or drugs), gastrectomy, chronic hemodialysis, and jejunoileal bypass surgery. In most patients, however, no predisposing factor can be identified.

Radiographically, reactivation or postprimary pulmonary TB usually presents as an infiltrate in the apical and posterior segments of the upper lobes. The patient can be entirely asymptomatic or have nonspecific symptoms of chronic respiratory infection (e.g., fever, weight loss, productive cough, and hemoptysis). The chest radiograph may reveal a somewhat nondescript fibronodular or fluffy alveolar filling process in the upper lung fields but frequently shows cavity formation, fibrosis with volume loss, or both. The process occasionally heals spontaneously but more frequently progresses locally in the absence of drug therapy. Advanced disease can be associated with rupture of a hypertrophied pulmonary artery (Rasmussen aneurysm) into a cavity, resulting in massive hemoptysis, although this is exceedingly uncommon in the era of effective therapy. Rapid progression of pulmonary disease with severe ventilation–perfusion disturbances presenting as the adult respiratory distress syndrome is also seen in rare instances. New hematogenous dissemination and extrapulmonary disease may follow pulmonary reactivation.

Routine laboratory studies in pulmonary TB are nonspecific. Hematologic studies often reveal a mild anemia, leukopenia, or a monocytosis, but more profound pancytopenia or leukocytosis has been reported. Hyponatremia, usually attributable to the syndrome of inappropriate antidiuretic hormone production, occurs in more than 10% of patients with pulmonary TB. Addison disease is a very rare cause of hyponatremia in patients with TB.

The definitive diagnosis of pulmonary TB depends on obtaining a positive culture from infected secretions or tissue. If cultures are negative or obtaining a culture is not possible, a presumptive diagnosis can be made from clinical inference and therapeutic trial. The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) provide information as to whether a tuberculous infection is present, but do not distinguish between disease and latent infection. False-negative TST and IGRA results may occur in immunosuppressed patients (advanced TB, itself, being sufficiently immunosuppressive). A typical chest radiograph is helpful but nonspecific: a variety of nontuberculous processes can have a similar appearance. Spontaneous or aerosol-induced sputum sampling (at least three specimens) is the initial method of choice for bacteriologic assessment. Initially, the specimens are stained by the Ziehl-Neelsen or fluorescent techniques for acid-fast bacilli (AFB). When sputum analyses are unrevealing, bronchoscopy with lavage, brushings, transbronchial biopsy, or needle aspiration may be considered. Bronchoscopic sampling can enhance both the speed and likelihood of making a diagnosis for an individual patient. Recent systematic studies have not found bronchoscopy to provide an aggregate diagnostic yield superior to aerosol-induced sputum sampling, however. All sputum, lavage, and tissue specimens should be cultured for mycobacteria. Cultures are essential, because (1) smears alone will miss up to 50% of active TB cases, (2) mycobacteria other than Mycobacterium tuberculosis can produce positive smears, and (3) cultures are necessary for drug susceptibility testing. Special culture media are required, and the laboratory should have proficiency in mycobacterial techniques.

One of the major limitations of mycobacterial culture in the past was that 6 to 8 weeks were required to obtain results. Newer laboratory diagnostic techniques significantly reduced culture times. With broth-based culture methods, mycobacterial growth can be detected in as few as 5 to 8 days, although on average it takes 2 to 3 weeks. DNA probe technology can provide a very rapid (within hours) method of differentiating Mycobacterium tuberculosis complex from non-tuberculous mycobacteria in growing cultures. This technique has proved to be highly specific and sensitive.

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