Microbiology

Tuberculosis (TB) is caused by organisms of the Mycobacterium tuberculosis complex, which includes M. tuberculosis, the most common and important agent of human mycobacterial disease, and M. bovis, which (like several other mycobacterial species) is acquired via ingestion of unpasteurized milk. M. tuberculosis is a thin aerobic bacillus that is neutral on Gram's staining but that, once stained, is acid-fast; i.e., it cannot be decolorized by acid alcohol because of the cell wall's high content of mycolic acids and other lipids.

Epidemiology

An estimated 10.4 million new cases of TB occurred worldwide in 2016, with ∼1.7 million TB-related deaths-almost entirely in low-income countries. Globally, TB rates are stable or falling.

• In the United States, TB primarily affects HIV-infected adults, immigrants, the elderly, and disadvantaged/marginalized populations.
• Isolates of M. tuberculosis that are multidrug-resistant (MDR; resistant to at least isoniazid and rifampin) and extensively drug-resistant (XDR; resistant to isoniazid, rifampin, and fluoroquinolones and to amikacin, kanamycin, or capreomycin) are increasing in frequency; ∼500,000 cases of MDR-TB may have emerged in 2016, of which ∼9.5% were probably XDR.
• Disease from a pt with pulmonary TB is spread by droplet nuclei that are aerosolized by coughing, sneezing, or speaking.
  • Droplets <5-10 µm in diameter may be suspended in air for several hours.
  • Transmission is determined by the intimacy and duration of contact with a pt with TB, the degree of infectiousness of the pt, and the shared environment.
  • Pts with cavitary or laryngeal disease are most infectious, with as many as 10⁵ -10⁷ acid-fast bacilli (AFB)/mL of sputum.
• Risk factors for development of active disease after M. tuberculosis infection include recent acquisition (i.e., within the preceding 18 months), comorbidity (e.g., HIV disease, diabetes, silicosis, immunosuppression, gastrectomy), malnutrition, tobacco smoking, and presence of fibrotic lesions.

Pathogenesis

AFB that reach alveoli are ingested by macrophages. The bacilli impair phagosome maturation, multiply, lyse the macrophages, and spread to regional lymph nodes, from which they may disseminate throughout the body. These initial stages of infection are generally asymptomatic and induce cellular and humoral immunity.

• About 2-4 weeks after infection, a tissue-damaging response resulting from delayed-type hypersensitivity (the basis for tuberculin skin testing [TST]) destroys nonactivated macrophages that contain multiplying bacilli, and a macrophage-activating response activates cells capable of killing AFB. A granuloma forms at the site of the primary lesion and at sites of dissemination. The lesions can then either heal by fibrosis or undergo further evolution. Despite “healing,” viable bacilli can remain dormant within macrophages or in necrotic material for years.
• Cell-mediated immunity confers partial protection against TB. Cytokines secreted by alveolar macrophages contribute to disease manifestations, granuloma formation, and mycobacterial killing.

Clinical Manifestations

TB is classified as pulmonary, extrapulmonary, or both. Extrapulmonary TB may occur in 10-40% of pts, with even higher rates among HIV-infected pts.

Pulmonary TB Primary disease may cause no or mild signs and symptoms (fever and occasional pleuritic chest pain) in contrast to the prolonged disease course that is common in postprimary or adult-type disease.

• Primary disease is frequently located in the middle and lower lobes. The primary lesion usually heals spontaneously, and a calcified nodule (Ghon focus) remains.
  • Transient hilar and paratracheal lymphadenopathy is common.
  • In immunosuppressed pts and children, primary disease may progress rapidly to significant clinical disease, with cavitation, pleural effusions, and hematogenous dissemination (miliary disease).
• Adult-type disease presents initially with nonspecific and insidious signs and symptoms, such as diurnal fever, night sweats, weight loss, anorexia, malaise, and weakness.
  • As the disease progresses, pts develop cough and purulent sputum production, often with blood streaking. Extensive cavitation may develop, with occasional massive hemoptysis following erosion of a vessel located in the wall of a cavity.
  • Disease is usually localized to the apical and posterior segments of the upper lobes and the superior segments of the lower lobes.

Extrapulmonary TB Any site in the body can be involved, but the most commonly affected sites are (in descending order of frequency) the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium. Up to two-thirds of HIV-infected pts with TB have extrapulmonary disease.

• Lymphadenitis occurs in 35% of extrapulmonary TB cases, especially among children and HIV-infected pts. Painless swelling of cervical and supraclavicular nodes (scrofula) is typical.
  • Nodes are discrete early on but can develop into a matted nontender mass with a fistulous tract.
  • Fine-needle aspiration or surgical-excision biopsy of the node is required for diagnosis. Cultures are positive in 70-80% of cases.
• Pleural involvement is common (∼20% of extrapulmonary cases) and results from a hypersensitivity response to mycobacterial antigens or contiguous spread of parenchymal inflammation.
  • Pleural fluid is straw-colored and exudative, with protein levels >50% of those in serum, normal to low glucose levels, a usual pH of ∼7.3 (occasionally <7.2), and pleocytosis (500-6000 cells/µL). The pleural concentration of adenosine deaminase, if low, virtually excludes TB.
  • Pleural biopsy is often required for diagnosis, with up to 80% of biopsy cultures and 75% of PCR tests positive. Direct smears, cultures, and PCR of pleural fluid are less sensitive.
  • Empyema is an uncommon complication of pulmonary TB and results from rupture of a cavity with many bacilli into the pleural space. In these cases, direct smears and cultures are often positive, and surgical drainage is usually required in addition to chemotherapy.
• In genitourinary disease, local symptoms predominate (e.g., urinary frequency, dysuria, hematuria, abdominal or flank pain), and up to 75% of pts have a CXR demonstrating previous or concomitant pulmonary disease. Disease is occasionally identified only after severe destructive lesions of the kidneys have developed.
  • In 90% of cases, urinalysis shows pyuria and hematuria with negative bacterial cultures.
  • Mycobacterial culture of three morning urine specimens is diagnostic in 90% of cases.
• Weight-bearing joints (spine, hips, and knees) are the most common sites of skeletal disease.
  • Spinal TB (Pott's disease) often involves two or more adjacent vertebral bodies; in adults, lower thoracic/upper lumbar vertebrae are usually affected. Disease spreads to adjacent vertebral bodies, later affecting the intervertebral disk and causing collapse of vertebral bodies in advanced disease (kyphosis, gibbus). Paravertebral cold abscesses may form.
• Meningitis occurs most often in young children and HIV-seropositive pts. Disease typically evolves over 1-2 weeks and often involves paresis of cranial nerves (particularly of ocular nerves). The ultimate evolution is toward coma, with hydrocephalus and intracranial hypertension.
  • CSF can have a high lymphocyte count, an elevated protein level, and a low glucose concentration. Cultures are positive in 80% of cases. PCR is ∼80% sensitive and is the preferred initial diagnostic option.
  • Neurologic sequelae are seen in ∼25% of treated pts; adjunctive glucocorticoids enhance survival among pts >14 years of age but do not reduce the frequency of neurologic sequelae.
• Gastrointestinal disease can affect any portion of the GI tract (with the terminal ileum and cecum most commonly involved), causing abdominal pain, obstruction, hematochezia, and often a palpable mass. TB peritonitis can follow spread of the organism from ruptured lymph nodes and intraabdominal organs; peritoneal biopsy is usually required for diagnosis.
• Pericarditis is characterized by an acute or subacute onset of fever, dull retrosternal pain, and sometimes a friction rub. Effusion is common. Chronic constrictive pericarditis is a potentially fatal complication, even in treated pts. Adjunctive glucocorticoids remain controversial; no conclusive data demonstrate a benefit.
• Miliary disease arises from hematogenous spread of M. tuberculosis throughout the body. Symptoms are nonspecific, and small (1- to 2-mm) granulomas may develop in many organs. Hepatomegaly, splenomegaly, lymphadenopathy, and choroidal tubercles of the eye may occur.

HIV-Associated TB The manifestations of TB vary with the stage of HIV infection. When cell-mediated immunity is only partly compromised, pulmonary TB presents as typical upper-lobe cavitary disease. In late HIV infection, a primary TB-like pattern may be evident, with diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoracic lymphadenopathy.

• Extrapulmonary disease occurs frequently; common forms include lymphadenitis, meningitis, pleuritis, pericarditis, mycobacteremia, and disseminated disease.
• Immune reconstitution inflammatory syndrome (IRIS), which may occur 1-3 months after initiation of antiretroviral therapy, may exacerbate the signs and symptoms of TB.

Diagnosis

The key to diagnosis is a high index of suspicion.

• AFB microscopy of diagnostic specimens-i.e., light microscopy of specimens stained with Ziehl-Neelsen basic fuchsin dyes or fluorescence microscopy of samples stained with auramine-rhodamine-can provide a presumptive diagnosis. In suspected pulmonary TB, two or three sputum samples should be examined.
• Definitive diagnosis requires growth of M. tuberculosis in culture or identification of the organism's DNA in clinical samples.
  • Liquid media and speciation by molecular methods have decreased the time required for diagnostic confirmation to 2-3 weeks (from 4 to 8 weeks).
  • Nucleic acid amplification is useful not only for rapid confirmation of TB in AFB-positive specimens but also for diagnosis of AFB-negative pulmonary and extrapulmonary TB.
• Drug susceptibility can be assessed via indirect testing on solid media (which takes ≥8 weeks), direct testing in liquid media (which takes ∼3 weeks), or PCR (which can provide results within hours).
• TST is of limited value in active disease because of low sensitivity and specificity but is the most widely used screening test for latent TB infection.
• Interferon γ; release assays (IGRAs) measure the release of interferon γ; by T cells after stimulation with TB-specific antigens and are more specific for M. tuberculosis than is TST.
  • In low-incidence settings, IGRAs may be more sensitive than TST.
  • In high TB- and/or HIV-burden settings, the performance of IGRAs has varied greatly, and cost considerations may currently limit wider use.

Prevention

• Vaccination: An attenuated strain of M. bovis, bacille Calmette-Guérin (BCG), protects infants and young children from serious forms of TB (e.g., meningitis and miliary disease) and is recommended for routine use in countries with high TB prevalence.
• Treatment of latent infection: Candidates for chemoprophylaxis are identified by TST or IGRA. Positive skin tests are determined by reaction size and risk group (Table 97-2 Tuberculin Reaction Size and Treatment of Latent Mycobacterium tuberculosis Infection ). Drug treatment should be considered for pts with evidence of latent infection (Table 97-3 Recommended Regimens and Drug Dosages for Treatment of Latent Mycobacterium tuberculosis Infectiona ). Isoniazid should not be given to persons with active liver disease.