In the lung, survival of the tuberculosis bacterium is determined, in part, by cell-wall mycolic acids and a lipoarabinomannan known as the cord factor. Mycolic acids, which are 50% of the dry weight of the cell wall (Figure 19-1), form a hydrophobic barrier that prevents the entry of drugs, disinfectants, and other harsh chemicals. Cord factor inhibits the interferon (IFN)–induced activation of macrophages and stimulates the production of tumor necrosis factor alpha (TNF-α).

In the second stage, which occurs 3 weeks after infection, CD4Th1 cells migrate from the lymph node to the infection site and undergo rapid proliferation. CD4Th1 and CD8 cells secrete TNF-α and IFN-γ. TNF-α is responsible for most of the lung damage noted in mycobacteria infections. IFN-γ– stimulated macrophages produce nitric oxide by oxidation of L-citrulline. Additional interactions between nitric oxide and singlet oxygen form peroxynitrite (ONOO–), which is microcidal. The role of CD8 cells in tuberculosis is unclear. They may contribute to the lesion by producing IFN-γ, by directly killing infected cells, or by both mechanisms (Figure 19-2).

In the third phase of the disease, macrophage-derived reactive oxygen species cause necrosis of lung tissue. The production of chemotactic factors causes an influx of activated monocytes into the area. In an attempt to destroy the bacteria, activated monocytes surround the caseous center and release additional cytotoxic molecules. Some monocytes become flattened and are known as epithelioid cells (Figure 19-3). Fusion of macrophage membranes often creates giant cells with multiple nuclei.

In a final attempt to contain the infection, fibroblasts are called into the area and produce collagen, which encapsulates the inflammatory cells surrounding the lesion. The accumulation of macrophages, lymphocytes, and fibroblasts is called a granuloma. Constant production of TNF and IFN-γ is required for the maintenance of the granuloma; if the granuloma is not maintained, it becomes unstable, liquefies, and creates a permissible environment for bacterial growth. As a consequence of rapid bacterial growth, the infection erodes into blood vessels and small airways. Dissemination in blood allows the organism to establish secondary infections in other organs and bone. This form of the disease is known as miliary tuberculosis. Mycobacteria in the airways also rapidly proliferate in the highly aerobic environment and are expelled from the lung by coughing or sneezing.

Exposure to tuberculosis generates a population of long-lived memory cells. The Mantoux, or PPD (purified protein derivative of tuberculosis), skin test is now the standard test to determine previous exposure to tuberculosis bacilli. In the Mantoux test, PPD is injected intradermally, and the reaction site is viewed at 48 and 72 hours. If memory cells are present, an influx of macrophages and lymphocytes around the injection site causes a hard, raised indurated area with clearly defined margins (Figure 19-4). The cellular development of a positive skin test response to tuberculosis is shown in Figure 19-5.

The interpretation of skin test reactions is difficult. A positive skin test only indicates previous exposure to tuberculosis or vaccination with an attenuated strain of M. bovis called Bacille Calmette-Guérin (BCG). However, a significant false-negative rate in the Mantoux test does occur. Between 20% and 25% of patients with active tuberculosis have a negative skin test. Clinical history, radiologic studies, and sputum cultures are used to support a tentative diagnosis of active tuberculosis.

The diagnosis of tuberculosis is based on clinical signs and symptoms, radiologic studies, and sputum cultures. Patients with acid-fast bacilli in their sputum can be presumptively diagnosed and treated with anti-tuberculosis therapy, which also may be appropriate in patients with a negative sputum smear but who have clinical and radiographic findings consistent with pulmonary tuberculosis. Therapy is designed to treat tuberculosis caused by M. tuberculosis, M. bovis, and M. africanum. Treatment of active tuberculosis uses a four-drug combination, consisting of isoniazid, rifampin, pyrazinamide, and ethambutol. Isoniazid and ethambutol are the critical therapeutic agents. These agents inhibit the synthesis of mycolic acids and increase the permeability of mammalian cells. This allows rifampin and pyrazinamide to enter the cells. The mechanism of action of each drug is provided in Table 19-2.

Infections caused by genetically related organisms in the Mycobacterium avium complex (MAC) are more difficult to treat because of their resistance to most antibiotics and anti-tuberculosis drugs. Treatment usually involves second-generation macrolides (e.g., azithromycin), ethambutol, and rifabutin.

Over the past 16 years, two forms of drug resistance have emerged. Multidrug-resistant tuberculosis (MDR-TB) is defined as a tuberculosis strain that is resistant to, at least, isoniazid and rifampin. Resistance is associated with random mutations that alter the structure or quantity of intracellular drug targets. In 2005, the overall rate of MDR-TB with resistance to isoniazid and rifampin was 1.2%, with the rates for individual states varying from 0 to 3.7%. Worldwide, the number of new MDR-TB cases in 2005 was estimated at 480,000. When second-line drugs for tuberculosis (Table 19-3) are mismanaged or misused, extensively drug-resistant tuberculosis (XDR-TB) strains develop. These strains are resistant to isoniazid and rifampin as well as any of the fluoroquinolones and any of the second-line drugs. An estimated 40,000 new cases of XDR-TB are reported yearly in the developing countries. Between 1993 and 2006, only 49 cases of XDR-TB were reported in the United States.

At ambient temperatures in the soil, the fungus grows as a mycelium with hyphae that produce macroconidia and microconidia (Figure 19-7). When soil is disturbed by occupational or recreational activities, conidia are easily aerosolized and inhaled. Conidia are ingested by alveolar macrophages and germinate into a single-cell yeast form (Figure 19-8).

The pathophysiology of the disease is similar to that of tuberculosis. The yeast form survives in alveolar macrophages by preventing NRAMP1 acidification of phagosomes. Some of the infected macrophages migrate to the hilar or mediastinal lymph, where they stimulate a cell-mediated response.

A cell-mediated response is mounted 10 to 14 days after infection. IFN-γ and TNF-α produced by CD4Th1 memory cells activate the fungistatic activities of the resident alveolar macrophages and peripheral blood monocytes. To contain the infection, lesions are ultimately encapsulated with collagen. Over a period of several years, calcium is deposited around the capsule, and the lesion becomes totally calcified.

A progressive form of histoplasmosis is an emerging problem in patients with secondary or therapy-induced immunodeficiencies. Individuals with AIDS have a high risk of developing progressive disease, in which the fungus or its toxic products disseminate throughout the body and cause septic shock and kidney and liver failure.

When the soil is disturbed, segmented hyphae rupture and release arthroconidia into the atmosphere. Arthroconidia are easily inhaled and localize in the alveoli, where they transform into multi-nucleated spherules that contain hundreds of endospores (Figure 19-9).

Rupture of the spherule releases the endospores into the lung alveoli. Some of the endospores are ingested by alveolar macrophages and monocytes, which migrate to local lymph nodes and stimulate a cell-mediated response. This is followed by an influx of monocytes, neutrophils, and CD4Th1 lymphocytes into the infected area. The evolution of the granuloma is similar to that described for tuberculosis. The granuloma, however, is unique in that B lymphocytes are found in the lesion, and antibodies to coccidioidal antigens are generated. Complement activation may also play a role in the immune response by generating neutrophil chemotactic factors.

Over 60% of infections are asymptomatic. Most active infections are confined to the lung and lung-associated lymph nodes. Less than 1% of individuals with clinical symptoms develop disseminated disease that spreads to the lungs, liver, brain, skin, heart, and pericardium. African Americans, Filipino Americans, and Hispanic Americans have a 10-fold higher risk for disseminated coccidioidomycosis compared with the general population. Disseminated disease is also found in individuals with secondary immunodeficiencies as a result of disease or therapeutic immunosuppression.