Mycobacteria

Mycobacterium Tuberculosis Complex

The tubercle bacilli that make up the M. tuberculosis complex (MTBC) include M. tuberculosis , M. bovis , M. bovis Bacille Calmette-Guérin strain (BCG), M. caprae , M. pinnipedii , M. africanum , M. microti , and M. canettii . The species that most commonly infects humans is M. tuberculosis . M. bovis , which infects many warm-blooded animals (e.g., cattle, dogs, cats, pigs, badgers, deer, elk, and some birds) as well as primates and humans, is responsible for a small fraction of tuberculosis (TB) cases today. M. bovis BCG is used for vaccine purposes in many countries outside the United States. It also is administered intravesically to induce immunostimulation against bladder cancer and, in such situations, rarely may cause disseminated disease. M. africanum causes TB in humans in tropical Africa but has been reported elsewhere, including the United States, primarily in persons who had lived in Africa. M. caprae predominantly infects goats, but also infects cattle and, rarely, humans ( ). M. microti was originally isolated from rodents but has caused TB in other warm-blooded animals and, rarely, in humans ( ). M. canettii was first collected in 1969 by Georges Canetti; it was recognized many years later as having the potential to cause disease in humans ( ; ; ). The natural host of M. pinnipedii is sea lions, but it can infect other animals and apparently may be transmitted to humans ( ).

Each year, the World Health Organization (WHO) issues the Global Tuberculosis Report, providing an update on the worldwide TB epidemic ( ). The 2018 report estimated 10 million (range, 9.0–11.1 million) new cases of TB: 1.0 million in children, 3.2 million in women, and 5.8 million in men. An estimated 558,000 of these cases (5%) were multidrug-resistant TB (MDR-TB), which is defined as resistance to at least isoniazid and rifampin. Two thirds of all cases were in eight countries: India (27%), China (9%), Indonesia (8%), the Philippines (6%), Pakistan (5%), Nigeria (4%), Bangladesh (4%), and South Africa (3%). Only 3% of cases occurred in the WHO European Region and 3% occurred in the WHO Region of the Americas. An estimated 1.6 million deaths were attributed to TB in 2017, with 300,000 of those occurring in the HIV-positive population. While the global burden of TB remains significant, the global incidence, absolute number of TB deaths, and TB mortality rate have all decreased since 2000 ( ).

In the United States, TB was the leading cause of death at the turn of the 20th century. Mortality then decreased, initially because of public health efforts and later because of the availability of antituberculous drugs. Between 1953, when TB became notifiable on a national basis, and 1984, the incidence of TB steadily decreased ( ). From 1985 to 1992, a resurgence of TB cases was seen, in large part because of the spread of the human immunodeficiency virus (HIV), deterioration of the health care infrastructure, and an increase in the number of cases reported among foreign-born persons. In addition to the resurgence, MDR-TB emerged and remains a concern, although to a much lesser degree than in developing countries. Since 1992, the incidence of TB in the United States has declined each year and MDR-TB has become uncommon ( ). In 2018, the Centers for Disease Control and Prevention (CDC) received report of 9029 new cases of TB in the United States, down 5.9% from the 9588 cases in 2013 ( ). The 2018 national incidence was 2.8 cases per 100,000 persons, with the highest incidence reported in Alaska (8.5) and the lowest in Wyoming (0.2). California, Florida, New York, and Texas are home to more than half of the TB cases in the country ( ). Of the 9029 TB cases in 2018, two thirds occurred in individuals born outside the United States, with persons of Asian origin having the highest incidence. For U.S.-born persons, the populations at highest risk for TB included the homeless, residents of correctional facilities, and residents of long-term care facilities. TB drug susceptibility data, available from 2017, showed 1.9% of U.S. TB cases classified as MDR-TB ( ).

Tubercle bacilli are transmitted primarily via inhalation of dried residues of small infectious droplets (1–10 μm in diameter). Infection also may be acquired by direct inoculation of abraded skin—an event most likely to occur when pathologists or other laboratory personnel handle infected tissues. In addition, M. bovis may be transmitted from cattle to humans by drinking contaminated raw milk or by respiratory exposure to live infected cattle or their carcasses, from humans to cattle via exposure to urine from persons with urinary tract infections due to M. bovis , and from cattle and wild reservoirs to cattle, probably by respiratory secretions.

The most important source of infection is an undiagnosed person with cavitary, sputum smear–positive pulmonary disease. The risk for active pulmonary disease is low after one exposure to the organism but increases under conditions of stress or in a confined environment where repeated exposures to the organism occur. Most persons who become infected with M. tuberculosis do not develop active disease. The lifetime risk for developing active disease is 5% to 10% for immunocompetent persons. For persons infected with both MTBC and HIV, in contrast, the risk for developing TB is 7% to 10% per year.

Persons at increased risk for MTBC infection are close contacts of those with known or suspected active TB, foreign-born persons from an area with a high incidence of active TB (e.g., Asia, Africa), persons who visit a country with a high prevalence of active TB, residents and employees of congregate settings whose clients are at increased risk for active TB (e.g., correctional facilities, homeless shelters), health care workers who care for patients at increased risk for active TB, and persons who abuse drugs or alcohol. Factors that increase the risk for progression of infection to active TB include HIV infection, age younger than 5 years, immunosuppressive therapy, infection with MTBC within the past 2 years, history of inadequately treated active TB, silicosis, diabetes mellitus, chronic renal failure, various cancers, gastrectomy or jejunoileal bypass, weight <90% of ideal body weight, cigarette smoking, and abuse of drugs and/or alcohol.

Based on analysis of its genomic sequence, M. tuberculosis does not appear to encode typical bacterial virulence factors (e.g., toxins). However, certain genes and gene products have been identified as key factors enabling M. tuberculosis to cause disease. PhoP, a transcription regulator, has been shown to have an important role in virulence because phoP mutants grow very poorly in macrophages and in mice ( ). Phthiocerol dimycocerosates, which are lipids found at the outermost layers of the cell envelope, are required for optimal multiplication and persistence of M. tuberculosis in mice lungs, and phenolic glycolipids are thought to be involved in the hypervirulence of certain M. tuberculosis strains ( ). In addition, the ESX secretion systems, which are specialized secretion systems present in many gram-positive bacteria, are important in pathogenesis because mutants lacking the system or its substrates are attenuated in cultured macrophages and animal models of infection. Mutants with a deletion spanning much of the ESX-1 locus demonstrate defective cell-to-cell spread, altered cytokine profiles, and failure to inhibit phagolysosome fusion in cultured cells ( ).

The usual host response to infection with MTBC is activation of the cell-mediated immune system. During primary (initial) infection, inhaled bacilli travel to the alveolar spaces, where they are ingested by resident macrophages. These macrophages are unable to kill the tubercle bacilli, which multiply intracellularly during the first several days after infection. Macrophages infected with mycobacteria migrate to regional tracheobronchial lymph nodes and present sensitizing antigen(s) to immunocompetent T cells or they enter the lymphatics and blood and travel back to the lungs (primarily the apices) and to distant organs such as lymph nodes, kidneys, epiphyseal areas of the long bones, vertebral bodies, and meninges, where bacilli continue to multiply until the cellular immune response is activated.

Immunocompetent T cells migrate from regional lymph nodes to the site of infection in the lung. There, they release chemotactic, migration-inhibitory, and mitogenic cytokines, which stimulate recruitment of blood-derived monocytes and lymphocytes, macrophage and lymphocyte division, and macrophage activation. Activated macrophages have enhanced microbicidal activity and produce cytokines such as interleukin-1, interferon-γ, and tumor necrosis factor, which stimulate or regulate other components of the immune system, properties that help control infection. The cytokines and lytic enzymes released by the macrophages also contribute to concomitant local tissue destruction. Over time, the activated T-cell population declines and is replaced by long-lived memory immune T cells, which protect against reinfection with MTBC and provide some cross-protection against infection with other mycobacteria. Despite the limitation of further mycobacterial multiplication in primary and metastatic foci by the activated macrophages and memory T cells, a residual nidus of infection remains indefinitely in the lung (most frequently in the apex, where the oxygen tension is high) and less often in distant sites. Therefore, the potential for reactivation of disease in these quiescent foci exists during periods of immunosuppression.

The primary focus of pulmonary infection, called the Gohn lesion , is usually subjacent to the pleura in the lower part of the upper lobes or in the upper part of the lower lobes of one lung, corresponding to areas of the lung that receive the greatest volume flow of inspired air. Lesions (tubercles) are well-circumscribed, 1- to 2-cm–diameter areas of grayish-white consolidation with soft to necrotic centers. Similar-appearing tubercles typically are found in the regional tracheobronchial lymph nodes; these plus the primary lung lesion are termed the Gohn complex . Microscopically, tubercles are composed of well-circumscribed caseating or noncaseating granulomas; organisms may be seen in sections stained with an acid-fast stain. Over time, these lesions are replaced by hyalinized fibrous tissue and eventually calcify. Lesions of miliary tuberculosis are small (one to several millimeters in diameter), distinct, yellow-white areas of consolidation without gross caseation that histologically resemble tubercles. The ability to form granulomas depends on the immunocompetence of the host. Individuals infected with HIV, for example, may have extensive necrosis, many neutrophils, microabscesses, and numerous acid-fast bacilli (AFB), without granulomas.

In the United States, pulmonary TB accounts for about 80% of cases of active disease. The clinical presentation may be insidious, with gradual onset of constitutional symptoms over months: catarrhal, with productive cough often attributed to a bad cold or lingering bronchitis; pneumonia- or flu-like, with high fever, aches and pains, and cough; hemoptoic, with acute-onset of blood-streaked sputum; or pleuritic. Extrapulmonary TB may be localized but more commonly involves multiple organs with or without concurrent lung infection. Multiorgan TB occurs predominantly in infants and young children, older adults, and immunocompromised individuals, especially those infected with both HIV and MTBC. Additionally, most infections with M. bovis in the United States are extrapulmonary, involving lymph nodes, the gastrointestinal tract, bones, and kidneys, and most commonly occur in children of Hispanic ethnicity ( ; ). Infrequently, infection follows intravesical instillation of M. bovis BCG for treatment of superficial bladder carcinoma ( ; ).

Nontuberculous Mycobacteria

The nontuberculous mycobacteria (NTM; also called mycobacteria other than tubercle bacilli ) may be categorized on the basis of colony pigmentation before and after exposure to light and growth rate on a solid medium as described by Runyon in 1959 ( Table 59.1 ) ( ). This classification system, however, has limits. For example, M. kansasii is usually a photochromogen but rarely is nonchromogenic or scotochromogenic. Members of the M. avium complex are nonchromogenic in Runyon’s scheme, but some isolates produce slightly pigmented colonies after prolonged incubation, potentially causing incorrect classification as a scotochromogen. M. szulgai is a scotochromogen at 37°C and a photochromogen at 25°C. Moreover, when a liquid medium is used for mycobacterial culture, as is currently recommended (discussed in the section regarding culture methods), growth rates used by Runyon for classification do not apply. M. leprae is unique among mycobacteria by virtue of the fact that it has not yet been cultivated in vitro.

In general, little is known about the antigens associated with virulence of the NTM, and the immune response to infection with these mycobacteria is poorly understood. With current molecular techniques, nearly 200 species of NTM have been identified. Select potential pathogens are reviewed in the following sections. An extensive description of the more recently described and infrequently isolated mycobacteria is found in the excellent review by Tortoli ( ).