Nontuberculous Mycobacteria

Jeffrey R. Starke

Mycobacteria other than Mycobacterium tuberculosis and M. leprae are known by several names, including nontuberculous, atypical, unclassified, environmental, and opportunistic mycobacteria. Nontuberculous mycobacteria (NTM) is probably the preferred and most accurate nomenclature. These organisms were discovered almost a century ago, but their role in causing pulmonary and lymph node disease was not described until 1948.

EPIDEMIOLOGY

In the early 1950s, 1% to 2% of the patients in tuberculosis sanatoria in Georgia and Florida had disease that was epidemiologically distinct from tuberculosis. Those with NTM disease were more likely to be older and white, and they usually had underlying chronic pulmonary disease, such as bronchiectasis or silicosis. Reaction to a tuberculin skin test occurred less commonly than among patients with tuberculosis, and close contacts tended to have negative test results for tuberculin. As more reports of NTM disease were published, marked geographic variability in the incidence of NTM disease and in the specific NTM species causing illness became apparent.

Between 1958 and 1970, large numbers of Navy recruits were skin-tested with purified protein derivative (PPD) from M. tuberculosis (PPD-S), M. intracellulare (PPD-B), and M. scrofulaceum (PPD-G). As many as 70% of the recruits from the southeastern states reacted to NTM skin test antigens, compared with 10% to 40% of recruits from the northern, midwestern, or western states. None of these sensitized recruits had ever experienced disease, thus demonstrating that most NTM infections are asymptomatic.

Although it has never been proved, NTM organisms probably are inhaled or introduced into the mouth, nose, or throat. NTM can be found in the environment in soil, water, or vegetation. The organisms may be present in some animals, but animal-to-human or person-to-person transmission has not been demonstrated. Certain mycobacteria that cause cutaneous granulomas may be present in water, including oceans, ponds, swimming pools, aquariums, and hot tubs. Children are more likely to have NTM cutaneous granulomas or superficial lymph node disease, and adults are more prone to pulmonary infections.

Changes in the epidemiology of NTM infections have occurred because of infections in adults and children with human immunodeficiency virus (HIV) and nosocomial infections. NTM disease occurs commonly in patients with advanced HIV infection (CD4+ count of less than 100) from all areas of the United States, even those where background infection rates (based on historic skin test results) are low. Their disease tends to be disseminated and difficult to control with current medications. The number of reports of instances or clusters of nosocomially acquired NTM infections in immunocompromised and immunocompetent hosts has grown, most associated with surgery or an indwelling catheter.

ETIOLOGY

At least 30 Mycobacterium species are associated with human disease, and several more may be encountered in clinical specimens. In 1959, Runyon proposed a grouping of mycobacteria exclusive of M. tuberculosis, M. bovis, and M. leprae based on pigmentation, growth rate, and colony morphology. Although
this grouping is one way of organizing the species, more sophisticated methods of species identification, based on DNA typing or high performance liquid chromatography (HPLC) analysis of the mycolic acids in the cell wall, now commonly are used. By conventional methods, using solid media, the growth of most of the NTMs is slow; exact speciation and susceptibility testing may take as long as 6 to 10 weeks. Only the so-called rapid-grower NTM (M. fortuitum, M. chelonae, and M. abscessus) can be isolated on solid media in less than 10 days. The radiometric culture system has reduced the time required for the isolation of most NTM to 2 weeks or less. A special substrate permits immediate differentiation of NTM from M. tuberculosis: NTMs grow freely in this substrate, but the growth of M. tuberculosis is inhibited.

Although isolation of an NTM is the best method to confirm disease, many NTMs are plentiful in the environment and can be encountered as colonizers. Five characteristics can help distinguish true infection from colonization: (a) quantity of growth, which increases with true disease; (b) repeated isolation of the same organism; (c) isolation from a deep-seated anatomic site, which is more meaningful; (d) whether the species of NTM isolated is known to cause disease at the site; and (e) whether the host has risk factors for NTM disease, such as immunocompromised state or cystic fibrosis.

PATHOGENESIS

Most people who encounter NTM have asymptomatic infection. Inhaled or ingested mycobacteria deposit on the mucous membranes of the nose, mouth, and throat. Local manifestations of infection are rare occurrences. When disease develops, the histopathologic findings are similar to those caused by M. tuberculosis infection. Lymph nodes affected by NTM develop necrosis within areas of caseation early in the course. Nonspecific acute and chronic inflammatory changes occur more often than do true granulomas. Acid-fast stains of tissue are positive in 30% to 60% of the cases. Even the most experienced pathologist cannot reliably differentiate NTM adenitis from tuberculous adenitis by microscopical or histologic examination.

Pulmonary disease is a rare occurrence in children, and the clinical picture includes hilar adenopathy, patchy infiltrates of multiple lobes, and lobar pneumonia. The pathologic and clinical findings are similar to those of tuberculosis in children.

Patients with coexistent NTM and HIV infections tend to have more severe and disseminated disease. NTM infection occurs primarily in the lungs, bone marrow, liver and spleen, gastrointestinal tract, and kidneys. Blood and stool culture results usually are positive. HIV-infected patients tend not to form granulomas; their inflammatory reaction is a less specific mix of chronic and acute changes. However, infected tissues may have an enormous number of organisms that are seen readily on acid-fast stain preparations.

CLINICAL MANIFESTATIONS AND COMPLICATIONS

Superficial Lymph Nodes

In children, the most common sites of clinically significant NTM infection are the superficial lymph nodes of the head and neck. When this clinical picture first was described, M. scrofulaceum was the most common infecting agent. More recent cases have been caused by M. avium and M. intracellulare (which together make up the M. avium complex), but M. kansasii and M. fortuitum occasionally cause this form of disease (Table 180.1). An increasing number of cases of NTM lymph node disease are caused by poorly characterized mycobacteria that cannot be isolated on usual media but can be demonstrated by polymerase chain reaction (PCR) testing of the tissue. Scrofula caused by NTM occurs most commonly in young children because of their tendency to put objects contaminated with soil, dust, or standing water into their mouths. The younger the child, the more likely that scrofula is caused by NTM.

TABLE 180.1. MOST COMMON SITES OF INFECTION FOR NONTUBERCULOUS MYCOBACTERIA

Site	Most Common Organisms
Lymph node	M. avium complex, M. kansasii, M. fortuitum, M. genavense, M. haemophilum, M. abscessus, poorly characterized mycobacteria
Pulmonary	M. kansasii, M. avium complex, M. xenopi, M. chelonae, M. fortuitum, M. haemophilum, M. szulgai, M. gordonae, M. malmoense
Disseminated	M. avium complex, M. kansasii, M. fortuitum, M. chelonae, M. xenopi, M. haemophilum, M. gordonae

Children living in rural or suburban settings are more likely to develop NTM cervical adenitis. Adenitis caused by NTM usually involves a group of nodes, most often located in the anterior superior cervical chain or submandibular area. Preauricular, postauricular, and submental lymph nodes also may be infected. In rare cases, infection of an axillary, epitrochlear, or inguinal node occurs secondary to cutaneous inoculation. The disease usually is unilateral. The nodal swelling may be explosive over the course of several days, but more often it develops insidiously, occasionally after an upper respiratory tract infection. The nodes usually are painless, nontender, and firm initially. As the infection progresses, the nodes soften and often develop fluctuance. The skin becomes shiny and thin, with an erythematous or violaceous hue. Untreated nodes frequently rupture through the skin, causing drainage and eventual formation of a sinus tract that can persist for months or years. Healing is marked by fibrosis and scarring of the skin. Low-grade fever may be present initially, but other systemic signs or symptoms are rare findings. A high fever or a toxic appearance of the child may indicate superinfection with pyogenic bacteria.

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