Jeffrey R. Starke
The nontuberculous mycobacteria (NTM) have been collectively identified by a variety of terms, including mycobacteria other than tuberculosis, atypical, nonpathogenic, unclassified, and environmental or opportunistic mycobacteria. Although grouping these organisms can be helpful, classification based on specific etiologic agent is preferable because this has implications for the predisposing factors, usual clinical course, diagnosis, and appropriate medical and surgical management of the infection.
Mycobacteria are true bacteria. They are nonmotile, nonspore-forming, slender pleomorphic rods. Their cell walls have a complex structure that includes a variety of proteins, carbohydrates, and lipids. Studies using high-pressure liquid chromatography (HPLC) reveal a variable species-related distribution of mycolic acids, each species having a distinct mycolic acid fingerprint that can be used for identification.
More than 60 species of Mycobacterium have been described, of which about half are pathogenic in humans. The most commonly encountered are Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium scrofulaceum, which are classified together as the M avium complex (MAC).
The direct detection of nontuberculous mycobacteria (NTM) is similar to that for Mycobacterium tuberculosis. All NTM are acid fast but these are visualized in fluid and tissue samples less than 50% of the time. Although even a single organism visualized on an entire slide is suspicious, false-positive results can be caused by contamination of stain solutions, tap water, distilled water, delivery tubes, or immersion oil. Direct detection of the various NTM by nucleic acid amplification is advancing, but appropriate primers and reagents are not yet commercially available for many species.
Methods used for the isolation of M tuberculosis from clinical samples are also useful for the isolation of NTM. All mycobacteria are obligate aerobes that grow best in the presence of 5% to 10% CO2. Isolation on solid media of slow-growing NTM takes 2 to 6 weeks. Only the rapid growers (Mycobacterium fortuitum, Mycobacterium chelonei, and Mycobacterium abscessus) form visible colonies in less than 10 days. Use of liquid media systems usually leads to isolation of any species of NTM within 14 days. Some newly recognized species of mycobacteria cannot be cultivated but can be detected by nucleic acid amplification. Many clinical laboratories now use high-pressure liquid chromatography (HPLC) analysis to speciate these organisms.
Determining the species of NTM causing infection is crucial to directing chemotherapy. Although drug susceptibility testing of MAC isolates is not predictive of clinical response and does not contribute significantly to care of the patient, susceptibility testing for the rapid-growing mycobacteria can be informative. For these mycobacteria, susceptibility testing to antibiotics such as amikacin, cefoxitin, doxycycline, sulfonamides, linezolid, and the macrolides may be particularly helpful.
Transmission of NTM to humans occurs from environmental sources, including soil, water, dust, and aerosols. NTM have been isolated from as many as 80% of soil samples, and certain strains of MAC are found in fresh and brackish waters in warmer climates. Other mycobacteria have been isolated from natural water supplies and tap water.1 Although mycobacteria are frequently found in animals, particularly swine and poultry, there is little evidence to suggest animal-to-human transmission. There is no evidence that person-to-person transmission occurs. Clusters and isolated cases of health care–associated disease due to NTM are being reported with increasing frequency. Most common are outbreaks caused by the rapid growers, which are associated with injectors, continuous ambulatory peritoneal dialysis, contaminated skin marking, and injection solutions and hemodialysis.
The true incidence and prevalence of NTM infections are difficult to determine because there is no mandatory reporting. Isolation of the organism does not prove infection, and distinguishing among saprophytes, colonizers, and pathogenic organisms can be difficult.2 A survey in the 1980s estimated the prevalence of NTM disease in the United States as 1.8 cases per 100,000 population, approximately 20% of the prevalence of tuberculosis. Rates were highest for disease due to MAC, Mycobacterium kansasii, and M fortuitum. The age distribution of NTM disease varies by mycobacterial species and site of disease. Pulmonary disease is rare in children, but occurs more often in older adults. The majority of cases of NTM lymph node infection occur in children younger than 5 years.
Clinical disease caused by NTM is common among both adults and children with untreated AIDS and other immunosuppressing conditions. Prior to the advent of antiretroviral therapy, almost 25% of deceased patients with AIDS in the United States had autopsy evidence of widespread disease caused by MAC.3 In one epidemiologic survey, 7.8% of children 0 to 9 years of age with AIDS had disseminated NTM infection; MAC caused more than 90% of cases. Patients with malignancies, especially leukemia and lymphoma, appear to have a higher incidence of NTM infections than the general population in the same geographic area. NTM infections are being diagnosed more often in transplant patients, including children.
The majority of NTM that cause human disease are of low virulence. Infections in immunocompetent hosts require an unusual exposure or direct route of inoculation such as trauma. These infections are generally characterized by findings limited to the inoculation site. NTM infections do not exhibit lymphohematogenous dissemination in normal hosts. Immunocompromised hosts are at increased risk for systemic and disseminated NTM infection, but these typically occur in the setting of extreme and prolonged immunocompromise, such as in individuals with advanced AIDS. Although the portal of entry for the MAC is usually the oropharynx or respiratory tract, the pattern of disseminated disease in patients with AIDS is most consistent with an intestinal portal.
The most common site of clinically significant nontuberculous mycobacteria (NTM) infection in children is the superficial lymph nodes of the head and neck.4 The vast majority of cases are caused by M avium complex (MAC). Lymph node infection as a result of NTM is most common in young children because of their tendency to put objects contaminated with soil, dust, or standing water into their mouths. Although NTM adenitis is more common in North America than is tuberculous adenitis, clinicians should never presume NTM to be the cause of apparent mycobacterial cervical adenitis until tuberculosis has been ruled out by a thorough epidemiologic history, evaluation of the family for tuberculosis, skin testing, and culture. The vast majority of children who develop NTM adenitis are immunologically normal.
Lymphadenitis caused by NTM usually involves a group of lymph nodes, most often located unilaterally, in the anterior cervical chain or submandibular region. Involvement of the supraclavicular lymph nodes is unusual and suggests infection with M tuberculosis or malignancy.
Lymph node enlargement usually occurs over weeks to months.5 Systemic signs or symptoms are rare in immunocompetent children. The involved lymph nodes are usually painless, firm, but not hard, and usually seem fixed to the underlying or overlying tissues. With further progression, the lymph nodes soften, become fluctuant, and may rupture through the skin, causing drainage and formation of a sinus tract that can persist for months or years. Healing is characterized by fibrosis and scarring of the skin, which can be extensive and disfiguring.
The standard tuberculin skin test may show a reaction with any NTM lymph node infection, but is more likely to cause a reaction with disease caused by M fortuitum or the MAC. The greatest difficulty in differential diagnosis is usually distinguishing between adenitis caused by NTM and M tuberculosis. The most important distinguishing feature is the epidemiologic setting, which determines whether children may have been exposed to M tuberculosis. Lack of contact with an adult with tuberculosis, a skin test reaction of less than 10 mm, and a poor response to standard antituberculosis chemotherapy suggest the diagnosis of NTM cervical adenitis.
Cutaneous and Soft Tissue
In immunocompetent hosts, the most common form of cutaneous nontuberculous mycobacteria infection is the skin granuloma, frequently called swimmer’s granuloma, caused by Mycobacterium marinum. These infections are associated with aquatic activities such as swimming, boating, fishing, or even care of tropical fish (Fig. 270-1). Direct trauma from contact with shrimp, barnacles, coral, or fish hooks may lead to infection. This mycobacterium can be isolated from swimming pools and natural sources of freshwater and saltwater. Cases of M marinum infection usually are sporadic, although outbreaks of swimming pool granuloma involving hundreds of people have been reported. Typical skin lesions are nontender inflammatory nodules that progress to ulcerated granuloma or to chronic warty lesions over several weeks to months. The most commonly affected sites are areas where trauma is frequent such as the elbows, knees, feet, and hands (Fig. 270-2). The typical lesion is 1 to 2 cm in diameter and is not accompanied by regional adenopathy. Most lesions heal spontaneously within a few months, but occasionally a nodular, sporotrichoidlike area spreads up an extremity. The clinical diagnosis is confirmed by culture of the discharge from the lesions or by biopsy. Many of these children have a highly reactive Mantoux tuberculin skin test.
FIGURE 270-1. Mycobacterium marinum infection of the hand. Granulomatous nodular lesion with central ulceration at the site of inoculation. (Source: Used with permission from A Kuhlwein, MD.)
In many tropical areas throughout the world, Mycobacterium ulcerans causes an itching nodule on the arms or legs, which then breaks down to form a shallow ulcer. This lesion is referred to as a Buruli ulcer. Isolation of M ulcerans is extremely difficult, and the diagnosis is usually made on clinical grounds. Excision of the lesion usually constitutes therapy, and treatment with several different antibiotics has led to variable success. (Additional information is provided in Chapter 272.)
An increasing number of mycobacterial cutaneous infections are caused by the rapidly growing mycobacteria, particularly M fortuitum, M abscessus, and M chelonei. These localized skin or subcutaneous lesions are associated with accidental or iatrogenic trauma. Manifestations usually include cellulitis, a draining abscess that may be single or multiple, or tender nodules. Seropurulent drainage, poor wound healing, and development of sinus tracts after an operative procedure should suggest this diagnosis.
The most common nontuberculous mycobacteria (NTM) infection in adults is pulmonary disease with M avium complex (MAC), with or without some form of underlying chronic lung disease. The clinical presentation includes cough, production of sputum, low-grade fever, and weight loss. In addition, hemoptysis, pleuritic chest pain, and night sweats may occur. Pleural effusions caused by NTM are rare. Mycobacterium kansasii is the most frequent cause of mycobacterial lung disease in the midwestern and southwestern United States. Some patients have underlying chronic lung disease, and the infection may resemble pulmonary tuberculosis. Dissemination beyond the lung is rare in immunocompetent patients, but is common in immunosuppressed hosts.
Pulmonary infection by NTM in children is rare. Strains of the MAC are the most frequent cause of pediatric NTM pulmonary infection. The majority of infected children are immunocompetent with no underlying pulmonary disease. The most common presentation is similar to the primary tuberculosis complex. Patients have mild cough and low-grade fever with few systemic signs or symptoms. Occasionally, localized wheezing is noted and the diagnosis of an aspirated foreign body should be considered. Enlargement of hilar or mediastinal lymph nodes is common. These species can be isolated from the gastric secretions of healthy children, so diagnosis requires repeated isolation of the same mycobacterium in association with pulmonary deterioration.
FIGURE 270-2. Mycobacterium marinum lesion showing a verrucous violaceous plaque with central spontaneous clearing at the the site of an abrasion on the hand sustained in a fish tank. (Source: Used with permission from Wolff K, Goldsmith LA, Katz SI, et al (eds). Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw-Hill; 2008.)
Special mention should be made of the association between NTM colonization and infection and cystic fibrosis (CF).6 Unfortunately, a standard definition of NTM disease in CF patients, using clinical, radiographic, and pulmonary function testing results, is not possible. A single isolation of an NTM in the sputum of a CF patient who is not experiencing a decline in pulmonary function probably represents colonization, and treatment is not necessary. However, repeated isolation of the same species of NTM in association with declining pulmonary function is more suggestive, but not diagnostic, of invasive NTM disease in the lung.
Several cases of osteomyelitis caused by the MAC have been described in children. In these cases, the bony lesions are usually the only sites of infection. The most frequent findings are lytic lesions of the long bones or lesions of the small bones of the hands, feet, skull, ribs, and sternum. In most patients, the lesions persist for several years, and then become inactive or resolve spontaneously.
Very few cases of NTM meningitis have been reported in children.7 The clinical presentation and laboratory values are generally similar to those commonly seen in patients with tuberculous meningitis. Before the AIDS epidemic, disseminated NTM infection had been reported in less than 20 children.8 Most of these children died. Lesions of the lungs, long bones, liver, gastrointestinal tract, and bone marrow were common.
NONTUBERCULOUS MYCOBACTERIA AND AIDS
The major risk factor for nontuberculous mycobacteria (NTM) infection in patients with AIDS is the level of immune dysfunction, reflected by the concentration of CD4+ cells in the blood. The mean concentration of CD4+ cells in patients with disseminated NTM infection is less than 60/mm3. The most frequent causative agent of disseminated NTM infection is the M avium complex (MAC), but disease also results from infection with M kansasii, M fortuitum, M chelonei, Mycobacterium xenopi, Mycobacterium haemophilum, and other novel, unidentified mycobacteria. The incidence of NTM infection in persons with AIDS is reduced dramatically by highly active antiretroviral therapy.
Disseminated NTM infection most commonly affects the blood, bone marrow, liver, spleen, and lymph nodes, but organisms have been recovered from virtually every organ of the body. Patients have a variety of signs and symptoms. The most common presentation is persistent fever with weight loss or failure to thrive. Gastrointestinal symptoms are common, especially chronic diarrhea, abdominal pain, and extrahepatic biliary obstruction. Radiographic imaging of the abdomen and physical examination often reveal marked hepatosplenomegaly, focal lesions in the liver or spleen, diffuse thickening of bowel walls, and enlarged mesenteric lymph nodes. Severe anemia requiring transfusion is frequent. Less commonly, cutaneous lesions, superficial lymph node enlargement, or endobronchial disease without pneumonia may occur. Many of the signs and symptoms described previously are common in patients with AIDS and other conditions or infections; however, fever, abdominal pain, diarrhea, anemia, and weight loss are significantly associated with disseminated NTM infection. Diagnosis of disseminated NTM infection is easily established by culture of a normally sterile site. Only one or two mycobacterial blood cultures are necessary to confirm the diagnosis in most cases.
The key to diagnosis of nontuberculous mycobacteria (NTM) infection is a high level of suspicion based on epidemiologic factors and clinical presentation.9 This etiology should be especially considered in patients with chronic cervical lymphadenitis, in cases of chronic cutaneous ulcers or other skin lesions with poor wound healing, and in immunosuppressed hosts.
Nonspecific laboratory tests such as blood counts, ESR, urinalysis, and serum chemistry tests are usually normal in children with NTM infections. Skin testing with purified protein derivative from M tuberculosis may be helpful in the detection of infections caused by NTM. These infections are usually associated with skin test reactions less than 10 mm in diameter, but larger areas of induration may be seen. A negative tuberculin skin test never eliminates consideration of NTM infection. Of course, similar reactions may be caused by M tuberculosis infection. NTM antigens for skin testing are no longer available commercially because of poor sensitivity and specificity, as well as a lack of quality control during production.
Acid-fast stains of appropriate patient samples may give an early clue to the presence of NTM infection but are frequently negative because the number of organisms is small. Histologic studies of affected tissues may be helpful if classic granulomatous changes are evident.
The most direct method for diagnosing NTM disease is culture of involved fluid or tissue specimens. Because of their ubiquity in the environment, isolation of NTM may represent colonization or infection without recognizable disease. Most experts suggest considering five clinical observations when determining whether an isolated NTM is the cause of disease9:
1. Quantity of growth is usually moderate to heavy, especially in respiratory tract specimens, when disease occurs.
2. Repeated isolation of the same mycobacterium from the same site is likely to indicate true infection.
3. The site of origin of a positive specimen is important. The majority of NTM isolated from urine, gastric aspirates, and oropharyngeal secretions are contaminants, whereas NTM isolation from closed aspiration of lymph nodes or abscesses, as well as from deep tissue fluids, biopsy specimens, or resected tissues, usually indicates disease.
4. The species of mycobacteria is important. Isolates of NTM that rarely cause human disease should be viewed with caution.
5. Host risk factors should be considered. In the presence of predisposing conditions, the index of suspicion should be raised so that less stringent criteria are applied to the evaluation of specimens that are culture positive for NTM.
Specific treatment of NTM disease depends on the location and extent of the infected tissue, the host immune system, and the mycobacteria species involved. In general, surgery plays a more important role in the management of NTM disease than in tuberculosis because chemotherapy is often ineffective for NTM, and most NTM infections are localized and therefore amenable to surgical excision.9 An important initial consideration is determination that M tuberculosis is not the causative pathogen. Until NTM are identified by culture, treatment is usually directed at M tuberculosis, both for therapeutic reasons and for infection control.
To properly direct chemotherapy, it is important to determine the infecting species of NTM. In general, M kansasii, M marinum, M xenopi, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium szulgai, and M haemophilum are susceptible to some or all standard antituberculosis drugs. Treatment of the rapidly growing mycobacteria and most strains of the MAC require other antibiotics.
In general, excisional biopsy remains the treatment of choice for cervical lymphadenitis caused by NTM. Incisional biopsy should not be performed because it frequently leads to development of a draining sinus tract or recurrent disease. Total excision of the inflammatory mass usually precludes persistence or recurrence. However, removal of all involved lymph nodes may be impossible due to the close proximity of vital structures. Excision is best performed early, in order to improve the cosmetic outcome before extension of disease into the subcutaneous structures occurs. Chemotherapy is not generally necessary for children with NTM lymphadenitis. If tuberculosis cannot be reasonably excluded, an initial course of antituberculosis therapy should be considered. Many cases of cervical adenitis caused by the M avium complex resolve during treatment with standard antituberculosis medications, although no controlled trials have been reported. In these cases, the causative organisms are usually not susceptible to the chemotherapeutic agents used, and spontaneous resolution may have occurred. In a small percentage of cases in which complete surgical excision is not possible, recurrence of adenitis is a problem. Chemotherapy may be helpful; the purpose is to prevent extension of recurrence so that a second surgical procedure is not necessary. The most commonly used regimen is a combination of at least two drugs, including clarithromycin, rifampin or rifabutin, and ethambutol.
Many cases of cutaneous disease caused by M marinum resolve spontaneously. Acceptable chemotherapy regimens for more extensive lesions include doxycycline, or rifampin plus ethambutol, administered for a minimum of 3 months. The rate of resolution is variable, but therapy must be given for at least 3 to 4 weeks before the clinical response can be evaluated. No controlled clinical trials for treatment of cutaneous or soft tissue disease caused by rapid-growing mycobacteria have been reported. Most isolates of M fortuitum are susceptible to amikacin, cefoxitin, ciprofloxacin, clarithromycin, and imipenem. Drug susceptibility for M chelonei and M abscessus is more variable. For serious disease, intravenous therapy with amikacin and cefoxitin is recommended until clinical improvement is evident. Removal of foreign bodies is essential for resolution of infection at these sites. In cases of extensive disease, surgical excision of affected tissue may shorten the duration and morbidity of the infection.
Pulmonary infections with NTM in children are rare, and no controlled therapy trials have been reported.9 Most isolates of MAC are resistant to antituberculosis drugs used singly. However, combination therapy with standard antituberculosis drugs generally has been successful in the treatment of adults with pulmonary MAC infection. If standard therapy is not effective, second-line drugs with significantly more side effects and greater toxicity must be used. Re-sectional surgery may be necessary for localized disease. Treatment of disease caused by M kansasii is usually successful because it is susceptible to rifampin, ethambutol, often isoniazid, and streptomycin. The usual length of recommended combination therapy is 12 to 18 months.
More recent studies show that certain multiple-drug regimens can provide symptomatic relief, prolong life, and lead to partial clearing or reduction in the level of NTM bacteremia in patients with AIDS.9However, treatment with various antimycobacterial agents may be associated with considerable toxicity. Patients with HIV infection usually have significantly higher rates of adverse reactions to most antimycobacterial drugs, just as they do to many other classes of drugs. The most commonly used drugs for patients with AIDS and disseminated MAC infection are clarithromycin, azithromycin, amikacin, ciprofloxacin, ethambutol, and rifampin or rifabutin. Although many different therapeutic regiments have been studied, recommendation of any specific drug regimen or duration of therapy for disseminated MAC disease in patients with AIDS is difficult. Most experts use the combination of clarithromycin, rifamycin, and ethambutol as initial therapy. Most experts recommend placing immunocompromised patients with AIDS who are at high risk for disseminated MAC infection with CD4+ counts of less than 100 cells/mm3 on a preventive medication such as clarithromycin or rifabutin (see Chapter 315 for details regarding children of specific ages).