Etiology

NTM are ubiquitous in the environment all over the world, existing as saprophytes in soil and water but also as opportunistic pathogens in animals, including swine, birds, and cattle. Many of the 130 validly published NTM species have been isolated from environmental and animal samples, implying that humans are constantly exposed to NTM from the environment, for instance during showering. Owing to the introduction of molecular identification tools such as 16S rDNA gene sequencing, the number of identified NTM species has grown to more than 130; the clinical relevance (i.e., the percentage of isolates that are causative agents of true NTM disease, rather than contamination) differs significantly by species.

In the USA, M. avium-intracellulare complex (MAC) and M. kansasii are most often isolated from clinical samples, yet the isolation frequency of these species differs significantly by geographical area. MAC bacteria have been commonly isolated from natural and synthetic environments in the USA, and cases of MAC disease have been successfully linked to home exposure to shower and tap water. Although the designation M. avium suggests that M. avium infections are derived from birds (avium being Latin for “of birds”), molecular typing has pointed out that M. avium strains that cause pediatric lymphadenitis and adult pulmonary disease represent the M. avium hominissuis subgrouping that is mainly found in humans and pigs and not in birds.

Some NTM have well-defined ecologic niches that help explain infection patterns. The natural reservoir for M. marinum is fish and other cold-blooded animals, and hence infections due to M. marinum follow skin injury in an aquatic environment. M. fortuitum complex bacteria and M. chelonae are ubiquitous in water and have caused clusters of nosocomial surgical wound and venous catheter–related infections. M. ulcerans is associated with severe, chronic skin infections (Buruli ulcer disease) and is endemic mainly in West Africa and Australia, although other foci exist. Its incidence is highest in children <15 yr old. Mycobacterium ulcerans had been commonly detected in environmental samples by polymerase chain reaction (PCR) but was only recently recovered by culture from a Water Strider (Gerris sp.) from Benin.

Epidemiology

Humans are exposed to NTM very commonly. In rural counties in the USA, where M. avium is prevalent in swamps, the prevalence of asymptomatic infections with M. avium complex as measured by skin test sensitization approaches 70% by adulthood. Still, the incidence and prevalence of the various NTM disease types remain largely unknown, especially for pediatric NTM disease. In Australian children, the overall incidence of NTM infection was found to be 0.84 per 100,000, with lymphadenitis accounting for two thirds of cases. The incidence of pediatric NTM disease in the Netherlands has been estimated at 0.77 infections per 100,000 children per year, with lymphadenitis making up 92% of all infections.

In comparison, estimations of the prevalence of NTM from respiratory samples in adults are 5-14.1/100,000 persons per year, with important differences between countries or regions. Because pulmonary NTM disease progresses slowly, over years rather than months, and usually takes several years to cure, the prevalence of pulmonary NTM disease is much higher than incidence rates would suggest.

The paradigm that NTM disease is a rare entity limited to developed countries is changing. In recent studies in African countries with a high prevalence of HIV infection, it has been found that NTM might play a much larger role as a cause of tuberculosis-like disease of children and adults than previously assumed.

Pathogenesis

The histologic appearances of lesions caused by M. tuberculosis and NTM are often indistinguishable. The classic pathologic lesion consists of caseating granulomas. Compared with M. tuberculosis infections, NTM infections are more likely to result in granulomas that are noncaseating, ill defined (nonpalisading), and irregular or serpiginous. Granuloma formation during NTM disease might even be absent, with only chronic inflammatory changes observed.

In patients with AIDS and disseminated NTM infection, the inflammatory reaction is usually scant and tissues are filled with large numbers of histiocytes packed with acid-fast bacilli. These disseminated NTM infections typically occur only after the number of CD4 T-lymphocytes has fallen below 50/µL, suggesting that specific T-cell products or activities are required for immunity to mycobacteria.

The pivotal roles of interferon-γ (IFN-γ), interleukin (IL)-12 and tumor necrosis factor (TNF)-α in pathogenesis are demonstrated by the high incidence of (mostly disseminated) NTM disease in children with interferon-γ and IL-12 pathway deficiencies and in persons treated with agents that neutralize TNF-α.

Observed differences in pathogenicity, clinical relevance, and spectrum of clinical disease associated with the various NTM species emphasize the importance of bacterial factors in the pathogenesis of NTM disease, though exact virulence factors remain unknown.

Clinical Manifestations

Lymphadenitis of the superior anterior cervical or submandibular lymph nodes is the most common manifestation of NTM infection in children (Table 209-1). Preauricular, posterior cervical, axillary, and inguinal nodes are involved occasionally. Lymphadenitis is most common in children 1-5 yr of age and has been related to their tendency to put objects contaminated with soil, dust, or standing water into their mouths. Given the constant environmental exposure to NTM, the occurrence of these infections might also reflect an atypical immune response of a subset of the infected children during or after their first contact with NTM.

Table 209-1 DISEASES CAUSED BY NONTUBERCULOUS MYCOBACTERIAL SPECIES

MAC, Mycobacterium avium complex.

* Not endemic in the USA.

^† Found primarily in Northern Europe.

From American Academy of Pediatrics: Red book: 2009 report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 703.

Affected children usually lack constitutional symptoms and present with a unilateral subacute and slowly enlarging lymph node or group of closely approximated nodes >1.5 cm that are firm, painless, freely movable, and not erythematous (Fig. 209-1). The involved nodes occasionally resolve without treatment, but most undergo rapid suppuration after several weeks (Fig. 209-2). The center of the node becomes fluctuant, and the overlying skin becomes erythematous and thin. Eventually, the nodes rupture and form cutaneous sinus tracts that drain for months or years, resembling the classic scrofula of tuberculosis (Fig. 209-3).

Figure 209-1 An enlarging cervical lymph node infected with Mycobacterium avium complex infection. The node is firm, painless, freely movable, and not erythematous.

Figure 209-2 A suppurating cervical lymph node infected with Mycobacterium avium complex.

Figure 209-3 A ruptured cervical lymph node infected with Mycobacterium avium complex, which resembles the classic scrofula of tuberculosis.

In the USA, M. avium complex accounts for approximately 80% of NTM lymphadenitis in children. Birds are an unlikely source of these M. avium complex infections, as molecular typing has shown that the lymphadenitis-associated M. avium bacteria are of the human or porcine subtype rather than the bird type. M. kansasii accounts for most other cases of lymphadenitis in the USA. M. malmoense and M. haemophilum are described. The former is only common in northwestern Europe; for the latter, underestimation is likely because the bacteria require specific culture conditions (hemin-enriched media, low incubation temperatures). On the basis of PCR analysis of lymph node samples from lymphadenitis cases in the Netherlands, M. haemophilum was the second most common cause of this infection after M. avium complex.

Cutaneous disease caused by NTM is rare in children (see Table 209-1). Infection usually follows percutaneous inoculation with fresh or salt water contaminated by M. marinum. Within 2-6 wk after exposure, an erythematous papule develops at the site of minor abrasions on the elbows, knees, or feet (swimming pool granuloma) and on the hands and fingers of fish tank owners, mostly inflicted during tank cleaning (fish tank granuloma). These lesions are usually nontender and enlarge over 3-5 wk to form violaceous plaques. Nodules or pustules can develop, and occasionally these lesions ulcerate, resulting in a serosanguineous discharge. The lesions sometimes resemble sporotrichosis, with satellite lesions near the site of entry, extending along the superficial lymphatics. Lymphadenopathy is usually absent. Although most infections remain localized to skin, penetrating M. marinum infections can result in tenosynovitis, bursitis, osteomyelitis, or arthritis.

M. ulcerans infection is the third most common mycobacterial infection in immunocompetent patients, after M. tuberculosis and M. leprae infection, and causes cutaneous disease in children living in tropical regions of Africa, South America, Asia, and parts of Australia. In some communities in West Africa, up to 16% of people have been affected. Infection follows percutaneous inoculation from minor trauma, such as pricks and cuts from plants or insect bites. After an incubation period of approximately 3 mo, lesions appear as an erythematous nodule, most commonly on legs or arms. The lesion undergoes central necrosis and ulceration. The lesion, often called a Buruli ulcer after the region in Uganda where a large number of cases was reported, has a characteristic undermined edge, expands over several weeks, and can result in extensive, deep soft tissue destruction or bone involvement. Lesions are typically painless, and constitutional symptoms are unusual. Lesions might heal slowly over 6-9 mo or might continue to spread, leading to deformities and contractures.

Skin and soft tissue infections caused by rapidly growing mycobacteria such as M. fortuitum, M. chelonae, or M. abscessus are rare in children and usually follow percutaneous inoculation from puncture or surgical wounds and minor abrasions. Clinical disease usually arises after a 4-6 wk incubation period and manifests as localized cellulitis, painful nodules, or a draining abscess. M. haemophilum can cause painful subcutaneous nodules, which often ulcerate and suppurate in immunocompromised patients, particularly after kidney transplantation.

NTM are an uncommon cause of catheter-associated infections but are becoming increasingly recognized in this respect. Infections caused by M. fortuitum, M. chelonae, or M. abscessus can manifest as bacteremia or localized catheter tunnel infections.

Otomastoiditis, or chronic otitis media, is a rare extrapulmonary NTM disease type that specifically affects children with tympanostomy tubes and a history of topical antibiotic or steroid use. M. abscessus is the most common causative agent, followed by M. avium complex (see Table 209-1). Patients present with painless, chronic otorrhea resistant to antibiotic therapy. CT imaging can reveal destruction of the mastoid bone with mucosal swelling (Fig. 209-4). Delayed or unsuccessful treatment can result in permanent hearing loss. In unusual circumstances, NTM causes other bone and joint infections that are indistinguishable from those produced by M. tuberculosis or other bacterial agents. Such infections usually result from operative incision or accidental puncture wounds. M. fortuitum infections from puncture wounds of the foot resemble infections caused by Pseudomonas aeruginosa and Staphylococcus aureus.

Figure 209-4 Computed tomography images of the middle ear of a 6 yr old child infected with Mycobacterium abscessus demonstrating extensive bone destruction in the right mastoid and associated right-sided mucosal swelling. A, Bone tissue window setting. B, Soft tissue window setting.

Pulmonary infections are the most common form of NTM illness in adults but are rare in children. M. avium complex bacteria, the most commonly identified organisms (see Table 209-1), are capable of causing acute pneumonitis, chronic cough, or wheezing associated with paratracheal or peribronchial lymphadenitis and airway compression in normal children. Associated constitutional symptoms such as fever, anorexia, and weight loss occur in 60% of these children. Chest radiographic findings are very similar to those for primary tuberculosis, with unilateral infiltrates and hilar lymphadenopathy (Fig. 209-5). Pleural effusion is uncommon. Rare cases of progression to endobronchial granulation tissue have been reported.

Figure 209-5 Chest radiograph of a 2 yr old child infected with Mycobacterium avium complex demonstrating a left upper lobe infiltrate and left hilar lymphadenopathy.

Pulmonary infections usually occur in adults with underlying chronic lung disease. The onset is insidious and consists of cough and fatigue, progressing to weight loss, night sweats, low-grade fever, and generalized malaise in severe cases. Thin-walled cavities with minimal surrounding parenchymal infiltrates are characteristic, but radiographic findings can resemble those of tuberculosis. A separate disease manifestation occurs in postmenopausal women and is radiologically characterized by bronchiectasis and nodular lesions, often affecting the middle lobe and lingula.

Chronic pulmonary infections specifically affect children with cystic fibrosis and are generally caused by M. abscessus and M. avium complex. M. abscessus primarily affects children, and M. avium complex is most common among adults. The percentage of patients with cystic fibrosis with at least one sputum culture positive for NTM is 6-8.1% overall and increases with age; in cystic fibrosis patients <12 yr of age, a prevalence of 3.9% has been reported. The strong representation of M. abscessus in these patients is remarkable, because this bacterium is an uncommon isolate in other categories of patients. There are indications that NTM infections in patients with cystic fibrosis further accelerate the decline in lung function; antimycobacterial therapy can result in weight gain and improved lung function in affected patients.

Disseminated disease is usually associated with M. avium complex infection and occurs in immunocompromised children. The first category of patients with disseminated disease includes persons with mutations in genes coding for the IFN-γ receptor (IFNGR) or the IL-12 receptor, or for IL-12 production. Patients with complete IFNGR deficiency have severe disease that is difficult to treat. Those with partial IFNGR deficiency or IL-12 pathway mutations have milder disease that can respond to interferon-γ and antimycobacterial therapy. Multifocal osteomyelitis is particularly prevalent in persons with the IFNGR1 818del4 mutation. Recurrences, even years after a course of treatment, and multiple infections have been well documented. The second category of patients affected by disseminated disease is patients with AIDS. Disseminated NTM disease in patients with AIDS usually appears when CD4 cell counts are <50 cells/mm³; in younger children (especially those <2 yr of age) these infections occur at higher CD4 cell counts. The most recent estimate of its incidence is 0.14-0.2 episodes per 100 person-years, a 10-fold decrease from its incidence before highly active antiretroviral therapy (HAART) was available.

Colonization of the respiratory or gastrointestinal tract probably precedes disseminated M. avium complex infections, but screening studies of respiratory secretions or stool samples are not useful to predict dissemination. Continuous high-grade bacteremia is common, and multiple organs are infected, most commonly including lymph nodes, liver, spleen, bone marrow, and gastrointestinal tract. Thyroid, pancreas, adrenal gland, kidney, muscle, and brain can also be involved. The most common signs and symptoms of disseminated M. avium complex infections in AIDS patients are fever, night sweats, chills, anorexia, marked weight loss, wasting, weakness, generalized lymphadenopathy, and hepatosplenomegaly. Jaundice, elevated alkaline phosphatase or lactate dehydrogenase levels, anemia, and neutropenia can occur. Imaging studies usually demonstrate massive lymphadenopathy of hilar, mediastinal, mesenteric, or retroperitoneal nodes. The survival in children with AIDS has improved considerably with the availability of HAART therapy.

Disseminated disease in children without any apparent immunodeficiency is exceedingly rare.

Diagnosis

For infections of lymph nodes, skin, bone, and soft tissues, isolation of the causative NTM bacteria by Mycobacterium culture, preferably with histologic confirmation of granulomatous inflammation, normally suffices for diagnosis. The differential diagnosis of NTM lymphadenitis includes acute bacterial lymphadenitis, tuberculosis, cat scratch disease (Bartonella henselae), mononucleosis, toxoplasmosis, brucellosis, tularemia, and malignancies, especially lymphomas. Differentiation between NTM and M. tuberculosis may be difficult, but children with NTM lymphadenitis usually have a Mantoux tuberculin skin test reaction of <15 mm induration, unilateral anterior cervical node involvement, a normal chest x-ray, and no history of exposure to adult tuberculosis. Definitive diagnosis requires excision of the involved nodes for culture and histology. Fine needle aspiration for PCR and culture can enable earlier diagnosis, before excisional biopsy.

The diagnosis of pulmonary NTM infection in children is difficult because many species of NTM, including M. avium complex, are omnipresent in our environment and can contaminate, or occasionally be present in, clinical samples. As a result, isolation of these bacteria from nonsterile specimens (respiratory and digestive tract) does not necessarily reflect true infection. To determine the clinical relevance of isolation of NTM, the diagnostic criteria of the American and British Thoracic Societies are an important support. These criteria take into consideration clinical features and radiologic, pathologic, and microbiologic findings. The hallmark of these criteria is the need for multiple positive cultures yielding the same NTM species to make a definitive diagnosis of pulmonary NTM disease. In children, definitive diagnosis often requires invasive procedures such as bronchoscopy and pulmonary or endobronchial biopsy; in cystic fibrosis patients, more-aggressive sample pretreatment is necessary to prevent overgrowth by other species, especially Pseudomonas spp. The chance that isolation of NTM is clinically relevant differs significantly by species; some species are more likely causative agents of true pulmonary disease (M. avium, M. kansasii, M. abscessus, M. malmoense), whereas others are most likely contaminants (M. gordonae, M. fortuitum, M. chelonae).

Blood cultures are 90-95% sensitive in AIDS patients with disseminated infection. M. avium complex may be detected within 7-10 days of inoculation in nearly all patients by radiometric or continuously monitored automated blood culture systems. Commercially available DNA probes differentiate NTM from M. tuberculosis. If DNA probes cannot identify the causative mycobacteria, DNA sequencing of bacterial housekeeping genes will always yield a clue to the identity of these NTM. Identification of histiocytes containing numerous acid-fast bacilli from bone marrow and other biopsy tissues provides a rapid presumptive diagnosis of disseminated mycobacterial infection.

Treatment

Therapy for NTM infections is long-term and cumbersome; expert consultation is advised. Therapy involves medical, surgical, or combined treatment (Chapter 206 and Table 206-3). Isolation of the infecting strain followed by drug susceptibility testing is ideal, because it provides a baseline for drug susceptibility. Important discrepancies exist between in vitro drug susceptibility and in vivo response to treatment, explained in part by synergism, mainly among first-line antituberculosis drugs. In vitro, slow growers (M. kansasii, M. marinum, M. xenopi, M. ulcerans, and M. malmoense) are usually susceptible to the first-line antituberculosis drugs rifampicin and ethambutol; M. avium complex bacteria are often resistant to these drugs alone but susceptible to the combination and have variable susceptibility to other antibiotics, most importantly the macrolides. Rapid growers (M. fortuitum, M. chelonae, M. abscessus) are highly resistant to antituberculosis drugs and often have inducible macrolide resistance mechanisms. Susceptibility to macrolides, aminoglycosides, carbapenems, tetracyclines, and glycylcyclines are most relevant for therapy guidance. In all NTM infections, multiple-drug therapy is essential to avoid development of resistance.

The preferred treatment of NTM lymphadenitis is complete surgical excision (Table 206-3). Nodes should be removed while still firm and encapsulated. Excision is more difficult if extensive caseation with extension to surrounding tissue has occurred, and complications of facial nerve damage or recurrent infection are more likely in such cases. Incomplete surgical excision is not advised, because chronic drainage can develop. If there is concern for possible M. tuberculosis infection, therapy with isoniazid, rifampin, ethambutol, and pyrazinamide should be administered until cultures confirm the cause to be NTM (Chapter 207). If for some reason surgery of NTM lymphadenitis cannot be performed, removal of infected tissue is incomplete, or recurrence or chronic drainage develops, a 3-6 mo trial of chemotherapy is warranted. Although there are no published controlled trials, several case reports and small series have reported successful treatment with chemotherapy alone or combined with surgical excision. Clarithromycin or azithromycin combined with rifabutin or ethambutol are the most commonly reported therapy regimens (Table 206-3).

Post-traumatic cutaneous NTM lesions in immunocompetent patients usually heal spontaneously after incision and drainage without other therapy (Table 206-3). M. marinum is susceptible to rifampin, amikacin, ethambutol, sulfonamides, trimethoprim-sulfamethoxazole, and tetracycline. Therapy with a combination of these drugs, particularly rifampin and ethambutol, may be given for 3-4 mo. Corticosteroid injections should not be used. Superficial infections with M. fortuitum or M. chelonae usually resolve after surgical incision and open drainage, but deep-seated or catheter-related infections require removal of infected central lines and therapy with parenteral amikacin plus cefoxitin or clarithromycin.

Some localized forms of M. ulcerans skin disease (Buruli ulcer) can heal spontaneously; for most forms, excisional surgery with primary closure or skin grafting is recommended. Provisional guidelines by the World Health Organization (WHO) recommend treatment with rifampin and streptomycin, with or without surgery. In clinical experience, a drug treatment duration of 8 wk generally leads to low recurrence levels. Physiotherapy after surgery is essential to prevent contractures and functional disabilities.

Pulmonary infections should be treated initially with isoniazid, rifampin, ethambutol, and pyrazinamide pending culture identification and drug susceptibility testing. For slow-growing NTM, a combination of rifampin or rifabutin, ethambutol, and clarithromycin is recommended; after culture conversion, treatment should be continued for at least 1 yr. In adult patients with pre-existing pulmonary disease, the role of the macrolides is still debated. For pulmonary disease caused by rapidly growing NTM, a combination of macrolides, fluoroquinolones, aminoglycosides, cefoxitin, and carbapenems is the optimal therapy; three or four-drug regimens are selected on the basis of drug susceptibility testing results. In cystic fibrosis patients, there may be a role for inhaled antibiotics.

Patients with disseminated M. avium complex and IL-12 pathway defects or IFNGR deficiency should be treated for at least 12 mo with clarithromycin or azithromycin combined with rifampin or rifabutin and ethambutol. Fluoroquinolones have some in vitro activity, though clinical studies have not settled their role in treatment regimens. In vitro susceptibility testing for clarithromycin and the fluoroquinolones is important to guide therapy. Once the clinical illness has resolved, lifelong daily prophylaxis with azithromycin or clarithromycin is advisable to prevent recurrent disease. The use of interferon adjunctive therapy is determined by the specific genetic defect.

In children with AIDS, prophylaxis with azithromycin or clarithromycin is indicated to prevent infection with M. avium complex. Although few pediatric studies exist, the U.S. Public Health Service recommends either azithromycin (20 mg/kg once weekly PO, maximum 1,200 mg/dose) or clarithromycin (7.5 mg/kg/dose twice daily PO, maximum 500 mg/dose) for HIV-infected children with significant immune deficiency as defined by the CD4 count (children ≥6 yr, CD4 count <50/µL; 2-6 yr, CD4 count <75/ µL; 1-2 yr, CD4 count <500/µL; <1 yr, CD4 count <750/µL). Prophylaxis may be safely discontinued in children aged >2 yr receiving stable HAART for >6 mo and experiencing sustained (>3 mo) CD4 cell recovery well above the age-specific target for initiation of prophylaxis: >100 cells/µL for children aged ≥6 yr and >200 cells/µL for children aged 2-5 yr. For children <2 yr of age, no specific recommendations for discontinuing MAC prophylaxis exist.