Several terms—nontuberculous mycobacteria (NTM), atypical mycobacteria, mycobacteria other than tuberculosis, and environmental mycobacteria—all refer to mycobacteria other than Mycobacterium tuberculosis, its close relatives (M. bovis, M. caprae, M. africanum, M. pinnipedii, M. canetti), and M. leprae. The number of identified species of NTM is growing and will continue to do so because of the use of DNA sequence typing for speciation. The number of known species currently exceeds 150. NTM are highly adaptable and can inhabit hostile environments, including industrial solvents.
NTM are ubiquitous in soil and water. Specific organisms have recurring niches, such as M. simiae in certain aquifers, M. fortuitum in pedicure baths, and M. immunogenum in metalworking fluids. Most NTM cause disease in humans only rarely unless some aspect of host defense is impaired, as in bronchiectasis, or breached, as by inoculation (e.g., liposuction, trauma). There are no known instances of human-to-human transmission of NTM. Because infections due to NTM are rarely reported to health agencies and because their identification is sometimes problematic, reliable data on incidence and prevalence are lacking. Disseminated disease denotes significant immune dysfunction (e.g., advanced HIV infection), whereas pulmonary disease, which is much more common, is highly associated with pulmonary epithelial defects but not with systemic immunodeficiency.
In the United States, the incidence and prevalence of pulmonary infection with NTM, mostly in association with bronchiectasis (Chap. 258), have for many years been several-fold higher than the corresponding figures for tuberculosis, and rates of the former are increasing among the elderly. Among patients with cystic fibrosis, who often have bronchiectasis, rates of clinical infection with NTM range from 3% to 15%, with even higher rates among older patients. Although NTM may be recovered from the sputa of many individuals, it is critical to differentiate active disease from commensal harboring of the organisms. A scheme to help with the proper diagnosis of pulmonary infection caused by NTM has been developed by the American Thoracic Society and is widely used. The bulk of nontuberculous mycobacterial disease in North America is due to M. kansasii, organisms of the M. avium complex (MAC), and M. abscessus.
In Europe, Asia, and Australia, the distribution of NTM in clinical specimens is roughly similar to that in North America, with MAC species and rapidly growing organisms such as M. abscessus encountered frequently. M. xenopi and M. malmoense are especially prominent in northern Europe. M. ulcerans causes the distinct clinical entity Buruli ulcer, which occurs throughout tropical zones, especially in western Africa. M. marinum is a common cause of cutaneous and tendon infections in coastal regions and among individuals exposed to fish tanks or swimming pools.
The true international epidemiology of infections due to NTM is hard to determine since the isolation of these organisms often is not reported and speciation often is not performed. The increasing ease of identification and speciation of these organisms should have a major impact on the description of their international epidemiology in the next few years.
Because exposure to NTM is essentially universal and disease is rare, it can be assumed that normal host defenses against these organisms must be strong and that otherwise healthy individuals in whom significant disease develops are highly likely to have specific susceptibility factors that permit NTM to become established, multiply, and cause disease. At the advent of HIV infection, CD4+ T lymphocytes were recognized as key effector cells against NTM; the development of disseminated MAC disease was highly correlated with a decline in CD4+ T lymphocyte numbers. Such a decrease has also been implicated in disseminated MAC infection in patients with idiopathic CD4+ T lymphocytopenia. Potent inhibitors of tumor necrosis factor α (TNF-α), such as infliximab, adalimumab, certolizumab, and etanercept, can neutralize this critical cytokine. The occasional result is severe mycobacterial or fungal infection; these associations indicate that TNF-α is a crucial element in mycobacterial control. However, in cases without the above risk factors, much of the genetic basis of susceptibility to disseminated infection with NTM is accounted for by specific mutations in the interferon γ (IFN-γ)/interleukin 12 (IL-12) synthesis and response pathways.
Mycobacteria are typically phagocytosed by macrophages, which respond with the production of IL-12, a heterodimer composed of IL-12p35 and IL-12p40 moieties that together make up IL-12p70. IL-12 activates T lymphocytes and natural killer cells through binding to its receptor (composed of IL-12Rβ1 and IL-12Rβ2/IL-23R), with consequent phosphorylation of STAT4. IL-12 stimulation of STAT4 leads to secretion of IFN-γ, which activates neutrophils and macrophages to produce reactive oxidants, increase expression of the major histocompatibility complex and Fc receptors, and concentrate certain antibiotics intracellularly. Signaling by IFN-γ through its receptor (composed of IFN-γR1 and IFN-γR2) leads to phosphorylation of STAT1, which in turn regulates IFN-γ-responsive genes, such as those coding for IL-12 and TNF-α. TNF-α signals through its own receptor via a downstream complex containing the nuclear factor κB (NFκB) essential modulator (NEMO). Therefore, the positive feedback loop between IFN-γ and IL-12/IL-23 drives the immune response to mycobacteria and other intracellular infections. These genes are known to be the critical ones in the pathway of mycobacterial control: specific Mendelian mutations have been identified in IFN-γR1, IFN-γR2, STAT1, IL-12A, IL-12Rβ1, and NEMO (Fig. 167-1). Despite the identification of genes associated with disseminated disease, only ∼50% of cases of disseminated nontuberculous mycobacterial infections that are not associated with HIV infection have a genetic diagnosis; the implication is that more mycobacterial susceptibility genes and pathways remain to be identified.
Cytokine interactions of infected macrophages (Mφ) with T and natural killer (NK) lymphocytes. Infection of macrophages by mycobacteria (AFB) leads to the release of heterodimeric interleukin 12 (IL-12). IL-12 acts on its receptor complex, with consequent STAT4 activation and production of homodimeric interferon γ (IFNγ). IFNγ acts through its receptor to activate STAT1, to stimulate the production of tumor necrosis factor α(TNFα), and to kill intracellular organisms such as mycobacteria, salmo-nellae, and some fungi. Homotrimeric TNFα acts through its receptor and requires nuclear factor κB essential modulator (NEMO) to activate nuclear factor κB, which also contributes to the killing of intracellular bacteria. Both IFNγ and TNFα lead to upregulation of IL-12. TNFα-blocking antibodies work either by blocking the ligand (infliximab, adalimumab, certolizumab) or by providing soluble receptor (etanercept). Mutations in IFNγR1, IFNγR2, IL-12p40, IL-12Rβ1, STAT1, and NEMO have been associated with a predisposition to mycobacterial infections. Other cytokines, such as IL-15 and IL-18, also contribute to IFNγ production. Signaling through the Toll-like receptor (TLR) complex and CD14 also upregulates TNFα production. LPS, lipopolysaccharide; NRAMP1, natural resistance-associated macrophage protein 1.
In contrast to the recognized genes and mechanisms associated with disseminated nontuberculous mycobacterial infection, the best-recognized underlying condition for pulmonary infection with NTM is bronchiectasis (Chap. 258). Most of the well-characterized forms of bronchiectasis, including cystic fibrosis, primary ciliary dyskinesia, STAT3-deficient hyper-IgE syndrome, and idiopathic bronchiectasis, have high rates of association with nontuberculous mycobacterial infection. The precise mechanism by which bronchiectasis predisposes to locally destructive but not systemic involvement is unknown.
Unlike disseminated or pulmonary infection, “hot-tub lung” represents pulmonary hypersensitivity to NTM—most commonly MAC organisms—growing in underchlorinated, often indoor hot tubs.
Disseminated MAC or M. kansasii infections in patients with advanced HIV infection are now uncommon in North America because of effective antimycobacterial prophylaxis and improved treatment of HIV infection. When such mycobacterial disease was common, the portal of entry was the bowel, with spread to bone marrow and the bloodstream. Surprisingly, disseminated infections with rapidly growing NTM (e.g., M. abscessus, M. fortuitum) are very rare in HIV-infected patients, even those with very advanced HIV infection. Because these organisms are of low intrinsic virulence and disseminate only in conjunction with impaired immunity, disseminated disease can be indolent and progressive over weeks to months. Typical manifestations of malaise, fever, and weight loss are often accompanied by organomegaly, lymphadenopathy, and anemia. Since special cultures or stains are required to identify the organisms, the most critical step in diagnosis is to suspect infection with NTM. Blood cultures may be negative, but involved organs typically have significant organism burdens, sometimes with a grossly impaired granulomatous response. In a child, disseminated involvement (i.e., involvement of two or more organs) without an underlying iatrogenic cause should prompt an investigation of the IFN-γ/IL-12 pathway. Recessive mutations in IFN-γR1 and IFN-γR2 typically lead to severe infection with NTM. In contrast, dominant negative mutations in IFN-γR1, which lead to overaccumulation of a defective interfering mutant receptor on the cell surface, inhibit normal IFN-γ signaling and thus lead to nontuberculous mycobacterial osteomyelitis. Dominant negative mutations in STAT1 and recessive mutations in IL-12Rβ1 can have variable phenotypes consistent with their residual capacities for IFN-γ synthesis and response. Male patients who have disseminated nontuberculous mycobacterial infections along with conical, peg, or missing teeth and an abnormal hair pattern should be evaluated for defects in the pathway that activates NFκB through NEMO. These patients may have associated immune globulin defects as well. A recently recognized group of patients that often develops disseminated infections with rapidly growing NTM (predominantly M. abscessus) as well as other opportunistic infections has high-titer neutralizing autoantibodies to IFN-γ. Thus far, this syndrome has been reported most frequently in East Asian female patients.
IV catheters can become infected with NTM, usually as a consequence of contaminated water. M. abscessus and M. fortuitum sometimes infect deep indwelling lines as well as fluids used in eye surgery, subcutaneous injections, and local anesthetics. Infected catheters should be removed.
Lung disease is by far the most common form of nontuberculous mycobacterial infection in North America and the rest of the industrialized world. The clinical presentation typically consists of months or years of throat clearing, nagging cough, and slowly progressive fatigue. Patients will often have seen physicians multiple times and received symptom-based or transient therapy before the diagnosis is entertained and samples are sent for mycobacterial stains and cultures. Because not all patients can produce sputum, bronchoscopy may be required for diagnosis. The typical lag between onset of symptoms and diagnosis is ∼5 years in older women. Predisposing factors include underlying lung diseases such as bronchiectasis (Chap. 258), pneumoconiosis (Chap. 256), chronic obstructive pulmonary disease (Chap. 260), primary ciliary dyskinesia (Chap. 258), alpha-1 antitrypsin deficiency (Chap. 309), and cystic fibrosis (Chap. 259). Bronchiectasis and nontuberculous mycobacterial infection often coexist and progress in tandem. This situation makes causality difficult to determine in a given index case, but bronchiectasis is certainly among the most critical predisposing factors that are exacerbated by infection.
MAC organisms are the most common causes of pulmonary nontuberculous mycobacterial infection in North America, but rates vary somewhat by region. MAC infection most commonly develops during the sixth or seventh decade of life in women who have had months or years of nagging intermittent cough and fatigue, with or without sputum production or chest pain. The constellation of pulmonary disease due to NTM in a tall and thin woman who may have chest wall abnormalities is often referred to as Lady Windermere's syndrome, after an Oscar Wilde character of the same name. In fact, pulmonary MAC infection does afflict older nonsmoking white women more than men, with onset at ∼60 years. Patients tend to be taller and thinner than the general population, with high rates of scoliosis, mitral valve prolapse, and pectus anomalies. Whereas male smokers with upper-lobe cavitary disease tend to carry the same single strain of MAC indefinitely, nonsmoking females with nodular bronchiectasis tend to carry several strains of MAC simultaneously, with changes over the course of their disease.
M. kansasii can cause a clinical syndrome that strongly resembles tuberculosis, consisting of hemoptysis, chest pain, and cavitary lung disease. The rapidly growing NTM, such as M. abscessus, have been associated with esophageal motility disorders such as achalasia. Patients with pulmonary alveolar proteinosis are prone to pulmonary nontuberculous mycobacterial and Nocardia infections; the underlying mechanism may be inhibition of alveolar macrophage function due to the autoantibodies to granulocyte-macrophage colony-stimulating factor found in these patients.
The most common form of nontuberculous mycobacterial infection among young children in North America is isolated cervical lymphadenopathy, most frequently caused by MAC organisms but also by other NTM. The cervical swelling is typically firm and relatively painless, with a paucity of systemic signs. Since the differential diagnosis of painless adenopathy includes malignancy, many children have infection with NTM diagnosed inadvertently at biopsy; cultures and special stains may not have been requested because mycobacterial disease was not ranked high in the differential. Local fistulae usually resolve completely with resection and/or antibiotic therapy. Likewise, the entity of isolated pediatric intrathoracic nontuberculous mycobacterial infection, which is probably related to cervical lymph node infection, is usually mistaken for cancer. In neither isolated cervical nor isolated intrathoracic infections with NTM have children with underlying immune defects been identified, nor do the affected children go on to develop other opportunistic infections.
Skin and Soft Tissue Disease
Cutaneous involvement with NTM usually requires a break in the skin for introduction of the bacteria. Pedicure bath–associated infection with M. fortuitum is more likely if skin abrasion (e.g., during leg shaving) has occurred just before the pedicure. Outbreaks of skin infection are often caused by rapidly growing NTM (especially M. abscessus, M. fortuitum, and M. chelonae) acquired via skin contamination from surgical instruments (especially in cosmetic surgery), injections, and other procedures. These infections are typically accompanied by painful, erythematous, draining subcutaneous nodules, usually without associated fever or systemic symptoms.
M. marinum lives in many water sources and can be acquired from fish tanks, swimming pools, barnacles, and fish scales. This organism typically causes papules or ulcers (“fish-tank granuloma”), but the infection can progress to tendonitis with significant impairment of manual dexterity. Lesions appear days to weeks after inoculation of organisms by a typically minor trauma (e.g., incurred during the cleaning of boats or the handling of fish). Tender nodules due to M. marinum can advance up the arm in a pattern also seen with Sporothrix schenckii (sporotricoid spread). The typical carpal tendon involvement may be the first presenting manifestation and may lead to surgical exploration or steroid injection. The index of suspicion must be high for M. marinum infections to ensure that proper specimens obtained during procedures are sent for culture.
M. ulcerans, another waterborne skin pathogen, is found mainly in the tropics, especially in tropical areas of Africa. Infection follows skin trauma or insect bites that allow admission to contaminated water. The skin lesions are typically painless, clean ulcers that slough and can cause osteomyelitis. The toxin mycolactone accounts for the modest host inflammatory response and the painless ulcerations.
NTM can be detected on acid-fast or fluorochrome smears of sputum or other body fluids. When the organism burden is high, the organisms may appear as gram-positive beaded rods, but this finding is unreliable. (In contrast, nocardiae may appear as gram-positive and beaded but filamentous bacteria.) Again, the requisite and most sensitive step in the diagnosis of any mycobacterial disease is to think of including it in the differential. In almost all laboratories, mycobacterial sample processing, staining, and culture are conducted separately from routine bacteriologic tests; thus many infections go undiagnosed because of the physician's failure to request the appropriate test. In addition, mycobacteria usually require separate blood culture media. NTM are broadly differentiated into rapidly growing (<7 days) and slowly growing (≥7 days) forms. Because M. tuberculosis typically takes ≥2 weeks to grow, many laboratories refuse to consider culture results final until 6 weeks have elapsed. Newer techniques using liquid culture media permit more rapid isolation of mycobacteria from specimens than is possible with traditional media. Species more readily detected with incubation at 30°C include M. marinum, M. haemophilum, and M. ulcerans. M. haemophilum prefers iron supplementation or blood, while M. genavense requires supplemented medium with the additive mycobactin J. Bacterial formation of pigment in light conditions (photochromogenicity) or dark conditions (scotochromogenicity) or a lack of bacterial pigment formation (nonchromogenicity) has been used to help categorize NTM. In contrast to NTM, M. tuberculosis is beige, rough, dry, and flat. Current identification schemes can reliably use biochemical, nucleic acid, or cell wall composition, as assessed by high-performance liquid chromatography or mass spectrometry, for speciation. With the remarkable decline in U.S. cases of tuberculosis over recent decades, NTM have become the mycobacteria most commonly isolated from humans in North America. However, not all isolations of NTM, especially from the lung, reflect pathology and require treatment. Whereas identification of an organism in a blood or organ biopsy specimen in a compatible clinical setting is diagnostic, the American Thoracic Society recommends that pulmonary infection due to NTM be diagnosed only when disease is clearly demonstrable—i.e., in an appropriate clinical and radiographic setting (nodules, bronchiectasis, cavities) and with repeated isolation of NTM from expectorated sputum or recovery of NTM from bronchoscopy or biopsy specimens. Given the large number of species of NTM and the importance of accurate diagnosis for the implementation of proper therapy, identification of these organisms is ideally taken to the species level.
The purified protein derivative (PPD) of tuberculin is delivered intradermally to evoke a memory T cell response to mycobacterial antigens. This test is variously referred to as the PPD test, the tuberculin skin test, and the Mantoux test, among other designations. Unfortunately, the cutaneous immune response to these tuberculosis-derived filtrate proteins does not differentiate well between infection with NTM and that with M. tuberculosis. Since intermediate reactions (∼10 mm) to PPD in latent tuberculosis and nontuberculous mycobacterial infections can overlap significantly, the progressive decline in active tuberculosis in the United States means that NTM probably account for increasing proportions of PPD reactivity. In addition, bacille Calmette-Guérin (BCG) can cause some degree of cross-reactivity, posing problems of interpretation for patients who have received BCG vaccine. Assays to measure the elaboration of IFN-γ in response to the relatively tuberculosis-specific proteins ESAT6 and CFP10 form the basis for IFN-γ-release assays (IGRAs). These assays can be performed with whole blood or on membranes. It is important to note that M. marinum, M. kansasii, and M. szulgai also have ESAT6 and CFP10 and may cause false-positive reactions in IGRAs. Despite cross-reactivity with NTM, large PPD reactions (>15 mm) most commonly signify tuberculosis.
Isolation of NTM from blood specimens is clear evidence of disease. Whereas rapidly growing mycobacteria may proliferate in routine blood culture media, slow-growing NTM typically do not; thus it is imperative to suspect the diagnosis and to use the correct bottles for cultures. Isolation of NTM from a biopsy specimen constitutes strong evidence for infection, but cases of laboratory contamination do occur. Identification of organisms on stained sections of biopsy material confirms the authenticity of the culture. Certain NTM require lower incubation temperatures (M. genavense) or special additives (M. haemophilum) for growth. Some NTM (e.g., M. tilburgii) remain noncultivable but can be identified molecularly in clinical samples.
The radiographic appearance of nontuberculous mycobacterial disease in the lung depends on the underlying disease, the severity of the infection, and the imaging modality used. The advent and increase in the use of CT has allowed the identification of characteristic changes that are highly consistent with nontuberculous mycobacterial infection, such as the “tree-in-bud” pattern of bronchiolar inflammation (Fig. 167-2). Involvement of the lingual and right-middle lobes is commonly seen on chest CT but is difficult to appreciate on plain film. Severe bronchiectasis and cavity formation are common in more advanced disease. Isolation of NTM from respiratory samples can be confusing. M. gordonae is often recovered from respiratory samples but is not usually seen on smear and is almost never a pathogen. Patients with bronchiectasis occasionally have NTM recovered from sputum culture with a negative smear. The American Thoracic Society has developed guidelines for the diagnosis of infection with MAC, M. abscessus, and M. kansasii. A positive diagnosis requires the growth of NTM from two of three sputum samples, regardless of smear findings; a positive bronchoscopic alveolar sample, regardless of smear findings; or a pulmonary parenchymabiopsy sample with granulomatous inflammation or mycobacteria found on section and NTM on culture. These guidelines probably apply to other NTM as well.
Chest CT of a patient with pulmonary MAC infection. Arrows indicate the "tree-in-bud" pattern of bronchiolar inflammation (peripheral right lung) and bronchiectasis (central right and left lungs).
While many laboratories use DNA probes to identify M. tuberculosis, MAC, M. gordonae, and M. kansasii, speciation of NTM helps determine the antimycobacterial therapy to be used. Only testing of MAC organisms for susceptibility to clarithromycin and of M. kansasii for susceptibility to rifampin is indicated; few data support other in vitro susceptibility tests, attractive though they appear. MAC isolates that have not been exposed to macrolides are almost always susceptible. NTM that have persisted beyond a course of antimicrobial therapy are often tested for antibiotic susceptibility, but the value and meaning of these tests are undetermined.
Prophylaxis of MAC disease in patients infected with HIV is started when the CD4+ T lymphocyte count falls to <50/μL. Azithromycin (1200 mg weekly), clarithromycin (1000 mg daily), or rifabutin (300 mg daily) is effective. Macrolide prophylaxis in immunodeficient patients who are susceptible to NTM (e.g., those with defects in the IFN-γ/IL-12 axis) has not been prospectively validated but seems prudent.
Treatment: Nontuberculous Mycobacteria
NTM cause chronic infections that evolve relatively slowly over a period of weeks to years. Therefore, it is rarely necessary to initiate treatment on an emergent basis before the diagnosis is clear and the infecting species is known. Treatment of NTM is complex, often poorly tolerated, and potentially toxic. Just as in tuberculosis, inadequate single-drug therapy is almost always associated with the emergence of antimicrobial resistance and relapse.
MAC infection often requires multidrug therapy, the foundation of which is a macrolide (clarithromycin or azithromycin), ethambutol, and a rifamycin (rifampin or rifabutin). For disseminated nontuberculous mycobacterial disease in HIV-infected patients, the use of rifamycins poses special problems—i.e., rifamycin interactions with protease inhibitors. For pulmonary MAC disease, thrice-weekly administration of a macrolide, a rifamycin, and ethambutol has been successful. Therapy is prolonged, generally continuing for 12 months after culture conversion; typically, a course lasts for at least 18 months. Other drugs with activity against MAC organisms include IV and aerosolized aminoglycosides, fluoroquinolones, and clofazimine. In elderly patients, rifabutin can exert significant toxicity. However, with only modest efforts, most antimycobacterial regimens are well tolerated by most patients. Resection of cavitary lesions or severely bronchiectatic segments has been advocated for some patients, especially those with macrolide-resistant infections. The success of therapy for pulmonary MAC infections depends on whether disease is nodular or cavitary and on whether it is early or advanced, ranging from 20% to 80%.
M. kansasii lung disease is similar to tuberculosis in many ways and is also effectively treated with isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg per day). Other drugs with very high-level activity against M. kansasii include clarithromycin, fluoroquinolones, and aminoglycosides. Treatment should continue until cultures have been negative for at least 1 year. In most instances, M. kansasii infection is easily cured.
Rapidly growing mycobacteria pose special therapeutic problems. Extrapulmonary disease in an immunocompetent host is usually due to inoculation (e.g., via surgery, injections, or trauma) or to line infection and is often treated successfully with a macrolide and another drug (with the choice based on in vitro susceptibility), along with removal of the offending focus. In contrast, pulmonary disease, especially that caused by M. abscessus, is extremely difficult to cure. Repeated courses of treatment are usually effective in reducing the infectious burden and symptoms. Therapy generally includes a macrolide along with an IV-administered agent such as amikacin, a carbapenem, cefoxitin, or tigecycline. Other oral agents (used according to in vitro susceptibility testing and tolerance) include fluoroquinolones, doxycycline, and linezolid. Because nontuberculous mycobacterial infections are chronic, care must be taken in the long-term use of drugs with neurotoxicities, such as linezolid and ethambutol. Prophylactic pyridoxine has been suggested in these cases. Durations of therapy for M. abscessus lung disease are difficult to predict since so many cases are chronic and require intermittent therapy. Expert consultation and management are strongly recommended.
Once recognized, M. marinum infection is highly responsive to antimicrobial therapy and is cured relatively easily with any combination of a macrolide, ethambutol, and a rifamycin. Therapy should be continued for 1–2 months after clinical resolution of isolated soft tissue disease; tendon and bone involvement may require longer courses in light of clinical evolution. Other drugs with activity against M. marinum include sulfonamides, trimethoprim-sulfamethoxazole, doxycycline, and minocycline.
Treatment of the other NTM is less well defined, but macrolides and aminoglycosides are usually effective, with other agents added as indicated. Expert consultation is strongly encouraged for difficult or unusual infections due to NTM.
The outcomes of nontuberculous mycobacterial infections are closely tied to the underlying condition (e.g., IFN-γ/IL-12 pathway defect, cystic fibrosis) and can range from recovery to death. With no or inadequate treatment, symptoms and signs can be debilitating, including persistent cough, fever, anorexia, and severe lung destruction. With treatment, patients typically regain strength and energy. The optimal duration of therapy when NTM persist in sputum is unknown, but treatment in this situation can be prolonged.