CHAPTER 76: NONTUBERCULOUS MYCOBACTERIAL INFECTIONS

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 few instances of human-to-human transmission of NTM, which occurs almost exclusively in cystic fibrosis. 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. 23), 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 because the isolation of these organisms often is not reported and speciation often is not performed for M. tuberculosis and NTM. The increasing ease of identification and speciation of these organisms is likely to 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, golimumab, 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, to increase expression of the major histocompatibility complex and Fc receptors, and to 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 (NF-κB) 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, GATA2, ISG15, IRF8, IL-12A, IL-12Rβ1, IL-12Rβ2, CYBB, and NEMO (Fig. 76-1). Despite the identification of genes associated with disseminated disease, only ~70% 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.

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. 23). 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 disease

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. Because 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 produce 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 NF-κB through NEMO. These patients may have associated immune globulin defects as well. Patients with myelodysplasia and mycobacterial disease should be investigated for GATA2 deficiency. 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.

Pulmonary disease

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. 23), pneumoconiosis, chronic obstructive pulmonary disease, primary ciliary dyskinesia, α₁ antitrypsin deficiency, and cystic fibrosis. 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 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.

Cervical lymph nodes

The most common form of nontuberculous mycobacterial infection among young children in North America is isolated cervical lymphadenopathy, caused most frequently by MAC organisms but also by other NTM. The cervical swelling is typically firm and relatively painless, with a paucity of systemic signs. Because 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 tendinitis 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 for M. marinum infections must be high 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, whereas 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 colonies, M. tuberculosis colonies are 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. Because 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 computed tomography (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. 76-2). 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 parenchyma biopsy sample with granulomatous inflammation or mycobacteria found on section and NTM found on culture. These guidelines probably apply to other NTM as well.

Although 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.

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.

In many countries, pulmonary tuberculosis is diagnosed by smear alone, which is also the method used for monitoring of response and relapse. However, examination of mycobacteria from the affected patients shows that a significant proportion of isolates are actually NTM. Overall, as rates of tuberculosis decline, the proportion of positive smears caused by NTM will increase. Advances in speciation will distinguish tuberculosis from nontuberculous mycobacterial infections and thereby affect rates of assumed relapse and resistance, leading to more targeted and appropriate therapy.