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* From the Division of Respiratory Medicine, University of Calgary Medical School and Tuberculosis Services, Calgary Health Region, Calgary, AB, Canada.
Correspondence: Stephen K. Field, MD, FCCP, Room 1410, Health Science Centre, 3330 Hospital Dr NW, Calgary, AB, Canada T2N 4N1; e-mail: sfield{at}ucalgary.ca
Abstract
As the prevalence of tuberculosis (TB) declines in the developed world, the proportion of mycobacterial lung disease due to nontuberculous mycobacteria (NTM) is increasing. It is not clear whether there is a real increase in prevalence or whether NTM disease is being recognized more often because of the introduction of more sensitive laboratory techniques, and that more specimens are being submitted for mycobacterial staining and culture as the result of a greater understanding of the role of NTM in conditions such as cystic fibrosis, posttransplantation and other forms of iatrogenic immunosuppression, immune reconstitution inflammatory syndrome, fibronodular bronchiectasis, and hypersensitivity pneumonitis. The introduction of BACTEC liquid culture systems (BD; Franklin Lakes, NJ) and the development of nucleic acid amplification and DNA probes allow more rapid diagnosis of mycobacterial disease and the quicker differentiation of NTM from TB isolates. High-performance liquid chromatography, polymerase chain reaction, and restriction fragment length polymorphism analysis have helped to identify new NTM species. Although treatment regimens that include the newer macrolides are more effective than the earlier regimens, failure rates are still too high and relapse may occur after apparently successful therapy. Moreover, treatment regimens are difficult to adhere to because of their long duration, adverse effects, and interactions with the other medications that these patients require. The purpose of this article is to review the common presentations of NTM lung disease, the conditions associated with NTM lung disease, and the clinical features and treatment of the NTM that most commonly cause lung disease.
Key Words: environmental mycobacteria • Mycobacterium abscessus • Mycobacterium avium • Mycobacterium fortuitum • Mycobacterium gordonae • Mycobacterium kansasii • Mycobacterium malmoense • Mycobacterium xenopi • nontuberculous mycobacteria • tuberculosis
Nontuberculous mycobacteria (NTM) is the term used to distinguish environmental mycobacteria from the mycobacteria that cause leprosy, Mycobacterium leprae, and tuberculosis (TB) [Mycobacterium tuberculosis].123 NTM are environmental organisms found primarily in water, both natural and tap water, but are also found in soil, dust, animals, and food.45 Mycobacteria benefit from water chlorination and ozonization that preferentially kill other bacteria that grow more quickly and compete with them for nutrients.6 The relatively slow growth of the mycobacterial species and their relatively impermeable cell walls, due to the presence of long-chain mycolic fatty acids, contribute to their resistance to chlorination.6 In most places, Mycobacterium avium complex (MAC) is the most common cause of NTM lung disease, but lung disease due to other NTM including Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium abscessus, and Mycobacterium xenopi also occurs.78910
Unlike M tuberculosis and M leprae, NTM are not obligate pathogens and do not normally cause disease in humans, nor is there evidence of person-to-person transmission. They are opportunistic free-living organisms that cause disease if host defenses are impaired, or if skin or mucosal barriers are disrupted. They most commonly cause skin and soft-tissue infections, lymphadenitis, and lung disease.1112 Disseminated infection may occur in patients with AIDS, and in patients with interleukin (IL)-12 and interferon (IFN)-
receptor abnormalities.131415161718192021222324 This article will review the common presentations of NTM lung disease, conditions associated with NTM lung disease, and clinical features and treatment of the NTM that most commonly cause lung disease.
Epidemiology
With the advent of effective treatment for TB in the 1950s, mycobacterial specimens began to be routinely cultured, and it was recognized that some of the apparent cases of TB were due to NTM.25 The prevalence of TB has declined in the developed world, and the proportion of mycobacterial disease due to NTM has increased. Surveys2627282930313233343536 have identified human disease due to NTM in most parts of the world. The paucity of reports of NTM disease from the developing world likely reflects the fact that mycobacterial specimens are presumed to be TB and are not routinely cultured. Moreover, TB is more prevalent in the developing world, and AIDS patients usually die of TB or other infections before their CD4+ counts fall low enough for NTM disease to develop.37
It is not clear whether there is a true increase in the prevalence of NTM lung disease in immunocompetent patients. The changing prevalence of NTM disease is usually estimated from the frequency of NTM cultures in microbiology laboratories, since disease due to NTM is not reportable in most jurisdictions. Laboratory surveys7891012 have shown increases in the number of NTM isolates. The use of both liquid (BACTEC; BD; Franklin Lakes, NJ) and solid media for mycobacterial culture has increased the diagnostic yield from human specimens, accounting for some of the increased recognition of NTM lung disease.38
NTM were estimated to account for 1 to 2% of the apparent cases of TB in the 1950s and 1960s.3940 The Centers for Disease Control and Prevention (CDC) reported that one third of mycobacterial isolates in the United States were NTM in 1979 to 1980.41 In Philadelphia during the 1980s, the prevalence of TB declined and the prevalence of NTM increased.42 The ratio of TB to NTM isolates declined from 3.2:1 between 1976 and 1981 to 1:1.6 between 1986 and 1991 in a South Carolina community hospital.43 The reported prevalence of NTM lung disease has increased in other countries too.444546474849 In most countries, MAC is the most common NTM isolated from sputum and lung specimens.78910
Some of the apparent increase can be explained by the greater awareness of NTM as a cause of disease in conditions such as fibronodular bronchiectasis and cystic fibrosis (CF), and the greater likelihood of specimens being collected for mycobacterial culture.5051 Other reasons offered to explain why the prevalence of NTM disease might increase in immunocompetent individuals include reduced immunity to mycobacteria in the population because of the reduced prevalence of TB and bacille Calmette-Guérin (BCG) vaccination, and greater exposure to NTM, primarily MAC, due to changes in personal hygiene habits from bathing to showering.525354 NTM are frequently present in tap water and are readily aerosolized in shower heads. Moreover, aerosolization concentrates the organisms, and they remain viable in aerosols.55
Some surveys78910 suggest that the prevalence of MAC lung disease has increased relative to other NTM. Its higher innate resistance to chlorination and ozonization compared to other NTM may explain the greater prevalence of disease due to MAC.6 The other more frequently isolated pathogens in patients with NTM lung disease are M kansasii, M malmoense, M xenopi, and the rapidly growing mycobacteria (RGM) M abscessus and Mycobacterium fortuitum. Mycobacterium gordonae is the second-most-commonly isolated NTM from respiratory specimens but rarely causes disease.9
Patterns in Lung Disease
Cavitary Lung Disease
The earliest recognized pattern of NTM lung disease was cavitary disease, predominantly involving the upper lobes, similar to the pulmonary TB seen in sanitarium patients.394056 Patients with NTM lung disease tended to be older than TB patients and were not infectious for family members or staff.39 They were predominantly male, often with a history of tobacco and/or alcohol abuse, and usually had underlying lung disease.2657 Patients are usually symptomatic, but it is hard to distinguish whether symptoms are due to the underlying lung disease or to the NTM infection. They experience cough and sputum production, but shortness of breath, hemoptysis, and systemic symptoms including fatigue, lassitude, weight loss, fever, and night sweats may occur, especially with advanced disease. NTM lung disease can progress to respiratory failure and death.
Fibronodular Bronchiectasis
Christensen et al58 reported that 12% of patients with MAC demonstrated a reticular, fibrotic radiograph pattern rather than cavitary disease. Ahn et al59 reported the radiologic features of patients with persistently positive sputum culture findings for either M kansasii or MAC. A minority, 43 of 226 MAC patients (19%) and 13 of 271 patients (5%) with M kansasii, had a radiologic pattern consistent with opacification and fibrosis but without cavitation (Fig 1
).59 Prince et al42 reported that 15 of 21 patients without preexisting lung disease or immunosuppression had fibronodular bronchiectasis in the absence of cavitation. Field and Cowie60 reported that all 30 patients with MAC lung disease had fibronodular bronchiectasis. Only 25% of the patients with sputum culture findings that repeatedly showed NTM, primarily MAC, had cavitary disease documented with high-resolution CT (HRCT).61 The increased proportion of fibronodular bronchiectasis is probably due to greater recognition of the condition but may also be due to a decrease in the numbers of patients with lung disease due to previous tuberculosis.
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Hypersensitivity Pneumonitis
A syndrome indistinguishable from hypersensitivity pneumonitis (HP) has been described in patients exposed to solutions that contain NTM.65666768697071727374757677 Granulomatous lung disease develops in some patients after exposure to hot tubs that contain MAC (Fig 2
).65666768697071727374 Approximately 50 cases of a condition termed hot tub lung have been published. Some patients have recovered without any specific therapy, but others have been treated with steroids, antibiotics, and combinations of steroids and antibiotics. Avoidance of further exposure is the most important intervention.78 Two cases in our practice were treated with steroids, and the patients completely recovered; another patient recovered by avoiding further hot tub exposure without steroid or antimycobacterial therapy.72 The observational study design of these reports precludes determining which, if any, treatment is best. HP may also develop in lifeguards working at indoor swimming pools.5 A similar syndrome has been described in metal grinding workers exposed to aerosols of metalworking fluid that contain Mycobacterium immunogenum, an RGM closely related to M abscessus.7677
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CF
NTM infection was first reported in a patient with CF in 1980.84 Overgrowth of mycobacterial cultures by other more rapidly growing bacteria in the sputum of patients with CF can lead to an underestimate of the true prevalence of NTM. To prevent this, specimens are treated with oxalic acid in addition to the traditional decontamination protocol.11 More recently, centers in Europe and the United States have reported prevalences of NTM between 4% and 20% in patients with CF.858687 The prevalence of NTM infection increases with age.8688 An American multicenter trial87 of CF patients 
10 years old found that 13% had provided a minimum of one sputum specimen that grew NTM on culture. MAC was grown in 72% and M abscessus was grown in 16% of the NTM cultures. Patients with NTM-positive sputum culture findings tended to be older, had relatively preserved pulmonary function, and were more likely to have Staphylococcus aureus and less likely to have Pseudomonas aeruginosa cultured from their sputum. CF patients in Israel who were treated with systemic steroids or whose CF was complicated by allergic bronchopulmonary aspergillosis were more likely to have NTM cultured from their sputum.89 Over 15 months, CF patients whose sputum had grown NTM had greater progression of their pulmonary parenchymal disease than the other CF patients, as determined by CT scanning.90
Bronchiectasis
The relationship between bronchiectasis and NTM is complex. Bronchiectasis is both a risk for and a consequence of NTM infection.51 Patients with bronchiectasis may have NTM colonization or infection; and NTM infection, especially MAC and M abscessus, can cause bronchiectasis.61 Bronchiectasis usually most severely affects the lower lobes and begins early in life, often in childhood. Its prevalence has declined since immunization for pertussis became routine.5191 Fibronodular bronchiectasis caused by MAC usually occurs in women > 60 years old and tends to most severely involve the lingula and the right middle lobe.42 It has been suggested that MAC causes peribronchial inflammation and thickening that may progress to severe cystic bronchiectasis.92
Chest Wall Disorders
Patients with MAC lung disease were compared to patients with pulmonary TB to investigate the observation that chest wall disorders were more common.9394 The overall prevalence of chest wall abnormalities including pectus excavatum and scoliosis was significantly greater in patients with MAC lung disease, 70% vs 18%, and was considerably greater than in the normal population.93 When the patients were analyzed by gender, the differences in the prevalence of chest wall abnormalities were statistically significant in women. Although chest wall abnormalities were twice as common in men with MAC compared to men with TB, the numbers were too small to show a statistically significant difference.93
PAP
In a report95 from North Carolina, 8 of 19 patients with PAP had lung lavage specimens that grew MAC. All had a smoking history. None required treatment for MAC, and their prognoses did not appear to be worse than the other PAP patients.95 The idiopathic variant accounts for 90% of the cases of PAP, and is associated with high titers of autoantibody to granulocyte macrophage-colony stimulating factor. Normally, granulocyte macrophage-colony stimulating factor stimulates the maturation of macrophages, but in PAP maturation does not proceed normally.96 Both mycobacterial and surfactant clearance in the lung depend on normal macrophage function, which may explain why these patients have MAC colonization.
NTM Lung Disease in Immunocompromised Patients
Transplantation
Infection with NTM has been reported in patients after solid-organ and hematopoietic stem-cell transplantation. Fortunately, NTM are not common in transplant recipients since drug interactions occur between the antibiotics used to treat NTM and the immunosuppressive medications.97
Pleuropulmonary infections were the most common type in lung transplant patients, accounting for 55% of the NTM infections; and MAC (32%) was the most common NTM isolated, followed by M abscessus (26%) and Mycobacterium hemophilum (18%).98 At an Australian center, 7% of patients undergoing lung or heart-lung transplantation acquired pulmonary NTM infection, primarily MAC, requiring treatment.99 This is considerably higher than the estimated prevalence of 8 per 100,000 in the community. The prevalence was 2.9% in a contemporaneous report100 from Chicago.
In renal transplant recipients, cutaneous and disseminated NTM disease were more common than pleuropulmonary disease, and infection with RGM and with M kansasii occurred more frequently than MAC disease.98 Two cases of M kansasii empyema have been reported.101 A recent American study102 confirmed that NTM infections were relatively unusual after renal transplantation. Among approximately 4,000 kidney transplants, NTM infections developed in 15 patients: 5 patients with MAC, 2 patients with M chelonae, 1 patient each with M fortuitum and Mycobacterium scrofulaceum, and the remainder were not characterized beyond "atypical" mycobacterium. Only five cases of NTM lung disease, all due to M kansasii, were identified in a cohort of 1,261 Spanish renal transplant patients.103 M hemophilum was the next most-frequent cause of NTM infection after M kansasii and Mycobacterium chelonae in renal transplants.98 Several renal transplant recipients with M xenopi lung disease have also been reported.103104
Catheter-related infections were the most common presentation of NTM disease (36%) but were closely followed by lung infections (30%) in hematopoetic stem-cell transplant recipients.98 MAC was the most common organism in patients with pulmonary NTM infection, whereas RGM were the most common cause of catheter-related NTM infections.98 NTM were cultured from 56 of 577 adult patients (9.7%) undergoing allogeneic stem-cell transplantation at Sloan-Kettering Cancer Center between 1993 and 2001.105 MAC was isolated in 15 of the 18 patients who met the American Thoracic Society (ATS) diagnostic criteria for NTM lung disease,11 and was the organism identified in 18 of 22 patients with positive NTM culture results from the respiratory tract but who did not meet the ATS criteria.105 Some of the apparent difference in prevalence between the different reports probably reflects geographic differences in NTM prevalence and differences in the prevalence of BCG vaccination and TB in the different populations.5253
Anti-Tumor Necrosis Factor Antagonists
Granulomatous inflammation accompanies control of infections due to intracellular pathogens including M tuberculosis, Listeria monocytogenes, Histoplasma capsulatum, and NTM.106107 Tumor necrosis factor (TNF)-
is a proinflammatory cytokine with a variety of actions, including the activation of macrophages and lymphocytes and the development and maintenance of granulomatous inflammation.108109 The TNF- antagonists infliximab and etanercept interfere with granuloma formation and are used to treat rheumatoid arthritis and Crohn disease, and have been used in a variety of other inflammatory conditions including other collagen diseases and sarcoidosis.106 Infections with intracellular pathogens, particularly TB, have been reported in patients treated with TNF- antagonists.107110 Iatrogenic immunosuppression with TNF- antagonists has also been reported to be a risk factor for NTM infection.107 The risk of infection is 2.1-fold greater with infliximab than with etanercept.107
HIV Infection
HIV infection causes a constellation of T-cell immune defects that predispose patients to disseminated NTM disease, usually when the CD4+ count is < 50/µL.111112 Fever, night sweats, anorexia, and weight loss are the most common symptoms in patients with disseminated MAC infection.111 Widespread involvement of the reticuloendothelial system is manifested by lymphadenopathy, hepatosplenomegaly, and anemia that may be severe enough to require repeated transfusions.111113 Paradoxically, patients with disseminated disease rarely have clinically important pulmonary disease.114 Among 1,071 French patients with HIV, 24 patients had disseminated M avium infection and 5 patients had M avium lung disease without dissemination.114 M avium is the most common cause of disseminated disease in the HIV population, but other NTM may also cause disseminated disease.112
M kansasii is more common in patients with HIV infection than in the non-HIV population, and an isolate from a respiratory specimen is more likely to represent infection and should be treated.115 In patients with HIV and M kansasii coinfection, a low CD4+ count and positive sputum smear results were associated with a poor prognosis; treatment, both for M kansasii infection and highly active antiretroviral therapy (HAART), improved survival.82116 Patients with AIDS and disseminated MAC can have culture-positive sputum in the absence of clinical lung disease.11 In contrast to the experience with MAC, patients with HIV and M kansasii infection are more likely to have lung disease without dissemination.116117 This likely reflects the fact that M kansasii is more pathogenic than MAC and, like TB, causes disease in patients with less immunosuppression. In South African gold miners, the median CD4+ count was 381 x 106/L in HIV patients presenting with M kansasii.118119120
There are important considerations to treating M kansasii infection in patients who are also receiving HAART. Both rifampin and rifabutin increase the clearance of the nucleoside reverse transcriptase inhibitors and the protease inhibitors, and may facilitate the development of HIV resistance to these drugs.121 The protease inhibitors also inhibit the metabolism of the rifamycins, increasing the risk of toxicity.121 M xenopi lung disease has also been reported in AIDS patients without concomitant disseminated disease.122 M xenopi, however, can also cause disseminated disease.114
Immune Reconstitution Inflammatory Syndrome
In the HIV population, NTM is a common cause of immune reconstitution inflammatory syndrome (IRIS). HAART has improved the prognosis of patients living with AIDS, but some experience a clinical deterioration and even death after beginning therapy.123124 Paradoxically, patients may experience a progression of symptoms associated with worsening lymphadenopathy, pulmonary infiltrates, and pleural effusions after beginning HAART.125 The fall in blood HIV RNA levels and the return of immune function, including an increase in CD4+ lymphocytes, restore the capacity to mount an inflammatory reaction to both infectious and noninfectious antigens; and patients with coinfection with other organisms, most commonly TB, MAC, or Cryptococcus neoformans, may experience clinical deterioration.126127128
M avium is the most common cause of IRIS due to NTM. In a recent report129 from Vancouver, Canada, 3.5% of HIV patients with a baseline CD4+ count <100/µL started on HAART acquired IRIS due to NTM. Among the 51 patients in their series, peripheral lymphadenitis, pulmonary intrathoracic disease, and intra-abdominal disease were the main clinical presentations occurring in 17, 15, and 13 patients, respectively. Six patients had disease at other sites. Other pathogens associated with IRIS include Pneumocystis jirovecki, M leprae, histoplasmosis, hepatitis B and C, Herpes simplex, Herpes zoster, Kaposi human herpes virus, and Papilloma virus.128 Latent or subclinical infection is believed to be responsible for most cases in which an infectious agent is not recognized, but some cases may be due to noninfectious inflammatory conditions such as sarcoidosis or autoimmune disease.126127 Patients with an opportunistic infection soon after initiation of HAART and patients with a more rapid decline in viral load are more likely to acquire IRIS.124 The median CD4+ counts were 20/µL at the time of initiation of HAART and 120/µL when IRIS was diagnosed.129 Histologically, the granulomatous inflammation seen in IRIS is not usually seen in AIDS, suggesting that the syndrome is due to restoration of the immune system.126 It is important to recognize IRIS as the cause of the clinical deterioration to avoid unnecessary invasive investigations for a possible coinfection.126127 Patients with milder cases may be observed without specific treatment for IRIS or treated with nonsteroidal anti-inflammatory medications. More serious cases will require corticosteroid therapy.116 Nine of the 51 patients in the Vancouver report129 were treated with steroids, and 8 responded favorably.
Laboratory
Patients with suspected NTM lung disease should submit a minimum of three sputum specimens in sterile disposable containers to be stained and cultured for mycobacteria.1112 Fluorochrome staining is preferred because it can be done more rapidly, and it is a more sensitive technique to identify mycobacteria than carbolfuchsin staining.130 Nucleic acid amplification techniques rapidly distinguish TB from NTM in both smear-positive and smear-negative respiratory specimens.130
In general, the processing of specimens for NTM is similar to that for suspected TB.11 Suspected NTM specimens are also treated with a solution of N acetylcysteine and sodium hydroxide (NaOH), followed by oxalic acid, to prevent overgrowth of P aeruginosa that may be present in patients with concomitant bronchiectasis. Similar to suspected TB cases, all respiratory specimens should also be cultured in both liquid and solid media.1112 Traditional culture methods show detectable growth, with most slowly growing NTM only after 3 to 6 weeks on solid media, and after 1 to 2 weeks in liquid media.11 Some species take even longer to show detectable growth.11130 BACTEC automated radiometric systems that incorporate carbon 14-labeled palmitate demonstrate higher recovery rates and faster detection times for mycobacteria than other liquid systems.131132 Radiolabeled carbon dioxide production from the palmitate is proportional to mycobacterial growth. Despite the superiority over solid media, it is recommended that specimens be cultured on both solid and liquid media because some isolates will only grow on the solid media.132 More recent BACTEC systems eliminate the need for sharp instruments for inoculation and replace the radioactive labels with fluorescent probes.132 Biphasic culture systems with both solid and liquid media are also commercially available.130
Traditionally, the identification of different mycobacterial species was based on their growth characteristics and biochemical testing. M tuberculosis, but not NTM, produce niacin, heat-sensitive catalase, and nitrate reductase. Species identification required a further 3 to 6 weeks or more after detectable growth was present, and could only be applied once there was sufficient growth from the NTM specimen on solid media.133 The para-nitro- acetylamino-ß hydroxypropiophenone test can be applied on cultured material to differentiate the TB complex species, which it inhibits, from the NTM, but it may take 3 to 5 days to complete.134
Commercial DNA probes that target ribosomal RNA are available that allow rapid identification of TB, MAC, M avium, Mycobacterium intracellulare, M gordonae, and M kansasii from cultured specimens within several hours with a > 90% accuracy.135 Other techniques to identify NTM include high-performance liquid chromatography (HPLC), and genetic techniques directed at the 65-kd heat shock protein genes and the 16S ribosomal RNA. These include amplification, probe hybridization, restriction fragment length polymorphism (RFLP) analysis, and DNA sequencing.
Most laboratories report the closely related species M avium and M intracellulare as MAC,136 but their distribution is different in patients with AIDS than in patients without HIV infection. Beggs et al137 found that 85% of the NTM isolates from HIV-positive patients were M avium, and 86% of the isolates from HIV-negative patients were M intracellulare. A similar distribution, predominately M avium in HIV-positive patients and M intracellulare in HIV-negative patients, has been reported from other centers in the United States, Europe, and Japan.138139140141 Most clinical laboratories do not use species-specific probes, since the kits are expensive and treatment is the same for the two species.137
RFLP can be used to identify all NTM species.5 RFLP and polymerase chain reaction have helped distinguish the members of MAC from closely related species such as M scrofulaceum, and can distinguish among members of the MAC including M intracellulare and the M avium subspecies M avium avium and M avium silvaticum that infect birds; M avium paratuberculosis, which is responsible for reproductive system, mammary gland, and gut infections in both wild and domestic ruminants, also known as Johne disease; and M avium hominissuis, which causes mycobacterial infections in humans and swine.133142
HPLC is also a reliable method to distinguish mycobacterial species.143 One comparative study144 with DNA probes found a 100% specificity and 99% sensitivity for identification of M tuberculosis. The results of HPLC are not as good to identify NTM. A recent comparative study145 of HPLC and polymerase chain reaction found discrepant results in 14% of 83 NTM samples; the discrepancy in 4% was due to polymycobacterial infection.
Susceptibility testing is only recommended for NTM isolates that are clinically significant. Susceptibility testing against clarithromycin is recommended for MAC isolates.146147 The recommendations are to avoid routine susceptibility testing with other antimicrobials, since the results do not correlate with the clinical response to treatment.148 Moreover, isolates may be more susceptible to combinations than to the individual antimycobacterials.149150 It is important to recognize that HIV patients may have polyclonal MAC infections, since the different isolates may have different drug susceptibility profiles.151
Susceptibility testing to rifampin is recommended for M kansasii isolates, since resistance predicts treatment failure.146147 Susceptibility testing to isoniazid, ethambutol, streptomycin, clarithromycin, amikacin, ciprofloxacin, cotrimoxazole, and rifabutin is recommended only for M kansasii isolates that are resistant to rifampin.147 The same primary and secondary drugs and concentrations should be used to test M xenopi, M malmoense, and M simiae isolates that are clinically significant. M gordonae isolates are usually not clinically significant. RGM have variable antimicrobial susceptibility profiles, and clinically significant isolates should be tested against amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, and cotrimoxazole.147
Diagnosis
Clinical suspicion and requesting that respiratory specimens be stained and cultured for mycobacteria are the first steps in the diagnosis of NTM lung disease. Whenever mycobacterial disease is considered, it is important rule out pulmonary TB. In patients without HIV infection, those with pulmonary TB are more likely to have systemic symptoms, such as fever, night sweats, and weight loss, and hemoptysis; but patients with more advanced NTM lung disease may have similar symptoms.42 Features that suggest TB include a history of a positive TB skin test result and history of residence in an endemic area, and it is less likely if patients were treated for latent TB infection.152 Other features that suggest TB, such as upper-lobe disease and cavitation, are not helpful in distinguishing TB from NTM lung disease.152 The laboratory methods to distinguish TB from NTM were discussed in the previous section.
The diagnosis of NTM lung disease should be considered in patients with bronchiectasis, especially those with involvement of the right middle lobe and lingula.153154 It should be considered in patients with structural lung disease who remain symptomatic despite treatment of their underlying condition, especially those who continue to cough or demonstrate progressive parenchymal changes on chest radiograph or CT.
Tuberculin skin testing is the traditional method to screen for TB. Unfortunately, patients who have received BCG vaccination or were sensitized to NTM may have a false-positive response to purified protein derivative, reducing its specificity. Serologic tests have been used in the past but are neither sensitive nor specific.155156
Assays of lymphocyte IFN- production have been developed that hold more promise for the differentiation of infection with TB, NTM, and BCG vaccination. The RD1 genomic segment of M tuberculosis, which encodes for the early secreted antigenic target 6-kd protein (ESAT-6) antigen, is deleted from all BCG strains.155157 The T lymphocytes from patients with TB infection respond more to ESAT-6, forming the basis for IFN- assays that recognize TB infection from immune responses to BCG with a sensitivity of > 90% and 100% specificity.158 ESAT-6 is also present in M kansasii, Mycobacterium marinum, and Mycobacterium szulgai; therefore, exposure to these NTM could result in false-positive test results.155
Conditions associated with NTM lung disease were discussed in the earlier sections of this review. The culture of NTM from respiratory specimens is required to confirm the diagnosis, since signs, symptoms, and radiologic findings are not specific enough to allow the identification of the organism in patients with NTM lung disease.11
Since the NTM are ubiquitous, may be present in water used in the laboratory, and may contaminate respiratory specimens, infection has to be distinguished from contamination.159160 Colonization is the term used to describe the benign presence of NTM isolated from patients who do not have evidence of active disease.161162 The presence of pulmonary infiltrates or cavitation in patients with NTM isolated from respiratory specimens not explained by other disease suggests disease rather than colonization.163 Colonization implies that NTM are present in the respiratory tract because of underlying damage or because of an immune deficiency but do not contribute to further injury. Some prefer the term indolent disease to colonization since it may not be evident that NTM are causing progressive disease unless the patients are followed up for several years.1112 Persistent symptoms, especially when associated with repeated isolation of the same NTM species from respiratory specimens, and progressive radiologic changes suggest infection rather than colonization. The ATS has published diagnostic criteria recommending repeated culture of specimens from nonsterile sites before committing a patient to long-term therapy with multiple antibiotics.11 The guidelines recommend that NTM be cultured a minimum of three times in the preceding year, or twice if one of the specimens is smear positive for mycobacteria in patients presenting with findings consistent with NTM lung disease before initiating therapy.11 It is mandatory that specimens be cultured and undergo DNA probe testing as quickly as possible to rule out TB.164 The diagnosis of NTM lung disease can also be confirmed if NTM are found with greater than "1 plus" density on stained smear, or on culture of BAL.11 The diagnosis can also be confirmed if a biopsy shows characteristic features of granulomatous infection in association with a sputum or BAL that contain NTM on smear or culture.11 Some researchers118 feel that the ATS criteria recommending repeated isolation of the organism are too strict for M kansasii, and consideration should be given to treating patients on the basis of a single positive culture result.
NTM
M avium
M avium is the most common cause of NTM lung disease in most parts of the world.78910293031323334 MAC can also cause lymphadenitis (usually in children), soft-tissue infections, and disseminated disease in immunocompromised patients, usually patients with AIDS with a CD4+ count < 50/µL.165166167168
In patients with underlying lung disease, MAC often causes cavitary disease, similar to the lung disease caused by other NTM.169170171 MAC can also cause lung disease in apparently immunocompetent patients without underlying lung disease.172 Fibronodular bronchiectasis, with a predilection for the right middle lobe and lingula, is the most common pattern of MAC lung disease seen in thin, elderly women (Fig 1).42 MAC can also cause an HP-like syndrome in patients exposed to MAC present in recreational hot tubs (Fig 2).65666768697071727374
MAC lung disease may have an insidious onset, and symptoms may be present for months or years before the diagnosis is made.42173174 Early cases may be asymptomatic and only discovered by routine screening chest radiographs.174175 Most patients experience chronic cough, usually productive of purulent sputum, but usually without hemoptysis.114281 Constitutional symptoms including fever, night sweats, weight loss, malaise, lethargy, and fatigue are not common unless patients have extensive lung disease.39 Patients with smear-positive sputum are more likely to have fever and hemoptysis.176 Assessment of symptoms is complicated in patients with preexisting lung disease.81
The two most common radiologic patterns are cavitary disease and fibronodular bronchiectasis.169 Cavitary disease is seen more commonly in patients with underlying lung disease, with a prevalence ranging from 44 to 88%.2658153171 Early reports8153154170 suggested that MAC-related cavities were thinner, with less surrounding parenchymal opacification than in TB. Opacification tended to be contiguous with less distal bronchogenic spread than in TB.11 Bronchiectasis is more common than in TB, with a predilection for the lingula and the right middle lobe.177178 Pleural effusions are not common, but pleural thickening may develop adjacent to parenchymal abnormalities in MAC lung disease.141
Chest radiographs are not as sensitive as HRCT scanning for detecting the abnormalities associated with NTM lung disease.141175179180181 Most of the HRCT studies of NTM lung disease have focused on MAC, but there are also reports170179180181182183184185186187 of the findings in lung disease due to M kansasii, M xenopi, and RGM.
In a report188 from Korea, one third of the patients with bilateral bronchiectasis had NTM infection; 50% of these were MAC, and 39% were M abscessus. Female gender, lifetime nonsmoking, widespread bronchiolitis, lobular consolidation, and presence of cavities were associated with NTM infection.188 Bronchiectasis was present in 94% of patients with MAC, compared to 27% of the TB patients; and the presence of multiple small nodules associated with bronchiectasis was predictive of MAC lung disease (91% vs 22%).177183 MAC was cultured from the sputum of one fourth of the patients with fibronodular bronchiectasis, and MAC infection was documented in one half if bronchoscopy with BAL and transbronchial biopsies was performed.182 Half of the patients have pleural thickening or adhesions, usually adjacent to the pulmonary parenchymal abnormalities on HRCT.63141180 Atelectasis (67%), consolidation (12%), "tree-in-bud," and ground-glass opacities (33%) occur in MAC lung disease.63180 Nonsmoking patients with MAC lung disease have evidence of gas trapping, with a mean residual volume of 161% of the predicted value.184
Serial CT scanning in MAC lung disease has shown that bronchiectasis tends to progress, and the nodules spread to other segments over time.141189 The appearance of nodules precedes the development of consolidation and ground-glass opacities. Some small nodules will disappear with successful treatment.186 Patients with cavitary lung disease are more likely to have mycobacterial smear-positive sputum results.3956575859148169175184
A comparative study141 of 10 patients with M avium lung disease to 36 patients with M intracellulare found that cavitation was more common in M avium. The distribution of disease, prevalence of pleural thickening, parenchymal consolidation, ground-glass opacities, nodules, bronchiectasis, and severity of bronchiectasis were similar in patients with M avium and M intracellulare.141 Compared to patients with other NTM infection, patients with MAC lung disease tend to have more nodules and more severe bronchiectasis.185 Bronchiectasis was graded as severe in 11 of 16 MAC patients compared with 18 of 41 patients with other NTM, and nodularity was graded at least grade 2 in 50% of MAC patients compared to only 14% of patients with other NTM.185
Patients with MAC lung disease have been treated with antimycobacterials since the 1950s.39 Since MAC demonstrates in vitro resistance to concentrations of antituberculous medications effective against M tuberculosis, combinations of up to six antimycobacterials have been necessary for successful therapy.190 The treatment success rate was satisfactory among patients able to tolerate the multidrug regimens.191 Unfortunately, not all patients could tolerate these medications long enough to sterilize the sputum.191 Since patients may respond clinically and convert to negative with antimycobacterials, it has been suggested that in vitro testing may not reflect drug concentrations in the macrophage or there may be a synergistic effect with combination therapy that in vitro testing does not evaluate.149 It was recommended that patients complete 24 months of antimycobacterial therapy for NTM lung disease.191 In addition to treatment failure or inability to tolerate treatment, the high mortality rates are due to underlying lung disease, other comorbidity, and advanced age.192
The importance of clarithromycin in the treatment of MAC was demonstrated in properly designed, randomized, controlled studies,193194 both for treatment and prophylaxis of disseminated MAC infection in patients with AIDS. On the basis of the encouraging results in AIDS patients, clarithromycin, and more recently azithromycin, have been used successfully for MAC lung disease.60192195196197198199200201202203204 M avium is an intracellular pathogen, and antibiotics that are highly concentrated intracellularly, such as azithromycin, are effective.205 Other antibiotics need to be administered to prevent the development of resistance.195 More recently, the preferred regimen has been a combination of a macrolide, ethambutol, and rifampin.60195196197198199200201202203204 Both rifampin and ethambutol appear to have a synergistic effect when combined with other antimycobacterials and are relatively well tolerated.149 Thrice-weekly regimens of clarithromycin or azithromycin, combined with ethambutol and rifampin, are effective, as is a regimen that substitutes rifampin with clofazimine.60198199 Unfortunately, controlled studies of the macrolide-containing regimens have not been done in MAC lung disease.206 It is recommended that the macrolide-containing regimens be continued for 12 months once patients convert to negative, since early relapses were seen in patients treated for < 10 months after sputum converted to negative, but not in patients treated for a further 12 months.11196
IFN- activates macrophages in the host defense against mycobacteria. Moreover, IFN- may enhance antibiotic penetration in infected macrophages and enhance their antimycobacterial action.207208 Patients with a congenital abnormality of the IFN- receptor are susceptible to disseminated mycobacterial disease.1415161718 Defective secretion of IFN- from CD3+ T-cells or IFN- autoantibodies may lead to undetectable serum IFN- levels and increased susceptibility to disseminated mycobacterial disease.209210 IL-12 or IL-18 receptor abnormalities, important cytokines in the production of IFN-, may also cause disseminated mycobacterial disease.212223 Apparent relapses in patients with fibronodular bronchiectasis occur due to different strains than the original infection, suggesting an abnormal susceptibility to the organism and that the relapse represents reinfection rather than relapse.211 The macrophages of patients with lung disease due to MAC and other NTM produce less IFN- in response to challenge with MAC antigen and purified protein derivative than normal individuals sensitized to MAC antigen or patients with TB, and levels remain low even after successful treatment.172209 There are several reports212213214 of patients with IFN- deficiency and NTM disease, or NTM lung disease refractory to antibiotic therapy, responding favorably to treatment with inhaled IFN-.
Surgery is advocated for patients with localized disease who fail medication therapy and have adequate pulmonary reserve. Postoperative morbidity and complications including bronchopleural fistula, hemorrhage, and empyema are common in these patients.215216217218219 To date, there are no controlled surgical trials for MAC lung disease.
M kansasii
M kansasii is most often isolated from tap water and is more commonly found in urban than in rural settings, unlike MAC, which is more widely distributed since it is also present in ground water.4121 M kansasii is the most common cause of NTM lung disease in the central United States, parts of the United Kingdom, in some coal mining areas, and in gold miners in South Africa.10118119120171220 In South African gold miners, M kansasii was the infecting NTM in 23 of 32 men who met the ATS case definition for NTM lung disease.118 In most places, it is the second- or third-most-common cause of NTM lung disease.78910221 Seven subtypes of M kansasii have been recognized, but most disease is due to type 1.222223 Underlying lung disease is a risk factor for M kansasii infection. Unlike patients with MAC lung disease, a small preliminary study45224225 did not find any abnormality of cell-mediated immunity in patients with M kansasii. Lung disease due to M kansasii may be hard to distinguish clinically or by radiologic criteria from TB. M kansasii usually causes cavitary lung disease, but less commonly it may cause fibronodular bronchiectasis similar to the pattern with MAC.58 M kansasii lung disease tends to have more cavities and more tree-in-bud opacities, and are more likely to have underlying emphysema than patients with MAC (Fig 3
).185 Similar to TB and unlike MAC, a single isolate of M kansasii is believed to represent disease in patients with evidence of lung disease, especially cavitary disease, and should be treated.118120 Antituberculous treatment is usually effective against M kansasii infections.121 This is fortunate, since patients are often initially treated for suspected TB until culture results are available. M kansasii is naturally resistant to pyrazinamide because of the absence of pyrazinamidase activity.226 Rifampin is the most effective of the antimycobacterial medications against M kansasii.121 The suggested regimens combine ethambutol and isoniazid with rifampin to prevent the emergence of drug resistance.11 As with other NTM infections, a further 12 months of treatment is recommended once culture findings are negative.11 Clarithromycin is very effective against M kansasiiin vitro and is recommended as an alternative for cases with rifampin-resistant organisms, and for patients who are intolerant of rifampin or one of the other medications.121 The results of several short-course regimens have been reported.227228229 The sputum of virtually all of the patients in a British Thoracic Society (BTS) trial228 converted to negative with a 9-month course of daily rifampin, 450 to 600 mg, and daily ethambutol, 15 mg/kg. However, 12% of the subjects relapsed during the 5 years after completing therapy.228 Patients with M kansasii lung disease were successfully treated with clarithromycin, rifampin, and ethambutol, all administered three times a week.230 The newer fluoroquinolones also have good in vitro activity against M kansasii.231232
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M xenopi
M xenopi lung disease occurs less frequently than lung disease due to MAC or M kansasii. However, M xenopi occurs more frequently in France, England, Southern Europe, and Ontario.148243244 M xenopi accounted for 30% of the NTM isolates in Italy between 1991 and 1996, compared to M avium, which only accounted for 28%.710 M xenopi can grow in biofilms and may be present in tap water, explaining the case clusters in which affected patients have shared the same hot water system.438245 Growth of M xenopi in a hospital hot water supply occurred when the temperature was decreased from 54.4 to 48.9°C.246 It is most commonly found in patients with underlying lung disease, primarily COPD, but is also reported in patients with previous TB, lung cancer, a variety of interstitial lung diseases, and various forms of immunosuppression.104243 It most commonly presents in the seventh decade of life and is seen more commonly in men than in women. Presentation is similar to lung disease due to other NTM. The most common symptom is a productive cough. Patients with more advanced disease may have systemic symptoms.148 Cavitary upper-lobe disease is the most common radiologic finding.185 As with M kansasii, M xenopi lung disease is associated with more cavities and more tree-in-bud opacities, and more likely to be found with emphysema than MAC lung disease (Fig 3).185 Reports243244 of M xenopi lung disease suggest a relatively high mortality. This is at least partly due to the comorbidities, including underlying lung disease, in these patients. Traditionally, patients were treated with standard antituberculous regimens.244247 In the BTS trial,244 only 7 of 42 patients were alive and disease free at 5 years. More recently, clarithromycin-based regimens have been favored.244248 Curative surgical resection has been reported in patients with localized lung disease.249
M gordonae
M gordonae, also called Mycobacterium aquae, is frequently cultured from sputum but rarely causes progressive lung disease.250 According to the CDC survey,9 M gordonae was the second-most-commonly reported NTM isolate by the state public health laboratories to the CDC in each year from 1993 to 1996. M gordonae was also the second-most-frequent NTM isolate in Denmark and in a large international survey.7 M gordonae is a frequent contaminant of tap water and has caused pseudoepidemics in several countries, including the United States,160 France,251 and Japan.252 The presence of M gordonae in hospital water systems has resulted in pseudoepidemics from the contamination of bronchoscopy specimens.253 In most cases, the presence of M gordonae represents contamination, but colonization can also occur in patients with underlying lung disease.250 This hypothesis is based on the assumption that the presence of M gordonae in only one of several specimens represents contamination, but repeated isolation of M gordonae from an individual represents colonization. Eckburg et al250 reviewed the cases of 19 patients with M gordonae grown in culture. Most had underlying lung disease, but the investigators could not attribute any of the disease to M gordonae.250 There are occasional reports of apparently progressive lung disease with M gordonae, and there are also occasional reports of disseminated disease in patients with HIV infection.254255 M gordonae is sensitive to rifampin and ethambutol but is relatively resistant to isoniazid and streptomycin.256 Clarithromycin appears to be quite effective against M gordonaein vitro,257258 and there are reports259260 of successful and partially successful treatment with clarithromycin.
RGM
RGM are distinguished from the other NTM, also called slow-growing mycobacteria, by their ability to form colonies in < 1 week and their in vitro resistance to antimycobacterials.6 These properties and comparative sequencing of the 16S ribosomal RNA gene suggest that the differences from other mycobacteria are great enough to justify placing RGM in a different genus.261262 Similar to other NTM, RGM are resistant to chlorination and other disinfecting solutions, including glutaraldehyde and formaldehyde, and may be present in tap water.77 RGM can cause lung disease in patients with and without underlying lung disease. RGM most commonly complicate lung disease due to previous mycobacterial disease, CF, malignancy,263 COPD, lipoid pneumonia, and conditions associated with chronic gastroesophageal reflux, or vomiting.264265 Compared to patients with MAC, patients with lung disease due to RGM are more likely to be younger and have underlying lung disease.185
M abscessus
M abscessus is the RGM that most commonly causes lung disease.266 It is closely related to M chelonae and only recently was recognized to be a distinct species. In a large survey,266 M abscessus accounted for 82% of the cases of lung disease caused by RGM. It most commonly causes fibronodular bronchiectasis and usually does not cause cavitary disease.64 The radiologic findings of M chelonae and M abscessus are similar to MAC. Bilateral nodular opacities, bronchiectasis, and cavities are seen on HRCT.186187 A recent comparative study267 found considerable overlap in the HRCT findings of MAC and M abscessus, but lobar volume loss, nodules, consolidation, and thin-walled cavities were more common in MAC. Unlike MAC, it does not commonly cause disseminated disease in immunocompromised patients. It most commonly complicates lung disease due to previous mycobacterial disease, CF, and conditions associated with chronic gastroesophageal reflux or vomiting.264265 In a large American multicenter survey87 of CF patients, M abscessus was the second-most-commonly isolated NTM after MAC. M abscessus is notoriously difficult to treat because of resistance to most antibiotics, including amoxicillin-clavulinate, ampicillin, cefoxitin, cephalothin, ciprofloxacin, doxycycline, erythromycin, sulfamethoxasole, and tobramycin.2 The recommended treatment regimen includes clarithromycin, amikacin, and possibly imipenem.268 There may be initial improvement on this regimen, but unfortunately it is not usually curative. Surgical resection is probably the best option if the lung disease is localized and pulmonary function is adequate.269270
M fortuitum
M fortuitum more commonly causes skin and soft-tissue infections, often in postsurgical wounds, but it can also cause lung disease. M fortuitum was isolated from 15% of patients with lung disease due to RGM, second in prevalence to M abscessus.266 It is a more indolent organism than M abscessus, and not all patients with positive isolates require therapy. M fortuitum is susceptible to a broader range of antibiotics than M abscessus. Individual isolates should undergo susceptibility testing against a wide range of antibiotics, including sulfonamides, amikacin, fluoroquinolones, doxycycline, cefoxitin, and imipenem.64 It is resistant to the macrolides because it has an ribosomal RNA methylase gene that methylates the macrolide-binding site on the ribosome.271
M chelonae
M chelonae rarely causes lung disease.272 M chelonae more commonly causes skin and soft-tissue infections. Like its close relative M abscessus, M chelonae is very resistant to antibiotics.272 M chelonae is resistant to disinfectants and can contaminate endoscope cleaning machines. Gluteraldehyde-tolerant M chelonae colonized bronchoscopes and was cultured from the BAL fluid of patients undergoing bronchoscopy, causing pseudoepidemics of apparent M chelonae infection.273274275276 True nosocomial infections due to M chelonae have occasionally occurred after bronchoscopy with contaminated equipment.277 There are guidelines addressing the problem of bronchoscopy-associated infection and pseudoinfection.277 M chelonae is the most common cause of bronchoscopy associated pseudoepidemics.277
Conclusion
The prevalence of NTM disease has increased because of the increased number of patients with immunosuppression. Although the reported prevalence of NTM lung disease in immunocompetent patients has increased, it is not clear whether this is a true increase or whether more sensitive laboratory techniques for the isolation and identification of NTM explain the apparent increase. Some of the apparently increased prevalence is due to greater appreciation of the role of NTM in different lung conditions, including fibronodular bronchiectasis and HP. Moreover, recognition of the high prevalence of NTM in conditions such as CF and PAP, and the increased testing for NTM in patients with these conditions have also contributed to the apparent increase in prevalence. Treatment results remain disappointing despite the improved detection of NTM lung disease and the better activity of some of the newer antimicrobials. Treatment success is limited by the inability of patients to complete the recommended regimens because of their very long duration, side effects, and drug interactions. Further research is needed to improve outcomes in patients with NTM lung disease.
Footnotes
Abbreviations: ATS = American Thoracic Society; BCG = bacille Calmette-Guérin; BTS = British Thoracic Society; CDC = Centers for Disease Control and Prevention; CF = cystic fibrosis; ESAT-6 = early secreted antigenic target 6-kd protein; HAART = highly active antiretroviral therapy; HPLC = high-performance liquid chromatography; HRCT = high-resolution CT; IFN = interferon; IL = interleukin; IRIS = immune reconstitution inflammatory syndrome; MAC = Mycobacterium avium complex; NTM = nontuberculous mycobacteria; PAP = pulmonary alveolar proteinosis; RFLP = restriction fragment length polymorphism; RGM = rapidly growing mycobacteria; TB = tuberculosis; TNF = tumor necrosis factor
Received for publication September 1, 2005. Accepted for publication December 19, 2005.
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