Nontuberculous Mycobacterial Disorders

Nontuberculous Mycobacterial Disorders



Octavian C. Ioachimescu, J. Walton Tomford



TAXONOMY


Mycobacteria other than Mycobacterium leprae, M. tuberculosis, and M. bovis were identified from human sources as early as 1885, but it was not until almost 65 years later that human infection was attributed to these organisms. Between the early 1950s and 1980s, there was increasing awareness of the spectrum of disease caused by the nontuberculous mycobacteria (NTM), although the number of cases was small. In the 1980s, in the early days of HIV infection, it was recognized that M. avium complex and M. kansasii organisms commonly caused disseminated infections in patients who were severely immunocompromised. Currently, the epidemiology and clinical features of the NTM diseases are dominated by their occurrence in patients with HIV infection and, more recently, in patients on tumor necrosis factor α (TNF-α) pathway blockers. However, disease caused by this group of organisms continues to occur in persons without detectable systemic immune dysfunction (e.g., recipients of prosthetic knees, fish tank granuloma, hot tub lung).


The genus Mycobacterium is composed of more than 100 species characterized by complex lipid-rich cell walls, which confer the acid-fast staining property. Mycobacterial species were classically differentiated using cultural and biochemical properties, but genetic differences are now used for this purpose, especially 16S ribosomal RNA sequence differences. The published mycobacterial species and subspecies, which number 139 (as of January 2008), are included in the List of Prokaryotic Names with Standing in Nomenclature. The genus Mycobacterium contains two obligate pathogens, the M. tuberculosis complex and M. leprae. The M. tuberculosis complex contains several related mycobacteria (i.e., M. bovis—including bacillus Calmette-Guérin [BCG], M. africanum, M. microti, and M. cannetti), which on DNA analysis are all variants of M. tuberculosis. The other species live freely in the environment (water and soil) and are thus often termed environmental mycobacteria or nontuberculous mycobacteria; we prefer the latter term.


NTM have been called in the past “atypical” mycobacterial species or mycobacteria other than tuberculosis (MOTT). These microbes share many common properties, such as acid fastness and the ability to cause pulmonary and extrapulmonary granulomatous disorders. As a group, they comprise diverse organisms with dissimilarities in their cultural characteristics and pathogenicity to humans compared with M. tuberculosis (MTB). There are many organisms in this group capable of causing human infections. Infections caused by M. avium-intracellulare (MAI) complex became common in patients with severe HIV infection—in patients with low CD4 lymphocyte counts—or in AIDS, for which it is a disease-defining condition. NTM cause significant lung disease in individuals with structural abnormalities (e.g., patients with bronchiectasis and chronic obstructive pulmonary disease with M. kansasii infection) and in those with immunodeficiency syndromes (e.g., M. avium infection in HIV-AIDS patients).



CLASSIFICATION


NTM classifications have generally not been helpful to the clinician. The most widely used classification in the past, the Runyon system, was based on microbiologic characteristics of the organisms, such as growth rate in cultures and colony pigment formation in the presence or absence of light. Familiarity with the Runyon system remains useful for presumptive laboratory identification of possible NTM pathogens; however, positive identification of NTM species is now largely based on biochemical and molecular biology techniques. Classification of NTMs based on the organ system of primary involvement (e.g., lungs, lymph nodes, disseminated, skin, and soft tissue) is more useful to the clinician and will be used hereafter (Table 1). Based on culture characteristics, NTM are subclassified into the following main groups: the slow, intermediate, and rapid growers, with varying nutritional requirements.


Table 1 Major Clinical Syndromes Associated with Nontuberculous Mycobacteria Infections


































Syndrome Common Causes Less-Common Causes
Pulmonary disease (especially in adults) Mycobacterium avium–intracellulare, M. kansasii, M. abscessus
Uncommon: M. fortuitum, M. malmoense, M. szulgai, M. scrofulaceum, M. smegmatis, M. simiae, M. xenopi

Rare: M. celatum, M. asiaticum, M. shimodei
Cervical and lymphadenitis (especially children) M. avium, M. intracellulare M. scrofulaceum, M. malmoense, M. abscessus, M. fortuitum
Skin and soft tissue disease M. fortuitum, M. chelonae, M. abscessus, M. marinum M. haemophilum, M. kansasi, M. smegmatis, M. ulcerans
Skeletal (bones, joints, tendons) disease M. marinum, M. avium complex, M. kansasii, M. fortuitum group, M. abscessus, M. chelonae M. haemophilum, M. scrofulaceum, M. smegmatis, M. terrae-nonchromogenicum complex
Catheter-related infections M. fortuitum, M. abscessus, M. chelonae M. mucogenicum
Disseminated infection HIV-seropositive host: M. avium, M. kansasii M. haemophilum, M. genavense, M. xenopi, M. marinum, M. simiae, M. intracellulare, M. scrofulaceum, M. fortuitum
HIV-seronegative host: M. abscessus, M. chelonae M. marinum, M. kansasii, M. haemophilum, M. fortuitum


Slow-Growing Mycobacteria


The slow-growing group includes species of mycobacteria that require usually more than 14 days of incubation for mature growth; some may require nutritional supplementation of routine mycobacterial media. The most common clinically important species found in this group include the M. avium complex (M. avium and M. intracellulare), M. kansasii, M. xenopi, M. simiae, M. szulgai, M. scrofulaceum, M. malmoense, M. terrae-nonchromogenicum complex, M. haemophilum, and M. genavense. These organisms grow best at 35° to 37° C, with the exception of M. haemophilum, which has a preference for lower temperatures (28° to 30° C) and the presence of iron, and M. xenopi, which grows optimally at 42° C. Newer isolated slow-growing species include M. celatum, M. interjectum, M. confluentis, M. triplex, M. lentiflavum, M. branderi, M. conspicuum, M. cookii, and M. asiaticum.



Intermediate-Growing Mycobacteria


The intermediate-growing group includes M. marinum and M. gordonae. These organisms are usually pigmented and require 7 to 10 days of incubation for mature growth. M. marinum has an optimal growth temperature of 30° C, whereas M. gordonae prefers 35° C. M. gordonae is seldom if ever pathogenic, except in severely immunocompromised hosts.



Rapid-Growing Mycobacteria


The rapid-growing group of organisms includes nonpigmented and pigmented species that produce mature growth on agar plates, usually within 7 to 10 days. Nonpigmented pathogenic species are mostly grouped within the M. fortuitum complex, which includes the M. fortuitum group (M. fortuitum, M. peregrinum, and M. fortuitum third biovariant complex) and the M. chelonae-abscessus group (M. chelonae, formerly M. chelonae subspecies chelonae, M. abscessus, formerly M. chelonae subspecies abscessus, and M. mucogenicum, formerly M. chelonae-like organism). M. smegmatis may be pigmented or nonpigmented.


Pigmented, rapid-growing species are difficult to identify by traditional laboratory methods. Rapid-growing pigmented species occasionally isolated in clinical disease include M. phlei, M. aurum, M. flavescens, M. neoaurum, M. vaccae, and the thermophilic species M. thermoresistible.



EPIDEMIOLOGY


In the United States, the number of significant NTM isolates continues to increase, in parallel with a recent increase in the number of immunocompetent patients with NTM disease (primarily lung disease) and a slow decline of tuberculosis (TB). Factors that may be contributing to this increase include the following:


• An increased number of clinical specimens submitted for acid-fast bacilli (AFB) stains and cultures

• Improved laboratory techniques, which have made identification and isolation of NTM more rapid and accurate

• Higher recognition of NTM disease, especially in chronic pulmonary disease and in immunocompetent patients (e.g., older women with MAI disease)

Evidence is mounting to show that the environment is the major source of human NTM infection. NTM are ubiquitous in the environment and have been isolated from water (most cases), soil, dust, domestic and wild animals, milk, and food. DNA fingerprinting techniques—restriction fragment length polymorphism analysis by pulsed field gel electrophoresis and major polymorphic tandem repeat probe sequence analysis—have been useful for epidemiologic investigation (e.g., point source epidemics). These techniques also may provide clues to pathophysiologic differences among NTM species. For example, there appears to be great genetic variability among MAI isolates from different patients and sometimes even from the same patient. In contrast, clinical M. kansasii isolates generally have similar genotypes, suggesting that most clinical isolates are clonal. This clonal nature of most clinical isolates of M. kansasii would seem unusual for environmental species such as MAI, and suggests that their colonization of environmental sites of human disease acquisition (e.g., municipal water supplies) is fairly recent and involves only select genotypes.


Unlike TB, disease caused by NTM is rarely if ever transmitted from patient to patient. Infection is acquired from the environment; pulmonary disease is probably caused by the inhalation of aerosols of water containing the mycobacteria. The incidence of disease caused by NTM is somewhat independent of that of TB, but is determined by the number, distribution, and species of NTM in the environment and the susceptibility of the human population. In regions where TB is common, only a small minority of cases of pulmonary mycobacterial disease will be caused by NTM. By contrast, in regions where TB is rare, such as rural areas of western Europe and the United States, a much higher proportion of pulmonary mycobacterial disease is caused by NTM. There are geographic variations in distribution of the species of NTM: whereas the MAI complex occurs worldwide, others, such as M. xenopi and M. malmoense, are restricted to certain regions. M. xenopi is the second most common NTM causative organism in Canada and the United Kingdom, and M. malmoense is the second most common NTM disease in Sweden and other northern European countries. M. ulcerans infections occur mostly in Australia and tropical countries. Although MAI disease has a worldwide distribution, disseminated MAI is rarely seen in people from central Africa who have AIDS, even though MAI can be recovered from that environment. One possible explanation is that those who have AIDS in Africa may die from infection with more aggressive pathogens such as M. tuberculosis before their immunosuppression becomes severe enough to develop disseminated MAI. In addition, the distribution of species varies with time, possibly as a result of environmental changes.


Immune reactions elicited by exposure to NTM have been postulated as a cause of the wide geographic variation in the protective efficacy of BCG. One possible explanation is that repeated contact with NTM leads to protective immunity equivalent to that conferred by BCG; in this case, BCG vaccination would not add any protective effect. Another explanation is that the immune response in TB is qualitatively different, eliciting protective immunity or a delayed hypersensitivity reaction, with possible disease progression. The switch between the two responses is determined by helper T cell 1 (Th1) versus helper T cell 2 (Th2) T lymphocyte selection in the immune response. A predominant Th1 response facilitates protective immunity, whereas a superimposed Th2 response seems to be associated with tissue necrosis. When given neonatally, BCG confers protection against TB inducing a Th1 response, but later in life it boosts or fails to downregulate an environmentally determined harmful Th2 component and therefore fails to protect from—and may even predispose to—active TB. A third hypothesis, supported by mouse models, is that environmental sensitization to M. avium (but not M. fortuitum and M. chelonae) prevents the multiplication of BCG in tissues, which is essential for the development of protective immunity. These hypotheses are not mutually exclusive.



VIRULENCE AND PATHOGENICITY


Many questions surround the determinants of virulence of M. tuberculosis and M. leprae, and even less is known about the virulence of NTM. A mouse model has revealed three patterns of pathogenicity. After intravenous inoculation in immunocompetent mice, most tested species were found to replicate progressively in the liver and spleen; some replicated in these organs in interferon gamma (IFN-γ)-deficient mice, but not in immunocompetent mice (e.g., M. heidelbergense and M. intermedium). Others were eliminated in both types of mice (e.g., M. confluentis and M. lentiflavum). The relevance of these findings to human disease remains to be established, but they suggest that IFN-γ is not a crucial determinant of protection in all forms of mycobacterial disease. For the clinician, it is important to emphasize that NTM disease can occur in immunocompetent hosts.


There are few data on the relative virulence of NTM in humans. Although some species such as MAI and M. kansasii are recognized as pathogens, others such as M. gordonae are often isolated as nonpathogenic contaminants of the respiratory tract but only occasionally as causes of overt disease. In the presence of immunosuppression, all NTM must be regarded as potential pathogens, but some species are particularly associated with disease. For unknown reasons, HIV-positive patients are particularly prone to develop disease caused by certain genetic variants of MAI.



CLINICAL SYNDROMES


Five major clinical syndromes have been described that are attributable to NTM (see Table 1): pulmonary disease; lymphadenitis; skin, soft tissue, and skeletal infections; catheter-related bloodstream infections; and disseminated disease, especially in persons with AIDS or severely immunocompromised hosts (e.g., individuals on high-dose corticosteroids). There is limited documentation (if any) of person-to-person transmission of NTM. Nosocomial infections and outbreaks caused by inadequate disinfection or sterilization of medical devices or environmental contamination of medications or medical devices have been described.



Pulmonary Disease


Pulmonary disease caused by NTM may occur as a component of disseminated infection, but often the disease affects only the lungs (Table 2). Four main categories of pulmonary disease can be nosologically identified. First, the disease occurs in middle-aged or older patients, usually men with a history of lung disease. Second, the disease occurs in otherwise apparently healthy persons, although some may have minor and covert immune defects. Third, the disease occurs in children with more severe immune defects or predisposing pulmonary disease, notably cystic fibrosis or severe fungal infection (e.g., invasive or semi-invasive Aspergillus disease). Fourth, the disease occurs in very immunosuppressed patients, of which HIV infection is the prevalent cause worldwide. Also, it is important to emphasize that patients with NTM diseases do not need to be isolated because of the noncontagiousness of these conditions.



Table 2 Clinical Settings for Nontuberculous Mycobacteria Lung Disease

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Patients with Predisposing Lung Disease


Most patients are men with a history of smoking, bronchiectasis, chronic obstructive lung disease, rheumatoid lung, healed TB, or exposure to industrial dusts as a result of mining, sandblasting, or welding. Risk factors have been evaluated in South African gold miners with pulmonary mycobacterial disease. In this study,1 51 patients with disease caused by NTM and 425 with TB were similar with regard to age, education, home region, and smoking habits. Those with disease caused by NTM were more likely to have been previously treated for TB, worked longer underground, or have evidence of silicosis. Patients with disease caused by NTM were less likely to be HIV-positive (35.3%) than those with TB (48.8%), although the difference was not statistically significant. Pulmonary disease caused by M. kansasii is particularly associated with underlying lung damage such as pneumoconiosis or silicosis, which leads to slowly progressive and insidious disease in miners and other workers. This species has been recognized since 1977 as the most common cause of NTM pulmonary disease in South African gold miners. The disease occurs in both HIV-positive and HIV-negative patients, and most have had radiologic evidence of silicosis. Disease caused by M. kansasii in HIV-positive gold miners differs from that occurring in HIV-positive patients without the risks associated with mining. Thus, in miners, the disease occurs much earlier in the course of HIV infection, with CD4+ T cell counts being significantly higher, and clinically it more closely resembles the disease in HIV-negative patients. It has been noted that assessment of the clinical significance of sputum isolates of M. kansasii in this group of patients by American Thoracic Society guidelines2 is not straightforward.


Old TB lesions may be colonized or infected by NTM. In one study in Japan, 75% of mycobacteria isolated from sputum more than 1 year after completion of therapy for TB were NTM. The presence of such mycobacteria could lead to a false diagnosis of recurrence of TB. In some cases, disease caused by M. xenopi has been superimposed on aspergillomas in old cavities; this disease has a generally poor prognosis and response to therapy.



Immunocompetent Hosts


A number of cases, mostly caused by MAI complex, have been reported in older people, principally nonsmoking women with no other evidence of lung disease except for the associated bronchiectasis. It has been postulated that such disease in women is associated with the practice of coughing quietly and covertly, thereby suppressing the clearance of sputum. The disease has accordingly been termed Lady Windermere syndrome after the fastidious aristocrat in Oscar Wilde’s play, “Lady Windermere’s Fan.”3 We prefer not to use “Lady Windermere syndrome,” mainly because the term is not comprehensive and does not illustrate the full spectrum of the disease. If the disorder continues undetected for years, cavities develop in the lungs and respiratory failure may ensue; however, the natural history of this disorder is unpredictable. The causative organisms include MAI and M. kansasii and, less frequently, M. xenopi, M. scrofulaceum, M. szulgai, M. malmoense, M. simiae, M. celatum, and M. chelonae. A similar but less common form of pulmonary disease caused by NTM has also been reported in apparently immunocompetent men.


A bizarre characteristic of 10 previously healthy patients with diffuse pulmonary disease caused by NTM (M. avium in 9 of the 10 cases) was that they all bathed in hot tubs. Although this serious condition was termed hot tub lung, further studies are required to confirm whether the use of such tubs is an important predisposing factor.4 Although the patients described appeared clinically and immunologically normal, it is possible that they had minor immune defects. On detailed investigation, some patients with pulmonary disease caused by NTM have been found to have such defects, although it is not clear whether these were a cause or consequence of the disease.



Children


Although rare in childhood, a few cases caused by MAI, M. chelonae, and M. fortuitum have been reported in children with cystic fibrosis. Children with deteriorating lung function should be screened for NTM because therapy can, in some cases, halt the deterioration. Familial susceptibility to NTM disease, but not to M. tuberculosis, can be linked to different mutations in four genes. These mutations result in eight different clinical syndromes, all characterized by impaired cell-mediated immune responses mediated by IFN-γ. Because these syndromes vary in severity and require different therapeutic strategies, identification of the underlying genetic defect is important.



Immunosuppressed Hosts


Mycobacteria, both M. tuberculosis and NTM, are common causes of lung disease in HIV-positive patients. In general, the isolation of NTM, and most notably of MAI complex, from the respiratory tract of an HIV-positive person is more likely to be clinically significant than from an HIV-negative person. Cough is a common complaint irrespective of HIV status, but HIV-positive patients are more likely to have fever. Abnormal chest radiographs are common, with HIV-positive patients being more likely to have diffuse abnormalities. In one study, a specific diagnosis was made in 20 of 25 HIV-positive patients with cavitating lung lesions.8 Bacteria, often more than one species, were the cause in 17 patients. Mycobacteria were isolated in 8 patients. Mediastinal or hilar lymphadenopathy and additional ill-defined, noncavitating, nodular opacities were seen more frequently in patients with mycobacterial pathogens.



Localized Cutaneous, Soft Tissue, and Bone Infections



Skin and Subcutaneous Diseases


Postinoculation lesions usually affect skin or subcutaneous tissues following a traumatic inoculation. This can take the form of swimming pool (or fish tank) granuloma or Buruli ulcer, the latter mainly outside the United States. Although all species of NTM have been incriminated in cutaneous NTM disease, M. marinum and rapid-growing mycobacteria most often cause localized skin infections. M. marinum causes an infection historically recognized as swimming pool or fish tank granuloma. Most infections occur 2 to 3 weeks after contact with contaminated fresh or salty water from one of these sources. The lesions are most often small violet papules on the hands and arms that may progress to shallow crusty ulcerations and scar formation. Lesions are usually singular. However, multiple ascending lesions resembling sporotrichosis (sporotrichoid disease) can occasionally occur; in our experience, the antifungal-resistant sporotrichosis is the most common presentation. Most patients are clinically healthy with a previous local hand injury that became infected while cleaning a fish tank, or patients may sustain scratches or puncture wounds from saltwater fish, shrimp, or fins contaminated with M. marinum. Diagnosis is made from culture and histologic examination of biopsy material, along with a compatible history of exposure. There is no treatment of choice for M. marinum; traditionally, the regimen has been a combination of rifampin and ethambutol or monotherapy with doxycycline, minocycline, clarithromycin, or trimethoprim-sulfamethoxazole, given for a minimum of 3 months. Clarithromycin has been used increasingly because of good clinical efficacy and minimal side effects, although published experience is limited. Because M. marinum grows better at lower temperatures, local heat can produce amelioration.


The rapid-growing species M. abscessus, M. fortuitum, and M. chelonae are probably the most common NTM involved in cases of community-acquired infections of skin and soft tissue. Localized traumatic injury, such as puncture wounds from stepping on a nail, and open lacerations or fractures are the usual scenarios. An outbreak in California was associated with contamination of a post–leg shaving solution, causing mycobacterial abscesses of the lower extremities.5 Occasionally, these infections may involve slow-growing species, including M. avium complex, M. kansasii, and M. terrae-nonchromogenicum complex.


Sporadic cases of nosocomial skin and soft tissue disease have also been described as possible point source outbreaks. These cases include infections of long-term IV or peritoneal catheters, postinjection abscesses, surgical wound infections such as those after cardiac bypass surgery, and augmentation mammaplasty. In ophthalmology, rapid-growing species may cause keratitis and corneal ulceration after surgery, as well as infection after local accidental trauma. Clustered outbreaks or pseudo-outbreaks of mycobacterial skin, soft tissue, or bone infections have been described and usually result from contaminated fluids such as ice made from tap water, water, injectable medicines, and topical skin solutions. Most of these outbreaks have involved the rapid-growing species M. fortuitum and M. abscessus. The reservoir for these outbreaks has generally been municipal or distilled (hospital) water supplies. These and other species such as M. avium complex and M. xenopi are incredibly resistant, can endure temperatures of 45° C and higher (MAI complex and M. xenopi), and may resist the activity of commonly used disinfectants.


Diagnosis of all types of skin and soft tissue infections is made by culture of specific NTM from drainage material or tissue biopsy (swabs are useless). Treatment may include amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, sulfonamides, and imipenem for the M. fortuitum group, whereas only amikacin, cefoxitin, imipenem, and clarithromycin or only amikacin, imipenem, tobramycin, and clarithromycin have activity against M. abscessus and M. chelonae, respectively. Clarithromycin is generally the first drug of choice for localized disease caused by M. fortuitum, M. chelonae, and M. abscessus, although its use in combination with at least one other drug is preferred. The duration of therapy is usually 4 to 6 months. Antituberculous agents have no efficacy against any of the rapidly growing mycobacteria other than ethambutol for M. smegmatis. Treatment of slow-growing species is similar to that for chronic lung disease, except that the duration of therapy may only be 6 to 12 months.


Two unusual species causing skin and soft tissue infections in select situations are M. ulcerans and M. haemophilum. M. ulcerans is not endemic in the United States, but is endemic in areas of Australia and tropical locations, where it is commonly known as the Buruli ulcer. This infection progresses from an itchy nodule, most often on the extremities, to a necrotic lesion that may result in severe deformity. Treatment success is common in early disease with excisional surgery, rifampin, sulfonamides, and clofazimine but, for advanced ulcerative disease, therapeutic response has generally been poor. Surgical débridement and skin grafting then become the usual therapeutic measures of choice. Studies have suggested that clarithromycin is highly active in vitro.


The second unusual species, M. haemophilum, causes cutaneous infections, primarily of the extremities, in immunosuppressed patients, especially in the setting of organ transplantation, long-term high-dose steroid use, or HIV. A review by Saubolle and coworkers has cited more than 50 cases of M. haemophilum, with almost 80% of them involving skin and soft tissue infections. Careful attention to culture technique is essential because this species requires heme or iron to grow in culture. Therapy for this species usually includes clarithromycin and rifampin or rifabutin.

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Jul 18, 2017 | Posted by in GENERAL SURGERY | Comments Off on Nontuberculous Mycobacterial Disorders

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