Practice Essentials
Atypical mycobacterial infection has been described in the medical literature since the mid-1950s. [1, 2, 3] The development and introduction of a rapid radiometric mycobacterial detection system has advanced the field of mycobacteriology over the past 20 years. This method has allowed the distinction of Mycobacterium tuberculosis from other mycobacteria and enabled the performance of antimicrobial susceptibility testing of mycobacteria. The increased frequency of atypical mycobacterial infection stems from advances in the diagnostic procedures concerning the infection paired with the prevalence of mycobacterial disease in immunocompromised patients infected with the human immunodeficiency virus (HIV).
Nontuberculous mycobacteria (NTM) are classified based on their growth rates. Rapidly growing NTM are categorized into pigmented and nonpigmented species. Mycobacterium fortuitum complex is nonpigmented and includes the M fortuitum group and the Mycobacterium chelonae/abscessus group. The pigmented species are rarely associated in clinical disease and include Mycobacterium phlei, Mycobacterium aurum, Mycobacterium flavescens, Mycobacterium vaccae, Mycobacterium neoaurum, and Mycobacterium thermoresistible. Mycobacterium smegmatis may be either pigmented or nonpigmented. [4, 5, 6, 7, 8]
Pathophysiology
Atypical mycobacteria are obligate aerobes that can be found in the environment in soil, water, vegetables, and even in domestic animals and dairy products. Mycobacterium avium complex (MAC) and Mycobacterium scrofulaceum are associated with lymphadenitis in immunocompetent children. All nodes in the cervical chain can be affected, but the nodes of the submandibular region appear to be the most commonly involved. [9] Disseminated infections are usually associated with HIV infection. [10] Host immunity seems to play a major role because a low CD4+ lymphocyte count (fewer than 100 cells/μL for adults and age-appropriate decreases in children) is associated with an increased frequency of disseminated MAC disease.
Some cytokines such as interleukin (IL)–1 alpha and IL-6 enhance extracellular growth of the organism. IL-6 also promotes intracellular growth of MAC, apparently by down-regulating membrane receptors for tumor necrosis factor (TNF)–alpha. [11, 12, 13] Other cytokines, such as interferon (IFN)–gamma and IL-2, work in the other direction. IL-2 enhances lymphocyte proliferation and cytotoxic activity and upregulates production of IFN-gamma. [14, 15, 16] Ongoing studies are establishing the additional roles of cytokines.
In immunocompromised patients, the intestinal tract is the primary route for MAC infection, followed by the respiratory tract as a secondary portal of entry. [17, 18] CD4+ lymphocytes but not CD8+ or gamma delta+ lymphocytes are required for host protection against MAC and dissemination through the intestinal route. [19] Abnormal immune response to MAC colonization may cause invasion of the epithelial cells of the gastrointestinal tract, followed by disseminated disease. [18] In one series of adult patients infected with HIV with positive respiratory or stool isolates, 75% developed mycobacteremia within a year (mean 6 mo) after the isolation. A preceding stool culture positive for isolates was present in 25-36% of the patients. [18] Pulmonary disease in adults without acquired immunodeficiency syndrome (AIDS) may occur.
Disseminated MAC in children without HIV has been described in the literature. It is associated in some cases with IFN-gamma receptor ligand-binding deficiency, which is a recently identified autosomal recessive inherited disorder. [20, 21, 22] Affected children show a severe and apparently selective susceptibility to weakly pathogenic mycobacteria (either Bacillus Calmette-Guérin or NTM. [23] This condition has revealed the importance of IFN-gamma in the control of mycobacterial disease in humans. The importance of immune reconstitution produced by highly active antiretroviral therapy (HAART) in reducing susceptibility to MAC infection may provide clues to the critical role of the host immune defense and may establish the basis for the use of immunotherapy in disseminated MAC disease.
MAC has also been associated with the pulmonary infection and bronchiectasis in elderly women without a preexisting lung disease. Pulmonary MAC infection in this population is believed to be due to voluntary cough suppression that results in stagnation of secretions, which is suitable for growth of the organisms. This particular type of infection is also referred to as Lady Windermere syndrome. [24]
Etiology
Numerous atypical mycobacterial infections are known. The most common forms of diseases are chronic pulmonary disease resembling tuberculosis (occurring mainly in adults), cervical adenopathy in children, skin and soft tissue infections, and disseminated disease in immunocompromised persons. [9, 18] Lymphadenitis is the most common manifestation in children. [9, 25] However, progressive immunodeficiency due to infection with HIV appears to be the most significant factor for disseminated MAC disease. [26, 18, 27]
A unique MAC syndrome that develops in patients with AIDS in the first 1-2 months following the initiation of HAART has been described by 3 groups of investigators. [28, 29, 30, 31] The symptom consists of fever and focal MAC lymphadenitis, with a blood culture negative for mycobacteria in most cases. The symptom is also known as immune reconstitution syndrome. It may occur in patients who already had subclinical MAC disease that becomes unmasked by HAART. The atypical mycobacteria observed in children are M avium-intracellulare complex, M scrofulaceum, and, rarely observed in children with AIDS, M kansasii.
Mycobacterium marinum is the causative agent of swimming pool granuloma. However, both rapidly growing and slow-growing species of NTM have been implicated in chronic granulomatous infections. Those infections mostly involve tendon sheaths, bursae, bones, and joints after direct inoculation through accidental trauma, surgical incisions, or puncture wounds. [4, 32] Tenosynovitis of the hand secondary to MAC and M marinum has been described. Osteomyelitis of the sternum caused by M abscessus has been found in clustered and sporadic outbreaks. M fortuitum and M chelonae strains, also known as the rapidly growing organisms, have occasionally been implicated in wound, soft tissue, pulmonary, and middle ear infections. [33, 9]
A population-based study by Marras et al that included data from 417,494 patients 66 years of age and older who have been treated for COPD, asthma, or both reported that adjusted odds ratios for NTM pulmonary disease were statistically significant for current inhaled corticosteroids use overall (AOR, 1.86). Adjusted odds ratio was statically significant for fluticasone (AOR, 2.09). [34]
A meta-analysis by Loebinger et al found that NTM pulmonary disease is significantly more likely to occur in patients with comorbid respiratory disease. Bronchiectasis is associated with the highest risk; other conditions significantly associated with increased risk include a history of tuberculosis, interstitial lung disease, and chronic obstructive pulmonary disease. [35]
Epidemiology
United States statistics
In the pre-HIV/AIDS era, pulmonary disease and lymphadenitis due to atypical mycobacteria were found all across the United States, with most cases located in the central and southern regions. [25] Because infections by NTM were not reportable in the past, few systematically collected data about their frequency and distribution are available. Early in the HIV epidemic, MAC disease was quite common in patients with AIDS. [36] However, frequency is decreasing among patients with HIV because of new treatment modalities, such as combination therapy with nucleoside reverse transcriptase inhibitors and protease inhibitors, as well as antimycobacterial prophylaxis.
International statistics
Distribution of atypical mycobacterial infection is worldwide. Mycobacterium ulcerans, the agent of a chronic ulcerative skin infection called Buruli ulcer, is widespread in Ghana, Cote d'Ivoire, Senegal, Uganda, and most central African countries. [37, 38, 39, 40]
Race-, sex-, and age-related demographics
Atypical mycobacterial infection has no racial predilection.
Both sexes are affected with equal frequency.
MAC and M scrofulaceum are associated with lymphadenitis in immunocompetent children aged 1-5 years. [9] Although disseminated MAC disease rarely occurs during the first year of life, its frequency increases with age and declining CD4+ lymphocyte count in children infected with HIV. [41, 42, 43]
Prognosis
In the early years of the HIV epidemic, descriptive and retrospective studies were mostly aimed at defining the population of children infected with HIV at risk for MAC infection and at analyzing the predictors of survival in patients with AIDS and disseminated MAC disease. [42, 44, 45] MAC was a contributor to mortality in HIV infection, and its presence was considered an indication that death is imminent. [26, 46]
The development of HAART has resulted in marked changes in the outcome of HIV disease, with reductions in hospitalizations and death as well as opportunistic infections, including MAC. [31] Established treatment, previously discussed, has reduced the morbidity and mortality caused by disseminated MAC disease. MAC infection is still a problem in developing countries where access to antiretroviral therapy is still limited and in severely immunocompromised patients whose adherence and tolerance to treatment raise a lot of questions. The prognosis for children without HIV with disseminated mycobacterial infection secondary to IFN-gamma receptor ligand-binding deficiency is poor.
Morbidity/mortality
Disseminated MAC disease is the second most common opportunistic infection in children with HIV infection after Pneumocystis carinii pneumonia. In the era before HAART, the frequency of disseminated MAC disease varied with age, history of prior opportunistic infections, and immunologic studies. [47] Disseminated MAC infection may occur in children with HIV and adolescents who are severely immunocompromised after starting antiretroviral therapy. [48]
A review of 58 deaths from a cohort monitored during a 7-year period in the pre-HAART era, with a mean age of 4.43 years, has shown that MAC was the most common isolate at the time of death, followed by P carinii pneumonia. [49] The risk increases in children infected with HIV with a CD4+ cell count fewer than 750/µL who are younger than 1 year; with a cell count fewer than 500/mL in children aged 1-2 years; with a cell count fewer than 75/µL in children aged 2-6 years; and with a cell count of 50/µL in children older than 6 years, the same threshold as in adults infected with HIV. [50, 51, 52] Atypical mycobacterial infection has been described in children with cystic fibrosis (CF). Although MAC is more common in the United States in the population with CF, M abscessus and M avium are reported to be more common in Europe. [53, 54]
Complications
Gastrointestinal obstruction and gastrointestinal bleeding caused by bulky intra-abdominal adenopathy or extensive ileal disease have been reported. [55] Pulmonary complications from disseminated MAC disease are uncommon in children. Culture and histologic evidence of infection have been reported in the heart, eye (keratitis), brain, skin, thyroid, tongue, adrenals, stomach, pancreas, skeletal system, and peripheral nerves. [56, 57, 58]
