Atypical Mycobacterial Infection

Updated: Jan 07, 2015
  • Author: Arry Dieudonne, MD; Chief Editor: Russell W Steele, MD  more...
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Overview

Background

Atypical mycobacterial infection has been described in the medical literature since the mid 1950s. [1, 2] 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. [3, 4, 5, 6]

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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. [7] Disseminated infections are usually associated with HIV infection. [8] 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. [9, 10, 11] 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. [12, 13, 14] 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. [15, 16] CD4+ lymphocytes but not CD8+ or gamma delta+ lymphocytes are required for host protection against MAC and dissemination through the intestinal route. [17] Abnormal immune response to MAC colonization may cause invasion of the epithelial cells of the gastrointestinal tract, followed by disseminated disease. [16] 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. [16] 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. [18, 19, 20] Affected children show a severe and apparently selective susceptibility to weakly pathogenic mycobacteria (either Bacillus Calmette-Guérin or NTM. [21] 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. [22]

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Epidemiology

Frequency

United States

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. [23] 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. [24] 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

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. [25, 26, 27, 28]

Mortality/Morbidity

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. [29] Disseminated MAC infection may occur in children with HIV and adolescents who are severely immunocompromised after starting antiretroviral therapy. [30]

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. [31] 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. [32, 33, 34] 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. [35, 36]

Race

Atypical mycobacterial infection has no racial predilection.

Sex

Both sexes are affected with equal frequency.

Age

MAC and M scrofulaceum are associated with lymphadenitis in immunocompetent children aged 1-5 years. [7] 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. [37, 38, 39]

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