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Mycobacterium avium complex (MAC) refers to multiple related species of nontuberculous mycobacteria (e.g., M.avium, M. intracellulare, M. paratuberculosis) that are widely distributed in the environment. Comprehensive guidelines on the diagnosis, prevention, and treatment of nontuberculous mycobacterial diseases were recently published (201Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/ IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367-416.). These guidelines highlight the tremendous advances in laboratory methods in mycobacteriology that have expanded the number of known nontuberculous mycobacterial species from 50 in 1997 to 125 in 2006.

MAC was the second most common OI among children with HIV infection in the United States after PCP during the pre-HAART era, but its incidence has greatly decreased from 1.3-1.8 episodes per 100 person-years during the pre-HAART era to 0.14-0.2 episodes per 100 person-years during the HAART era (3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300., 4Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120:00 100–9.). MAC is ubiquitous in the environment and presumably is acquired by routine exposures through inhalation, ingestion, or inoculation (202Perez Mato S, van Dyke RB. Pulmonary infections in children with HIV infection. Semin Respir Infect 2002;17:33-46. Vol. 58 / RR-11 Recommendations and Reports 105). A recent populationbased study in Florida of adults and children associated soil exposure, along with black race and birth outside the United States, with MAC infection (203Reed C, von Reyn CF, Chamblee S, et al. Environmental risk factors for infection with Mycobacterium avium complex. Am J Epidemiol 2006;164:32-40.). Respiratory and GI colonization can act as portals of entry that can lead to disseminated infection (204Peacock KH, Lewis L, Lavoie S. Erosive mediastinal lymphadenitis associated with Mycobacterium avium infection in a pediatric acquired immunodeficiency syndrome patient. Pediatr Infect Dis J 2000;19:576-8.).

MAC can appear as isolated lymphadenitis among HIVinfected children. Disseminated infection with MAC in pediatric HIV infection rarely occurs during the first year of life; its frequency increases with age and declining CD4 count, and it is a complication of advanced immunologic deterioration among HIV-infected children (202Perez Mato S, van Dyke RB. Pulmonary infections in children with HIV infection. Semin Respir Infect 2002;17:33-46. Vol. 58 / RR-11 Recommendations and Reports 105, 205Hartmann P, Plum G. Immunological defense mechanisms in tuberculosis and MAC-infection. Diagn Microbiol Infect Dis 1999; 34:147-52., 206Keller C, Kirkpatrick S, Lee K, et al. Disseminated Mycobacterium avium complex presenting as hematochezia in an infant with rapidly progressive acquired immunodeficiency syndrome. Pediatr Infect Dis J 1996;15:713-5.). Disseminated MAC can occur at higher CD4 cell counts among younger HIV-infected children than among older children or adults, especially among HIV-infected children aged <2 years.

Respiratory symptoms are uncommon among HIV-infected children who have disseminated MAC, and isolated pulmonary disease is rare. Early symptoms can be minimal and may precede mycobacteremia by several weeks. Symptoms commonly associated with disseminated MAC infection among children include persistent or recurrent fever, weight loss or failure to gain weight, sweats, fatigue, persistent diarrhea, and persistent or recurrent abdominal pain. Lymphadenopathy, hepatomegaly, and splenomegaly can occur. Laboratory abnormalities include anemia, leukopenia, and thrombocytopenia. Although serum chemistries are usually normal, some children may have elevated alkaline phosphatase or lactate dehydrogenase. These signs and symptoms also are relatively common in the absence of disseminated MAC among HIV-infected children with advanced immunosuppression.

Procedures used to diagnose MAC in children are the same as those used for HIV-infected adults (16CDC. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.). MAC is definitively diagnosed by isolation of the organism from blood or from biopsy specimens from normally sterile sites (e.g., bone marrow, lymph node). Multiple mycobacterial blood cultures over time may be required to yield a positive result. Use of a radiometric broth medium or lysis-centrifugation culture technique can enhance recovery of organisms from blood.

Histology demonstrating macrophage-containing acid-fast bacilli strongly indicates MAC in a patient with typical signs and symptoms, but culture is essential to differentiate nontuberculous mycobacteria from M. tuberculosis, determine which nontuberculous mycobacterium is causing infection, and perform drug-susceptibility testing. Testing of MAC isolates for susceptibility to clarithromycin or azithromycin is recommended (BIII). The BACTEC^™method for radiometric susceptibility testing can be used. Susceptibility thresholds for clarithromycin are minimal inhibitory concentrations of ≥32 µg/mL and a minimal inhibitory concentration of ≥256 µg/mL for azithromycin (207Wong DA, Yip PC, Cheung DT, et al. Simple and rational approach to the identification of Mycobacterium tuberculosis, Mycobacterium avium complex species, and other commonly isolated mycobacteria. J Clin Microbiol 2001;39:3768-71.).

On the basis of both randomized controlled trials and observational data, primary prophylaxis for MAC can be safely discontinued in HIV-infected adults who respond to antiretroviral therapy with an increase in CD4 count. In a study of discontinuing OI prophylaxis among HIV-infected children whose CD4 percentages were ≥20% for those aged >6 years and ≥25% for those aged 2-6 years, 63 HIV-infected children discontinued MAC prophylaxis, and no MAC events were observed during ≥2 years of follow up (46Nachman S, Gona P, Dankner W, et al. The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis. Pediatrics 2005;115:e488-94.). On the basis of both these findings and data from studies in adults, primary prophylaxis can be discontinued in HIV-infected children aged >2 years receiving stable HAART for ≥6 months and experiencing sustained (>3 months) CD4 cell recovery well above the age-specific target for initiation of prophylaxis (e.g., similar to adults, >100 cells/mm³, for children aged ≥6 years; and >200 cells/mm³ for children aged 2-5 years) (BII). No specific recommendations exist for discontinuing MAC prophylaxis in HIV-infected children aged <2 years.

Clinically, most patients improve substantially during the first 4-6 weeks of therapy. A repeat blood culture for MAC should be obtained 4-8 weeks after initiation of antimycobacterial therapy in patients who fail to respond clinically to their initial treatment regimen. Improvement in fever can be expected within 2-4 weeks after initiation of appropriate therapy. However, for those with more extensive disease or advanced immunosuppression, clinical response might be delayed, and elimination of the organism from the blood might require up to 12 weeks of effective therapy.

IRIS in patients receiving MAC therapy during HAART has been reported among HIV-infected adults and children (211Race EM, Adelson-Mitty J, Kriegel GR, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet 1998;351:252-5., 212Phillips P, Chan K, Hogg R, et al. Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program. Clin Infect Dis 2002;34:371-8., 213Steenhoff AP, Wood SM, Shah SS, et al. Cutaneous Mycobacterium avium complex infection as a manifestation of the immune reconstitution syndrome in a human immunodeficiency virus-infected child. Pediatr Infect Dis J 2007;26:755-7.). New onset of systemic symptoms, especially fever or abdominal pain, leukocytosis, and focal lymphadenitis (cervical, thoracic, or abdominal) associated with preexisting but relatively asymptomatic MAC infection has occurred after start of HAART. Before initiation of HAART among HIV-infected children with low CD4 counts, an assessment for MAC should be considered and treatment provided if MAC is identified. However, recent data indicate that MAC prophylaxis with azithromycin did not prevent IRIS (212Phillips P, Chan K, Hogg R, et al. Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program. Clin Infect Dis 2002;34:371-8.). Children with moderate symptoms of IRIS can be treated symptomatically with nonsteroidal anti-inflammatory drugs or, if unresponsive to nonsteroidals, a short course (e.g., 4 weeks) of systemic corticosteroid therapy while continuing to receive HAART (CIII).

Adverse effects from clarithromycin and azithromycin include nausea, vomiting, abdominal pain, abnormal taste, and elevations of liver transaminase levels or hypersensitivity reactions. The major toxicity associated with ethambutol is optic neuritis, with symptoms of blurry vision, central scotomata, and red-green color blindness, which usually is reversible and rare at doses of 15-25 mg/kg among children with normal renal function. Assessments of renal function, ophthalmoscopy, and (if possible) visual acuity and color vision should be performed before starting ethambutol and monitored regularly during treatment with the agent (AIII).

Patients receiving clarithromycin plus rifabutin should be observed for the rifabutin-related development of leukopenia, uveitis, polyarthralgias, and pseudojaundice. Tiny, almost transparent, asymptomatic peripheral and central corneal deposits that do not impair vision have been observed in some HIV-infected children receiving rifabutin as part of a multidrug regimen for MAC (210Smith JA, Mueller BU, Nussenblatt RB, Whitcup SM. Corneal endothelial deposits in children positive for human immunodeficiency virus receiving rifabutin prophylaxis for Mycobacterium avium complex bacteremia. Am J Ophthalmol 1999;127:164-9.).

Treatment failure is defined as the absence of clinical response and the persistence of mycobacteremia after 8-12 weeks of treatment. Repeat susceptibility testing of MAC isolates is recommended in this situation, and a new multidrug regimen of two or more drugs not previously used and to which the isolate is susceptible should be administered (AIII). Drugs that should be considered for this scenario include rifabutin, amikacin, and a quinolone. In HIV-infected adults, data from treating MAC in HIV-uninfected patients indicate an injectable agent such as amikacin or streptomycin should be considered (CIII) (201Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/ IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367-416.). Because dosing of these agents in children can be problematic, drug-resistant disseminated MAC should be treated with input from an expert in this disease (AIII). Optimization of antiretroviral therapy is especially important adjunct to treatment for patients in whom initial MAC therapy has failed.

Children with a history of disseminated MAC should be administered lifelong prophylaxis to prevent recurrence (AII).

On the basis of immune reconstitution data in adults and data in children discontinuing primary prophylaxis, some experts recommend discontinuation of secondary prophylaxis in HIV-infected children aged >2 years who have completed ≥12 months of treatment for MAC, who remain asymptomatic for MAC, and who are receiving stable HAART (i.e., HAART not requiring change for viral or immune failure) and have sustained (≥6 months) CD4 cell recovery well above the agespecific target for initiation of primary prophylaxis (e.g., similar to adults, >100 cells/mm³, for children aged >6 years and >200 cells/mm³ for children aged 2-6 years) (CIII). Secondary prophylaxis should be reintroduced if the CD4 count falls below the age-related threshold.