If it isn't something, it's something else ...

Disseminated disease due to nontuberculous mycobacteria (NTM) is among the most severe infections in persons with advanced HIV infection. The overwhelming majority (>90%) of these infections are caused by Mycobacterium avium complex (MAC). (1-6) Disseminated disease due to MAC occurs only in persons who are severely immunocompromised with an average CD4+ T-cell count at presentation less than 25 cells/[micro]L. (3,4) Untreated, disseminated MAC is associated with very high mortality. In one study from the preantiretroviral era, only 13% of AIDS patients diagnosed with disseminated MAC survived one year without treatment. (7)

Successful treatment of disseminated MAC in persons with AIDS is accomplished with macrolide-containing treatment regimens combined with effective antiretroviral therapy. MAC treatment may be stopped with a low risk of reoccurrence in patients who are asymptomatic, and have achieved a CD4+ T-cell count of over 100 cells/[micro]L for at least 12 months. (8) Because of the severe morbidity and mortality associated with disseminated MAC, preventive therapy with a macrolide is recommended for all HIV-infected patients with less than 50 CD4+ T-cells/[micro]L. (9) Preventive therapy may be discontinued for patients who have had a nadir CD4+ T-cell count less than 50 cells/[micro]L and, due to antiretroviral treatment, have a rise in CD4+ T-cell count to more than 100 cells/[micro]L for at least 3 months. (9) Together, the development of highly active anti-retroviral (HAART) therapy for AIDS and effective macrolide-based prophylaxis and treatment regimens against disseminated MAC almost relegated MAC infection in AIDS patients to a problem of the past, but not quite.

The report by Corrales-Medina et al in this issue of the Southern Medical Journal reminds us that not only has disseminated MAC infection in AIDS patients not been eradicated, but that MAC infection can appear in unexpected and, in this instance, a particularly pernicious form. (10) In addition to the common clinical presentation of MAC infection in AIDS patients, persons who have initiated antiretroviral therapy can develop local inflammatory symptoms related to their underlying MAC infection, a syndrome that has been labeled immune reconstitution inflammatory syndrome (IRIS). (11-14) Lymphadenopathy, with swollen and painful cervical, axillary, or inguinal nodes, is the most common manifestation of this syndrome. While there is not a precise definition of IRIS, there appear to be at least 2 components. First, there is an augmented inflammatory response following HAART therapy which leads to clinical worsening despite improvements in HIV viral loads and CD4+ cell counts. Second, treatment frequently includes protecting the patient against the effects of the inflammatory response, without compromising antimicrobial or antiviral therapy.

For patients such as those in this report, an intense inflammatory response associated with immune reconstitution may be the initiating event for the destructive process in bone and associated abscess formation. (10) It is not clear, however, that this syndrome meets the second criterion, as the role of anti-inflammatory therapy for amelioration of this process is not established. (10) Clearly, however, the syndrome described in this report represents a progressive focal MAC infection that would be difficult to treat effectively even for patients with intact immune function.

The syndrome described in this report also strongly suggests hematogenous seeding of the vertebral bodies most likely at a time of very poor immune function and associated with very low CD4+ cell counts and high HIV viral loads. Autopsy studies have demonstrated that AIDS patients with MAC have involvement of most internal organs, even if localizing signs and symptoms are not apparent. (15) This seeding may be due to subclinical and/or transient MAC dissemination in some patients not diagnosed with disseminated MAC and treated only with prophylaxis regimens against disseminated MAC. Alternatively, MAC seeding also occurs in some patients who have frank and clinically recognizable MAC dissemination that is not completely eliminated with multidrug antimycobacterial therapy and immune reconstitution. Early recognition of vertebral infection with MAC could prompt alternative treatment pathways with either initiation of multidrug therapy for patients on prophylaxis regimens or prolonged multidrug treatment of MAC for those already receiving therapy for disseminated MAC.

There are too few cases of this syndrome to define confidently the natural history of this process. Other IRIS associated MAC processes reportedly have good prognoses but several factors could blunt or inhibit a favorable response with this syndrome. (14) MAC is difficult to treat effectively under any circumstance and requires multiple potentially toxic and expensive drugs over long periods of time. Aggressive drug therapy including parenteral agents may be necessary to prevent potentially debilitating vertebral destruction. MAC therapy is further complicated in these patients by the location of the infection, the need for surgical intervention (for abscess drainage or spine stabilization), and the potential for significant and severe drug-drug interactions between HAART agents and MAC antibiotics. As noted, it is unknown if anti-inflammatory strategies are beneficial for this syndrome.

This report raises a number of important questions about how to prevent and manage this syndrome in the future. Who are the AIDS patients most at risk for developing this syndrome? Are they patients with diagnosed disseminated MAC, patients who have low CD4+ cell counts and MAC isolated from sputum or stool without positive blood cultures, or any patient who has very low CD4+ cell counts? Does prophylaxis against MAC while the CD4+ cell count is low protect against this syndrome? Does the timing of discontinuation of MAC therapy or prophylaxis influence the onset of this syndrome? Are modifications necessary for current recommendations about cessation of MAC treatment and prophylaxis? And, lastly, can a diagnostic strategy be devised to identify patients with an occult focus of active MAC infection in the spine? It will take many more reports such as this one to answer these important questions.

References

1. Zakowski P, Fligiel S, Berlin OGW, et al. Disseminated Mycobacterium avium-intracellulare infection in homosexual men dying of acquired immunodeficiency. JAMA 1982;248:2980-2982.

2. Greene JB, Sidhu GS, Lewin S, et al. Mycobacterium avium-intracellulare a cause of disseminated life-threatening infection in homosexuals and drug abusers. Ann Intern Med 1982;97:539-546.

3. Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992;165:1082-1085.

4. Horsburgh CR Jr., Gettings J, Alexander LN, et al. Mycobacterium avium-complex disease among patients infected with human immunodeficiency virus, 1985-2000. Clin Infect Dis 2001;33:1938-1943.

5. French AL, Benator DA, Gordin FM. Nontuberculous mycobacterial infections. Medical Clinics of North America 1997;81:361-379.

6. Horsburgh CR. Mycobacterium avium complex infection in the acquired immuno-deficiency syndrome. N Engl J Med 1991;324:1332-1338.

7. Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infections in AIDS. N Engl J Med 1993;329:828-833.

8. Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons. Morb Mortal Wkly Rep 2002;51 (RR-8):1-52.

9. El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med 2000;342:1085-1092.

10. Corrales-Medina V, Symes S, Valdivia-Arenas M. et al. Localized mycobacterium avium complex infection of vertebral and paravertebral structures in and HIV patient on highly active antiretroviral therapy. South Med J 2006;99:174-177.

11. Hassell M, French MA. Mycobacterium avium infection and immune restoration disease after highly active antiretroviral therapy in a patient with HIV and normal CD4+ counts. Eur J Clin Microbiol Infect Dis 2001;20:889-891.

12. Phillips P, Kwiatkowski MB, Coplan M, et al. Mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy JAIDS 1999;20:122-128.

13. Lange CG, Lederman MM. Immune reconstitution with antiretroviral therapies in chronic HIV-I infection. Journal of Antimicrobial Chemotherapy 2003;51:1-4.

14. Shelburne AS, Hamill RJ. The Immune Reconstitution Inflammatory Syndrome. AIDS Rev 2003;5:67-79.

15. Horsburgh CR Jr, Mason UG, Farhi DC, et al. Disseminated infection with Mycobacterium avium-intracellulare. Medicine 1985;64:36-48.</p> <pre> Drive thy business or it will drive thee. --Benjamin Franklin </pre> <p>David E. Griffith, MD

From the University of Texas Health Center, Tyler, TX.

Reprint requests to David E. Griffith, Professor of Medicine, University of Texas Health Center, Tyler 11937 US Highway 271 Tyler, TX 75708. Email: [e-mail]

Accepted October 10, 2005.