Human immunodeficiency virus-associated immune reconstitution disease

Abstract

Since 1996, when the use of potent combination antiretroviral therapy for patients with human immunodeficiency virus (HIV) infection became common, there have been several reports describing localized inflammatory disease caused by opportunistic infectious agents that developed soon after the patient began combination therapy. Generally, these cases occur within the first few months after combination therapy is begun, are self-limited in duration, and involve either worsening of a previously resolved opportunistic infection or the appearance of a previously subclinical infection. Several recent review articles have discussed this phenomenon, which is now generally called immunorestoration disease or immune reconstitution disease (1,2). The report by Domingo et al (3) in this issue of The American Journal of Medicine adds to the fund of knowledge about these unusual clinical syndromes (3). The authors describe herpes zoster infection in 24 of 316 HIVinfected patients who started combination antiretroviral therapy. In all cases, zoster occurred within 4 months of initiation; all cases were localized and responded clinically to standard acyclovir therapy. The source of these 316 patients was not described, so it is not clear if this was a representative sample of HIV-infected patients or whether some kind of selection bias was introduced. Nevertheless, in a case-control analysis of the data, a remarkable finding was that patients in whom zoster developed soon after starting recombination therapy had a significantly greater increase in their peripheral blood absolute CD8 T lymphocyte count than did patients who did not develop zoster. In a multivariate analysis, the only clinical or laboratory characteristic that was associated with the development of zoster was an increase in the T-lymphocytes that were CD8. These findings confirm those from several smaller studies that reported a high incidence of herpes zoster infection among HIV-infected patients who had recently begun combination therapy (4,5). One of these studies also reported that the risk of zoster correlated with an increase in the percentage of CD8 T-lymphocytes (5). Reports such as these have obvious value to clinicians. Because HIV-related immune reconstitution disease appears to result from improved immune function, clinicians and patients can be reassured that, despite the signs and symptoms of infection, the overall prognosis is excellent for patients who continue both antiretroviral therapy and antimicrobial treatment for the opportunistic infection. In addition, awareness of this syndrome can prevent unnecessary invasive diagnostic procedures and hospitalization. For example, I have seen several patients with acquired immunodeficiency syndrome (AIDS) who had quiescent disseminated Mycobacterium avium complex infection and who, after initiating combination antiretroviral therapy, developed localized retroperitoneal or perihilar mycobacterial abscesses that resolved with antiretroviral and antimycobacterial therapy. No surgical or invasive diagnostic procedures were required. These reports may also advance our knowledge of how to best prevent and control opportunistic infections. It is perhaps surprising to consider how little we understand about the mechanisms of pathogen-specific protective immunity for AIDS-related opportunistic infections. Although the human immune responses to infection with HIV-associated pathogens such as Pneumocystis carinii, M. avium complex, and cytomegalovirus are well-described, the critical components of the protective immune responses needed to prevent opportunistic disease with these pathogens are still not clear. There have been no studies of the protective immune responses to human strains of P. carinii in AIDS patients with and without P. carinii pneumonia. Likewise, the relative importance of human adaptive versus innate immune response in protecting AIDS patients against disseminated M. avium complex infection is unresolved. Of the most serious AIDS-associated opportunistic infections, cytomegalovirus is the pathogen for which we probably have the greatest knowledge about protective immunity. That knowledge stems primarily from studies involving HIV-negative bone marrow transplant recipients in whom the critical component of protective immunity is cytomegalovirus-specific, CD4 T-lymphocytedependent, cytotoxic (CD8) T-lymphocyte activity (7). Most studies of cytomegalovirus-protective immunity in AIDS patients have focused on virus-specific CD4 T-cell Am J Med. 2001;110:662– 663. From the Department of Medicine, University of California San Francisco, and the Positive Health Program, San Francisco General Hospital, San Francisco, California. Requests for reprints should be addressed to Mark A. Jacobson, Department of Medicine, University of California San Francisco, and the Positive Health Program, San Francisco General Hospital, 995 Potrero, San Francisco, California 94110.