Published ahead of print on January 17, 2008, doi:10.1164/rccm.200709-1311PP Am. J. Respir. Crit. Care Med., Volume 177, Number 7, April 2008, 680-685 A more recent version of this article appeared on April 1, 2008
Submitted on September 5, 2007 Immune Reconstitution and "Unmasking" of Tuberculosis during Antiretroviral TherapyStephen D Lawn1*,1 University of Cape Town, Institute for Infectious Disease and Molecular Medicine, The Desmond Tutu HIV Centre, Faculty of Health Sciences, Cape Town, South Africa; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Clinical Research Unit, London, United Kingdom, 2 Department of Medicine, University of Cape Town, Institute of Infectious Disease and Molecular Medicine, Mycobacterial Immunology, Cape Town, South Africa; Imperial College, Division of Medicine, London, United Kingdom; National Institute for Medical Research, Mill Hill, London, United Kingdom, 3 Department of HIV Medicine, Royal Free Hospital, London, United Kingdom, 4 University of Cape Town, Institute for Infectious Disease and Molecular Medicine, The Desmond Tutu HIV Centre, Faculty of Health Sciences, Cape Town, South Africa * To whom correspondence should be addressed. E-mail: stevelawn{at}yahoo.co.uk.
Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed sub-clinical disease present prior to starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune reconstitution disease -a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of sub-clinical disease. However, while some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time-dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (i) shortening of the time for sub-clinical TB to become symptomatic (a phenomenon often referred to as 'unmasking'); (ii) increased rapidity of initial onset of TB symptoms, and (iii) heightened intensity of clinical manifestations. We suggest that the term 'ART-associated TB' be used to refer collectively to all cases of TB presenting during ART and that 'immune reconstitution disease' be used to refer to the sub-set of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease. Key words: HIV, tuberculosis, antiretroviral, immune reconstitution, IRIS
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