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Immune reconstitution syndrome is not a single entity

Price, Patriciaa,b; Lim, Andrewa,b; French, Martyna,b

doi: 10.1097/QAD.0b013e3282f82b86

aClinical Immunology and Immunogenetics, Royal Perth Hospital, Australia

bPathology and Laboratory Medicine, University of Western Australia, Australia.

Received 7 January, 2008

Accepted 14 January, 2008

Correspondence to Patricia Price, Perth, Australia. E-mail:

The article presented by Cianchetta-Sivori et al. [1] addresses a very important issue with regard to the pathogenesis and prediction of immune reconstitution syndrome (IRS). Studies of this type have been limited by access to longitudinal sample sets and follow-up data from patients beginning antiretroviral therapy with low CD4 T-cell counts. However, we are concerned that this article suggests a predictive marker without specifying the initiating pathogens or the diagnostic criteria used. Differences in clinical presentation, timing and genetic factors show that IRS initiated by mycobacteria, cryptococci, herpesviruses, hepatitis B and C, etc., are a diverse group of conditions with distinct pathogenic bases [2]. For example, only herpesvirus IRS associate with high baseline plasma soluble CD30 and IL-6, and with specific alleles of IL12B and TNF [3]. Hence, it is not informative to discuss IRS without specifying the cause.

We also question the assumption that CD8+CD25+ cells have a regulatory role. Regulatory cells are classically CD4+CD25+ or CD4+CD25hi, but, in HIV patients, these populations include activated cells that do not express more specific ‘T-reg’ markers, FoxP3+ or CD127lo. High percentages of CD8+FoxP3+ cells and activated T cells of all subsets are observed in immunodeficient HIV patients [4]. Herpesvirus and mycobacterial IRS are more common in previously immunodeficient patients [2], so the nadir CD4 T-cell counts should be considered when defining prognostic markers. Moreover, high proportions of CD8 T cells expressing CD25 may mark patients starting therapy with active viral infections. These need to be differentiated from IRS using defined and standardized criteria. On a technical level, interpretation of the CD8+CD25+ phenotype would be aided by information regarding the level of CD25 expression (e.g. was this a distinct population?) and coexpression of other activation and regulatory molecules. These details will enable a proper interpretation of the data.

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1. Cianchetta-Sívori M, Raso S, Fernández-Guerrero M, Górgolas M, García R. Do CD8(+)CD25(+) cells predict immune reconstitution syndrome in HIV-positive patients who begin HAART? AIDS 2007; 21:2347–2349.
2. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18:1615–1627.
3. Stone SF, Price P, French MA. Immune restoration disease: a consequence of dysregulated immune responses after HAART. Curr HIV Res 2004; 2:235–242.
4. Lim A, Tan D, Price P, Kamarulzaman A, Tan HY, James I, French MA. Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy. AIDS 2007; 21:1525–1534.
© 2008 Lippincott Williams & Wilkins, Inc.