The article presented by Cianchetta-Sivori et al.  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 . For example, only herpesvirus IRS associate with high baseline plasma soluble CD30 and IL-6, and with specific alleles of IL12B and TNF. 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 . Herpesvirus and mycobacterial IRS are more common in previously immunodeficient patients , 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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