There are no accepted diagnostic tests for an IRIS. Diagnosis of an IRIS is therefore made clinically on the basis of the temporal relationship between starting ART and disease onset, disease manifestations including exclusion of alternative diagnoses, a fall in plasma HIV viral load (indicating that ART is effective) and direct or indirect evidence of the restoration of cellular immune responses against the triggering pathogen. Diagnostic criteria for an IRIS have been proposed (7-9) but with low consensus, in part because studies have been undertaken in different geographical settings. On the other hand, consensus clinical case definitions for TB-IRIS (10) and C-IRIS (11) have been reported. Clinical case definitions for CMV immune recovery retinitis have also been proposed (12).
Despite uncertainty about diagnostic criteria for an IRIS, it is possible to provide guiding principles that are, at least, applicable for diagnosing an IRIS in Australasia. Thus, a diagnosis of an IRIS is justifiable when there is an initial presentation or exacerbation of disease associated with an HIV-related infection or cancer following commencement of effective ART, especially when disease manifestations are exaggerated and/or atypical, with exclusion of recurrent or new infections and drug hypersensitivity reactions, associated with a decline in plasma HIV RNA level by >1log10 copies/mL. Direct or indirect evidence of the restoration of a cellular immune response against the triggering pathogen provides additional evidence and is particularly important when information about change in HIV viral load is not available. This evidence includes (a) an atypical inflammatory response in affected tissues, such as granulomas in the context of severe CD4+ T cell depletion, tissue necrosis and suppuration, and CD8+ T cell infiltrates in PML-IRIS lesions of the brain; (b) Spontaneous resolution of disease without specific antimicrobial therapy or tumour chemotherapy with continuation of ART; (c) increase in an immune response specific to the relevant pathogen, eg. delayed-type hypersensitivity skin test response to mycobacterial antigens; (d) increased blood CD4+ T cell count after ART. However, while an increased blood CD4+ T cell count is commonly observed, it is not a prerequisite for a diagnosis of an IRIS.
The major differential diagnosis is relapse of the infection that triggered the IRIS or occurrence of another infection. Clinicians should think broadly for other causes of presenting symptoms and signs. Inflammation that arises from an IRIS is not uncommonly misinterpreted as an opportunistic infection, but the process is one of restoration, rather than loss of pathogen-specific immune responses (13). Differentiation of these conditions is essential as clinical management differs. The validity of an IRIS diagnosis may vary both in clinical practice and research studies. In research studies, an IRIS is often classified as definite, probable or possible – this approach may also be helpful in routine clinical management.