We conducted a Medline search for articles published up to June, 2010, to identify English-language cohort studies, case-control studies, case series, and case reports describing or enumerating cases of cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected patients. The search terms used were (“HIV” OR “HIV infections”) AND ([“immune reconstitution inflammatory syndrome” OR “immune”] AND [“reconst*” OR “restor*”] AND [“syndrome” OR “disease”]) AND (“cryptococc*” OR
ReviewCryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions
Introduction
Cryptococcal disease is a major cause of morbidity and mortality in people with advanced HIV/AIDS, particularly in Africa and southeast Asia.1, 2, 3, 4 Cryptococcal immune reconstitution inflammatory syndrome (IRIS) presents as a clinical worsening or new presentation of cryptococcal disease after rapid reversal of immune deficiency.5 In patients with HIV-1 infection, this reversal is driven by antiretroviral therapy (ART), but the syndrome can also occur after solid-organ transplantation (estimated incidence 4·8%),6 and in pregnancy.7 Cryptococcal IRIS is thought to be triggered by recovery of immune responses to Cryptococcus spp, resulting in exaggerated host inflammatory responses.
The International Network for the Study of HIV-associated IRIS (INSHI) was established in 2006, to promote research collaboration and standardisation of practices and terminology among IRIS researchers worldwide. Generic definitions of IRIS are limited in their application because of the highly heterogeneous spectrum of underlying disease and clinical features. Here we review the clinical and diagnostic features of cryptococcal IRIS reported in cohort and case-control studies (table 1)8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and case series and case reports (table 2)26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 and put forward consensus case definitions for the syndrome that can be used in resource-limited and resource-rich settings.
Section snippets
Classification and terminology
Similar to the INSHI case definition of tuberculosis-associated IRIS,53 two distinct modes of presentation of cryptococcal IRIS are recognised. First, in up to a third of patients with cryptococcosis diagnosed before the initiation of ART, so-called paradoxical cryptococcal IRIS occurs during treatment. This form presents as a worsening of disease or as recurrent disease in the same or new anatomical sites, despite microbiological evidence of effective antifungal treatment.8, 9, 10, 11 Second,
Proposed case definitions for cryptococcal IRIS
We have developed case definitions for paradoxical cryptococcal IRIS and ART-associated cryptococcosis in patients with HIV that are based on published data on clinical and diagnostic features. The case definition for paradoxical cryptococcal IRIS (panel 1) applies to patients who have cryptococcal disease that was recognised before initiation of ART and worsens during treatment. The definition of ART-associated cryptococcosis (panel 2) applies to patients without recognised cryptococcosis at
Prevention and management
Prevention of paradoxical cryptococcal IRIS has been used as a justification for delaying ART, yet the evidence for such a rationale is unclear. In two retrospective studies, ART initiation less than 4–8 weeks after antifungal therapy was started was associated with increased risk of cryptococcal IRIS,9, 11 but in two prospective observational cohorts, timing of ART initiation was not associated with IRIS.20, 22 Two randomised, controlled trials to address the question of when to start ART have
Assessment of case definitions
Our structured case definitions for cryptococcal IRIS and ART-associated cryptococcosis provide approaches for future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS in HIV-infected patients, as they enable investigators to standardise diagnostic criteria and facilitate comparison of studies' designs and findings, pooling of data, and meta-analysis. Specifically, we recommend future reports avoid assessing and reporting findings for paradoxical cryptococcal IRIS
Search strategy and selection criteria
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