Review
Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions

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Summary

Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.

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

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

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