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Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings

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Summary

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

Introduction

The immune reconstitution inflammatory syndrome (IRIS; also known as immune reconstitution disease, immune reconstitution syndrome, or immune restoration disease) is a widely recognised phenomenon that can complicate antiretroviral therapy (ART).1, 2 The condition results from rapid restoration of pathogen-specific immune responses to opportunistic infections, causing either the deterioration of a treated infection or the new presentation of a previously subclinical infection. IRIS typically occurs during the initial months of ART and is associated with a wide spectrum of pathogens, most commonly mycobacteria, herpesviruses, and deep fungal infections such as cryptococcal meningitis.1, 2, 3

In recent years, access to ART has increased rapidly in resource-limited settings, reaching over 2 million people by December, 2006, with an estimated 1 340 000 of these individuals living in sub-Saharan Africa.4 Since the burden of HIV/tuberculosis co-infection is very high in many low-income and middle-income countries,5 many of the patients who enter ART programmes in these settings have a current diagnosis of tuberculosis, or later develop tuberculosis following initiation of ART. For example, one South African study reported that 238 (25%) of 944 patients attending a community-based ART programme were receiving tuberculosis treatment at ART initiation and in the first year of ART the incidence of tuberculosis was 13·4 cases per 100 person-years (95% CI 10·4–16·9).6 Up to one-third of patients with HIV/tuberculosis co-infection who begin ART in such settings could be at risk of developing tuberculosis-associated IRIS (also known as TB-IRIS),3 and this condition is emerging as an important clinical challenge in resource-limited settings.7, 8, 9, 10

Since there is no diagnostic test for IRIS, confirmation of the disease relies heavily upon case definitions incorporating clinical and laboratory data. However, clinical management and research on IRIS are hindered by the lack of consensus case definitions and definitions that are specific to particular opportunistic infections. To address this shortcoming, an international meeting of researchers working in this field was convened in Kampala, Uganda, in November, 2006, and the International Network for the Study of HIV-associated IRIS (INSHI) was formed. The specific aim of the meeting was to develop consensus case definitions for tuberculosis-associated IRIS that are appropriate for low-income settings where laboratory capacity is often limited, and that can be used by researchers working in different settings to permit comparability of results. We present these consensus case definitions in this paper.

Section snippets

Participants and consensus methods

The need for a public-health definition for tuberculosis-associated IRIS was first proposed at the WHO consultation on tuberculosis and HIV research priorities in resource-limited settings in February, 2005.11 The organisers of the meeting in Kampala contacted individuals involved in research related to tuberculosis-associated IRIS, particularly those working in resource-limited settings or collaborating with researchers in these settings. Contacting these individuals was dependent on whether

Changes to existing case definitions

General case definitions for IRIS have previously been published (panel 1).2, 12, 13, 14 These case definitions include the following criteria: confirmed HIV diagnosis, temporal association with initiation of ART, demonstration of response to ART (ie, plasma viral load reduction, blood CD4 cell count increase, or another marker of immune recovery such as conversion of tuberculin skin test from negative to positive for mycobacterial IRIS), clinical deterioration with an inflammatory process, and

Categories of tuberculosis-associated IRIS

Tuberculosis-associated IRIS can present as one of two main syndromes: (1) a paradoxical reaction after the start of ART in patients receiving tuberculosis treatment (here termed paradoxical tuberculosis-associated IRIS), or (2) a new presentation of tuberculosis that is “unmasked” in the weeks following initiation of ART with an exaggerated inflammatory clinical presentation or complicated by a paradoxical reaction (here termed unmasking tuberculosis-associated IRIS).

Case definitions

With the rationale described above, we have developed case definitions for “paradoxical tuberculosis-associated IRIS” (panel 2), “ART-associated tuberculosis” (panel 3), and “unmasking tuberculosis-associated-IRIS” (panel 3). The case definitions are presented schematically in figure 3. These case definitions have been designed for use in resource-limited settings and are consensus case definitions that need validation in clinical practice.

Conclusions

The use of standardised case definitions in different populations will help to provide greater insight into the incidence, clinical manifestations, risk factors, and impact of tuberculosis-associated IRIS, ultimately leading to better prevention and management strategies for this condition. Further clinical and immunological research on patients with ART-associated tuberculosis is needed to better differentiate the subset of cases that have unmasking tuberculosis-associated IRIS and to further

Search strategy and selection criteria

Data for this Personal View were obtained by searching Medline for articles published from 1990 to 2008. Search terms included “immune reconstitution”, “immune restoration”, “immune recovery”, “IRIS”, “antiretroviral”, “tuberculosis”, and “paradoxical reaction”. Only English language papers were reviewed. Additionally, unpublished data and tuberculosis-associated IRIS case definitions presented by researchers at the INSHI meeting were used.

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