Immune reconstitution inflammatory syndrome in HIV-infected patients

Abstract

Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.

Keywords: IRIS; antiretroviral therapy; complications; diagnosis; tuberculosis.

Figure 1

Schematic demonstrating sequence of key events in paradoxical immune reconstitution inflammatory syndrome (IRIS) (A) and unmasking IRIS (B). Note: Unmasking IRIS is one possible presentation of an antiretroviral therapy (ART)-associated opportunistic infection (OI), and is characterized by an atypically inflammatory or localized presentation, unlike other forms of ART-associated OI (points 2 and 3 in [B]).

Figure 2

A conceptual model of immune reconstitution inflammatory syndrome (IRIS) pathophysiology with three key features represented in central rectangles. Notes: Excess antigen is a feature of tuberculosis (TB) IRIS, cryptococcal IRIS and Kaposi’s sarcoma IRIS. This may result from extreme immunosuppression prior to antiretroviral therapy (ART) initiation, which increases the risk of opportunistic infection (OI) dissemination (in TB), and is associated with paucity of inflammation in cryptococcal meningitis (CM), especially in those patients who go on to develop IRIS. Antigen is likely to be more abundant if the OI is untreated, or if treatment has recently started. Immune cell dysfunction following ART has been described in IRIS, although the mechanism of this is incompletely understood. It may involve uncoupling of innate and acquired immune responses, restoration of exuberant pathogen-specific cellular responses, and defective or delayed regulatory responses. An excess of proinflammatory cytokines has been associated with TB-IRIS, and cryptococcal IRIS, in blood and cerebrospinal fluid. Possible relationships between the three key components are depicted by differentially weighted arrows. However, the direction of causality is not clear. It is probable that the presence of high antigen in IRIS drives proinflammatory cytokine responses directly through stimulation of innate immune responses and indirectly when adaptive immunity recovers. Further studies are required to improve understanding of these interactions.

Figure 3

This series of three chest radiographs demonstrates features of paradoxical tuberculosis (TB) immune reconstitution inflammatory syndrome in a 21-year-old antiretroviral therapy (ART)-naïve patient, with CD4 count 34 cells/mm³, who was diagnosed with drug-sensitive pulmonary TB on sputum culture. Notes: At TB diagnosis, chest radiograph showed bilateral hilar and mediastinal lymphadenopathy, right middle and right upper lobe infiltrates, and a right-sided pleural effusion (A). These abnormalities improved with TB therapy (B) and 10 weeks later ART was initiated. Nine days following ART initiation, she presented with recurrence of cough, right-sided chest pain, fatigue, and weight loss. On examination, tachycardia, tachypnea, and tender hepatomegaly were observed. CD4 count had increased to 161 cells/mm³. Chest radiograph showed a marked deterioration, particularly of the right-sided pulmonary infiltrates, which became more extensive than at the time of initial presentation with TB (C).