Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections

Abstract

Immune deficiency of diverse etiology, including human immunodeficiency virus (HIV), antineoplastic agents, immunosuppressive agents used in solid organ recipients, immunomodulatory therapy, and other biologics, all promote invasive fungal infections. Subsequent voluntary or unintended immune recovery may induce an exaggerated inflammatory response defining immune reconstitution inflammatory syndrome (IRIS), which causes significant mortality and morbidity. Fungal-associated IRIS raises several diagnostic and management issues. Mostly studied with Cryptococcus, it has also been described with other major fungi implicated in human invasive fungal infections, such as Pneumocystis, Aspergillus, Candida, and Histoplasma. Furthermore, the understanding of IRIS pathogenesis remains in its infancy. This review summarizes current knowledge regarding the clinical characteristics of IRIS depending on fungal species and existing strategies to predict, prevent, and treat IRIS in this patient population, and tries to propose a common immunological background to fungal IRIS.

Keywords: fungal immunity; immune reconstitution inflammatory syndrome; invasive fungal infections; mycoses.

Figure 1

Proposed immune pathophysiology of IRIS. Precursor T helper cells (Th0) differentiate into Th1, Th17, or Th2 cells or Tregs according to cytokines produced in the surrounding milieu through induction of specific transcription factor expression: FOXP3/STAT-5, GATA-3/STAT-6, T-bet/STAT-4, and ROR-γt/STAT-3 for Treg, Th2, Th1, and Th17, respectively [60,61]. Th1 and Th17 cells are pro-inflammatory cells and produce IFN-γ driving macrophage differentiation into M1 macrophages and their activation. M1 macrophages promote granuloma formation and subsequently produce more IFNγ, thus creating an amplification loop leading to an inflammation burst [62]. HIV drives depletion of all Th cell subsets and favors an anti-inflammatory response in remaining cells through a change in cytokine balance [63,64]. Pregnancy hormones inhibit differentiation of naive Th0 cells into Th1 cells, thus promoting a Th2 environment [65]. Biologic agents, such as infliximab, inhibit the pro-inflammatory cytokine TNFα [66]. Immunosuppressive therapeutics inhibit Th1/Th17 response and allow graft acceptance in solid organ transplant [3]. Neutropenia resulting from chemotherapy or conditioning for hematopoeitic stem cell therapy leads to a decrease in IFNγ production through cytokinic interaction with T-cell production; however, data are lacking [67]. Many feedback loops exist between these different players depending on cytokine production. Sudden dysregulation at any level may create an exaggerated inflammatory response with an IFN-γ-unregulated increase leading to IRIS. FOXP3, fox head box P3; IFN, interferon; IL, interleukin; PMN, polymorphonuclear; TGF, transforming growth factor; ROR, retinoid orphan receptor; STAT, signal transducer and activation of transcription; HSCT, Hematopoietic Stem Cell Therapy.