Tuberculosis IRIS: Pathogenesis, Presentation, and Management across the Spectrum of Disease

Abstract

Antiretroviral therapy (ART), while essential in combatting tuberculosis (TB) and HIV coinfection, is often complicated by the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Depending on the TB disease site and treatment status at ART initiation, this immune-mediated worsening of TB pathology can take the form of paradoxical TB-IRIS, unmasking TB-IRIS, or CNS TB-IRIS. Each form of TB-IRIS has unique implications for diagnosis and treatment. Recently published studies have emphasized the importance of neutrophils and T cell subtypes in TB-IRIS pathogenesis, alongside the recognized role of CD4 T cells and macrophages. Research has also refined our prognostic understanding, revealing how the disease can impact lung function. While corticosteroids remain the only trial-supported therapy for prevention and management of TB-IRIS, increasing interest has been given to biologic therapies directly targeting the immune pathology. TB-IRIS, especially its unmasking form, remains incompletely described and more data is needed to validate biomarkers for diagnosis. Management strategies remain suboptimal, especially in the highly morbid central nervous system (CNS) form of the disease, and further trials are necessary to refine treatment. In this review we will summarize the current understanding of the immunopathogenesis, the presentation of TB-IRIS and the evidence for management recommendations.

Keywords: acquired immunodeficiency syndrome; immune reconstitution inflammatory syndrome; tuberculosis; tuberculous meningitis.

Figure 1

Diagnostic categories of TB-associated immune reconstitution inflammatory syndrome (TB-IRIS).

Figure 2

Model of TB-IRIS Pathogenesis. (A). HIV-related immune suppression leads to proliferation of TB in macrophages. (B). Antiretroviral therapy leads to increasing CD4 T cell counts, while the Th1 cell response remains dysregulated. Interferon signaling leads to an exuberant immune response against TB-infected cells. (C). This primed immune response to TB involves activation of Toll-like receptors, which leads to a two-pronged inflammatory cascade involving the inflammasome., with subsequent caspase activation and tissue damage, as well as activation of cytokines including TNF, IL6, and IL12. (D). Neutrophils are activated by this inflammatory cascade, especially IL-1, and they migrate to affected organs, leading to tissue damage mediated by matrix metalloproteinases (MMPs).