Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

Abstract

Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.

Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV

“…A proportion of PLWH experiences a paradoxical clinical worsening or unmasking of TB within the first few weeks after ART initiation, a phenomenon known as immune reconstitution inflammatory syndrome (IRIS) (3,4). The reported incidence of TB-related IRIS is associated with TB epidemiological settings and ranges from 8 to 54% (5,6).…”

“…Interestingly, factors such as advanced immunological deterioration coupled with high viral loads, short interval between antitubercular treatment (ATT) and ART initiation, as well as the abundance of Mycobacterium tuberculosis (Mtb) antigens at the time of immune restoration also play a pivotal role in IRIS pathogenesis (7). Clinical manifestations are largely variable ranging from fever and lymph node enlargement to severe and rapid worsening of respiratory symptoms, and even death (4). Since current TB-IRIS diagnostic tools remain suboptimal, newer accurate methods for early diagnosis and prediction are critical for better patient care and management.…”

Plasma Metabolomics Reveals Dysregulated Metabolic Signatures in HIV-Associated Immune Reconstitution Inflammatory Syndrome

“…This condition, termed immune reconstitution inflammatory syndrome (IRIS), presents with clinical manifestations such as worsening lymphadenopathy, fever, malaise, and worsening pulmonary infiltrates even with microbiologic control of the underlying co-infection. Notably, mycobacterial co-infections, such as Mycobacterium tuberculosis (TB) and Mycobacterium avium complex (MAC), are frequently associated with IRIS that can lead to higher morbidity and mortality rates (2)(3)(4)(5). The incidence of IRIS can vary from <5% to as high as 50% and is dependent on several risk factors including severe lymphopenia prior to starting ART as well as disseminated infection with high antigen load (6).…”

“…Furthermore, the role of pro-inflammatory cytokines in mediating IRIS pathogenesis is elucidated through blockade or ablation of IFN-g, TNF, and IL-6 in a MAC-IRIS murine model as well as in IRIS patients who are refractory to steroid treatment (10,11,19). Such robust systemic inflammation observed in IRIS may be reflected in substantial immunometabolic shifts (5). Indeed, IRIS was recently linked with higher metabolic activity monitored by nuclear imaging technique 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET).…”

“…The incidence of IRIS can vary from <5% to as high as 50% and is dependent on several risk factors including severe lymphopenia prior to starting ART as well as disseminated infection with high antigen load ( 6 ). Current management for IRIS involves clinical observation, drainage of inflammatory collections, use of non-steroid anti-inflammatory drugs (NSAIDs), or use of corticosteroids for either prevention or treatment in high-risk TB patients ( 5 , 7 , 8 ).…”