What is Immune Reconstitution Inflammatory Syndrome (IRIS)?

From the Guidelines

Immune Reconstitution Inflammatory Syndrome (IRIS) is a condition that occurs when the immune system responds to a previously acquired infection or disease after the initiation of antiretroviral therapy (ART), leading to an exacerbation of symptoms.

Characteristics of IRIS

• IRIS is characterized by a paradoxical worsening of symptoms, signs, or clinical manifestations of a disease, such as tuberculosis, after beginning antituberculosis and antiretroviral treatments 1
• It is attributed to the reconstitution of immune responsiveness brought about by ART
• IRIS can manifest as high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system (CNS) lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses 1

Risk Factors for IRIS

• Patients with HIV infection and tuberculosis are at an increased risk of developing IRIS, particularly those with earlier ART initiation and CD4+ lymphocyte counts <50 cells/μL 1
• The relative risk of developing IRIS for patients who receive ART during therapy for tuberculosis is 1.88 (95% CI, 1.31–2.69) 1

Management of IRIS

• Management of IRIS is symptomatic, and for most patients with mild IRIS, tuberculosis and antiretroviral therapies can be continued with the addition of anti-inflammatory agents such as ibuprofen 1
• For more severe cases of IRIS, treatment with corticosteroids is effective, with prednisone 1.25 mg/kg/day significantly reducing the need for hospitalization or surgical procedures 1
• However, glucocorticoids are generally contraindicated in Kaposi sarcoma-associated IRIS, as they can exacerbate the disease 1

Clinical Considerations

• IRIS can be challenging to differentiate from treatment failure, but decreasing HIV viral load and improving CD4 count should point to IRIS 1
• The management of IRIS in patients with CNS tuberculosis requires careful consideration, as it may cause severe or fatal neurological complications 1

From the Research

Definition of Immune Reconstitution Inflammatory Syndrome (IRIS)

• IRIS is a phenomenon observed in patients recovering from immunodeficiency, characterized by the unmasking of covert infections or the worsening of overt conditions 2.
• It occurs when a patient is recovering from a transient immunodeficiency and results in an uncontrolled inflammatory response to infectious agents and tissue damage 3.
• IRIS is due to the restoration of pathogen-specific immune responses, leading to worsening clinical, laboratory, or radiologic findings despite improvements in the HIV RNA level and CD4 count after the introduction of antiretroviral therapy 4.

Risk Factors for IRIS

• Low baseline CD4-cell count 5, 6.
• Excellent virological response 5, 6.
• Increased antigenic burden of an opportunistic infection 5.
• Early initiation of ART after an opportunistic infection 5.
• Using a boosted protease inhibitor (BPI) 6.
• Nadir CD4 count <100 cells/mm(3) 6.
• Plasma HIV viral RNA decrease of more than 2.5 log at the time of IRIS compared with RNA levels before the initiation of HAART 6.

Clinical Presentation of IRIS

• The clinical presentation of IRIS involves the unmasking of covert infections or the worsening of overt conditions 2.
• Symptoms such as fever and radiological signs seem to paradoxically appear or worsen, unmasking a previously unrecognized infection 3.
• The manifestations depend on the trigger antigen, which can be an infective agent (viable or nonviable), a host antigen, or a tumor antigen 2.
• Most IRIS cases are self-limiting, but a few cases can be overwhelming and life-threatening; hence, early recognition is important 2.

Treatment and Prevention of IRIS

• Treatment options include discontinuation of ART, corticosteroids, or pathogen-specific therapy 5.
• In most cases, there is no need to discontinue the antiretroviral therapy, although in the more severe cases, other clinical intervention may be necessary 2.
• Adopting one case definition and performing more research regarding diagnosis and treatment of IRIS are important recommendations for future studies 5.