Immune Reconstitution Inflammatory Syndrome (IRIS) describes a complex immune response where a recovering immune system, often after starting treatment for a compromised state, reacts with an exaggerated inflammatory response. This can lead to a paradoxical worsening of symptoms related to an existing infection or autoimmune condition that was previously subclinical or well-controlled, or unmask a previously unrecognized infection.
Understanding How IRIS Develops
IRIS develops when a suppressed immune system begins to recover, often due to therapies like antiretroviral therapy (ART) for HIV or the withdrawal of immunosuppressive drugs. This recovery allows the immune system to mount a strong inflammatory response against antigens from pre-existing opportunistic infections or autoimmune conditions, leading to a paradoxical intensification of symptoms.
The underlying mechanism involves a shift in the balance of pro-inflammatory and anti-inflammatory cytokines. As immune cells, particularly CD4+ T cells, increase in number and function, they react vigorously to pathogens or antigens previously tolerated by the weakened immune system. This rapid restoration of pathogen-specific immune responses drives the inflammatory reaction, causing clinical worsening despite overall immune health improvement. The process often includes an initial rapid increase in memory CD4+ T cells, followed by a slower increase in naive CD4+ T cells, enhancing cell-mediated and antibody-mediated immunity.
Who is Most Affected
IRIS is most commonly observed in individuals with HIV who begin antiretroviral therapy (ART). This is particularly true for patients with very low CD4 cell counts, typically below 100 cells/µL, before starting ART. The rapid increase in CD4 cell count and suppression of viral load following ART initiation are significant risk factors for developing IRIS. Studies suggest that between 10% and 30% of HIV patients starting ART may experience IRIS.
The syndrome can unmask various opportunistic infections, such as tuberculosis, cryptococcosis, or cytomegalovirus. IRIS can also manifest in other patient populations, including transplant recipients discontinuing immunosuppressive agents, where it may be linked to infections like cryptococcosis, cytomegalovirus, or tuberculosis. Additionally, postpartum individuals may experience IRIS due to the reversal of pregnancy-induced immune suppression, potentially leading to flare-ups of conditions like cryptococcosis or autoimmune diseases.
Recognizing the Signs
The clinical presentation of IRIS varies widely, depending on the specific underlying infection or condition. Common features include fever and a worsening of existing symptoms related to the opportunistic infection. New symptoms or the unmasking of infections can also occur. The majority of IRIS cases typically develop within 4 to 8 weeks after starting or changing ART, though onset can range from a few days to several months or even years.
For example, in tuberculosis-associated IRIS, patients might experience worsening lung symptoms, new pulmonary infiltrates, or enlarged lymph nodes. Cryptococcal IRIS can lead to neurological symptoms like headaches and fever, potentially causing brain injury due to increased inflammation. Cytomegalovirus (CMV) IRIS may affect the eyes, presenting as retinitis, vitritis, or uveitis, which can sometimes lead to vision loss. Other manifestations can include skin lesions such as shingles or warts, or elevated liver enzymes in cases of hepatitis B or C co-infection.
Diagnosis and Treatment Approaches
Diagnosing IRIS primarily relies on clinical assessment, considering the patient’s history, recent immune recovery, and the exclusion of other possible causes for symptom worsening, such as treatment failure or drug toxicity. There are currently no specific laboratory tests that definitively diagnose IRIS, making it a diagnosis of exclusion. Clinicians must differentiate IRIS from medication side effects, new infections, or progression of the original disease.
Management of IRIS generally involves supportive care and continuing the underlying therapy that led to immune recovery, such as ART. For mild cases, symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) may be sufficient. In more severe or life-threatening situations, anti-inflammatory medications like corticosteroids (e.g., prednisone) are often used to reduce inflammation. For instance, prednisone at 1-2 mg/kg for 1-2 weeks, followed by a taper, may be considered, though careful monitoring for opportunistic infections is necessary. Certain conditions, like cryptococcal meningitis and Kaposi’s sarcoma, are exceptions where corticosteroids may be avoided due to potential for poorer outcomes or exacerbation of the disease.