Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. IRIS may also be referred to as immune reconstitution syndrome, immune reconstitution disease, immune recovery disease, and immune restoration disease. Systemic or local inflammatory responses may occur with improvement in immune function. While this inflammatory reaction is usually self-limited, there is risk of long-term symptoms and death, particularly when the central nervous system is involved. Management generally involves symptom control and treatment of the underlying infection. In severe cases of IRIS, corticosteroids are commonly used. Important exceptions to using corticosteroids include cryptococcal meningitis and Kaposi's sarcoma, as they have been associated with poorer outcomes.
Mechanism There are two common IRIS scenarios. The first is the "unmasking" of an occult opportunistic infection. The second is the "paradoxical" symptomatic relapse of a prior infection despite microbiologic treatment success. Often in paradoxical IRIS, microbiologic cultures are sterile. In either scenario, there is hypothesized reconstitution of antigen-specific T cell-mediated immunity with activation of the immune system against persisting antigen, whether present as intact organisms, dead organisms, or debris.
In HIV infection and immunosuppression The suppression of CD4 T cells by HIV (or by immunosuppressive drugs) causes a decrease in the body's normal response to certain infections. Not only does this make it more difficult to fight the infection, it may mean that a level of infection that would normally produce symptoms is instead undetected (subclinical infection). If the CD4 count rapidly increases (due to effective treatment of HIV, or removal of other causes of immunosuppression), a sudden increase in the inflammatory response produces nonspecific symptoms such as fever, and in some cases a worsening of damage to the infected tissue. Though these symptoms can be dangerous, they also indicate that the body may now have a better chance to defeat the infection. The best treatment for this condition is unknown. In paradoxical IRIS reactions, the events will usually spontaneously get better with time without any additional therapy. In unmasking IRIS, the most common treatment is to administer antibiotic or antiviral drugs against the infectious organism. In some severe cases, anti-inflammatory medications, such as corticosteroids are needed to suppress inflammation until the infection has been eliminated. Infections most commonly associated with IRIS include Mycobacterium tuberculosis and cryptococcal meningitis. Persons living with AIDS are more at risk for IRIS if they are starting HAARTTooltip HAART for the first time, or if they have recently been treated for an opportunistic infection (OI). It is generally advised that when patients have a low initial CD4 T cell count and OI at the time of their HIV diagnosis, they receive treatment to control the OIs before HAART is initiated approximately two weeks later. This is true for most OIs, except for OIs involving the central nervous system.
In individuals without HIV/AIDS Since the HIV/AIDS epidemic in the 1980s, IRIS is now mostly associated with the initiation of HIV treatment with highly active antiretroviral therapy (HAART), also referred to as antiretroviral therapy (ART). However, IRIS can still occur in the following conditions that do not involve HIV:
Solid organ transplant recipients After undergoing solid organ transplant (liver, kidney, pancreas, etc.), patients are prescribed immunosuppressive agents, such as tacrolimus or cyclosporine. These medications target CD4 immune cells, suppressing their function. IRIS in these patients is thought to be due to the pro-inflammatory response after withdrawal of immunosuppressants. Common infections associated with IRIS in these patients are cryptococcosis, cytomegalovirus (CMV), and tuberculosis. Neutropenic patients When the absolute neutrophil count (ANC) is less than 500 per microliter, there is an increased risk of fungal and viral opportunistic infections (OI), such as Aspergillus or CMV. While the patient is immunosuppressed, these infections may remain latent and asymptomatic. However, when the ANC improves, the infections may become symptomatic and present as IRIS. Common infections associated with IRIS in these patients are invasive pulmonary aspergillosis and chronic disseminated candidiasis. Postpartum patients During pregnancy, the immune system is relatively suppressed to prevent fetal rejections or miscarriages. In the immediate postpartum period (3 to 6 weeks), this process is reversed, resulting in a relative pro-inflammatory state. There is an increased risk of IRIS during this period. Common infections associated with IRIS in these patients include cryptococcosis, human papillomavirus reactivation, herpes virus, tuberculosis, leprosy, viral hepatitis. Flare-ups of autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis may also occur during this period. Patients on tumor necrosis factor antagonists Patients with chronic inflammatory conditions (Crohn's disease, ulcerative colitis, sarcoidosis, etc.) are often treated with TNF antagonists, such as infliximab, adalimumab, and etanercept. Tumor necrosis factors are critical in macrophage activation and subsequent granuloma formation. Therefore, TNF antagonists impair the host immune response against infections such as tuberculosis. While the patient is taking TNF antagonists, these infections may remain latent and asymptomatic. However, when these medications are discontinued, there may be an associated pro-inflammatory response causing the infection to be uncovered.
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