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IRIS - Immune Reconstitution Inflammatory Syndrome


Updated May 20, 2014

Immune Reconstitution Inflammatory Syndrome (IRIS) is a condition whereby a person’s immune system begins to recover, only to respond so vigorously to a pre-existing opportunistic infection (OI) as to create an extreme—and sometimes dangerous—inflammatory response.

Understanding IRIS

When infected with HIV, a person will generally experience a gradual deterioration CD4+ T cells vital to an immune defense. This immune suppression reduces the body’s ability to fight off OIs that might otherwise be harmless to a person with an intact immune system. Effective antiretroviral therapy inhibits HIV’s ability to infect and destroy CD4 cells, thereby allowing for the restoration of the body’s immune defenses.

IRIS occurs when a person’s CD4 count rises so dramatically and suddenly that it triggers an acute inflammatory response that can result in fever, pain, swelling, and occasionally the worsening of a known or previously undiagnosed OI.

Inflammation is simply the body’s natural response to any substance or infective agent that can cause harm or irritation. When IRIS occurs, the body’s reactivated immune response overproduces so-called “inflammatory mediators” (soluble molecules that act locally at the site of infection) to such a degree that it can sometimes worsen rather than heal tissues damaged by infection.

Although IRIS is generally associated with the initiation of combination antiretroviral therapy (cART), it can infrequently occur when treating an OI alone.

Recognizing IRIS

The severity of IRIS can range from mild to life-threatening, and can be triggered in response to any number of disease-causing pathogens, including:

IRIS occurs most frequently in treatment naïve patients (i.e., those starting cART for the first time), in those with very low pre-treatment CD4 counts (under 50-100 cells/mL), or in those who have been recently or currently treated for an OI.

Additionally, a rapid decline in viral load following the initiation of cART (particularly in the first three months) is also associated with increased IRIS risk. Moreover, persons with disseminated OIs (i.e., OIs that spread widely from the site of primary presentation) are more likely to experience IRIS than those with localized infection.

IRIS generally occurs within weeks or months after initiating cART. Diagnosis is based almost entirely on clinical presentation, weighing the clinical manifestations of a specific OI with the timing of therapy.

However, IRIS can often be difficult to identify, as a worsening clinical presentation is non-specific. Also, there are no specific laboratory markers to identify IRIS specifically. Therefore, the physician must determine whether the condition is caused by failure of therapy, due either to poor treatment adherence or drug resistance.

IRIS can be especially difficult for patients with cryptococcal meningitis as the increased inflammation can cause brain damage and, occasionally, death.

Treatment and Prevention of IRIS

It is worth noting that most cases of IRIS are not life-threatening, with symptoms often resolving spontaneously with no additional treatment interventions. If indicated, anti-inflammatory drugs (non-steroid or corticosteroids) may be prescribed to reduce inflammation.

Although there is no specific literature relating to the prevention or avoidance of IRIS, timing of cART should be considered for patients with CD4 counts of less than 50-100 cells/mL. Depending upon the severity of the OI, drug toxicities, drug-drug interactions, etc., initiation of cART may sometimes be delayed for 1-2 weeks after OI therapy has begun.

In cases of cryptococcal or mycobacterial disease, considerations should be made as to whether cART should be delayed for even longer, particularly when the central nervous system is involved (such as with cryptococcal meningitis). In such instances, an HIV specialist should always be consulted.

Also Known As: Immune Recovery Syndrome


Jacobson M. “Clinical Implications of Immune Reconstitution in AIDS.” HIV InSite Knowledge Base [textbook online]. UCSF Center for HIV Information, San Francisco, 2006.

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