Ward 86 Management Recommendations
Diagnosis and Management of Immune Reconstitution Inflammatory Syndrome Associated with the Initiation of Antiretroviral Therapy
updated April 2016
Contributors: Mark A. Jacobson, MD
Carina Marquez, MD
Annie Luetkemeyer, MD
Antiretroviral therapy (ART)-associated immune reconstitution inflammatory syndrome (IRIS) is a heterogeneous collection of distinct syndromes, each representing an overly robust immune response to a specific underlying etiologic condition. Each IRIS syndrome (eg, tuberculosis, cryptococcus) has a unique incidence, natural history, and optimal management. In addition to IRIS associated with AIDS-related opportunistic infections (OIs) or Kaposi sarcoma (KS), there can be an IRIS related to chronic hepatitis B and C, the worsening or unmasking of noninfectious autoimmune conditions (eg, sarcoid, Graves disease), inflammatory skin conditions (acne, rosacea, eosinophilic folliculitis), or an idiopathic encephalitis that may occur after initiation of ART.
IRIS is a clinical diagnosis that may be made when signs and symptoms consistent with an infectious or inflammatory condition are temporally related to the initiation of ART. There are two categories of IRIS:
Paradoxical IRIS may be diagnosed when clinical deterioration occurs in a patient already known to have a specific underlying condition (eg, an OI or KS) after an initial improvement on therapy for that condition.(1) Paradoxical IRIS is a diagnosis of exclusion. The signs and symptoms of paradoxical IRIS cannot be explained by the expected clinical course of this underlying condition, another infection, inadequate treatment of the initial condition (owing to resistance or poor adherence), or the side effects of medications. Most IRIS cases reported in the United States have been paradoxical IRIS, which generally has a higher frequency in patients who have a low CD4 cell count when ART is initiated and who begin ART soon after OI treatment is started.
Unmasking IRIS is a de novo diagnosis of an OI, KS, or other underlying condition in a patient who recently initiated ART.(1) Most cases of unmasking IRIS reported in literature have occurred in resource-limited settings and are related to tuberculosis.
Little is known about IRIS pathogenesis, but it likely varies between underlying etiologic conditions. For example, tuberculosis IRIS is known to be associated with an explosive increase in circulating tuberculosis antigen-specific cytotoxic T cells that occurs soon after ART is initiated. On the other hand, immune recovery uveitis, a cytomegalovirus (CMV) retinitis-related IRIS, is clearly not associated with an exaggerated increase in systemic CMV-specific T cells.
Most IRIS syndromes cause self-limited morbidity and rarely cause mortality. Hence, ART should be continued after a diagnosis of IRIS is made. The exception is when IRIS presents as encephalitis, a condition with high mortality and morbidity. ART always should be held in a patient diagnosed with IRIS encephalitis until the condition has resolved and any persistent neurologic deficits have stabilized. Timing of ART initiation after the diagnosis of specific OIs is discussed in the sections Initiating Antiretroviral Therapy in Hospitalized HIV-Infected Patients and Treatment of Tuberculosis and Latent Mycobacterium tuberculosis Infection in HIV-Infected Patients.
- A diagnosis of IRIS should be considered whenever signs and symptoms consistent with an infectious or inflammatory condition occur in temporal relation to initiation of an ART regimen. Note that the temporal relationship between starting ART and the onset of IRIS varies for different IRIS syndromes (see Table 1).
- Characteristic features of the more common IRIS syndromes are described in Table 1.(2,3,4) There are no confirmatory laboratory tests for the diagnosis of IRIS.
- Most IRIS cases resolve in several weeks by continuing ART and anti-OI medications.
- Invasive diagnostic procedures can be avoided if the clinical setting and presentation is typical for IRIS.
- A brief course of prednisone can be beneficial in cases of severe IRIS when tuberculosis or Mycobacterium avium complex infection is the underlying etiology.(5) We start prednisone dosing at 1 mg/kg/day and begin tapering the dosage as soon as a clinical response is observed. There is no evidence to support use of systemic steroid therapy for any other forms of IRIS. Prednisone is absolutely contraindicated for KS IRIS.
- There are uncontrolled case series that suggest intraocular steroid injections may be beneficial in CMV immune recovery uveitis (IRU); however, there are also case reports of such injections causing reactivation of CMV retinitis. Any patient with CMV IRU, which can cause permanent visual impairment, should be examined by an ophthalmologist with experience in treating this condition so that optimal treatment can be based on the specific features of the case.
- Haddow LJ, Easterbrook PJ, Mosam A, et al. Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clin Infect Dis. 2009 Nov 1;49(9):1424-32.
- Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005 Mar 4;19(4):399-406.
- Lortholary O, Fontanet A, Mémain N, et al; French Cryptococcosis Study Group. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV- associated cryptococcosis in France. AIDS. 2005 Jul 1;19(10):1043-9.
- Jagannathan P, Davis E, Jacobson M, et al. Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series. AIDS. 2009 Aug 24;23(13):1794-6.
- Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010 Sep 24;24(15):2381-90.
Table 1. Clinical Characteristics of Common Paradoxical IRIS Syndromes
|1 Interval between ART initiation and onset of paradoxical IRIS signs and symptoms|
2 Incidence of paradoxical IRIS in patients who already have been diagnosed and are in treatment for the underlying OI or other etiologic condition