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Ward 86 Management Recommendations

Diagnosis and Management of Immune Reconstitution Inflammatory Syndrome Associated with the Initiation of Antiretroviral Therapy

updated July 2018

Contributors: Mark A. Jacobson, MD
Carina Marquez, MD
Annie Luetkemeyer, MD

  1. 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.

  2. 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:

    1. 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.

    2. 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.

  3. 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.

  4. 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.

  5. 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).

  6. 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.

  7. Most IRIS cases resolve in several weeks by continuing ART and anti-OI medications.

  8. Invasive diagnostic procedures can be avoided if the clinical setting and presentation is typical for IRIS.

  9. Treatment for IRIS

    1. MAC IRIS can be prolonged and occasionally severe. We and others have anecdotally found prednisone to be beneficial in severe IRIS when Mycobacterium avium complex infection is the underlying etiology. We start prednisone dosing at 1 mg/kg/day and begin tapering the dosage as soon as a clinical response is observed.

    2. For TB IRIS, results of a double-blind, placebo-controlled, randomized trial have shown that prednisone, 1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 more weeks, improved clinical outcomes.(5)

    3. Systemic corticosteroids are contraindicated in patients with current, active KS, unless necessary for another serious condition. There have been many reports of rapid progression of KS as well as other human-herpesvirus-8-associated malignancies, fatal in some cases, among patients with active KS who have received corticosteroids.

    4. There is little evidence to support use of systemic corticosteroid therapy for any nonmycobacterial forms of IRIS. However, two situations in which a limited course of corticosteroid therapy may be appropriate are as follows:

      1. CMV immune-recovery uveitis (CMV IRU): Uncontrolled case series suggest that intraocular steroid injections may be beneficial in treating CMV IRU; however, there also are 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.
      2. Severe cryptococcal meningitis IRIS: Several case reports have been published describing patients with severe cryptococcal meningitis IRIS, in which cerebrospinal inflammation and high fluid pressure have led to persistent neurologic deficits or deterioration, and these individuals have not responded to appropriate pressure management. In these cases, the patients have clinically improved with prednisone or dexamethasone therapy.


  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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

PathogenTypical Interval1Incidence2Typical Presentation
Mycobacterium avium complex1-12 weeks30%
  • Does not occur until CD4 count is >50 cells/µL
  • Fever and necrotizing lymphadenitis
  • Less common: pulmonary infiltrates, osteomyelitis
  • Mycobacterial blood cultures are typically negative
Tuberculosis1-16 weeks15%
  • Fever, new pulmonary infiltrates, necrotizing lymphadenitis
  • Less common: pleural effusion, abscess, osteomyelitis, hypercalcemia, meningitis, encephalitis
  • In paradoxical TB IRIS, there can be new site of disease
  • Risk of paradoxical TB IRIS is greater the lower the CD4 count at ART onset and the shorter the interval between starting TB medications and ART
  • IRIS may occur without an increase in CD4 count
CMV retinitis4 weeks to 2 years15%
  • Does not occur until CD4 count is >50 cells/µL
  • Early manifestations: vitreitis presenting as visual blurring or new opacified retinal lesions (usually asymptomatic)
  • Late manifestation: Immune recovery uveitis, which can lead to macular edema and/or cataracts
Cryptococcal meningitis1 week to 3 years15%
  • Headache, fever, meningismus, CSF pleocytosis
Pneumocystis pneumonia3-6 weeks<1%; few well-documented case reports
  • This is a difficult clinical diagnosis to make as oxygenation often worsens during prednisone taper in severe cases
  • Avoid prolonging prednisone taper, which can lead to new OIs
HBV/HCV1-12 weeksUnknown
  • Transaminitis flare associated with abdominal pain, nausea, and/or fever
Kaposi sarcomaUnknownUnknown
  • Rapid progression of KS lesions, local tissue edema, local or visceral lymphadenopathy
  • Fatal cases have been reported in some patients with pulmonary KS at time of ART initiation; prednisone is absolutely contraindicated
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