13. Immune Reconstitution Inflammatory Syndrome (IRIS)

Overview

HIV-associated immune reconstitution inflammatory syndrome (IRIS) is a complication of ART initiation and describes a heterogeneous collection of inflammatory disorders resulting from a robust immune response to an underlying condition.

Etiology

  • HIV-associated IRIS has been seen in multiple AIDS-related OIs (especially TB, MAC, Cryptococcus, and CMV) and other infections (such as hepatitis B and C) or inflammatory conditions.
  • Risk factors include lower CD4 count and higher viral load at ART initiation as well as rapid increase in CD4 count with treatment.
  • There are two categories of IRIS:
    • Paradoxical IRIS: clinical deterioration due to worsening of known underlying infection.
    • Unmasking IRIS: clinical deterioration due to worsening of previously unrecognized infection.

Evaluation

The clinical features of IRIS vary based on the driving underlying condition. Diagnosis is made from consistent signs or symptoms of the underlying condition with recent ART initiation (with variable timing of onset for different IRIS syndromes). Paradoxical IRIS is a diagnosis of exclusion. 

Clinical Characteristics of Common Paradoxical IRIS Syndromes

Pathogen

Typical Interval

Incidence

Typical Presentation

Mycobacterium avium complex

1-12 weeks

30%
  • 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

Tuberculosis

1-16 weeks

15%
  • 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 retinitis

4 weeks to 2 years

15%
  • 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 meningitis

1 week to 3 years

15%
  • Headache, fever, meningismus, CSF pleocytosis

Pneumocystis pneumonia

3-6 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/HCV

1-12 weeks

Unknown
  • Transaminitis flare associated with abdominal pain, nausea, and/or fever

Kaposi sarcoma

Unknown

Unknown
  • 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

Chart from Jacobson MA Diagnosis and Management of Immune Reconstitution Syndrome Associated with Initiation of Antiretroviral Therapy. HIVInSite 2018.

Management

  • IRIS management typically involves ART continuation for most cases and targeted treatment of the underlying infection. Please see section Initiation of Antiretrovirals in Acute OI for further guidance on timing for ART initiation following the diagnosis of specific OIs.
  • Adjunctive corticosteroid therapy may be considered in cases with severe symptoms.
  • Consult an ID specialist for all cases of suspected IRIS.

Key Points

  • HIV-associated IRIS represents a heterogeneous collection of inflammatory disorders resulting from a robust immune response to an underlying condition with ART initiation.
  • ID should be consulted for all cases of suspected IRIS.

Kenneth H. Mayer, Hans H. Hirsch, Gilbert Kaufmann, Pedram Sendi, Manuel Battegay, Immune Reconstitution in HIV-Infected Patients, Clinical Infectious Diseases, Volume 38, Issue 8, 15 April 2004, Pages 1159–1166, https://doi.org/10.1086/383034

Jacobson MA Diagnosis and Management of Immune Reconstitution Syndrome Associated with Initiation of Antiretroviral Therapy. HIVInSite 2018.

Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on June 1, 2020).