Immune reconstitution inflammatory syndrome

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Immune reconstitution inflammatory syndrome
Skin-coloured plaques over the bridge of nose, erythematous and hyperpigmented plaques over the ala of nose and cheek

Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of 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.[1]

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.[citation needed]

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 following HIV therapy against persisting antigen, whether present as intact organisms, dead organisms, or debris.[2]

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.[citation needed]

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 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 low initial CD4 T cell count and opportunistic infection at the time of their HIV diagnosis, they receive treatment to control the opportunistic infections before HAART is initiated approximately two weeks later. This is true for most OIs, except for OIs involving the central nervous system.[citation needed]

In cryptococcal meningitis

IRIS is particularly problematic in cryptococcal meningitis as IRIS is fairly common and can be fatal.[3]

IRIS has been described in immunocompetent hosts who have meningitis caused by Cryptococcus gattii and Cryptococcus neoformans var. grubii, environmental fungi which often affect immunocompetent hosts. Several weeks or even months into appropriate treatment, there is a sudden onset deterioration with worsening meningitis symptoms and progression or development of new neurological symptoms.[citation needed]

Magnetic resonance imaging shows increase in the size of brain lesions, and CSF abnormalities (white cell count, protein, glucose) increase. CSF culture is typically sterile, and there is no increase in CSF cryptococcal antigen titer.[4]

The increasing inflammation can cause brain injury or be fatal.[5][6][7]

The general mechanism behind IRIS is increased inflammation as the recovering immune system recognizes the antigens of the fungus as immunosuppression is reversed. Cryptococcal IRIS has three phases:

  1. before HAART, with a paucity of cerebrospinal fluid (CSF) inflammation and defects in antigen clearance;
  2. during initial HAART immune recovery, with pro-inflammatory signaling by antigen-presenting cells without an effector response; and
  3. at IRIS, a cytokine storm with a predominant type-1 helper T-cell interferon-gamma response.[3][4][8]

Three clinical predictors of cryptococcal-related paradoxical IRIS risk include:[citation needed]

  1. lack of initial CSF pleocytosis (i.e. low CSF white blood cell count);
  2. elevated C-reactive protein;
  3. failure to sterilize the CSF before immune recovery.

IRIS may be the cause of paradoxically worse outcomes for cryptococcal meningitis in immunocompetent compared with immunocompromised hosts, in whom Cryptococcus neoformans is the usual pathogen. Treatment with systemic corticosteroids during IRIS may be beneficial in preventing death or progressive neurological deterioration. Steroids given to persons with anti-fungal treatment failure / cryptococcal relapse (in whom CSF cultures are not sterile) can be a fatal iatrogenic error.[9]


Bats recovering from white-nose syndrome (WNS) may be the first natural occurrence of IRIS, in a report released by the USGS.[10] WNS is typified by a cutaneous infection of the fungus Pseudogymnoascus destructans during hibernation, when the immune system is naturally suppressed to conserve energy through the winter. This study suggests that bats undergoing an intense inflammation at the site of infection after a return to euthermia is a form of IRIS.[11]

See also


  1. Shelburne, Samuel A; Visnegarwala, Fehmida; Darcourt, Jorge; Graviss, Edward A; Giordano, Thomas P; White, A Clinton; Hamill, Richard J (March 2005). "Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy". AIDS. 19 (4): 399–406. doi:10.1097/01.aids.0000161769.06158.8a. PMID 15750393. S2CID 2062992.
  2. Bohjanen, Paul R.; Boulware, David R. (2008). "HIV Immune Reconstitution Inflammatory Syndrome". Global HIV/AIDS Medicine. pp. 193–205. doi:10.1016/B978-1-4160-2882-6.50022-8. ISBN 978-1-4160-2882-6.
  3. 3.0 3.1 Boulware, David R.; Meya, David B.; Bergemann, Tracy L.; Wiesner, Darin L.; Rhein, Joshua; Musubire, Abdu; Lee, Sarah J.; Kambugu, Andrew; Janoff, Edward N.; Bohjanen, Paul R. (21 December 2010). "Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study". PLOS Medicine. 7 (12): e1000384. doi:10.1371/journal.pmed.1000384. PMC 3014618. PMID 21253011.
  4. 4.0 4.1 Boulware, David R.; Bonham, Shulamith C.; Meya, David B.; Wiesner, Darin L.; Park, Gregory S.; Kambugu, Andrew; Janoff, Edward N.; Bohjanen, Paul R. (15 September 2010). "Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome". The Journal of Infectious Diseases. 202 (6): 962–970. doi:10.1086/655785. PMC 2924457. PMID 20677939.
  5. Lane, M.; McBride, J.; Archer, J. (23 August 2004). "Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis". Neurology. 63 (4): 713–714. doi:10.1212/01.wnl.0000134677.29120.62. PMID 15326249. S2CID 42308361.
  6. Einsiedel, L.; Gordon, D. L.; Dyer, J. R. (15 October 2004). "Paradoxical Inflammatory Reaction during Treatment of Cryptococcus neoformans var. gattii Meningitis in an HIV-Seronegative Woman". Clinical Infectious Diseases. 39 (8): e78–e82. doi:10.1086/424746. PMID 15486830.
  7. Ecevit, Ismail Zafer; Clancy, Cornelius J.; Schmalfuss, Ilona M.; Nguyen, M. Hong (2006). "The Poor Prognosis of Central Nervous System Cryptococcosis among Nonimmunosuppressed Patients: A Call for Better Disease Recognition and Evaluation of Adjuncts to Antifungal Therapy". Clinical Infectious Diseases. 42 (10): 1443–1447. doi:10.1086/503570. JSTOR 4484756. PMID 16619158.
  8. Wiesner, Darin L.; Boulware, David R. (4 August 2011). "Cryptococcus-Related Immune Reconstitution Inflammatory Syndrome (IRIS): Pathogenesis and its Clinical Implications". Current Fungal Infection Reports. 5 (4): 252–261. doi:10.1007/s12281-011-0064-8. PMC 3289516. PMID 22389746.
  9. Musubire, AK; Meya, BD; Mayanja-Kizza, H; Lukande, R; Wiesner, LD; Bohjanen, P; R Boulware, RD (2012). "Challenges in diagnosis and management of Cryptococcal immune reconstitution inflammatory syndrome (IRIS) in resource limited settings". African Health Sciences. 12 (2): 226–230. doi:10.4314/ahs.v12i2.23. PMC 3462548. PMID 23056032.
  10. "White-Nose Syndrome Bat Recovery May Present Challenges Similar to Those in Some Recovering AIDS Patients" (Press release). USGS. November 19, 2012. Archived from the original on April 26, 2020. Retrieved February 22, 2020.
  11. Meteyer, Carol; Barber, Daniel; Mandl, Judith (2012-11-15). "Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome". Virulence. 3 (7): 583–588. doi:10.4161/viru.22330. PMC 3545935. PMID 23154286.

Further reading