Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS) (also known as immune recovery syndrome) 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.
IRIS 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.
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.
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.
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.
IRIS in cryptococcal meningitis
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.
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.
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:
- before HAART, with a paucity of cerebrospinal fluid (CSF) inflammation and defects in antigen clearance;
- during initial HAART immune recovery, with pro-inflammatory signaling by antigen-presenting cells without an effector response; and
- at IRIS, a cytokine storm with a predominant type-1 helper T-cell interferon-gamma response.
Three clinical predictors of cryptococcal-related paradoxical IRIS risk include:
- lack of initial CSF pleocytosis (i.e. low CSF white blood cell count);
- elevated C-reactive protein;
- 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.
IRIS in bats recovering from white-nose syndrome
Bats recovering from white-nose syndrome (WNS) may be the first natural occurrance of IRIS, in a report released by the USGS. 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 the bats that undergo an intense inflammation at the site of infection after a return to euthermia is a form of IRIS.
- Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.[page needed]
- Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White Jr AC, Hamill RJ. (2005) "Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy" AIDS 19, 399-406.
- Bohjanen PR. Boulware DR. "Chapter 18: Immune Reconstitution Inflammatory Syndrome." In: Volberding P, Sande MA, Lange J, Greene W. editors. Global HIV/AIDS Medicine. Philadelphia: Elsevier. 2007. 193-205.
- 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.
- Boulware, David R.; Bonham, Shulamith C.; Meya, David B.; Wiesner, Darin L.; Park, Gregory S.; Kambugu, Andrew; Janoff, Edward N.; Bohjanen, Paul R. (2010). "Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome". Journal of Infectious Diseases 202 (6): 962–970. doi:10.1086/655785. PMC 2924457. PMID 20677939.
- Lane M, McBride J and Archer J "Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis", Neurology 2004;63;713-714
- Einsiedel L, Gordon DL, and Dyer JR, "Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman", CID 2004;39:e78–82
- Ecevit IZ, Clancy CJ, Schmalfuss IM, and Nguyen MH, "The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: A call for better disease recognition and evaluation of adjuncts to antifungal therapy", CID 2006;42:1443–7.
- Wiesner, DL; Boulware, DR (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.
- Meteyer, Carol; Demas, Alex; Mandl, Judith (2012-11-19). "White-Nose Syndrome Bat Recovery May Present Challenges Similar to Those in Some Recovering AIDS Patients". U.S Geological Survey. Archived from the original on 2013-09-03. Retrieved 2015-08-27.
- 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. Retrieved 2015-08-27.
- "Immune Reconstitution Syndrome" at TheBody.com (by Nicholas Cheonis, Winter 2004/2005)