• Syndrome Identified
• Conditions Associated With Inflammatory Reactions
• Mechanism of Action
• Incidence
• Risk Factors
• Management
• Grounds for Optimism
• Selected Sources

Immune reconstitution, or the reversal of HIV-related immune system decline, is one of the primary goals of highly active antiretroviral therapy (HAART). Reconstitution involves an increase in functional CD4 cells to guide the immune response against pathogens such as HIV, resulting in the suppression of viral load and other beneficial outcomes.

However, immune reconstitution may trigger an inflammatory reaction in some people soon after they begin anti-HIV therapy and show signs of immunological improvement. Known as immune reconstitution syndrome (IRS) or immune reconstitution inflammatory syndrome (IRIS), this set of symptoms often resembles an AIDS-defining illness or other condition seen in people with HIV. While in most cases the symptoms of IRIS resolve after a few weeks, the syndrome may be severe or mistaken for true disease progression, and should be properly diagnosed and treated.

Syndrome Identified

Joseph A. DeSimone, MD, and colleagues from Thomas Jefferson University in Philadelphia first attempted to define IRIS in an article published in the September 19, 2000 edition of the Annals of Internal Medicine. These researchers had noted case reports in the medical literature in which HIV positive people appeared to develop a spectrum of illnesses after they had started and responded to HAART, with increases in CD4 cell counts and decreases in viral load. Remarkably, the individuals in these cases developed conditions associated with poor immune system function, such as Mycobacterium avium complex (MAC) and cryptococcal meningitis, at a time when their immune function was actually improving.

DeSimone's team also noted that such scenarios had been seen before in HIV negative people after withdrawal of immunosuppressive medications. In these cases, the presumed reason for the apparent onset of illness was restoration of cellular (CD4 cell-guided) immunity, setting off a hypersensitivity reaction to an existing microbe or antigen in the body.

DeSimone's team concluded that the "paradoxical reactions" seen in people with HIV were also inflammatory responses to pathogens (viruses, bacteria) that were either latent (inactive, asymptomatic) or controlled by drug treatment when the immune system was seriously weakened. Once the immune system was reactivated thanks to HAART, its early, exaggerated responses were directed against these pathogens. The inflammation therefore did not signal a reactivation or worsening of a disease, but rather a protective process initiated by the body. As the immune system continued to improve with the help of HAART, the IRIS inflammation usually resolved, though often accompanied by some form of treatment (see "Management," below).

DeSimone and his colleagues named this relatively uncommon phenomenon immune reconstitution syndrome. Their hypothesis on the nature of IRIS has since been echoed in reports by other clinicians.

Conditions Associated With Inflammatory Reactions

Immune reconstitution syndrome is associated with a variety of latent or subclinical infections, many of which are more commonly seen in people with very low CD4 cell counts. IRIS is perhaps most typically associated with mycobacterial infections (such as M. avium, which causes MAC) and herpesvirus infections (such as herpes zoster [shingles] and cytomegalovirus [CMV]). Skin conditions such as folliculitis (inflammation of hair follicles) or genital warts (associated with human papillomavirus, or HPV) may be manifestations of IRIS, as may complications related to hepatitis B virus (HBV) or hepatitis C virus (HCV). (See table below for a more complete listing.)

In its July 2002 recommendations for antiretroviral therapy in countries with limited resources, the World Health Organization (WHO) made an important distinction between IRIS and clinical failure while on anti-HIV therapy:

"Clinical failure is defined as clinical disease progression with development of an opportunistic infection or malignancy when the drugs have been given sufficient time to induce a protective degree of immune restoration. This needs to be differentiated from an immune reconstitution syndrome which can be seen within the first several weeks after the institution of therapy if a subclinical infection is present at baseline."

The atypical patterns of many cases of IRIS may help providers differentiate between clinical progression of an underlying disease and an immune reconstitution reaction. For example, the hallmarks of IRIS in someone previously responding to treatment for tuberculosis would be a new or worsening fever, new effusions (escape of fluid), new or worsening lymphadenopathy (enlarged lymph glands), and other uncharacteristic reactions, rather than progression of the lung disease itself. A mild case of herpes zoster or a local M. avium infection without bacteremia (bacteria in the blood), both seen in IRIS, would be unusual in an HIV positive individual not taking HAART. Similarly, two eye conditions -- immune recovery vitritis (IRV; inflammation of the gelatinous substance filling the eyeball) and immune recovery uveitis (IRU; inflammation of the pigmented layer of the iris) -- are seen exclusively in people with previous CMV retinitis infection who respond to anti-HIV therapy. (CMV retinitis is characterized by inflammation of the retina and may lead to blindness.)

Clinicians should keep in mind that a true case of progression of an underlying disease might be caused by resistance to antimicrobial drugs, nonadherence to antimicrobial therapy, an adverse drug reaction, a drug-drug interaction, or other factors. Diagnosing viral hepatitis after the initiation of HAART can be especially problematic, as hepatitis symptoms might be due to liver toxicity caused by a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) drug. Also, contrary to the WHO statement above, symptoms of IRIS may develop up to a year after beginning anti-HIV therapy.

Mechanism of Action

Immune reconstitution syndrome remains poorly understood. Its development appears to be linked not only to increases in CD4 cell levels, but also to higher CD8 cell counts induced by HAART. An elevated CD8 cell count has been suggested as a prime contributing factor in worsening of both herpes zoster and hepatitis B or C symptoms after the initiation of anti-HIV therapy.

Researchers have also proposed that the increased activity of cytokines (chemical messengers that coordinate and regulate immune responses) contributes to some forms of IRIS. DeSimone's group pointed out that decreases in HIV viral load may alter levels of interleukin 12 (IL-12), a mediator of anticryptococcal activity, resulting in meningitis symptoms. Guillaume Foulon and colleagues from Hôpital Tenon in Paris found that interleukin 2 (IL-2) and interferon-gamma appeared to speed the development of sarcoidosis in two subjects in the early stages of anti-HIV therapy. (Sarcoidosis is a chronic disease of unknown origin characterized by inflammatory nodules in the lymph nodes, lungs, skin, and bones.) The study authors also noted a case of sarcoidosis appearing two months after IL-2 was added to an existing antiretroviral regimen.

Incidence

The incidence (rate of new cases) of IRIS varies depending on the study, the population under investigation, and the associated pathogens involved. In one cohort of 52 subjects with previously diagnosed CMV retinitis, 19 of 30 (63%) who responded to HAART developed symptomatic IRV, compared with no cases in those who did not respond to therapy. In a different cohort of 33 similar subjects with CMV retinitis, only six (18%) developed symptomatic IRU. In a casecontrol study of 200 ethnically diverse subjects at King's College Hospital in London, 42 (21%) experienced an IRIS event a median of 12 weeks after starting HAART. The median CD4 cell count when HAART was started in this cohort was 172 cells/mm³, and the median HIV viral load was 36,878 copies/mL.

Though most individuals starting HAART are not likely to experience IRIS, clinicians should remain alert for any paradoxical reactions. The U.S. Food and Drug Administration (FDA) appears to be encouraging greater vigilance. In January 2004 the FDA approved package labeling revisions for indinavir (Crixivan), including a warning that "immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (CART), including Crixivan ... which may necessitate further evaluation and treatment." A similar labeling change has since been made for other antiretroviral drugs, including efavirenz (Sustiva) and Kaletra (lopinavir/ritonavir).

Risk Factors

While IRIS appears to be most prevalent in people with a severely compromised immune system at baseline, other risk factors common to the widely varying manifestations of IRIS are difficult to identify and are often challenging to establish even within single cohorts. In the ethnically diverse cohort from London, in which 59% of subjects were black African, 10.5% were black Caribbean, 29.5% were white, and 49% were female, the most common IRIS symptoms were more severe or recurrent genital herpes and other dermatological infections. The study authors found no well-defined, independent predisposing factors.

A multivariate, retrospective analysis of 115 subjects in Houston with Cryptococcus neoformans infection found only two risk factors for IRIS: timing of antiretroviral therapy (initiation of HAART within 30 days of C. neoformans diagnosis), and a higher initial level of C. neoformans antigen in the cerebrospinal fluid, which suggests a greater intensity of initial infection. Interestingly, demographics, baseline CD4 cell count (which was very low among all subjects, though significantly higher in those with IRIS), type of antiretroviral therapy, and type of antifungal agents used were not associated with developing immune reconstitution syndrome. (C. neoformans is the fungus that causes cryptococcal meningitis, an inflammation of the membranes surrounding the brain and spinal cord, and other forms of cryptococcosis.)

Use of cytokines such as IL-2 to treat HIV infection might put some individuals at risk for developing IRIS. Furthermore, people with certain genetic mutations of their innate cytokines may be more likely to experience an inflammatory reaction after starting HAART. As Patricia Price and colleagues from Royal Perth Hospital in Australia reported in the October 18, 2002 issue of AIDS, cytokine mutations play a role in forms of IRIS related to mycobacterial and herpesvirus infections. For example, a certain tumor necrosis factor (TNF)-alpha mutation was found in 13 of 25 subjects (52%) with herpesvirus-related IRIS but in none of 11 subjects with mycobacterium-related IRIS.

Management

In cases in which IRIS and not disease progression can be diagnosed, different approaches to treatment have been used. Inflammatory reactions may be treated with antimicrobial agents directed at the underlying infection, including possible intensification of medications already in use. Clinicians might also treat the inflammatory component with steroids or nonsteroidal anti-inflammatory agents. Continued use of HAART may be all that is necessary for IRIS to resolve. In fact, the consensus is that antiretroviral therapy should not be stopped in almost all cases of paradoxical inflammation.

These interventions are mostly based on published case reports and other anecdotal clinical evidence, as there are currently no guidelines for managing IRIS. Nevertheless, outcomes are almost invariably better in people with IRIS than in those who are HIV positive with clinical progression of a given disease. Some outcomes, as in the French study of sarcoidosis, are similar in people with IRIS and in HIV negative individuals who develop the genuine disease.

Grounds for Optimism

While HAART-associated inflammatory reactions may be bothersome and occasionally severe, Bruce Walker, MD, of Harvard Medical School claims that the syndrome should be "grounds for great optimism." According to Walker, the IRIS phenomenon shows that functional immunity can be restored in HIV positive individuals, and that subsequent, specific immune responses can be directed toward common pathogens. The hope is that researchers will eventually find a way to bolster the body's immune responses against HIV itself using HIV-specific CD4 cells to naturally suppress the virus.

Nicholas Cheonis is editor of BETA.

Selected Sources

1. Chaisson, R.E. Immune reconstitution syndrome. Johns Hopkins AIDS Service: Clinician Forum. http://qa.hopkins-aids.org/forum/view_question.html?section_id=62
   &id=42969&category_id=113. October 14, 2001.

2. DeSimone, J.A. and others. Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy. Annals of Internal Medicine 133(6): 447-454. September 19, 2000.

3. Foulon, G. and others. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clinical Infectious Diseases 38(3): 418-425. February 1, 2004.

4. John, M. and others. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 12(17): 2289-2293. December 3, 1998.

5. Karavellas, M.P. and others. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. Journal of Infectious Diseases 179(3): 697-700. March 1999.

6. Nguyen, Q.D. and others. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. American Journal of Ophthalmology 129(5): 634-639. May 2000.

7. Price, P. and others. Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS 16(15): 2043-2047. October 18, 2002.

8. Rao, G.P. and others. Paradoxical progression of tuberculous lesions during chemotherapy of central nervous system tuberculosis. Journal of Neurosurgery 83(2): 359-362. August 1995.

9. Saurborn, D. and Boiselle, P.M. Recognizing the radiologic signs of mycobacterial infections: pleural effusion may be the only sign in some patients. Journal of Respiratory Diseases 24(10): 454-461. October 2003.

10. Shelburne III, S. and others. Incidence and risk factors for immune reconstitution inflammatory syndrome (IRIS) among patients with Cryptococcus neoformans infection. 11th Conference on Retroviruses and Opportunistic Infections. San Francisco. February 8-11, 2004. Abstract 770.

11. Thevarajan, I. and others. Epidemiology of immune reconstitution inflammatory syndrome (IRIS) in an ethnically diverse HIV infected cohort. 9th European AIDS Conference. Warsaw. October 25-29, 2003. Abstract F4/4.

12. Walker, B.D. Immune reconstitution and immunotherapy in HIV infection. Medscape Clinical Update. www.medscape.com/viewprogram/2435_pnt. June 12, 2003.

13. World Health Organization: Regional Office for South-East Asia, New Delhi. The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries. http://w3.whosea.org/en/Section10/Section18/Section356/Section408.htm. July 2002.

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