TAKE-HOME POINTS
■ Improving immune function can be associated with an inflammatory process that poses a significant threat to patients even though their immune status is improving.
■ The onset of immune reconstitution inflammatory syndrome (IRIS) symptoms can occur as early as 1 week after the initiation of antiretroviral treatment. Yet, symptoms may also manifest as late as 1 year or more after treatment initiation.
■ IRIS is estimated to affect approximately one-quarter of patients who start antiretroviral therapy.
■ A paradoxical worsening of symptoms has been noted with other disease processes that are similar to HIV infection. Thus, although most of the information we have focuses on HIV, the implications for IRIS may be broader.
Patients being treated for immune system diseases are expected to improve as the treatment progresses. However, recent guidelines and the medical literature show that an inflammatory process that poses a significant threat to these patients can occur even though their immune status is improving.1-3 Guidelines from a few years ago recognized the importance of reconstituting immune function to prevent opportunistic infections.4 In the past several years, a growing number of papers have described this inflammatory reaction to antiretroviral treatment in patients infected with HIV. The phenomenon is referred to as immune reconstitution inflammatory syndrome (IRIS)5,6 or immune restoration disease.7
The onset of IRIS symptoms can occur as early as 1 week after the initiation of antiretroviral treatment. Yet, symptoms may also manifest as late as 1 year or more after initiation of treatment. More than 75% of patients symptomatic for IRIS, however, will have manifestations within 90 days of starting antiretroviral therapy.2,3
Pathogenesis The constellation of issues that arise as a result of immune reconstitution are driven by pathogen and host-specific factors.2,5,8 Whereas reduced CD4+ T cells lie at the heart of HIV pathology, IRIS may be a manifestation of immune regulators in addition to pathogen-specific reactions. IRIS has two characteristic presentations or classifications: unmasking and paradoxical.3,5 Both represent symptoms that manifest as immune function begins to improve and cells in the immune system are restored.
In the unmasking presentation, the patient has an unrecognized infection or neoplasm that, consequently, is not being treated. The symptoms of the infection or skin lesions increase as antiretroviral therapy reestablishes immune function. The goal is to identify the underlying infectious agent and administer appropriate treatment. Commonly unmasked conditions are tuberculosis, Mycobacterium avium infection, and leprosy.3,5-7,9
In the paradoxical reaction, the patient is receiving appropriate therapy for a recognized infection. However, as the immune deficiency is corrected, the symptoms of the infection worsen. This causes concern as other causes for the worsening symptoms must be ruled out. The antimicrobial therapy may not have been optimal, and the worsening symptoms indicate the breakthrough of a resistant agent.
All clinicians should be aware that IRIS is a fairly common result of treatments that increase immune function in patients with HIV/AIDS. However, certain underlying conditions may further increase a patient's risk of developing IRIS.3,5,6 The inflammatory reaction is more likely to occur in patients with higher disease burden at the start of treatment. If the CD4+ T cell count is low—certainly less than 200 cells/ L, but most likely less than 50 cells/ L—and the viral load is high—100,000 HIV viral copies/ L or more—the patient is more likely have the reaction. Ironically, the faster the immune system clears the viral load in HIVinfected patients, the greater the risk of developing IRIS.3 A patient who is antiretroviral naive is more likely to develop symptoms.
This case report illustrates the phenomenon. Infectious disease specialists treated a 30-year-old woman with HIV/AIDS and pulmonary M avium infection with ethambutol, clarithromycin, efavirenz, zidovudine, and lamivudine while she was in the hospital. In clinic approximately 3 months later, her HIV viral load was reduced but still detectable. Resistance typing indicated the HIV was resistant to lamivudine. Her antiretrovirals were changed to abacavir, tenofovir, darunavir, and ritonavir. Following this change, her HIV viral load decreased from 10 million HIV RNA copies/ L of blood plasma to 4,000 copies in 1 month; and her CD4+ count increased from 134 to 176 cells/ L. Within a few more weeks, she presented to her primary care provider with worsening shortness of breath and pleuritic chest pain. She was readmitted to the hospital, and bronchoscopy reconfirmed infection with M avium. The patient experienced a paradoxical worsening of symptoms brought on by the recurring M avium infection. This type of phenomenon is becoming more common in this era of highly active antiretroviral therapy.2-4
IRIS is not an obscure reaction or an occasional occurrence. It is estimated to affect approximately one-quarter of patients who start antiretroviral therapy, especially those patients placed on effective antiretroviral therapy who experience at least a log rhythmic reduction in HIV viral burden.
As an inflammatory response, IRIS is self-limiting. An increase in mortality associated with onset is not apparent, but morbidity and symptoms may require hospitalization to institute supportive measures.3 Obviously, this would pose a bigger threat in the setting of limited resources or in areas with tremendous disease burden.