For most patients, initiating antiretroviral therapy (ART) improves immune responses to a wide range of opportunistic pathogens. The process of ART-induced immune reconstitution typically is uneventful. However, a small percentage of patients develop inflammatory disease in response to specific opportunistic pathogens within a few weeks or months after initiating therapy. This exuberant inflammatory response has been called the immune reconstitution inflammatory syndrome (IRIS), also known as immune reconstitution syndrome (IRS) or immune reconstitution disease (IRD).
The term IRIS is used to describe two distinct entities:
IRIS may occur in response to many pathogens, including Mycobacterium tuberculosis, Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Cryptococcus, Pneumocystis, Toxoplasma, hepatitis B, and varicella-zoster virus.
Many of the IRIS cases described in the medical literature occurred within a few months after initiating ART and in the context of a rapid and marked rise in CD4 cell count from very low pretreatment levels (often <50-100 cells/µL). IRIS also can occur in the absence of ART, as has been reported during tuberculosis (TB) treatment. The specific mechanisms involved in the pathogenesis of IRIS are not well understood and may vary from one infection to another. However, experts believe that IRIS is caused by an enhanced immune response to disease-specific antigens, which leads to an overproduction of inflammatory mediators.
IRIS may be difficult to identify in clinical practice because the clinical presentation is nonspecific and, currently, there are no laboratory markers to identify the syndrome. To make the diagnosis of IRIS, the following must be excluded:
The severity of IRIS varies widely, from mild to life-threatening. Treatment varies according to the specific pathogen and clinical situation, but typically includes continuing ART if possible, treating the OI as indicated, and adding antiinflammatory therapy as needed.
IRIS is largely a clinical diagnosis, and other conditions must be excluded, as indicated above. To consider IRIS in the differential diagnosis, clinicians must recognize the clinical findings (typical or atypical) of a specific OI and the temporal association with treatment (usually after ART initiation, but IRIS may occur with treatment of the OI alone). For example, for a patient with TB who has recently initiated ART after responding to treatment of TB, the "red flags" for a diagnosis of IRIS (rather than progression of the TB) would include new or worsening fever, new effusions, and new or worsening lymphadenopathy, in the absence of poor adherence to TB treatment and the absence of drug-resistant TB.
The clinical manifestations of IRIS associated with some common OIs are described below. (This is not an exhaustive list, but it includes most of the important IRIS manifestations seen in patients with HIV infection.)
The signs and symptoms of TB IRIS may include high fevers, new or worsening pulmonary symptoms and infiltrates, and new or increasing pleural effusions. Nonpulmonary presentations may include expanding central nervous system (CNS) lesions, lymphadenopathy (mediastinal or peripheral), skin or visceral abscesses, bone lesions, and hypercalcemia. In a patient who is receiving therapy for active TB, the onset of TB IRIS typically occurs within 3-6 months after the patient begins ART and is more common among patients with low CD4 cell counts at the time of ART initiation (see chapter Mycobacterium tuberculosis).
Lymphadenitis and fever are the characteristic symptoms of MAC IRIS, but pulmonary and other symptoms may develop. These and the other signs and symptoms of MAC IRIS may be clinically indistinguishable from active MAC. In contrast to disseminated MAC, MAC IRIS is associated with a rapid and striking increase in CD4 count (usually from <50 cells/µL to ≥100 cells/µL), and bacteremia usually is absent. MAC IRIS can be mild and localized or it can be severe, requiring systemic antiinflammatory therapy in addition to anti-MAC therapy.
CMV retinitis may occur in patients with a history of CMV retinitis or in patients with no previous evidence of retinitis. In those with a previous diagnosis of CMV retinitis, a new opacified retinal lesion develops, frequently at the site of an earlier lesion. CMV retinitis IRIS is identical to active CMV retinitis on ophthalmologic examination. Clinical information, therefore, will guide the diagnosis, and patients should be monitored closely. As with other IRIS reactions, symptoms often are associated temporally with initiation of ART. For patients who were adequately treated for CMV and who experience IRIS, serial ophthalmologic examinations will reveal that the lesions clear without a new or different therapy for CMV. This clinical picture differs from that of retinal lesions caused by active CMV infection and uncontrolled CMV replication, in which lesions will increase in size or new lesions will appear, if CMV therapy has not been introduced or changed (see chapter Cytomegalovirus).
CMV vitreitis and CMV uveitis are seen exclusively in patients with previous CMV retinitis infection who responded to ART:
CMV vitreitis IRIS is an alarming syndrome, but a benign one. Patients who are receiving anti-CMV therapy typically present with acute onset of blurred vision and "floaters" caused by posterior segment inflammation. Ophthalmologic examination reveals numerous inflammatory cells in the vitreous humor. Symptoms usually resolve in 1 month without specific treatment and without any lasting visual effects.
In patients with a history of CMV retinitis, CMV uveitis IRIS may occur within months of ART initiation, but typically is a late complication, occurring about 3 years after patients begin ART. Uveitis is painless and primarily involves inflammation in the iris, the ciliary body, and the choroid layers. However, CMV uveitis may have serious sequelae. It often results in macular edema, epiretinal membrane formation, or cataracts, which can lead to permanent vision loss. Because of the risk of vision loss, clinicians should have a high index of suspicion for CMV uveitis.
In patients with or without previously diagnosed cryptococcal meningitis, presentation of cryptococcal IRIS typically includes fever, headache, and meningeal signs and symptoms. Onset has been reported between 1 week and 11 months after initiation of ART. Lymphadenitis also has been reported (see chapter Cryptococcal Disease).
Pneumocystis jiroveci pneumonia (PCP) IRIS may occur in patients with current or recent PCP who are starting ART in the early weeks after initiation of PCP treatment. IRIS may present as worsening pulmonary symptoms and high fever in patients who had been improving on PCP therapy or in patients with recent successful treatment of PCP. Chest X rays may show worsening lung involvement, and oxygen saturation or arterial blood gas measurements may show worsening hypoxia or alveolar-arterial oxygen gradient. PCP IRIS sometimes causes severe acute respiratory failure (see chapter Pneumocystis Pneumonia).
Symptoms of IRIS will vary according to the specific illness.
Include the following in the history:
Obtain vital signs, including temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation.
Perform a thorough physical examination based on symptoms and suspicion of systems involved.
In the appropriate clinical setting (especially in patients with advanced AIDS who recently initiated ART), IRIS should be considered in the differential diagnosis of patients who present with new or worsening symptoms. In these patients, the differential is broad, and causes other than IRIS should be considered carefully, including:
Perform the appropriate diagnostic tests to exclude other etiologies. Consider consulting with an HIV specialist if the diagnosis is in question.
It is important to rule out new, incompletely treated, or untreated infections; malignancy; and other illnesses before concluding the patient has IRIS.
The workup of the patient with possible IRIS will depend on the specific clinical presentation. Perform laboratory tests, blood cultures, and other diagnostic tests as appropriate for the individual patient. These may include the following:
Prevention and treatment recommendations from randomized prospective trials are lacking for most IRIS syndromes. However, the majority of cases of IRIS reported in the medical literature are not life-threatening and appear to have resolved within a matter of weeks to months with the following:
For patients with recent OIs that resolved with a full course of appropriate therapy, it is not always necessary to resume antimicrobial therapy or to change maintenance therapy. For example, if a patient with TB IRIS has finished a full course of treatment for TB, repeat treatment is not indicated. If a patient with previously treated cryptococcal meningitis is receiving maintenance therapy and IRIS develops, the therapy does not need to be altered. However, if IRIS reveals a new, untreated OI, that infection should be treated appropriately. For instance, if new cryptococcal meningitis presents as IRIS, the cryptococcus should be treated as indicated. If treatment is in question, consult with an HIV specialist.
The risk of IRIS is highest for patients who start ART with low CD4 counts (<50-100 cells/µL) and those for whom ART is initiated soon after OI treatment is begun. The optimal time for ART initiation in the setting of an OI is not known, but one randomized controlled trial suggests a mortality benefit to early ART initiation in patients with newly diagnosed OIs. Decisions about the timing of ART initiation may depend on a number of variables, including the specific pathogen, the severity of the OI, whether the CNS is involved (IRIS in the CNS may be life-threatening), the medication burden, and the potential for drug toxicity or drug interactions. In most cases, ART initiation should be considered within 1-2 weeks after initiation of OI therapy. For patients with cryptococcal or mycobacterial disease who are otherwise stable and for whom ART can be deferred temporarily, many specialists would recommend delaying ART until they have received appropriate OI treatment for 2-6 weeks. Ongoing trials will better define timing of ART in patients with TB and cryptococcal meningitis.
For decisions about initiating ART in patients with active OIs, consult with an HIV specialist.
As access to ART improves in resource-limited countries, IRIS increasingly is being recognized in patients receiving ART. Clinicians should include IRIS in the differential diagnosis when evaluating patients who recently have begun ART and present with new or worsening symptoms of an OI. However, limited diagnostic testing resources may make it difficult to establish IRIS and other diagnoses.
Given that coinfection with HIV and TB is epidemic in many countries, and because IRIS is not uncommon in patients with TB, clinicians should be particularly vigilant about symptoms that may signal IRIS. As in resource-sufficient countries, consultation with a clinician trained in caring for patients with HIV is recommended if diagnosis or treatment is in question.