A 30-year old HIV-positive male presents with productive cough, low-grade fever and weight loss. A chest X-ray showed mediastinal lymphadenopathy and a minimal lower left lung infiltrate; sputum smear tests positive. Upon questioning, he gives a history of unprotected sexual encounters, and tests positive for HIV. His CD4 count is 50 cells/mm³. He receives standard 4 drug anti-TB therapy. Two weeks after initiating anti-TB therapy, he begins treatment with efavirenz, tenofovir and emtricitabine.

Ten days later, the patient returns with complaints of fever, chills and rigors. A chest X-ray showed increased mediastinal widening and worsening lower left lung infiltrates. This could be an undesired effect caused by a reconstituted immune system or could indicate progression of TB as a result of treatment failure.

Some patients initiating antiretroviral therapy experience unique symptoms during immune system recovery. In these patients, clinical deterioration occurs despite increased CD4 counts and decreased plasma HIV viral loads. This clinical deterioration is the result of an inflammatory response of the immune system to antigenic stimuli. This syndrome has been referred to as IRIS, or immune reconstitution inflammatory syndrome.

As the use of antiretroviral therapy increases around the world, physicians managing patients with HIV infection will encounter increasing numbers of patients with IRIS. Management of these conditions is often problematic, in particular their differentiation from opportunistic infections or drug toxicity.

Clinicians should include IRIS in the differential diagnosis when evaluating patients who recently have begun antiretroviral therapy and present with new or worsening symptoms of an opportunistic infection.

This booklet discusses various aspects of IRIS, such as why, when and how it occurs, diagnostic criteria and management approaches.

The introduction of combination antiretroviral therapy (ART) has dramatically improved outcomes for persons living with HIV infection. Successful suppression of viral replication is followed by an increase in CD4 lymphocytes and a partial recovery of T-cell specific immune responses. This correlates with decreased susceptibility to opportunistic pathogens.¹ In other words, ART results in beneficial immune reconstitution for patients with advanced HIV disease.

The majority of patients whose plasma HIV RNA levels remain below the level of detection on ART eventually achieve absolute CD4 counts that are in the normal range.²

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 of initiating therapy. This exuberant inflammatory response has been called the immune reconstitution inflammatory syndrome (IRIS). It is also known as immune reconstitution syndrome (IRS) or immune reconstitution disease (IRD) ³ (Figure 1).

IRIS may present as the following:³

IRIS results from restored immunity to specific infectious or non-infectious antigens. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli.

The clinical deterioration is a result of an inflammatory response or "dysregulation" of the immune system to both intact subclinical pathogens and residual antigens. Resulting clinical manifestations of this syndrome are diverse and depend on the infectious or noninfectious agent involved. These manifestations include mycobacterial-induced lymphadenitis, paradoxical tuberculosis reactions, worsening of progressive multifocal leukoencephalopathy (PML), recurrence of cryptococcosis and Pneumocystis jiroveci pneumonia (PCP), Cytomegalovirus (CMV) retinitis, shingles, and viral hepatitis, as well as non-infectious phenomena.⁴

The interval between the start of ART and the onset of IRIS is highly variable, ranging from less than 1 week to several months, but the majority of events occur within the first 8 weeks after ART initiation and occur in patients with low mean CD4 counts.⁵

In a study by Shelburne et al⁶, the median time between starting ART and diagnosing IRIS in 57 patients was 46 days, with the shortest time being 3 days and the longest 658 days (Figure 2). Presentation was within 60 days for 34 (60%) and within 90 days for 41 (72%) of beginning ART. There were no significant differences between the underlying Ol and the time to onset of IRIS after commencing ART.

Further, the investigators also examined how the timing of initiating ART relative to starting therapy for the OI influenced the subsequent development of IRIS. In patients who developed IRIS, the median number of days between beginning treatment for the OI and commencing ART was 27 days, while for patients who did not develop IRIS it was 50 days (p< 0.001).

Thus, it is important to adequately treat Ols with appropriate antimicrobial therapy and stabilize patients before starting ART.

IRIS is recognized as a potential complication that can occur after potent ART. The frequency of IRIS has not been reported conclusively, but it may be estimated to occur in 10% - 25% of patients who receive ART.⁵

The incidence is dependent on the population studied and its underlying opportunistic infectious burden. ⁴

Mycobacterial antigens are frequently implicated in IRIS, and together they represent almost one-third of all reported cases.⁵ A study from south India has reported that the incidence of IRIS in HIV/TB coinfected patients was 15.2 cases per 100 person years.⁷

Immune restoration disease may have infectious or non-infectious aetiologies, as follows:

When cases of infectious IRIS were first reported, there was uncertainty as to whether they were a consequence of the restoration of an immune response against opportunistic pathogens, or Ols resulting from residual defects of cell-mediated immunity. Subsequently, there has been acceptance that they are a consequence of immune reconstitution in patients who experience a virological response to ART. However, this response is immunopathological rather than protective. A variety of pathogens may be involved (see Table 2).

Sarcoid-like disease and autoimmune diseases are observed less frequently in patients responding to ART and also appear to have an immunological basis. These may also be considered under IRIS.⁸

Granulomatous inflammation of the lungs, which has the characteristics of sarcoidosis, has been described in patients responding to ART. Granulomatous inflammation of other organs has also been described, including the skin, kidneys, liver and duodenum. It is important to exclude infectious IRIS as a cause of granulomatous inflammation because this may occur in patients infected by mycobacteria, cryptococci and histoplasma. Sarcoid IRIS may resolve spontaneously with continuation of ART, but corticosteroid therapy is sometimes necessary.⁸

Autoimmune diseases presenting for the first time, or as an exacerbation of established disease, have also been reported in HIV patients responding to ART. Patients with systemic lupus erythematosus, polymyositis or rheumatoid arthritis usually present during the first few months of therapy. It is presumed that the immune dysregulation underlying the autoimmune disease is precipitated or exacerbated by the immunological changes that occur after suppression of HIV replication. Guillain-Barre syndrome may also present in the first few weeks of ART. Graves' disease is an uncommon but well-recognized complication of immune reconstitution in severely immunodeficient HIV patients. ⁸

IRIS is largely a clinical diagnosis, and requires a high index of suspicion. In fact, it is a diagnosis of exclusion. ^3,9

To consider IRIS in the differential diagnosis, the clinician must recognize not only the clinical findings (typical or atypical) of a specific OI, but also the temporal association with initiation of ART and increase in the CD4 count. ³

The following points help in the diagnosis of IRIS:¹⁰

Culturing the microorganism in body fluids may provide a clue for an active OI, which would warrant anti-microbial therapy.

It is important to rule out new, incompletely treated, or untreated infections; malignancy; and other illnesses before concluding that the patient has IRIS.³

The work-up for a patient with possible IRIS will depend on the specific clinical presentation. Perform laboratory tests, blood cultures, and other diagnostic tests as appropriate to the individual patient. These may include the following:³

It is important to define IRIS as a clinical entity to facilitate diagnosis and further characterization of this disease. ¹ A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating ART characterizes this syndrome.⁴

Proposed diagnostic criteria for infectious IRIS are outlined in Table 1. A diagnosis of IRIS would require both major criteria or criterion A and two minor criteria.⁸

The following table depicts the pathogens commonly implicated in IRIS, along with their respective manifestations and characteristics.

IRIS in response to the simultaneous occurrence of two entities (i.e. CMV and Cryptococcus species) has been reported.⁵

Identified risk factors for infectious IRIS are: ¹⁰

Many of the IRIS cases reported in the literature have occurred within a few months of initiating ART and in the context of a rapid and marked rise in CD4 count from very low pretreatment levels (often < 50-100 cells/mm³)³

Prevention and treatment recommendations from randomized, prospective trials are lacking for IRIS. However, most cases of IRIS reported in the literature appeared to resolve within a matter of weeks with the following: ^3,10

For patients with recent Ols 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 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.³

In the majority of cases, ART can be safely continued ithout need for interruption. Discontinuation of ART should be considered if:¹⁰

IRIS may be more frequent in patients with advanced HIV disease who are initiating ART. Hence, starting ART earlier (i.e. before CD4 counts decrease to < 200 cells/mm³) would help avoid IRIS.⁵

Further, stabilizing patients who have Ols before initiating ART can prevent IRIS. For example, in HIV/TB coinfected patients with CD4<200 cells/mm³, it is recommended that ART be initiated about 2-6 weeks after anti-TB therapy is initiated.¹⁰

Although there may be short-term ciated with IRIS, these patients appear to have comparably good long-term outcomes.

Shelburne et al¹¹ have reported that after 24 months of ART, patients with IRIS were more likely to have a successful viral suppression and immune reconstitution than patients without the syndrome. There was no significant mortality difference between the two groups of patients. In fact, the survival trend was in favour of the IRIS patients, which may be a reflection of the durable viral suppression and immune reconstitution seen in these patients.⁶

The following points should be communicated:⁹