Immune Reconstitution Inflammatory Syndrome

Background

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:

• An exacerbation of a partially or successfully treated opportunistic infection (OI), referred to as paradoxical IRIS
• An inflammatory response to a previously undiagnosed (subclinical) OI, often more pronounced than the typical presentation of this OI, referred to as unmasking IRIS

IRIS may occur in response to many pathogens. IRIS commonly occurs in association with Mycobacterium tuberculosis, Mycobacterium avium complex (MAC), cytomegalovirus (CMV), and Cryptococcus, and it may occur with Pneumocystis, Toxoplasma, hepatitis B and C, human herpes virus 8 (HHV-8, which causes Kaposi sarcoma), JC virus (which causes progressive multifocal leukoencephalopathy, PML), and varicella-zoster virus.

Risk factors for development of paradoxical IRIS include low CD4 cell count (particularly <50 cells/µL) at time of ART initiation and high baseline HIV RNA. Starting ART in close proximity to initiation of treatment for a recognized OI also increases the risk of IRIS, though accumulating data also show that earlier ART initiation tends to reduce mortality and AIDS progression, particularly in persons with advanced immunosuppression (see "Timing of ART initiation," below).

Paradoxical 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 and dysregulated 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:

• Presence of a new OI or concomitant illness
• Failure of treatment for HIV infection (e.g., owing to poor adherence or drug resistance)
• Failure of treatment for a known OI (e.g., owing to drug resistance, inadequate treatment, or poor adherence)

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 (including corticosteroids) as needed.

Clinical Presentation

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.)

Tuberculosis

The signs and symptoms of TB IRIS may include various clinical or radiologic features (e.g., new or worsening enlarged lymph nodes, fevers, weight loss, pulmonary symptoms, and radiographic features of TB such as infiltrates and pleural effusions). Nonpulmonary presentations may include expanding central nervous system (CNS) deficits or lesions, lymphadenopathy (mediastinal or peripheral), ascites, pericardial effusions, 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).

Mycobacterium avium Complex

Lymphadenitis and fever are the characteristic symptoms of MAC IRIS, but pulmonary symptoms, abdominal pain, bone and hepatic involvement, and CNS manifestations may develop. 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 MAC bacteremia usually is absent. MAC IRIS can be mild and localized or it can be severe, requiring systemic antiinflammatory therapy (sometimes for long periods), in addition to anti-MAC therapy.

Cytomegalovirus

CMV IRIS is usually localized to the eye, as described below. However, CMV IRIS will rarely present with extraocular disease such as colitis, pancreatitis, or pneumonitis.

CMV retinitis

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.

In order to initiate appropriate treatment, and to avoid IRIS, an ophthalmic examination to assess for the presence of CMV retinal infection should be performed for all patients with CD4 cell counts of <50 cells/µL), preferably prior to the initiation of ART. This is particularly important for patients who report visual symptoms such as floaters or abnormal vision.

For patients who experience IRIS after being adequately treated for CMV retinitis, 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 appropriate CMV therapy has not been introduced (see chapter Cytomegalovirus Disease).

CMV vitreitis and CMV uveitis

CMV vitreitis and CMV uveitis are seen exclusively in patients with previous CMV retinitis infection who responded to ART.

CMV vitreitis

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.

CMV uveitis

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.

Cryptococcal Meningitis

In patients with or without previously diagnosed cryptococcal meningitis, presentation of cryptococcal IRIS typically includes fever, headache, eye pain, and photophobia, and may include meningeal signs. In cryptococcal IRIS, analysis of cerebrospinal fluid (CSF) is characterized by high opening pressure and, unlike initial presentation of cryptococcal meningitis, an elevated white blood cell count and sterile fungal cultures. Onset has been reported between 1 week and 11 months after initiation of ART. Lymphadenitis, pulmonary disease, and cutaneous involvement also have been reported (see chapter Cryptococcal Disease).

Pneumocystis jiroveci Pneumonia

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 (typically after corticosteroids given for the initial PCP treatment have been tapered or discontinued) 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).

S: Subjective

Symptoms of IRIS will vary according to the specific illness.

Include the following in the history:

• Specific symptoms and time course of symptoms
• History of OIs, including recently diagnosed OIs
• Treatment of OIs, including date of initiation, medication adherence, duration of therapy, and clinical response
• ART initiation date, specific antiretroviral regimen, medication adherence, and previous history of ART
• CD4 cell count and HIV viral load before ART initiation
• Current CD4 cell count and HIV viral load, if known
• Other medications, especially new medications, including over-the-counter and herbal preparations

O: Objective

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.

A: Assessment

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:

• Worsening or progression of a known OI despite treatment (e.g., owing to drug resistance or inadequate therapy)
• A new infection or illness
• Drug toxicity (e.g., hypersensitivity reaction)
• Failure of ART; progression of AIDS

Perform the appropriate diagnostic tests to exclude other etiologies. Consider consulting with an HIV specialist if the diagnosis is in question.

P: Plan

Diagnostic Evaluation

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:

• Complete blood count (CBC) with differential, electrolytes and creatinine, liver function tests
• CD4 cell count and HIV viral load
• Blood cultures for bacteria, acid-fast bacteria (MAC), fungi
• Chest X ray; other radiographic studies
• Sputum stain and culture
• Biopsy or culture of skin or other lesions
• Lumbar puncture and cerebrospinal fluid studies, if a CNS process is suspected>
• Ophthalmologic examination
• Drug resistance testing for the OI being treated, if indicated

Treatment

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:

• Continuing the current ART regimen (unless the clinical presentation was life-threatening)
• Treating any newly identified, untreated OI
• If indicated, administering antiinflammatory medications to suppress the inflammatory process (prednisone was shown in one study to decrease hospital days and improve symptoms in TB IRIS in sub-Saharan Africa; anecdotal data support the use of NSAIDs in mild-to-moderate IRIS)

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, once recurrent TB infection has been ruled out. 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.

Timing of ART initiation

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 many OIs is not known, but one randomized controlled trial suggests a mortality benefit to early ART initiation in patients with a variety of newly diagnosed OIs. For patients with TB and HIV infection, data from three randomized studies show reductions in mortality and/or AIDS progression with early initiation of ART, though the urgency of ART varied with CD4 count: for those with CD4 counts <50 cells/µL, benefit was seen if ART was initiated within 2 weeks of TB treatment start (compared with delaying until week 8-12 of TB treatment). For those with CD4 counts of 50-200 cells/µL, data support ART initiation between 2 weeks and 2 months after the start of TB treatment. ART should not be deferred until after TB treatment for any patient, regardless of the CD4 cell count. In cryptococcal meningitis, optimal timing of ART has not been defined; one randomized controlled trial did not find a benefit to early ART initiation, but in that study, mortality was remarkably high in both the earlier and later treatment arms.

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, particularly in patients with TB and CD4 counts of <50 cells/µL. For patients with cryptococcal meningitis or other CNS infections, many specialists would recommend delaying ART until they have received appropriate OI treatment for at least 2 weeks. For decisions about initiating ART in patients with active OIs, consult with an HIV specialist.

IRIS in resource-limited settings

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.

Patient Education

• Patients starting ART who have CD4 counts of <100 cells/µL or known concomitant OIs should be counseled about the likelihood of IRIS.
• All patients starting ART should be advised to contact the clinic promptly if they experience new or worsening symptoms.
• Advise patients to take their medications for HIV and for the treatment or prevention of OIs exactly as prescribed.

References

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