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Immune Reconstitution Syndrome

July 2006


Chapter Contents

Background

Clinical Presentation

Subjective

Objective

Assessment

Plan

Patient Education

References

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

IRS may present as the following:

  • An exacerbation of a partially or successfully treated opportunistic infection (OI)
  • A previously undiagnosed (subclinical) OI

IRS may occur in response to many pathogens, including Mycobacterium tuberculosis (TB), Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Cryptococcus , Pneumocystis , Toxoplasma , hepatitis B, and varicella zoster virus.

Many of the IRS 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/µL). The specific mechanisms involved in the pathogenesis of IRS are not well understood and may vary from one infection to another. However, experts believe that IRS is caused by an enhanced immune response to disease-specific antigens, which leads to an overproduction of inflammatory mediators.

IRS may be difficult to identify in clinical practice because the clinical presentation is nonspecific. IRS must be distinguished from other causes of disease such as the presentation of a new OI or other illness, failure of treatment of a previously identified OI, or drug toxicity. The severity of IRS 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.

Clinical Presentation

IRS is largely a clinical diagnosis. To consider IRS 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. For example, in a patient with TB who has recently initiated ART after responding to treatment for TB, the "red flags" for a diagnosis of IRS (rather than progression of the TB) would include new or worsening fever, new effusions, new or worsening lymphadenopathy, and other uncharacteristic signs or symptoms.

The clinical manifestations of IRS associated with some common OIs may include the following. (This is not an exhaustive list, but it includes most of the important IRS manifestations of patients with HIV infection.)

Tuberculosis

The signs and symptoms of TB IRS may include high fevers, new or worsening lymphadenopathy (mediastinal or peripheral), worsening of pulmonary symptoms and infiltrates, and new or increasing pleural effusions. Nonpulmonary presentations may include expanding central nervous system lesions, skin or visceral abscesses, bone lesions, or hypercalcemia. In a patient who is receiving therapy for active TB, the onset of TB IRS typically occurs 1-6 weeks after the patient begins ART. (See chapter Tuberculosis Treatment in Resource-Limited Settings ).

Mycobacterium avium Complex

Lymphadenitis and fever are the characteristic symptoms of MAC IRS, but pulmonary and other symptoms may develop. These and the other signs and symptoms of MAC IRS may be clinically indistinguishable from active MAC. In contrast to disseminated MAC, MAC IRS 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 IRS can be mild and localized or it can be severe, requiring systemic antiinflammatory therapy in addition to anti-MAC therapy.

Cytomegalovirus

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 IRS is identical to active CMV retinitis on ophthalmologic examination. Clinical information, therefore, will inform the diagnosis, and patients should be monitored closely. As with other IRS reactions, symptoms will be associated temporally with initiation of ART and a recent increase in CD4 count. In patients who were adequately treated for CMV and who experience IRS, serial ophthalmologic exams 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.

CMV vitreitis and CMV uveitis

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

CMV vitreitis

IRS 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 exam 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 IRS 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 IRS typically includes fever, headache, and meningeal signs and symptoms. Onset has been reported between 1 week and 11 months after initiating ART. Lymphadenitis also has been reported. (See chapter Cryptococcal Disease ).

Pneumocystis jiroveci Pneumonia

Pneumocystis jiroveci pneumonia (PCP) IRS may occur in patients with current or recent PCP who are starting ART in the early weeks after initiation of PCP treatment. IRS 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 IRS may sometimes cause severe acute respiratory failure. (See chapter Pneumocystis Pneumonia ).

S: Subjective

Symptoms of IRS 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 count and HIV viral load before ART initiation
  • Current CD4 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), IRS 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 IRS should be considered carefully:

  • IRS: either a paradoxical worsening of a previously recognized OI or a new manifestation of a previously subclinical infection
  • Worsening or progression of a known OI despite treatment
  • A new infection or illness
  • Drug toxicity (eg, 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 the patient has IRS.

The workup of the patient with possible IRS 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:

  • Complete blood count (CBC) with differential, electrolytes and creatinine, liver function tests
  • CD4 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
  • Ophthalmologic examination

Treatment

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

  • Continuing the current ART regimen (unless the clinical presentation was life threatening)
  • Treating the OI as indicated (see below)
  • If indicated, administering antiinflammatory medications (nonsteroidal drugs or systemic corticosteroids) to suppress the inflammatory process

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 IRS 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 IRS develops, the therapy does not need to be altered. However, if IRS reveals a new, untreated OI, that infection should be treated appropriately. For instance, if new cryptococcal meningitis presents as IRS, the cryptococcus should be treated as indicated. If treatment is in question, consult with an HIV specialist.

Timing of Antiretroviral Therapy Initiation

The risk of IRS is not well understood for patients who start ART with low CD4 counts (<50-100 cells/µL). In general, it appears that the risk of IRS is higher if ART is initiated soon after OI treatment is begun and if the CD4 count rises sharply in the early weeks or months of ART. However, the optimal timing of ART initiation in relation to treatment of the OI is not yet clear, and may depend in part on several variables. Prominent among these is the risk of AIDS progression if ART is deferred. Other considerations include the particular OI pathogen, the severity of the OI, and the medication burden and potential for drug toxicity or interactions if therapy with multiple drugs is initiated at the same time. For patients with cryptococcal or mycobacterial disease who are otherwise stable and in whom ART can be deferred temporarily, many specialists would recommend delaying ART until the patients have received appropriate OI treatment for 4-8 weeks. For decisions about initiating ART in patients with active OIs, consult with an HIV specialist.

Immune Reconstitution Syndrome in Resource-Constrained Settings

As access to ART improves in resource-constrained countries, IRS is increasingly being recognized in patients receiving ART. Clinicians should include IRS 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 IRS or other diagnoses.

Given that coinfection with HIV and TB is epidemic in many countries, and because IRS is not uncommon in patients with TB, clinicians should be particularly vigilant about symptoms that may signal IRS. As in resource-abundant countries, a consultation is recommended with a clinician trained in caring for patients with HIV if diagnosis or treatment is in question.

Patient Education

  • When patients are initiating ART, advise them to contact the clinic promptly if they experience new or worsening symptoms.
  • Advise patients to take their antiretroviral medications exactly as prescribed.
  • Advise patients to take their medications for the treatment or prevention of OIs exactly as prescribed.

References

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Related Resources
AETC NRC Initiating Antiretroviral Therapy page
Opportunistic Infection Prophylaxis
TB Treatment in Resource-Limited Settings
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