OVERVIEW: What every practitioner needs to know

Are you sure your patient has immune reconstitution inflammatory syndrome? What should you expect to find?

Immune reconstitution inflammatory syndrome (IRIS) represents the worsening of a recognized (paradoxical IRIS) or unrecognized (unmasking IRIS) pre-existing infection in the setting of improved immunologic function.

IRIS has been reported to occur in response to many different pathogens but most commonly represents a reaction to mycobacteria (e.g., Mycobacterium tuberculosis and M. avium complex), fungi (e.g., Cryptococcus neoformans), and viruses (e.g., Cytomegalovirus and human herpesvirus [HHV]-8).

The presentation of IRIS partly depends on the presenting pathogen but there are a number of common features:

Those who develop IRIS generally have at least a 2 log decrease in viral load in response to antiretroviral therapy (ART) and almost universally at least a 1 log decrease. Cluster of differentiation (CD)4 response is variable but is generally increased at the time of IRIS.

If virologic testing is not available due to resource limitations, documentation of excellent adherence to first-line ART can substitute for the requirement of a documented virologic response
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The median time to the development of IRIS is approximately 1 month after the initiation of ART but occasionally can present up to and even after a year of therapy, particularly in those with a delayed response to ART

For paradoxical IRIS, by definition, the patient must have a transient improvement prior to the development of new symptoms or to the worsening of existing symptoms.

For unmasking IRIS, the usual presentation of a new opportunistic infection (OI) must be excluded, that is to say that the presentation of the new OI which is being unmasked by IRIS must be unusually severe or have atypical clinical features.

The physical findings of IRIS depend on the pathogen involved:

Tuberculosis (TB) IRIS resembles the presentation of TB in other circumstances and may manifest as fever, new or enlarging lymph nodes, cold abscesses, or other focal tissue involvement (e.g., arthritis), new or worsening central nervous system findings (e.g., focal neurologic deficits or meningismus), new or worsening serositis (e.g., signs of pleural effusion, ascites, or pericardial effusion), and hepatosplenomegaly.

Mycobacterium avium complex (MAC) IRIS most commonly presents with fever and focal lymphadenitis (cervical or abdominal in most cases) but can also present with increasing hepatosplenomegaly, vertebral and paravertebral abscesses, or subcutaneous nodules.

In contrast to cryptococcal meningitis in untreated human immunodeficiency virus (HIV), cryptococcal IRIS generally is associated with meningeal signs due to an intense inflammatory reaction and elevated intracranial pressure. Additionally, pulmonary disease (signs consistent with a new pneumonia), lymphadenitis, or focal neurologic signs (from intracranial or spinal cryptococcomas) also can occur.

Cytomegalovirus (CMV) IRIS typically presents with signs of retinitis or with signs of vitritis, uveitis, papillitis, cataracts, fibrovascular membranes, or macular edema.

How did the patient develop immune reconstitution inflammatory syndrome?

The pathophysiology of IRIS is not well defined, but the prevailing view is that IRIS represents an overexuberant restoration of pathogen-specific immune response.

Which individuals are of greater risk of developing immune reconstitution inflammatory syndrome?

Patients at highest risk for IRIS are those at the initiation of antiretroviral therapy with advanced immunosuppression, with certain opportunistic infections, and at high risk of having undiagnosed opportunistic infections because of their epidemiologic risk factors.

Patients with CD4 T-cell counts of less than 100 cells/uL are at highest risk for the development of IRIS as individuals at this level of immunosuppression are at higher risk of having undiagnosed OIs.

Patients with mycobacterial and cryptococcal disease at the time of initiation of ART are at higher risk of developing IRIS with an approximate risk of 15%.

Patients originating from endemic areas for tuberculosis and cryptococcal disease are at higher risk of developing IRIS.

The relationship between the timing of ART during an acute OI and the development of IRIS is complex and likely pathogen-specific.

In TB, in randomized studies, earlier ART (e.g., within 2 weeks compared with at 6 weeks) increases the risk of IRIS.

In Cryptococcus, prospective studies do not show a relationship between earlier start of ART and IRIS, although earlier ART has been associated with increased mortality in cryptococcal meningitis in two randomized studies conducted in resource-limited settings.

In other OIs, earlier ART has not been associated with the development of IRIS.

However, in general, for most OIs, the potential increased risk of IRIS with earlier ART is outweighed by the survival benefits associated with ART during an acute OI in an individual with advanced immunosuppression. Therefore, fear of IRIS is not a sufficient reason to defer ART in a patient being treated for an active OI.

Low CD4⁺ cell count or CD4 percentage at ART initiation have been found consistently to be a risk factor for IRIS.

Greater severity of the presenting opportunistic infection, as measured by the presence of fungemia in Cryptococcus or disseminated disease in tuberculosis has also been associated with the development of IRIS.

A more robust response to ART as measured by a larger decrease in HIV ribonucleic acid (RNA) level or increase in CD4 T-cell count is associated with IRIS.

Beware: there are other diseases that can mimic immune reconstitution inflammatory syndrome:

IRIS is a diagnosis of exclusion.

One must exclude other potential diagnoses including:

OI treatment failure or OI relapse due to nonadherence, pharmacologic failure (e.g., wrong dose), or drug resistance

The typical presentation of a new OI

Medication toxicity

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

An adequate virologic response to ART—generally a 2 log reduction in viral load or greater (but at least a 1 log reduction).

Most patients have an increase in CD4 from baseline at the time of IRIS diagnosis.

Results that confirm the diagnosis

IRIS is a diagnosis of exclusion so there is no gold standard for diagnosis and no specific laboratory test is available.

The diagnosis of unmasking IRIS generally requires microbiologic confirmation that may require an invasive procedure.

In paradoxical IRIS, reasonable efforts should be made to exclude a new process. For instance, in possible paradoxical IRIS to Pneumocystis jirovecii pneumonia (PCP), respiratory specimens should be obtained to rule out other causes of a respiratory decompensation.

What imaging studies will be helpful in making or excluding the diagnosis of immune reconstitution inflammatory syndrome?

The imaging studies for evaluating potential cases of IRIS will be based largely on the presenting symptoms of the patient.

For possible mycobacterial IRIS, chest X-ray ($) (or computed tomography [CT]—$$) and abdominal CT with contrast ($$$) are frequently used to evaluate the extent of disease. For those with central nervous system symptoms, a head CT with contrast should be performed ($$$).

For cryptococcal IRIS, a head CT with contrast ($$$) should be performed prior to a repeat lumbar puncture to rule out the presence of a mass lesion or other contraindication to lumbar puncture. Those with pulmonary symptoms will benefit from a chest X-ray ($).

CMV IRIS is a clinical diagnosis based on an experienced ophthalmologic examination and generally does not require imaging.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has IRIS, what therapies should you initiate immediately?

In general, ART should be continued and should be stopped only if absolutely necessary if serious concerns of possible toxicity are present (e.g., nevirapine/abacavir hypersensitivity or serious hepatotoxicity).

Antimicrobial therapy to the identified pathogen should be initiated or continued.

In general, management is expectant and supportive.

2. Other key therapeutic modalities

Corticosteroids, initiated at 1.5 mg/kg/day and tapered over a 4 week course, have been shown to improve symptoms and shorten hospitalization time in paradoxical TB IRIS.

Corticosteroids should also be considered in other causes of IRIS involving the central nervous or respiratory systems.

In the setting of PCP, IRIS may require prolonging the course of corticosteroids beyond what is typically recommended as part of the treatment of severe PCP.

Anecdotally, nonsteroidal anti-inflammatory drugs can be helpful in cases involving fever or pain.

What complications could arise as a consequence of immune reconstitution inflammatory syndrome?

What should you tell the family about the patient's prognosis?

IRIS generally is not associated with adverse long-term outcomes but may result in the need for hospitalization or invasive procedures.

The dreaded consequence of IRIS from TB and cryptococcal disease is death from respiratory failure or elevated intracranial pressure. However, with aggressive respiratory support and management of elevated intracranial pressure as is routinely available in developed settings, IRIS is rarely fatal.

What-if scenarios:

A frequent concern is determining the optimal timing of initiating ART in the setting of an acute OI.

In TB, three randomized studies show early ART (at 2 weeks after initiation of antituberculous therapy) reduces mortality in those with CD4+ T-cell counts less than 50 cells/uL.

In those with TB and higher CD4
⁺ T-cell counts, it appears that therapy can be safely delayed until approximately 6 weeks after initiation of antituberculous therapy.

In a population with high mortality, early ART did not affect the mortality rate in patients with severe TB meningitis, likely due to the overall poor prognosis in this population.

In PCP, one randomized study (and several retrospective studies) showed a reduction in acquired immunodeficiency syndrome (AIDS) progression or death with early therapy.

Early ART in cryptococcal disease led to increased mortality in two randomized studies in resource-limited settings. The increased mortality appeared driven by those with the most severe disease.

In individuals with less severe cryptococcal meningitis settings (e.g., normal mental status) in settings where amphotericin and aggressive management of intracranial pressure are available, early ART may reduce death and AIDS progression.

How frequent is immune reconstitution inflammatory syndrome?

Estimates for the prevalence of IRIS in asymptomatic HIV patients initiating ART vary from 3% to 38%. The wide range is likely due to a number of factors including the lack of a consensus case-definition for IRIS, the degree of immunosuppression prior to initiation of ART, and the burden of opportunistic infections in the population studied. In the West, where there are relatively low rates of tuberculosis and cryptococcosis, the rates are at the low end of the range indicated. A secondary analysis of a large randomized study (AIDS Clinical Trials Group study A5202) reported the prevalence of IRIS in the 1,848 subjects who initiated ART to be 2.8%. Randomized studies suggest IRIS occurs in approximately 15% of patients with mycobacterial or cryptococcal infections who initiate ART.

What pathogens are responsible for this disease?

Mycobacteria

IRIS to Mycobacterium tuberculosis generally occurs within the first 60 days of ART. While paradoxical reactions also occur in HIV-uninfected individuals initiating antituberculous therapy, these reactions are more common in HIV-infected patients. It may be difficult to distinguish between the unmasking of a subclinical infection that was present before initiation of ART versus new acquisition of disease as TB occurs at increased rates in all stages of HIV disease. To help standardize reporting, the International Network for the Study of HIV-associated IRIS (INSHI) has established criteria for the diagnosis of unmasking and paradoxical TB IRIS. (Available at: http://www.med.umn.edu/inshi/. Accessed 9 June 2014.) The INSHI criteria for unmasking TB IRIS require the diagnosis to be made within the first 3 months of ART initiation and to be associated with a heightened intensity of clinical manifestations and an excessive inflammatory response.

Paradoxical TB IRIS is often characterized by the return of constitutional symptoms and the worsening of respiratory symptoms with worsening parenchymal lesions or enlargement of intrathoracic lymph nodes on chest X-ray. Patients with extrapulmonary disease may have worsening lymphadenitis or pleural effusions or potentially fatal reactions such as expanding intracranial tuberculomas, peritonitis, or bowel perforation. However, overall paradoxical TB IRIS is rarely fatal. Although there are reports of up to 25% mortality in unmasking TB IRIS, mortality with an active opportunistic infection, particularly in treatment-limited resources, is also high, and these case fatalities might have died without ART as well, albeit likely with different clinical manifestations.

MAC IRIS (either unmasking or paradoxical) presents most commonly as fever and focal (and occasionally suppurating) lymphadenitis (cervical or abdominal in most cases), usually within the first 2 months of ART initiation. Increasing hepatosplenomegaly and abdominal pain are also commonly described in paradoxical MAC IRIS. More unusual case reports of MAC IRIS have included osteomyelitis, vertebral and paravertebral abscesses, granulomatous hepatitis, brain abscesses, worsening lung infiltrates, subcutaneous nodules, and hypercalcemia. Biopsies of involved tissues generally show relatively few acid-fast bacilli with many well-formed granulomas. As opposed to disseminated MAC in a patient with untreated AIDS, bone marrow and blood cultures in MAC IRIS are usually negative.

Fungal pathogens

Cryptococcal IRIS most commonly presents with central nervous system findings but can also present with pulmonary disease and/or lymphadenitis.Figure 1 is an example of cryptococcal IRIS. The meningitis with cryptococcal IRIS may have a higher cerebrospinal fluid white blood cell count and a lower cryptococcal antigen titer than is typical for cryptococcal meningitis in AIDS patients. Commonly, elevated intracranial pressures are a component of the IRIS reaction. Cerebrospinal fluid fungal cultures will frequently be negative. Cryptococcal IRIS can also present with intracranial or spinal cryptococcomas. Perhaps because of the long-term persistence of cryptococcal antigen, cryptococcal IRIS can be substantially delayed after the initiation of ART (reportedly up to 2 years). INSHI has also established consensus definitions for unmasking and paradoxical cryptococcal IRIS.

Cryptococcal immune reconstitution inflammatory syndrome manifesting as lymphadenitis.

PCP is occasionally complicated by IRIS. In a large US randomized study in individuals with acute OI, four out of 171 (2%) subjects with PCP initiating ART developed paradoxical IRIS. Typically, IRIS to PCP develops within the first 8 weeks of initiating ART, often after discontinuation of corticosteroids, and presents with recurrent cough, fever, dyspnea, and worsening chest X-ray. Bronchoalveolar lavage shows a predominance of inflammatory cells, including a relatively high CD4/CD8 ratio and a lack of pathogenic organisms.

Viruses

It has been documented that patients develop herpes zoster infection at substantially increased frequency during the first few months of ART. Typically, the zoster involves a single dermatome and responds to aciclovir. In this regard, there is little that distinguishes varicella zoster virus IRIS from zoster that can occur at varying CD4⁺ cell counts during the course of HIV infection. Given this difficulty, some investigators do not consider this entity to represent true IRIS when applying their case definition of IRIS. Varicella zoster virus IRIS also can less typically present as transverse myelitis associated with a focal spinal lesion.

IRIS has been frequently reported in response to Kaposi sarcoma (i.e., IRIS to HHV-8) after the initiation of ART. A prospective study from Mozambique reported the prevalence of paradoxical IRIS in patients initiating ART with Kaposi sarcoma to be 12% (8/69). In a prospective study in Uganda, Martin et al reported very frequent transient worsening of Kaposi sarcoma lesions after initiation of antiretroviral treatment. Kaposi sarcoma lesions frequently became tender (75%), warm (50%), swollen (61%), and developed paresthesias (42%) within the first 12 weeks of therapy initiation. In addition, new pulmonary lesions developed in 19% of the initial 55 patients with Kaposi sarcoma, and two of these patients died. One study indicated that KS IRIS was less frequent when chemotherapy was used in addition to ART (rather than just ART alone) for the treatment of KS. Additionally, KS IRIS occurred more frequently with higher HIV RNA levels, more advanced KS, and with detectable plasma HHV-8 DNA.

IRIS to hepatitis B virus or hepatitis C virus, presenting as a worsening hepatitis, has been reported in co-infected patients initiating ART. However, distinguishing IRIS from other causes of hepatic injury such as medication toxicity or active viral hepatitis can be challenging. IRIS generally occurs within the first 8 weeks of ART initiation with relatively nonspecific symptoms of fevers, night sweats, nausea, fatigue, and jaundice. The liver biopsy typically shows necrotizing liver inflammation with increased CD8⁺ T-cell infiltration. Microbiologic evaluation for other causes of liver disease is negative, and no signs of drug toxicity such as eosinophilia or granulomas are observed.

Most patients with progressive multifocal leukoencephalopathy (PML) secondary to John Cunningham (JC) virus respond favorably to ART but approximately 10% of patients may develop new or worsening neurologic symptoms associated with enlarging central nervous system lesions that show secondary enhancement with contrast agents (a finding atypical for PML). Biopsy in IRIS cases reveals extensive demyelination and surrounding inflammation.

How can immune reconstitution inflammatory syndrome be prevented?

The most effective prevention of IRIS would involve initiation of ART before the development of advanced immunosuppression. IRIS is uncommon in individuals who initiate antiretroviral treatment with a CD4⁺ T-cell count greater than 100 cells/uL.

Aggressive efforts should be made to detect asymptomatic mycobacterial or cryptococcal disease prior to the initiation of ART, especially in areas endemic for these pathogens and with CD4 T-cell counts less than 100 cells/uL.

Two prospective randomized studies are evaluating prednisone and meloxicam for the prevention of paradoxical TB IRIS.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Randomized studies addressing optimal management of IRIS

Meintjes, G, Wilkinson, RJ, Morroni, C. “Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome”. AIDS. vol. 24. 2010. pp. 2381-2390. (Randomized study comparing prednisone [1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks] to placebo in 110 patients with paradoxical TB IRIS in South Africa. The receipt of corticosteroids led to a decrease in symptoms and hospitalization days and an increase in quality of life. There was a slight increase in nonsevere infections in those given prednisone.)

Randomized studies addressing optimal timing of ART in setting of acute OI

Karim, SS, Abdool Naidoo, K, Grobler, A. “Timing of initiation of antiretroviral drugs during tuberculosis therapy”. N Engl J Med. vol. 362. 2010. pp. 697-706.

Abdool Karim, SS, Naidoo, K, Grobler, A. “Integration of antiretroviral therapy with tuberculosis treatment”. New Engl J Med. vol. 365. 2011. pp. 1492-1501. (Randomized study of 642 patients comparing early integrated [ART within 4 weeks after the start of tuberculosis therapy], late integrated (ART within 4 weeks after the completion of the intensive phase of tuberculosis, versus sequential ART [ART within 4 weeks after the completion of tuberculosis therapy] in the setting of TB and HIV in South Africa. Integrated ART [combining the results in the two integrated arms] decreased mortality compared with sequential therapy. The second publication reported similar mortality in patients randomized to either of the integrated arms, but decreased mortality with early integrated therapy in the subgroup of patients with CD4 T-cells <50 cells/uL.)

Blanc, FX, Sok, T, Laureillard, D. “Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis”. New Engl J Med. vol. 365. 2011. pp. 1471-1481. (Randomized study of 661 patients with HIV-TB coinfection showed reduced mortality with early [e.g., at 2 weeks after initiation of TB treatment] versus delayed [e.g., at 8 weeks after initiation of TB treatment] ART [18% vs 26%, respectively])

Boulware, DR, Meya, D, Muzoora, C. “ART initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial”. (Randomized study compared early ART [median 8 days after treatment initiation for cryptococcal meningitis] to delayed ART [median 36 days after treatment initiation of cryptococcal meningitis]. The trial was stopped prematurely [n = 177 of 500 participants randomized] due to excess mortality in the early ART arm [55% vs 70%, p = 0.03]. This difference occurred despite an apparently similar incidence of CM-IRIS in the two groups [13% v. 10%]).

Havlir, DV, Kendall, MA, Ive, P. “Timing of antiretroviral therapy for HIV-1 infection and tuberculosis”. New Engl J Med. vol. 365. 2011. pp. 1482-1491. (Randomized study of 806 patients with TB and HIV and CD4 T-cell counts <250 cells/uL comparing early [2 weeks after start of TB treatment] versus delayed ART [within 8 to 12 weeks after start of TB treatment]. No difference in mortality in patients assigned to the different arms but in the subgroup of patients with CD4 T-cell counts <50 cells/uL, early ART decreased mortality compared with delayed ART [16% vs 27%, respectively].)

Makadzange, AT, Ndhlovu, CE, Takarinda, K. “Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-Saharan Africa”. Clin Infect Dis. vol. 50. 2010. pp. 1532-1538. (54 patients with HIV and cryptococcal meningitis [CM] on fluconazole were randomized to immediate ART [within 72 hours of treatment for CM] or deferred ART [after at least 10 weeks of treatment for CM]. Death was more frequent with immediate ART compared with delayed ART [88% vs 54%, respectively].)

Török, ME, Yen, N, Chau, T. “Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis”. Clin Infect Dis. vol. 52. 2011. pp. 1374-1383. (Randomized study of immediate versus delayed [after 2 months of antituberculous therapy] ART in 253 patients with HIV and tuberculous meningitis in Vietnam. Mortality did not differ between those assigned to the immediate versus deferred arms [60% and 56%, respectively].)

Zolopa, AR, Andersen, J, Komarow, L. “Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: A multicenter randomized strategy trial”. PLoS ONE. vol. 4. 2009. pp. e5575(Randomized 282 subjects [mostly from the United States] with acute opportunistic infections to early ART [ART started a median of 12 days after initiation of treatment for acute OI] or deferred ART [ART started a median of 42 days after initiation of treatment for acute OI]. Early ART reduced combined endpoint of death or new opportunistic infection compared with deferred ART [14% vs 24%, respectively].)

Bicanic, T, Meintjes, G, Rebe, K. “Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study”. J Acquir Immune Defic Syndr. vol. 51. 2009. pp. 130-134. (Prospective observational study of 65 patients with CM and HIV in South Africa. 17% of patients developed IRIS but earlier ART was not associated with its development.)

Grant, P, Komarow, L, Andersen, J. “Risk factor analyses for immune reconstitution inflammatory syndrome (IRIS) during a randomized study of early vs deferred ART during an acute opportunistic infection (ACTG A5164)”. PLoS One. vol. 5. 2010. pp. e11416(Secondary analysis of ACTG A5164 showing that early ART did not lead to increased rates of IRIS in a randomized study of the timing of ART.)

Laureillard, D, Marcy, O, Madec, Y. “Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial”. AIDS (London, England). vol. 27. 2013. pp. 2577-2586. (Secondary analysis of CAMELIA showed increased rates of IRIS with early ART in HIV/TB.)

Luetkemeyer, AF, Kendall, MA, Nyirenda, M. “Tuberculosis immune reconstitution inflammatory syndrome in A5221 STRIDE: timing, severity and implications for HIV-TB programs”. J Acquir Immune Defic Syndr. vol. 65. 2014. pp. 423-428. (Secondary analysis of STRIDE study showing increased rates of IRIS with early ART in HIV-TB.)

Naidoo, K, Yende-Zuma, N, Padayatchi, N. “The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial”. Ann Intern Med. vol. 157. 2012. pp. 313-324. (Secondary analysis of SAPiT study showing increased rates of IRIS with early ART in HIV/TB.)

Sungkanuparph, S, Filler, SG, Chetchotisakd, P. “Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study”. Clin Infect Dis. vol. 49. 2009. pp. 931-934.

DRG CODES and expected length of stay

Expected length of stay is variable depending on presenting symptoms.

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