Immune reconstitution inflammatory syndrome

INTRODUCTION — The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy (ART) in HIV-infected individuals [1-6]. Preexisting infections in individuals with IRIS may have been previously diagnosed and treated or they may be subclinical and unmasked by the host's regained capacity to mount an inflammatory response [7].

If immune function improves rapidly following the commencement of ART, systemic or local inflammatory reactions may occur at the site or sites of the preexisting infection. This inflammatory reaction is usually self-limited, especially if the preexisting infection is effectively treated. However, long-term sequelae and fatal outcomes may rarely occur, particularly when neurologic structures are involved.

This topic focuses on the immunobiology, pathogenesis, and clinical features of IRIS. Topic reviews that discuss when to initiate ART are presented separately. (See "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

TERMS — Many synonyms exist for IRIS [2,8,9]:

●Immune recovery disease

●Immune reconstitution disease

●Immune reconstitution syndrome

●Immune restoration disease

●Immune rebound illness

●Steroid-withdrawal disease

●Immunorestitution disease

●Immune response reactions

Paradoxical inflammatory syndromes similar to those seen in HIV-infected patients have also been described in HIV-uninfected patients following treatment for tuberculosis [10-13] or lepromatous leprosy [14]. Similar illnesses have also occurred in some HIV-uninfected patients following corticosteroid withdrawal, discontinuation of antitumor necrosis factor alpha therapy, recovery of neutropenia after cytotoxic chemotherapy, withdrawal of immunosuppression in transplant recipients infected with Cryptococcus neoformans, and engraftment of stem cell transplantation [8,15,16].

IMMUNOBIOLOGY AND PATHOGENESIS — HIV infection produces both quantitative and qualitative time-dependent deleterious effects on the immune system. The likelihood and severity of IRIS correlates with two interrelated factors: 1) the extent of CD4+ T cell immune suppression prior to the initiation of antiretroviral therapy (ART) and 2) the degree of viral suppression and immune recovery following the initiation of ART.

As the half-life of HIV is generally between one and four days, ART may produce a greater than 90 percent reduction in the overall HIV viral burden within one to two weeks of starting treatment. This decline in viral load usually persists during the next 8 to 12 weeks and then stabilizes. Declines in the viral load are even faster with integrase strand transfer inhibitors. An increase in immune effector cells occurs in inverse proportion to the fall in HIV viral load in most treated individuals. (See "Patient monitoring during HIV antiretroviral therapy".)

The typical recovery of CD4+ T lymphocyte count following initiation of ART is biphasic [17-19]. A rapid increase in CD4+ cells occurs during the first three to six months of ART. This initial rise is mainly due to an increase in the numbers of CD45RO+ memory T cells and is presumed to be due to a combination of decreased lymphocyte apoptosis and simultaneous redistribution of lymphocytes from peripheral lymphoid tissues into the circulation. Thereafter, a slower increase of predominately naive CD4+ T cells (CD45RA+, CD62L+) occurs in most treated individuals. This secondary increase in CD4+ T cells is thought to be due to expansion of T cell clones produced by the thymus prior to its age-related functional decline and/or occurs secondary to thymopoiesis [20-22]. CD8+ T lymphocytes also increase rapidly after the initiation of ART. However, the total numbers of CD8+ T lymphocytes eventually stabilize as memory CD8+ cells subsequently decline and are replaced by naive CD8+ T lymphocytes [18].

Increases in T lymphocytes after initiation of ART are also accompanied by increased in vitro lymphocyte proliferation responses, increased markers of immune activation, and pathogen-specific delayed hypersensitivity [18,19,23,24]. As an example, one group of investigators studying a small group of HIV-infected patients demonstrated that inducible lymphocyte proliferation increased almost threefold after three weeks of ART, ultimately rose fourfold, then stabilized for the next two years [18]. In vitro lymphocyte proliferation against Candida antigens as well as increases in stimulation indices with CMV antigens and tuberculin also typically occur after initiation of ART in HIV-infected patients [19,23]. Another study demonstrated that 90 percent of HIV-infected patients had cutaneous anergy prior to starting ART; 12 weeks later, 30 percent of these patients had recovered their ability to respond to skin test antigens [23].

DIAGNOSTIC CRITERIA FOR IRIS — There is no universally agreed-upon definition for the immune reconstitution inflammatory syndrome (IRIS). However, it is generally accepted that the diagnosis of IRIS requires the worsening of a recognized ("paradoxical" IRIS) or unrecognized preexisting infection ("unmasking" IRIS) in the setting of improving immunologic function [25,26]. Most or all of the following features should be present in order to make the diagnosis:

●The presence of AIDS with a low pretreatment CD4 count (often less than 100 cells/microL) [27,28]. One important exception to this general rule is tuberculosis. IRIS secondary to preexisting M. tuberculosis infection may occur in individuals with CD4 counts >200 cells/microL.

●A positive virologic and immunological response to antiretroviral therapy (ART) [29,30].

●The absence of evidence of drug-resistant infection, bacterial superinfection, drug allergy or other adverse drug reactions, patient noncompliance, or reduced drug levels due to drug-drug interactions or malabsorption after appropriate evaluation for the clinical presentation.

●The presence of clinical manifestations consistent with an inflammatory condition.

●A temporal association between ART initiation and the onset of clinical features of illness.

When a diagnosis of IRIS is considered highly likely, further or repeated invasive diagnostic procedures to locate an occult infection may be reasonably delayed, deferred, or altogether avoided. However, localized drainage (with appropriate cultures) is indicated for symptomatic relief of mycobacterial lymphadenitis as well as for diagnostic purposes.

Although the hypersensitivity reaction seen with abacavir may be difficult to distinguish from systemic IRIS, this complication of abacavir is exceedingly rare in individuals negative for HLA-B*57:01. Prevention, diagnosis, and management of abacavir hypersensitivity is discussed elsewhere. (See "Abacavir hypersensitivity reaction".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of an immune reconstitution inflammatory syndrome is broad and includes progression of the initial opportunistic infection (OI) due to antimicrobial resistance or nonadherence to prescribed drug regimens, development of a new OI, or drug toxicity.

INCIDENCE — Early retrospective case series studies suggested that up to 30 percent of patients who responded to antiretroviral therapy (ART) developed one or more inflammatory syndromes consistent with an immune reconstitution inflammatory syndrome (IRIS) [2,27]. However, subsequent data have suggested that the incidence is probably much lower, particularly in patients where ART was initiated before severe CD4 decline occurs.

Data from prospective and retrospective studies suggest that the incidence of IRIS following ART is largely dependent on two things: 1) the likelihood of a preexisting opportunistic infection and 2) the likelihood of a viral and immunologic response to ART. The following studies illustrate the incidence of cases that have been reported in a variety of settings and the range of infections that have been described:

●In a systematic review and meta-analysis of about 13,000 HIV patients, 13 percent of subjects developed IRIS [31]. Some of the most common diagnoses included tuberculosis, herpes infections, cryptococcal meningitis, CMV retinitis, and PML.

●In a prospective trial that evaluated the optimum management of patients with AIDS-related opportunistic infections (A5164), the incidence of IRIS was 7.6 percent, which occurred a median of 33 days after the initiation of ART [26].

●In another prospective cohort study in South Africa, an overall incidence rate of 25 cases of IRIS per 100 patient-years was reported, affecting approximately 10 percent of subjects [32].

PATHOGENS ASSOCIATED WITH IRIS — Many different pathogens have been associated with the development of an immune reconstitution inflammatory syndrome (IRIS) [3,32-45]. The leading pathogens include:

●Mycobacterium tuberculosis

●Mycobacterium avium complex

●Cytomegalovirus

●Cryptococcus neoformans

●Pneumocystis jirovecii

●Herpes simplex virus

●Hepatitis B virus

●Human herpes virus 8 (associated with Kaposi sarcoma)

Some case reports have also documented IRIS associated with: hepatitis C virus, parvovirus B19 [33], Candida albicans, Epstein Barr Virus, herpes simplex, Bartonella henselae, Histoplasma capsulatum [34], dermatophytosis [35], leprosy [36-38], bacillus Calmette-Guérin (BCG) [39], Talaromyces (Penicillium) marneffei [40], Schistosoma mansoni [41], and molluscum contagiosum virus. In addition, some patients with Kaposi sarcoma have developed an IRIS-like syndrome when antiretroviral therapy (ART) was initiated [32,43,44], and other patients have developed Grave's thyrotoxicosis or recurrence of sarcoidosis after starting ART.

RISK FACTORS — Several studies have demonstrated that lower CD4 cell counts or high HIV RNA at the time of treatment initiation increase the risk of developing an immune reconstitution inflammatory syndrome (IRIS) [2,26-28,32,45]. Response to antiretroviral therapy (ART) also plays an important role in predicting risk.

In one prospective trial of 282 patients with AIDS-related OIs, the risk of IRIS was related to low CD4 counts at baseline (HR = 0.79 per 10 additional CD4 cells/microL; 95% CI 0.65, 0.97) and degree of immunologic improvement on ART (HR = 1.08 per additional 10 CD4 cells/microL; 95% CI 1.03, 1.13) [26]. Similarly, the risk of IRIS was also associated with a higher level of viremia at baseline (HR = 2.5 per 1 log increase in HIV RNA; 95% CI 1.19, 5.21) and the degree of viral decline on ART (HR = 0.43 per 1 log increase in HIV RNA; 95% CI 0.24, 0.78). Fungal infections (except for Pneumocystis) were also associated with an increased risk of IRIS in the multivariate analysis.

Initial observational data suggested that integrase strand transfer inhibitor (INSTI)-based regimens, with their faster reduction in HIV viral load, might induce a higher risk of IRIS. However, randomized comparative trials do not show a difference between INSTI and non-INSTI-based treatments in the incidence of IRIS [46-48].

CLINICAL MANIFESTATIONS — Most patients with an immune reconstitution inflammatory syndrome (IRIS) develop symptoms within one week to a few months after the initiation of antiretroviral therapy (ART). One prospective study found that patients developed IRIS a median of 48 days (29 to 99 days) after ART initiation [32].

The clinical features of IRIS are strongly related to the type and location of preexisting opportunistic infection. Furthermore, preexisting infections may or may not be clinically apparent prior to the initiation of ART. Since the clinical features of IRIS vary so widely, IRIS due to specific pathogens are discussed in the sections that follow. However, a few generalizations can be made. Symptoms of IRIS can be localized or systemic. About three-fourths of patients with mycobacterial or cryptococcal-related immune reconstitution syndromes develop fever [8]. In contrast, fever occurs infrequently in IRIS related to previously recognized or subclinical infection with cytomegalovirus.

IRIS associated with mycobacterial infections

Tuberculosis — For patients with tuberculosis, IRIS may be associated with initiation of antituberculosis therapy and/or antiretroviral therapy. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Prior to the widespread emergence of HIV infection, an IRIS-like paradoxical inflammatory response was known to occur in some patients treated for tuberculosis (TB) [10-12,49]. Paradoxical clinical deterioration in HIV-uninfected patients with pulmonary TB following the initiation of antituberculous therapy is assumed to be a self-limited phenomenon in most cases.

The paradoxical reaction that follows the commencement of antituberculosis therapy for pulmonary TB is usually characterized by fever, malaise, weight loss, and worsening respiratory symptoms. Transient worsening of radiographic abnormalities, including new parenchymal opacities and progressive intrathoracic lymph node enlargement may also occur in such patients. Rarely pulmonary involvement may progress to severe respiratory compromise and adult respiratory distress syndrome.

Patients with extrapulmonary TB may develop worsening lymphadenitis [10,50], new pleural effusions [51,52], the reappearance of fever with new infiltrates [53], or expansion of preexisting intracranial tuberculomas [11,54-56] after antituberculosis therapy is begun. Aspiration of fluctuant lymph nodes often reveals purulent material, but mycobacterial cultures are typically sterile and acid fast stains yield relatively few or no organisms. When mycobacteria are recovered in patients with paradoxical reactions, these organisms usually have not developed new antituberculous drug resistance [49].

The mechanism for paradoxical reactions is not well understood, but it appears to be immune mediated. Changes in the ability to respond to tuberculin proteins occur in some patients following the initiation of antituberculous therapy. For example, in one study, 74 percent of patients who were initially anergic had reversion of their previously negative tuberculin skin tests within two weeks of starting antituberculous therapy [57]. The incidence of paradoxical reactions in HIV-uninfected patients may be higher in patients who develop TB while receiving the immunomodulator infliximab [13]. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".)

The incidence of paradoxical worsening associated with pulmonary TB is higher in HIV-infected individuals following ART initiation compared with those who are not coinfected with HIV [58-60]. As an example, in a prospective study paradoxical inflammatory reactions were documented in 12 of 33 patients (36 percent) coinfected with HIV and treated with ART, but similar reactions occurred in only 1 of 55 patients (2 percent) without HIV [61]. A retrospective review found severe transient worsening of chest radiograph appearance in 7 of 31 patients (23 percent) who were coinfected with HIV and TB and treated for both, and in 2 of 56 patients (4 percent; 26 patients with HIV coinfection and 30 patients without HIV) who were only receiving therapy for TB [62]. In a retrospective cohort of 144 HIV patients with TB coinfection, 11 (8 percent) had a paradoxical reaction after a median time of 47 days following ART initiation and an incidence rate of 15 cases per 100 patient-years [63].

Patients who are coinfected with TB and HIV may also develop IRIS that manifests as tuberculous lymphadenitis [64], cutaneous lesions [61], peritonitis [65], epididymitis [65], bowel perforation [66], or granulomatous nephritis [67]. The time interval from initiation of ART to the onset of IRIS associated with TB has varied from 10 to 180 days [3], but tends to occur within the first 60 days of starting ART therapy [6,68].

Mycobacterium avium complex — Patients coinfected with HIV and M. avium complex (MAC) may develop inflammatory reactions following the initiation of antiretroviral therapy (picture 1 and image 1 and picture 2) [69-72]. IRIS due to MAC often manifests as fever and painful lymphadenitis that occurs one to eight weeks after ART is commenced [3,71-73]. The majority of patients with IRIS due to treated MAC infection have negative blood and bone marrow cultures. In contrast to findings in patients with AIDS and untreated MAC infection, biopsies of lymph nodes of patients with IRIS secondary to MAC can reveal well-formed granulomas with relatively few visible organisms [74]. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Lymphadenitis'.)

Individual case reports or small case series also exist describing IRIS syndrome manifesting as necrotic subcutaneous nodules, osteomyelitis, bursitis [1], granulomatous hepatitis, paravertebral abscesses [3], brain abscess [75], worsening lung infiltrates, or diffuse intestinal involvement presenting with abdominal pain [76]. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Uncommon manifestations'.)

IRIS associated with preexisting cryptococcal infection — HIV-infected patients previously infected with Cryptococcus spp. may develop symptoms of IRIS localized to the central nervous system (CNS) or the lungs [77]. Symptoms often occur within two months after commencement of therapy, but may be delayed for more than six months [77-79]. Despite the use of concurrent antifungal therapy, patients with preexisting cryptococcal meningoencephalitis may develop fever, increased headache, nausea, eye pain, photophobia, and nuchal rigidity following the initiation of ART [80]. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Immune reconstitution inflammatory syndrome'.)

At the time of initial cryptococcal meningoencephalitis diagnosis, a paucity of CSF inflammation (eg, WBC <25 cells/microL) have been associated with development of IRIS [81]. Conversely, follow-up lumbar puncture in patients with IRIS associated with cryptococcal meningitis often reveals more inflammatory cells than were found prior to the initiation of antifungal therapy and ART; however, cultures usually remain sterile. One retrospective study found that compared with classic forms of AIDS-related cryptococcal meningitis, patients with IRIS-related cryptococcal meningitis had significantly higher opening pressures, CSF WBC counts (56 versus 12 cells/microL), CD4 cell counts, and lower HIV viral loads [82,83].

HIV-infected patients with preexisting cryptococcal pulmonary infection may develop cavitary lung lesions, hypoxia, respiratory failure, and ARDS following the initiation of ART [3,84]. Rarely, patients with disseminated cryptococcal infections may develop mediastinal lymphadenitis, hypercalcemia, and cutaneous abscesses as part of the IRIS syndrome [84,85].

IRIS associated with cytomegalovirus — IRIS due to prior cytomegalovirus (CMV) infection has been termed "immune recovery uveitis" (IRU) or "immune recovery vitritis" by various investigators [86,87]. IRIS has been reported in 16 to 63 percent of HIV-infected patients with CMV retinitis following the initiation of ART [29,87,88]. In one study the median time to IRU following ART initiation was 43 weeks, but onset can occur as early as four weeks or as late as four years in some patients [86,87]. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes'.)

IRU may manifest with some or all of the following: painless floaters, blurred vision, photopia (the sensation of flashing lights), decreased visual acuity, or ocular pain. Patients with IRIS due to preexisting CMV retinitis may develop extensive vitritis, papillitis, cataracts, epiretinal membrane formation, and cystoid macular edema. Although visual loss is most commonly due to macular edema, patients may develop proliferative vitreoretinopathy, spontaneous vitreal hemorrhage, and vitreomacular traction leading to retinal detachment.

Fundoscopic examination of such patients reveals an intense inflammatory reaction far beyond that usually seen with CMV retinitis (which usually manifests as necrosis of the retina with minimal intraocular inflammation) [89]. Despite treatment efforts, a significant proportion of patients with IRU may develop a chronic inflammatory condition resulting in significant visual complications lasting for months or years [90].

Although CMV-associated IRIS usually manifests as IRU or worsening retinitis, preexisting CMV infection may rarely result in IRIS manifesting as pneumonitis [91], colitis, pancreatitis, or submandibular inflammation [92]. Some cases of CMV-associated IRIS have occurred in HIV-infected patients with absolute CD4 counts above 100 cells/microL, a remarkable finding in contrast to that seen in HIV-infected patients during the era prior to the introduction of potent ART, when <1 percent of patients with CD4 counts above 100 cells/microL developed symptoms attributable to CMV infection [93].

IRIS due to preexisting infection with JC virus — HIV-infected patients co-infected with JC virus may develop progressive multifocal leukoencephalopathy (PML) after CD4 cell counts drop below 200/microL. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)

Although some HIV-infected patients with PML improve following the initiation of ART, about 10 to 20 percent of patients may develop new or worsening neurologic symptoms associated with enlarging CNS lesions that show secondary enhancement after infusion of contrast agents (a finding not typically present in AIDS patients with PML) [94-96]. It can be challenging clinically to distinguish PML disease progression from PML IRIS. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Inflammatory PML (PML-IRIS)'.)

Most cases of IRIS associated with JC virus infections occur three to six weeks after ART is begun [94]. Biopsy in such cases reveals extensive demyelination and surrounding inflammation [97,98]. Patients may experience clinical improvement or stabilization after three to six months of continued ART, but IRIS associated with JC virus may directly or indirectly result in a fatal outcome despite an excellent virologic response to ART [94,95,98,99]. The role of empiric corticosteroids and other adjunctive therapies remains controversial. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'PML-IRIS'.)

IRIS associated with Pneumocystis jirovecii infection — Many HIV-infected patients with Pneumocystis jirovecii pneumonia (PCP) develop a paradoxical inflammatory response following the initiation of antimicrobial therapy directed against Pneumocystis. For this reason adjunctive corticosteroids are routinely used in patients with moderate to severe disease. (See "Treatment and prevention of Pneumocystis infection in patients with HIV".)

IRIS associated with P. jirovecii infection in patients with advanced HIV infection results in similar symptoms as the infection itself. IRIS can be suspected when the onset correlates more closely with ART initiation than with treatment for PCP.

One to three weeks after initiating ART, some patients who were previously treated with both antipneumocystis therapy and corticosteroids and responded well go on to develop IRIS manifesting as recurrent fever, increased cough, chest discomfort, dyspnea, hypoxia, and progressive radiographic pulmonary opacification. Repeat bronchoscopy may reveal large numbers of inflammatory cells in bronchoalveolar lavage fluid [100-102].

IRIS associated with herpes zoster — A study that compared the incidence of symptomatic varicella-zoster virus (VZV) infection in HIV-infected patients with and without concurrent antiretroviral therapy found that symptomatic herpes zoster occurred two to nine times as often in HIV-infected patients treated with ART as compared to HIV-infected patients who did not receive ART.

Almost all such cases are limited to a localized dermatomal distribution and respond well to oral acyclovir or famciclovir. Some patients with preexisting ocular infection with VZV develop striking keratitis and/or iritis within the first one to four months following the initiation of ART [103].

IRIS associated with hepatitis B and C — Coinfection with HIV alters the natural history of patients with hepatitis B and C virus infections even in the absence of treatment for HIV. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

Symptoms and laboratory abnormalities suggesting worsening hepatitis may occur in patients coinfected with HCV or HBV following ART [104-108]. Affected patients typically have elevated serum liver enzymes accompanied by fevers, night sweats, anorexia, nausea, fatigue, tender hepatomegaly, and jaundice. Some patients have developed symmetric inflammatory polyarthralgias, sometimes associated with mixed cryoglobulinemia [109], while others have developed porphyria cutanea tarda [106]. IRIS associated with hepatitis viruses B and C usually occurs within two to eight weeks of initiation of ART but onset may be delayed for up to nine months.

The incidence of clinical hepatitis among ART responders who are coinfected with HBV or HCV is estimated to be 1 to 5 percent. Because elevated liver enzymes in coinfected patients treated with ART can be due to a variety of causes such as hepatotoxic drug effects (as can be seen with protease inhibitors or nevirapine), drug-induced lactic acidosis, withdrawal of antiviral therapy in a patient with underlying HBV, Kaposi sarcoma, or other infectious causes such as new infection with other hepatotrophic viruses, it is often difficult to establish a definitive diagnosis of IRIS. However, in cases of presumed IRIS due to preexisting hepatitis B or C viruses, patients undergoing liver biopsy show dramatic liver necrosis and inflammatory activity with markedly increased CD8+ T cell infiltration in the absence of microbiological evidence of infection with other infectious agents that cause hepatic injury [104,108].

In a few cases, patients with symptomatic hepatitis due to IRIS related to HCV or HBV infection underwent documented virus-specific seroconversion. In the cases involving HCV, these patients were often previously undiagnosed with HCV because they tested antibody-negative. When stored serum (which was drawn one to two years prior to ART initiation) was retrospectively tested for HCV by PCR, it revealed detectable levels of HCV RNA, indicating prior subclinical infection [106]. In at least one case of IRIS associated with a known chronic HBV carrier, hepatitis B core antibody and hepatitis B e antibody titers significantly increased and hepatitis B e antigen was cleared from the serum [104].

The prognosis of HBV and HCV-related IRIS appears to depend in part on the underlying hepatic functional reserve. The treatment of the HIV-infected patient with underlying hepatitis C or hepatitis B infection is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV" and "Treatment of chronic hepatitis B in patients with HIV".)

Leishmaniasis — Cases of IRIS involving visceral and cutaneous manifestations of leishmaniasis have been reported in patients with advanced AIDS who initiated ART [110]. Immunologic reconstitution led to a resurgence of inflammation resulting in severe infiltrative plaques and ulcers.

Kaposi sarcoma — There have been reports of patients with Kaposi sarcoma (KS) developing an IRIS-like syndrome that can include rapid clinical progression of KS when ART is initiated [43,44]. In some resource-limited settings where KS is relatively more common, this clinical issue has taken on greater importance with the greater availability of potent ART.

One study in Uganda evaluated 55 patients with cutaneous KS who were participating in a randomized trial of two different ART regimens [111]. Over a 12-week period, a variety of clinical changes were noted, including marked lesional swelling, increased tenderness, and peripheral edema. Although most of these findings resolved spontaneously on continued ART, a minority of patients with suspected pulmonary involvement required chemotherapy; two patients died.

In the United States, fatal cases of KS-related IRIS have been reported, particularly among those with visceral involvement [112,113]. (See "AIDS-related Kaposi sarcoma: Staging and treatment".)

Miscellaneous syndromes possibly associated with IRIS — A few autoimmune and other noninfectious conditions may dramatically worsen or appear after ART is begun, suggesting that inflammation induced by an IRIS-like syndrome is responsible. Whether such associations represent a casual or a coincidental finding is unproven at present.

Sarcoidosis has occurred in some HIV-infected patients soon after initiation of ART [114-116]. Prior to the introduction of ART, progressive sarcoidosis and advanced HIV infection were considered to be divergent disease processes because CD4+ T cells (which are usually depleted in patients with advanced HIV infection) were believed to be essential for granuloma formation. However the occurrence of sarcoidosis immediately following ART suggests that immune reconstitution may "trigger" the reactivation or appearance of preexisting subclinical sarcoidosis. Indeed some but not all patients with IRIS-associated sarcoidosis had preexisting known sarcoidosis that became inactive years earlier. IRIS-associated sarcoidosis typically occurs >12 months after ART commencement. Most reported cases have responded to corticosteroid therapy.

Several authors have reported that autoimmune thyroiditis and Graves' disease can appear soon after starting ART [117-119]. Although the mechanism for this phenomenon is not fully understood, expansion of the T cell receptor repertoire along with pathologic immune dysregulation may lead to formation of autoreactive immune cells that in turn produce anti-thyrotropin receptor and other autoantibodies.

MANAGEMENT — Patients who develop an immune reconstitution inflammatory syndrome (IRIS) leading to a diagnosis of an opportunistic infection (OI) should continue antiretroviral therapy. In addition, they should be treated for the underlying OI as soon as possible. In cases of paradoxical worsening of a previously diagnosed OI, therapy directed at that infection should be continued. Adjunctive therapies such as glucocorticoids may be needed for patients who develop severe symptoms. Detailed discussions of the management of IRIS are presented elsewhere. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Management of IRIS' and "Toxoplasmosis in patients with HIV", section on 'Toxoplasmosis and immune reconstitution syndrome (IRIS)' and "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes' and "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Adjunctive therapy for IRIS' and "Treatment of pulmonary tuberculosis in adults with HIV infection: Follow-up after initiation of therapy", section on 'Immune reconstitution inflammatory syndrome'.)

INITIATING ANTIRETROVIRAL THERAPY — Treatment guidelines recommend initiating antiretroviral therapy (ART) within two weeks for most opportunistic infections [120,121]. Exceptions to this recommendation include cryptococcal meningitis and tuberculous meningitis, in which the benefits of immediate ART may be outweighed by induction of a potentially serious immune reconstitution inflammatory syndrome. Disease specific recommendations for when to initiate ART are found within the individual topic reviews. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention" and "Toxoplasmosis in patients with HIV" and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Timing of ART initiation' and "Treatment of AIDS-related cytomegalovirus retinitis", section on 'When to initiate antiretroviral therapy' and "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'When to initiate antiretroviral therapy' and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Central nervous system tuberculosis: Treatment and prognosis", section on 'Paradoxical worsening'.)

In the setting of pulmonary tuberculosis, glucocorticoids may also reduce the risk of developing IRIS in select patients with low CD4 counts [122]. This is discussed in detail elsewhere. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Preventing IRIS'.)

SUMMARY AND RECOMMENDATIONS

●In HIV-infected patients, the term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of a preexisting infectious processes following the initiation of antiretroviral therapy (ART). (See 'Introduction' above and 'Terms' above.)

●HIV infection produces both quantitative and qualitative time-dependent deleterious effects on the immune system. The likelihood and severity of IRIS correlates with the extent of CD4 cell immune suppression and HIV RNA level prior to the initiation of ART and the degree of viral suppression and immune recovery following initiation. (See 'Immunobiology and pathogenesis' above.)

●It is generally accepted that the diagnosis of IRIS requires the worsening of a recognized ("paradoxical" IRIS) or unrecognized preexisting infection ("unmasking" IRIS) in the setting of improving immunologic function. (See 'Diagnostic criteria for IRIS' above.)

●Most patients with IRIS develop symptoms within one week to a few months after the initiation of ART. The clinical features of IRIS are strongly related to the type and location of the preexisting opportunistic infection. (See 'Clinical manifestations' above.)

●Patients should be treated for the underlying opportunistic infection as soon as possible. Adjunctive therapies, such as glucocorticoids, may also be needed in certain settings. (See 'Management' above.)

●Treatment guidelines generally recommend initiating ART within two weeks for most opportunistic infections. However, in the setting of certain opportunistic infections (eg, cryptococcal and tuberculosis meningitis), ART may be delayed since the benefits of early ART are outweighed by induction of a potentially serious immune reconstitution inflammatory syndrome. (See 'Initiating antiretroviral therapy' above.)

ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.