Version August 2024
INTRODUCTION — The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of a preexisting infectious process. IRIS is typically seen in persons with human immunodeficiency virus (HIV) after starting antiretroviral therapy (ART) but can also occur in immunocompromised patients without HIV when immunosuppression is reduced.
For persons with HIV, IRIS occurs following virologic suppression and immune reconstitution after initiation of ART [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].
When IRIS occurs, systemic or local inflammatory reactions typically 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, on rare occasions, long-term sequelae and fatal outcomes may occur, particularly when neurologic structures are involved.
This topic will provide an overview of the immunobiology, pathogenesis, clinical features, diagnosis, and management of IRIS. The diagnosis and management of specific conditions are discussed within specific topic reviews. (See 'Considerations for selected pathogens' below.)
IRIS IN PERSONS WITH HIV
Epidemiology
Incidence — Data from prospective and retrospective studies suggest that the incidence of IRIS following antiretroviral therapy (ART) is largely dependent on the likelihood of a preexisting opportunistic infection (OI) and the likelihood of a viral and immunologic response to ART.
Early retrospective case series studies suggested that up to 30 percent of patients who responded to ART developed one or more inflammatory syndromes consistent with IRIS [2,8]. However, subsequent data have suggested that the incidence is probably much lower, particularly in patients who initiate ART before severe CD4 decline occurs.
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 approximately 13,000 HIV patients, 13 percent of subjects developed IRIS [9]. Some of the most common diagnoses included tuberculosis (TB), herpes infections, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, and progressive multifocal leukoencephalopathy (PML).
●In a prospective trial that evaluated the optimum management of patients with acquired immunodeficiency syndrome (AIDS)-related OIs (A5164), the incidence of IRIS was 7.6 percent, which occurred a median of 33 days after the initiation of ART [10].
●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 [11].
Risk factors — Several studies have demonstrated that lower CD4 counts and/or high HIV ribonucleic acid (RNA) at the time of treatment initiation increase the risk of developing IRIS [2,8,10-14]. In one report that described 370 cases of IRIS, the median and nadir CD4 cell counts at ART initiation were 90 and 43 cells/microL respectively; the median viral load was 2.7 log10 copies/mL [14].
Response to ART also plays an important role in predicting risk. As an example, in a prospective trial of 282 patients with AIDS-related OIs, the risk of IRIS was related to low CD4 counts at baseline (hazard ratio [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) [10]. 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.
The specific ART regimen does not appear to impact the risk of IRIS. Although some observational data suggested that integrase strand transfer inhibitor (INSTI)-based regimens might induce a higher risk of IRIS, randomized trials do not show a difference between INSTI and non-INSTI-based treatments in the incidence of IRIS [15-18].
Immunobiology and pathogenesis — The likelihood and severity of IRIS correlate with two interrelated factors: the extent of CD4 cell immune suppression prior to the initiation of ART and the degree of viral suppression and immune recovery following the initiation of ART, as discussed above. (See 'Risk factors' above.)
As the half-life of HIV in plasma is less than one day [19], ART may produce a greater than 90 percent reduction in the overall HIV viral burden within one to two weeks of starting treatment. 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 cells following initiation of ART is biphasic [20-22]. 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 cells (CD45RA+, CD62L+) occurs in most treated individuals. This secondary increase in CD4 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 [23-25]. CD8 lymphocytes also increase rapidly after the initiation of ART. However, the total numbers of CD8 lymphocytes eventually stabilize as memory CD8 cells subsequently decline and are replaced by naive CD8 lymphocytes [21].
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 [21,22,26,27]. As an example, one group of investigators studying a small group of persons with HIV found that inducible lymphocyte proliferation increased almost threefold after three weeks of ART, ultimately rose fourfold, then stabilized for the next two years [21]. 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 persons with HIV [22,26]. Another study demonstrated that 90 percent of persons with HIV 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 [26].
Clinical manifestations — Most patients with IRIS develop symptoms within a week to a few months after the initiation of ART. One prospective study found that patients developed IRIS a median of 48 days (29 to 99 days) after ART initiation [11]. Preexisting infections may or may not be clinically apparent prior to the initiation of ART.
The signs and symptoms of IRIS vary widely and are related to the location and type of the preexisting OI. As an example, approximately three-fourths of patients with mycobacterial or cryptococcal-related immune reconstitution syndromes develop fever [28]. In contrast, fever occurs infrequently in IRIS related to previously recognized or subclinical infection with CMV.
The clinical features of selected infections are summarized below. (See 'Considerations for selected pathogens' below.)
Diagnosis — The diagnosis of IRIS is typically based on clinical criteria. The diagnosis requires worsening of a recognized infection ("paradoxical" IRIS) or presentation of a previously unrecognized infection ("unmasking" IRIS) in the setting of improved immunologic function and/or viral control [10,29].
Although there are no established criteria, the diagnosis of IRIS should be considered in a patient who:
●Presents with advanced HIV disease with a low pretreatment CD4 count (often less than 100 cells/microL) [8,12].
●Has a robust virologic and usually corresponding immunological response to ART [30,31].
●Has clinical manifestations consistent with an inflammatory condition.
●A temporal association between ART initiation and the onset of clinical features of illness (typically within a few months).
In cases where an infection has been unmasked (ie, there were no symptoms prior to initiating ART), an initial evaluation is needed to determine the pathogen. In patients with worsening of a known infection, it is important to evaluate for evidence of progression of the initial OI due to antimicrobial resistance or nonadherence to prescribed drug regimens; bacterial superinfection or a new concurrent OI; or a new drug allergy or other adverse drug reactions.
Management
●Treatment of underlying infection – Patients 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.
●Antiretroviral therapy (ART) – Patients who develop IRIS leading to a diagnosis of an OI should continue ART if possible. Without ART there cannot be immune recovery, and in most patients, IRIS is self-limited or responds to adjunctive treatment with corticosteroids. This approach is extrapolated in part from studies that show delaying or discontinuing ART put individuals at risk for developing additional complications associated with immunosuppression [32-34].
●Adjunctive therapies – Adjunctive therapies such as glucocorticoids may be needed for patients who develop severe symptoms (eg, in the setting of mycobacterial or cryptococcal infection). The dose and duration of glucocorticoids will depend on the severity and extent of the underlying infection and may be prolonged in some cases. Detailed recommendations on dosing and duration are discussed separately. (See 'Mycobacterial infections' below and 'Cryptococcal infection' below.)
In addition, localized drainage (with appropriate cultures) may be indicated for symptomatic relief in some settings (eg, mycobacterial lymphadenitis). (See 'Mycobacterial infections' below.)
Prevention — The best way to prevent IRIS is to initiate ART early in the course of disease, before the patient has a decline in their CD4 count. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Timing of treatment'.)
However, some patients with HIV will present for the first time with an OI. In this setting, IRIS cannot always be avoided, as most patients should initiate ART within two weeks of presentation. Available data have found the benefits of immune recovery outweigh the risk of IRIS in most cases [35,36]. Exceptions to this recommendation include cryptococcal meningitis and sometimes tuberculosis (TB), in which the benefits of immediate ART may be outweighed by induction of potentially serious IRIS or drug toxicity. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'When to initiate antiretroviral therapy' and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
There may also be a benefit of administering preventive glucocorticoids in patients with newly diagnosed HIV and TB. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Preventing IRIS'.)
Considerations for selected pathogens — Most OIs have been linked to IRIS [3,11,13,37-48]. The leading pathogens include:
●Mycobacterium tuberculosis (most common in endemic areas)
●Mycobacterium avium complex (MAC; most common in US)
●CMV
●Cryptococcus neoformans
●Pneumocystis jirovecii
●Herpes simplex virus (HSV)
●Hepatitis B virus (HBV)
●Human herpes virus 8 (associated with Kaposi sarcoma [KS])
Some case reports have also documented IRIS associated with hepatitis C virus (HCV), parvovirus B19 [37], Candida albicans, Epstein Barr Virus, Bartonella henselae, Histoplasma capsulatum [38], dermatophytosis [39], leprosy [40-42], bacillus Calmette-Guérin [43], Talaromyces (Penicillium) marneffei [44], Schistosoma mansoni [45], and molluscum contagiosum virus. In addition, some patients with KS and lymphoma have developed an IRIS-like syndrome when ART was initiated [11,47-49], and other patients have developed Grave's thyrotoxicosis or recurrence of sarcoidosis after starting ART.
Mycobacterial infections
●Tuberculosis – For patients with HIV and TB, IRIS can be seen after initiating ART. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
Patients who are coinfected with TB and HIV can develop IRIS that manifests as tuberculous lymphadenitis [50], cutaneous lesions [51], peritonitis [52], epididymitis [52], bowel perforation [53], or granulomatous nephritis [54]. The time interval from initiation of ART to the onset of IRIS associated with TB tends to occur within the first 60 days of starting ART, although the range has varied from 10 to 180 days [3]. Detailed information on the clinical manifestations of IRIS is presented separately. (See "Treatment of pulmonary tuberculosis in adults with HIV infection: Follow-up after initiation of therapy", section on 'Immune reconstitution inflammatory syndrome'.)
In the setting of pulmonary TB, glucocorticoids may be used for the management of IRIS. (See "Treatment of pulmonary tuberculosis in adults with HIV infection: Follow-up after initiation of therapy", section on 'Immune reconstitution inflammatory syndrome'.)
In people with HIV and TB, ART should generally be started within two weeks of initiating TB treatment if the CD4 cell count is <50 cells/microL and within eight weeks if the CD4 cell count is ≥50 cells/microL. Glucocorticoids may also reduce the risk of developing IRIS in selected patients with low CD4 counts [55]. This is discussed in detail in a separate topic review. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Preventing IRIS' and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Antiretroviral therapy'.)
●M. avium complex (MAC) – Patients coinfected with HIV and MAC may develop inflammatory reactions following the initiation of ART (picture 1 and image 1 and picture 2) [56-59]. IRIS due to MAC often manifests as fever and painful lymphadenitis that occurs one to eight weeks after ART is commenced [3,58-60]. 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 [61]. (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 [62], worsening lung infiltrates, or diffuse intestinal involvement presenting with abdominal pain [63].
More detailed information on the clinical presentation and management of IRIS in patients with MAC is presented in a separate topic review. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Uncommon manifestations' and "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Adjunctive therapy for IRIS'.)
Viral infections
●Cytomegalovirus (CMV) – IRIS due to prior CMV infection has been termed "immune recovery uveitis" (IRU) or "immune recovery vitritis" by various investigators [64,65]. IRIS has been reported in 16 to 63 percent of patients with HIV and CMV retinitis following the initiation of ART [30,65,66]. 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 [64,65]. The clinical manifestations and management of ocular CMV IRIS are discussed in detail elsewhere. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes'.)
CMV infection may rarely result in IRIS manifesting as pneumonitis [67], colitis, pancreatitis, or submandibular inflammation [68]. Some cases of CMV-associated IRIS have occurred in patients with HIV and absolute CD4 counts above 100 cells/microL, a remarkable finding in contrast to that seen in patients prior to the introduction of effective ART, when <1 percent of patients with CD4 counts above 100 cells/microL developed symptoms attributable to CMV infection [69].
●JC virus – Patients with HIV who are coinfected with JC virus may develop PML after CD4 cell counts drop below 200/microL. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)
Although some patients with PML improve following the initiation of ART, approximately 10 to 20 percent of patients develop new or worsening neurologic symptoms associated with enlarging central nervous system (CNS) lesions that show secondary enhancement after infusion of contrast agents (a finding not typically present in patients with AIDS and PML) [70-72]. Most cases of IRIS associated with JC virus infections occur three to six weeks after ART is begun [70]. It can be clinically challenging to distinguish PML disease progression from PML. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Inflammatory PML (PML-IRIS)'.)
Patients with IRIS 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 [70,71,73,74]. The role of empiric corticosteroids and other adjunctive therapies remains controversial. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'PML-IRIS'.)
●Herpes zoster virus – Some patients develop herpes zoster as an immune reconstitution syndrome [9,75]. In one study that followed 193 patients with a CD4 count <100 cells/microL who initiated a potent ART regimen, 14 patients developed zoster, with 86 percent developing symptoms between weeks 4 and 16 after starting ART [76]. Most cases were limited to a localized dermatomal distribution and responded well to oral acyclovir, valacyclovir, or famciclovir. Other reports have found that some patients with preexisting ocular infection with varicella-zoster virus develop a recurrence of those symptoms during the first one to four months following the initiation of ART [77].
●Herpes simplex virus (HSV) – IRIS related to HSV-2 infection is characterized by an increased severity of ulcerative disease or an increased frequency of recurrences after the initiation of ART. The use of suppressive therapy in the first three to six months after ART initiation may decrease the risk of HSV-2 genital ulcerative disease and shedding, particularly for those with a low CD4 count. The treatment and prevention of HSV infection in persons with HIV is presented in a separate topic review. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Immune reconstitution syndrome'.)
●Hepatitis B and C – The incidence of clinical hepatitis among ART responders who are coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) is estimated to be 1 to 5 percent. IRIS associated with HBV and HCV usually occurs within two to eight weeks of initiation of ART, but onset may be delayed for up to nine months.
Symptoms and laboratory abnormalities suggesting worsening hepatitis may occur in patients coinfected with HCV or HBV following ART [78-82]. 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 [83], while others have developed porphyria cutanea tarda [80].
The prognosis of HBV and HCV-related IRIS appears to depend in part on the underlying hepatic functional reserve. The treatment of patients with HIV and concurrent 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".)
●Mpox – In some patients with advanced HIV and mpox, an IRIS-like syndrome may occur after initiation of ART. In a report of 382 patients with advanced HIV and mpox, IRIS was suspected as the cause of clinical deterioration in 21 (25 percent) of the 85 people who initiated or reinitiated ART [84]. However, similar to most other OIs, we do not delay the initiation of ART in people with HIV and mpox, since the benefit of immune recovery outweighs the risk of IRIS. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Prognosis and risk for severe disease' and "Treatment and prevention of mpox (monkeypox)", section on 'Persons with HIV'.)
Cryptococcal infection — Patients previously infected with Cryptococcus spp. may develop symptoms of IRIS localized to the CNS or the lungs [85]. Symptoms often occur within two months after commencement of therapy but may be delayed for more than six months [85-87]. 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 [88].
Patients with preexisting cryptococcal pulmonary infection may develop cavitary lung lesions, hypoxia, respiratory failure, and acute respiratory distress syndrome following the initiation of ART [3,89]. Rarely, patients with disseminated cryptococcal infections may develop mediastinal lymphadenitis, hypercalcemia, and cutaneous abscesses as part of the IRIS syndrome [89,90].
To prevent IRIS in patients with cryptococcal meningitis, initiation of ART should generally be delayed several weeks after starting antifungal therapy. In addition, asymptomatic individuals with newly diagnosed HIV and a CD4 cell count <200 cells/microL should have a serum cryptococcal antigen checked at their baseline evaluation, since some people with advanced HIV may have cryptococcal disease with mild or even no symptoms. This is discussed in detail in separate topic reviews. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'When to initiate antiretroviral therapy' and "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Immune reconstitution inflammatory syndrome'.)
Pneumocystis jirovecii infection — IRIS associated with P. jirovecii infection in patients with HIV infection results in similar symptoms as the infection itself. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Clinical Features of Pulmonary disease'.)
Pneumocystis pneumonia (PCP)-related IRIS typically presents one to three weeks after starting ART. IRIS should be suspected when a patient who responded well to initial antipneumocystis therapy and corticosteroids then goes on to develop symptoms such as recurrent fever, increased cough, chest discomfort, dyspnea, hypoxia, and progressive radiographic pulmonary opacification [91-93]. Repeat bronchoscopy may reveal large numbers of inflammatory cells in bronchoalveolar lavage fluid. (See "Treatment and prevention of Pneumocystis infection in patients with HIV".)
In some cases, it can be difficult to distinguish if the symptoms are due to IRIS or due the paradoxical inflammatory response that can be seen following the initiation of antimicrobial therapy directed against Pneumocystis. In this setting, it is reasonable to initiate corticosteroids if the patient meets the criteria used for treatment of PCP (eg, have moderate to severe disease) or has worsening symptoms after initiation of ART. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Use of corticosteroids'.)
Leishmaniasis — Cases of IRIS involving visceral and cutaneous manifestations of leishmaniasis have been reported in patients with advanced AIDS who initiated ART [94]. Immunologic reconstitution can lead to a resurgence of inflammation, resulting in severe infiltrative plaques and ulcers. (See "Use and impact of antiretroviral therapy for HIV infection in resource-limited settings", section on 'Leishmaniasis'.)
Kaposi sarcoma — Patients with Kaposi sarcoma (KS) can develop an IRIS-like syndrome that includes rapid clinical progression of KS when ART is initiated [47,48,95]. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Immune reconstitution inflammatory syndrome'.)
One study in Uganda evaluated 55 patients with cutaneous KS who were participating in a randomized trial of two different ART regimens [96]. 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.
KS-associated IRIS should be differentiated from Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS), a syndrome characterized by severe inflammatory symptoms [97-99]. Patients with KICS are often critically ill, and many require management in the intensive care unit. One way to distinguish the two is by measuring HHV-8 viral load levels, which are very high in patients with KICS but low in patients with KS-associated IRIS [100]. KICS is discussed in greater detail elsewhere. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis", section on 'Inflammatory cytokine syndrome'.)
Noninfectious 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 patients with HIV soon after initiation of ART [101-103]. Prior to the introduction of ART, progressive sarcoidosis and advanced HIV infection were considered to be divergent disease processes, because CD4 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.
Autoimmune thyroiditis and Graves' disease can appear after starting ART, and in some cases, it can be significantly delayed [104-106]. 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, which in turn produce anti-thyrotropin receptors and other autoantibodies.
Cases of lymphoma have also been diagnosed soon after ART initiation. In one report of 482 patients with HIV and lymphoma, 56 (12 percent) developed symptoms within six months of starting ART [49]. (See "HIV-related lymphomas: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)
IRIS IN PERSONS WITHOUT HIV — Paradoxical inflammatory syndromes, similar to those seen in persons with HIV, have also occurred in some 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 [28,107,108].
Inflammatory syndromes have also been described in patients without HIV following treatment for lepromatous leprosy [109] or for tuberculosis (TB) [110-114]. 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 acute respiratory distress syndrome.
Patients with extrapulmonary TB may develop worsening lymphadenitis [110,115], new pleural effusions [116,117], the reappearance of fever with new infiltrates [118], or expansion of preexisting intracranial tuberculomas [111,119-121] 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 [114].
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 [122]. The incidence of paradoxical reactions in HIV-uninfected patients may be higher in patients who develop TB while receiving the immunomodulator infliximab [113]. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)
SUMMARY AND RECOMMENDATIONS
●Terminology – The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders that present as a worsening of a recognized ("paradoxical" IRIS) or unrecognized ("unmasking" IRIS) pre-existing infection or condition in the setting of improving immunologic function. IRIS can be seen in persons with HIV after starting antiretroviral therapy (ART) and can also occur in immunocompromised patients without HIV when immunosuppression is reduced. (See 'Introduction' above.)
●IRIS in persons with HIV – HIV infection produces both quantitative and qualitative time-dependent deleterious effects on the immune system. Low CD4 counts and/or high HIV RNA levels when ART is initiated increase the risk of developing IRIS. The likelihood of developing IRIS also correlates with the degree of viral suppression and immune recovery following ART initiation. (See 'Immunobiology and pathogenesis' above and 'Risk factors' above.)
•Clinical features – Most patients with IRIS develop symptoms within one week to a few months after initiating ART. (See 'Clinical manifestations' above.)
The clinical features of IRIS can vary and are usually related to the type and location of a preexisting opportunistic infection (OI). (See 'Considerations for selected pathogens' above.)
Autoimmune and other noninfectious conditions (eg, sarcoidosis, autoimmune thyroiditis, lymphoma) may also worsen or appear after ART is begun, although the presentation may be significantly delayed. (See 'Noninfectious syndromes possibly associated with IRIS' above.)
•Diagnosis – IRIS should be suspected in patients who have clinical manifestations consistent with an inflammatory condition if they have a low pretreatment CD4 count (often less than 100 cells/microL), a robust virologic and immunological response to ART, and there is a temporal association between ART initiation and the onset of illness. (See 'Diagnosis' above.)
•Management – For patients who develop IRIS, we recommend ART be continued (Grade 1B). Without ART there cannot be immune recovery, and in most patients, IRIS is self-limited or responds to adjunctive treatment with corticosteroids.
ART should be used in addition to therapy for the underlying OI or condition. Adjunctive therapies, such as glucocorticoids, may also be needed in certain settings (eg, cryptococcal meningitis or mycobacterial infections). (See 'Management' above and 'Considerations for selected pathogens' above.)
•Prevention – The best way to prevent IRIS is to initiate ART early in the course of HIV infection, before the patient has a decline in their CD4 count. (See "When to initiate antiretroviral therapy in persons with HIV".)
In patients who present with an OI prior to initiating ART, ART should be initiated within two weeks for most OIs. However, in the setting of certain infections (eg, cryptococcal meningitis and sometimes tuberculosis [TB]), ART should be temporarily delayed since the benefits of early ART are outweighed by induction of potentially serious IRIS. (See 'Prevention' above.)
There may also be a benefit of administering preventive glucocorticoids in patients with newly diagnosed HIV and TB coinfection. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Preventing IRIS'.)
●IRIS in other immunocompromised groups – Paradoxical inflammatory syndromes, similar to those seen in persons with HIV, have also occurred in some patients following corticosteroid withdrawal, discontinuation of antitumor necrosis factor alpha therapy, recovery of neutropenia after cytotoxic chemotherapy, withdrawal of immunosuppression in transplant recipients with Cryptococcus neoformans, and engraftment after stem cell transplantation. (See 'Iris in persons without hiv' above.)
Inflammatory syndromes have also been described in patients without HIV following treatment for lepromatous leprosy or TB.
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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