CHAPTER 367 2292 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS TABLE 367-1 EXAMPLES OF IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME PATHOGEN 367 IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN HIV/AIDS MARTYN A. FRENCH AND GRAEME MEINTJES DEFINITION Treatment of human immunodeficiency virus (HIV) infection with combination antiretroviral therapy (ART) results in the restoration of protective pathogen-specific immune responses and the regression or prevention of opportunistic infections and cancers in most individuals (Chapter 365). However, restoration of an immune response against a pathogen may also result in immunopathology at body sites infected by the pathogen. This has been referred to as immune restoration disease to differentiate it from immunodeficiency disease, but it is now commonly known as immune reconstitution inflammatory syndrome (IRIS) because an inflammatory illness is the most common clinical feature.1,2 Essentially any pathogen that causes an infection as a result of HIV-induced cellular immunodeficiency may be associated with IRIS after ART is commenced.3 However, the clinical characteristics and severity of IRIS associated with each type of pathogen vary greatly (Table 367-1). For example, IRIS associated with Mycobacterium tuberculosis, cryptococcal, or JC polyomavirus infection is manifested differently from an opportunistic infection caused by these pathogens, and the resulting illness is often severe and may result in death (Chapter 346). In contrast, herpes zoster after ART is usually indistinguishable from that occurring before ART, and it is only the timing of onset and its increased frequency during early ART that suggest that it results from IRIS. IRIS develops mainly during the first 3 months of ART but occasionally later. Two patterns are recognized. Paradoxical IRIS refers to the worsening or atypical manifestation (or both) of an established opportunistic infection after ART is commenced. In most cases the infection had been treated before ART was initiated, and the immune response appears to be against residual antigens of the pathogen or the dying organism. Unmasking IRIS refers to disease that occurs for the first time after ART is commenced and appears to result from an immune response against a subclinical infection by an opportunistic pathogen or a missed diagnosis of an opportunistic infection. Typically, unmasking IRIS manifests with accelerated or exaggerated inflammatory presentations of the infection. EPIDEMIOLOGY The reported incidence of IRIS has varied from 8% to over 40% in different studies. To some extent, the large variation reflects the lack of universally accepted diagnostic criteria. It also probably reflects differences in risk factors in the populations of patients studied. The most important risk factors for IRIS are a low CD4+ T-cell count when ART is initiated and, in patients in whom paradoxical IRIS develops, disseminated infection and a short time interval between treatment of the infection and commencement of ART. PATHOGENESIS Information about the pathogenesis of IRIS has been obtained mostly by studying patients who experience disease associated with a mycobacterial infection.4 Both clinicopathologic and immunologic studies have shown an association with a TH1 cellular immune response against mycobacterial antigens, which has been demonstrated by measuring delayed-type hypersensitivity skin test responses or the frequency of circulating antigen-specific T cells that produce interferon (IFN)-γ. However, there is increasing evidence that innate immune responses by myeloid cells (monocytes, macrophages, and neutrophils) and their mediators also contribute to the immunopathology, particularly in paradoxical tuberculosis-associated IRIS. Patients who develop IRIS tend to have severe immunosuppression with high levels of C-reactive protein prior to starting anti-retroviral therapy.4b The immunopathogenesis NOMENCLATURE TYPICAL CHARACTERISTICS OF THE DISEASE Mycobacterium tuberculosis TB-IRIS Paradoxical exacerbation of TB Nontuberculous mycobacteria (NTM) NTM-IRIS Mainly lymphadenitis, also pulmonary and abdominal disease Bacille Calmette-Guérin (BCG) BCG-IRIS Necrotizing regional lymphadenitis Mycobacterium leprae Leprosy-associated IRIS Borderline and type 1 reactional state Cryptococcus neoformans C-IRIS Mainly meningitis, also lymphadenitis Pneumocystis jiroveci Pneumocystosis-associated IRIS Paradoxical exacerbation of pneumonitis Cytomegalovirus (CMV) CMV retinitis after ART or immune recovery uveitis Acute retinitis after commencing ART or uveitis JC polyomavirus PML-IRIS Multifocal leukoencephalopathy with inflammatory features Human herpesvirus 8 KS-IRIS Rapid progression of existing and/or new KS lesions Hepatitis B or C virus Hepatitis B or C virus-associated IRIS (that may mimic DILI) Hepatitis flare and/or liver enzyme elevation Varicella-zoster virus Dermatomal or multidermatomal zoster and rarely myelitis after ART Herpes simplex virus Herpes lesions with exaggerated inflammation and rarely myelitis or encephalitis after ART Molluscum contagiosum virus Inflammatory molluscum contagiosum Inflamed molluscum lesions Malassezia spp. Inflammatory seborrheic dermatitis Abnormally inflamed seborrheic dermatitis ART = antiretroviral therapy; DILI = drug-induced liver injury; C = cryptococcosis; IRIS = immune reconstitution inflammatory syndrome; KS = Kaposi sarcoma; PML = progressive multifocal leukoencephalopathy; TB = tuberculosis. of IRIS associated with other pathogens is less well understood and appears to vary depending on the provoking pathogen.5 For example, IRIS associated with JC polyomavirus infection (progressive multifocal leukoencephalopathy IRIS) is characterized by an inflammatory cell infiltrate dominated by CD8+ T cells in affected areas of the brain. Other forms of IRIS associated with virus infections also appear to be CD8+ T-cell mediated. CLINICAL MANIFESTATIONS The clinical manifestations of IRIS are different for each associated pathogen and will therefore be described for individual pathogens. Only disease that presents a significant patient management problem will be discussed. Tuberculosis-associated IRIS M. tuberculosis is the most common pathogen involved in IRIS, with estimates of paradoxical tuberculosis-associated IRIS incidence ranging from 4 to 54% of patients with HIV infection and treated tuberculosis. Most tuberculosis-associated IRIS develops within the first 3 months after the initiation of ART. Patients in whom paradoxical tuberculosis-associated IRIS develops typically give a history of having severe immunosuppresion5b and improving with the treatment of tuberculosis before initiation of ART. After starting ART, recurrent, worsening, or new clinical or radiologic manifestations of tuberculosis develop. Common manifestations include fever, enlargement of lymph nodes, and worsening radiographic pulmonary infiltrates. Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved. 2292.e4 ABSTRACT CHAPTER 367 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS HIV patients commencing antiretroviral therapy (ART) with very low CD4+ T cell counts are at risk of developing an immune reconstitution inflammatory syndrome (IRIS) resulting from the restoration of immune responses against pathogens that cause exaggerated and often atypical inflammation. The inflammation appears to be a paradoxical worsening of the infection (paradoxical IRIS) or was subclinical and unmasked by the immune response (unmasking IRIS). Most cases of IRIS are associated with an infection by Mycobacterium tuberculosis or Mycobacterium avium complex, but IRIS may also be associated with infections by fungi and viruses. Almost all cases of IRIS occur during the first 3 months of ART and often during the first 2 weeks. Prevention of an IRIS is achievable by commencing ART before CD4+ T cell counts become low (<350/mL) and by optimally treating opportunistic infections before commencing ART. Deferment of ART until an opportunistic infection is optimally treated is particularly important when the infection affects the central nervous system. Management of an IRIS generally includes continuing ART and the use of anti-inflammatory therapy, which may include corticosteroids in tuberculosis-associated IRIS. ART should only be stopped in exceptional circumstances. KEYWORDS HIV antiretroviral therapy immune reconstitution IRIS paradoxical IRIS unmasking IRIS Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved. CHAPTER 367 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS Tracheal compression by intrathoracic lymph nodes or massive pleural effusions can cause life-threatening dyspnea. Respiratory failure as a result of worsening pulmonary infiltrates and acute respiratory distress syndrome have occasionally been reported. In a prospective case series from South Africa, neurologic tuberculosis-associated IRIS accounted for 12% of cases of paradoxical tuberculosis-associated IRIS. Meningitis, tuberculoma, or both were the most common manifestations. Tuberculosis-associated IRIS may cause granulomatous hepatitis, typically with tender hepatomegaly and cholestatic liver function derangement. Peritonitis due to IRIS-mediated peritoneal inflammation and peritonitis secondary to bowel perforation or splenic rupture are other unusual presentations. Although usually negative, mycobacterial cultures may be positive, particularly if IRIS occurs early during anti-tubercular therapy and in patients with multidrug-resistant tuberculosis. Histologic examination often reveals necrotizing granulomas. High rates of tuberculosis have been reported during ART, especially in the initial months of treatment in ART programs in resource-limited settings. This type of tuberculosis has been referred to as ART-associated tuberculosis because the mechanisms underlying the manifestations of tuberculosis after initiating ART are likely to be heterogeneous. Diagnoses of active tuberculosis before initiation of ART may be missed because of the inherent insensitivity of tuberculosis diagnostics in this patient group and only later be diagnosed during ART. Because ART-induced immune recovery is a time-dependent process and some patients fail to respond immunologically, a proportion of cases may develop as a result of persisting immunodeficiency. Other patients may have active subclinical disease at the time of ART initiation or a missed diagnosis of tuberculosis, and progression to symptomatic disease may be accelerated with exaggerated inflammatory features by ART-induced restoration of a cellular immune response against M. tuberculosis antigens. Of patients in this latter group, some have exuberant inflammatory clinical features that are consistent with a diagnosis of unmasking tuberculosis-associated IRIS. Nontuberculous Mycobacterial IRIS Atypical manifestations of Mycobacterium avium complex (MAC) disease in patients who had commenced zidovudine monotherapy were the first indication that IRIS may be a complication of ART. MAC and other nontuberculous mycobacteria have been associated with IRIS in up to 4% of patients who commence combination ART with a CD4+ T-cell count lower than 100/µL. Disease is usually localized, as opposed to the disseminated nontuberculous mycobacterial disease of patients with acquired immunodeficiency syndrome (AIDS) not on ART, and is most commonly manifested as fever, night sweats, and lymphadenitis. Unmasking disease is most common. Peripheral lymphadenitis may suppurate and sometimes cause chronically discharging fistulas to the skin. Abdominal disease frequently causes pain, which is usually associated with lymphadenitis and occasionally with omental masses, hepatitis, and inflammation of the spleen (Fig. 367-1). Pulmonary and thoracic disease 2293 usually causes cough that is sometimes associated with chest pain. Microscopic examination of biopsy material or aspirates from affected tissues often reveals mycobacteria, but these may not be cultured. In HIV-seropositive children vaccinated with bacille Calmette-Guérin (BCG), a BCG-associated lymphadenitis with or without abscess formation may develop after starting ART (Fig. 367-2). Leprosy-associated IRIS is usually manifested as unmasking of previous subclinical Mycobacterium leprae infection, with a borderline and type I reactional state (Chapter 310). Cryptococcosis-IRIS The proportion of patients with HIV infection and treated cryptococcosis in whom cryptococcosis-IRIS develops ranges from 8 to 49%. Themajority represent a recurrence of previously treated cryptococcal meningitis.Unmasking inflammatory reactions to unrecognized meningeal infection during the first few weeks of ART have also been reported.6 The time of onset of cryptococcosis-IRIS varies from 4 days to around 3 years after initiation of ART. In addition to recurrent meningitis, the central nervous system (CNS) features of cryptococcosis-IRIS include intracranial cryptococcoma or abscesses, spinal cord abscesses, recalcitrant raised intracranial pressure, optic disc swelling, cranial nerve lesions, dysarthria, hemiparesis, and paraparesis. Extracranial manifestations of cryptococcosis-IRIS include lymphadenitis, eye disease, suppurating soft tissue lesions, and pulmonary disease that may include cavitating or nodular lesions. At the diagnosis of cryptococcal meningitis, cerebrospinal fluid (CSF) white blood cell counts of 25 cells/µL or less and protein levels of 50 mg/dL or less are associated with the development of cryptococcosis-IRIS. On the other hand, CSF profiles at the moment of paradoxical cryptococcosis-IRIS may show an increased white blood cell count and an increased opening pressure of greater than 25 cm H2O, but these features overlap significantly with those observed in patients with non–IRIS-related relapses of cryptococcal meningitis. A positive CSF cryptococcal culture prior to commencing ART is a predictor for paradoxical cryptococcosis-IRIS. Cultures of CSF or tissue samples obtained at the time of paradoxical cryptococcosis-IRIS are usually negative even when cryptococci can beseen on microscopy. The importance of cryptococcosis-IRIS is emphasized by the finding that earlier (1 to 2 weeks) ART initiation in cryptococcal meningitis results in higher mortality compared with deferred (5 weeks) ART initiation likely due to enhanced immune cell recruitment and activation when ART is started very early in thecontext of a partially treated CNS infection.7,8 Histoplasmosis-IRIS Histoplasmosis-IRIS is uncommon but reported in areas in which the fungal agent is endemic (Chapter 316), including the Ohio River Valley of the U.S. and French Guiana. Histoplasmosis-IRIS can generate significant morbidity, so screening for latent or subclinical histoplasmosis should be considered before initiating antiretroviral therapy in endemic areas.8b Pneumocystosis-IRIS Patients who have been treated for P. jiroveci pneumonitis may experience pulmonary inflammation after ART is commenced. It is usually characterized by fever, cough, dyspnea, chest discomfort, and patchy alveolar infiltrates on the chest radiograph (Fig. 367-3). In some patients, organizing pneumonia develops. This condition is relatively rare, occurring in less than 5% of patients treated for P. jiroveci pneumonitis prior to ART. FIGURE 367-2. Bacille Calmette-Guérin (BCG)–associated immune reconstitution FIGURE 367-1. Mycobacterium avium complex–associated immune reconstitution inflammatory syndrome manifested as necrotizing inflammation in the spleen and abdominal lymph nodes. inflammatory syndrome after starting antiretroviral therapy for human immunodeficiency virus infection in a child who received BCG vaccination shortly after birth. A biopsy specimen from the larger lesion demonstrated necrotizing granulomatous inflammation. Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved. 2294 CHAPTER 367 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS Liver Disease after ART Associated with Hepatitis B and C Virus Infection FIGURE 367-3. Pneumocystosis-associated immune reconstitution inflammatory syndrome. Left, Before treatment of the P. jiroveci infection. Right, After treatment of the P. jiroveci infection and commencing antiretroviral therapy. Progressive Multifocal Leukoencephalopathy IRIS Progressive multifocal leukoencephalopathy of the brain occurs when cellular immune responses fail to control JC polyomavirus infection of oligodendrocytes and astrocytes. It is characterized by a paucity of inflammatory cells in brain lesions (Chapter 346). ART is effective in some patients, presumably because it enhances cellular immune responses against JC polyomavirus antigens. However, ART may also result in a paradoxical worsening of established progressive multifocal leukoencephalopathy or in unmasking of subclinical JC polyomavirus infection and appearance of progressive multifocal leukoencephalopathy for the first time. These manifestations of progressive multifocal leukoencephalopathy on ART are often atypical in that imaging studies of the brain demonstrate changes associated with inflammation, and brain biopsy specimens demonstrate inflammatory cell infiltrates with a prominence of CD8+ T cells. Between 19 and 23% of cases of progressive multifocal leukoencephalopathy in HIV-infected patients are due to paradoxical or unmasking progressive multifocal leukoencephalopathy IRIS. The median time at onset is 7 weeks on ART, and most cases occur within the first 3 months but very occasionally as late as 26 months after commencing ART. Predictors of progressive multifocal leukoencephalopathy IRIS have not been identified. Other CNS manifestations of IRIS, which vary greatly in incidence following ART, may include cryptococcal meningitis and meningoencephalitis, cerebral toxoplasmosis, primary CNS lymphoma, and HIV encephalitis,9 as well as stroke.10 KS-IRIS A prospective study of Kaposi sarcoma (KS) in patients from Mozambique commencing ART found that paradoxical KS-IRIS developed in 31% of patients with pre-ART KS, and that unmasking KS-IRIS developed in 7% of patients without pre-ART KS. Clinical manifestations included an increased number of preexisting skin lesions that sometimes exhibited increased nodularity and ulceration, new skin or mucosal lesions, and lymphedema. Independent risk factors for the development of KS-IRIS were KS before ART, human herpesvirus 8 DNA detectable in plasma, a hematocrit of less than 30%, and a plasma HIV RNA level greater than 5 log10 copies/mL. This form of IRIS may be life-threatening when there is worsening of pulmonary KS or airway obstruction due to enlarging KS lesions. Some cases of KS-IRIS will resolve without treatment, but chemotherapy is usually necessary. Cytomegalovirus-associated IRIS Eye disease is the most common manifestation of IRIS associated with cytomegalovirus infection. Retinitis usually develops during the first few weeks of ART as a “paradoxical” worsening of treated retinitis or as a new manifestation of cytomegalovirus retinitis. Previously treated cytomegalovirus infection is the most common cause of immune recovery uveitis, which presumably results from the restoration of an immune response against residual cytomegalovirus antigens in the eye. The risk for development of cytomegalovirus-associated immune recovery uveitis is greatest in patients who had a large proportion of the retina affected by cytomegalovirus infection. It may develop up to 21 months after ART is commenced, and the clinical manifestations vary in severity from a transient vitreitis to persistent uveitis, papillitis, cystoid macular edema, and detachment of epiretinal membranes. Elevations of serum liver enzyme levels occur in up to 18% of patients after ART is initiated. Several causes have been defined, but the most important risk factor is concomitant infection with hepatitis B virus or hepatitis C virus. Prospective studies of patients with HIV infection who are coinfected with hepatitis B virus, hepatitis C virus, or both, who commenced ART demonstrated that 22 to 24% of patients with hepatitis B coinfection, 13.5% of patients with hepatitis C coinfection, and 50% of patients with both hepatitis B and C coinfection experienced a “flare” of hepatitis. Flares of hepatitis B were associated with increased plasma levels of several immune mediators, suggesting that at least some of these cases were due to IRIS related to hepatitis B in the liver. Patients who experienced flares of hepatitis B had higher plasma hepatitis B virus DNA levels and serum alanine transaminase levels before ART was commenced. Severe hepatitis after ART in patients with HIV infection and coinfection with hepatitis B or hepatitis C is uncommon but can occasionally result in liver decompensation and death. It is difficult to determine with certainty in an individual case whether this phenomenon is due to direct drug hepatoxicity or IRIS associated with hepatitis viruses. Herpes Simplex Virus and Varicella Zoster Virus Disease after ART Recurrence or exacerbation of mucocutaneous herpes simplex virus disease may occur after ART is initiated. Sometimes lesions become hemorrhagic and exhibit significant tissue necrosis. Rarely herpes simplex virus infection of the brain or spinal cord may be unmasked by commencing ART and be manifested as encephalitis or myelitis. Dermatomal or multidermatomal zoster lesions may also develop after commencing ART and are usually indistinguishable from zoster that occurs in patients not receiving ART. Rarely, myelitis may be associated with varicella-zoster virus infection. DIAGNOSIS Immunologic tests for diagnosing IRIS are currently not available for routine use. In the absence of diagnostic tests, IRIS may be established with diagnostic criteria that take into consideration the timing, clinical characteristics, and pathology of the disease, as well as the virologic response to the ART as measured by HIV viral load. TREATMENT The general approach to the treatment of IRIS is to continue ART and provide appropriate antimicrobial therapy for the provoking infection. Cessation of ART should be considered only in patients with life-threatening disease when all other measures have failed. Anti-inflammatory therapy should not be given routinely but be reserved for patients with severe inflammation, particularly when it is life-threatening, or significant symptoms. Corticosteroid therapy is used most often, but its effectiveness may vary from one type of IRIS to another. Thus, a randomized controlled trial in South Africa demonstrated that corticosteroids (prednisone 1.5 mg/kg/day for 2 weeks, then 0.75 mg/kg/day for 2 weeks) are a safe and effective treatment option for paradoxical tuberculosis-associated IRIS.A1 In contrast, in an analysis of data from previously reported cases of progressive multifocal leukoencephalopathy IRIS, it was suggested that corticosteroid therapy is not effective, although it was indicated that it may be effective if used early in the course. There is anecdotal evidence suggesting that corticosteroid therapy can be effective in other types of IRIS, but there are potential risks to using corticosteroid therapy in HIV patients who are already very immunodeficient, and it should be started only after weighing all considerations. Corticosteroid therapy for IRIS affecting the eye should be supervised by an ophthalmologist. Corticosteroid therapy may cause worsening of KS. PREVENTION Given that a low CD4+ T-cell count is a major risk factor for the development of IRIS, commencing ART at a CD4+ T-cell count higher than 350/µL, as recommended by treatment guidelines, will prevent most cases. However, this is not possible in patients who are seen for the first time with an opportunistic infection or low CD4+ T cell count. Other strategies to prevent paradoxical IRIS are therefore under investigation. A randomized controlled trial demonstrated that the risk of paradoxical tuberculosis-associated IRIS could be Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved. CHAPTER 367 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS reduced by 30% in high-risk patients (CD4+ T-cell count ≤100 cells/µL) with HIV-associated tuberculosis starting ART by prescribing prednisone for the first 4 weeks of ART (40 mg daily for 2 weeks then 20 mg daily for 2 weeks).A2 Several observations indicate that a high pathogen load is an important risk factor for IRIS, including the association with disseminated tuberculosis, a shorter duration of treatment of tuberculosis or cryptococcal meningitis, and positive CSF cultures for cryptococcal or Mycobacterium tuberculosis infections prior to commencing ART. Therefore, delaying the introduction of ART so that the opportunistic infection can be fully treated might be beneficial. However, doing so may increase the risk for development of other opportunistic infections or cancers and of mortality. The results of an AIDS Clinical Trial Group study provided evidence supporting the introduction of ART within 1 to 2 weeks of starting antimicrobial therapy, particularly in patients with P. jiroveci pneumonitis. In addition, randomized controlled trials demonstrated that for patients with HIV-associated tuberculosis and CD4+ T-cell count less than 50 cells/µL, the survival benefit of starting ART within the first 2 weeks of tuberculosis therapy outweighs the risk for IRIS and other adverse events.A3-A6 Nevertheless, a more recent clinical trial of the effect of timing of ART initiation on outcomes of tuberculosis treatment for HIV-positive patients with CD4+ T-cell counts of 220 cells/µL or more showed that ART can be delayed until after completion of 6 months of tuberculosis treatment in this population.A7 In contrast, commencing ART at the same time as treatment of cryptococcal meningitis has been shown to increase mortality when compared with delaying ART until 5 to 6 weeks after starting antifungal treatment.A8 It seems probable that IRIS affecting the CNS is more likely than other types of IRIS to result in morbidity and mortality. Therefore, a single approach to this issue may not be possible, and a strategy for commencing antimicrobial therapy and ART may have to be determined for each pathogen or for infections of the CNS. PROGNOSIS The prognosis for patients in whom IRIS develops is highly variable because of differences in the extent of the infection by the provoking pathogen, the characteristics of the immunopathology caused by the restored immune response, and the body site affected. Most cases of IRIS are self-limited, and outcomes are usually good. However, mortality rates of up to 66% have been reported for cryptococcosis-IRIS. The mortality rate for tuberculosis-associated IRIS is much lower, but hospital admissions are common. Mortality and hospitalization rates are particularly high when tuberculosis-associated IRIS or cryptococcosis-IRIS affects the CNS. Indeed, involvement of the CNS by 2295 any type of IRIS may result in death or permanent neurologic disability. For example, mortality rates of 53% have been reported for paradoxical progressive multifocal leukoencephalopathy IRIS and 31% for unmasking progressive multifocal leukoencephalopathy IRIS. Furthermore, patients who survive progressive multifocal leukoencephalopathy IRIS may have neurologic sequelae such as hemiparesis or seizures. Patients with lymphadenitis resulting from tuberculosisassociated IRIS11 or nontuberculous mycobacterial IRIS and those with meningitis or cerebral lesions resulting from cryptococcosis-IRIS may experience recurrent relapses. Autoimmune Disease and Sarcoidosis Patients with HIV infection who are receiving ART have an increased susceptibility to some autoimmune diseases, mainly Graves disease, and sarcoidosis. Although sometimes referred to as types of IRIS, they appear to have a different immunopathogenesis. Grade A References A1.Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010;24:2381-2390. A2.Meintjes G, Stek C, Blumenthal L, et al. PredART Trial Team. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med. 2018;379:1915-1925. A3.Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362:697-706. A4.Blanc FX, Sok T, Laureillard D, et al. CAMELIA (ANRS 1295–CIPRA KH001) Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471-1481. A5.Havlir DV, Kendall MA, Ive P, et al. AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482-1491. A6.Uthman OA, Okwundu C, Gbenga K, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and metaanalysis. Ann Intern Med. 2015;163:32-39. A7.Mfinanga SG, Kirenga BJ, Chanda DM, et al. Early versus delayed initiation of highly active antire‑troviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomized, placebo-controlled trial. Lancet Infect Dis. 2014;14:563-571. A8.Eshun-Wilson I, Okwen MP, Richardson M, et al. Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis. Cochrane Database Syst Rev. 2018;7: CD009012. GENERAL REFERENCES For the General References and other additional features, please visit Expert Consult at https://expertconsult.inkling.com. Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved. CHAPTER 367 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS GENERAL REFERENCES 1.Manzardo C, Guardo AC, Letang E, et al. Opportunistic infections and immune reconstitution inflammatory syndrome in HIV-1-infected adults in the combined antiretroviral therapy era: a comprehensive review. Expert Rev Anti Infect Ther. 2015;13:751-767. 2.Church LWP, Chopra A, Judson MA. Paradoxical reactions and the immune reconstitution inflammatory syndrome. Microbiol Spectr. 2017;5:1-5. 3.Boulougoura A, Sereti I. HIV infection and immune activation: the role of coinfections. Curr Opin HIV AIDS. 2016;11:191-200. 4.Walker NF, Stek C, Wasserman S, et al. The tuberculosis-associated immune reconstitution inflammatory syndrome: recent advances in clinical and pathogenesis research. Curr Opin HIV AIDS. 2018;13:512-521. 4b. Sereti I, Sheikh V, Shaffer D, et al. Prospective international study of incidence and predictors of immune reconstitution inflammatory syndrome and death in people living with human immunodeficiency virus and severe lymphopenia. Clin Infect Dis. 2020;71:652-660. 5.Nelson AM, Manabe YC, Lucas SB. Immune reconstitution inflammatory syndrome (IRIS): what pathologists should know. Semin Diagn Pathol. 2017;34:340-351. 5b. Vinhaes CL, Sheikh V, Oliveira-de-Souza D, et al. An inflammatory composite score predicts mycobacterial immune reconstitution inflammatory syndrome in people with advanced HIV: a prospective international cohort study. J Infect Dis. 2021;223:1275-1283. 6.Elsegeiny W, Marr KA, Williamson PR. Immunology of cryptococcal infections: developing a rational approach to patient therapy. Front Immunol. 2018;9:1-9. 2295.e1 7.Scriven JE, Rhein J, Hullsiek KH, et al. Early ART after cryptococcal meningitis is associated with cerebrospinal fluid pleocytosis and macrophage activation in a multisite randomized trial. J Infect Dis. 2015;212:769-778. 8.Yoon HA, Nakouzi A, Chang CC, et al. Association between plasma antibody responses and risk for Cryptococcus-associated immune reconstitution inflammatory syndrome. J Infect Dis. 2019;219:420-428. 8b. Melzani A, de Reynal de Saint Michel R, Ntab B, et al. Incidence and trends in immune reconstitution inflammatory syndrome associated with Histoplasma capsulatum among people living with human immunodeficiency virus: a 20-year case series and literature review. Clin Infect Dis. 2020;70:643-652. 9.Bowen L, Nath A, Smith B. CNS immune reconstitution inflammatory syndrome. Handb Clin Neurol. 2018;152:167-176. 10.Benjamin LA, Allain TJ, Mzinganjira H, et al. The role of human immunodeficiency virus-associated vasculopathy in the etiology of stroke. J Infect Dis. 2017;216:545-553. 11.Lai RP, Meintjes G, Wilkinson RJ. HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Semin Immunopathol. 2016;38:185-198. Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved. 2295.e2 CHAPTER 367 Immune Reconstitution Inflammatory Syndrome in HIV/AIDS REVIEW QUESTIONS 1.A major risk factor for developing paradoxical tuberculosis immune reconstitution inflammatory syndrome (tuberculosis-associated IRIS) is: A.Starting antiretroviral therapy (ART) in a patient with a low CD4+ T-cell count B.Starting ART in a patient with a high CD4+ T-cell count C.Starting ART in a patient with pulmonary tuberculosis D.Starting a protease inhibitor–containing regimen E.Starting ART in a patient with rifampin-resistant tuberculosis Answer: A Tuberculosis-associated IRIS has been associated with a low CD4+ T-cell count (usually <50/µL) in several studies, probably because it is a marker of a high pathogen load and an increased susceptibility to restoration of a pathogen-specific immune response that causes immunopathology. All ART regimens may cause tuberculosis-associated IRIS, and tuberculosis-associated IRIS may develop in patients with all types of tuberculosis, including patients with multidrug-resistant tuberculosis. 2.Which of the following statements is correct? A.In an HIV-infected patient with cryptococcal meningitis, ART should be started within 2 weeks after the start of the cryptococcal treatment. B.In an HIV-infected patient with cryptococcal meningitis, ART should be started at least 4 weeks after the start of the cryptococcal treatment. C.In an HIV-infected patient with cryptococcal meningitis and a CD4+ T-cell count below 50 cells/µL, ART should be started within 2 weeks after the start of the cryptococcal treatment. D.In an HIV-infected patient with cryptococcal meningitis and very few leucocytes in the cerebrospinal fluid (CSF), ART can be started together with the start of the cryptococcal treatment. Answer: B Commencing ART within the first 2 weeks after starting cryptococcal meningitis treatment is associated with increased mortality compared with starting ART at least 4 weeks after the start of the cryptococcal treatment. The presence of very few leukocytes in the CSF is a further risk factor for developing cryptococcal IRIS. 3.Which of the following statements is correct? A.All patients with IRIS should be treated with prednisone. B.Patients with IRIS should never be treated with prednisone. C.In patients with IRIS, ART should be stopped. D.In patients with tuberculosis-associated IRIS, prednisone may be beneficial. Answer: D The effectiveness of prednisone as treatment for IRIS varies from one type of IRIS to another. A randomized controlled trial in South Africa demonstrated that prednisone therapy is a safe and effective treatment option for paradoxical tuberculosis-associated IRIS. For progressive multifocal leukoencephalopathy IRIS, only early use of corticosteroid therapy may be effective. For Kaposi sarcoma (KS)-IRIS, corticosteroids are likely to be harmful. Potential risks of using corticosteroid therapy in patients with HIV infection who are very immunodeficient should always be considered. 4.IRIS can be prevented by which one of the following? A.Early ART at a high CD4+ T-cell count B.Prophylaxis for opportunistic infections C.Early diagnosis and treatment of opportunistic infections D.All of the above Answer: D Commencing ART at a high CD4+ T-cell count, as well as prophylaxis for opportunistic infections, will prevent the occurrence of opportunistic infections and therefore IRIS. Earlier diagnosis and treatment of opportunistic infections will reduce the pathogen load and therefore the risk of developing IRIS. Downloaded for Masatommi Mohammad (masatommi.mohammad@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on May 19, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.