C17 Immune reconstitution inflammatory syndrome
Antiretroviral therapy (ART) in HIV/AIDS patients leads to dramatic reductions in plasma viral load and improvement in CD4 cell counts which translate clinically to reduction in the frequency of opportunistic infections (OI) and prolonged survival. However, some patients experience clinical deterioration as a consequence of rapid and dysregulated restoration of antigen specific immune responses during the treatment. This paradox was first reported following the introduction of zidovudine monotherapy in the early 1990s, when localised forms of Mycobacterium avium-intracellulare (MAI) infection were observed in association with the recovery of cellular immune responses. This phenomenon is known by different names including “immune reconstitution inflammatory syndrome (IRIS)”, “immune reconstitution”, “immune restoration disease (IRD)”, and “immune reconstitution syndrome (IRS)”. The commonly used term “immune reconstitution inflammatory syndrome (IRIS)” is used in this Chapter.
IRIS in HIV-infected individuals is described as a collection of pathological inflammatory response to viable pathogens or non-viable pathogens or their residual antigen(s) associated with immune recovery, which typically occurs a few weeks to months after initiation of ART. It manifests clinically as local inflammatory reaction at the site or sites of preexisting infection or disease process with or without a systemic inflammatory response. The estimated incidence of IRIS in HIV-infected populations following ART initiation varies from 10% to over 30%. The wide range of estimates is likely due to a number of factors including the differences in case definition for IRIS, characteristics of study populations with differing risk profiles such as degree of immunosuppression before initiation of ART and the burden of OIs. IRIS is usually self-limiting but can sometimes be associated with considerable morbidity and mortality. The overall mortality of IRIS ranges from 0% to 15% in different studies with a particularly high mortality reported in IRIS affecting central nervous system (CNS) such as cryptococcal meningitis-associated IRIS and tuberculosis meningitis-associated IRIS.
Immunopathogenesis of IRIS
The immunopathogenesis of IRIS remains largely speculative. It is generally believed that IRIS results from a dysregulated immune response to a variety of antigenic stimuli following initiation of ART. The immunopathology of IRIS is determined by the inciting pathogen. The antigenic stimulus in infectious conditions is either intact viable organisms or dead organisms and their residual antigens. Box 17.1 gives an overview of the inter-relationship between different factors associated with the pathogenesis of IRIS.
The pathophysiology of the syndrome is linked with several factors, such as the reconstitution of immune cell numbers and function, redistribution of lymphocytes, defects in regulatory function, changes in T helper cell profile, the underlying antigenic burden, and host genetic susceptibility. IRIS is most often associated with CD4+ Th1-mediated immune response; however, both CD4+ and CD8+ effector T-cells are also involved in the pathogenesis. The syndrome occurs as a result of an unbalanced immune reconstitution of effector and regulatory T cells among patients receiving ART. The pro-inflammatory Th17 cell and the regulatory T cell (Treg) play an important role in the immunopathophysiology of IRIS. Th17 cells, characterised by the production of IL-17, IL-21 and IL-22, are known to promote potent proinflammatory responses in pathogen eradication. Tregs actively maintain physiological equilibrium of the immune system and T-cell homeostasis, and prevent collateral damage from exuberant inflammatory responses. During immune reconstitution, Tregs may be defective in either numbers or function, and show blunted ability to suppress the release of pro-inflammatory cytokines. Macrophages and natural killer (NK) cells are also suspected to play a role in IRIS. Their role has been suggested in herpes IRIS. Inappropriate activation of macrophages has been reported in TB-IRIS. Increased circulating level of inflammatory markers, chemokines and cytokines such as tumour necrosis factor (TNF)-α, IFN-γ inducible protein-10 (IP-10), D-dimer, C-reactive protein (CRP), interferon (IFN)-γ, interleukins (ILs), CCL2 and CXCL10 are not uncommonly found in IRIS and they are considered to be useful biomarkers that signify an excessive activation of immune system.
Further studies are warranted to elucidate the immunopathogenesis of IRIS and to identify markers for screening patients at risk. Understanding the immunopathogenesis can also be useful in the development of better therapeutics and monitoring of response to therapy in patients with IRIS.
Box 17.1. Immunopathogenesis of IRIS
Diagnosis of IRIS
IRIS is a highly heterogeneous condition. There is neither uniform consensus on the definition of IRIS nor definitive diagnostic test for the syndrome. Despite the proposal of a number of case definitions for IRIS, they lack specificity and can hardly cover all varieties of the syndrome. To diagnosis IRIS, it is generally accepted that there should be temporal association between initiation of ART and subsequent development of symptoms (usually within 3 months), with evidence of immune restoration (virological and immunological response demonstrated by a decrease in plasma HIV RNA level and/or an increase in CD4 cell count from baseline), and the patients must exhibit clinical symptoms and signs consistent with an inflammatory process. The International Network for the Study of HIV-associated IRIS (INSHI) has published disease specific case definitions for cryptococcal- and tuberculosis-associated IRIS in low-resource areas. To facilitate their use in resource-constrained settings, CD4 count and HIV viral load responses are not included in these definitions. These definitions are generally not used in clinical practice in developed countries. Specific consensus case definitions for other forms of IRIS are lacking.
IRIS manifests clinically either as worsening of a previously recognised disease (“paradoxical IRIS”) or emergence of an unrecognised pre-existing infection or disease process (“unmasking IRIS”) in the setting of improving immunologic function after ART initiation. Before the diagnosis of IRIS can be made, common causes of patients’ clinical deterioration must be examined. For individuals suspected to have “paradoxical IRIS”, drug toxicity arising from ART or treatment for OI should be excluded. Poor drug adherence to antimicrobials or antimicrobial drug resistance of OI can also be the cause of clinical deterioration. Other undiagnosed and new OIs should also be considered as a differential diagnosis of IRIS. The diagnosis of “unmasking IRIS” generally requires the evidence of microbiologic proof for an untreated OI and the presence of favourable immunological recovery 1-3 months after the initiation of ART.
The clinical features of IRIS vary greatly and are closely related to the type and location of preexisting OI or disease process. They are summarised in Box 17.2.
Box 17.2. Pathogens and key clinical features of associated IRIS 
|Condition||Clinical features of IRIS|
|Mycobacterium tuberculosis||Fever, lymphadenitis, new/worsening pulmonary infiltrates, pleural effusions, hepatomegaly, paradoxical or unmasking TB meningitis (TBM)/tuberculoma|
|NTM||Fever, lymphadenitis (painful/suppurative), pulmonary infiltrates and cavitation, inflammatory masses|
|BCG||Paediatric, vaccine associated; local reaction, lymphadenitis|
|Mycobacterium leprae||Typically tuberculoid or borderline forms, type 1 reactions, neuritis|
|Bartonella spp.||Granulomatous splenitis|
|Chlamydia trachomatis||Reiter’s syndrome|
|CMV||Immune recovery uveitis (usually following previous history of retinitis), retinitis (typically unmasking)|
|VZV||Dermatologic reactivation (shingles), encephalitis, transverse myelitis, stromal keratitis|
|HSV-1, HSV-2||Mucocutaneous ulceration, encephalomyelitis|
|EBV||New presentation of non-Hodgkins’s lymphoma, Burkitt’s lymphoma|
|HHV-8||Kaposi’s sarcoma- IRIS, multicentric Castleman’s disease|
|Hepatitis B, Hepatitis C||Hepatitis flare, rapidly progressive cirrhosis|
|JC virus||Paradoxical PML (clinical deterioration, progression of lesions) or unmasking PML (new diagnosis)|
|Molluscum contagiosum virus||Acute new or recurrent cutaneous papules with florid/extensive distribution|
|Parvovirus B19||Pure red cell aplasia, encephalitis|
|HPV||Warts (acute recurrence/relapse or enlargement)|
|Cryptococcus neoformans||Meningitis with raised intracranial pressure, lymphadenitis, pneumonitis, ocular and soft tissue inflammation|
|Pneumocystis jirovecii||Unmasking PCP, paradoxical deterioration during or shortly after treatment with worsening hypoxia and new pulmonary infiltrates, organizing pneumonia (rare)|
|Histoplasma spp||Acute fistulous lymphadenopathy|
|Candida spp||Typically unmasking; mucocutaneous (oral/oesophageal)|
|Tinea corporis||Inflammatory cutaneous presentation|
|Toxoplasma gondii||New or enlarging intracerebral lesions (ring-enhancing appearance on contrast neuroimaging)|
|Schistosoma mansoni||Eosinophilia, enteritis, colitis/polyposis|
|Cryptosporidium spp||Terminal ileitis, duodenitis, cholangitis, gastrointestinal ulceration|
|BCG, Bacillus Calmette-Guérin; CMV, cytomegalovirus; CNS, central nervous system; EBV, Epstein-Barr virus, HSV, Herpes simplex virus; HHV-8, Human herpes virus-8 (Kaposi’s sarcoma virus); HPV, human papilloma virus; IRIS, immune reconstitution inflammatory syndrome; JC, John Cunningham; NTM, nontuberculous mycobacteria; OI, opportunistic infection; PCP, Pneumocystis jirovecii pneumonia; PML, progressive multifocal leukoencephalopathy; TBM, tuberculosis meningitis; VZV, Varicella zoster virus.|
Presence of OI at the time of initiation of ART is a clear risk factor for the development of IRIS. Although IRIS can occur at any CD4 count, baseline CD4 count is found to play an important role in IRIS development. Low baseline CD4 count, low baseline CD4 percentage or low baseline CD4 to CD8 ratio at ART initiation has been found consistently to be a risk factor for IRIS. Apart from the baseline status, a greater increase in CD4 count or CD4 percentage and a rapid decline in HIV RNA while on ART have been found to be associated with IRIS. Box 17.3 summarises the risk factors reported to be associated with the development of IRIS following initiation of ART.
Box 17.3. Risk factors for HIV associated IRIS
|Host-related||Low CD4 count at initiation of ART|
|Opportunistic infection or TB prior to ART initiation|
|Genetic predisposition: eg, HLA-A, -B44, -DR4 (associated with herpes virus IRIS); TNFA-308*1, IL6-174*G (associated with mycobacterial IRIS)|
|Paucity of immune response at OI diagnosis (in the case of C-IRIS)|
|Pathogen-related||High pre-ART HIV viral load|
|Degree of dissemination of OI/burden of infection (eg, TB, KS, cryptococcosis)|
|Treatment-related||Shorter duration of OI treatment prior to starting ART (paradoxical IRIS)|
|Rapid suppression of HIV viral load|
|C-IRIS, cryptococcal-associated IRIS; IRIS, immune reconstitution inflammatory syndrome; KS, Kaposi’s
sarcoma; OI, opportunistic infection; TB, tuberculosis.
The timing of ART initiation in relation to the diagnosis/treatment of OI also impact the development of IRIS and is likely dependent on the presenting OI. Tuberculosis is among one of the most studied OIs. Several randomised controlled studies including the SAPiT, CAMELIA, and ACTG 5221 studies have investigated the effect of different timing of ART initiation in TB HIV Co-infected patients. The risk of TB-associated IRIS in all three studies was higher among patients randomised to receive ART earlier during TB treatment. 
Moreover, IRIS has also been found to be associated with host related factors such as certain human leucocyte antigen (HLA) profiles and regulatory cytokine gene polymorphisms which may be specific to certain pathogens.
Clinical management and prognosis
Therapeutic strategy for IRIS largely depends on the initiation or optimisation of appropriate antimicrobial treatment to control underlying causative opportunistic pathogen. It is reasonable to continue ART in majority of cases as most are mild and self-limiting, for which only supportive and symptomatic treatments are required.
Symptoms such as fever or pain can often be managed successfully with non-steroidal anti-inflammatory drugs (NSAIDs). In severe, life-threatening cases like CNS IRIS or compromised respiratory conditions, systemic corticosteroids and temporary ART interruption should be considered. The side effects associated with the use of systemic corticosteroid including the increasing risk of OI should be monitored. It is generally recommended that prednisone can be started at 1-2 mg/kg/day for 1-2 weeks, followed by dose tapering over a period that has to be individualised according to clinical response and severity of IRIS with close monitoring for recurrence of symptoms. However, corticosteroid may be harmful in Kaposi sarcoma (KS)-related IRIS due to the risk of further compromise of cellular immunity permitting HHV-8 replication and tumour growth. Other immunomodulatory therapies such as thalidomide, montelukast and TNF inhibitors have been used in the management of TB-IRIS but they have not been tested in randomised controlled studies.
Majority of patients with IRIS have a self-limiting disease course. While IRIS is not commonly associated with mortality, it usually warrants hospitalisation for further workup. Morbidity and mortality rates vary according to the pathogens and organs involved. Occasionally, severe IRIS may threaten a patient’s functional status or cause permanent disability such as neurological complications from cryptococcal meningitis and vision loss from CMV retinitis. In IRIS of OIs involving the CNS such as cryptococcal meningitis, the exuberant response in a relatively closed space can lead to significant increase in intracranial pressures (ICP), causing potentially irreversible damage. High mortality rates have been reported for cryptococcal meningitis associated IRIS.
Prevention/Prophylaxis of IRIS
Initiation of ART before the development of advanced immunosuppression can help to prevent IRIS. Careful evaluation for subclinical OI before initiation of ART will also reduce the likelihood of the occurrence of “unmasking IRIS”. After initiating ART in patients at highest risk for IRIS, including those with CD4 count < 100/μL or known concomitant OIs, signs and symptoms of IRIS should be monitored carefully and these patients should also be counselled about the risk of developing IRIS at the time of ART initiation.
For TB-IRIS, although early ART increases the risk of TB-associated IRIS in co-infected patients, this risk should be weighed against the survival benefit of early HIV treatment. Deferral of the initiation of ART in patients with higher CD4 counts has been shown to reduce the risks of IRIS without increasing the risk of AIDS or death. It is recommended that ART should ideally be initiated within the first 2 weeks of TB treatment for patients with CD4 cell counts <50/μL and by 8 weeks of TB treatment initiation for patients with CD4 cell counts ≥50/μL. Alternatively, it has been demonstrated that prednisone treatment (at a dose of 40 mg per day for 14 days, then 20 mg per day for 14 days) during the first 4 weeks after the initiation of ART in HIV-TB co-infected patients lowered incidence of tuberculosis-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers.
As cryptococcal meningitis-associated IRIS is associated with high mortality, DHHS guideline from United States suggests to delay initiation of ART at least until after completion of antifungal induction therapy (the first 2 weeks) and possibly until the total induction / consolidation phase (10 weeks) has been completed. Delay in ART may be particularly important in those with evidence of increased ICP or in those with low CSF white blood cell counts. If effective ART is to begin prior to the end of the first 10 weeks, the treating physicians should be prepared to aggressively address complications caused by IRIS, such as elevated ICP. Both EACS and WHO guidelines recommend to defer ART by 4 weeks from the initiation of antifungal treatment.
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