Immune reconstitution inflammatory syndrome and other immune reconstitution disorders

Christina C. Chang : Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne VIC
Martyn A. French : UWA Medical School and School of Biomedical Sciences, The University of Western Australia, Perth WA
 

The advent of antiretroviral therapy (ART) revolutionised the care of patients with human immunodeficiency virus (HIV) infection. However, from the late 1980s, when zidovudine monotherapy was introduced, through to the late 1990s, when combination ART became standard of care, clinicians began to recognise that some patients experienced an exacerbation of a previously treated opportunistic infection or initial presentation of a new infection despite increased CD4+ T cell counts after commencing ART.[1]. These disease episodes were characterised by exaggerated and/or atypical inflammation and involved a wide variety of opportunistic pathogens, including non-tuberculous mycobacteria (NTM), Mycobacterium tuberculosis, Pneumocystis, Cryptococcus, varicella zoster virus (VZV), John Cunningham (JC) virus and cytomegalovirus (CMV). Notably, Mycobacterium avium complex (MAC) disease was associated with the restoration of immune responses against mycobacteria. These conditions were therefore referred to as immune restoration disease to differentiate them from immunodeficiency disease, though the term immune reconstitution inflammatory syndrome (IRIS) is now more commonly used.[2]. IRIS events occur in patients who are very immunodeficient when ART is commenced, mostly in the first 6 months of therapy but may also occur in the setting of ART intensification. Importantly, IRIS is not limited to individuals with HIV but also occurs in non-HIV settings, particularly solid organ transplant and haematopoietic stem cell transplant recipients in the setting of immune recovery after withdrawal of immunosuppressant drug therapy[3], [4], and in multiple sclerosis patients who experience progressive multifocal leucoencephalopathy (PML) during natalizumab therapy and an exacerbation of PML with inflammatory features after natalizumab withdrawal[5].

Terminology and classification

An IRIS is best described in relation to the type of provoking pathogen e.g. tuberculosis-associated IRIS (TB-IRIS) or cryptococcosis-associated IRIS (C-IRIS) because the immunopathogenesis may differ for different types of pathogen. Further classification is based on the body locality or organ involved, e.g. cryptococcal meningitis IRIS (CM-IRIS), or MAC-IRIS lymphadenitis. The temporal relationship between recognition of a pathogen causing an IRIS and ART commencement is also important. Unmasking IRIS is the term used when ART unmasks a previously unrecognised infection whereas paradoxical IRIS is the term used when a previously treated opportunistic infection flares post-ART. For example, unmasking TB-IRIS is diagnosed when an ART-naive patient with no recognisable features of Mycobacterium tuberculosis infection, commences ART and soon after develops tuberculosis (TB). The term ‘ART-associated TB’ is also sometimes used if the TB is not characterised by unusual inflammation. In contrast, paradoxical CM-IRIS is said to occur when an ART-naive HIV patient presents with cryptococcal meningitis (CM), undergoes and displays improvement on CM treatment, then starts ART, after which a exacerbation of CM develops. This detailed classification system helps the clinician predict outcomes and produce a management algorithm. Furthermore, it assists in research on the immunopathogenesis of the various forms of IRIS and the development of strategies for prevention and treatment.

IRIS definitions and diagnosis

Diagnosis of an IRIS is made clinically on the basis of the temporal relationship between starting ART and disease onset, disease manifestations including exclusion of alternative diagnoses; and a fall in plasma HIV viral load (Table 1). While an increased blood CD4+ T cell count is commonly observed, it is not a prerequisite for a diagnosis of an IRIS. The major differential diagnosis is relapse of the infection that triggered the IRIS or occurrence of another infection. Clinicians should think broadly for other causes of presenting symptoms and signs. Inflammation that arises from an IRIS is not uncommonly misinterpreted as an opportunistic infection, but the process is one of restoration, rather than loss of pathogen-specific immune responses.[6] Differentiation of these conditions is essential as clinical management differs.

Diagnostic criteria for an IRIS have been proposed[7], [8], [9] but with low consensus, in part because studies have been undertaken in different geographical settings. On the other hand, consensus clinical case definitions for TB-IRIS [10] and C-IRIS[11] have been reported. Clinical case definitions for CMV immune recovery retinitis have also been proposed.[12].  However, there are no accepted diagnostic tests for an IRIS and the validity of an IRIS diagnosis may vary both in clinical practice and research studies. In research studies, an IRIS is often classified as definite, probable or possible – this approach may also be helpful in routine clinical management.

Table 1. Criteria for the diagnosis of an IRIS

Major criteria

1. Initial presentation or exacerbation of disease associated with an HIV-related infection or cancer following commencement of effective ART, especially when disease manifestations are exaggerated and/or atypical, with exclusion of recurrent or new infections and drug hypersensitivity reactions

2. Decrease in plasma HIV RNA level by >1log10 copies/mL

Minor criteria

1.  Atypical inflammatory response in affected tissues, eg.

      - Granulomas in the context of severe CD4+ T cell depletion

      - Tissue necrosis and suppuration

      - CD8+ T cell infiltrates in PML-IRIS

2.  Increased blood CD4+ T cell count after ART

3.  Increase in an immune response specific to the relevant pathogen, eg. delayed-type hypersensitivity skin test response to mycobacterial antigens

4.  Spontaneous resolution of disease without specific antimicrobial therapy or tumour chemotherapy with continuation of anti-retroviral therapy

* Diagnosis of an IRIS requires both major criteria or major criterion 1 and 2 minor criteria.

#Adapted from [13], [14], [15] 

Although research studies on the immunopathogensis of IRIS, particularly MAC-IRIS, TB-IRIS and CM-IRIS, have illuminated pathogenic mechanisms, none of the abnormalties demonstrated so far have led to the development of laboratory assays that can you be used to predict or diagnose an IRIS.  

Immunopathogenesis of an IRIS

An IRIS is an undesirable outcome of restoring immune responses against an active (sometimes unrecognised) infection by an opportunistic pathogen or antigens of non-viable pathogens remaining after treatment of the infection.[16] The strongest risk factors for an IRIS are a low CD4+ T cell count (usually <50/mL) and a high pathogen load[17][18][19] The latter is a consequence of decreased pathogen-specific immune responses associated with severe CD4+ T cell deficiency as well as depletion and/or dysfunction of other immune cells, which include B cells in the case of C-IRIS.[20] with mycobacterial and fungal IRIS being associated with granulomatous and/or suppurative inflammation, while tissue inflammation in an IRIS associated with infections by viruses, such as herpes simplex virus (HSV) or JC virus, is usually characterised by CD8+ T-cell infiltration. The immunopathogenesis of IRIS is reviewed elsewhere[21][22] and knowledge about this has been increased by recent research studies.

The majority of research has been undertaken on mycobacterial and cryptococcal IRIS and has provided information about mechanisms of inflammation that have contributed to the deveolpment of novel therapies for mycobacterial IRIS. TB-IRIS and MAC-IRIS are associated with an increase in the frequency of pathogen-specific CD4+ T cells producing multiple cytokines (interferon-gamma, tumour necrosis factor and interleukin-2) and with cytotoxic activity[23]; [24]. An increase in pathogen-specific T cell responses has not been demonstated in C-IRIS[25], though this was examined using whole blood interferon gamma reaease assays. There is also convincing evidence that activation of monocytes and neutrophils contributes to the immunopathology of TB-IRIS, particularly through activation of monocyte inflammasome pathways [26], [27], [28], MAC-IRIS[29] and C-IRIS {ref}Chang CC, Omarjee S, Lim A et al. Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patients with cryptococcal meningitis and cryptococcosis-associated immune reconstitution inflammatory syndrome. J Infect Dis. 2013;208:1604-12.{/ref}; [30]. It therefore appears that an IRIS associated with mycobacterial and cryptococcal infections reflects the restoration of diverse cellular immune responses with pro-inflammatory activity against pathogens, which generates an exaggerated inflammatory response.

Clinical presentation of an IRIS

An IRIS mostly occurs between 2 weeks and 3 months after ART commencement or ART intensification, but may occur earlier (within days) and as late as a year after treatment. Temporal onset of an IRIS is particularly difficult to attribute in patients with erratic ART adherence. Typically, patients with a very low CD4+ T cell count when ART is commenced, present with fever and clinical manifestations suggestive of an opportunistic infection or cancer, which often exhibit atypical characteristics. Practically any chronic viral, mycobacterial, fungal or protozoan infection that is usually controlled by cellular immune responses may be associated with an IRIS (Table 2). Further information on clinical characteristics of different types of IRIS is available elsewhere.[31] and showed reduction in a combined endpoint of duration of hospitalisation and number of procedures, and improvement in symptoms and wellbeing but increased concurrent infections and glucocorticoid reactions. In PML-IRIS, corticosteroid therapy has been reported to be effective in individual cases[32]  but overall, there is insufficient evidence to recommend routine use. Results of randomised controlled trials of corticosteroid therapy for the treatment of PML-IRIS are needed. 

Of note, as some IRIS manifestations may be very protracted and also recur, patience in the use of corticosteroid therapy is necessary. Some manifestations notoriously recur in the setting of decreased corticosteroid dosing, thus often resulting in extremely long durations of therapy and its accompanying risks, including immunosuppression. In this setting, blockade of tumour necrosis factor (TNF) activity through the use of monoclonal antibodies to TNF has been shown to be effective in MAC- and TB-IRIS in case reports.[33]

Surgical measures are occasionally necessary, such as drainage or excision of large lymph nodes or abscesses in mycobacterial-IRIS).

Prevention of an IRIS

Given that severe CD4+ T cell deficiency when ART is commenced is a risk factor for an IRIS, prevention of CD4+ T cell depletion through early diagnosis and treatment of HIV infection regardless of CD4+ T cell count, as supported by the findings of the START study[34] is the most effective measure for reducing the risk of developing an IRIS. However, 'late presenters' with advanced immunodeficiency continue to present and they must be assessed carefully for HIV-related infections that might trigger an IRIS when ART is commenced. Those patients without obvious signs or symptoms of an HIV-related infection should be screened for a subclinical infection. At a minimum, a chest x-ray and assay of serum for cryptococcal antigen and HBV surface antigen should be performed.

Decisions about the optimal timing of ART commencement in patients with an established HIV-related infection should take into consideration the CD4+ T cell count and the site of infection. In general, commencement of ART early in the course of therapy for the infection is recommended, particularly when the CD4+ T cell count is <50/mL[35][36]. Several studies examining the timing of ART commencement in the setting of pulmonary TB have also produced results favouring early commencement of ART[37][38][39]. The survival benefit seen in early ART commencement is best seen in patients with CD4+ T cell counts <50/μL.{ref}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 meta-analysis. Ann Intern Med 2015;163:32-9{/ref}. However, deferrment of ART to optimally treat the TB and reduce the risk of TB-IRIS is reasonable in patients with relatively preserved CD4+ T cell counts (>220/μL)[40]

Special consideration must be given to the timing of ART commencement in patients with an opportunistic infection of the CNS because inflammation resulting from an IRIS in this site carries a particularly high risk of morbidity and mortality. Thus, deferrment of ART is recommended in HIV patients with TB meningitis.[41] and in the setting of CM, randomised studies suggest ART should be deferred until >10 days post CM diagnosis.[42][43][44]. In PML, deferrment of ART is usually not an issue because it is the only therapy that may be effective for this condition. There is insufficient evidence to make recommendations about the optimal timing of ART commencement in patients with Toxoplasma encephalitis.

As well as timing of ART, the ART regimen used also has some special consideration. Patients with HBV infection should receive an ART regimen that includes nucleos(t)ide analogues with activity against both HIV and HBV to minimise the risk of a hepatitis flare (HBV-IRIS). Integrase strand inhibitors have been reported to be associated with an increased risk of developing an IRIS in observational studies[45], [46]. This class of antiretroviral drugs should therefore be used with caution in patients who have severe CD4+ T cell depletion and an active HIV-related infection or cancer until the findings of randomised controlled trials become availalble. Inclusion of maraviroc in the ART regimen of patients commencing ART with a CD4+ T cell count of <100/μL was explored as a means of preventing an IRIS in the CADIRIS study [47] but was ineffective.

Autoimmune disease and immune-mediated inflammatory disease in patients receiving ART

Autoimmune diseases and immune-mediated inflammatory diseases may also be encountered in patients receiving ART[48]and many appear to be immune reconstitution disorders. Pathogenic mechanisms, however, are distinct from those in an IRIS associated with HIV-related infections or cancers. Psoriasis, sarcoidosis, rheumatoid arthritis, ankylosing spondyloarthritis, Grave's disease, autoimmune hemolytic anemia, immune thrombocytopenia and inflammatory bowel disease are most common whereas systemic lupus erythematosus and multiple sclerosis are rarely encountered. Graves’ disease is encountered mostly in patients who commence ART at very low CD4+ T cell counts and in contrast to the many types of IRIS, presents at a median time of 21 months after starting ART[49] It appears to be a consequence of an acquired disorder of central immune tolerance[50]. Sarcoidosis may present in HIV patients not receiving ART but is much more common after commencement of ART. It is also more common in patients who have received interferon-alpha or interleukin-2 therapy. Taken together, these characteristics suggest that sarcoidosis in HIV patients is the result of an acquired disorder of immune regulation that leads to a granulomatous inflammatory response against unknown antigens. From a clinical perspective, it is important to differentiate sarcoidosis from an IRIS associated with a mycobacterial or fungal pathogen, which may also present with granulomatous tissue inflammation[51] Sarcoidosis in HIV patients may affect various body sites including lungs, lymph nodes and skin.

 

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French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004;18:1615-27 
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Robertson J, Meier M, Wall J et al. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis. 2006;42:1639-46. 
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Haddow LJ, Easterbrook PJ, Mosam A et al. Defining Immune Reconstitution Inflammatory Syndrome: Evaluation of Expert Opinion versus 2 Case Definitions in a South African Cohort. Clin Infect Dis 2009;9:1424-1432. 
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French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004;18:1615-27 
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French MA. Immune reconstitution inflammatory syndrome: immune restoration disease 20 years on. Med J Aust 2012;196:318-21 
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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. 2018 Jul 16. doi: 10.1093/infdis/jiy447. [Epub ahead of print]. The disease-causing inflammatory response in an IRIS is largely determined by the provoking pathogen.{ref}French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009;48:101-7 
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Chang CC, Lim A, Omarjee S, et al. Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-gamma responses before antiretroviral therapy but not higher T-cell responses during therapy. J Infect Dis 2013;208:898-906 
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Andrade BB, Singh A, Narendran G, et al. Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome. PLoS Pathog 2014;10:e1004433 
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Table 2. The most common types of immune reconstitution inflammatory syndrome that may occur in very immunodeficient HIV patients after commencing ART*

Pathogens associated with an IRIS resulting from restoration immune responses against that pathogen Clinical characteristics Common abbreviations

Mycobacteria

Mycobacterium avium complex Initial presentation or exacerbation of MAC disease, eg. fever, lymphadenitis MAC-IRIS
Mycobacterium tuberculosis Initial presentation or exacerbation of TB, eg. fever, lymphadenitis, pneumonitis, pleural or pericardial effusions, meningoencephalitis TB-IRIS or TBM-IRIS when meningitis is the only clinical manifestation
Bacille Calmette-Guerin Regional lymphadenitis BCG-IRIS

Fungi

Cryptococcus neoformans Initial presentation or exacerbation of cryptococcal meningoencephalitis C-IRIS or CM-IRIS when meningitis is the only clinical manifestation
Pneumocystis jirovecii Exacerbation of pneumonitis P-IRIS

Viruses

Cytomegalovirus CMV retinitis presenting after commencement of ART CMV immune recovery retinitis
Uveitis after previously treated CMV retinitis

IRU (immune recovery uveitis)

Kaposi’s sarcoma-associated herpesvirus

Initial presentation or exacerbation of KS

KS-IRIS
Varicella zoster virus Dermatomal or multidermatomal zoster
  Rarely, myelitis or encephalitis  
Herpes simplex virus Genital or oral herpes with atypical inflammation
  Rarely, myelitis or encephalitis  
JC virus Initial presentation or exacerbation of PML with inflammatory characteristics PML-IRIS
Hepatitis B virus Hepatitis flare HBV-IRIS
Hepatitis C virus Hepatitis flare HCV-IRIS

Protozoa

Toxoplasma gondii Initial presentation or exacerbation of Toxoplasma encephalitis  TE-IRIS
 

Uncertain pathogens

 
  Lymphoma presentation after commencing ART  
  • Many other pathogens have also been associated with the development of an IRIS. 

General approach to the management of an IRIS

For patients with a suspected paradoxical IRIS, the initial consideration is exclusion of a recurrence of the associated infection or development of a new infection. For example, when suspecting paradoxical TB-IRIS, considerations should include non-adherence to TB medications, infection with drug-resistant mycobacteria, new community-acquired pneumonia, PJP and viral infections. Investigations should include sputum microscopy and culture for bacterial and mycobacterial infection, chest X-ray or CT scan of chest or both. Similarly, a patient being considered for paradoxical CM-IRIS, should have a CT scan of brain and lumbar puncture to measure the opening pressure and obtain CSF to determine cell counts and to culture for bacteria, mycobacteria and fungi. When evaluating cultures, it is important to note that while cultures are often negative in an IRIS (in keeping with the concept that non-viable organisms may be antigenic and provoke an immune response), the presence of a positive culture does not exclude an IRIS, as viable pathogens are clearly also antigenic.

After the exclusion of alternative diagnoses, symptomatic management of an IRIS is usually sufficient. For example, therapeutic lumbar punctures and non-steroidal anti-inflammatory drugs often relieve symptoms in paradoxical CM-IRIS. Escalation of antimicrobial therapy is only necessary when there is a clear microbiological relapse of the infection. Importantly, ART should not be ceased unless the patient's condition becomes critical. While many clinicians consider the use of corticosteroid therapy for an IRIS, the evidence for use of this therapy is not strong and it should only be considered in cases of severe symptomatic IRIS refractory to simple measures. A randomised placebo-controlled trial in South Africa, used 4 weeks of prednisolone (1.5 mg then 0.75 mg/kg/day) in patients with paradoxical pulmonary TB-IRIS,{ref}Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381-90 

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