Immune reconstitution inflammatory syndrome

INTRODUCTION

The introduction of antiretroviral therapy (ART) has led to improved outcomes for individuals with HIV infection. A reduction in HIV viral replication is followed by a recovery of CD4+ T cell lymphocyte numbers and at least a partial restoration of overall immune function and a reduction in the frequency of opportunistic infection. ¹ This process is known as immune reconstitution. However, since the introduction of ART it has been observed that some individuals experience a clinical deterioration despite apparent virological and immunological response to therapy. This was first noted following the introduction of zidovudine monotherapy in the early-1990s, when atypical forms of Mycobacterium avium complex (MAC) causing painful and extensive lymphadenitis were observed in association with the recovery rather than failure of cellular immune responses. ² Following the introduction of combination ART, symptomatic deterioration in some treated individuals has been described in relation to a number of pre-existing subclinical infections, inflammatory disorders and autoimmune diseases. This phenomenon is now well-recognized and thought to be related to a disorder of immune reconstitution after ART initiation resulting in a pathological inflammatory process.

TERMINOLOGY AND DEFINITIONS

Various terms have been used to describe this disorder including immune reconstitution syndrome, immune restoration disease and immune reconstitution inflammatory syndrome (IRIS). ^3–5 This terminology has been used interchangeably and refers to the same broad underlying process referred to as IRIS here.

IRIS is best considered as a group of disorders occurring after some degree of immune restoration, and incorporates disease resulting from pathological inflammation to pathogens and their antigens, immune-mediated inflammatory disease and autoimmune disease. ^5,6 It is distinct from the development of new opportunistic infection, which is a function of immune deficiency rather than restoration.

There is no gold standard definition of IRIS. However, it is generally accepted that in order to diagnose IRIS, certain minimum criteria should be met. The individual must be HIV-positive receiving ART with virological and immunological response (measured by a decrease in HIV RNA level and an increase in CD4+ T cell count from baseline) and must exhibit clinical symptoms and signs consistent with an inflammatory process, which is neither consistent with the usual course of an established infection or a new infectious process; nor should the symptoms and signs be explained by drug toxicity. More exclusive case definitions have been proposed, ⁵ however, most definitions are limited by a lack of specificity.

INFECTIONS AND IRIS

IRIS can be provoked by infections. The inflammatory response may be to viable pathogens or to the antigens of non-viable pathogens. There are two main recognized patterns of disease. The first, frequently termed ‘unmasking disease’ or ‘unmasking IRIS’ can be considered as an immune response against a pathogen that was not causing overt disease before ART was introduced. Unmasking disease usually involves viable pathogens. The second is referred to as ‘paradoxical disease’ or ‘paradoxical IRIS’. Here, the infection is known (and appropriately treated) but there is deterioration when ART is commenced. This may be a response to living pathogens or a response to the antigens of non-viable pathogens.

When IRIS is provoked by pathogens it usually becomes apparent within the first three months, but is recognized to occur up to 24 months from ART introduction. IRIS occurring within three months is usually precipitated by a reaction to viable organisms, whereas later presentations are commonly a reaction to persisting antigens of non-viable pathogens. Clinical manifestations vary depending on the pathogen involved and some of the more frequently encountered are summarized in Table 1.

Among the most commonly reported infectious precipitant of IRIS is Mycobacterium tuberculosis. TB-IRIS most commonly presents as paradoxical disease occurring in patients who are improving on anti-tuberculous therapy. It usually presents within the first two months and commonly in the first two to three weeks of ART. Patients experience recurrence or worsening of constitutional symptoms, such as high fever and enlargement of nodes, which may become suppurative; and is often accompanied by worsening chest radiographic appearances. ^7–9 Central nervous system (CNS) involvement is associated with severe illness. IRIS precipitated by MAC presents atypically as localized inflammatory disease with high fever, in contrast to the disseminated disease typically seen in immunocompromised patients not receiving ART. ^7,10,11 MAC-IRIS usually presents within the first three months of ART and both unmasking and paradoxical forms are recognized. ⁵ Cryptococcal IRIS can represent unmasking or paradoxical recurrent disease. It most commonly presents as recurrent meningitis with neuroimaging suggestive of inflammation and inflammatory cerebrospinal fluid (CSF) (which is typically culture negative), however, it may present atypically many months after highly active antiretroviral therapy (HAART) initiation (and prior antifungal therapy). ^12,13 Genital ulceration resulting from the presence of herpes simplex virus and genital warts related to human papillomavirus have been found by a recent retrospective study to be among the most common presentations of IRIS, ¹⁴ and are likely to occur more frequently and be more severe in this context. ^15,16 Herpes zoster IRIS usually results in uncomplicated mono-dermatomal disease but also occurs more frequently in patients receiving ART than would be expected. ^17,18 Eye disease is the most common presentation of cytomegalovirus (CMV) IRIS. It can present as new or recurrent retinitis, usually within the first three months of ART. ^5,19 In addition, ‘immune recovery uveitis’ associated with previous CMV retinitis is a well-recognized form of IRIS, which more commonly presents months later, and involves vitritis, papillitis, macular oedema. ²⁰ IRIS provoked by hepatitis B and C viruses may be characterized by hepatitic flare; ²¹ rapid progression of cirrhosis has been recognized but is rare. ²² Progressive multifocal leukoencephalopathy (PML)-IRIS presents either as paradoxical or unmasking disease associated with marked inflammatory changes on histology and neuroimaging. ^6,23

While the majority of cases of IRIS are precipitated by infection it is important to recognize and differentiate these from other forms of IRIS, such as immune-mediated inflammatory disease and autoimmune diseases.

IMMUNE-MEDIATED INFLAMMATORY DISEASE AND IRIS

Granulomatous inflammation affecting the lung and other organs, closely resembling sarcoidosis, has been described in patients responding to HAART. The pathogenesis of this inflammatory process appears distinct from sarcoidosis occurring in HIV-positive individuals not receiving HAART and is recognized as a form of IRIS. ^24,25

AUTOIMMUNE DISEASE AND IRIS

Patients may present with autoimmune disease when receiving and responding to HAART. This may be a new presentation of autoimmune disease or an exacerbation of the existing disease. Graves' disease is a well-recognized, albeit uncommon, manifestation of IRIS. ²⁶ It has been suggested that appearance of other autoimmune conditions such as systemic lupus erythematosus, ²⁷ polymyositis, ²⁸ rheumatoid arthritis, ²⁹ and Guillain Barre ³⁰ also represent IRIS.

PATHOGENESIS

The pathogenesis of IRIS is poorly understood. The clinical features suggest an excessive immune response. However, the cellular and immunological pathway is not universal and the various manifestations of IRIS appear to be driven by differing mechanisms. IRIS related to infections seems to be precipitated by a restoration of specific immune responses to the pathogen and/or its antigens. This was first noted in the context of atypical MAC disease after ART, which was characterized by granulomatous inflammation and a restoration of cutaneous delayed type hypersensitivity (DTH) responses to mycobacterial antigens. ² TB-IRIS also appears to be precipitated by an antigen-specific type 1 cellular response; and in addition to restoration of DTH responses to intradermal mycobacterial antigens, ⁹ a salient finding has been a high number of CD4+ T cells specific for purified protein derivative producing interferon-γ. ³¹ When IRIS is precipitated by viral pathogens the immune pathway may be different, for example in the context of PML-IRIS there appears to be a predominance of CD8+ T cells. ³² Immune-mediated inflammatory disease IRIS is characterized by granulomatous inflammation with a CD4+ T cell infiltrate, ^24,25 in contrast to the predominance of CD8 T-cells in HIV-associated sarcoidosis occurring in patients not on ART. ³³ The precipitants in this process and in autoimmune disease IRIS are unclear. The immune responses leading to all forms of IRIS not only appear excessive but also unregulated. It has been suggested that both the numbers and function of regulatory T cells are compromised in HIV and restoration of both following ART may be delayed, leading to defective regulatory immune mechanisms and uncontrolled antigen-specific responses. ³⁴ Further studies in this field are required.

It has been proposed that the pathogenesis of IRIS is a complex interaction between a precipitant and host factors including genetic and immune factors. ⁵ Certain risk factors for infection-related IRIS have been identified that may be used to predict its development.

RISK FACTORS

Active or subclinical opportunistic infection or presence of non-viable pathogens and/or their antigens are clear risk factors for the development of IRIS. Disseminated infection before initiation of ART has been demonstrated to be associated with increased risk of development of IRIS in patients with TB ^35,36 and cryptococcal disease. ³⁷ In addition, a low CD4 T-cell count, below 50 × 10⁶ cells/L, appears to be a major risk factor for both. ^37–39 It has been proposed that low CD4+ T-cell counts may reflect a high pathogen load and/or an increased propensity to immune dysregulation during immune reconstitution. ⁵ In contrast, studies have not consistently demonstrated a clear relationship between the baseline viral load and development of IRIS. The time interval between the diagnosis (and treatment) of opportunistic infection and the initiation of ART also appears important. In the context of TB-IRIS, a clear relationship exists with a much higher risk of IRIS development with a shorter time interval. ^36,38,40 In one study there was an almost 70-fold increase in risk when ART was commenced within 30 days of TB diagnosis compared with >90 days. ³⁸ There may also be a genetic predisposition: certain genes are thought to be associated with an increased susceptibility to the development of IRIS in the presence of mycobacteria and to herpes viruses. ^5,41 The combination of a patient with a disseminated infection, a low baseline CD4 T-cell count and the early initiation of ART appears particularly to be at high risk for development of IRIS.

INCIDENCE OF IRIS

Studies have demonstrated that 10–32% of patients initiating ART will develop IRIS. ^14,17,39,40 Rates of paradoxical IRIS occurring in patients with TB receiving ART have been reported between 8% and 43%, ^{9,35,36,40,42} and for paradoxical IRIS in cryptococcal disease, between 8% and 50%. ^12,13,37 The differing rates reported reflect differences in case definitions, differing study design, and perhaps most importantly, differences in study populations with differing risk profiles. Incidence rates may vary across different settings.

PROGNOSIS

In the majority of patients IRIS is self-limiting, however, outcomes vary from minimal morbidity to fatality. Mortality associated with IRIS is relatively uncommon. In the largest three retrospective studies, most of the diagnoses of IRIS represented cutaneous or genital disease and two deaths were reported in a combined total of 142 patients with IRIS. ^14,17,43 Mortality rates of individuals with IRIS associated with infections vary according to the pathogen and organs involved, for example high mortality rates are reported for cryptococcal and TB-IRIS affecting the central nervous system. ^44,45 Mortality rates among patients with mycobacterial disease and IRIS in general, appear to be relatively low. ^38,40 However, it may be that outside of research settings these rates are higher. Despite low mortality rates, morbidity associated with IRIS can be considerable for the individual patient and IRIS is associated with increased rates of hospitalization, ^40,46 and is likely to pose a significant burden to health-care facilities particularly in resource-poor settings.

PREVENTION

Given the above risk profile it is generally recommended that ART is commenced before the onset of severe immunodeficiency and after the identification and treatment of opportunistic infections. Thorough screening for opportunistic infections should be performed before ART initiation. Individuals with high risk features for the development of IRIS should be identified. In clinical practice it is not always possible or practical to prevent IRIS. In the presence of opportunistic infection, the benefit of reducing the likelihood of IRIS by deferring ART must be balanced with the risk of delaying ART, particularly in patients with advanced immunosuppression. In the case of HIV-TB co-infection, we defer to guidelines produced by the British HIV Association (BHIVA) concerning the time of ART initiation following anti-tuberculous therapy. ⁴⁷ The optimal time for ART initiation following treatment of other opportunistic infection is unclear.

MANAGEMENT

There are no prospective trials concerning the management of IRIS in any of its forms, and guidance on its management is derived from evidence of case series and expert opinion. Key to management is accurate diagnosis and alternative diagnoses such as drug toxicity and new infection should be systematically excluded. If IRIS has been provoked by an opportunistic infection, this should be optimally treated. Non-steroidal anti-inflammatory agents and corticosteroids have been used widely in patients with IRIS to control the inflammatory response, particularly in those with severe manifestations. However, there are no randomized controlled trails to show how safe and effective this approach is and the risks of steroid-induced immunosuppression (particularly if there is diagnostic doubt) and adverse effects should be considered. It is generally accepted that ART should be continued wherever possible, unless IRIS causes severe illness and/or becomes life-threatening. ART interruption will lead to increased risk of additional opportunistic infection and IRIS may occur upon its re-introduction. Management should be considered on an individual patient basis.

CONCLUSION

Paradigms in HIV management change and as current guidelines advise an earlier commencement of ART, we may see fewer patients presenting with this syndrome. Nevertheless, we also have data to suggest that increasing proportions are seen as late presenters particularly in the resource-poor settings. These patients will still pose a major challenge and strain on resource-poor health systems with poor diagnostic and therapeutic facilities. The burden of IRIS, largely, seems to be on fungal and mycobacterial disease and as we develop a better understanding of the pathological process we need better diagnostic tools for these infections. This together with better predictive criteria and therapeutic options will allow us to better manage this complex condition.