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Immune reconstitution inflammatory syndrome in HIV-infected patients.

Walker NF, Scriven J, Meintjes G, Wilkinson RJ - HIV AIDS (Auckl) (2015)

Bottom Line: While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal.Timing of ART initiation is critical to reduce IRIS-associated morbidity.Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London, London, UK ; Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa ; Department of Medicine, University of Cape Town, Cape Town, South Africa.

ABSTRACT
Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.

No MeSH data available.


Related in: MedlinePlus

A conceptual model of immune reconstitution inflammatory syndrome (IRIS) pathophysiology with three key features represented in central rectangles.Notes: Excess antigen is a feature of tuberculosis (TB) IRIS, cryptococcal IRIS and Kaposi’s sarcoma IRIS. This may result from extreme immunosuppression prior to antiretroviral therapy (ART) initiation, which increases the risk of opportunistic infection (OI) dissemination (in TB), and is associated with paucity of inflammation in cryptococcal meningitis (CM), especially in those patients who go on to develop IRIS. Antigen is likely to be more abundant if the OI is untreated, or if treatment has recently started. Immune cell dysfunction following ART has been described in IRIS, although the mechanism of this is incompletely understood. It may involve uncoupling of innate and acquired immune responses, restoration of exuberant pathogen-specific cellular responses, and defective or delayed regulatory responses. An excess of proinflammatory cytokines has been associated with TB-IRIS, and cryptococcal IRIS, in blood and cerebrospinal fluid. Possible relationships between the three key components are depicted by differentially weighted arrows. However, the direction of causality is not clear. It is probable that the presence of high antigen in IRIS drives proinflammatory cytokine responses directly through stimulation of innate immune responses and indirectly when adaptive immunity recovers. Further studies are required to improve understanding of these interactions.
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f2-hiv-7-049: A conceptual model of immune reconstitution inflammatory syndrome (IRIS) pathophysiology with three key features represented in central rectangles.Notes: Excess antigen is a feature of tuberculosis (TB) IRIS, cryptococcal IRIS and Kaposi’s sarcoma IRIS. This may result from extreme immunosuppression prior to antiretroviral therapy (ART) initiation, which increases the risk of opportunistic infection (OI) dissemination (in TB), and is associated with paucity of inflammation in cryptococcal meningitis (CM), especially in those patients who go on to develop IRIS. Antigen is likely to be more abundant if the OI is untreated, or if treatment has recently started. Immune cell dysfunction following ART has been described in IRIS, although the mechanism of this is incompletely understood. It may involve uncoupling of innate and acquired immune responses, restoration of exuberant pathogen-specific cellular responses, and defective or delayed regulatory responses. An excess of proinflammatory cytokines has been associated with TB-IRIS, and cryptococcal IRIS, in blood and cerebrospinal fluid. Possible relationships between the three key components are depicted by differentially weighted arrows. However, the direction of causality is not clear. It is probable that the presence of high antigen in IRIS drives proinflammatory cytokine responses directly through stimulation of innate immune responses and indirectly when adaptive immunity recovers. Further studies are required to improve understanding of these interactions.

Mentions: In summary, recent evidence suggests that innate immune dysfunction in the context of high antigen load plays a role in driving pathological proinflammatory responses in IRIS. The role of pathogen-specific cell-mediated immunity and regulatory mechanisms are less clear (see Figure 2). Studies of patients are frequently limited by small sample size and examination of peripheral blood rather than tissue immune responses. Development of animal models of IRIS may better allow dissection of precise pathophysiological mechanisms, which may differ for paradoxical and unmasking IRIS, and for different forms of pathogen-associated IRIS.75


Immune reconstitution inflammatory syndrome in HIV-infected patients.

Walker NF, Scriven J, Meintjes G, Wilkinson RJ - HIV AIDS (Auckl) (2015)

A conceptual model of immune reconstitution inflammatory syndrome (IRIS) pathophysiology with three key features represented in central rectangles.Notes: Excess antigen is a feature of tuberculosis (TB) IRIS, cryptococcal IRIS and Kaposi’s sarcoma IRIS. This may result from extreme immunosuppression prior to antiretroviral therapy (ART) initiation, which increases the risk of opportunistic infection (OI) dissemination (in TB), and is associated with paucity of inflammation in cryptococcal meningitis (CM), especially in those patients who go on to develop IRIS. Antigen is likely to be more abundant if the OI is untreated, or if treatment has recently started. Immune cell dysfunction following ART has been described in IRIS, although the mechanism of this is incompletely understood. It may involve uncoupling of innate and acquired immune responses, restoration of exuberant pathogen-specific cellular responses, and defective or delayed regulatory responses. An excess of proinflammatory cytokines has been associated with TB-IRIS, and cryptococcal IRIS, in blood and cerebrospinal fluid. Possible relationships between the three key components are depicted by differentially weighted arrows. However, the direction of causality is not clear. It is probable that the presence of high antigen in IRIS drives proinflammatory cytokine responses directly through stimulation of innate immune responses and indirectly when adaptive immunity recovers. Further studies are required to improve understanding of these interactions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334287&req=5

f2-hiv-7-049: A conceptual model of immune reconstitution inflammatory syndrome (IRIS) pathophysiology with three key features represented in central rectangles.Notes: Excess antigen is a feature of tuberculosis (TB) IRIS, cryptococcal IRIS and Kaposi’s sarcoma IRIS. This may result from extreme immunosuppression prior to antiretroviral therapy (ART) initiation, which increases the risk of opportunistic infection (OI) dissemination (in TB), and is associated with paucity of inflammation in cryptococcal meningitis (CM), especially in those patients who go on to develop IRIS. Antigen is likely to be more abundant if the OI is untreated, or if treatment has recently started. Immune cell dysfunction following ART has been described in IRIS, although the mechanism of this is incompletely understood. It may involve uncoupling of innate and acquired immune responses, restoration of exuberant pathogen-specific cellular responses, and defective or delayed regulatory responses. An excess of proinflammatory cytokines has been associated with TB-IRIS, and cryptococcal IRIS, in blood and cerebrospinal fluid. Possible relationships between the three key components are depicted by differentially weighted arrows. However, the direction of causality is not clear. It is probable that the presence of high antigen in IRIS drives proinflammatory cytokine responses directly through stimulation of innate immune responses and indirectly when adaptive immunity recovers. Further studies are required to improve understanding of these interactions.
Mentions: In summary, recent evidence suggests that innate immune dysfunction in the context of high antigen load plays a role in driving pathological proinflammatory responses in IRIS. The role of pathogen-specific cell-mediated immunity and regulatory mechanisms are less clear (see Figure 2). Studies of patients are frequently limited by small sample size and examination of peripheral blood rather than tissue immune responses. Development of animal models of IRIS may better allow dissection of precise pathophysiological mechanisms, which may differ for paradoxical and unmasking IRIS, and for different forms of pathogen-associated IRIS.75

Bottom Line: While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal.Timing of ART initiation is critical to reduce IRIS-associated morbidity.Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London, London, UK ; Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa ; Department of Medicine, University of Cape Town, Cape Town, South Africa.

ABSTRACT
Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.

No MeSH data available.


Related in: MedlinePlus