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The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum.

ABSTRACT: Cryptococcal meningitis causes significant mortality among HIV-infected patients, despite antifungal therapy and use of antiretroviral therapy (ART). In patients with cryptococcal meningitis, ART is often complicated by immune reconstitution inflammatory syndrome (IRIS), manifesting as unmasking of previously unrecognized subclinical infection (unmasking CM-IRIS) or paradoxical worsening of symptoms in the central nervous system after prior improvement with antifungal therapy (paradoxical CM-IRIS). We review our current understanding of the pathogenesis of this phenomenon, focusing on unifying innate and adaptive immune mechanisms leading to the development of this often fatal syndrome.We propose that HIV-associated CD4 T-cell depletion, chemokine-driven trafficking of monocytes into cerebrospinal fluid in response to cryptococcal meningitis, and poor localized innate cytokine responses lead to inadequate cryptococcal killing and clearance of the fungus. Subsequent ART-associated recovery of T-cell signaling and restored cytokine responses, characterized by IFN-? production, triggers an inflammatory response. The inflammatory response triggered by ART is dysregulated because of impaired homeostatic and regulatory mechanisms, culminating in the development of CM-IRIS.Despite our incomplete understanding of the immunopathogenesis of CM-IRIS, emerging data exploring innate and adaptive immune responses could be exploited to predict, prevent and manage CM-IRIS and associated morbid consequences.

SUBMITTER: Meya DB

PROVIDER: S-EPMC4689618 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum.

Meya David B DB Manabe Yukari C YC Boulware David R DR Janoff Edward N EN

Current opinion in infectious diseases 20160201 1

<h4>Purpose of review</h4>Cryptococcal meningitis causes significant mortality among HIV-infected patients, despite antifungal therapy and use of antiretroviral therapy (ART). In patients with cryptococcal meningitis, ART is often complicated by immune reconstitution inflammatory syndrome (IRIS), manifesting as unmasking of previously unrecognized subclinical infection (unmasking CM-IRIS) or paradoxical worsening of symptoms in the central nervous system after prior improvement with antifungal t ...[more]

PMID: 26658650

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Project description:BackgroundCryptococcal meningitis remains the leading cause of adult meningitis in Sub-Saharan Africa. Immune Reconstitution Inflammatory Syndrome (IRIS) following anti-retroviral therapy (ART) initiation is an important complication. Here we report the first documented case of a IRIS reaction presenting as an ischemic stroke.Case presentationA 38 year old newly diagnosed HIV-infected, ART naive Malawian male presented to a tertiary referral hospital in Blantyre, Malawi with a 2 week history of headache. A diagnosis of cryptococcal meningitis was made and the patient was started on 1200 mg fluconazole once daily and flucytosine 25 mg/kg four times daily as part of the Advancing Cryptococcal Treatment for Africa (ACTA) clinical trial. There was an initial clinical and microbiological response to anti-fungal treatment and anti-retroviral therapy was started at week 4. The patient re-presented 16 days later with recurrence of headache, fever, and a sudden onset of left sided weakness in the context of rapid immune reconstitution; peripheral CD4 count had increased from a baseline of 29 cells/?l to 198 cells/?l. Recurrence of cryptococcal meningitis was excluded through CSF examination and fungal culture. Magnetic Resonance Imaging (MRI) of the brain demonstrated multi-focal DWI (diffusion weighted imaging) positive lesions consistent with an ischemic stroke. Given the temporal relationship to ART initiation, these MRI findings in the context of sterile CSF with raised CSF protein and a rapid immune reconstitution, following an earlier favorable response to treatment is most consistent with a paradoxical Immune Reconstitution Inflammatory Syndrome.ConclusionsStroke is an increasing cause of morbidity and mortality amongst HIV infected persons. Ischemic stroke is a recognized complication of cryptococcal meningitis in the acute phase and is thought to be mediated by an infectious vasculitis. This is the first time an ischemic stroke has been described as part of a paradoxical IRIS reaction. This report adds to the spectrum of clinical IRIS presentations recognized and highlights to clinicians the potential complications encountered at ART initiation in severely immunocompromised patients.

Project description:Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-?, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p?0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001).Pre-ART increases in Th(17) and Th(2) responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-?, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.

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The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum.

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The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum.

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