Plasma But Not Cerebrospinal Fluid Interleukin 7 and Interleukin 5 Levels Pre-Antiretroviral Therapy Commencement Predict Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome.

BACKGROUND: Patients with human immunodeficiency virus/AIDS-associated cryptococcal meningitis (CM) frequently experience clinical deterioration, known as cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), upon initiation of antiretroviral therapy (ART). The immunological mechanisms underlying C-IRIS are incompletely defined and no reliable predictive biomarkers exist. We investigated whether plasma or cerebrospinal fluid (CSF) levels of cytokines and chemokines predicted C-IRIS and are potential predictive biomarkers. METHODS: Patients with CM who experienced C-IRIS (N = 27) upon ART initiation were compared to CD4+ T-cell count-matched patients without C-IRIS (N = 27). Plasma and CSF collected pre-ART were assayed for cytokines and chemokines using a 17-plex Luminex kit or enzyme-linked immunosorbent assay. Cox proportional hazards regression and principal component analyses were also performed. RESULTS: Plasma interleukin (IL) 2, IL-4, IL-5, IL-7, IL-17, interferon-γ, and tumor necrosis factor-α levels were higher in C-IRIS patients compared to controls (all P < .05), with IL-5 and IL-7 significant after Bonferroni-Holm correction. In multivariate Cox proportional hazards regression, high IL-5 (hazard ratio [HR], 5.76 [95% confidence interval {CI}, .77-43.0]; P = .088) and IL-7 (HR, 9.30 [95% CI, 1.96-44.0]; P = .005) were predictive of C-IRIS. Plasma IL-5 (P = .0008) and IL-10 (P = .0089) were lower in those who achieved CSF cryptococcal culture negativity compared to those with positive cultures pre-ART. There were no significant differences in CSF cytokine or chemokine levels between cases and controls. CONCLUSIONS: High plasma IL-5 and IL-7 levels pre-ART were associated with increased risk of developing C-IRIS. High IL-5 levels may reflect a Th2 environment associated with impaired clearance of cryptococci while high IL-7 levels may reflect IL-7/IL-7R pathway dysfunction in T cells, both of which could be associated with C-IRIS immunopathogenesis.

Contribution of arterial spin-labelling MRI in a case with immune reconstitution inflammatory syndrome.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS), which occurs most often in HIV-infected patients, is an exacerbation of inflammatory reactions related to opportunistic infections as well as primary CNS malignancies both of which mostly occur in HIV-infected patients. However, differential diagnoses are challenging both clinically and radiologically. We describe a patient with CNS-IRIS due to toxoplasmosis whose 11C-methionine uptake suggested lymphoma but whose arterial spin-labelling MRI led to the correct diagnosis.

Natalizumab treatment reduces L-selectin (CD62L) in CD4+ T cells.

BACKGROUND: The purpose of this research was to validate the low expression of L-selectin (CD62L) in natalizumab (NTZ)-treated patients. CD62L is involved in rolling and transmigration of leukocyte cells. A correlation between CD62LCD4+ T cells low expression and progressive multifocal leukoencephalopathy (PML) development has been suggested in multiple sclerosis (MS) patients treated with NTZ. METHODS: We performed a flow cytometric analysis on peripheral blood mononuclear cells (PBMC); we collected from 23 healthy donors and 225 MS patients: untreated (n = 19) or treated with NTZ (n = 113), interferon-beta (n = 26), glatiramer acetate (n = 26), fingolimod (n = 23) and rituximab (n = 18). We have also analysed two PML/IRIS (immune reconstitution inflammatory syndrome) patients and four longitudinal samples of a NTZ-treated patients before and during the development of a clinical asymptomatic magnetic resonance imaging (MRI) lesion confirmed as PML by cerebrospinal fluid (CSF) examination. Thirty-five NTZ-treated patients were studied longitudinally with three samples taken 4 months apart. RESULTS: The NTZ-treated patients showed a lower percentage of CD62L (33.68%, n = 113) than first-line treated patients (44.24%, n = 52, p = 0.0004). NTZ effect was already clear during the first year of treatment (34.68 ; p = 0.0184); it persisted in the following years and disappeared after drug withdrawal (44.08%). Three percent of longitudinally analysed patients showed a percentage of CD62LCD4+ T cells under a hypothetical threshold and one patient with asymptomatic PML belongs to a group which expressed low percentage of CD62LCD4+ T cells. CONCLUSIONS: Our research confirms that NTZ has a specific effect on CD62LCD4+ T cells consisting in decreasing of the number of positive cells. The low level of CD62L found in a clinically asymptomatic PML patient strengthens its potential usefulness as a biomarker of high PML risk in NTZ-treated patients. A larger study is required to better confirm the data.

Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.

Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA). PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS following peripheral immune reconstitution with ART. These results provide a rational basis for future studies of immune modulation in CM, and demonstrate the potential of baseline immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.

Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome.

BACKGROUND: The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS. METHODS: We performed lumbar puncture at 3-5 time points in human immunodeficiency virus (HIV)-infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18). RESULTS: At TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline. CONCLUSIONS: A high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS.

Varicella zoster virus central nervous system immune reconstitution inflammatory syndrome presenting in a child.

A HIV-positive child presented with acute onset of right hemiplegia, facial palsy and dysphasia 4 weeks after commencing highly active antiretroviral therapy. Magnetic resonance imaging confirmed a left-sided cerebral infarct. Cerebrospinal fluid polymerase chain reaction was positive for varicella zoster virus. This is the first reported pediatric case of varicella zoster virus-related immune reconstitution inflammatory syndrome involving the central nervous system.

Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome.

BACKGROUND: Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART. METHODS: We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM-IRIS. RESULTS: Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non-TBM-IRIS patients (median, 50 vs 3 cells ×10(6)/L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4-62.2). The combination of high CSF tumor necrosis factor (TNF)-α and low interferon (IFN)-γ at TBM diagnosis predicted TBM-IRIS (area under the curve = 0.91 [95% CI, .53-.99]). CONCLUSIONS: TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-γ and TNF-α concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART.

[Inflammatory reconstitution immune syndrome associated to antiretroviral therapy and meningeal cryptococcosis]. / Síndrome de restauración inmune asociado a tratamiento antirretroviral y criptococosis meníngea. Caso clínico.

The objective of high activity antiretroviral therapy (HAART) in patients with AIDS, is to obtain immune restoration. This means a reduction of the viral load and restitution of the CD4 cell count. A decreased rate of HIV replication improves both the number and function of CD4 cells. Nevertheless, this treatment sometimes results in the reappearance of previous symptoms from treated conditions due to opportunistic infections (ie: tuberculosis, criptococcosis, hepatitis, Pneumocystis jirovesi, toxoplasmosis, etc) or non infectious condition such as sarcoidosis, Graves disease or Kaposi sarcoma. This is known as Inflammatory Reconstitution Immune Syndrome (IRIS). We report a 37 year-old woman in stage C3-AIDS with a previous criptococcal meningitis. She was treated, achieving a marked improvement with treatment and subsequent suppressive therapy with fluconazole 200 mg/day. IRIS appeared after 8 months of ongoing antiretroviral therapy with immune restoration with the development of aseptic meningitis and intracranial hypertension. The opportunistic agent could not be identified by cultures. Additional laboratory tests excluded toxoplasmosis, tuberculosis, bacterial cerebral abscesses, syphilitic cerebral gummas, and lymphoma. Brain CT and magnetic resonance studies were compatible with brain vasculitis and leptomeningitis. The patient condition improved with general measures, such as a repeated lumbar punctures and non steroidal anti-inflammatory drugs. We conclude that this patient had an IRIS due to a Cryptococcus neoformans antigen.

Síndrome de restauración inmune asociado a tratamiento antirretroviral y criptococosis meníngea: Caso clínico / Inflammatory reconstitution immune syndrome associated to antiretroviral therapy and meningeal cryptococcosis

The objective of high activity antiretroviral therapy (HAART) in patients with AIDS, is to obtain immune restoration. This means a reduction of the viral load and restitution of the CD4 cell count. A decreased rate of HIV replication improves both the number and function of CD4 cells. Nevertheless, this treatment sometimes results in the reappearance of previous symptoms from treated conditions due to opportunistic infections (ie: tuberculosis, criptococcosis, hepatitis, Pneumocystis jirovesi, toxoplasmosis, etc) or non infectious condition such as sarcoidosis, Graves disease or Kaposi sarcoma. This is known as Inflammatory Reconstitution Immune Syndrome (IRIS). We report a 37 year-old woman in stage C3-AIDS with a previous criptococcal meningitis. She was treated, achieving a marked improvement with treatment and subsequent suppressive therapy with fluconazole 200 mg/day. IRIS appeared after 8 months of ongoing antiretroviral therapy with immune restoration with the development of aseptic meningitis and intracranial hypertension. The opportunistic agent could not be identified by cultures. Additional laboratory tests excluded toxoplasmosis, tuberculosis, bacterial cerebral abscesses, syphilitic cerebral gummas, and lymphoma. Brain CT and magnetic resonance studies were compatible with brain vasculitis and leptomeningitis. The patient condition improved with general measures, such as a repeated lumbar punctures and non steroidal anti-inflammatory drugs. We conclude that this patient had an IRIS due to a Cryptococcus neoformans antigen.