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1.
Mediators Inflamm ; 2020: 8818044, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33177951

RESUMEN

BACKGROUND: Though peripheral blood is a crucial sample to study immunology, it is unclear whether the immune environment in the peripheral vasculature correlates with that at the end-organ site of infection. Using cryptococcal meningitis as a model, we investigated the correlation between serum and cerebrospinal fluid biomarkers over time. METHODS: We analyzed the cerebrospinal fluid and serum of 160 subjects presenting with first episode cryptococcal meningitis for soluble cytokines and chemokines measured by Luminex assay. Specimens were collected at meningitis diagnosis, 1-week, and 2-week post cryptococcal diagnosis. We compared paired samples by Spearman's correlation and the p value was set at <0.01. RESULTS: Of the 21 analytes tested at baseline, there was no correlation detected between nearly all analytes. A weak negative correlation was found between serum and cerebrospinal fluid levels of interferon-gamma (Rho = -0.214; p = .007) and interleukin-4 (Rho = -0.232; p = .003). There was no correlation at 1-week post cryptococcal diagnosis. However, at 2-week post cryptococcal diagnosis, there was a weak positive correlation of granulocyte-macrophage colony-stimulating factor levels (Rho = 0.25; p = .007) in serum and cerebrospinal fluid. No cytokine or chemokine showed consistent correlation overtime. CONCLUSION: Based on our analysis of 21 biomarkers, serum and cerebrospinal fluid immune responses do not correlate. There appears to be a distinct immune environment in terms of soluble biomarkers in the vasculature versus end-organ site of infection. While this is a model of HIV-related cryptococcal meningitis, we postulate that assuming the blood compartment is representative of the immune function at the end-organ site of infection may not be appropriate.


Asunto(s)
Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Meningitis Criptocócica/sangre , Meningitis Criptocócica/líquido cefalorraquídeo , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Factor Estimulante de Colonias de Granulocitos/metabolismo , Infecciones por VIH/complicaciones , Humanos , Sistema Inmunológico , Huésped Inmunocomprometido , Interferón gamma/sangre , Interferón gamma/líquido cefalorraquídeo , Interleucina-4/sangre , Interleucina-4/líquido cefalorraquídeo , Masculino , Meningitis Criptocócica/complicaciones , Reproducibilidad de los Resultados
2.
J Infect Dis ; 213(11): 1725-34, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-26768248

RESUMEN

BACKGROUND: Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation. METHODS: A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis. RESULTS: Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan. CONCLUSIONS: Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Interleucina-10/sangre , Meningitis Criptocócica/mortalidad , Monocitos/inmunología , Polisacáridos/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Adulto , Estudios de Cohortes , Citocinas/metabolismo , Citometría de Flujo , Humanos , Masculino , Meningitis Criptocócica/sangre , Meningitis Criptocócica/inmunología , Estudios Prospectivos , Sudáfrica , Análisis de Supervivencia
3.
J Clin Microbiol ; 54(3): 802-4, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26719441

RESUMEN

Fungal burden in the cerebrospinal fluid is an important determinant of mortality in cryptococcal meningitis, but its use in aiding clinical decision making is hampered by the time involved to perform quantitative cultures. Here, we demonstrate the potential of flow cytometry as a novel and rapid technique to address this issue.


Asunto(s)
Líquido Cefalorraquídeo/microbiología , Cryptococcus neoformans/aislamiento & purificación , Citometría de Flujo , Meningitis Criptocócica/diagnóstico , Meningitis Criptocócica/microbiología , Recuento de Colonia Microbiana/métodos , Citometría de Flujo/métodos , Humanos
4.
J Infect Dis ; 212(5): 769-78, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25651842

RESUMEN

INTRODUCTION: Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation (1-2 weeks vs 5 weeks postmeningitis diagnosis). We hypothesized this was due to ART-associated immune pathology, without clinically recognized immune reconstitution inflammatory syndrome. METHODS: Three macrophage activation markers and 19 cytokines/chemokines were measured from cryopreserved cerebrospinal fluid (CSF) and serum during the Cryptococcal Optimal ART Timing (COAT) trial. Comparisons were made between trial arms (early vs deferred) at 1, 8, 14, and 21 days following meningitis diagnosis. RESULTS: More participants with early ART initiation had CSF white cell count (WCC) ≥5/µL at day 14 (58% vs 40%; P = .047), after a median of 6-days ART. Differences were mainly driven by participants with CSF WCC <5/µL at meningitis diagnosis: 28% (10/36) of such persons in the early ART group had CSF WCC ≥5/µL by day 14, compared with 0% (0/27) in the deferred arm (P = .002). Furthermore, Kampala participants (the largest site) receiving early ART had higher day-14 CSF levels of interleukin-13 (P = .04), sCD14 (P = .04), sCD163 (P = .02), and CCL3/MIP-1α (P = .02), suggesting increased macrophage/microglial activation. CONCLUSIONS: Early ART initiation in cryptococcal meningitis increased CSF cellular infiltrate, macrophage/microglial activation, and T helper 2 responses within the central nervous system. This suggests that increased mortality from early ART in the COAT trial was immunologically mediated.


Asunto(s)
Terapia Antirretroviral Altamente Activa/métodos , Líquido Cefalorraquídeo/citología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Leucocitosis/inducido químicamente , Activación de Macrófagos , Meningitis Criptocócica/diagnóstico , Adulto , Terapia Antirretroviral Altamente Activa/efectos adversos , Citocinas/metabolismo , Femenino , Humanos , Masculino , Prevención Secundaria , Análisis de Supervivencia
6.
Am J Trop Med Hyg ; 102(3): 574-577, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31933459

RESUMEN

Human infection with the trematode Fasciola occurs with a worldwide prevalence of up to 17 million. Sheep and cattle are the normal host. Infection typically results in hepatobiliary disease, but extrahepatic manifestations are occasionally reported. Here, we present the case of a previously healthy 31-year-old Kurdish woman, admitted to hospital with a subarachnoid hemorrhage, eosinophilic meningitis, and lung and liver disease. A diagnosis of Fasciola infection was made based on strongly positive serology in blood and cerebrospinal fluid. The patient improved following treatment with triclabendazole and prednisolone.


Asunto(s)
Fascioliasis/complicaciones , Fascioliasis/patología , Meningitis/parasitología , Hemorragia Subaracnoidea/parasitología , Adulto , Anticuerpos Antihelmínticos/sangre , Fascioliasis/tratamiento farmacológico , Femenino , Humanos , Inmunoglobulina G/sangre , Meningitis/diagnóstico , Meningitis/patología , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/patología , Triclabendazol/uso terapéutico
7.
Med Mycol Case Rep ; 19: 38-40, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29379704

RESUMEN

We present a 27-year-old lady with HIV-1 infection who died due to rapidly worsening respiratory failure one day after commencing amphotericin B deoxycholate therapy for cryptococcal meningitis. Chest x-ray appearances were consistent with pneumocystis pneumonia but post mortem examination showed evidence of severe necrotizing cryptococcal pneumonia. Cryptococcal pneumonia is an underrecognized condition and should be considered in the differential of patients with HIV-1 infection and low CD4 count who develop respiratory symptoms.

8.
Curr Opin Microbiol ; 40: 95-103, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29154044

RESUMEN

Modulation of host immunity in invasive fungal infection is an appealing but as yet mostly elusive treatment strategy. Animal studies in invasive candidiasis and aspergillosis have demonstrated beneficial effects of colony stimulating factors, interferon-gamma and monoclonal antibodies. More recent studies transfusing leukocytes pre-loaded with lipophilic anti-fungal drugs, or modulated T-cells, along with novel vaccination strategies show great promise. The translation of immune therapies into clinical studies has been limited to date but this is changing and the results of new Candida vaccine trials are eagerly awaited. Immune modulation in HIV-associated mycoses remains complicated by the risk of immune reconstitution inflammatory syndrome and although exogenous interferon-gamma therapy may be beneficial in cryptococcal meningitis, early initiation of anti-retroviral therapy leads to increased mortality. Further study is required to better target protective immune responses.


Asunto(s)
Hongos/fisiología , Infecciones Fúngicas Invasoras/inmunología , Animales , Citocinas/genética , Citocinas/inmunología , Hongos/genética , Hongos/inmunología , Humanos , Infecciones Fúngicas Invasoras/genética , Infecciones Fúngicas Invasoras/microbiología
9.
J Acquir Immune Defic Syndr ; 75(3): 299-307, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28346317

RESUMEN

BACKGROUND: Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). METHODOLOGY: We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). FINDINGS: CSF was available from 57 persons (median CD4 34/µL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14 and 35% CD14 monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4, CD8, and CD4CD8 T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4CD8 T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. CONCLUSIONS: Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.


Asunto(s)
Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Activación de Macrófagos/efectos de los fármacos , Meningitis Criptocócica/líquido cefalorraquídeo , Meningitis Criptocócica/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/líquido cefalorraquídeo , Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Adulto , Relación CD4-CD8 , Citocinas/líquido cefalorraquídeo , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/inmunología , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Meningitis Criptocócica/complicaciones , Meningitis Criptocócica/patología , Estudios Prospectivos , Índice de Severidad de la Enfermedad
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