RESUMEN
INTRODUCTION: Coccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown. METHODS: Phase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness. OBJECTIVES: The primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality. DISCUSSION: This trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed.
RESUMEN
Apnea-induced hypoxia and reoxygenation, which generates reactive oxygen species, may activate the oxidant-sensitive, proinflammatory transcription factor nuclear factor kappaB (NF-kappaB), increasing systemic inflammation in obstructive sleep apnea. We measured NF-kappaB activity in circulating neutrophils and plasma levels of NF-kappaB-controlled gene products, soluble E (sE)-selectin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in control subjects and in obstructive sleep apnea (OSA) patients. To confirm a causal link with OSA, we reassessed these parameters after nasal continuous positive airway pressure (CPAP) therapy. Twenty-two subjects undergoing evaluation for symptoms of sleep-disordered breathing were grouped by apnea hypopnea index: control, less than 5/h; mild to moderate OSA, 11-40/h; severe OSA, more than 40/h. A morning venous blood sample was obtained. Neutrophils were isolated, and NF-kappaB activity was determined by electrophoretic mobility shift assay. Plasma sE-selectin and sVCAM-1 were assayed by enzyme-linked immunosorbent assay. Neutrophils in mild to moderate and severe OSA patients showed 4.8- and 7.9-fold greater NF-kappaB binding activity compared with control subjects (p<0.0001). The degree of NF-kappaB activation was positively correlated with indices of apnea severity. In five severe OSA patients, 1 month of CPAP therapy decreased neutrophil NF-kappaB activation to control levels. sE-selectin and sVCAM concentrations were reduced by CPAP in four of these five subjects. OSA leads to NF-kappaB activation, which may constitute an important pathway linking OSA with systemic inflammation and cardiovascular disease.
Asunto(s)
Inflamación/sangre , FN-kappa B/sangre , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/fisiopatología , Adulto , Índice de Masa Corporal , Enfermedades Cardiovasculares/sangre , Presión de las Vías Aéreas Positiva Contínua/métodos , Progresión de la Enfermedad , Selectina E/sangre , Femenino , Humanos , Masculino , FN-kappa B/fisiología , Neutrófilos/metabolismo , Polisomnografía , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/terapia , Molécula 1 de Adhesión Celular Vascular/sangreRESUMEN
Obstructive sleep apnea (OSA) is an important risk factor for cardiovascular morbidity and mortality. The mechanisms through which OSA promotes the development of cardiovascular disease are poorly understood. In this study, we tested the hypotheses that chronic exposure to intermittent hypoxia and reoxygenation (CIH) is a major pathologic factor causing cardiovascular inflammation, and that CIH-induces cardiovascular inflammation and pathology by activating the NF-kappaB pathway. We demonstrated that exposure of mice to CIH activated NF-kappaB in cardiovascular tissues, and that OSA patients had markedly elevated monocyte NF-kappaB activity, which was significantly decreased when obstructive apneas and their resultant CIH were eliminated by nocturnal CPAP therapy. The elevated NF-kappaB activity induced by CIH is accompanied by and temporally correlated to the increased expression of iNOS protein, a putative and important NF-kappaB-dependent gene product. Thus, CIH-mediated NF-kappaB activation may be a molecular mechanism linking OSA and cardiovascular pathologies seen in OSA patients.