The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine,University Hospital of South Manchester NHS Foundation Trust, Oxford Rd., Manchester, United Kingdom.
Antimicrob Agents Chemother. 2010 Nov;54(11):4879-86. doi: 10.1128/AAC.00673-10. Epub 2010 Aug 16.
Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1→3)-β-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1→3)-β-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1→3)-β-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1→3)-β-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at ≥48 h postinoculation is associated with suboptimal therapeutic outcomes.
急性侵袭性肺曲霉病是一种进展迅速且常致命的感染。对于发病机制和细胞壁生物标志物半乳甘露聚糖和（1→3）-β-d-葡聚糖之间的关系的早期事件，人们知之甚少。抗真菌治疗延迟的后果也定义得很差。本研究使用持续中性粒细胞减少的兔侵袭性肺曲霉病模型，描述了早期侵袭性肺曲霉病的组织病理学和半乳甘露聚糖和（1→3）-β-d-葡聚糖的动力学。使用群体方法学对这两种分子的时间过程进行了数学建模，并进行了蒙特卡罗模拟。在接种后 24、48、72 和 96 小时分别延迟给予两性霉素 B 脱氧胆酸盐 1mg/kg，研究了真菌负荷、肺重、肺梗死评分和存活率的影响。组织病理学显示接种后 4 小时肺泡巨噬细胞吞噬了孢子。在 12 至 24 小时，出现了进行性局灶性炎症反应，伴有孢子萌发和菌丝延伸。随后，菌丝侵入相邻的肺。半乳甘露聚糖和（1→3）-β-d-葡聚糖具有相似的轨迹，并且两者都表现出相当大的个体间变异性，这在蒙特卡罗模拟中得到了反映。在出现肺出血性梗死之前，<24 小时接种后两种分子的浓度开始升高。两性霉素 B 延迟 72 和 96 小时给药，真菌负荷和肺重分别与对照组无明显差异。半乳甘露聚糖和（1→3）-β-d-葡聚糖具有相似的动力学，是早期侵袭性肺曲霉病的可比生物标志物。接种后≥48 小时进行抗真菌治疗与治疗效果不理想有关。
