title: The initial 96 hours of invasive pulmonary aspergillosis: histopathology, comparative kinetics of galactomannan and (1->3) β-d-glucan and consequences of delayed antifungal therapy.
abstract: 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.
authors: 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. william.hope@manchester.ac.uk
authors: William W
authors: WW
authors: Hope
authors: Vidmantas
authors: V
authors: Petraitis
authors: Ruta
authors: R
authors: Petraitiene
authors: Tamarra
authors: T
authors: Aghamolla
authors: John
authors: J
authors: Bacher
authors: Thomas J
authors: TJ
authors: Walsh
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity; D003840:Deoxycholic Acid / Q000627:therapeutic use*; D004338:Drug Combinations; D005690:Galactose / Q000031:analogs & derivatives; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000378:metabolism*; D008351:Mannans / Q000378:metabolism*; D011509:Proteoglycans; D011817:Rabbits; D047071:beta-Glucans / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D008351:Mannans; D011509:Proteoglycans; D047071:beta-Glucans; D003840:Deoxycholic Acid; C012990:galactomannan; C010770:polysaccharide-K; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D005690:Galactose