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. Academic Article uri icon

Overview

MeSH

  • Animals
  • Aspergillus fumigatus
  • Drug Combinations
  • Rabbits

MeSH Major

  • Amphotericin B
  • Antifungal Agents
  • Deoxycholic Acid
  • Invasive Pulmonary Aspergillosis
  • Mannans
  • beta-Glucans

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.

publication date

  • November 2010

has subject area

  • Amphotericin B
  • Animals
  • Antifungal Agents
  • Aspergillus fumigatus
  • Deoxycholic Acid
  • Drug Combinations
  • Invasive Pulmonary Aspergillosis
  • Mannans
  • Rabbits
  • beta-Glucans

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2976140

Digital Object Identifier (DOI)

  • 10.1128/AAC.00673-10

PubMed ID

  • 20713673

Additional Document Info

start page

  • 4879

end page

  • 4886

volume

  • 54

number

  • 11