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Antimicrobial Agents and Chemotherapy, April 2006, p. 1510-1517, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1510-1517.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Multidimensional Volumetric Imaging of Pulmonary Infiltrates for Measuring Therapeutic Response to Antifungal Therapy in Experimental Invasive Pulmonary Aspergillosis

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,¹ SAIC-Frederick, Inc., Frederick, Maryland,² Medical Numerics, Inc., Sterling, Virginia,³ Department of Radiology, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland,⁴ Departments of Radiology, Kaunas University of Medicine, Kaunus, Lithuania,⁵ Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Maryland⁶

Received 11 August 2005/ Returned for modification 28 November 2005/ Accepted 6 February 2006

Pulmonary infiltrates in neutropenic hosts with invasive pulmonary aspergillosis are caused by vascular invasion, hemorrhagic infarction, and tissue necrosis. Monitoring the dynamics of pulmonary infiltrates of invasive aspergillosis is an important tool for assessing response to antifungal therapy. We, therefore, introduced a multidimensional volumetric imaging (MDVI) method for analysis of the response of the volume of pulmonary infiltrates over time to antifungal therapy in experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. We developed a semiautomatic method to measure the volume of lung lesions, which was implemented as an extension of the MEDx visualization and analysis software using ultrafast computerized tomography (UFCT). Volumetric infiltrate measures were compared with UFCT reading, histopathological resolution of lesions, microbiological clearance of Aspergillus fumigatus, and galactomannan index (GMI). We also studied the MDVI method for consistency and reproducibility in comparison to UFCT. Treatment groups consisted of deoxycholate amphotericin B (DAMB) at 0.5 or 1 mg/kg of body weight/day and untreated controls (UC). Therapeutic monitoring of pulmonary infiltrates using MDVI demonstrated a significant decrease in the infiltrate volume in DAMB-treated rabbits in comparison to UC (P 0.001). Volumetric data by MDVI correlated with conventional CT pulmonary scores (r = 0.83, P 0.001). These results correlated with validated biological endpoints: pulmonary infarct scores (r = 0.85, P 0.001), lung weights (r = 0.76, P 0.01), residual fungal burden (r = 0.65, P 0.05), and GMI (r = 0.78, P 0.01). MDVI correlated with key biological markers, improved the objectivity of radiological assessment of therapeutic response to antifungal therapy, and warrants evaluation for monitoring therapeutic response in immunocompromised patients with invasive aspergillosis.