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

Abstract

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.

Galactomannan antigen detection in the diagnosis of invasive aspergillosis

“…In neutropenic rabbits, pulmonary disease is characterized by intensive hyphal growth and high fungal burden; by comparison, in corticosteroid-treated animals, pulmonary inflammation and decreased fungal burden are the hallmarks [48]. Given the association between the GM levels and the pulmonary tissue burden of A. fumigatus not only in animal models [27,28], but also in the clinical setting, it seems to be the case that the host's immune status may play a role in the results of the assay [30]. Therefore, the sensitivity of the assay is dependent on the cut-off used for positivity, concomitant antifungal therapy, and the population studied.…”

“…Subsequent studies of experimental IPA in persistently neutropenic rabbits demonstrated a direct quantitative relationship between serum levels of GM, and other markers of severity of infections: residual pulmonary burden (logCFU/g), lung weights, pulmonary infarct scores and CT scan infiltrate index [26][27][28].…”

Preemptive antifungal therapy: still a way to go

“…Many clinically important issues, however, still remain unanswered: does the assay correlate with fungal burden and what is the behavior of the test over time [13,14]? What is the impact of antimold prophylaxis or therapy on test performance [15,16 ]?…”

Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: In Vitro and In Vivo Correlations of the Concentration- and Dose- Dependent Interactions between Anidulafungin and Voriconazole by Bliss Independence Drug Interaction Analysis

“…Computerized tomography was performed to measure the response of pulmonary infiltrates to antifungal therapy (38). A semiautomatic method was then used to measure the volume of lung lesions, as previously described (27).…”