Abstract
Molecular imaging has gained attention as a possible approach for the study of the progression of inflammation and disease dynamics. Herein we used [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) as a radiotracer for PET imaging coupled with CT (FDG-PET/CT) to gain insight into the spatiotemporal progression of the inflammatory response of ferrets infected with a clinical isolate of a pandemic influenza virus, H1N1 (H1N1pdm). The thoracic regions of mock- and H1N1pdm-infected ferrets were imaged prior to infection and at 1, 2, 3 and 6 days post-infection (DPI). On 1 DPI, FDG-PET/CT imaging revealed areas of consolidation in the right caudal lobe which corresponded with elevated [18F]-FDG uptake (maximum standardized uptake values (SUVMax), 4.7–7.0). By days 2 and 3, consolidation (CT) and inflammation ([18F]-FDG) appeared in the left caudal lobe. By 6 DPI, CT images showed extensive areas of patchy ground-glass opacities (GGO) and consolidations with the largest lesions having high SUVMax (6.0–7.6). Viral shedding and replication were detected in most nasal, throat and rectal swabs and nasal turbinates and lungs on 1, 2 and 3 DPI, but not on day 7, respectively. In conclusion, molecular imaging of infected ferrets revealed a progressive consolidation on CT with corresponding [18F]-FDG uptake. Strong positive correlations were measured between SUVMax and bronchiolitis-related pathologic scoring (Spearman’s ρ = 0.75). Importantly, the extensive areas of patchy GGO and consolidation seen on CT in the ferret model at 6 DPI are similar to that reported for human H1N1pdm infections. In summary, these first molecular imaging studies of lower respiratory infection with H1N1pdm show that FDG-PET can give insight into the spatiotemporal progression of the inflammation in real-time.
Highlights
In March of 2009, an outbreak of a novel variant of H1N1 influenza A virus was reported in cases of influenza illness in Mexico [1]
To test the hypothesis that FDG-positron emission tomography (PET)/CT imaging could reveal the spatiotemporal nature of H1N1 pandemic strain (H1N1pdm) inflammation and disease progression, we chose the ferret model of H1N1pdm influenza infection. For these studies we chose a low passage clinical isolate, A/Kentucky/180/2010 or KY/180, which has a change in the HA1 gene, D222G, which correlates with increased severity of disease in patient cases from several countries [37,38,39,40]
Our results show for the first time, the spatiotemporal progression of inflammation with CT and PET using [18F]-FDG in ferrets infected with H1N1pdm in conjunction with histopathology and viral titers over a seven day period
Summary
In March of 2009, an outbreak of a novel variant of H1N1 influenza A virus was reported in cases of influenza illness in Mexico [1]. This novel H1N1 pandemic strain (H1N1pdm) tended to affect younger healthier populations and had an increased risk of morbidity and mortality [2,3,4] with 12–30% of the population developing clinical influenza, 4% of those requiring hospital admission, and 1 in 5 requiring critical care [5]. Infection of the H1N1pdm was relatively mild in most persons, a fatal viral pneumonia with acute respiratory distress syndrome occurred in approximately 18,000 cases. In contrast to seasonal influenza in human cases, H1N1pdm infections showed a tropism for the lung similar to H5N1 [6]. The ability of H1N1pdm viruses to infect the lower respiratory track has been attributed to a broader specificity in the binding of the viral hemagglutinin (HA) to a2-3- in addition to a2-6-linked sialic acid (SA) receptors [7,8]. Data from limited human autopsies and animal studies of various pandemic strains suggest contribution of the host innate immune response and the virus in the progression of disease [13,14,15,16]
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