Modeling [18F]-FDG lymphoid tissue kinetics to characterize nonhuman primate immune response to Middle East respiratory syndrome-coronavirus aerosol challenge

Background: The pathogenesis and immune response to Middle East respiratory syndrome (MERS) caused by a recently discovered coronavirus, MERS-CoV, have not been fully characterized because a suitable animal model is currently not available. F-18-Fluorodeoxyglucose ([F-18]-FDG)-positron emission tomography/computed tomography (PET/CT) as a longitudinal noninvasive approach can be beneficial in providing biomarkers for host immune response. [F-18]-FDG uptake is increased in activated immune cells in response to virus entry and can be localized by PET imaging. We used [F-18]-FDG-PET/CT to investigate the host response developing in nonhuman primates after MERS-CoV exposure and applied kinetic modeling to monitor the influx rate constant (K-i) in responsive lymphoid tissue. Methods: Multiple [F-18]-FDG-PET and CT images were acquired on a PET/CT clinical scanner modified to operate in a biosafety level 4 environment prior to and up to 29 days after MERS-CoV aerosol exposure. Time activity curves of various lymphoid tissues were reconstructed to follow the [F-18]-FDG uptake for approximately 60 min (3,600 s). Image-derived input function was used to calculate K-i for lymphoid tissues by Patlak plot. Results: Two-way repeated measures analysis of variance revealed alterations in K-i that was associated with the time point (p < 0.001) after virus exposure and the location of lymphoid tissue (p = 0.0004). As revealed by a statistically significant interaction (p < 0.0001) between these two factors, the pattern of K-i changes over time differed between three locations but not between subjects. A distinguished pattern of statistically significant elevation in K-i was observed in mediastinal lymph nodes (LNs) that correlated to K-i changes in axillary LNs. Changes in LNs K-i were concurrent with elevations of monocytes in peripheral blood. Conclusions: [F-18]-FDG-PET is able to detect subtle changes in host immune response to contain a subclinical virus infection. Full quantitative analysis is the preferred approach rather than semiquantitative analysis using standardized uptake value for detection of the immune response to the virus.