title: Modeling [(18)F]-FDG lymphoid tissue kinetics to characterize nonhuman primate immune response to Middle East respiratory syndrome-coronavirus aerosol challenge.
abstract: 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. (18)F-Fluorodeoxyglucose ([(18)F]-FDG)-positron emission tomography/computed tomography (PET/CT) as a longitudinal noninvasive approach can be beneficial in providing biomarkers for host immune response. [(18)F]-FDG uptake is increased in activated immune cells in response to virus entry and can be localized by PET imaging. We used [(18)F]-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 [(18)F]-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 [(18)F]-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
  [(18)F]-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.
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA. schefer@mail.nih.gov.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Chefer
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Thomasson
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Seidel
authors.affiliation: Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.|Present address: Visiting Scientist, Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Reba
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: J Kyle
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Mathew G
authors.initials: MG
authors.lastname: Lackemeyer
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bartos
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Sayre
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Bollinger
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.|Emerging Viral Pathogens Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jahrling
authors.affiliation: Emerging Viral Pathogens Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
authors.forename: Reed F
authors.initials: RF
authors.lastname: Johnson
keywords: Animal models; Kinetic modeling; MERS-CoV; [18F]-FDG-PET