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. 2022 Apr 15;25(4):104101.
doi: 10.1016/j.isci.2022.104101. Epub 2022 Mar 17.

Computed tomography and [18F]-FDG PET imaging provide additional readouts for COVID-19 pathogenesis and therapies evaluation in non-human primates

Thibaut Naninck  1 , Nidhal Kahlaoui  1 , Julien Lemaitre  1 , Pauline Maisonnasse  1 , Antoine De Mori  1 , Quentin Pascal  1 , Vanessa Contreras  1 , Romain Marlin  1 , Francis Relouzat  1 , Benoît Delache  1 , Cécile Hérate  1 , Yoann Aldon  2 , Marit van Gils  2 , Nerea Zabaleta  3   4   5   6 , Raphaël Ho Tsong Fang  1 , Nathalie Bosquet  1 , Rogier W Sanders  2   7 , Luk H Vandenberghe  3   4   5   6 , Catherine Chapon  1 , Roger Le Grand  1
Affiliations

Computed tomography and [18F]-FDG PET imaging provide additional readouts for COVID-19 pathogenesis and therapies evaluation in non-human primates

Thibaut Naninck et al. iScience. .

Abstract

Non-human primates (NHPs) are particularly relevant as preclinical models for SARS-CoV-2 infection and nuclear imaging may represent a valuable tool for monitoring infection in this species. We investigated the benefit of computed X-ray tomography (CT) and [18F]-FDG positron emission tomography (PET) to monitor the early phase of the disease in a large cohort (n = 76) of SARS-CoV-2 infected macaques. Following infection, animals showed mild COVID-19 symptoms including typical lung lesions. CT scores at the acute phase reflect the heterogeneity of lung burden following infection. Moreover, [18F]-FDG PET revealed that FDG uptake was significantly higher in the lungs, nasal cavities, lung-draining lymph nodes, and spleen of NHPs by 5 days postinfection compared to pre-infection levels, indicating early local inflammation. The comparison of CT and PET data from previous COVID-19 treatments or vaccines we tested in NHP, to this large cohort of untreated animals demonstrated the value of in vivo imaging in preclinical trials.

Keywords: Medical imaging; Medical microbiology; Virology.

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Conflict of interest statement

No potential conflicts of interest relevant to this article exist.

Figures

None
Graphical abstract
Figure 1
Figure 1
Monitoring of SARS-CoV-2 infection in cynomolgus macaques (A and B) Nasopharynx genomic (A) and subgenomic (B) SARS-CoV-2 RNA copies per milliliter evolution over time following infection. (C) Viral RNA titers evaluated in bronchoalveolar lavages at 3 days postinfection. Dotted lines represent the limit of quantification. (D–F) White blood cells (D), lymphocytes (E), and neutrophils (F) counts in blood over time. (D–F) Dotted lines represent the average baseline values. (G–I) Plasma concentrations of IL1-RA (G), MCP-1 (H) and IL-15 (I) over time. Paired t-tests: ∗∗∗∗: p < 0.0001, ∗∗∗: p < 0.001, ∗∗: p < 0.01, ∗: p < 0.05. Mean values are represented in red.
Figure 2
Figure 2
Representative examples of lung lesions observed at 2–3 days.p.i. in transversal chest CT slices in individual SARS-CoV-2-infected cynomolgus macaques (A) Low-density ground-glass opacity (GGO), arrow. (B) Pleural peripheral GGO (left arrow) and peribronchial (right arrow) GGO of higher density. (C) Extended reticulated GGO (circled). (D) Focal pleural consolidation (arrow). (E and F) Tracheobronchial lymph node, showing an increase in volume (E: before exposure, (F) 2 days post-infection (d.p.i.), red lines).
Figure 3
Figure 3
Chest CT scan scoring analysis (A) CT scores at 2–3 days post-infection (d.p.i.) in SARS-CoV-2-exposed cynomolgus macaques according to the inoculum dose. Mock: exposed to PBS. (B) CT scores at 2–3 days.p.i. in SARS-CoV-2 exposed (105 PFU) cynomolgus versus rhesus macaques. (C) Evolution of the CT score between 2 and 3 days.p.i. and 10–14 days.p.i. for exposed cynomolgus macaques (∗: p = 0.0203). (D) Correlation between CT scores and the percentage change in lung hyperdensity (PCLH) for n = 12 cynomolgus macaques; linear regression (R = 0.70, p = 0.016). ns: non statistically significant, Mann–Whitney unpaired (A, B) or paired (C) t-tests. PFU: plaque-forming units. Mean values are represented in red with associated SD.
Figure 4
Figure 4
3D representation of regions of interest studied in SARS-CoV-2-infected macaques for [18F]-FDG uptake assessment (A) Coronal view, (B) Sagittal view. ROI of lungs (pink), liver (brown), spleen (green), nasal cavity (blue), tonsils (red), and lung-draining lymph nodes (yellow) are represented in 3D.
Figure 5
Figure 5
Representative PET/CT fusion images of [18F]-FDG signals in the thoracic area and spleen following infection in cynomolgus macaques (A) PET signal observed in the thoracic area before and at 5 days post-infection (d.p.i.), when an increased signal could be observed in lung-draining lymph nodes (pink arrows) and lung lesions (white arrows). Lungs were segmented (white delimitations) using CT. [18F]-FDG signal on PET-CT fused images observed in CT-segmented spleen (white delimitation) before and after SARS-CoV-2 exposure. Highest standardized uptake value (SUV) values in the spleen were delimitated in green to help in the comparison. (B) Frontal chest PET/CT fusion slices at baseline, 2 days post-infection (d.p.i.), 5 days.p.i., 7 days.p.i, 12 days.p.i, and 19 days.p.i. indicating longitudinal thoracic lymph node [18F]-FDG uptake over time (red circles indicate lymphatic [18F]-FDG signals).
Figure 6
Figure 6
Quantitative [18F]-FDG-PET analysis in the lungs, nasal cavity, lung-draining lymph nodes, and spleen of SARS-CoV-2- or PBS-exposed cynomolgus macaques (A–D) Mean standard uptake values (SUVmean) are expressed as an individual ratio to baseline values in whole lungs (A), nasal cavity (B), lung-draining lymph nodes (C), and spleen (D) over time. ∗: p < 0.05, Paired t-tests. Mean values are represented in red with associated SD.
Figure 7
Figure 7
Comparison of treated or vaccinated cynomolgus macaques with control animals for CT scores and [18F]-FDG uptake by PET (A) CT scores at 2 days post-infection (d.p.i.) following exposure of macaques under hydroxychloroquine (HCQ, in maroon) or no treatment. (B) CT scores at 3 days.p.i. following exposure of macaques to a monoclonal COVA 1–18 treatment (blue) or not. (C) CT scores at 5 days.p.i. following exposure of macaques immunized with an AAV-based COVID-19 vaccine (green) or not. (D–F) Comparison of the mean standardized uptake value (SUVmean) ratios with the baseline for the lungs (D), lung-draining lymph nodes (E), and spleen (F) 5 days.p.i. of AAV-based COVID-19 vaccinated animals or unvaccinated animals. ns: non-statistically significant, ∗∗∗: p < 0.001, ∗∗: p < 0.01, ∗: p < 0.05. Mann–Whitney t-tests. Mean values are represented in red with associated SD.
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