18F-FDG brain PET hypometabolism in patients with long COVID
Authors: C Eldin
P Dudouet
S Guis
H Tissot-Dupont
J Y Campion
M Million
F Bregeon
F Barthelemy
D Raoult
E Kaphan
P Habert
M Ceccaldi
E Guedj
S Cammilleri
Journal: European Journal of Nuclear Medicine and Molecular Imaging (2021)
Discipline: CLINICAL MEDICINE
Keywords: 18F-FDG; Angiotensin-converting enzyme; Anosmia; COVID-19; Complaints
Affiliations: APHM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, CERIMED, Nuclear Medicine Department, Aix-Marseille University, Marseille, France. ., APHM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, CERIMED, Nuclear Medicine Department, Aix-Marseille University, Marseille, France., IHU-Méditerranée Infection, Marseille, France., IRD, APHM, MEPHI, Aix-Marseille University, Marseille, France., APHM, Service de Neurologie, Hôpital de la Timone, Marseille, France., Service des Explorations Fonctionnelles Respiratoires, CHU Nord, APHM, Marseille, France., Service de Rhumatologie, Hôpital de Sainte Marguerite, AP-HM, CNRS, CRMBM-CEMEREM, UMR CNRS 7339, Aix-Marseille Université, Marseille, France., Radiology Department, La Timone Hospital, APHM, 264 Rue Saint Pierre, 13005, Marseille 05, France., LIIE, Aix-Marseille University, Marseille, France., INSERM, Inst Neurosci Syst, & APHM, Service de Neurologie et de Neuropsychologie, CHU Timone, Aix-Marseille University, Marseille, France., IRD, AP-HM, SSA, VITROME, Aix-Marseille University, Marseille, France.

Abstract:  Purpose: In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as "long COVID." We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection. Methods: PET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients' characteristics and functional complaints. Results: In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel &lt; 0.001 uncorrected, p-cluster &lt; 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p &lt; 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p &lt; 0.001). Conclusion: This study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients' symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism. 

Retracted: No

PubPeer comments:
 The authors mention in this paper that they have requested no ethical approval for this retrospective study. Indeed, the study used 2 types of recruitments: - Patients recruited  retrospectively from May 18, 2020, to September 30, 2020. - Healthy volunteers before the Covid19 crisis. For the patients group, the authors mention: * This data collection was retrospective with no ethical approval requirement other than informed consent according to the French and European regulations. * For the heathy volunteers group, the authors mention the data from a previous interventional study done before 2020. The author mentions that this study was approved by the CPP Sud Meditterranu00e9e. The authors don t mention any approval number, any date of approval or any date of recruitment. This CPP approval cover a previous interventional study. It don t cover this retrospective study. The authors mention no approval from any ethics committee for this retrospective study. However, the Editor policy specify that: * ethics approval may be required dependent on the law and the national ethical guidelines of a country. Authors should check with their institution to make sure they are complying with the specific requirements of their country. * [Editor s policy] In France, the reuse of the data from a clinical trials for a new scientific purpose must obtain the approval of the healthy participants of this previous study for this reuse ([Article L1122-1-2 of French Public Health Code] ) Can the author explain how the healthy volunteers from a previous interventional study have been informed and have given their consent on the reuse of the data ? Otherwise, regarding the control group reused in this retrospective study, a study using radiopharmaceutical and PET scan on healthy volunteers falls under the scope of the EU Clinical Trials Directive. This study must have been registered in EudraCT (european clinical trials database). Can the author provide the EudraCT number of this interventional study which have been reused to provide the data of healthy participants? , 
 Thank you for your comment The number of registration of the interventional study in healthy subjects is mentioned in the  Funding part at the end of article:  The local PET database of healthy controls was funded by APHM (NCT00484523) I cc the link of the declaration to ClinicalTrials.gov: https: clinicaltrials.gov ct2 show study NCT00484523 As mentioned in the brief summary of this declaration, the objective of this study was precisely the  Constitution of a Standardized Neural Imaging Database in Healthy Subjects  to be able to objectively quantify anomalies observed in patients, at the scale of a group or an individual, for the diagnosis and surveillance of neurological diseases. The subjects were thus informed at inclusion of the further use of their data for brain mapping studies in patients, it was rightly the objective of this interventional study You will find the elements you mentioned on this same page of clinicaltrials.gov. I add them on this response for transparency (the readers of our article can find them with the NCT reference that was thus included in the text) - approval number of CPP Sud Meditterranu00e9e: 2007-A00180-53 - date of approval: May 15th 2007 - study start date: July 2nd 2007 In addition, I confirm that in accordance with Editor s policy, we have checked with our APHM institution (which is also the promoter of this previous interventional study), that this retrospective study as described in our article complies with specific french requirements, including the correct use of healthy subjects data of our previous study, with a written response of our institution on the following reference: MY7FFP. To sum up: - the healthy subjects were recruited in an interventional study with the objective to use these data for further brain mapping studies in patients groups. This study was approved by a CPP (2007-A00180-53) and registered in clinicaltrials.gov (NCT00484523, mentioned in the article) - the retrospective part of this study in patient doesn t require ethical approval in current french regulatory rules after verification and written response of our institution (MY7FFP), but an information of non-opposition and a GPDR registration (PADS20-296, mentioned in the article) I hope that these elements will help to clarify the points you raised Best Regards Prof. Eric Guedj , 
 I add for #1, and on a more general purpose, that you wrongly interpreted the L1122-1-2 article of the French Public Health Code you cited, on the possible reuse of data from a previous study for further research You mention that  In France, the reuse of the data from a clinical trials for a new scientific purpose must obtain the approval of the healthy participants of this previous study for this reuse ; and further, you consequently asked  how the healthy volunteers from a previous interventional study have been informed and have given their consent on the reuse of the data ? The L1122-1-2 article you cited explains that the reuse of data is allowed if this possibility had been included in the initial informed consent. The subject can of course withdraw his her consent or use of his her right of opposition at any time, but an update of the approval is not required (again if the initial consent included the possible reuse of these data for further research projects). You have to refer to MR-004 research type I cc the whole paragraph of the L1122-1-2 article:  Le promoteur peut demander u00e0 la personne se pru00eatant u00e0 une recherche au moment ou00f9 celle-ci donne son consentement u00e9clairu00e9 lorsqu il est requis d accepter que ses donnu00e9es soient utilisu00e9es lors de recherches ultu00e9rieures exclusivement u00e0 des fins scientifiques. La personne peut retirer son consentement u00e0 cette utilisation ultu00e9rieure ou exercer sa facultu00e9 d opposition u00e0 tout moment. https: www.legifrance.gouv.fr codes section_lc LEGITEXT000006072665 LEGISCTA000006171000 ,