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Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging 10/2021

07.03.2021 | Original Article

Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study

verfasst von: Martina Sollini, Silvia Morbelli, Michele Ciccarelli, Maurizio Cecconi, Alessio Aghemo, Paola Morelli, Silvia Chiola, Fabrizia Gelardi, Arturo Chiti

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 10/2021

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Abstract

Purpose

The present study hypothesised that whole-body [18F]FDG-PET/CT might provide insight into the pathophysiology of long COVID.

Methods

We prospectively enrolled 13 adult long COVID patients who complained for at least one persistent symptom for >30 days after infection recovery. A group of 26 melanoma patients with negative PET/CT matched for sex/age was used as controls (2:1 control to case ratio). Qualitative and semi-quantitative analysis of whole-body images was performed. Fisher exact and Mann-Whitney tests were applied to test differences between the two groups. Voxel-based analysis was performed to compare brain metabolism in cases and controls. Cases were further grouped according to prevalent symptoms and analysed accordingly.

Results

In 4/13 long COVID patients, CT images showed lung abnormalities presenting mild [18F]FDG uptake. Many healthy organs/parenchyma SUVs and SUV ratios significantly differed between the two groups (p ≤ 0.05). Long COVID patients exhibited brain hypometabolism in the right parahippocampal gyrus and thalamus (uncorrected p < 0.001 at voxel level). Specific area(s) of hypometabolism characterised patients with persistent anosmia/ageusia, fatigue, and vascular uptake (uncorrected p < 0.005 at voxel level).

Conclusion

[18F]FDG PET/CT acknowledged the multi-organ nature of long COVID, supporting the hypothesis of underlying systemic inflammation. Whole-body images showed increased [18F]FDG uptake in several “target” and “non-target” tissues. We found a typical pattern of brain hypometabolism associated with persistent complaints at the PET time, suggesting a different temporal sequence for brain and whole-body inflammatory changes. This evidence underlined the potential value of whole-body [18F]FDG PET in disclosing the pathophysiology of long COVID.
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Literatur
1.
Zurück zum Zitat Treglia G. Diagnostic performance of 18F-FDG PET/CT in infectious and inflammatory diseases according to published meta-analyses. Contrast Media Mol Imaging. Hindawi Ltd. and John Wiley and Sons, Inc.; 2019;2019:3018349. Treglia G. Diagnostic performance of 18F-FDG PET/CT in infectious and inflammatory diseases according to published meta-analyses. Contrast Media Mol Imaging. Hindawi Ltd. and John Wiley and Sons, Inc.; 2019;2019:3018349.
2.
Zurück zum Zitat Qin C, Liu F, Yen TC, Lan X. 18F-FDG PET/CT findings of COVID-19: a series of four highly suspected cases. Eur J Nucl Med Mol Imaging. 2020. Qin C, Liu F, Yen TC, Lan X. 18F-FDG PET/CT findings of COVID-19: a series of four highly suspected cases. Eur J Nucl Med Mol Imaging. 2020.
3.
Zurück zum Zitat Annunziata S, Delgado Bolton RC, Kamani CH, Prior JO, Albano D, Bertagna F, et al. Role of 2-[18f]fdg as a radiopharmaceutical for pet/ct in patients with covid-19: a systematic review. Pharmaceuticals. 2020. Annunziata S, Delgado Bolton RC, Kamani CH, Prior JO, Albano D, Bertagna F, et al. Role of 2-[18f]fdg as a radiopharmaceutical for pet/ct in patients with covid-19: a systematic review. Pharmaceuticals. 2020.
5.
Zurück zum Zitat Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ. British Medical Journal Publishing Group; 2020;370:m3026. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ. British Medical Journal Publishing Group; 2020;370:m3026.
6.
Zurück zum Zitat The Lancet. Facing up to long COVID. Lancet. 2020. The Lancet. Facing up to long COVID. Lancet. 2020.
7.
Zurück zum Zitat Meeting the challenge of long COVID. Nat Med. 2020;26:1803. Meeting the challenge of long COVID. Nat Med. 2020;26:1803.
8.
Zurück zum Zitat Delorme C, Paccoud O, Kas A, Hesters A, Bombois S, Shambrook P, et al. COVID-19-related encephalopathy: a case series with brain FDG-positron-emission tomography/computed tomography findings. Eur J Neurol Eur J Neurol. 2020;27:2651–7.CrossRef Delorme C, Paccoud O, Kas A, Hesters A, Bombois S, Shambrook P, et al. COVID-19-related encephalopathy: a case series with brain FDG-positron-emission tomography/computed tomography findings. Eur J Neurol Eur J Neurol. 2020;27:2651–7.CrossRef
9.
Zurück zum Zitat Guedj E, Million M, Dudouet P, Tissot-Dupont H, Bregeon F, Cammilleri S, et al. 18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders? Eur J Nucl Med Mol Imaging. Eur J Nucl Med Mol Imaging. 2020. Guedj E, Million M, Dudouet P, Tissot-Dupont H, Bregeon F, Cammilleri S, et al. 18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders? Eur J Nucl Med Mol Imaging. Eur J Nucl Med Mol Imaging. 2020.
10.
Zurück zum Zitat Kas A, Soret M, Pyatigoskaya N, Habert M-O, Hesters A, Le Guennec L, et al. The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study. Eur J Nucl Med Mol Imaging. Eur J Nucl Med Mol Imaging. 2021. Kas A, Soret M, Pyatigoskaya N, Habert M-O, Hesters A, Le Guennec L, et al. The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study. Eur J Nucl Med Mol Imaging. Eur J Nucl Med Mol Imaging. 2021.
11.
Zurück zum Zitat Guedj E, Campion JY, Dudouet P, Kaphan E, Bregeon F, Tissot-Dupont H, et al. 18F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging. Springer; 2021;1–11. Guedj E, Campion JY, Dudouet P, Kaphan E, Bregeon F, Tissot-Dupont H, et al. 18F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging. Springer; 2021;1–11.
12.
Zurück zum Zitat Ling Y, Xu S-B, Lin Y-X, Tian D, Zhu Z-Q, Dai F-H, et al. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl). 2020;133:1039–43.CrossRef Ling Y, Xu S-B, Lin Y-X, Tian D, Zhu Z-Q, Dai F-H, et al. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl). 2020;133:1039–43.CrossRef
13.
Zurück zum Zitat Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20:e276–88.CrossRef Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20:e276–88.CrossRef
14.
Zurück zum Zitat Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan S, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection — United Kingdom and United States, March–August 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1450–6.CrossRef Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan S, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection — United Kingdom and United States, March–August 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1450–6.CrossRef
15.
Zurück zum Zitat Maiese A, Manetti AC, La Russa R, Di Paolo M, Turillazzi E, Frati P, et al. Autopsy findings in COVID-19-related deaths: a literature review. Forensic Sci Med Pathol. 2020. Maiese A, Manetti AC, La Russa R, Di Paolo M, Turillazzi E, Frati P, et al. Autopsy findings in COVID-19-related deaths: a literature review. Forensic Sci Med Pathol. 2020.
16.
Zurück zum Zitat Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe KJ, et al. EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med. 2013;54:647–58.CrossRef Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe KJ, et al. EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med. 2013;54:647–58.CrossRef
17.
Zurück zum Zitat Love C, Tomas MB, Tronco GG, Palestro CJ. FDG PET of infection and inflammation. RadioGraphics. 2005;25:1357–68.CrossRef Love C, Tomas MB, Tronco GG, Palestro CJ. FDG PET of infection and inflammation. RadioGraphics. 2005;25:1357–68.CrossRef
18.
Zurück zum Zitat Boellaard R, Delgado-Bolton R, Oyen WJG, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2014:42, 328–354. Boellaard R, Delgado-Bolton R, Oyen WJG, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2014:42, 328–354.
19.
Zurück zum Zitat Sollini M, Ciccarelli M, Cecconi M, Aghemo A, Morelli P, Gelardi F, et al. Vasculitis changes in COVID-19 survivors with persistent symptoms: an [18F]FDG-PET/CT study. Eur J Nucl Med Mol Imaging. 2020. Sollini M, Ciccarelli M, Cecconi M, Aghemo A, Morelli P, Gelardi F, et al. Vasculitis changes in COVID-19 survivors with persistent symptoms: an [18F]FDG-PET/CT study. Eur J Nucl Med Mol Imaging. 2020.
20.
Zurück zum Zitat Slart RHJA. FDG-PET/CT(a) imaging in large vessel vasculitis and polymyalgia rheumatica: joint procedural recommendation of the EANM, SNMMI, and the PET Interest Group (PIG), and endorsed by the ASNC. Eur J Nucl Med Mol ImagingSpringer. 2018;45:1250–69.CrossRef Slart RHJA. FDG-PET/CT(a) imaging in large vessel vasculitis and polymyalgia rheumatica: joint procedural recommendation of the EANM, SNMMI, and the PET Interest Group (PIG), and endorsed by the ASNC. Eur J Nucl Med Mol ImagingSpringer. 2018;45:1250–69.CrossRef
21.
Zurück zum Zitat Huang YC, Hsu CC, Huang P, Yin TK, Chiu NT, Wang PW, et al. The changes in brain metabolism in people with activated brown adipose tissue: a PET study. Neuroimage. 2011. Huang YC, Hsu CC, Huang P, Yin TK, Chiu NT, Wang PW, et al. The changes in brain metabolism in people with activated brown adipose tissue: a PET study. Neuroimage. 2011.
22.
Zurück zum Zitat Hua C, Merchant TE, Li X, Li Y, Shulkin BL. Establishing age-associated normative ranges of the cerebral 18F-FDG uptake ratio in children. J Nucl Med. 2015;56:575–9.CrossRef Hua C, Merchant TE, Li X, Li Y, Shulkin BL. Establishing age-associated normative ranges of the cerebral 18F-FDG uptake ratio in children. J Nucl Med. 2015;56:575–9.CrossRef
23.
Zurück zum Zitat Friston KJ, Holmes AP, Worsley KJ, Poline J-P, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1994;2:189–210.CrossRef Friston KJ, Holmes AP, Worsley KJ, Poline J-P, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1994;2:189–210.CrossRef
24.
Zurück zum Zitat Della Rosa PA, Cerami C, Gallivanone F, Prestia A, Caroli A, Castiglioni I, et al. A standardized [18F]-FDG-PET template for spatial normalization in statistical parametric mapping of dementia. Neuroinformatics. 2014;12:575–93.CrossRef Della Rosa PA, Cerami C, Gallivanone F, Prestia A, Caroli A, Castiglioni I, et al. A standardized [18F]-FDG-PET template for spatial normalization in statistical parametric mapping of dementia. Neuroinformatics. 2014;12:575–93.CrossRef
25.
Zurück zum Zitat Hajian-Tilaki K. Sample size estimation in diagnostic test studies of biomedical informatics. J Biomed Inform. Elsevier Inc.; 2014;48:193–204. Hajian-Tilaki K. Sample size estimation in diagnostic test studies of biomedical informatics. J Biomed Inform. Elsevier Inc.; 2014;48:193–204.
26.
Zurück zum Zitat Lieberman MD, Cunningham WA. Type I and type II error concerns in fMRI research: re-balancing the scale. Soc Cogn Affect Neurosci. 2009;4:423–8.CrossRef Lieberman MD, Cunningham WA. Type I and type II error concerns in fMRI research: re-balancing the scale. Soc Cogn Affect Neurosci. 2009;4:423–8.CrossRef
27.
Zurück zum Zitat Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020;41:3038–44.CrossRef Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020;41:3038–44.CrossRef
28.
Zurück zum Zitat Karimi-Galougahi M, Yousefi-Koma A, Bakhshayeshkaram M, Raad N, Haseli S. 18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19. Acad Radiol. 2020;27:1042–3.CrossRef Karimi-Galougahi M, Yousefi-Koma A, Bakhshayeshkaram M, Raad N, Haseli S. 18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19. Acad Radiol. 2020;27:1042–3.CrossRef
29.
Zurück zum Zitat Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128:1764–77.CrossRef Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128:1764–77.CrossRef
30.
Zurück zum Zitat Marini C, Morbelli S, Cistaro A, Campi C, Caponnetto C, Bauckneht M, et al. Interplay between spinal cord and cerebral cortex metabolism in amyotrophic lateral sclerosis. Brain. 2018;141:2272–9.CrossRef Marini C, Morbelli S, Cistaro A, Campi C, Caponnetto C, Bauckneht M, et al. Interplay between spinal cord and cerebral cortex metabolism in amyotrophic lateral sclerosis. Brain. 2018;141:2272–9.CrossRef
31.
Zurück zum Zitat Bai Y, Xu J, Chen L, Fu C, Kang Y, Zhang W, et al. Inflammatory response in lungs and extrapulmonary sites detected by [18F] fluorodeoxyglucose PET/CT in convalescing COVID-19 patients tested negative for coronavirus. Eur J Nucl Med Mol Imaging. Eur J Nucl Med Mol Imaging. 2021. Bai Y, Xu J, Chen L, Fu C, Kang Y, Zhang W, et al. Inflammatory response in lungs and extrapulmonary sites detected by [18F] fluorodeoxyglucose PET/CT in convalescing COVID-19 patients tested negative for coronavirus. Eur J Nucl Med Mol Imaging. Eur J Nucl Med Mol Imaging. 2021.
32.
Zurück zum Zitat Chefer S, Thomasson D, Seidel J, Reba RC, Bohannon JK, Lackemeyer MG, et al. Modeling [18F]-FDG lymphoid tissue kinetics to characterize nonhuman primate immune response to Middle East respiratory syndrome-coronavirus aerosol challenge. EJNMMI Res. 2015;5:65.CrossRef Chefer S, Thomasson D, Seidel J, Reba RC, Bohannon JK, Lackemeyer MG, et al. Modeling [18F]-FDG lymphoid tissue kinetics to characterize nonhuman primate immune response to Middle East respiratory syndrome-coronavirus aerosol challenge. EJNMMI Res. 2015;5:65.CrossRef
33.
Zurück zum Zitat Becker RC. COVID-19 update: Covid-19-associated coagulopathy. J Thromb Thrombolysis Nature Publishing Group. 2020;50:54–67.CrossRef Becker RC. COVID-19 update: Covid-19-associated coagulopathy. J Thromb Thrombolysis Nature Publishing Group. 2020;50:54–67.CrossRef
34.
Zurück zum Zitat Becker RC. COVID-19-associated vasculitis and vasculopathy. J Thromb Thrombolysis Springer. 2020:1–13. Becker RC. COVID-19-associated vasculitis and vasculopathy. J Thromb Thrombolysis Springer. 2020:1–13.
35.
Zurück zum Zitat Pijl JP, Kwee TC, Slart RHJA, Yakar D, Wouthuyzen-Bakker M, Glaudemans AWJM. Clinical implications of increased uptake in bone marrow and spleen on FDG-PET in patients with bacteremia. Eur J Nucl Med Mol Imaging. 2020. Pijl JP, Kwee TC, Slart RHJA, Yakar D, Wouthuyzen-Bakker M, Glaudemans AWJM. Clinical implications of increased uptake in bone marrow and spleen on FDG-PET in patients with bacteremia. Eur J Nucl Med Mol Imaging. 2020.
36.
Zurück zum Zitat Bahce I, Vos CG, Dickhoff C, Hartemink KJ, Dahele M, Smit EF, et al. Metabolic activity measured by FDG PET predicts pathological response in locally advanced superior sulcus NSCLC. Lung Cancer. 2014;85:205–12.CrossRef Bahce I, Vos CG, Dickhoff C, Hartemink KJ, Dahele M, Smit EF, et al. Metabolic activity measured by FDG PET predicts pathological response in locally advanced superior sulcus NSCLC. Lung Cancer. 2014;85:205–12.CrossRef
37.
Zurück zum Zitat Kazama T, Swanston N, Podoloff DA, Macapinlac HA. Effect of colony-stimulating factor and conventional- or high-dose chemotherapy on FDG uptake in bone marrow. Eur J Nucl Med Mol Imaging. 2005;32:1406–11.CrossRef Kazama T, Swanston N, Podoloff DA, Macapinlac HA. Effect of colony-stimulating factor and conventional- or high-dose chemotherapy on FDG uptake in bone marrow. Eur J Nucl Med Mol Imaging. 2005;32:1406–11.CrossRef
38.
Zurück zum Zitat Dyall J, Johnson RF, Chefer S, Leyson C, Thomasson D, Seidel J, et al. [18F]-Fluorodeoxyglucose uptake in lymphoid tissue serves as a predictor of disease outcome in the nonhuman primate model of monkeypox virus infection. McFadden G, editor. J Virol. 2017;91. Dyall J, Johnson RF, Chefer S, Leyson C, Thomasson D, Seidel J, et al. [18F]-Fluorodeoxyglucose uptake in lymphoid tissue serves as a predictor of disease outcome in the nonhuman primate model of monkeypox virus infection. McFadden G, editor. J Virol. 2017;91.
39.
Zurück zum Zitat Stephen G. Baum M. Adult multisystem inflammatory syndrome associated with COVID-19. NEJM J Watch; 2020;2020. Stephen G. Baum M. Adult multisystem inflammatory syndrome associated with COVID-19. NEJM J Watch; 2020;2020.
40.
Zurück zum Zitat Xiang YT, Yu X, Ungvari GS, Correll CU, Chiu HFK. Outcomes of SARS survivors in China: not only physical and psychiatric co-morbidities. East Asian Arch Psychiatr. 2014;24:37–8. Xiang YT, Yu X, Ungvari GS, Correll CU, Chiu HFK. Outcomes of SARS survivors in China: not only physical and psychiatric co-morbidities. East Asian Arch Psychiatr. 2014;24:37–8.
41.
Zurück zum Zitat Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018.
42.
Zurück zum Zitat Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv. Cold Spring Harbor Laboratory Press; 2020;2020.10.19.20214494. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv. Cold Spring Harbor Laboratory Press; 2020;2020.10.19.20214494.
Metadaten
Titel
Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study
verfasst von
Martina Sollini
Silvia Morbelli
Michele Ciccarelli
Maurizio Cecconi
Alessio Aghemo
Paola Morelli
Silvia Chiola
Fabrizia Gelardi
Arturo Chiti
Publikationsdatum
07.03.2021
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 10/2021
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-021-05294-3

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