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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 29-04-2022 | SARS-CoV-2 | Original Article

Lymphopenia in patients affected by SARS-CoV-2 infection is caused by margination of lymphocytes in large bowel: an [¹⁸F]FDG PET/CT study

Authors: Alberto Signore, Chiara Lauri, Marzia Colandrea, Marco Di Girolamo, Erika Chiodo, Chiara Maria Grana, Giuseppe Campagna, Antonio Aceti

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 10/2022

Abstract

Background

To investigate the cause of lymphopenia in patients with newly diagnosed COVID-19, we measured [¹⁸F]FDG uptake in several tissues, including the ileum, right colon, and caecum at diagnosis and after recovery and correlated these measurements with haematological parameters.

Methods

We studied, by [¹⁸F]FDG PET/CT, 18 newly diagnosed patients with COVID-19. Regions of interest were drawn over major organs and in the terminal ileum, caecum, and right colon, where the bowel wall was evaluable. Five patients were re-examined after recovery, and three of them also performed a white blood cell scan with ^99mTc-HMPAO-WBC on both occasions. Complete blood count was performed on both occasions, and peripheral blood lymphocyte subsets were measured at diagnosis. Data were analysed by a statistician.

Results

Patients had moderate severity COVID-19 syndrome. Basal [¹⁸F]FDG PET/CT showed focal lung uptake corresponding to hyperdense areas at CT. We also found high spleen, ileal, caecal, and colonic activity as compared to 18 control subjects. At recovery, hypermetabolic tissues tended to normalize, but activity in the caecum remained higher than in controls. Regression analyses showed an inverse correlation between CD4 + lymphocytes and [¹⁸F]FDG uptake in the caecum and colon and a direct correlation between CD8 + lymphocytes and [¹⁸F]FDG uptake in lungs and bone marrow. WBC scans showed the presence of leukocytes in the caecum and colon that disappeared at recovery.

Conclusions

These findings indicate that lymphopenia in COVID-19 patients is associated with large bowel inflammation supporting the hypothesis that CD4 + lymphocytes migrate to peripheral lymphoid tissues in the bowel.

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Sarzi-Puttini P, Giorgi V, Sirotti S, Marotto D, Ardizzone S, Rizzardini G, Antinori S, Galli M. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020;38(2):337–42.CrossRef

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `cytokine storm’ in COVID-19. J Infect. 2020;80(6):607–13. https://doi.org/10.1016/j.jinf.2020.03.037 (Epub 2020 Apr 10. PMID: 32283152; PMCID: PMC7194613).CrossRefPubMedPubMedCentral

He L, Ding Y, Zhang Q, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol. 2006;210:288–97.CrossRef

Okabayashi T, Kariwa H, Yokota S, et al. Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections. J Med Virol. 2006;78:417–24.CrossRef

Inoue K, Goto R, Okada K, Kinomura S, Fukuda H. A bone marrow F-18 FDG uptake exceeding the liver uptake may indicate bone marrow hyperactivity. Ann Nucl Med. 2009;23(7):643–9. https://doi.org/10.1007/s12149-009-0286-9.CrossRefPubMed

Ahn SS, Hwang SH, Jung SM, et al. Evaluation of spleen glucose metabolism using ¹⁸F-FDG PET/CT in patients with febrile autoimmune disease. J Nucl Med. 2017;58(3):507–13. https://doi.org/10.2967/jnumed.116.180729.CrossRefPubMed

Ahn SS, Hwang SH, Jung SM, et al. The clinical utility of splenic fluorodeoxyglucose uptake for diagnosis and prognosis in patients with macrophage activation syndrome. Medicine (Baltimore). 2017;96(34):e7901. https://doi.org/10.1097/MD.0000000000007901.CrossRef

Boursier C, Duval X, Mahida B, et al. Hypermetabolism of the spleen or bone marrow is an additional albeit indirect sign of infective endocarditis at FDG-PET. J Nucl Cardiol. 2021;28:2533–42. https://doi.org/10.1007/s12350-020-02050-2.CrossRefPubMed

De Vries EF, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2010. 37(4):842-8. Erratum in Eur J Nucl Med Mol Imaging. 2010;37(6):1235.CrossRef

10.

Signore A, Glaudemans AW, Malviya G, Lazzeri E, Prandini N, Viglietti AL, De Vries EF, Dierckx RA. Development and testing of a new disposable sterile device for labelling white blood cells. Q J Nucl Med Mol Imaging. 2012;56(4):400–8.PubMed

11.

Signore A, Sconfienza LM, Borens O, Glaudemans AWJM, Cassar-Pullicino V, Trampuz A, Winkler H, Gheysens O, Vanhoenacker FMHM, Petrosillo N, et al. Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement). Eur J Nucl Med Mol Imaging. 2019;46:971–88.CrossRef

12.

Signore A, Jamar F, Israel O, Buscombe J, Martin-Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging. 2018;45:1816–31.CrossRef

13.

Bai Y, Xu J, Chen L, Fu C, Kang Y, Zhang W, Fakhri GE, Gu J, Shao F, Wang M. 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. 2021;9:1–12. https://doi.org/10.1007/s00259-020-05083-4.CrossRef

14.

Li Y, Xia L. Coronavirus Disease 2019 (COVID-19): Role of chest CT in diagnosis and management. AJR Am J Roentgenol. 2020;4:1–7. https://doi.org/10.2214/AJR.20.22954.CrossRef

15.

Li M, Lei P, Zeng B, Li Z, Yu P, Fan B, Wang C, Li Z, Zhou J, Hu S, Liu H. Coronavirus disease (COVID-19): spectrum of CT findings and temporal progression of the disease. Acad Radiol. 2020;27(5):603–8. https://doi.org/10.1016/j.acra.2020.03.003 (Epub 2020 Mar 20).CrossRefPubMedPubMedCentral

16.

Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, Diao K, Lin B, Zhu X, Li K, Li S, Shan H, Jacobi A, Chung M. Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology. 2020;20:200463. https://doi.org/10.1148/radiol.2020200463.CrossRef

17.

Yeh R, Elsakka A, Wray R, Johnston RP, Gangai NC, Yarmohammadi H, Schoder H, Pandit-Taskar N. FDG PET/CT imaging features and clinical utility in COVID-19. Clin Imaging. 2021;80:262–7. https://doi.org/10.1016/j.clinimag.2021.08.002 (Epub 2021 Aug 8. PMID: 34418873; PMCID: PMC8349436).CrossRefPubMedPubMedCentral

18.

Deng Y, Lei L, Chen Y, Zhang W. The potential added value of FDG PET/CT for COVID-19 pneumonia. Eur J Nucl Med Mol Imaging. 2020;21:1–2. https://doi.org/10.1007/s00259-020-04767-1 (Online ahead of print).CrossRef

19.

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunologic features in severe and moderate coronavirus disease 2019. J Clin Invest. 2020;27:137244. https://doi.org/10.1172/JCI137244.CrossRef

20.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China Lancet. 2020;395(10223):497–506. https://doi.org/10.1016/S0140-6736(20)30183-5.CrossRefPubMed

21.

Malviya G, D’Alessandria C, Bonanno E, Vexler V, Massari R, Trotta C, Scopinaro F, Dierckx R, Signore A. Radiolabeled humanized anti-CD3 monoclonal antibody visilizumab for imaging human T-lymphocytes. J Nucl Med. 2009;50(10):1683–91. https://doi.org/10.2967/jnumed.108.059485 (Epub 2009 Sep 16 PMID: 19759100).CrossRefPubMed

22.

Haberecker M, Schwarz EI, Steiger P, Frontzek K, Scholkmann F, Zeng X, Höller S, Moch H, Varga Z. Autopsy-based pulmonary and vascular pathology: pulmonary endotheliitis and multi-organ involvement in COVID-19 associated deaths. Respiration. 2022;101(2):155–65. https://doi.org/10.1159/000518914 (Epub 2021 Sep 15).CrossRefPubMed

23.

Falasca L, Nardacci R, Colombo D, Lalle E, Di Caro A, Nicastri E, Antinori A, Petrosillo N, Marchioni L, Biava G, D’Offizi G, Palmieri F, Goletti D, Zumla A, Ippolito G, Piacentini M, Del Nonno F. Postmortem findings in Italian patients with COVID-19: a descriptive full autopsy study of cases with and without comorbidities. J Infect Dis. 2020;222(11):1807–15. https://doi.org/10.1093/infdis/jiaa578 (PMID:32914853;PMCID:PMC7543426).CrossRefPubMed

24.

Buscarini E, Manfredi G, Brambilla G, Menozzi F, Londoni C, Alicante S, Iiritano E, Romeo S, Pedaci M, Benelli G, Canetta C, La Piana G, Merli G, Scartabellati A, Viganò G, Sfogliarini R, Melilli G, Assandri R, Cazzato D, Rossi DS, Usai S, Tramacere I, Pellegata G, Lauria G. GI symptoms as early signs of COVID-19 in hospitalised Italian patients. Gut. 2020;69(8):1547–8. https://doi.org/10.1136/gutjnl-2020-321434 (Epub 2020 May 14. PMID: 32409587; PMCID: PMC7246093).CrossRefPubMed

25.

Brogna B, Brogna C, Petrillo M, Conte AM, Benincasa G, Montano L, Piscopo M. SARS-CoV-2 detection in fecal sample from a patient with typical findings of COVID-19 pneumonia on CT but negative to multiple SARS-CoV-2 RT-PCR tests on oropharyngeal and nasopharyngeal swab samples. Medicina (Kaunas). 2021;57(3):290. https://doi.org/10.3390/medicina57030290 (PMID:33804646;PMCID:PMC8003654).CrossRef

26.

Trevelin SC, Pickering S, Todd K, Bishop C, Pitcher M, Garrido Mesa J, Montorsi L, Spada F, Petrov N, Green A, Shankar-Hari M, Neil SJD, Spencer J. Disrupted Peyer’s patch microanatomy in COVID-19 including germinal centre atrophy independent of local virus. Front Immunol. 2022;13:838328. https://doi.org/10.3389/fimmu.2022.838328 (PMID:35251032; PMCID: PMC8893224).CrossRefPubMedPubMedCentral

27.

Zheng J, Liu Y. 99mTc-leukocyte scintigraphy revealed viral pulmonary infection in a COVID-19 patient. Clin Nucl Med. 2020;45(10):821–3. https://doi.org/10.1097/RLU.0000000000003219 (PMID:32701817;PMCID:PMC7473795).CrossRefPubMedPubMedCentral

28.

Liu C, Zhou J, Xia L, Cheng X, Lu D. 18F-FDG PET/CT and serial chest CT findings in a COVID-19 patient with dynamic clinical characteristics in different period. Clin Nucl Med. 2020;45(6):495–6. https://doi.org/10.1097/RLU.0000000000003068 (PMID:32332319;PMCID:PMC7268872).CrossRefPubMed

29.

Colandrea M, Gilardi L, Travaini LL, Fracassi SLV, Funicelli L, Grana CM. 18F-FDG PET/CT in asymptomatic patients with COVID-19: the submerged iceberg surfaces. Jpn J Radiol. 2020;38(11):1007–11. https://doi.org/10.1007/s11604-020-01006-3 (Epub 2020 Jun 23. PMID: 32577869; PMCID: PMC7310604).CrossRefPubMedPubMedCentral

30.

Halsey R, Priftakis D, Mackenzie S, Wan S, Davis LM, Lilburn D, Thornton A, Papathanasiou N, Gnanasegaran G, Bomanji J. COVID-19 in the act: incidental 18F-FDG PET/CT findings in asymptomatic patients and those with symptoms not primarily correlated with COVID-19 during the United Kingdom coronavirus lockdown. Eur J Nucl Med Mol Imaging. 2021;48(1):269–81. https://doi.org/10.1007/s00259-020-04972-y (Epub 2020 Aug 5. PMID: 32761260; PMCID: PMC7406218).CrossRefPubMed

31.

Tavaré R, McCracken MN, Zettlitz KA, Salazar FB, Olafsen T, Witte ON, Wu AM. Immuno-PET of murine T cell reconstitution postadoptive stem cell transplantation using anti-CD4 and anti-CD8 cys-diabodies. J Nucl Med. 2015;56(8):1258–64. https://doi.org/10.2967/jnumed.114.153338 (Epub 2015 May 7. PMID: 25952734; PMCID: PMC4859343).CrossRefPubMed

32.

Di Gialleonardo V, Signore A, Glaudemans AW, Dierckx RA, De Vries EF. N-(4–18F-fluorobenzoyl)interleukin-2 for PET of human-activated T lymphocytes. J Nucl Med. 2012;53(5):679–86. https://doi.org/10.2967/jnumed.111.091306 (Epub 2012 Apr 12 PMID: 22499614).CrossRefPubMed

Title: Lymphopenia in patients affected by SARS-CoV-2 infection is caused by margination of lymphocytes in large bowel: an [18F]FDG PET/CT study
Authors: Alberto Signore
Chiara Lauri
Marzia Colandrea
Marco Di Girolamo
Erika Chiodo
Chiara Maria Grana
Giuseppe Campagna
Antonio Aceti
Publication date: 29-04-2022
Publisher: Springer Berlin Heidelberg
Keywords: SARS-CoV-2
Lymphopenia
Pneumonia
COVID-19
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 10/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05801-0

At a glance: The STEP trials

Springer Medicine

Lymphopenia in patients affected by SARS-CoV-2 infection is caused by margination of lymphocytes in large bowel: an [¹⁸F]FDG PET/CT study

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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