Top

Published in:

Open Access 01-11-2021 | SARS-CoV-2 | Original Article

Longitudinal Analysis of Inflammatory Response to SARS-CoV-2 in the Upper Respiratory Tract Reveals an Association with Viral Load, Independent of Symptoms

Authors: Diem-Lan Vu, Paola Martinez-Murillo, Fiona Pigny, Maria Vono, Benjamin Meyer, Christiane S. Eberhardt, Sylvain Lemeille, Elodie Von Dach, Géraldine Blanchard-Rohner, Isabella Eckerle, Angela Huttner, Claire-Anne Siegrist, Laurent Kaiser, Arnaud M. Didierlaurent

Published in: Journal of Clinical Immunology | Issue 8/2021

Abstract

Background

SARS-CoV-2 infection leads to high viral loads in the upper respiratory tract that may be determinant in virus dissemination. The extent of intranasal antiviral response in relation to symptoms is unknown. Understanding how local innate responses control virus is key in the development of therapeutic approaches.

Methods

SARS-CoV-2-infected patients were enrolled in an observational study conducted at the Geneva University Hospitals, Switzerland, investigating virological and immunological characteristics. Nasal wash and serum specimens from a subset of patients were collected to measure viral load, IgA specific for the S1 domain of the spike protein, and a cytokine panel at different time points after infection; cytokine levels were analyzed in relation to symptoms.

Results

Samples from 13 SARS-CoV-2-infected patients and six controls were analyzed. We found an increase in CXCL10 and IL-6, whose levels remained elevated for up to 3 weeks after symptom onset. SARS-CoV-2 infection also induced CCL2 and GM-CSF, suggesting local recruitment and activation of myeloid cells. Local cytokine levels correlated with viral load but not with serum cytokine levels, nor with specific symptoms, including anosmia. Some patients had S1-specific IgA in the nasal cavity while almost none had IgG.

Conclusion

The nasal epithelium is an active site of cytokine response against SARS-CoV-2 that can last more than 2 weeks; in this mild COVID-19 cohort, anosmia was not associated with increases in any locally produced cytokines.

Available only for authorised users

Wang Y, Zhang L, Sang L, Ye F, Ruan S, Zhong B, et al. Kinetics of viral load and antibody response in relation to COVID-19 severity. J Clin Invest. 2020;130(10):5235–44. https://doi.org/10.1172/JCI138759.CrossRefPubMedPubMedCentral

Vetter P, Eberhardt CS, Meyer B, Martinez Murillo PA, Torriani G, Pigny F, et al. Daily viral kinetics and innate and adaptive immune response assessment in COVID-19: a case series. mSphere. 2020. https://doi.org/10.1128/mSphere.00827-20.CrossRefPubMedPubMedCentral

Sun J, Tang X, Bai R, Liang C, Zeng L, Lin H, et al. The kinetics of viral load and antibodies to SARS-CoV-2. Clin Microbiol Infect. 2020;26(12):1690 e1–e4. https://doi.org/10.1016/j.cmi.2020.08.043.CrossRef

Cevik M, Tate M, Lloyd O, Maraolo AE, Schafers J, Ho A. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe. 2020. https://doi.org/10.1016/S2666-5247(20)30172-5.CrossRefPubMedPubMedCentral

Ra SH, Lim JS, Kim GU, Kim MJ, Jung J, Kim SH. Upper respiratory viral load in asymptomatic individuals and mildly symptomatic patients with SARS-CoV-2 infection. Thorax. 2020. https://doi.org/10.1136/thoraxjnl-2020-215042.CrossRefPubMed

Lee IT, Nakayama T, Wu CT, Goltsev Y, Jiang S, Gall PA, et al. ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nat Commun. 2020;11(1):5453. https://doi.org/10.1038/s41467-020-19145-6.CrossRefPubMedPubMedCentral

Kim SE, Jeong HS, Yu Y, Shin SU, Kim S, Oh TH, et al. Viral kinetics of SARS-CoV-2 in asymptomatic carriers and presymptomatic patients. Int J Infect Dis. 2020;95:441–3. https://doi.org/10.1016/j.ijid.2020.04.083.CrossRefPubMedPubMedCentral

Sungnak W, Huang N, Becavin C, Berg M, Queen R, Litvinukova M, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681–7. https://doi.org/10.1038/s41591-020-0868-6.CrossRefPubMedPubMedCentral

Hou YJ, Okuda K, Edwards CE, Martinez DR, Asakura T, Dinnon KH 3rd, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell. 2020;182(2):429-46 e14. https://doi.org/10.1016/j.cell.2020.05.042.CrossRefPubMedPubMedCentral

10.

Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020;382(12):1177–9. https://doi.org/10.1056/NEJMc2001737.CrossRefPubMedPubMedCentral

11.

Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020;26(6):842–4. https://doi.org/10.1038/s41591-020-0901-9.CrossRefPubMed

12.

Alon R, Sportiello M, Kozlovski S, Kumar A, Reilly EC, Zarbock A, et al. Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19. Nat Rev Immunol. 2020. https://doi.org/10.1038/s41577-020-00470-2.CrossRefPubMedPubMedCentral

13.

Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020;277(8):2251–61. https://doi.org/10.1007/s00405-020-05965-1.CrossRefPubMedPubMedCentral

14.

Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2020. https://doi.org/10.1038/s41593-020-00758-5.CrossRefPubMed

15.

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, et al. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza. Nat Immunol. 2018;19(6):625–35. https://doi.org/10.1038/s41590-018-0111-5.CrossRefPubMedPubMedCentral

16.

Oshansky CM, Gartland AJ, Wong SS, Jeevan T, Wang D, Roddam PL, et al. Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load. Am J Respir Crit Care Med. 2014;189(4):449–62. https://doi.org/10.1164/rccm.201309-1616OC.CrossRefPubMedPubMedCentral

17.

Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, et al. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe. 2020;27(6):883-90 e2. https://doi.org/10.1016/j.chom.2020.04.017.CrossRefPubMedPubMedCentral

18.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. 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.CrossRefPubMedPubMedCentral

19.

Gustine JN, Jones D. Immunopathology of hyperinflammation in COVID-19. Am J Pathol. 2020. https://doi.org/10.1016/j.ajpath.2020.08.009.CrossRefPubMed

20.

Ramlall V, Thangaraj PM, Meydan C, Foox J, Butler D, Kim J, et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med. 2020;26(10):1609–15. https://doi.org/10.1038/s41591-020-1021-2.CrossRefPubMedPubMedCentral

21.

Montalvo Villalba MC, Valdes Ramirez O, Mune Jimenez M, Arencibia Garcia A, Martinez Alfonso J, Gonzalez Baez G, et al. Interferon gamma, TGF-beta1 and RANTES expression in upper airway samples from SARS-CoV-2 infected patients. Clin Immunol. 2020;220:108576. https://doi.org/10.1016/j.clim.2020.108576.CrossRefPubMedPubMedCentral

22.

Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Castaneda G, et al. Upper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses. Nat Commun. 2020;11(1):5854. https://doi.org/10.1038/s41467-020-19587-y.CrossRefPubMedPubMedCentral

23.

Lieberman NAP, Peddu V, Xie H, Shrestha L, Huang ML, Mears MC, et al. In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. PLoS Biol. 2020;18(9):e3000849. https://doi.org/10.1371/journal.pbio.3000849.CrossRefPubMedPubMedCentral

24.

Gallo O, Locatello LG, Mazzoni A, Novelli L, Annunziato F. The central role of the nasal microenvironment in the transmission, modulation, and clinical progression of SARS-CoV-2 infection. Mucosal Immunol. 2020. https://doi.org/10.1038/s41385-020-00359-2.CrossRefPubMedPubMedCentral

25.

Butler DJ, Mozsary C, Meydan C, Danko D, Foox J, Rosiene J et al. Shotgun transcriptome and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactions. bioRxiv. 2020. https://doi.org/10.1101/2020.04.20.048066.

26.

Lopez J, Mommert M, Mouton W, Pizzorno A, Brengel-Pesce K, Mezidi M, et al. Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs. J Exp Med. 2021. https://doi.org/10.1084/jem.20211211.CrossRefPubMedPubMedCentral

27.

Hospital GU. Procèdure selon le type de prélèvement: Frottis naso-pharyngé (FNP), frottis oro-pharyngé (FOP), rinçage nasal. Geneva University Hospital; 2020.

28.

Calame A, Mazza L, Renzoni A, Kaiser L, Schibler M. Sensitivity of nasopharyngeal, oropharyngeal, and nasal wash specimens for SARS-CoV-2 detection in the setting of sampling device shortage. Eur J Clin Microbiol Infect Dis. 2020. https://doi.org/10.1007/s10096-020-04039-8.CrossRefPubMedPubMedCentral

29.

Kaiser L, Fritz RS, Straus SE, Gubareva L, Hayden FG. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol. 2001;64(3):262–8. https://doi.org/10.1002/jmv.1045.CrossRefPubMed

30.

Gritzfeld JF, Wright AD, Collins AM, Pennington SH, Wright AK, Kadioglu A, et al. Experimental human pneumococcal carriage. J Vis Exp. 2013. https://doi.org/10.3791/50115.CrossRefPubMedPubMedCentral

31.

Schibler M, Yerly S, Vieille G, Docquier M, Turin L, Kaiser L, et al. Critical analysis of rhinovirus RNA load quantification by real-time reverse transcription-PCR. J Clin Microbiol. 2012;50(9):2868–72. https://doi.org/10.1128/JCM.06752-11.CrossRefPubMedPubMedCentral

32.

Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020. https://doi.org/10.2807/1560-7917.ES.2020.25.3.2000045.CrossRefPubMedPubMedCentral

33.

Baggio S, L’Huillier AG, Yerly S, Bellon M, Wagner N, Rohr M, et al. SARS-CoV-2 viral load in the upper respiratory tract of children and adults with early acute COVID-19. Clin Infect Dis. 2020. https://doi.org/10.1093/cid/ciaa1157.CrossRef

34.

Meyer B, Torriani G, Yerly S, Mazza L, Calame A, Arm-Vernez I, et al. Validation of a commercially available SARS-CoV-2 serological immunoassay. Clin Microbiol Infect. 2020;26(10):1386–94. https://doi.org/10.1016/j.cmi.2020.06.024.CrossRefPubMedPubMedCentral

35.

Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363–74. https://doi.org/10.1038/s41577-020-0311-8.CrossRefPubMed

36.

Bonaventura A, Vecchie A, Wang TS, Lee E, Cremer PC, Carey B, et al. Targeting GM-CSF in COVID-19 pneumonia: rationale and strategies. Front Immunol. 2020;11:1625. https://doi.org/10.3389/fimmu.2020.01625.CrossRefPubMedPubMedCentral

37.

Hartenian E, Nandakumar D, Lari A, Ly M, Tucker JM, Glaunsinger BA. The molecular virology of coronaviruses. J Biol Chem. 2020;295(37):12910–34. https://doi.org/10.1074/jbc.REV120.013930.CrossRefPubMedPubMedCentral

38.

Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369(6504):718–24. https://doi.org/10.1126/science.abc6027.CrossRefPubMedPubMedCentral

39.

Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181(5):1036-45 e9. https://doi.org/10.1016/j.cell.2020.04.026.CrossRefPubMedPubMedCentral

40.

Xu G, Qi F, Li H, Yang Q, Wang H, Wang X, et al. The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. Cell Discov. 2020;6:73. https://doi.org/10.1038/s41421-020-00225-2.CrossRefPubMedPubMedCentral

41.

Sterlin D, Mathian A, Miyara M, Mohr A, Anna F, Claër L, et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med. 2021;13(577):2223. https://doi.org/10.1126/scitranslmed.abd2223.CrossRef

42.

Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, et al. Immunology of COVID-19: current state of the science. Immunity. 2020;52(6):910–41. https://doi.org/10.1016/j.immuni.2020.05.002.CrossRefPubMedPubMedCentral

43.

Saussez S, Lechien JR, Hopkins C. Anosmia: an evolution of our understanding of its importance in COVID-19 and what questions remain to be answered. Eur Arch Otorhinolaryngol. 2020. https://doi.org/10.1007/s00405-020-06285-0.CrossRefPubMedPubMedCentral

44.

Chen M, Shen W, Rowan NR, Kulaga H, Hillel A, Ramanatha Jr. M, et al. Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J. 2020. https://doi.org/10.1183/13993003.01948-2020.CrossRefPubMedPubMedCentral

45.

Laham FR, Israele V, Casellas JM, Garcia AM, Lac Prugent CM, Hoffman SJ, et al. Differential production of inflammatory cytokines in primary infection with human metapneumovirus and with other common respiratory viruses of infancy. J Infect Dis. 2004;189(11):2047–56. https://doi.org/10.1086/383350.CrossRefPubMed

46.

Hansel TT, Tunstall T, Trujillo-Torralbo MB, Shamji B, Del-Rosario A, Dhariwal J, et al. A comprehensive evaluation of nasal and bronchial cytokines and chemokines following experimental rhinovirus infection in allergic asthma: increased interferons (IFN-gamma and IFN-lambda) and Type 2 inflammation (IL-5 and IL-13). EBioMedicine. 2017;19:128–38. https://doi.org/10.1016/j.ebiom.2017.03.033.CrossRefPubMedPubMedCentral

47.

Cangiano G, Proietti E, Kronig MN, Kieninger E, Sadeghi CD, Gorgievski M, et al. Lactate dehydrogenase concentration in nasal wash fluid indicates severity of rhinovirus-induced wheezy bronchitis in preschool children. Pediatr Infect Dis J. 2014;33(12):1285–7. https://doi.org/10.1097/INF.0000000000000420.CrossRefPubMed

48.

Cagigi A, Yu M, Falck-Jones S, Vangeti S, Österberg B, Åhlberg E et al. Airway antibodies wane rapidly after COVID-19 but B cell memory is generated across disease severity. medRxiv. 2020. https://doi.org/10.1101/2020.11.25.20238592.

49.

Cervia C, Nilsson J, Zurbuchen Y, Valaperti A, Schreiner J, Wolfensberger A, et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. J Allergy Clin Immunol. 2021;147(2):545-57.e9. https://doi.org/10.1016/j.jaci.2020.10.040.CrossRefPubMed

50.

Dos Santos JMB, Soares CP, Monteiro FR, Mello R, DoAmaral JB, Aguiar AS, et al. In nasal mucosal secretions, distinct IFN and IgA responses are found in severe and mild SARS-CoV-2 infection. Front Immunol. 2021;12:595343. https://doi.org/10.3389/fimmu.2021.595343.CrossRefPubMedPubMedCentral

Title: Longitudinal Analysis of Inflammatory Response to SARS-CoV-2 in the Upper Respiratory Tract Reveals an Association with Viral Load, Independent of Symptoms
Authors: Diem-Lan Vu
Paola Martinez-Murillo
Fiona Pigny
Maria Vono
Benjamin Meyer
Christiane S. Eberhardt
Sylvain Lemeille
Elodie Von Dach
Géraldine Blanchard-Rohner
Isabella Eckerle
Angela Huttner
Claire-Anne Siegrist
Laurent Kaiser
Arnaud M. Didierlaurent
Publication date: 01-11-2021
Publisher: Springer US
Keywords: SARS-CoV-2
Cytokines
Anosmia
Published in: Journal of Clinical Immunology / Issue 8/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-021-01134-z

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Longitudinal Analysis of Inflammatory Response to SARS-CoV-2 in the Upper Respiratory Tract Reveals an Association with Viral Load, Independent of Symptoms

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 8/2021

CD8 + T Cells Exhibit an Exhausted Phenotype in Hemophagocytic Lymphohistiocytosis

Self-Limited COVID-19 in a Patient with Artemis Hypomorphic SCID

Long-Term Efficacy of Anakinra in Cryopyrin-Associated Periodic Syndrome: Focus on Destructive Arthropathy

Argentinian X-MAID Siblings with One of Them Manifesting a Rare Ophthalmological Complication

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

Perceptions Around Lung Transplant–Associated Hypogammaglobulinemia

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page