Inflammatory Markers, Pulmonary Function, and Clinical Symptoms in Acute COVID-19 Among Non-Hospitalized Adolescents and Young Adults

Lise Lund Berven, Joel Selvakumar, Lise Havdal, Tonje Stiansen-Sonerud, Gunnar Einvik, Truls Michael Leegaard, Trygve Tjade, Annika E Michelsen, Tom Eirik Mollnes, Vegard Bruun Bratholm Wyller, Lise Lund Berven, Joel Selvakumar, Lise Havdal, Tonje Stiansen-Sonerud, Gunnar Einvik, Truls Michael Leegaard, Trygve Tjade, Annika E Michelsen, Tom Eirik Mollnes, Vegard Bruun Bratholm Wyller

Abstract

Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers.

Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 - 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group.

Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively.

Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1β, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers.

Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

Keywords: SARS-CoV-2; adolescents; cohort study; inflammatory markers; non-hospitalized.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Lund Berven, Selvakumar, Havdal, Stiansen-Sonerud, Einvik, Leegaard, Tjade, Michelsen, Mollnes and Wyller.

Figures

Figure 1
Figure 1
Flowchart of the LoTECA project (Long-Term Effects of COVID-19 in Adolescents). The present study report findings from baseline investigations. Follow-up is ongoing.

References

    1. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. . A Pneumonia Outbreak Associated With a New Coronavirus of Probable Bat Origin. Nature (2020) 579(7798):270–3. doi: 10.1038/s41586-020-2012-7
    1. Lucas C, Wong P, Klein J, Castro TBR, Silvia J, Sundaram M, et al. . Longitudinal Analyses Reveal Immunological Misfiring in Severe COVID-19. Nature (2020) 584(7821):463–9. doi: 10.1038/s41586-020-2588-y
    1. Blanco-Melo D, Nilsson-Payant BE, Liu W-C, Uhl S, Hoagland D, Møller R, et al. . Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell (2020) 181(5):1036–45.e9. doi: 10.1016/j.cell.2020.04.026
    1. 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. doi: 10.1016/S0140-6736(20)30183-5
    1. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, et al. . Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease 2019. Clin Infect Dis (2020) 71(8):1937–42. doi: 10.1093/cid/ciaa449
    1. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. . Elevated Levels of IL-6 and CRP Predict the Need for Mechanical Ventilation in COVID-19. J Allergy Clin Immunol (2020) 146(1):128–36.e4. doi: 10.1016/j.jaci.2020.05.008
    1. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. . Pathological Findings of COVID-19 Associated With Acute Respiratory Distress Syndrome. Lancet Respir Med (2020) 8(4):420–2. doi: 10.1016/S2213-2600(20)30076-X
    1. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. . Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis (2020) 71(15):762–8. doi: 10.1093/cid/ciaa248
    1. Kwon JS, Kim JY, Kim M-C, Park SY, Kim B-N, Bae S, et al. . Factors of Severity in Patients With COVID-19: Cytokine/Chemokine Concentrations, Viral Load, and Antibody Responses. Am J Trop Med Hyg (2020) 103(6):2412–8. doi: 10.4269/ajtmh.20-1110
    1. Gavriilaki E, Brodsky RA. Severe COVID-19 Infection and Thrombotic Microangiopathy: Success Does Not Come Easily. Br J Haematol (2020) 189(6):e227–30. doi: 10.1111/bjh.16783
    1. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. . Coagulopathy and Antiphospholipid Antibodies in Patients With Covid-19. N Engl J Med (2020) 382(17):e38. doi: 10.1056/NEJMc2007575
    1. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. . Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol (2020) 11:827. doi: 10.3389/fimmu.2020.00827
    1. Moon C. Fighting COVID-19 Exhausts T Cells. Nat Rev Immunol (2020) 20(5):277. doi: 10.1038/s41577-020-0304-7
    1. Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. . Functional Exhaustion of Antiviral Lymphocytes in COVID-19 Patients. Cell Mol Immunol (2020) 17(5):533–5. doi: 10.1038/s41423-020-0402-2
    1. Brodin P. Why Is COVID-19 So Mild in Children? Acta Paediatr (2020) 109(6):1082–3. doi: 10.1111/apa.15271
    1. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. . Estimates of the Severity of Coronavirus Disease 2019: A Model-Based Analysis. Lancet Infect Dis (2020) 20(6):669–77. doi: 10.1016/S1473-3099(20)30243-7
    1. Peart Akindele N, Kouo T, Karaba AH, Gordon O, Fenstermacher KZJ, Beaudry J, et al. . Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding. J Infect Dis (2021) 224(4):606–15. doi: 10.1093/infdis/jiab285
    1. Sandler CX, Wyller VBB, Moss-Morris R, Buchwald D, Crawley E, Hautvast J, et al. . Long COVID and Post-Infective Fatigue Syndrome: A Review. Open Forum Infect Dis (2021) 8(10):ofab440. doi: 10.1093/ofid/ofab440
    1. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. . Sex Differences in Immune Responses That Underlie COVID-19 Disease Outcomes. Nature (2020) 588(7837):315–20. doi: 10.1038/s41586-020-2700-3
    1. Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G, et al. . Prevalence and Determinants of Fatigue After COVID-19 in Non-Hospitalized Subjects: A Population-Based Study. Int J Environ Res Public Health (2021) 18(4):1–11. doi: 10.3390/ijerph18042030
    1. Bergseth G, Ludviksen JK, Kirschfink M, Giclas PC, Nilsson B, Mollnes TE. An International Serum Standard for Application in Assays to Detect Human Complement Activation Products. Mol Immunol (2013) 56(3):232–9. doi: 10.1016/j.molimm.2013.05.221
    1. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. . Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med (2019) 200(8):e70–88. doi: 10.1164/rccm.201908-1590ST
    1. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. . Multi-Ethnic Reference Values for Spirometry for the 3-95-Yr Age Range: The Global Lung Function 2012 Equations. Eur Respir J (2012) 40(6):1324–43. doi: 10.1183/09031936.00080312
    1. Pedersen M, Asprusten TT, Godang K, Leegaard TM, Osnes LT, Skovlund E, et al. . Predictors of Chronic Fatigue in Adolescents Six Months After Acute Epstein-Barr Virus Infection: A Prospective Cohort Study. Brain Behav Immun (2019) 75:94–100. doi: 10.1016/j.bbi.2018.09.023
    1. Elliott J, Whitaker M, Bodinier B, Eales O, Riley S, Ward H, et al. . Predictive Symptoms for COVID-19 in the Community: REACT-1 Study of Over 1 Million People. PLoS Med (2021) 18(9):e1003777. doi: 10.1371/journal.pmed.1003777
    1. Vono M, Huttner A, Lemeille S, Martinez-Murillo P, Meyer B, Baggio S, et al. . Robust Innate Responses to SARS-CoV-2 in Children Resolve Faster Than in Adults Without Compromising Adaptive Immunity. Cell Rep (2021) 37(1):109773. doi: 10.1016/j.celrep.2021.109773
    1. Zhang Z, Ai G, Chen L, Liu S, Gong C, Zhu X, et al. . Associations of Immunological Features With COVID-19 Severity: A Systematic Review and Meta-Analysis. BMC Infect Dis (2021) 21(1):738. doi: 10.1186/s12879-021-06457-1
    1. Iwamura APD, Tavares da Silva MR, Hümmelgen AL, Soeiro Pereira PV, Falcai A, Grumach AS, et al. . Immunity and Inflammatory Biomarkers in COVID-19: A Systematic Review. Rev Med Virol (2021) 31(4):e2199. doi: 10.1002/rmv.2199
    1. Shafiek HK, Abd El Lateef HM, Boraey NF, Nashat M, Abd-Elrehim GAB, Abouzeid H, et al. . Cytokine Profile in Egyptian Children and Adolescents With COVID-19 Pneumonia: A Multicenter Study. Pediatr Pulmonol (2021) 56:3924–33. doi: 10.1002/ppul.25679
    1. Grifoni E, Valoriani A, Cei F, Lamanna R, Grazia Gelli AM, Ciambotti B, et al. . Interleukin-6 as Prognosticator in Patients With COVID-19. J Infect (2020) 81(3):452–82. doi: 10.1016/j.jinf.2020.06.008
    1. Aziz M, Fatima R, Assaly R. Elevated Interleukin-6 and Severe COVID-19: A Meta-Analysis. J Med Virol (2020) 92(11):2283–5. doi: 10.1002/jmv.25948
    1. Sun D, Li H, Lu X-X, Xiao H, Ren J, Zhang F-R, et al. . Clinical Features of Severe Pediatric Patients With Coronavirus Disease 2019 in Wuhan: A Single Center's Observational Study. World J Pediatr (2020) 16(3):251–9. doi: 10.1007/s12519-020-00354-4
    1. Soraya GV, Ulhaq ZS. Interleukin-6 Levels in Children Developing SARS-CoV-2 Infection. Pediatr Neonatol (2020) 61(3):253–4. doi: 10.1016/j.pedneo.2020.04.007
    1. Holter JC, Pischke SE, de Boer E, Lind A, Jenum S, Holten AR, et al. . Systemic Complement Activation Is Associated With Respiratory Failure in COVID-19 Hospitalized Patients. Proc Natl Acad Sci USA (2020) 117(40):25018–25. doi: 10.1073/pnas.2010540117
    1. Sinkovits G, Mező B, Réti M, Müller V, Iványi Z, Gál J, et al. . Complement Overactivation and Consumption Predicts In-Hospital Mortality in SARS-CoV-2 Infection. Front Immunol (2021) 12:663187. doi: 10.3389/fimmu.2021.663187
    1. Harboe M, Thorgersen EB, Mollnes TE. Advances in Assay of Complement Function and Activation. Adv Drug Deliv Rev (2011) 63(12):976–87. doi: 10.1016/j.addr.2011.05.010
    1. Gaya da Costa M, Poppelaars F, van Kooten C, Mollnes TE, Tedesco F, Würzne R, et al. . Age and Sex-Associated Changes of Complement Activity and Complement Levels in a Healthy Caucasian Population. Front Immunol (2018) 9:2664. doi: 10.3389/fimmu.2018.02664
    1. Suresh R, Chandrasekaran P, Sutterwala FS, Mosser DM. Complement-Mediated 'Bystander' Damage Initiates Host NLRP3 Inflammasome Activation. J Cell Sci (2016) 129(9):1928–39. doi: 10.1242/jcs.179291
    1. Diaz-Del-Olmo I, Worboys J, Martin-Sanchez F, Gritsenko A, Ambrose AR, Tannahill GM, et al. . Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1beta Secretion in Human Macrophages. Front Immunol (2021) 12:720655. doi: 10.3389/fimmu.2021.720655
    1. Barratt-Due A, Pischke SE, Nilsson PH, Espevik T, Mollnes TE, et al. . Dual Inhibition of Complement and Toll-Like Receptors as a Novel Approach to Treat Inflammatory Diseases-C3 or C5 Emerge Together With CD14 as Promising Targets. J Leukoc Biol (2017) 101(1):193–204. doi: 10.1189/jlb.3VMR0316-132R
    1. Eksombatchai D, Wongsinin T, Phongnarudech T, Thammavaranucupt K, Amornputtisathaporn N, Sungkanuparph S. Pulmonary Function and Six-Minute-Walk Test in Patients After Recovery From COVID-19: A Prospective Cohort Study. PLoS One (2021) 16(9):e0257040. doi: 10.1371/journal.pone.0257040
    1. Ordinola Navarro A, Cervantes-Bojalil J, de Jesús Cobos Quevedo O, Martínez AA, Hernández-Jiménez CA, Álvarez EP, et al. . Decreased Quality of Life and Spirometric Alterations Even After Mild-Moderate COVID-19. Respir Med (2021) 181:106391. doi: 10.1016/j.rmed.2021.106391
    1. Cortes-Telles A, López-Romero S, Figueroa-Hurtado E, Pou-Aguilar YN, Wong AW, Milne KM, et al. . Pulmonary Function and Functional Capacity in COVID-19 Survivors With Persistent Dyspnoea. Respir Physiol Neurobiol (2021) 288:103644. doi: 10.1016/j.resp.2021.103644
    1. Anastasio F, Barbuto S, Scarnecchia E, Cosma P, Fugagnoli A, Rossi G, et al. . Medium-Term Impact of COVID-19 on Pulmonary Function, Functional Capacity and Quality of Life. Eur Respir J (2021) 58(3):1–11. doi: 10.1183/13993003.04015-2020
    1. Lerum TV, Aaløkken TM, Brønstad E, Aarli B, Ikdahl E, Aarberg Lund KM, et al. . Dyspnoea, Lung Function and CT Findings 3 Months After Hospital Admission for COVID-19. Eur Respir J (2021) 57(4):1–8. doi: 10.1183/13993003.03448-2020
    1. Bottino I, Patria MF, Milani GP, Agostoni C, Marchisio P, Lelii M, et al. . Can Asymptomatic or Non-Severe SARS-CoV-2 Infection Cause Medium-Term Pulmonary Sequelae in Children? Front Pediatr (2021) 9:621019. doi: 10.3389/fped.2021.621019
    1. Leftin Dobkin SC, Collaco JM, McGrath-Morrow SA. Protracted Respiratory Findings in Children Post-SARS-CoV-2 Infection. Pediatr Pulmonol (2021) 56:3682–7. doi: 10.22541/au.162513383.35044135/v1
    1. Doykov I, Hällqvist J, Gilmour KC, Grandjean L, Mills K, Heywood WE. 'The Long Tail of Covid-19' - The Detection of a Prolonged Inflammatory Response After a SARS-CoV-2 Infection in Asymptomatic and Mildly Affected Patients. F1000Res (2020) 9:1349. doi: 10.12688/f1000research.27287.1
    1. Garcia-Abellan J, Padilla S, Fernández-González M, García J, Agulló V, Andreo M, et al. . Antibody Response to SARS-CoV-2 Is Associated With Long-Term Clinical Outcome in Patients With COVID-19: A Longitudinal Study. J Clin Immunol (2021) 41(7):1490–501. doi: 10.1007/s10875-021-01083-7
    1. Matta J, Wiernik E, Robineau O, Carrat F, Touvier M, Severi G, et al. . Association of Self-Reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic. JAMA Intern Med (2021) 182:19–25. doi: 10.1001/jamainternmed.2021.6454

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera