PREDICTION OF CHANGES IN VAGUS NERVE MORPHOLOGY BASED ON BIOCHEMICAL MARKERS OF INFLAMMATION IN COVID 19 INFECTION
Abstract
Background. Prediction of cross-sectional area n. vagus on the sonogram, based on the values of some inflammation biomarkers in the blood
Methods. In 68 patients with a PCR test (+) for SARS-COV 2, the cross-sectional area of the nerve (CSA) was measured by ultrasound, as an average of three measurements. The values of CRP, fibrinogen and ferritin were determined. CSA values from both sides and all biomarkers were classified as (0)- within normal limits and (1)- all other values. Logistic linear regression was performed and a strong linear relationship between predictors was excluded. A neural network and binary logistic regression model was formed for the CSA values on the right side, on the left side the connection between the selected predictors and the CSA of the left vagus was not established.
Results. On the right side, CSA is 1.32±0.3; on the left 1.2±0.28. In the study, 11.8%, 22.1% and 8.82% had normal values of CRP, fibrinogen and ferritin respectively. A strong linear association of predictors was ruled out by linear logistic regression. A neural network with two hidden layers and 6 number of units in either hidden layer was formed in 2 seconds. The accuracy percentage of the model in training is 91.5% and in testing it is 90.5%. The AUC of this model is 0.76 (p=0.018, p<0.05). Logistic binary regression model: logitX2D= 18.018+ (20.752x CRP values)+ (-38.77x fibrinogen values)+(2.175x ferritin values), where X2D- is the cross-sectional area of the right n. vagus, given by the model. Exp(B) of the model is 7.5, Psample = 0.88, OR=56.25, accuracy of the model is 91.2%, Omnibus test: χ2=14.193, p=0.003(p<0.05). Model reliability coefficient -2LogLH=35.068 and AUC =0.76, p=0.018. Overall model quality 0.61 (limit is 0.5). On the left side, the value of CSA n.vagus cannot be predicted using selected predictors.
References
2. Chigr F., Merzouki M., Najmi M. Authonomic brain centers and pahtophysiology of COVID-19. ACS Chem. Neurosci.2020; 11(11):1520-2. doi.org/10.3389/fnins.2021.727060
3.Logmin K.,Karam.,Schihel T.,Harmel J.,Wojtecki L. Non-epileptic seazures in autonomic disfunction as the initial symptom of COVID-19. J Neurol 2020; 267(9):2490-1. doi: 10.1007/s00415-020-09904-2
4. Calabrese LH., Cytokine storm and the prospects for immunotherapy with COVID-19. Cleve Clin J Med 2020; 87(7): 389-93. doi: 10.3949/ccjm.87a.ccc008.
5. Tang Y., Liu J., Zhang D., Xu Z., Ji J., Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol 2020; 11: 1708. doi: 10.3389/fimmu.2020.01708
6. Figueroa J.J., Cheshire W.P., Claydon V.E., Norclife-Kaufmann L.,Peltier A., Singer W et al. Autonomic function testing in the COVID-19 pandemic an American Autonomic Society position statement. Clin Auton Res 2020; 30(4): 295-7. doi: 10.1007/s10286-020-00702-4.
7.Pavlov V.A.,Chavan SS., Tracey KJ., Bioelectronic medicine from preclinical studies on the inflammatory refleks to new approachesin these diagnosis and treatment . Cold Spring Harb Prospect Med 2020; 10(3): a034140. doi: 10.1101/cshperspect.a034140.
8. Tarnawski L., Reardon C., Caravaca AS., Rosas-Ballina M., Tusche MW., Drake AR., et al. Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. Front Immunol 2018; 9: 2648. doi: 10.3389/fimmu.2018.02648. eCollection 2018
9.Wu YJ., Wang L.,Ji CE., Gu SE., Yin Q., Yuo J. The role of alfa7nAChR-mediated cholinergic anti-inflammatory patway in immune cells. Inflammation 2021; 44(3): 821-34.
10.Goldstain Ds. The extended autonomic system , dyshomeostasis, and COVID-19. Clin Auton Res2020; 30(4):299-315. doi: 10.1007/s10286-020-00714-0
11. R.Ader ed.Psichoneuroimmunology(4th ed),NY.Elsevier Inc.,2007:85-96.
12. Kohoutova M., Horak j., JarkovskaD., Martinkova V., Tegl V., Nalos L.,et al. Vagus nerve stimulation attenuates multiple organ dysfunction in resuscitated porcine progressive sepsis. Crit Care Med 2019; 47(6):461-9. doi: 10.1097/CCM.0000000000003714.
13.Fonseca RC., Bassi GS., Brito CC., Rosa LB., David BA., Araujo AM., et al. Vagus nerve regulates the phacytic and secretory activity of resident macrophages in the liver. Brain Behav Immunol 2019; 81: 444-54. doi: 10.1016/j.bbi.2019.06.041.
14. Staats P., Giannakopoulos G., Blake J., Liebler E., Levy RM. The use of non-invasive vagus nerve stimulation to treat respiratory symptoms associated with COVID-19: a theoretical hypothesis and early clinical expirience.Neuromodulation 2020; 23(6): 784-8.
15.Bonaz B., Sinniger V.,Pellissier S. Targeting the cholinergic anti-inflammatory with vagus nerve stimulation in patients with COVID-19?Bioelectron Med 2020; 6:15. doi: 10.1186/s42234-020-00051-7.
16.Boezaart AP., Botha DA. Treatment of stage 3 COVID-19 with transcutaneous auricular vagus nerve stimulation drastically reduces interleukin-6 blood levels: a report on two cases. Neuromodulation 2020, 24(1): 166-7. doi: 10.1111/ner.13293.
17. Hajiasgharzadeh K., Jafarlou M., Mansoori B., Dastmalchi N., Baradaran B., Khabbazi A. Inflammatory reflex disruption in COVID-19. Clin Exp Neuroimmunol. 2022; 10.1111/cen3.12703. doi:10.1111/cen3.12703. 18.Burger AM., D’Agostini M. Responce to „The use of non-invasive vagus nerve stimulation to treat respiratory symptoms associated with COVID-19: a theoretical hypothesis and early clinical expirience.“Neuromodulation 2020; 23(7): 1042-3.
19. Occhinegro A, Wong CY, Chua BY, Jackson DC, McKinley MJ, McAllen RM, et al. The endogenous inflammatory reflex inhibits the inflammatory response to different immune challenges in mice. Brain Behav Immun. 2021;97:371–5. doi: 10.1016/j.bbi.2021.07.019.
20.Pum A, Ennemoser M, Adage T, Kungl AJ. Cytokines and chemokines in SARS‐CoV‐2 infections—therapeutic strategies targeting cytokine storm. Biomolecules. 2021;11(1):91.
21. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62–75. doi: 10.1016/j.cytogfr.2020.06.001
22. Tizabi Y, Getachew B, Copeland RL, Aschner M. Nicotine and the nicotinic cholinergic system in COVID-19. FEBS J. 2020;287(17): 3656–63. doi: 10.1111/febs.15521.
23. Kloc M, Ghobrial RM, Kubiak JZ. How nicotine can inhibit cytokine storm in the lungs and prevent or lessen the severity of COVID-19 infection? Immunol Lett. 2020;224:28–9.
24.Ali N. Elevated level of C-reaktive protein may be an early marker to predict risk for severity of COVID19. J Med Virol. 2020; 92(11): 2409–11. doi: 10.1002/jmv.26097
25. Stringer D., Braude Ph., Myint Ph.K., Evans L., Collins J.T., Verduri A. et al.The role of C-reactive protein as a prognostic marker in COVID-19. Int J Epidemiol. 2021;50(2):420-9. doi: 10.1093/ije/dyab012.
26.Kaushal K., Kaur H., Sarma P., Bhattacharyya A., Sharma D.J., Prajapat M., et al.Serum ferritin as a predictive biomarker in COVID-19. A systematic review, meta-analysis and meta-regression analysis. J Crit Care. 2022 Feb; 67: 172–181. doi: 10.1016/j.jcrc.2021.09.023
27. Alroomi M., Rajan R., Omar A.A., Alsaber A., Pan J., Fatemi M., et al. Ferritin level: A predictor of severity and mortality in hospitalized COVID-19 patients. Immun Inflamm Dis. 2021; 9(4):1648-55. doi: 10.1002/iid3.517.
28. Sui J., Noubouossie D.F. , Gandotra S., Cao L. Elevated Plasma Fibrinogen Is Associated With Excessive Inflammation and Disease Severity in COVID-19 Patients. Front Cell Infect Microbiol. 2021 Aug 3;11:734005. doi: 10.3389/fcimb.2021.734005.
29. Rostami M., Khoshnegah Z., Mansouritorghabeh H. Hemostatic System (Fibrinogen Level, D-Dimer, and FDP) in Severe and Non-Severe Patients With COVID-19: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost. 2021;27:10760296211010973. doi: 10.1177/10760296211010973.
30. Jones S.A.,, Hunter Ch. A. Is IL-6 a key cytokine target for therapy in COVID-19? Nat Rev Immunol. 2021 Jun;21(6):337-339. doi: 10.1038/s41577-021-00553-8.
31. Cruz A.S., Mendes-Frias A., Oliveira A.I., Dias L., Matos A.R., Carvalho A. et al. Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia, Front Immunol. 2021 Feb 18;12:613422. doi: 10.3389/fimmu.2021.613422.
32. Pelz J.O., Belau E., Henn Ph., Hammer N., Classen J., Weise D.. Sonographic evaluation of the vagus nerves: protocol, reference values, and side-to-side differences. Muscle Nerve. 2018;57(5):766-71. doi: 10.1002/mus.25993.
33. Horsager J., Walter U. Fedorova T.D.,Andersen K.B., Skjærbæk C., Knudsen K., et al. Vagus Nerve Cross-Sectional Area in Patients With Parkinson's Disease-An Ultrasound Case-Control Study. Front Neurol. 2021;12: 681413. doi: 10.3389/fneur.2021.681413.
34. Grimm A., Décard B.F., Athanasopoulou I., Schweikert K., Sinnreich M., Axer H.. Nerve ultrasound for differentiation between amyotrophic lateral sclerosis and multifocal motor neuropathy. J Neurol. 2015;262(4):870-80. doi: 10.1007/s00415-015-7648-0.
35. Tawfik E.A., Walker F.O., Cartwright M.S. Neuromuscular ultrasound of cranial nerves. J Clin Neurol 2015; 11(2): 109-21. doi: 10.3988/jcn.2015.11.2.109
36.Tornera C., Vallejo R., Cedeno D., Orduna Jpastor E.,Belaouchi M., et al.A prospective, randomized controlled study acessing vagus nerve stimulation using the gammaCore(R)-Sapphire devices for patient with moderate to severe COVID-19 respiratory symptoms (SAVIOR): a structured summary of a study protocol for a randomised controlled trial. Trials 2020; 21: 576.
37. Kelly M.J., Breathnach C., Tracey K.J.,3 and Donnelly S.C. Manipulation of the inflammatory reflex as a therapeutic strategy. Cell Reports Medicine 2022; 3(7):100696 doi: org/10.1016/j.xcrm.2022.100696
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