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Endocrine, Metabolic & Immune Disorders - Drug Targets


ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Neurosensory Alterations and Interleukins Cascade in SARS-CoV-2 Infection - Results from a Retrospective Cohort of COVID-19 Inpatients

Author(s): Luigi Santacroce, Angela Pia Cazzolla*, Roberto Lovero, Vincenzo Brescia, Domenico Ciavarella, Francesca Spirito, Marica Colella, Massimo Bilancia, Lorenzo Lo Muzio and Francesca Di Serio

Volume 23, Issue 9, 2023

Published on: 14 April, 2023

Page: [1162 - 1172] Pages: 11

DOI: 10.2174/1871530323666230216145027

Price: $65


Objectives: The aim of this study was to relate IL-6 and IL-1β serum levels with the severity of olfactory disorders and with the type of unperceived odors.

Methods: 82 inpatients (45 men aged 62.3 ± 14.2 and 37 women aged 57.1 ± 12.8) with only smell dysfunctions were divided into two groups. The evaluation of the smell disorder was carried out with a questionnaire to define which sensitivity is most compromised in COVID-19 patients. Cytokine levels were measured with chemiluminescence and ELISA assay. Statistical analyses were performed with the Wilcoxon Rank test, Welch's T-test, and Mann-Whitney test (p < 0.05).

Results: Statistically significant differences in IL-6 and IL-1 β levels were found in moderate disease patients when there was an impairment of trigeminal sensitivity (p <0.05) and trigeminal and olfactory sensitivity.

Conclusions: The results obtained showed that in COVID-19 patients the impairment of trigeminal sensitivity in association with olfactory sensitivity was more prevalent in moderate than in mild forms.

Keywords: SARS-CoV-2, COVID-19, immune response, cytokines, inflammation, neurosensory disorders.

Graphical Abstract
Lechien, J.R.; Chiesa-Estomba, C.M.; De Siati, D.R.; Horoi, M.; Le Bon, S.D.; Rodriguez, A.; Dequanter, D.; Blecic, S.; El Afia, F.; Distinguin, L.; Chekkoury-Idrissi, Y.; Hans, S.; Delgado, I.L.; Calvo-Henriquez, C.; Lavigne, P.; Falanga, C.; Barillari, M.R.; Cammaroto, G.; Khalife, M.; Leich, P.; Souchay, C.; Rossi, C.; Journe, F.; Hsieh, J.; Edjlali, M.; Carlier, R.; Ris, L.; Lovato, A.; De Filippis, C.; Coppee, F.; Fakhry, N.; Ayad, T.; Saussez, S. 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), 2251-2261.
[] [PMID: 32253535]
Lechien, J.R.; Chiesa-Estomba, C.M.; Hans, S.; Barillari, M.R.; Jouffe, L.; Saussez, S. Loss of smell and taste in 2013 European patients with mild to moderate COVID-19. Ann. Intern. Med., 2020, 173(8), 672-675.
[] [PMID: 32449883]
Russell, B; Moss, C; Rigg, A; Hopkins, C; Papa, S; Van Hemelrijck, M Anosmia and ageusia are emerging as symptoms in patients with COVID-19: What does the current evidence say? Ecancermedicalscience, 2020, 14.
Spinato, G.; Fabbris, C.; Polesel, J.; Cazzador, D.; Borsetto, D.; Hopkins, C.; Boscolo-Rizzo, P. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA, 2020, 323(20), 2089-2090.
[] [PMID: 32320008]
Vaira, L.A.; Salzano, G.; De Riu, G. The importance of olfactory and gustatory disorders as early symptoms of coronavirus disease (COVID-19). Br. J. Oral Maxillofac. Surg., 2020, 58(5), 615-616.
[] [PMID: 32362452]
Xydakis, M.S.; Dehgani-Mobaraki, P.; Holbrook, E.H.; Geisthoff, U.W.; Bauer, C.; Hautefort, C.; Herman, P.; Manley, G.T.; Lyon, D.M.; Hopkins, C. Smell and taste dysfunction in patients with COVID-19. Lancet Infect. Dis., 2020, 20(9), 1015-1016.
[] [PMID: 32304629]
Cirillo, N.; Bizzoca, M.E.; Lo Muzio, E.; Cazzolla, A.P.; Lo Muzio, L. Gustatory dysfunction in COVID-19 patients: a rapid systematic review on 27,687 cases. Acta Odontol. Scand., 2021, 79(6), 418-425.
[] [PMID: 33450165]
Cirillo, N.; Colella, G. Self-reported smell and taste alteration as the sole clinical manifestation of SARS-CoV-2 infection. Oral Surg. Oral Med. Oral Pathol. Oral Radiol., 2021, 131(4), e95-e99.
[] [PMID: 33487583]
Santacroce, L.; Charitos, IA.; Del Prete, R. COVID-19 in Italy: An overview from the first case to date. Electron J Gen Med, 2020, 17(6), em235.
Santacroce, L.; Bottalico, L.; Charitos, I.A. The impact of COVID-19 on Italy: a lesson for the future. Int. J. Occup. Environ. Med., 2020, 11(3), 151-152.
[] [PMID: 32225178]
Giacomelli, A.; Pezzati, L.; Conti, F.; Bernacchia, D.; Siano, M.; Oreni, L.; Rusconi, S.; Gervasoni, C.; Ridolfo, A.L.; Rizzardini, G.; An-tinori, S.; Galli, M. Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study. Clin. Infect. Dis., 2020, 71(15), 889-890.
[] [PMID: 32215618]
Turkmen, M. Current advances in geography, environment and earth sciences, 6th ed; Book Publisher International, 2022.
Turkmen, M. Challenging issues on environment and earth science. Book Publisher International, 2021, 6, 1-139.
Turkmen, M. Emerging challenges in environment and earth science. Book Publisher International, 2022, 3, 1-67.
Holbrook, E.H.; Leopold, D.A. An updated review of clinical olfaction. Curr. Opin. Otolaryngol. Head Neck Surg., 2006, 14(1), 23-28.
[] [PMID: 16467634]
Hummel, T.; Whitcroft, K.L.; Andrews, P.; Altundag, A.; Cinghi, C.; Costanzo, R.M.; Damm, M.; Frasnelli, J.; Gudziol, H.; Gupta, N.; Haehne, A.; Holbrook, E.; Hong, S.C.; Hornung, D.; Hüttenbrink, K.B.; Kamel, R.; Kobayashi, M.; Konstantinidis, I.; Landis, B.N.; Leopold, D.A.; Macchi, A.; Miwa, T.; Moesges, R.; Mullol, J.; Mueller, C.A.; Ottaviano, G.; Passali, G.C.; Philpott, C.; Pinto, J.M.; Ramakrishnan, V.J.; Rombaux, P.; Roth, Y.; Schlosser, R.A.; Shu, B.; Soler, G.; Stjärne, P.; Stuck, B.A.; Vodicka, J.; Welge-Luessen, A. Position paper on olfactory dysfunction. Rhinology, 2017, 54(26), 1-30.
[] [PMID: 29528615]
Kanjanaumporn, J.; Aeumjaturapat, S.; Snidvongs, K.; Seresirikachorn, K.; Chusakul, S. Smell and taste dysfunction in patients with SARS-CoV-2 infection: A review of epidemiology, pathogenesis, prognosis, and treatment options. Asian Pac. J. Allergy Immunol., 2020, 38(2), 69-77.
[PMID: 32563234]
Love, K.; Ahmed, S. Olfactory dysfunction. BMJ, 2010, 341.
Maci, L. Aspetti medico-legali del danno olfattivo, Argomenti di otorinolaringoiatria moderna. AIOLP, 2008, 8(15), 8-21.
Brand, G. Olfactory/trigeminal interactions in nasal chemoreception. Neurosci. Biobehav. Rev., 2006, 30(7), 908-917.
[] [PMID: 16545453]
Filiou, R.P.; Lepore, F.; Bryant, B.; Lundström, J.N.; Frasnelli, J. Perception of trigeminal mixtures. Chem. Senses, 2015, 40(1), 61-69.
[] [PMID: 25500807]
Czerniawska, E.; Zegardło, E.; Wojciechowski, J. Memories evoked by odors stimulating the olfactory nerve versus odors stimulating both the olfactory and trigeminal nerves: possible qualitative differences? Percept. Mot. Skills, 2013, 117(1), 248-256.
[] [PMID: 24422354]
Cometto-Muñiz, J.E.; Cain, W.S. Thresholds for odor and nasal pungency. Physiol. Behav., 1990, 48(5), 719-725.
[] [PMID: 2082372]
Purves, D.; Augustine, G.J.; McNamara, J.O.; Williams, S.M. Neuroscience, 2 ed; Sinauer Associates: Sunderland, MA, 2001, p. 680.
Wong, D.K.C.; Gendeh, H.S.; Thong, H.K.; Lum, S.G.; Gendeh, B.S.; Saim, A.; Salina, H. A review of smell and taste dysfunction in COVID-19 patients. Med. J. Malaysia, 2020, 75(5), 574-581.
[PMID: 32918429]
Maßberg, D.; Hatt, H. Human olfactory receptors: novel cellular functions outside of the nose. Physiol. Rev., 2018, 98(3), 1739-1763.
[] [PMID: 29897292]
Reith, M.E. Cerebral Signal Transduction: From First to Fourth Messengers; Springer Science & Business Media, 2000.
Suzuki, M.; Saito, K.; Min, W.P.; Vladau, C.; Toida, K.; Itoh, H.; Murakami, S. Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope, 2007, 117(2), 272-277.
[] [PMID: 17277621]
Soler, Z.M.; Patel, Z.M.; Turner, J.H.; Holbrook, E.H., Eds.; A primer on viral‐associated olfactory loss in the era of COVID‐19. International forum of allergy & rhinology; Wiley Online Library, 2020.
O’Brien, E.K.; Leopold, D.A. Olfaction and Gustation: Implications of Viral, Toxic Exposure, Head Injury, Aging, and Drugs. Rhinology and Facial Plastic Surgery; Springer, 2009, pp. 97-103.
Torabi, A.; Mohammadbagheri, E.; Akbari Dilmaghani, N.; Bayat, A.H.; Fathi, M.; Vakili, K.; Alizadeh, R.; Rezaeimirghaed, O.; Hajiesmaeili, M.; Ramezani, M.; Simani, L.; Aliaghaei, A. Proinflammatory cytokines in the olfactory mucosa result in covid-19 induced anosmia. ACS Chem. Neurosci., 2020, 11(13), 1909-1913.
[] [PMID: 32525657]
de Melo, G.D.; Lazarini, F.; Levallois, S.; Hautefort, C.; Michel, V.; Larrous, F.; Verillaud, B.; Aparicio, C.; Wagner, S.; Gheusi, G.; Kergoat, L.; Kornobis, E.; Donati, F.; Cokelaer, T.; Hervochon, R.; Madec, Y.; Roze, E.; Salmon, D.; Bourhy, H.; Lecuit, M.; Lledo, P.M. COVID-19–related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Sci. Transl. Med., 2021, 13(596), eabf8396.
[] [PMID: 33941622]
Vaira, L.; Salzano, G.; Deiana, G.; De Riu, G. Anosmia and ageusia common findings in COVID-19 patients [published online April 1. Laryngoscope, 2020, 130(7), 1787.
[ 10.1002/lary.28692] [PMID: 32237238]
Mao, L.; Jin, H.; Wang, M.; Hu, Y.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; Miao, X.; Li, Y.; Hu, B. Neurologic mani-festations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol., 2020, 77(6), 683-690.
[] [PMID: 32275288]
Åkerlund, A.; Bende, M.; Murphy, C. Olfactory threshold and nasal mucosal changes in experimentally induced common cold. Acta Otolaryngol., 1995, 115(1), 88-92.
[] [PMID: 7762392]
Khan, M; Yoo, S-J; Clijsters, M; Backaert, W; Vanstapel, A Speleman, K Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb. Cell., 2021, 184(24), 5932-5949.
Cazzolla, A.P.; Lovero, R.; Lo Muzio, L.; Testa, N.F.; Schirinzi, A.; Palmieri, G.; Pozzessere, P.; Procacci, V.; Di Comite, M.; Ciavarella, D.; Pepe, M.; De Ruvo, C.; Crincoli, V.; Di Serio, F.; Santacroce, L. Taste and smell disorders in COVID-19 patients: role of interleukin-6. ACS Chem. Neurosci., 2020, 11(17), 2774-2781.
[] [PMID: 32786309]
Henkin, R.I.; Schmidt, L.; Velicu, I. Interleukin 6 in Hyposmia. JAMA Otolaryngol. Head Neck Surg., 2013, 139(7), 728-734.
[] [PMID: 23868430]
Glezer, I.; Bruni-Cardoso, A.; Schechtman, D.; Malnic, B. Viral infection and smell loss: The case of COVID‐19. J. Neurochem., 2021, 157(4), 930-943.
[] [PMID: 32970861]
Santacroce, L.; Charitos, I.A.; Carretta, D.M.; De Nitto, E.; Lovero, R. The human coronaviruses (HCoVs) and the molecular mechanisms of SARS-CoV-2 infection. J. Mol. Med. , 2021, 99(1), 93-106.
[] [PMID: 33269412]
Santacroce, L. Letter regarding the article “Enhancing immunity in viral infections, with special emphasis on COVID-19: A review”. Diabetes Metab. Syndr., 2020, 14(5), 927.
[] [PMID: 32585601]
Butowt, R.; Meunier, N.; Bryche, B.; von Bartheld, C.S. The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models. Acta Neuropathol., 2021, 141(6), 809-822.
[] [PMID: 33903954]
Brann, D.H.; Tsukahara, T.; Weinreb, C.; Lipovsek, M.; Van den Berge, K.; Gong, B.; Chance, R.; Macaulay, I.C.; Chou, H.J.; Fletcher, R.B.; Das, D.; Street, K.; de Bezieux, H.R.; Choi, Y.G.; Risso, D.; Dudoit, S.; Purdom, E.; Mill, J.; Hachem, R.A.; Matsunami, H.; Logan, D.W.; Goldstein, B.J.; Grubb, M.S.; Ngai, J.; Datta, S.R. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci. Adv., 2020, 6(31), eabc5801.
[] [PMID: 32937591]
Xu, H.; Zhong, L.; Deng, J.; Peng, J.; Dan, H.; Zeng, X.; Li, T.; Chen, Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral Sci., 2020, 12(1), 8.
[] [PMID: 32094336]
Moein, S.T.; Hashemian, S.M.; Mansourafshar, B.; Khorram‐Tousi, A.; Tabarsi, P.; Doty, R.L. Smell dysfunction: a biomarker for COVID‐19. Int. Forum Allergy Rhinol., 2020, 10(8), 944-950.
Schirinzi, A.; Pesce, F.; Laterza, R.; D’Alise, M.G.; Lovero, R.; Fontana, A.; Contino, R.; Di Serio, F. Pentraxin 3: Potential prognostic role in SARS-CoV-2 patients admitted to the emergency department. J. Infect., 2021, 82(4), 84-123.
[] [PMID: 33147434]
Balzanelli, M.G.; Distratis, P.; Aityan, S.K.; Amatulli, F.; Catucci, O.; Cefalo, A. An Alternative “Trojan Horse” Hypothesis for COVID-19: Immune Deficiency of IL-10 and SARS-CoV-2 Biology. Endocr. Metab. Immune Disord. Drug Targets, 2021, 22(1), 1-5.
[] [PMID: 33504318]
Meng, X.; Pan, Y. COVID-19 and anosmia: The story so far. Ear Nose Throat J., 2021, 1455613211048998.
[] [PMID: 34587819]
Taniguchi, K; Karin, M. IL-6 and related cytokines as the criticallynchpins between inflammation and cancer. Seminars in immunology, 26(1), 54-74.
[] [PMID: 24552665]
Yang, Y; Li, W; Wang, Z; Sun, G; Zhou, P; Han, X Clinical significance of interleukin-6 and-8 in patients with chronic periodontal disease and acute exacerbation of chronic obstructive pulmonary disease. Zhonghua Kou Qiang Yi Xue Za Zhi., 2018, 53(5), 312-317.
Najafloo, R.; Majidi, J.; Asghari, A.; Aleemardani, M.; Kamrava, S.K.; Simorgh, S.; Seifalian, A.; Bagher, Z.; Seifalian, A.M. Mechanism of anosmia caused by symptoms of COVID-19 and emerging treatments. ACS Chem. Neurosci., 2021, 12(20), 3795-3805.
[] [PMID: 34609841]
Soy, M.; Keser, G.; Atagündüz, P.; Tabak, F.; Atagündüz, I.; Kayhan, S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin. Rheumatol., 2020, 39(7), 2085-2094.
[] [PMID: 32474885]
Mardi, A.; Meidaninikjeh, S.; Nikfarjam, S.; Majidi Zolbanin, N.; Jafari, R. Interleukin-1 in COVID-19 infection: immunopathogenesis and possible therapeutic perspective. Viral Immunol., 2021, 34(10), 679-688.
[] [PMID: 34882013]
Dinarello, C.A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood, 2011, 117(14), 3720-3732.
[] [PMID: 21304099]
Iravani, B.; Arshamian, A.; Ravia, A.; Mishor, E.; Snitz, K.; Shushan, S.; Roth, Y.; Perl, O.; Honigstein, D.; Weissgross, R.; Karagach, S.; Ernst, G.; Okamoto, M.; Mainen, Z.; Monteleone, E.; Dinnella, C.; Spinelli, S.; Mariño-Sánchez, F.; Ferdenzi, C.; Smeets, M.; Touhara, K.; Bensafi, M.; Hummel, T.; Sobel, N.; Lundström, J.N. Relationship between odor intensity estimates and COVID-19 prevalence prediction in a Swedish population. Chem. Senses, 2020, 45(6), 449-456.
[] [PMID: 32441744]
Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia(Trial Version 7). Chin. Med. J. (Engl .), 133(9), 1087-1095.
Hopkins, C.; Gillett, S.; Slack, R.; Lund, V.J.; Browne, J.P. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin. Otolaryngol., 2009, 34(5), 447-454.
[] [PMID: 19793277]
Charitos, I.A.; Ballini, A.; Bottalico, L.; Cantore, S.; Passarelli, P.C.; Inchingolo, F.; D’Addona, A.; Santacroce, L. Special features of SARS-CoV-2 in daily practice. World J. Clin. Cases, 2020, 8(18), 3920-3933.
[] [PMID: 33024749]
Passarelli, P.; Passarelli, G.; Charitos, I.; Rella, E.; Santacroce, L.; D’Addona, A. COVID-19 and oral diseases: How can we manage hospital-ized and quarantined patients while reducing risks? Electron J Gen Med., 2020, 17(6), em238.
Santacroce, L.; Charitos, I.A.; Ballini, A.; Inchingolo, F.; Luperto, P.; De Nitto, E.; Topi, S. The human respiratory system and its microbiome at a glimpse. Biology , 2020, 9(10), 318.
[] [PMID: 33019595]
Schirinzi, A.; Cazzolla, A.P.; Lovero, R.; Lo Muzio, L.; Testa, N.F.; Ciavarella, D.; Palmieri, G.; Pozzessere, P.; Procacci, V.; Di Serio, F.; Santacroce, L. New insights in laboratory testing for COVID-19 patients: looking for the role and predictive value of Human epididymis secretory protein 4 (HE4) and the innate immunity of the oral cavity and respiratory tract. Microorganisms, 2020, 8(11), 1718.
[] [PMID: 33147871]
Conti, P.; Ronconi, G.; Caraffa, A.; Gallenga, C.E.; Ross, R.; Frydas, I.; Kritas, S.K. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J. Biol. Regul. Homeost. Agents, 2020, 34(2), 327-331.
[PMID: 32171193]
Karunanayaka, P.R.; Lu, J.; Yang, Q.X.; Sathian, K. Neural basis of olfactory and trigeminal integration. bioRxiv, 2020, 2020.06.24.168989.
Viana, F. Chemosensory properties of the trigeminal system. ACS Chem. Neurosci., 2011, 2(1), 38-50.
[] [PMID: 22778855]
Nilius, B.; De Tombe, P.; Gudermann, T.; Jahn, R.; Lill, R.; Petersen, O.H. Reviews of Physiology, Biochemistry and Pharmacology; Springer, 2018, Vol. 174, .
Saunders, C.J.; Christensen, M.; Finger, T.E.; Tizzano, M. Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation. Proc. Natl. Acad. Sci., 2014, 111(16), 6075-6080.
[] [PMID: 24711432]
Dinh, Q.T.; Groneberg, D.A.; Mingomataj, E.; Peiser, C.; Heppt, W.; Dinh, S.; Arck, P.C.; Klapp, B.F.; Fischer, A. Expression of substance P and vanilloid receptor (VR1) in trigeminal sensory neurons projecting to the mouse nasal mucosa. Neuropeptides, 2003, 37(4), 245-250.
[] [PMID: 12906843]
Ichikawa, H.; Sugimoto, T. The co-expression of ASIC3 with calcitonin gene-related peptide and parvalbumin in the rat trigeminal ganglion. Brain Res., 2002, 943(2), 287-291.
[] [PMID: 12101052]
Spehr, J.; Spehr, M.; Hatt, H.; Wetzel, C.H. Subunit-specific P2X-receptor expression defines chemosensory properties of trigeminal neu-rons. Eur. J. Neurosci., 2004, 19(9), 2497-2510.
[] [PMID: 15128403]
Alimohammadi, H.; Silver, W.L. Evidence for nicotinic acetylcholine receptors on nasal trigeminal nerve endings of the rat. Chem. Senses, 2000, 25(1), 61-66.
[] [PMID: 10667995]
Silver, W.L.; Clapp, T.R.; Stone, L.M.; Kinnamon, S.C. TRPV1 receptors and nasal trigeminal chemesthesis. Chem. Senses, 2006, 31(9), 807-812.
[] [PMID: 16908491]
Emir, TLR. Neurobiology of TRP channels; CRC Press/Taylor & Francis: Boca Raton, FL, 2017.

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