Taste and Smell Disorders in COVID-19 Patients: Role of Interleukin-6

Angela P Cazzolla, Roberto Lovero, Lorenzo Lo Muzio, Nunzio F Testa, Annalisa Schirinzi, Giuseppe Palmieri, Pietro Pozzessere, Vito Procacci, Mariasevera Di Comite, Domenico Ciavarella, Maria Pepe, Caterina De Ruvo, Vito Crincoli, Francesca Di Serio, Luigi Santacroce, Angela P Cazzolla, Roberto Lovero, Lorenzo Lo Muzio, Nunzio F Testa, Annalisa Schirinzi, Giuseppe Palmieri, Pietro Pozzessere, Vito Procacci, Mariasevera Di Comite, Domenico Ciavarella, Maria Pepe, Caterina De Ruvo, Vito Crincoli, Francesca Di Serio, Luigi Santacroce

Abstract

The rapid recovery of smell and taste functions in COVID-19 patients could be attributed to a decrease in interleukin-6 levels rather than central nervous system ischemic injury or viral damage to neuronal cells. To correlate interleukin-6 levels in COVID-19 patients with olfactory or gustatory dysfunctions and to investigate the role of IL-6 in the onset of these disorders, this observational study investigated 67 COVID-19 patients with taste or smell disorders or both, who did not require intensive care admission, admitted at COVID Hospital of Policlinico of Bari from March to May 2020. Interleukin-6 was assayed in COVID-19 patients with taste or smell disturbances at the time of admission and at the time of swab negativization. At the same time, patients have been given a specific survey to evaluate the severity of taste and smell disturbances. Of 125 patients with smell or taste dysfunctions at onset of disease, 67 fulfilled the inclusion criteria, while 58 were excluded because 35 of them required intensive care admission, 5 were unable to answer, 5 died, 7 had finished chemotherapy recently, and 5 refused to participate. The evaluation of taste and smell disorders was carried out using a survey performed at the time of admission and at the time of swab negativization. Sinonasal outcome test 22 (SNOT-22) was used as a reference for olfactory function assessment, and Taste and Smell Questionnaire Section of the US NHANES 2011-2014 protocol (CDC 2013b) was used as reference for gustatory function assessment. A venous blood sample was taken for each patient to measure IL-6 levels upon entry and at swab negativization. Interleukin-6 levels in COVID-19 patients in relation to olfactory or gustatory disorders were correlated from the time of their admission to the time of swab negativization. Statistically significant correlations were obtained between the decrease of interleukin-6 levels and the improvement of smell (p value < 0.05) and taste (p = 0.047) functions at swab negativization. The acquired results demonstrate the key role of interleukin-6 in the pathogenesis of chemosensitive disorders in COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; anosmia; dysgeusia; immune-mediated neurological syndromes; interleukin-6 (IL-6).

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Sex distribution of IL-6 levels at the first evaluation; (b) sex distribution of IL-6 levels at the second evaluation; (c) sex distribution of the delta (values at the first evaluation minus values at the second evaluation) value of IL-6 levels; (d) sex distribution of the delta score of smell; (e) sex distribution of the delta score of taste.
Figure 2
Figure 2
(a) IL-6 and (b) smell and (c) taste score distributions in COVID-19 patients at first and second evaluation.

References

    1. Park S. E. (2020) Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19). Clin Exp Pediatr. 63 (4), 119–124. 10.3345/cep.2020.00493.
    1. Mousavizadeh L.; Ghasemi S. (2020) Genotype and phenotype of COVID-19: Their roles in pathogenesis. J. Microbiol Immunol Infect. 10.1016/j.jmii.2020.03.022.
    1. Zou X.; Chen K.; Zou J.; Han P.; Hao J.; Han Z. (2020) Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 14 (2), 185–192. 10.1007/s11684-020-0754-0.
    1. Zhang H., Kang Z., Gong H., Xu D., Wang J., Li Z., Cui X., Xiao J., Meng T., Zhou W., Liu J., and Xu H. (2020) The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv, 10.1101/2020.01.30.927806 (Available at , last accessed June 30, 2020).
    1. Baig A. M.; Khaleeq A.; Ali U.; Syeda H. (2020) Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host–virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 11 (7), 995–998. 10.1021/acschemneuro.0c00122.
    1. Xu H.; Zhong L.; Deng J.; Peng J.; Dan H.; Zeng X.; Li T.; Chen Q. (2020) High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral Sci. 12 (1), 8.10.1038/s41368-020-0074-x.
    1. Sungnak W.; Huang N.; Bécavin C.; Berg M.; Queen R.; Litvinukova M.; Talavera-López C.; Maatz H.; Reichart D.; Sampaziotis F.; Worlock K. B.; Yoshida M.; Barnes J. L. (2020) HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 26 (5), 681–687. 10.1038/s41591-020-0868-6.
    1. Santacroce L.; Charitos I. A.; Del Prete R. (2020) COVID-19 in Italy: An Overview from the First Case to Date. Electron J. Gen Med. 17 (6), em23510.29333/ejgm/7926.
    1. Passarelli P. C.; Lopez M. A.; Mastandrea Bonaviri G. N.; Garcia-Godoy F.; D’Addona A. (2020) Taste and smell as chemosensory dysfunctions in COVID-19 infection. Am. J. Dent. 33 (3), 135–137.
    1. Milanetti E., Miotto M., Di Rienzo L., Monti M., Gosti G., and Ruocco G. (2020) In-Silico evidence for two receptors based strategy of SARS-CoV-2, bioRxiv 10.1101/2020.03.24.006197 (Available at , last access June 30, 2020).
    1. Witt M.; Miller I. J. Jr (1992) Comparative lectin histochemistry on taste buds in foliate, circumvallate and fungiform papillae of the rabbit tongue. Histochemistry 98 (3), 173–182. 10.1007/BF00315876.
    1. Pushpass R. G.; Pellicciotta N.; Kelly C.; Proctor G.; Carpenter G. H. (2019) Reduced Salivary Mucin Binding and Glycosylation in Older Adults Influences Taste in an In Vitro Cell Model. Nutrients 11 (10), 2280.10.3390/nu11102280.
    1. Deems D. A.; Doty R. L.; Settle R. G.; Moore-Gillon V.; Shaman P.; Mester A. F.; Kimmelman C. P.; Brightman V. J.; Snow J. B. Jr (1991) Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch. Otolaryngol., Head Neck Surg. 117 (5), 519–528. 10.1001/archotol.1991.01870170065015.
    1. Prescott J. (2012) Multimodal chemosensory interactions and perception of flavor, in The Neural Bases of Multisensory Processes (Murray M. M., and Wallace M. T., Eds.), CRC Press/Taylor & Francis, Boca Raton FL.
    1. Dubé M.; Le Coupanec A.; Wong A. H.; Rini J. M.; Desforges M.; Talbot P. J. (2018) Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J. Virol. 92 (17), e00404-1810.1128/JVI.00404-18.
    1. Koyuncu O. O.; Hogue I. B.; Enquist L. W. (2013) Virus infections in the nervous system. Cell Host Microbe 13 (4), 379–393. 10.1016/j.chom.2013.03.010.
    1. Desforges M.; Le Coupanec A.; Dubeau P.; Bourgouin A.; Lajoie L.; Dubé M.; Talbot P. J. (2020) Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?. Viruses 12 (1), 14.10.3390/v12010014.
    1. Zhou G.; Chen S.; Chen Z. (2020) Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies. Front Med. 14 (2), 117–125. 10.1007/s11684-020-0773-x.
    1. Wan S., Yi Q., Fan S., Lv J., Zhang X., Guo L., Lang C., Xiao Q., Xiao K., Yi Z., Qiang M., Xiang J., Zhang B., and Chen Y. (2020) Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP), MedRxiv 10.1101/2020.02.10.20021832 (Available at , last accessed June 30, 2020).
    1. Tanaka T.; Narazaki M.; Kishimoto T. (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspect. Biol. 6 (10), a01629510.1101/cshperspect.a016295.
    1. Henkin R. I.; Schmidt L.; Velicu I. (2013) Interleukin 6 in hyposmia. JAMA Otolaryngol Head Neck Surg. 139 (7), 728–34. 10.1001/jamaoto.2013.3392.
    1. Mori I. (2018) 1918 H1N1 Influenza Virus Infection–Induced Proinflammatory Cytokines in the Olfactory Bulb Could Trigger Lethargic Disease. J. Infect. Dis. 218 (10), 1686–1687. 10.1093/infdis/jiy380.
    1. de Wit E.; Siegers J. Y.; Cronin J. M.; Weatherman S.; van den Brand J. M.; Leijten L. M.; van Run P.; Begeman L.; van den Ham H. J.; Andeweg A. C.; Bushmaker T.; Scott D. P.; Saturday G.; Munster V. J.; Feldmann H.; van Riel D. (2018) 1918 H1N1 influenza virus replicates and induces proinflammatory cytokine responses in extrarespiratory tissues of ferrets. J. Infect. Dis. 217 (8), 1237–1246. 10.1093/infdis/jiy003.
    1. De Jong M. D.; Simmons C. P.; Thanh T. T.; Hien V. M.; Smith G. J.; Chau T. N.; Hoang D. M.; Van Vinh Chau N.; Khanh T. H.; Dong V. C.; Qui P. T.; Van Cam B.; Ha D. Q.; Guan Y.; Peiris J. S.; Chinh N. T.; Hien T. T.; Farrar J. (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12 (10), 1203–1207. 10.1038/nm1477.
    1. Hanisch U. K. (2002) Microglia as a source and target of cytokines. Glia. 40 (2), 140–155. 10.1002/glia.10161.
    1. Frei K.; Malipiero U. V.; Leist T. P.; Zinkernagel R. M.; Schwab M. E.; Fontana A. (1989) On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 19 (4), 689–694. 10.1002/eji.1830190418.
    1. Righi M.; Mori L.; De Libero G.; Sironi M.; Biondi A.; Mantovani A.; Donini S. D.; Ricciardi-Castagnoli P. (1989) Monokine production by microglial cell clones. Eur. J. Immunol. 19 (8), 1443–1448. 10.1002/eji.1830190815.
    1. Bilinska K.; Butowt R. (2020) Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism. ACS Chem. Neurosci. 11, 2152.10.1021/acschemneuro.0c00406.
    1. Hopkins C.; Gillett S.; Slack R.; Lund V. J.; Browne J. P. (2009) Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 34 (5), 447–454. 10.1111/j.1749-4486.2009.01995.x.
    1. Rawal S.; Hoffman H. J.; Honda M.; Huedo-Medina T. B.; Duffy V. B. (2015) The Taste and Smell Protocol in the 2011–2014 US National Health and Nutrition Examination Survey (NHANES): Test-Retest Reliability and Validity Testing. Chemosens. Percept. 8 (3), 138–148. 10.1007/s12078-015-9194-7.
    1. Suzuki M.; Saito K.; Min W. P.; Vladau C.; Toida K.; Itoh H.; Murakami S. (2007) Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope 117 (2), 272–277. 10.1097/01.mlg.0000249922.37381.1e.
    1. Vaira L. A.; Deiana G.; Fois A. G.; Pirina P.; Madeddu G.; De Vito A.; Babudieri S.; Petrocelli M.; Serra A.; Bussu F.; Ligas E.; Salzano G.; De Riu G. (2020) Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head Neck. 42 (6), 1252–1258. 10.1002/hed.26204.
    1. 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. (2020) 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. 277 (8), 2251–2261. 10.1007/s00405-020-05965-1.
    1. Yan C. H.; Faraji F.; Prajapati D. P.; Boone C. E.; DeConde A. S. (2020) Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int. Forum Allergy Rhinol. 10 (7), 806–813. 10.1002/alr.22579.
    1. Turski W. A.; Wnorowski A.; Turski G. N.; Turski C. A.; Turski L. (2020) AhR and IDO1 in pathogenesis of Covid-19 and the “Systemic AhR Activation Syndrome:” Translational review and therapeutic perspectives. Restor. Neurol. Neurosci. 10.3233/RNN-201042.
    1. Netland J.; Meyerholz D. K.; Moore S.; Cassell M.; Perlman S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82 (15), 7264–7275. 10.1128/JVI.00737-08.
    1. Wang H.; Zhou M.; Brand J.; Huang L. (2007) Inflammation activates the interferon signaling pathways in taste bud cells. J. Neurosci. 27 (40), 10703–10713. 10.1523/JNEUROSCI.3102-07.2007.
    1. Wang H.; Zhou M.; Brand J.; Huang L. (2009) Inflammation and taste disorders: mechanisms in taste buds. Ann. N. Y. Acad. Sci. 1170, 596–603. 10.1111/j.1749-6632.2009.04480.x.
    1. Di Serio F.; Lovero R.; D’Agostino D.; Nisi L.; Miragliotta G.; Contino R.; Man A.; Ciccone M. M.; Santacroce L. (2016) Evaluation of procalcitonin, Vitamin D and C-reactive protein levels in septic patients with positive emocoltures. Our preliminary experience. Acta Medica Mediterr. 32, 1911–1914. 10.19193/0393-6384_2016_6_182.
    1. Wehling E.; Naess H.; Wollschlaeger D.; Hofstad H.; Bramerson A.; Bende M.; Nordin S. (2015) Olfactory dysfunction in chronic stroke patients. BMC Neurol. 15, 199.10.1186/s12883-015-0463-5.
    1. Rousseaux M.; Muller P.; Gahide I.; Mottin Y.; Romon M. (1996) Disorders of Smell, Taste, and Food Intake in a Patient With a Dorsomedial Thalamic Infarct. Stroke 27 (12), 2328–2330. 10.1161/01.STR.27.12.2328.
    1. Santacroce L.; Bottalico L.; Charitos I. A. (2020) The Impact of COVID-19 on Italy: A Lesson for the Future. Int. J. Occup. Environ. Med. 11 (3), 151–152. 10.34172/ijoem.2020.1984.
    1. Troyer E. A.; Kohn J. N.; Hong S. (2020) Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, Behav., Immun. 87, 34–39. 10.1016/j.bbi.2020.04.027.
    1. Serrano-Castro P. J.; Estivill-Torrús G.; Cabezudo-García P.; Reyes-Bueno J. A.; Ciano Petersen N.; Aguilar-Castillo M. J.; Suárez-Pérez J.; Jiménez-Hernández M. D.; Moya-Molina MÁ; Oliver-Martos B.; Arrabal-Gómez C.; Rodríguez de Fonseca F. (2020) Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?. Neurologia. 35 (4), 245–251. 10.1016/j.nrl.2020.04.002.
    1. Butler M. J.; Barrientos R. M. (2020) The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain, Behav., Immun. 87, 53–54. 10.1016/j.bbi.2020.04.040.
    1. Santacroce L. (2020) Letter in response to the article “Enhancing immunity in viral infections, with special emphasis on COVID-19: A review (Jayawardena et al.). Diabetes Metab Syndr. 14 (5), 927.10.1016/j.dsx.2020.06.009.
    1. Elsayed Y.; Khan N. A. (2020) Immunity-Boosting Spices and the Novel Coronavirus. ACS Chem. Neurosci. 11 (12), 1696–1698. 10.1021/acschemneuro.0c00239.
    1. Mitrani R. D.; Dabas N.; Goldberger J. J. (2020) COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm 10.1016/j.hrthm.2020.06.026.
    1. Lasrado N.; Reddy J. (2020) An overview of the immune mechanisms of viral myocarditis [published online ahead of print, 2020 Jul 28]. Rev. Med. Virol. e213110.1002/rmv.2131.

Source: PubMed

3
구독하다