DOI QR코드

DOI QR Code

Oral symptom manifestations in patients with COVID-19: gustatory and saliva secretion dysfunctions and pathogenetic hypotheses

  • Joungmok Kim (Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University) ;
  • Jeong Hee Kim (Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University)
  • Received : 2024.08.29
  • Accepted : 2024.09.10
  • Published : 2024.09.30

Abstract

Coronavirus disease 2019 (COVID-19) is a highly contagious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is characterized by a wide spectrum of symptoms, ranging from mild to severe, including fatal outcomes. This study aims to review gustatory and salivary secretion dysfunctions and determine their potential pathogenic mechanisms. Gustatory impairment and salivary dysfunction are prevalent among patients with acute COVID-19 and those recovering from the disease. The mouth serves as a critical entry route for SARS-CoV-2. The cells within the oral epithelium, taste buds, and minor and major salivary glands express key entry factors for SARS-CoV-2, including angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin. The co-occurrence of gustatory and salivary secretion dysfunctions possibly has pathogenetic association with the following factors: the expression of SARS-CoV-2 cellular entry receptors in the taste buds and salivary glands and SARS-CoV-2-induced zinc deficiency, which is crucial for normal taste perception and saliva secretion. Furthermore, the cytokine storm triggered by COVID-19 contributes to secondary damage affecting gustatory and salivary functions.

Keywords

References

  1. Liu Y, Wang Z, Rader B, Li B, Wu CH, Whittington JD, Zheng P, Stenseth NC, Bjornstad ON, Brownstein JS, Tian H. Associations between changes in population mobility in response to the COVID-19 pandemic and socioeconomic factors at the city level in China and country level worldwide: a retrospective, observational study. Lancet Digit Health 2021;3:e349-59. doi: 10.1016/S2589-7500(21)00059-5
  2. World Health Organization (WHO). WHO COVID-19 dashboard [Internet]. Geneva: WHO; 2024 [cited 2024 Aug 22]. Available from: https://data.who.int/dashboards/covid19/cases?n=c
  3. Korea Disease Control and Prevention Agency (KDCA). COVID-19 positive case (sample) surveillance status [Internet]. Cheongju: KDCA; 2024 [cited 2024 Aug 22]. Available from: https://ncv.kdca.go.kr/pot/cv/trend/dmstc/selectMntrgSttus.do
  4. Sun K, Wang W, Gao L, Wang Y, Luo K, Ren L, Zhan Z, Chen X, Zhao S, Huang Y, Sun Q, Liu Z, Litvinova M, Vespignani A, Ajelli M, Viboud C, Yu H. Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2. Science 2021;371:eabe2424. doi: 10.1126/science.abe2424
  5. U.S Centers for Disease Control and Prevention (CDC). Symptoms of COVID-19 [Internet]. Atlanta: CDC; 2024 [cited 2024 Aug 22]. Available from: https://www.cdc.gov/covid/signs-symptoms/index.html
  6. Tsuchiya H. Oral Symptoms associated with COVID-19 and their pathogenic mechanisms: a literature review. Dent J (Basel) 2021;9:32. doi: 10.3390/dj9030032
  7. Huang N, Perez P, Kato T, Mikami Y, Okuda K, Gilmore RC, Conde CD, Gasmi B, Stein S, Beach M, Pelayo E, Maldonado JO, Lafont BA, Jang SI, Nasir N, Padilla RJ, Murrah VA, Maile R, Lovell W, Wallet SM, Bowman NM, Meinig SL, Wolfgang MC, Choudhury SN, Novotny M, Aevermann BD, Scheuermann RH, Cannon G, Anderson CW, Lee RE, Marchesan JT, Bush M, Freire M, Kimple AJ, Herr DL, Rabin J, Grazioli A, Das S, French BN, Pranzatelli T, Chiorini JA, Kleiner DE, Pittaluga S, Hewitt SM, Burbelo PD, Chertow D; NIH COVID-19 Autopsy Consortium; HCA Oral and Craniofacial Biological Network; Frank K, Lee J, Boucher RC, Teichmann SA, Warner BM, Byrd KM. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med 2021;27:892-903. doi: 10.1038/s41591-021-01296-8
  8. Doty RL. Olfactory dysfunction in COVID-19: pathology and long-term implications for brain health. Trends Mol Med 2022;28:781-94. doi: 10.1016/j.molmed.2022.06.005
  9. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post-Coronavirus dsease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis 2022;226:1593-607. doi: 10.1093/infdis/jiac136
  10. Kayaaslan B, Eser F, Kalem AK, Kaya G, Kaplan B, Kacar D, Hasanoglu I, Coskun B, Guner R. Post-COVID syndrome: a single-center questionnaire study on 1007 participants recovered from COVID-19. J Med Virol 2021;93:6566-74. doi: 10.1002/jmv.27198
  11. Tsuchiya H. COVID-19 oral sequelae: persistent gustatory and saliva secretory dysfunctions after recovery from COVID-19. Med Princ Pract 2023;32:166-77. doi: 10.1159/000531373
  12. Appelman B, Charlton BT, Goulding RP, Kerkhoff TJ, Breedveld EA, Noort W, Offringa C, Bloemers FW, van Weeghel M, Schomakers BV, Coelho P, Posthuma JJ, Aronica E, Joost Wiersinga W, van Vugt M, Wust RCI. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 2024;15:17. doi: 10.1038/s41467-023-44432-3
  13. Goldstein DS. Post-COVID dysautonomias: what we know and (mainly) what we don't know. Nat Rev Neurol 2024;20:99-113. doi: 10.1038/s41582-023-00917-9
  14. Greene C, Connolly R, Brennan D, Laffan A, O'Keeffe E, Zaporojan L, O'Callaghan J, Thomson B, Connolly E, Argue R, Meaney JFM, Martin-Loeches I, Long A, Cheallaigh CN, Conlon N, Doherty CP, Campbell M. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci 2024;27:421-32. doi: 10.1038/s41593-024-01576-9
  15. Sk Abd Razak R, Ismail A, Abdul Aziz AF, Suddin LS, Azzeri A, Sha'ari NI. Post-COVID syndrome prevalence: a systematic review and meta-analysis. BMC Public Health 2024;24:1785. doi: 10.1186/s12889-024-19264-5
  16. Mastrangelo A, Bonato M, Cinque P. Smell and taste disorders in COVID-19: from pathogenesis to clinical features and outcomes. Neurosci Lett 2021;748:135694. doi: 10.1016/j.neulet.2021.135694
  17. SeyedAlinaghi S, Bagheri A, Razi A, Mojdeganlou P, Mojdeganlou H, Afsahi AM, Afzalian A, Paranjkhoo P, Shahidi R, Mirzapour P, Pashaei Z, Habibi MA, Shahbazi P, Nooralioghli Parikhani S, Farizani Gohari NS, Popoola Y, Mehraeen E, Hackett D. Late cmplications of COVID-19; an umbrella review on current systematic reviews. Arch Acad Emerg Med 2023;11:e28. doi: 10.22037/aaem.v11i1.1907
  18. Bungenberg J, Hohenfeld C, Costa AS, Heine J, Schwichtenberg K, Hartung T, Franke C, Binkofski F, Schulz JB, Finke C, Reetz K. Characteristic functional connectome related to Post-COVID-19 syndrome. Sci Rep 2024;14:4997. doi: 10.1038/s41598-024-54554-3
  19. Garmoe W, Rao K, Gorter B, Kantor R. Neurocognitive impairment in post-COVID-19 condition in adults: narrative review of the current literature. Arch Clin Neuropsychol 2024;39:276-89. doi: 10.1093/arclin/acae017
  20. Jaywant A, Gunning FM, Oberlin LE, Santillana M, Ognyanova K, Druckman JN, Baum MA, Lazer D, Perlis RH. Cognitive symptoms of post-COVID-19 condition and daily functioning. JAMA Netw Open 2024;7:e2356098. doi: 10.1001/jamanetworkopen.2023.56098
  21. Sharetts R, Moein ST, Khan R, Doty RL. Long-term taste and smell outcomes after COVID-19. JAMA Netw Open 2024;7:e247818. doi: 10.1001/jamanetworkopen.2024.7818
  22. Tsuchiya H. Gustatory and saliva secretory dysfunctions in COVID-19 patients with zinc deficiency. Life (Basel) 2022;12:353. doi: 10.3390/life12030353
  23. Barbara JM, Gatt J, Xuereb RA, Tabone Adami N, Darmanin J, Erasmi R, G Xuereb R, Barbara C, Stephen F, Jane Magri C. Clinical outcomes at medium-term follow-up of COVID-19. J R Coll Physicians Edinb 2022;52:220-7. doi: 10.1177/14782715221124617
  24. Vaira LA, Gessa C, Deiana G, Salzano G, Maglitto F, Lechien JR, Saussez S, Piombino P, Biglio A, Biglioli F, Boscolo-Rizzo P, Hopkins C, Parma V, De Riu G. The effects of persistent olfactory and gustatory dysfunctions on quality of life in long-COVID-19 ptients. Life (Basel) 2022;12:141. doi: 10.3390/life12020141
  25. Oliveira WQ, Sousa PHM, Pastore GM. Olfactory and gustatory disorders caused by COVID-19: how to regain the pleasure of eating? Trends Food Sci Technol 2022;122:104-9. doi: 10.1016/j.tifs.2022.01.022
  26. Yom-Tov E, Lekkas D, Jacobson NC. Association of COVID19-induced anosmia and ageusia with depression and suicidal ideation. J Affect Disord Rep 2021;5:100156. doi: 10.1016/j.jadr.2021.100156
  27. Matuck BF, Dolhnikoff M, Duarte-Neto AN, Maia G, Gomes SC, Sendyk DI, Zarpellon A, de Andrade NP, Monteiro RA, Pinho JRR, Gomes-Gouvea MS, Souza SC, Kanamura C, Mauad T, Saldiva PHN, Braz-Silva PH, Caldini EG, da Silva LFF. Salivary glands are a target for SARS-CoV-2: a source for saliva contamination. J Pathol 2021;254:239-43. doi: 10.1002/path.5679
  28. France K, Glick M. Long COVID and oral health care considerations. J Am Dent Assoc 2022;153:167-74. doi: 10.1016/j.adaj.2021.08.007
  29. Naqvi AR, Schwartz J, Brandini DA, Schaller S, Hussein H, Valverde A, Naqvi RA, Shukla D. COVID-19 and oral diseases: assessing manifestations of a new pathogen in oral infections. Int Rev Immunol 2022;41:423-37. doi: 10.1080/08830185.2021.1967949
  30. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020;5:536-44. doi: 10.1038/s41564-020-0695-z
  31. Azzi L, Carcano G, Gianfagna F, Grossi P, Gasperina DD, Genoni A, Fasano M, Sessa F, Tettamanti L, Carinci F, Maurino V, Rossi A, Tagliabue A, Baj A. Saliva is a reliable tool to detect SARS-CoV-2. J Infect 2020;81:e45-50. doi: 10.1016/j.jinf.2020.04.005
  32. Marchesan JT, Warner BM, Byrd KM. The "oral" history of COVID-19: primary infection, salivary transmission, and postacute implications. J Periodontol 2021;92:1357-67. doi: 10.1002/JPER.21-0277
  33. Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, Warren JL, Geng B, Muenker MC, Moore AJ, Vogels CBF, Petrone ME, Ott IM, Lu P, Venkataraman A, Lu-Culligan A, Klein J, Earnest R, Simonov M, Datta R, Handoko R, Naushad N, Sewanan LR, Valdez J, White EB, Lapidus S, Kalinich CC, Jiang X, Kim DJ, Kudo E, Linehan M, Mao T, Moriyama M, Oh JE, Park A, Silva J, Song E, Takahashi T, Taura M, Weizman OE, Wong P, Yang Y, Bermejo S, Odio CD, Omer SB, Dela Cruz CS, Farhadian S, Martinello RA, Iwasaki A, Grubaugh ND, Ko AI. Saliva or nasopharyngeal swab specimens for detection of SARS-CoV-2. N Engl J Med 2020;383:1283-6. doi: 10.1056/NEJMc2016359
  34. Mariz BALA, Brandao TB, Ribeiro ACP, Lopes MA, Santos-Silva AR. New insights for the pathogenesis of COVID-19-related dysgeusia. J Dent Res 2020;99:1206. doi: 10.1177/0022034520936638
  35. Pitones-Rubio V, Chavez-Cortez EG, Hurtado-Camarena A, Gonzalez-Rascon A, Serafin-Higuera N. Is periodontal disease a risk factor for severe COVID-19 illness? Med Hypotheses 2020;144:109969. doi: 10.1016/j.mehy.2020.109969
  36. Fisher J, Monette DL, Patel KR, Kelley BP, Kennedy M. COVID-19 associated parotitis. Am J Emerg Med 2021;39:254. e1-3. doi: 10.1016/j.ajem.2020.06.059
  37. Amorim Dos Santos J, Normando AGC, Carvalho da Silva RL, De Paula RM, Cembranel AC, Santos-Silva AR, Guerra ENS. Oral mucosal lesions in a COVID-19 patient: new signs or secondary manifestations? Int J Infect Dis 2020;97:326-8. doi: 10.1016/j.ijid.2020.06.012
  38. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020;5:562-9. doi: 10.1038/s41564-020-0688-y
  39. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3. doi: 10.1038/s41586-020-2012-7
  40. 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;12:8. doi: 10.1038/s41368-020-0074-x
  41. Xu J, Li Y, Gan F, Du Y, Yao Y. Salivary glands: potential reservoirs for COVID-19 asymptomatic infection. J Dent Res 2020;99:989. doi: 10.1177/0022034520918518
  42. Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022;23:3-20. doi: 10.1038/s41580-021-00418-x
  43. Doyle ME, Premathilake HU, Yao Q, Mazucanti CH, Egan JM. Physiology of the tongue with emphasis on taste transduction. Physiol Rev 2023;103:1193-246. doi: 10.1152/physrev.00012.2022
  44. Rodriguez YA, Roebber JK, Dvoryanchikov G, Makhoul V, Roper SD, Chaudhari N. "Tripartite synapses" in taste buds: a role for type I glial-like taste cells. J Neurosci 2021;41:9860-71. doi: 10.1523/JNEUROSCI.1444-21.2021
  45. Roper SD. Chemical and electrical synaptic interactions among taste bud cells. Curr Opin Physiol 2021;20:118-25. doi: 10.1016/j.cophys.2020.12.004
  46. Wilson CE, Lasher RS, Yang R, Dzowo Y, Kinnamon JC, Finger TE. Taste bud connectome: implications for taste information processing. J Neurosci 2022;42:804-16. doi: 10.1523/JNEUROSCI.0838-21.2021
  47. Rass V, Tymoszuk P, Sahanic S, Heim B, Ausserhofer D, Lindner A, Kofler M, Mahlknecht P, Boehm A, Hufner K, Pizzini A, Sonnweber T, Kurz K, Pfeifer B, Kiechl S, Peball M, Kindl P, Putnina L, Fava E, Djamshidian A, Huber A, Wiedermann CJ, Sperner-Unterweger B, Woll E, Beer R, Schiefecker AJ, Bellmann-Weiler R, Bachler H, Tancevski I, Pfausler B, Piccoliori G, Seppi K, Weiss G, Loffler-Ragg J, Helbok R. Distinct smell and taste disorder phenotype of post-acute COVID-19 sequelae. Eur Arch Otorhinolaryngol 2023;280:5115-28. doi: 10.1007/s00405-023-08163-x
  48. Okada Y, Yoshimura K, Toya S, Tsuchimochi M. Pathogenesis of taste impairment and salivary dysfunction in COVID-19 patients. Jpn Dent Sci Rev 2021;57:111-22. doi: 10.1016/j.jdsr.2021.07.001
  49. Nanjo Y, Okuma T, Kuroda Y, Hayakawa E, Shibayama K, Akimoto T, Murashima R, Kanamori K, Tsutsumi T, Suzuki Y, Namba Y, Makino F, Nagashima O, Sasaki S, Takahashi K. Multiple types of taste disorders among patients with COVID-19. Intern Med 2022;61:2127-34. doi: 10.2169/internal-medicine.9065-21
  50. Tuter G, Yerebakan M, Celik B, Kara G. Oral manifestations in SARS-CoV-2 infection. Med Oral Patol Oral Cir Bucal 2022;27:e330-9. doi: 10.4317/medoral.25259
  51. Katz J. Prevalence of dry mouth in COVID-19 patients with and without Sicca syndrome in a large hospital center. Ir J Med Sci 2021;190:1639-41. doi: 10.1007/s11845-020-02480-4
  52. Melo TS, Beltrao RC, Mendonca AFT, Duarte ALBP, Gueiros LA. Sicca symptoms in post-acute COVID-19 syndrome. Oral Dis 2022;28 Suppl 2:2620-1. doi: 10.1111/odi.14159
  53. Tarcha R, Khalayli N, Kudsi M. Sicca syndrome as complication of COVID-19 infection: a case report. Clin Case Rep 2024;12:e9177. doi: 10.1002/ccr3.9177
  54. Wang P, Luo R, Zhang M, Wang Y, Song T, Tao T, Li Z, Jin L, Zheng H, Chen W, Zhao M, Zheng Y, Qin J. A cross-talk between epithelium and endothelium mediates human alveolar-capillary injury during SARS-CoV-2 infection. Cell Death Dis 2020;11:1042. doi: 10.1038/s41419-020-03252-9
  55. Zhu N, Wang W, Liu Z, Liang C, Wang W, Ye F, Huang B, Zhao L, Wang H, Zhou W, Deng Y, Mao L, Su C, Qiang G, Jiang T, Zhao J, Wu G, Song J, Tan W. Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells. Nat Commun 2020;11:3910. doi: 10.1038/s41467-020-17796-z
  56. Doyle ME, Appleton A, Liu QR, Yao Q, Mazucanti CH, Egan JM. Human type II taste cells express angiotensin-converting enzyme 2 and are infected by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Am J Pathol 2021;191:1511-9. doi: 10.1016/j.ajpath.2021.05.010
  57. Nguyen HT, Zhang S, Wang Q, Anang S, Wang J, Ding H, Kappes JC, Sodroski J. Spike glycoprotein and host cell determinants of SARS-CoV-2 entry and cytopathic effects. J Virol 2021;95:e02304-20. doi: 10.1128/JVI.02304-20
  58. Henin D, Pellegrini G, Carmagnola D, Lanza Attisano GC, Lopez G, Ferrero S, Amendola A, De Angelis D, Tanzi E, Dellavia C. Morphological and immunopathological aspects of lingual tissues in COVID-19. Cells 2022;11:1248. doi: 10.3390/cells11071248
  59. Goncalves TJM, Goncalves SEAB, Guarnieri A, Risegato RC, Guimaraes MP, de Freitas DC, Razuk-Filho A, Junior PBB, Parrillo EF. Association between low zinc levels and severity of acute respiratory distress syndrome by new Coronavirus SARS-CoV-2. Nutr Clin Pract 2021;36:186-91. doi: 10.1002/ncp.10612
  60. Chou HC, Chien CL, Huang HL, Lu KS. Effects of zinc deficiency on the vallate papillae and taste buds in rats. J Formos Med Assoc 2001;100:326-35.
  61. Wessels I, Rolles B, Rink L. The potential impact of zinc supplementation on COVID-19 pathogenesis. Front Immunol 2020;11:1712. doi: 10.3389/fimmu.2020.01712
  62. Abdelmaksoud AA, Ghweil AA, Hassan MH, Rashad A, Khodeary A, Aref ZF, Sayed MAA, Elsamman MK, Bazeed SES. Olfactory disturbances as presenting manifestation among egyptian patients with COVID-19: possible role of zinc. Biol Trace Elem Res 2021;199:4101-8. doi: 10.1007/s12011-020-02546-5
  63. Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol 2021;93:250-6. doi: 10.1002/jmv.26232
  64. Sawa Y, Ibaragi S, Okui T, Yamashita J, Ikebe T, Harada H. Expression of SARS-CoV-2 entry factors in human oral tissue. J Anat 2021;238:1341-54. doi: 10.1111/joa.13391
  65. Dai Q, Xu M, Yao M, Sun B. Angiotensin AT1 receptor antagonists exert anti-inflammatory effects in spontaneously hypertensive rats. Br J Pharmaco 2007;152:1042-8. doi: 10.1038/sj.bjp.0707454
  66. Lyoo KS, Kim HM, Lee B, Che YH, Kim SJ, Song D, Hwang W, Lee S, Park JH, Na W, Yun SP, Kim YJ. Direct neuronal infection of SARS-CoV-2 reveals cellular and molecular pathology of chemosensory impairment of COVID-19 patients. Emerg Microbes Infect 2022;11:406-11. doi: 10.1080/22221751.2021.2024095
  67. Small DM, Prescott J. Odor/taste integration and the perception of flavor. Exp Brain Res 2005;166:345-57. doi: 10.1007/s00221-005-2376-9