Fabio Maglitto

Francesco Antonio Salzano

Giacomo De Riu

Giovanni Salzano

Jerome R Lechien

Luigi Angelo Vaira

Sven Saussez

English

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BRIEF COMMUNICATIONGustatory Dysfunction: A Highly Specific and Smell-IndependentSymptom of COVID-19Luigi Angelo Vaira1 • Jerome R. Lechien2,3 • Giovanni Salzano4 •Francesco Antonio Salzano5 • Fabio Maglitto4 • Sven Saussez2,3 • Giacomo De Riu1Received: 30 August 2020 / Accepted: 23 September 2020 Association of Otolaryngologists of India 2020Abstract Chemosensitive dysfunctions are now consid-ered as frequent and early symptoms of coronavirus disease2019 (COVID-19). In the last few weeks, researchers’greatest efforts have been focusing mainly on the analysisof olfactory disorders, neglecting taste dysfunctions.According to our psychophysical evaluations, it can beinferred that the pathogenesis of taste disorders in COVID-19 patients is largely smell-independent. Moreover, iso-lated gustatory disorders are highly specific of SARS-CoV-2 infection. For these reasons, it is essential that gustatorydysfunctions, like olfactory disorders, are included in theCOVID-19 guidelines.Keywords COVID-19  SARS-CoV-2  Coronavirus Chemosensitive dysfunction  Olfactory dysfunction Ageusia  Taste  Gustatory dysfunction  AnosmiaIntroductionChemosensitive dysfunctions are now considered as fre-quent and early symptoms of coronavirus disease 2019(COVID-19) in Europe and America, affecting 60–80% ofpatients [1–4]. In the last few weeks, researchers’ greatestefforts have been focusing mainly on the analysis ofolfactory disorders, neglecting taste dysfunctions, for twomain reasons. According to a first hypothesis, the olfactorypathway could represent a way of access to the centralnervous system for the coronavirus [5]. Therefore, olfac-tory dysfunctions could represent a sign of neuroinvasion,while ageusia and hypogeusia would not have any possibleinteresting pathogenetic implication. Secondly, the gusta-tory disturbances have generally been classified as a con-sequence of the retronasal olfactory loss and for this reasonthey have been often overlooked [6].After the outbreak of the severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2) pandemic in Italy, weimmediately began evaluating patients with psychophysi-cal tests [7–10]. In this way, we were able to obtain a largeamount of objective data that allowed us to evaluate therelationships between olfactory and gustatory disorders inCOVID-19 patients.MethodologyA standardized and validated test, which investigates theability to perceive four primary tastes (sweet, salty, sourand bitter) was used to evaluate the gustatory function inpatients with confirmed diagnosis of SARS-CoV-2 infec-tion [7–10]. Four solutions, one for each primary taste,were prepared as follows [11]:& Luigi Angelo Vairaluigi.vaira@gmail.com1 Maxillofacial Surgery Operative Unit, University Hospital ofSassari, Viale San Pietro 43/B, 07100 Sassari, Italy2 COVID-19 Task Force of the Young-Otolaryngologists of theInternational Federations of Oto-Rhino-LaryngologicalSocieties (YO-IFOS), Mons, Belgium3 Department of Human and Experimental Oncology, Facultyof Medicine UMONS Research Institute for Health Sciencesand Technology, University of Mons (UMons), Mons,Belgium4 Maxillofacial Surgery Unit, University Hospital of Naples‘‘Federico II’’, Via Pansini 5, 80131 Naples, Italy5 Otolaryngology Operative Unit, Department of Medicine,Surgery and Dentistry, ‘‘Scuola Medica Salernitana’’,University of Salerno, 84081 Baronissi, Salerno, Italy123Indian J Otolaryngol Head Neck Surghttps://doi.org/10.1007/s12070-020-02182-4• Salted solution: 30 g of table salt were added to 1 L ofdeionized water.• Sweet solution: 30 g of refined sugar were dissolved in1 L of deionized water.• Sour solution: 90 mL of commercial 100% lemon juiceadded to 1 L of deionized water.• Bitter solution: unsweetened decaffeinated coffee.Deionized water was used as control. During the trial,1 ml of each solution was dropped onto the center of thepatient tongue. Taste score ranged from 0 to 4 allowing toclassify the patients into four categories: Normal (score 4),mild hypogeusia (score 3), moderate hypogeusia (score 2),severe hypogeusia (score 1) and ageusia (score 0). At thesame time, all the patients underwent olfactory assessmentwith the Connecticut Chemosensory Clinical ResearchCenter orthonasal olfaction test and a self-administeredpsychophysical olfactory test recently validated by ourgroup [7–10].ResultsWith this methodology, we obtained objective assessmentsof the olfactory and gustatory functions of 556 patients,many of which have been prospectively assessed severaltimes. In the 801 evaluations performed, isolated tastedisturbances were found in 9.4% of cases. Considering alsosubjects with combined dysfunctions, a total of 51.1% ofpatients reported gustatory disorders. Moreover, in 17.9%of patients with combined dysfunctions, taste disorderswere more severe than the olfactory ones. This frequency isprobably underestimated as 74.4% of these evaluationswere performed over 10 days after the symptom onset. Asa matter of fact, in most patients the gustatory dysfunctiontends to regress completely within 10 days, while therecovery of the olfactory disorder takes longer [7, 9, 12].Taking into consideration only the 205 assessments thattook place within 10 days after clinical onset, patients withgustatory disorders rose to 69.2% with a frequency ofisolated disorders of 11.6%. In this early stage subgroup,26.3% of patients who presented combined chemosensitivedisorders had a gustatory dysfunctions more severe than theolfactory one (Table 1).DiscussionThe studies currently present in the literature, have notbeen able to detect these results as they are based exclu-sively on anamnestic data or on psychophysical evaluationof patients in the late stage of the disease, when the gus-tatory disorder had already regressed. Only the objectiveevaluation of the patients during the early stage of theinfection permits to appropriately compare the frequencyand severity of the two chemosensitive disorders.According to these results, it can be inferred that thepathogenesis of taste disorders in COVID-19 patients islargely smell-independent. Anosmia is typically associatedwith viral infections while ageusia could represent a furthermanifestation, related to the loss of the retronasal olfactoryfunction. The ability of SARS-CoV-2 to induce gustatorydisturbances in the absence of olfactory dysfunctions isinstead a unique peculiarity for a virus.The mechanism by which SARS-CoV-2 is capable ofcausing gustatory disturbances could be twofold. First, thevirus uses the angiotensin converting enzyme 2 (ACE2),receptors widely expressed on the taste buds, to infect cells.Ageusia is a well known side effect of ACE2-inhibitors andit is caused by a complex mechanism which involvessodium channel and G-protein-coupled protein present intaste receptors. SARS-CoV-2, binding these receptors,might inactivate them, hindering the conversion of chem-ical gustatory signals into action potential, consequentlyprecluding the sensory perception of taste [13, 14].Moreover, SARS-CoV-2 might bind to sialic acidreceptors [15]. Sialic acid is a fundamental component ofthe salivary mucin and protects the glycoproteins thatconvey gustatory molecules inside the taste pores frompremature enzymatic degradation. A reduction of sialicacid in the saliva is associated with an increase in thegustatory threshold. Therefore, SARS-CoV-2 could occupythe binding sites of sialic acid on the taste buds, acceler-ating the degradation of the gustatory particles [13].From a diagnostic point of view, isolated gustatorydisorders are very important as they are highly specific ofSARS-CoV-2 infection. In fact, olfactory dysfunction isalso present in 12% of cases of common flu [16] and,although useful as a screening marker, it can give a sig-nificant number of false positives. At the beginning of theepidemic in Italy, an abnormal number of patients turned toour clinic for the detection of sudden onset ageusia, notassociated with any other symptoms. Punctually, SARS-CoV-2 infection was then diagnosed in these patients fol-lowing the further onset of fever and cough.ConclusionOtorhinolaryngologists, maxillofacial surgeons, neurolo-gists and dentists should be warned that in patients seekingassistance for the isolated sudden onset of ageusia, suspi-cion of ongoing coronavirus infection should be consideredin differential diagnosis. For these reasons, in our opinion itis essential that gustatory dysfunctions, like olfactory dis-orders, are included in the COVID-19 guidelines as they123Indian J Otolaryngol Head Neck Surgare frequent, highly specific and smell-independent symp-toms of SARS-CoV-2 infection.Funding None declared.Compliance with Ethical StandardsConflict of interest The authors declare that they have no conflict ofinterest.Ethical Approval The evaluation protocol was approved by anindependent ethical committee (No. 378-2020-OSS-AUSLBO).Informed Consent All patients gave their consent to participate inthe study.References1. Spinato G, Fabbris C, Polesel J (2020) Alterations in smell ortaste in mildly symptomatic outpatients with SARS-CoV-2infection. JAMA 323:2089–20902. Lechien JR, Ducarme M, Place S (2020) Objective olfactoryfindings in hospitalized severe COVID-19 patients. Pathogens9:6273. Vaira LA, Salzano G, Deiana G, Riu De G (2020) Ageusia andanosmia: common findings in COVID-19 patients. Laryngoscope130:17874. Vaira LA, Salzano G, Riu De G (2020) The importance ofolfactory and gustatory disorders as early symptoms of coron-avirus disease (COVID-19). Br J Oral Maxillofac Surg58:615–6165. Vavougios GD (2020) Potentially irreversible olfactory andgustatory impairments in COVID-19. Indolent versus fulminantSARS-CoV-2 neuroinfection. Brain Behav Immun 87:107–1086. Whitcroft KL, Hummel T (2020) Olfactory dysfunction inCOVID-19. Diagnosis and management. JAMA 323:2512–25147. Vaira LA, Hopkins C, Petrocelli M (2020) Do olfactory andgustatory psychophysical scores have a prognostic value inCOVID-19 patients? A prospective study of 106 patients. J Oto-laryngol Head Neck Surg 49:568. Vaira LA, Salzano G, Petrocelli M, Deiana G, Salzano FA, RiuDe G (2020) Validation of a self-administered olfactory andgustatory test for the remotely evaluation of COVID-19 patientsin home quarantine. Head Neck 42:1570–15769. Vaira LA, Hopkins C, Salzano G (2020) Olfactory and gustatoryfunction impairment in COVID-19 patients: an Italian objectivemulticenter-study. Head Neck 42:1560–156910. Petrocelli M, Ruggiero F, Baietti AM (2020) Remote psy-chophysical evaluation of olfactory and gustatory functions inearly-stage coronavirus disease 2019 patients: the Bolognaexperience of 300 cases. J Laryngol Otol 134:571–57611. Massarelli O, Vaira LA, Biglio A (2018) Sensory recovery ofmyomucosal flap oral cavity reconstructions Head Neck40:467–47412. Vaira LA, Hopkins C, Petrocelli M (2020) Smell and tasterecovery in coronavirus disease 2019 patients: a 60-day objectiveand prospective study. J Laryngol Otol 134:703–70913. Vaira LA, Salzano G, Fois AF, Piombino P, Riu De G (2020)Potential pathogenesis of ageusia and anosmia in COVID-19patients. Int Forum Allergy Rhinol 10:1103–110414. Lechien JR, Radulesco T, Calvo-Henriquez C (2020) ACE2 &TMPRSS2 expressions in head & neck tissues: a systematicreview. Head Neck Pathol. https://doi.org/10.1007/s12105-020-01212-515. Milanetti M, Miotto M, Di Rienzo L, Monti M, Gosti G, RuoccoG (2020) In-Silico evidence for two receptors based strategy ofSARS-CoV-2. ArXiv. https://doi.org/2003.1110716. Lechien JR, Hopkins C, Saussez S (2020) Letter to the editorabout the Beltràn-Corbellini et al. Publication: ‘‘acute-onset smelland taste disordes in the context of Covid-19: a pilot multicenterPCR-based case-control study’’. Eur J Neurol. https://doi.org/10.1111/ene.14357Publisher’s Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.Table 1 Chemosensitive function psychophysical analysis resultsOverall (No. 801) \ 10 days (No. 205)Isolated taste dysfunction 76 (9.4%) 23 (11.6%)Combined dysfunction 334 (41.7%) 114 (57.6%)Taste[ smell 36 (10.8%) 30 (26.3%)Taste = smell 107 (32%) 51 (44.7%)Taste\ smell 191 (57.2%) 33 (28.9%)Isolated olfactory dysfunction 217 (27.1%) 35 (17.7%)No dysfunction 174 (21.7%) 35 (17.7%)123Indian J Otolaryngol Head Neck Surg

Gustatory Dysfunction: A Highly Specific and Smell-Independent Symptom of COVID-19

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Gustatory Dysfunction: A Highly Specific and Smell-Independent Symptom of COVID-19

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