Taste and Smell Impairment in COVID-19: an AAO-HNS Anosmia Reporting Tool

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1 Taste and smell impairment in COVID-19: An AAO-HNS anosmia reporting tool-

2 based comparative study

4 İbrahim Sayin1 MD, Kadriye Kart Yaşar2 MD, Zahide Mine Yazici1 MD.

5 1: Department of Otolaryngology Head and Neck Surgery, Bakırköy Dr.Sadi Konuk

6 Teaching and Research Hospital, Istanbul, Turkey.

7 2: Department of Infectious Diseases, Bakırköy Dr.Sadi Konuk Teaching and

8 Research Hospital, Istanbul, Turkey.

10 Corresponding author: Ibrahim Sayin, MD

11 Department of Otolaryngology Head and Neck Surgery Bakırköy Dr. Sadi Konuk

12 Teaching and Research Hospital, Tevfik sağlam Caddesi, No:11. 34147,

13 Bakırköy/İstanbul

14 Telephone/Telefax: +90 414 7253/+90 212 542 44 91

15 E-mail: [email protected]

16 Funding: None Conflicts of interest: None

17 Ibrahim Sayin: conception and design of the work, collecting data, analysis, writing

18 manuscript, final approval of manuscript

19 Kadriye Kart Yaşar: conception of the work, data collection, drafting work, final

20 approval of manuscript

21 Zahide Mine Yazıcı: design of the work, collecting data, analysis, drafting the work,

22 final approval of manuscript

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23 Abstract

24 Objective: To identify the taste and smell impairment in COVID-19 positive subjects

25 and compare the findings with COVID-19 negative subjects using the American

26 Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) Anosmia Reporting

27 Tool.

28 Setting: Tertiary referral center/COVID-19 pandemic hospital

29 Study design: Comparative study

30 Subjects and Methods: After power analysis 128 subjects were divided into two

31 groups according to Real-time Polymerase Chain Reaction (RT-PCR) COVID-19

32 testing results. Subjects were called via telephone and the AAO-HNS Anosmia

33 Reporting Tool was used to collect responses.

34 Results: The mean age of the study group was 38.63 ± 10.08 years old. At the time

35 of sampling rhinorrhea were significantly high in the COVID-19 negative group,

36 whereas those complaints described as ‘’other’’ were significantly high in the COVID-

37 19 positive group. There was a significant difference in the smell/taste impairment

38 rates of the groups (n = 46-71.9% for the COVID-19 positive group vs n = 17-26.6%

39 for the COVID-19 negative group, p = 0.001). For subjects with a smell impairment,

40 anosmia rates did not differ between the groups. The rates of hyposmia and

41 parosmia were significantly high in the COVID-19 positive group. For the subjects

42 with taste impairment, ageusia rates did not differ between groups. The rate of

43 hypogeusia and dysgeusia was significantly high in the COVID-19 positive group.

44 Logistic regression analysis indicates that smell/taste impairment in COVID-19

45 positive subjects increases the ODDS ratio by 6.956 (95% CI: 3.16-15.29) times.

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46 Conclusion: COVID-19 positive subjects are strongly associated with smell/taste

47 impairment.

48 Keywords: COVID-19, coronavirus, chemosensory, anosmia, dysgeusia

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66 Introduction

67 The world was faced with a novel form of coronavirus, named COronaVIrus Disease

68 2019 (COVID-19) by the World Health Organization (WHO) in December 2019.

69 According to the Coronavirus Study Group (CSG) of the International Committee the

70 virus became known as SARS-CoV-2 .1

71 Since there is no specific treatment or effective vaccine, the outbreak can only be

72 controlled by strict isolation and hygiene rules. COVID-19 is a form of Upper

73 Respiratory Tract Infection (URTI) and the clinical course of every URTI is different,

74 so presenting and alarm symptoms are needed to restrict transmission.2

75 In the early phases of the outbreak, fever, dyspnea, coughing, and travel to endemic

76 counties were used as the main screening parameters. However, during the course

77 of the outbreak, different symptomatology including headache, sore throat, nasal

78 congestion, rhinorrhea, fatigue, tonsil swelling, and conjunctivitis began to be

79 published.3 Among these, frequent chemosensory involvement, as evaluated by

80 smell and taste dysfunctions, were reported.4,5,6

81 During the outbreak many authors reported an increase in the presence of anosmia

82 in COVID-19 subjects. After initial reports, a few studies indicated that anosmia

83 presenting in COVID-19 subjects is more frequent than expected for a routine upper

84 respiratory tract infection. Although most of these reports were not comparative,

85 these findings are also in the Centers for Disease Control and Prevention (CDC) list

86 of symptoms and, according to the CDC, “new loss of taste or smell” can occur within

87 2-14 days of exposure.7 Chemosensory involvement can also occur as a first sign of

88 the disease. This is important because, given that there is no specific treatment or

89 effective vaccine, the outbreak can only be controlled by strict isolation and hygiene

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90 measures.1,2 In addition, these subjects are potential ENT clinic patients in the future

91 for sustained taste and smell loss. The clinical course, along with other symptoms

92 and their timing, requires specialist monitoring to identify its properties. Clarifying the

93 chemosensory involvement not only provides valuable data for clinical evaluation but

94 also gives important clinical information of the virus characteristics, which may be

95 used by researchers from different disciplines.

96 The American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) are

97 continuously screening the outbreak and providing Otolaryngology Head and Neck

98 Surgery specialists with information about various aspects of the outbreak. As a

99 result of cumulative anecdotal evidence of anosmia/dysgeusia around the world

100 during the outbreak, the COVID-19 Anosmia Reporting Tool was developed in March

101 2020 by the AAO-HNS.8 This tool was developed by two committees of the AAO-

102 HNS; the Infectious Disease, and Patient Safety Quality Improvement committees.

103 The tool is completed online either by the medical provider or the patient, and

104 consists of 17 questions relating to demographic factors, COVID status, risk factors,

105 symptoms, and onset of anosmia/dysgeusia etc., and may be found at

106 https://www.entnet.org/content/reporting-tool-patients-anosmia-related-covid-19. This

107 anosmia reporting tool collects data to establish the importance of smell and taste

108 impairment in the clinical course of COVID-19. For this purpose we used the tool and

109 conducted a comparative study with COVID-19 negative subjects.

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114 Methods

115 This study was conducted at Bakırköy Dr.Sadi Konuk Teaching and Research

116 Hospital, with ethical approval obtained from Bakırköy Dr.Sadi Konuk Teaching and

117 Research Hospital local ethics committee. Subjects with upper respiratory tract

118 infection symptoms who had been assessed as COVID-19 positive were enrolled. All

119 subjects underwent Real-time Polymerase Chain Reaction (RT-PCR) testing.

120 The exclusion criteria included subjects under the age of 18 and those without upper

121 respiratory tract infection symptoms. These subjects had undergone routine COVID-

122 19 testing as relatives of COVID-19 subjects and healthcare workers etc. In addition,

123 the exclusion criteria included subjects with pending results, those who had tested

124 negative for COVID-19 but were regarded as COVID-19 positive based on their

125 clinical presentations (presumed positive), and subjects required to remain in an

126 intensive care unit.

127 Subjects were divided into two groups; COVID-19 Positive (Group A) and COVID-19

128 Negative (Group B) according to RT-PCR results. Two questionnaires were

129 prepared, based on the AAO-HNS Anosmia Reporting Tool, for groups A and B

130 respectively.

131 According to power analysis, 64 subjects were required for each group. All

132 questionnaires were uploaded to Google Forms, and subjects admitted to clinics and

133 hospital began screening. All subjects were contacted by telephone and asked to

134 confirm they fulfill the inclusion criteria. Where the subject fulfilled the inclusion

135 criteria and informed consent was then obtained, the questionnaire was completed

136 with the assistance of physicians(1, 2, 3) and recorded to Google Forms.

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138 Questionnaires

139 Questionnaire of COVID-19 positive subjects ( Supplemental questionnaire 1)

140 The AAO-HNS Anosmia Reporting Tool was used to evaluate subjects.8 The

141 questionnaire included 17 questions, with one question asking about both anosmia

142 and dysgeusia. To obtain more detailed data, we expanded this question and

143 separated anosmia and dysgeusia questions from each other. Subjects were asked

144 to identify the type of smell and taste impairments separately, with a smell

145 impairment sub-grouped as anosmia, hyposmia and parosmia, and a taste

146 impairment sub-grouped as ageusia, hypogeusia and dysgeusia. If hyposmia or

147 hypogeusia were reported, then subjects were asked to rate the relative decrease in

148 taste and smell in a 10-graded Visual Analog Scale (VAS).

149 Questionnaire for COVID-19 negative subjects (Supplemental questionnaire 2)

150 The AAO-HNS Anosmia Reporting Tool was issued to subjects with COVID-19. This

151 study also contains a subject group with COVID-19 negative test results and, to

152 maintain consistency and comparability of findings, questions relating to the presence

153 of COVID-19 were removed and questionnaire 2 was created.

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160 Statistical analysis

161 NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, USA) software

162 was used for the statistical analysis of the results, with descriptive statistical methods

163 (mean, standard deviation, median, frequency, ratio, minimum and maximum) used

164 when evaluating the study data. The suitability of quantitative data for normal

165 distribution was tested using the Shapiro-Wilk test and graphical evaluations. A

166 Student's t-test was used to compare two groups of normal distribution variables and

167 a Pearson chi-square test and Fisher’s Exact test were used for comparison of

168 qualitative data with normal distribution. Logistic regression analysis was used in the

169 multivariate analysis. Significance was evaluated at p <0.05.

170 Power analysis

171 To determine the sample size, power analysis was performed using G * Power

172 (v3.1.7). According to Cohen's effect size coefficients, assuming the evaluation being

173 made between two independent groups will have a medium effect size (d = 0.5), the

174 results showed that a total sample of 128 participants with two equally sized groups

175 of n = 64 would be required to achieve a power of .80.

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182 Results

183 In total 170 subjects were screened for the study. Forty two (n=42) out of 170

184 subjects did not meet the inclusion criteria. Finally 128 subjects were enrolled. (figure

185 1 shows a flow chart of the study). Both COVID-19 positive and COVID-19 negative

186 groups consisted of 64 subjects each, with 48 (n = 48-37.5%) out of the total 128

187 subjects being male and the remaining 80 subjects being female. The mean age of

188 the study group was 38.63 ± 10.08 (range between 21 and 77).

189 The groups did not differ in terms of age, gender, risk factors for COVID-19 infection

190 and comorbidities (p>0.05 for all comparisons) (table 1). At the time of sampling only

191 rhinorrhea and those complaints described as ‘’other’’ were significantly different

192 between the two groups. Rhinorrhea was significantly high in the COVID-19 negative

193 group (n = 21-32.8% for COVID-19 negative group vs n = 11-17.2% for COVID-19

194 positive group, p = 0.041) whereas “other” complaints were significantly high in the

195 COVID-19 positive groups (n = 12-18.8% for COVID-19 positive group vs n = 4-6.3%

196 for COVID-19 negative group = 0.033).

197 For COVID-19 positive subjects, in 28 (43, 8%) of the 64 subjects the source of

198 infection was not known. In 46 (n = 46-71.9%) of the 64 subjects the COVID-19

199 infection status was active and in 34 (53.1%) out of 64 subjects the smell/taste

200 impairment was observed before diagnosis. All subjects received treatment for

201 COVID-19 (n = 64-100%). Fifty (78.1%) of 64 subjects were treated on an outpatient

202 basis and the remaining 14 (21.9%) subjects were treated as inpatients (table 2).

203 There was a significant difference between the smell/taste impairment rates between

204 the groups (n = 46-71.9% for the COVID-19 positive group vs n = 17-26.6% for the

205 COVID-19 negative group, p = 0.001) (table 3).

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206 For subjects with smell impairment, anosmia rates did not differ between the groups

207 (n = 8-12.5% for the COVID-19 positive group vs n = 3-4.7% for the COVID-19

208 negative group, p = 0.115). The rates of hyposmia (n = 33-51.6% for the COVID-19

209 positive group vs n = 10-15.6% for the COVID-19 negative group, p = 0.001) and

210 parosmia (n = 11-17.2% for the COVID-19 positive group vs n = 2-3.1% for the

211 COVID-19 negative group, p = 0.008) were significantly high in the COVID-19

212 positive group. For subjects with hyposmia, VAS scales were significantly lower

213 within the COVID-19 positive group (5.48±2.18 for the COVID-19 positive group vs

214 7.00±2.05 for the COVID-19 negative group, p = 0.049).

215 For the subjects with a taste impairment, ageusia rates did not differ between the

216 groups (n = 8-12.5% for the COVID-19 positive group vs n = 3-4.7% for the COVID-

217 19 negative group, p = 0.115). The rates of hypogeusia (n = 36-56.3% for the

218 COVID-19 positive group vs n = 10-15.6% for COVID-19 negative group, p = 0.001)

219 and dysgeusia (n = 16-25% for the COVID-19 positive group vs n = 4-6.3% for the

220 COVID-19 negative group, p = 0.003) were significantly high in the COVID-19

221 positive group. For subjects with hypogeusia VAS scales did not differ between the

222 groups (5.61±2.09 for the COVID-19 positive group vs 6.70±2.26 for the COVID-19

223 negative group, p = 0.145).

224 In the COVID-19 positive group 3 (4.7%) subjects reported isolated taste impairment.

225 In the COVID-19 negative group 4 (6.2%) subjects reported isolated taste impairment

226 and 2 (3.1%) subjects reported isolated smell impairment.

227 Symptoms at the time of smell/taste impairment, symptoms before the development

228 of smell/taste impairment, patient’s condition observed after the smell/taste

229 impairment, smell/taste impairment resolution rates were not significantly different

230 between groups(p>0.05 for all comparisons). 10

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231 When we evaluate the factors affecting the COVID-19 positive subjects with

232 Backward Logistic regression analysis, the model was found to be significant and

233 explanatory. The coefficient of the model (72.7%) was good. It was identified that the

234 effect of the taste and smell impairment on COVID-19 positive subjects increases the

235 ODDS ratio by 6.956 (95% CI: 3.16-15.29) times. Rhinorrhea is also close to the limit

236 of significance but not significant. No other significant factor was determined in

237 multivariate analysis.

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252 Discussion

253 In a power-analyzed comparative setting we included 128 subjects for the study.

254 These were in two groups (COVID-19 positive and COVID-19 negative) consisting of

255 64 subjects each. The test results were based on RT-PCR testing. Both groups

256 underwent assessment via the anosmia reporting tool developed by AAO-HNS in

257 March 2020. When compared with the COVID-19 negative subjects, multivariate

258 analysis indicates that subjects testing positive for COVID-19 experienced taste and

259 smell impairment approximately 7 times higher than those testing negative for

260 COVID-19. Taste and smell impairment occurred mainly in the forms of

261 hyposmia/hypogeusia.

262 COVID-19 related smell impairments were initially outlined in anecdotal reports and

263 the experiences of physicians around the world.6 Immediately after these reports the

264 AAO-HNS released an anosmia reporting tool to collect data and to clarify this

265 observational finding.8 The tool was modified a few times but serves as a basis for

266 systematic evaluation of the situation. Following the publication of the initial results

267 from the reporting tool, of the first 237, in 26.6% of the subjects anosmia was the

268 initial symptom of COVID-19.9 In 73% of the subjects, anosmia was reported

269 occurring before diagnosis and 85% of the subjects who reported anosmia improved

270 in the first ten days, indicating that anosmia can be a presenting symptom with good

271 spontaneous recovery rate.

272 We conducted our study according to this tool, as it allows for a precise evaluation of

273 subjects. To identify the subjects’ smell and taste impairment in detail, we changed

274 the ‘’anosmia/dysgeusia’’ term to ‘’smell/taste impairment’’ for all related questions. In

275 addition, we expanded the question ‘’Did the patient have smell/taste impairment?’’

276 and asked subjects to identify their impairment as anosmia/hyposmia/parosmia for a 12

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277 smell impairment and as ageusia/hypogeusia/dysgeusia for a taste impairment.

278 Where the subject reported hyposmia or hypogeusia, they were then asked to

279 indicate their loss in a 10 grade VAS scale. This expansion allowed us to evaluate

280 the type of smell/taste impairment in much greater detail. For subjects testing

281 negative for COVID-19 a second questionnaire was developed; given that the

282 anosmia reporting tool contained some questions for subjects with COVID-19, these

283 questions were not applicable for the subjects testing negative for COVID-19. This

284 second questionnaire is similar to the anosmia reporting tool; however questions

285 relating to COVID-19 presence have been removed. The reason we used the

286 anosmia reporting tool as a control is to provide comparability and internal

287 consistency within the study.

288 Our results indicate that the COVID-19 positive subjects experienced significantly

289 higher smell/taste impairment than COVID-19 negative subjects. However most of

290 these impairments were not in the anosmia/ageusia form but, rather, in the

291 hyposmia/hypogeusia and parosmia/dysgeusia form. Although not significant

292 between groups, at the time of study, 45.7% of the subjects in the COVID-19 positive

293 group and 64.7% of the subjects in the COVID-19 negative group; taste and smell

294 impairment return to normal. Although not significant in multivariate analysis, the

295 presence of rhinorrhea was significantly high among the COVID-19 negative

296 subjects, and those complaints described as ‘’other’’ were significantly high among

297 COVID-19 positive subjects. This may indicate a need for more detailed

298 symptomology questions within the anosmia reporting tool.

299 Recorded levels of smell/taste impairment vary from location to location, with most

300 studies reporting single arm data on COVID-19 positive subjects. Vaira et al. have

301 reported the incidence of chemosensory dysfunction as 19.4% among the first 320

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302 subjects.5 However they noted that this incidence may be low as most subjects were

303 not asked about taste and smell impairment. In a multicenter study within Europe, of

304 417 respondents, 85.6% and 88.0% of subjects reported smell and taste

305 impairment.10 Anosmia was recorded as the first symptom among 11.8% of these

306 subjects. Females were generally more affected, and the early recovery rate was

307 44%.

308 Comparative studies may be helpful to differentiate certain disease characteristics.

309 Comparing COVID-19 positive subjects with negative ones may provide clearer

310 comparisons. Yan et al. compared 59 COVID-19 positive subjects with 203 COVID-

311 19 negative subjects. Olfactory impairment (68% for COVID-19 positive subjects vs

312 16% of COVID-19 negative subjects) and gustatory involvement (71% for COVID

313 positive subjects vs 17% of COVID-19 negative subjects) were both significantly high

314 in COVID-19 positive subjects.4 Their results indicated that, among these complaints,

315 smell and taste impairment were strongly associated with COVID-19 positivity and

316 presence of sore throat was independently associated with COVID-19 negativity.

317 COVID-19 positive subjects were 10 times more likely to experience a taste and

318 smell impairment; however, COVID-19 negative subjects were 4 - 5 times more likely

319 to report a sore throat. At the time of the survey, around 29 out of 40 (72.5%)

320 subjects who experienced smell loss improved in one month. Yan et al. reported

321 approximately a two times higher smell/taste impairment than Giacomelli et al.’s

322 study, which was undertaken with hospitalized subjects.6 The authors evaluated 59

323 hospitalized subjects and reported that 20 out of 59 subjects (33.9%) experienced at

324 least one taste or olfactory disorder, and 11 out of 59 (18.6%) experienced both

325 disorders. Yan et al. proposed that two forms of the disease may exist, as nasal-

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326 centric and pulmonary-centric, according to a comparison of these findings. Hopkins

327 et al. reported that one of six subjects experience anosmia as an isolated symptom.11

328 Upper respiratory infections are known etiologically as olfactory loss.12 The

329 prevalence following an URTI was reported to be as high as 20-40% by some

330 centers.2 Current data indicate that SARS-COV-2 significantly impairs smell and

331 taste functions. Although the exact mechanisms are unknown, a number of

332 hypotheses exist. Coronavirus is known as a neuro-invasive and neurotrophic virus.

333 Sensory olfactory epithelium and respiratory epithelium are the main parts of nasal

334 epithelium. Key genes responsible for SARS-COV-2 entry are ACE2 and TMPRSS2.

335 Among all epithelial cell lines, nasal epithelial cells have the highest ACE2.13 This

336 finding may explain why nasal epithelial cells are the viral targets or reservoirs for

337 SARS–COV-2. However olfactory sensory neurons/olfactory bulb neurons did not

338 express ACE2 and TMPRSS2. Brann et al. reported that only non-neural cell types

339 (stem cells, TMPRSS2 support cells, and perivascular cells) express ACE2.14 Instead

340 of direct involvement with olfactory sensory neurons, olfactory involvement relating to

341 SARS-COV-2 may be due to non-neural cell impairment. The involvement of non-

342 neural structures may result in an inflammatory response and deteriorated signaling

343 of olfactory sensory neurons. In addition, diffuse architectural damage to the olfactory

344 epithelium is also possible; however, an unreported viral receptor mechanism or a

345 central mechanism cannot be ruled out with current data. The olfactory epithelium is

346 in continuation with the brain and serves as a route for brain involvement.12

347 There is no suggested treatment for COVID-19-related olfactory loss, although nasal

348 steroid use may be offered. The European Academy of Allergy and Clinical

349 Immunology (ARIA-EAACI) statement suggested continuation of intranasal

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350 corticosteroids in subjects with allergic rhinitis, as cessation of their use was not

351 advised. However these data need further clarification.15

352 Although we set up our study with a 0.50 effect size, this report presents the

353 experiences of a single institution. In addition, we need to note that the study was

354 made within a limited time and some of the subjects in the COVID negative group

355 may have had false negative testing results. At the beginning of the outbreak,

356 subjects over the age of 65, within the country this study was located in, were

357 forbidden to leave their homes, and had to remain in isolation. This is why the

358 subjects were generally not within an older age bracket. This lower number of older

359 patients will limit the outcome of the study. Our study will expand to the analysis of

360 subgroups and may be regarded as a pilot for future studies. In addition, assessment

361 of subjects using objective testing methods is required; however, due to the high

362 transmission possibility of the disease, this is not possible at this time.

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372 Conclusion

373 In the last few months all subspecialties have been working to identify the various

374 aspects of COVID-19 in patients. Among other symptoms, taste and smell

375 impairment have emerged as potential screening symptoms, as research findings

376 strongly suggest that subjects diagnosed as COVID-19 positive can present with

377 smell and taste impairment.

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393 Implications of practice

394 Smell/taste impairment is 7 times higher in subjects testing positive for COVID-19

395 and, as a result, it may be considered useful as a screening tool. The American

396 Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) anosmia reporting

397 tool is a brief, concise and easy to use tool that can be generalized to collect data

398 around the world.

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414 Acknowledgements

415 The authors thank Emire Bor, EMPIAR Statistics for performing statistical analysis of

416 the study

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468 13. Sungnak W, Huang N, Bécavin C et al. SARS-CoV-2 entry factors are highly

469 expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020

470 Apr 23. doi: 10.1038/s41591-020-0868-6.

471 14. Brann DH, Tsukahara T, Weinreb C et al. Non-neuronal expression of SARS-

472 CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-

473 19-associated anosmia. bioRxiv. doi: https://doi.org/10.1101/2020.03.25.009084

474 15. Bousquet J, Akdis C, Jutel M et al. Intranasal corticosteroids in allergic rhinitis in

475 COVID-19 infected patients: An ARIA-EAACI statement. Allergy. 2020 Mar 31. doi:

476 10.1111/all.14302.

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478 Figure legends

479 Figure 1: Flow chart of the study

480 Table 1: Age, gender, risk factors for COVID-19 infection, comorbidities, and

481 complaints of subjects who underwent smell/taste evaluation via AAO-HNS Anosmia

482 Reporting Tool.

483 Table 2: COVID-19 (+) subjects’ data according to source, current status of the

484 infection and onset of smell/taste impairment.

485 Table 3: Comparison of smell/taste impairment between groups.

486 Supplemental questionnaire 1. Questionnaire used to evaluate COVID-19 positive

487 subjects (Adopted from the American Academy of Otolaryngology-Head and Neck

488 Surgery COVID-19 Anosmia Reporting tool)

489 Supplemental questionnaire 2. Questionnaire used to evaluate COVID-19 negative

490 subjects (Adopted from the American Academy of Otolaryngology-Head and Neck

491 Surgery COVID-19 Anosmia Reporting tool)

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500 Table 1: Age, gender, risk factors for COVID-19 infection, comorbidities and complaints of

501 subjects who underwent smell/taste evaluation via AAO-HNS Anosmia Reporting Tool.

COVID-19 (+) COVID-19 (-) (n=64) (n=64) p n (%) n (%) Age (years) Min-Max (Median) 21-77 (39) 22-62 (40,5) a0.341 Mean±SD 37.78±11.34 39.48±8.64

Gender Male 25 (39.1) 23 (35.9) b0.715 Female 39 (60.9) 41 (64.1)

Risk factors for Healthcare worker 50 (78.1) 52 (81.3) b0.660 COVID-19 b infectionx Close contact with a 34 (53.1) 41 (64.1) 0.209 confirmed case Congregant living 2 (3.1) 3 (4.7) c1.000 Travel to known areas with 1 (1.6) 1 (1.6) c1.000 widespread community transmission

Risk factors Smoking 14 (21.9) 21 (32.8) b0.165 /comorbiditiesx Head trauma 9 (14.1) 14 (21.9) b0.250 Sinusitis/allergy 9 (14.1) 10 (15.6) b0.804 Chronic respiratory 4 (6.3) 3 (4.7) c1.000 disease/Asthma Cardiac disease 2 (3.1) 1 (1.6) c1.000 Other 5 (7.8) 11 (17.2) b0.109 Complaints Fever 18 (28.1) 24 (37.5) b0.259 when the sample b is received from Chills 19 (29.7) 11 (17.2) 0.095 x the patients Malaise 41 (64.1) 35 (54.7) b0.280 Cough 28 (43.8) 38 (59.4) b0.077 Headache 20 (31.3) 29 (45.3) b0.102 Nasal congestion 18 (28.1) 19 (29.7) b0.845 Rhinorrhea 11 (17.2) 21 (32.8) b0.041* Gastrointestinal distress 11 (17.2) 15 (23.4) b0.380 Pneumonia 15 (23.4) 12 (18.8) b0.516 Other 12 (18.8) 4 (6.3) b0.033* 502 aStudent t Test, bPearson Chi-Square Test, cFisher’s Exact Test, *p<0.05, VAS: Visual analog scale, 503 xMore than one answer exists 504

505

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506 Table 2: COVID-19 (+) subjects’ data according to source, current status of the infection and

507 onset of smell/taste impairment.

COVID-19 (+) subjects n (%) Is the source of the COVID-19 infection Yes 28 (43.8) identifiable? No 36 (56.3) What is the patient’s current COVID-19 Active 46 (71.9) infection status? Recovered 18 (28.1) Did the patient receive treatment? Yes 64 (100) No 0 (0) When was the anosmia (loss of sense of Before diagnosis 34 (53.1) smell) or dysgeusia (alteration of sense of After diagnosis 12 (18.8) taste) first noticed by the patient? No impairment in 18 (28.1) smell/taste What was the condition of the COVID-19 Inpatient /hospitalized 14 (21.9) infection at the time the smell/taste impairment was observed? Outpatient 50 (78.1) 508

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522 Table 3: Comparison of smell/taste impairment between groups.

COVID-19 (+) COVID-19 (-) (n=64) (n=64) p n (%) n (%) Did the patient have smell/taste Absent 18 (28.1) 47 (73.4) b0.001** impairment Present 46 (71.9) 17 (26.6)

Definition of smell impairmentx Anosmia 8 (12.5) 3 (4.7) b0.115 Hyposmia 33 (51.6) 10 (15.6) b0.001** Parosmia 11 (17.2) 2 (3.1) b0.008** Normal 21 (32.8) 51 (79.7) b0.001** VAS of subjects with hyposmia Min-Max (Median) 2-9 (5) 2-9 (7.5) d0.049* Mean±SD 5.48±2.18 7.00±2.05 Definition of taste impairmentx Ageuisa 8 (12.5) 3 (4.7) b0.115 Hypogeusia 36 (56.3) 10 (15.6) b0.001** Dysgeusia 16 (25.0) 4 (6.3) b0.003** Normal 18 (28.1) 49 (76.6) b0.001**

VAS of subjects with Min-Max (Median) 2-9 (5) 3-9 (7.5) d0.145 hypogeusia Mean±SD 5.61±2.09 6.70±2.26

Any other symptoms before the Yes 32 (69.6) 15 (88.2) c0.195 development of smell/taste impairment No 14 (30.4) 2 (11.8) What symptoms did the patient Fever 11 (23.9) 7 (41.2) c0.216 have at the time of smell/taste c impairment?x Chills 14 (30.4) 2 (11.8) 0.195 Malaise 24 (52.2) 9 (52.9) b0.957 Cough 18 (39.1) 10 (58.8) b0.163 Headache 18 (39.1) 9 (52.9) b0.325 Nasal Congestion 11 (23.9) 5 (29.4) c0.747 Rhinorrhea 6 (13.0) 5 (29.4) c0.149 Gastrointestinal 6 (13.0) 4 (23.5) c0.438 Pneumonia 9 (19.6) 5 (29.4) c0.498 Other 4 (8.7) 1 (5.9) c1.000

Did the patient’s condition Worsen 19 (41.3) 4 (23.5) b0.193 worsen or improve after the smell/taste impairment was Improved 27 (58.7) 13 (76.5) observed? Did the smell/taste impairment Yes 21 (45.7) 11 (64.7) b0.179 resolve No 25 (54.3) 6 (353) 523 bPearson Chi-Square Test, cFisher’s Exct Test, dMann Whitney U Test, *p<0.05 **p<0.01 , VAS: 524 Visual analog scale, xMore than one answer exists

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525 The English in this document has been checked by at least two professional editors, 526 both native speakers of English. For a certificate, please see: 527 528 http://www.textcheck.com/certificate/5DCRKU 529 530

This manuscript has been accepted for publication in Otolaryngology-Head and Neck Surgery. Supplemental Data

This manuscript has been accepted for publication in Otolaryngology-Head and Neck Surgery.

Q1. Questionnaire used to evaluate COVID-19 positive subjects (Adopted from the

American Academy of Otolaryngology-Head and Neck Surgery COVID-19 Anosmia

Reporting tool)

Questions Please indicate the answer here Q1. Name/Surname Q2. Phone /e-mail address Q3. Age (numbers) Q4. Gender  Female •Male Q5. Please list any risk factors for  None COVID-19 infection present  Healthcare worker  Close contact with a confirmed case  Homeless  Congregant living (dorms, fraternities/sororities, shelters, jail, prison, skilled nursing, assisted living, adult family home)  Travel to known areas with widespread community transmission  Other Q6. Other risk factors/comorbidities  None  Smoking  Head trauma  Sinusitis/allergy  Chronic respiratory disease/Asthma  Cardiac disease  Neurologic disease (e.g. Parkinson’s)  Other Q7. Complaints when the sample is  None received from the patients  Fever  Chills  Malaise  Cough  Headache  Nasal congestion  Rhinorrhea  Gastrointestinal distress  Pneumonia  Other Q8. Is the source of the COVID-19  Yes infection identifiable?  No Q9. What is the patient’s current  Active COVID-19 infection status?  Recovered Q10 Did the patient receive  Yes treatment?  No Q11. Did the patient have smell/taste  Yes impairment?  No Q12. Definition of smell impairment  Anosmia

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(ıf present)  Hyposmia  Parosmia Q12a. Please indicate the degree of 0 1 2 3 4 5 6 7 8 9 10 hyposmia on 10 scale VAS (10 indicate normal ) (indicate number) Q13. Definition of taste impairment  Ageuisa (ıf present)  Hypogeusia  Dysgeusia Q13a. Please indicate the degree of 0 1 2 3 4 5 6 7 8 9 10 hypogeusia on 10 scale VAS (10 indicate normal ) (indicate number) Q14. What was the condition of the  Inpatient /hospitalized COVID-19 infection at the time  Outpatient the smell/taste impairment was observed? Q15. When was the smell/taste  Before diagnosis impairment first noticed by the  After diagnosis patient Q16. Did the patient have any other  Yes symptoms before the  No development of smell/taste impairment? Q17. What symptoms did the patient  None have at the tıme of smell/taste  Fever impairment?  Chills  Malaise  Cough  Headache  Nasal congestion  Rhinorrhea  Gastrointestinal distress  Pneumonia  Other Q18. Did the patient’s condition  Worsen worsen or improve after the  Improve smell/taste impairment was observed? Q19. Did the smell/taste impairment  Yes resolve?  No

This manuscript has been accepted for publication in Otolaryngology-Head and Neck Surgery. Supplemental Data

This manuscript has been accepted for publication in Otolaryngology-Head and Neck Surgery.

Q2. Questionnaire used to evaluate COVID-19 negative subjects (Adopted from the

American Academy of Otolaryngology-Head and Neck Surgery COVID-19 Anosmia

Reporting tool)

Questions Please indicate the answer here Q1. Name/Surname Q2. Phone /e-mail address Q3. Age (numbers) Q4. Gender  Female • Male Q5. Please list any risk factors for  None COVID-19 infection present  Healthcare worker  Close contact with a confirmed case  Homeless  Congregant living (dorms, fraternities/sororities, shelters, jail, prison, skilled nursing, assisted living, adult family home)  Travel to known areas with widespread community transmission  Other Q6. Other risk factors/comorbidities  None  Smoking  Head trauma  Sinusitis/allergy  Chronic respiratory disease/Asthma  Cardiac disease  Neurologic disease (e.g. Parkinson’s)  Other Q7. Complaints when the sample is  None received from the patients  Fever  Chills  Malaise  Cough  Headache  Nasal congestion  Rhinorrhea  Gastrointestinal distress  Pneumonia  Other Q8. Did the patient have smell/taste  Yes impairment?  No Q9. Definition of smell impairment  Anosmia (if present)  Hyposmia  Parosmia Q9a. Please indicate the degree of 0 1 2 3 4 5 6 7 8 9 10 hyposmia on 10 scale VAS (10 indicate normal ) (indicate number) Q10. Definition of taste impairment  Ageuisa

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(if present)  Hypogeusia  Dysgeusia Q10a. Please indicate the degree of 0 1 2 3 4 5 6 7 8 9 10 hypogeusia on 10 scale VAS (10 indicate normal ) (indicate number) Q11. Did the patient have any other  Yes symptoms before the  No development of smell/taste impairment? Q12. What symptoms did the patient  None have at the time of smell/taste  Fever impairment?  Chills  Malaise  Cough  Headache  Nasal congestion  Rhinorrhea  Gastrointestinal distress  Pneumonia  Other Q13. Did the patient’s condition  Worsen worsen or improve after the  Improve smell/taste impairment was observed? Q14. Did the smell/taste impairment  Yes resolve?  No

This manuscript has been accepted for publication in Otolaryngology-Head and Neck Surgery.