key: cord-0743709-wy9wbm0g
authors: Kang, Yun Jin; Cho, Jin Hee; Lee, Min Hyeong; Kim, Yeon Ji; Park, Chan-Soon
title: The diagnostic value of detecting sudden smell loss among asymptomatic COVID-19 patients in early stage: The possible early sign of COVID-19
date: 2020-06-09
journal: Auris Nasus Larynx
DOI: 10.1016/j.anl.2020.05.020
sha: 0d1875492a9f3620292a71fdc9d0060bb11b7d0c
doc_id: 743709
cord_uid: wy9wbm0g

IMPORTANCE: The newly emerged coronavirus disease 19 (COVID-19), is threatening the world. Olfactory or gustatory dysfunction is reported as one of the symptoms worldwide. As reported so far, different clinical features have been reported according to outbreak sites and gender; most of the patients, who complained of anosmia or hyposmia, were Europeans. We had a fast review for novel articles about COVID-19 infection and olfactory function. OBSERVATIONS: Rapid reviews for COVID-19 or other viral infection and olfactory and/or gustatory dysfunctions were done in this review. Up to date, a lot of reports have shown that olfactory dysfunction is related to viral infections but no exact mechanism, clinical course, and definite treatment have been discovered, which is also same in COVID-19. In general, intranasal steroid (INS) and oral steroid for short time help improve the recovery of the olfactory function in case of olfactory dysfunction after virus infection. Considering severe respiratory complications and immunocompromised state of COVID-19, the use of steroid should be limited and cautious because we do not have enough data to support the usage of steroid to treat olfactory dysfunction in the clinical course of COVID-19. CONCLUSIONS AND RELEVANCE: In the days of pandemic COVID-19, we should keep in mind that olfactory dysfunctions, even without other upper respiratory infection or otolaryngologic symptoms, might be the early signs of COVID-19.

All over the world, severe Acute Respiratory Syndrome tum and sore throat [ 6 , 7 ] . In fact, however, many patients are 17 asymptomatic or have mild symptoms in early stages, and 18 so they do not realize being infected. Since COVID-19 is 19 highly contagious in early stages, such lack of recognition 20 can cause serious problems for the prevention of the spread 21 of COVID-19. Therefore, detection of COVID-19 in early, 22 even asymptomatic, stages will help us reduce transmission. 23 Recently, olfactory or gustatory dysfunction is often re- 24 ported as a symptom [ 8 , 9 ] . We need to pay more attention 25 because the symptom might be easily overlooked in clinical 26 field and so the diagnosis could be delayed. In this review, 27 we reviewed recent findings of the viral infection-related ol- 28 factory or gustatory dysfunctions to identify a correlation be- 29 tween the olfactory or gustatory symptoms and corona virus, 30 and the values of olfactory dysfunction as an early sign of 31 COVID-19, even in asymptomatic patients. 32 33 We searched the articles using PubMed and Embase. The 34 first keyword was viral infection, coronavirus, rhinovirus, in- 35 fluenza, COVID, SARS or MERS. The second keyword was 36 anosmia, smell, or olfactory. The full search strategy has been 37 reported in table ( Table 1 ) . 38 The articles that could not be obtained in the full text, Finally, we could find 21 papers that directly described 50 COVID-19 and olfactory symptoms; some of them also men-51 tioned gustatory dysfunction or ageusia. From these 21 pa-52 pers, 7 papers were clinical studies and others were com-53 mentary, letters, and editorial review ( Fig. 1 ) . The details 54 of these 7 articles were demonstrated in table ( Table 2 ) . A 55 study reported patients who initially complained of acute on-56 set anosmia (not COVID-19 infection) but finally diagnosed 57 with COVID-19 infection [10] . 58 There were no restrictions for gender, age and national-59 ity. The studies with inclusion criteria were checked inde-60 pendently by 2 reviewers. Reviewers apply inclusion criteria 61 based on the title and abstracts. If the title and abstract were 62 adequate, the full text was checked by the same reviewers. 63 3. Clinical presentation 64 The common symptoms in COVID-19 patients were cough, 65 fever, myalgia, dyspnea, headache and loss of appetite. The 66 most common ENT symptoms were facial pain and nasal con-67 gestion [9] . 68 However, it has been recently reported that 33.9% of 59 69 COVID-19 patients in Italy complained of olfactory and/or 70 gustatory dysfunction and 11% complained of both dysfunc-71 tions [11] . 47% of 114 COVID-19 patients in France com-72 plained anosmia [12] . 31.65% and 35.44% of 79 COVID-19 73 patients in Spain complained olfactory and gustatory dysfunc-74 tions. These proportions were more prominent in COVID-19 75 patients than influenza patients [13] . According to the paper 76 from USA reported that 68% and 71% of 59 patients had ol-77 factory and gustatory dysfunction, respectively [14] . 98% of 78 60 patients from Iran were confirmed smell dysfunction by 79 University of Pennsylvania smell identification test (UPSIT) 80 [15] . And few articles said that COVID-19 patients without 81 severe symptoms complained these olfactory and/or gustatory 82 dysfunctions. According to the larger-scale research from Eu-83 rope, 85.6% of the 417 mild-to-moderate COVID-19 patients 84 had olfactory dysfunctions and 88.8% gustatory dysfunctions. 85 Phantosmia and parosmia were 12.6% and 32.4%, respec-86 tively. Among the patients who did not complain of nasal 87 stuffiness and rhinorrhea, the rates of anosmia and hyposmia 88 were 66.2% and 13.5% [9] . From the other Italian article, 89 64.4% of 202 mild symptomatic COVID-19 patients were 90 reported alternations in smell or taste. About 37% of them 91 complained severe alternations. 68.3% of COVID-19 patients 92 with smell or taste alternations reported fatigue and 34.6% 93 reported nasal stuffiness [16] . 94 Contrary to the above papers, only 5.1% of 214 patients 95 complained of hyposmia and 5.6% hypogeusia in China [8] . 96 Considering the papers, the rate of olfactory or gustatory dys-97 function is supposed to be different between Europe/USA and 98 China (or Asia). 99 Another issue is the onset of olfactory dysfunction, which 100 varied among many papers. The onset of olfactory or gusta-101 tory dysfunction in the clinical course of COVID-19 might be 102 important. A multicenter study in Europe showed that 85.6% 103 and 88% of total patients ( n = 417) reported olfactory and 104 gustatory dysfunctions, respectively, and 11.8% of COVID-105 19 patients with olfactory dysfunction appeared before other 106 general symptoms, 65.4% after the general symptoms, and 107 22.8% at the same time [9] . In Italy, 20.3% of COVID-19 108 patients reported olfactory dysfunction before other general 109 symptoms and 13.5% during hospitalization [11] . From the 110 other study of Italy, 11.9% of COVID-19 patients ( n = 130) 111 complained of smell or taste alternations prior to other symp-112 for COVID-19 infection; only 74% of the tested patients were 133 positive and most of the responders were young [10] . 134 From a case report, olfactory dysfunction was described as 135 'isolated sudden onset anosmia' because a patient with con-136 firmed COVID-19 complained of sudden onset anosmia with-137 out any other symptoms [21] . According to the other study 138 from Italy, 3% of COVID-19 patients ( n = 130) reported smell 139 or taste alternations as the sole symptom [16] . However, there 140 is also an article reporting that ENT symptoms can be accom-141 panied by anosmia [12] . 142 In Korea, Korean center for disease control (KCDC) re-143 cently (on 6 April 2020) announced in a press release that 144 proportion of asymptomatic case was 33.3% based on the 145 presence or absence of symptoms at the time of confirmation 146 of COVID-19 (10,284 confirmed as positive among 466,804 147 tested, in republic of Korea until 6, April 2020) [22] . 148 There is a study showing that most of gustatory dysfunc-149 tion appeared as an early symptom before hospitalization [11] . 150 Besides, there might be close correlation between olfactory 151 and gustatory dysfunction ( p < 0.001) [9] . Considering above, 152 6 Y.J. Kang Barr viruses and some other coronavirus can be explained. 180 However, in some cases, even if the acoustic rhinometry re-181 sult was normal, the olfactory function did not recover [28] . 

The validated tests which could quickly and accurately 210 diagnose the olfactory dysfunction in the highly suspicious 211 COVID-19 patients are needed. The short version of the Ques-212 tionnaire of Olfactory Disorders Negative Statements (sQOD-213 NS) can be used to assess the quality of life of the COVID-19 214 patients with anosmia or hyposmia [9] . The score was sig-215 nificantly lower in patients with anosmia than hyposmia or 216 normosmia. 217 Besides subjective questionnaires, commonly used olfac-218 tory tests are as follows: UPSIT, Cross-cultural Smell Identi-219 fication Test (CC-SIT; Sensonic, Inc, Haddon Heights, NJ), 220 T&T Olfactometry test (Daiichi Yakuhin Sangyo, Tokyo, 221 Japan), and other olfactory threshold tests [36] . Recently, few 222 cases of COVID-19 patients with olfactory dysfunction were 223 confirmed by UPSIT. There was no correlation between UP-224 SIT result and awareness of olfactory dysfunction in COVID-225 19 patients [15] . 226 Also, acoustic rhinometry, rhinomanometry, CT, or MRI 227 could identify the mechanism of olfactory dysfunction mainly 228 due to conductive problems and identify other causes. How-229 ever, the usage of nasal endoscopy is not recommended in the 230 highly suspicious COVID-19 patients because it may provide 231 other people unnecessary virus exposure [37] . 232 6. Treatments 233 In general, spontaneous recovery rates have been reported 234 higher in post-viral patients than post-traumatic patients, and 235 there are no definite treatment guidelines in the post-viral 236 patients presenting with olfactory or gustatory dysfunction, 237 including COVID-19. There are 2 issues on anosmia treatment 238 in COVID-19 patients. 239 The first issue is that early anomia treatment in COVID-19 240 patients can change clinical course of COVID-19. But due to 241 lack of information, this issue is hard to be answered but early 242 detection appears more likely to be meaningful rather than 243 early treatment for COVID-19. The second one is whether 244 empirical oral steroid treatment for acute anosmia can do 245 harm to COVID-19 patients without any other symptom or 246 22.5% only gustatory dysfunction and 23.6% both remaining 320 olfactory and gustatory dysfunctions [9] . 321 The time to decide the recovery of olfactory function was 322 suggested to be 2 weeks, because the viral loading signifi-323 cantly reduces in about 14 days [ 9 , 44 ] . But the further study 324 requires to decide the time to recovery and follow up long 325 term later. 326 Considering from the other viral infections, the partial or 327 complete recovery of olfactory function could take several 328 months [45] . And in case of anosmia after SARS, the patient 329 was reported to suffer from anosmia continuously more than 330 2 years [18] . 331

The ongoing COVID-19 epidemic is still rapidly spreading 333 all over the world. So it is very important to notice the early 334 sign of COVID-19 and get the information about progression 335 as soon as possible. Most of COVID-19 patients complain 336 of no symptoms or mild symptoms in early stages though 337 coughing, fever and difficulty breathing are main symptoms. 338 Up to date, the number of the COVID-19 patients with ol-339 factory and/or gustatory symptoms is rapidly increasing and, 340 though the onset of olfactory and/or gustatory symptoms in 341 the COVID-19 patients was reported varied, in general, most 342 of these 2 symptoms might precede or be accompanied by 343 other main mild general symptoms or no other symptoms 344 [16] . Moreover, many cases (18.2%) have been reported for 345 the COVID-19 patients to complain of these 2 symptoms sud-346 denly without any other otolaryngologic symptoms, like rhi-347 norrhea or nasal obstructions [9] . 348 Based on the previous paper, the rates of asymptomatic 349 cases out of all SARS-CoV positive cases were reported 13% 350 among Singaporean health care workers [46] . Furthermore, 351 according to WHO report for MERS-CoV, 21% of the 2228 352 cases from all over the world were reported to have no or 353 mild symptoms [47] . 354 Asymptomatic case proportion of COVID-19 was 33.3% 355 based on the presence or absence of symptoms at the time of 356 confirmation, which was higher than SARS-CoV and MERS-357 CoV, according to KCDC report (on 6 April 2020) [22] . 358 Therefore, we should pay more attention to olfactory 359 and/or gustatory symptoms in the suspicious COVID-19 pa-360 tients with or without the main COVID-19 symptoms because 361 asymptomatic COVID-19 infection (and/or transmission) is a 362 major public health issue at present. However, the exact rate 363 of asymptomatic COVID-19 all over the world has not known 364 and further analysis should be done. 365 Even though the pathophysiologic mechanism of olfactory 366 or gustatory dysfunctions in COVID-19 patients has not been 367 clearly identified yet, it is also very interesting that the clini-368 cal manifestations of olfactory or gustatory dysfunctions were 369 different according to gender or races. 370 Moreover, it is necessary to follow the clinical course and 371 the long-term results of olfactory and/or gustatory dysfunc-372 tions in the cured COVID-19 patients. 

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