key: cord-0854812-6umzcixp
authors: Cheng, Meng-Yu; Hsih, Wen-Hsin; Ho, Mao-Wang; Lai, Yi-Chyi; Liao, Wei-Chih; Chen, Chih-Yu; Chen, Tsung-Chia; Lee, Yu-Lin; Liu, Po-Yu; Kao, Chih-Chuan; Chou, Chia-Huei; Lin, Po-Chang; Chi, Chih-Yu; Leong, Lih-Ying; Tai, Chih-Jaan; Lu, Min-Chi
title: Younger adults with mild-to-moderate COVID-19 exhibited more prevalent olfactory dysfunction in Taiwan
date: 2021-02-08
journal: J Microbiol Immunol Infect
DOI: 10.1016/j.jmii.2021.01.006
sha: 46890894933d4e7e6c949f733fc271ea53d8aaa3
doc_id: 854812
cord_uid: 6umzcixp

Background Coronavirus Disease 2019 (COVID-19) is rapidly transmitted from person to person, causing global pandemic since December 2019. Instantly detecting COVID-19 is crucial for epidemic prevention. In this study, olfactory dysfunction is a significant symptom in mild to moderate COVID-19 patients but relatively rare in other respiratory viral infections. The Taiwan smell identification test (TWSIT) is a speedy and inexpensive option for accurately distinguishing anosmia that also quantifies the degree of anosmia. Using TWSIT in the outpatient clinic for early identifying the patients with mild to moderate COVID-19 can be promising. Methods Nineteen patients confirmed COVID-19 in central Taiwan were collected and divided into two groups: olfactory dysfunction and non-olfactory dysfunction. Demographic characteristics, laboratory findings, and the results of the olfactory test were compared between these two groups. Findings Thirteen (68.4%) of the 19 patients had olfactory dysfunction. The patients with olfactory dysfunction were younger than those without this symptom. The statistical difference in age distribution was significant between these two groups (IQR: 25.5-35.5 vs. IQR: 32.5-60.3; p-value: 0.012). There was no significant difference in gender, smoking history, comorbidities, travel history, respiratory tract infection symptoms, and laboratory findings between these two groups. Conclusion This study demonstrated that young adults were prone to develop olfactory dysfunctions. In the flu season, olfactory dysfunction is considered a specific screening criterion for early detecting COVID-19 in the community. TWSIT can serve as a decent test for quantifying and qualifying olfactory dysfunction.

Veterans General Hospital, Taichung, Taiwan crucial for epidemic prevention. In this study, olfactory dysfunction is a significant 52 symptom in mild to moderate COVID-19 patients but relatively rare in other 53 respiratory viral infections. The Taiwan smell identification test (TWSIT) is a speedy 54 and inexpensive option for accurately distinguishing anosmia that also quantifies the 55 degree of anosmia. Using TWSIT in the outpatient clinic for early identifying the 56 patients with mild to moderate COVID-19 can be promising. 57

Nineteen patients confirmed COVID-19 in central Taiwan were collected and divided 59 into two groups: olfactory dysfunction and non-olfactory dysfunction. Demographic 60 characteristics, laboratory findings, and the results of the olfactory test were compared 61 between these two groups. 62

Thirteen (68.4%) of the 19 patients had olfactory dysfunction. The patients with 64 olfactory dysfunction were younger than those without this symptom. The statistical 65 difference in age distribution was significant between these two groups (IQR: 25.5-66 35.5 vs. IQR: 32.5-60.3; p-value: 0.012). There was no significant difference in 67 gender, smoking history, comorbidities, travel history, respiratory tract infection 68 symptoms, and laboratory findings between these two groups. 69

This study demonstrated that young adults were prone to develop olfactory 71 dysfunctions. In the flu season, olfactory dysfunction is considered a specific 72 J o u r n a l P r e -p r o o f Introduction 77

December 2019, and its pathogen, known as severe acute respiratory syndrome 79 coronavirus 2 (SARS-CoV-2), can transmit from person to person by exhaled droplets. 80 1 Owing to pre-symptomatic and asymptomatic transmission, COVID-19 spreads 81 rapidly in the community. Pre-symptomatic transmission of COVID-19 is probably 82 caused by the shorter duration of serial interval than that of the incubation period. 2,3 83 Therefore, early detection of COVID-19 patients is essential for the prevention and 84 control of this endemic infection. 85

In this pandemic period, those presenting with mild to moderate symptoms 86 occupy the majority of COVID-19 patients, nearly 80% of patients reported from the 87 study of China. 4, 5 Flu-like syndrome includes fever, dry or productive cough, 88 rhinorrhea, stuffy nose, myalgia, sore throat, headache, chills, diarrhea, and nausea; 89 these are the major presentations of COVID-19. The oxygen saturation of these 90 patients often maintained above 94% without an additional oxygen supply, and 91 lymphopenia, and elevations of C-reactive protein, d-dimer, lactate dehydrogenase, 92 and ferritin may be present. 2,6-8 93 In the 2019-2020 flu season, many countries were flooded with COVID-19 94 patients. Additional respiratory viruses, including Influenza A/B, Coronavirus 95 229E/OC43, and Adenovirus 9 , were circulating at the same time, and their yielded 96 symptoms and signs were similar to those of SARS-Cov-2-infected patients. Recent 97 reports demonstrated that quite a few patients suffered from a loss of taste or smell as 98 their initial presentation. 10, 11 Post-respiratory non-SARS-CoV-2 infection, like 99

Influenza or other pathogens, may induce olfactory dysfunction, the rate of which has 100 been less than 20%. 12 The prevalence of olfactory dysfunction was high in COVID-101 19 patients of western countries. One study revealed the prevalence rate of subjective 102 olfactory dysfunction reached 85.6%, and another study employed the University of 103 Pennsylvania Smell Identification Test (UPSIT) which objectively disclosed an even 104 higher prevalence rate. 11,13 105 Examination of olfactory dysfunction could be valuable as initial screen method 106 to differentiate COVID-19 from other viral respiratory infections, however, the 107 supportive data was limited and none from Asian population. Quantifying the degree 108 of anosmia, along with subjective description of smell loss, could be essential for 109 clinical identification of COVID-19 patients. UPSIT has been one of the most widely 110 used tests to evaluate the olfactory function, and Traditional Chinese version of the 111 UPSIT (UPSIT-TC) was modified according to the cultural differences. 14 Pearson 112 correlation revealed a significant positive correlation between the two tests. 15 As it 113 was revised from UPSIT and UPSIT-TC and its test items were chosen for Taiwanese 114 according to their culture, Taiwan smell identification test (TWSIT) was designed for 115

Taiwanese. Since the correlation between TWSIT and UPSIT-TC was high, TWSIT 116 has been widely used to discover olfactory dysfunction caused by infection, head 117 trauma, surgery, age, toxin or medication 16 . It evaluates the grade of anosmia or 118 hyposmia more reliably than a subjective loss of smell and is a faster, convenient, and 119 low expense. Most standard tests for the diagnosis of COVID-19 patients are confined 120 to specific microbiologic laboratories and time-consuming. TWSIT is likely useful, in 121 the community setting, to recognize SARS-CoV-2-infected patients on an outpatient 122 basis. As loss of smell is one of the major symptoms in COVID-19 patients, we 123 conducted a innovative study and applied TWSIT to assess the smell sense of were pictured and sent to the investigators by e-mail. Some of the patients did 138

TWSIT soon after they were admitted, and others did TWSIT days or up to 4 weeks 139 after they were hospitalized. 140

Demographic characteristics, comorbidities, travel or contact history, clinical 142 symptoms, and signs were retrospectively collected from medical records. All the 143 patients were subjected to blood tests and chest-X-ray during their admission in 144 negative pressure isolation rooms. The criterion for patients to be discharged was 145 fulfilling three successive results of negative SARS-CoV-2 RT-PCR tests. TWSIT 146 was given either in a negative pressure isolation room or in the outpatient clinic 147 during the illness day 5 to 60. The ENT doctors were consulted for the prescription 148 and the evaluation of the result of TWSIT. 149

including anosmia, hyposmia, or smell decay detected by unbiased TWSIT. Anosmia 152 and hyposmia denote loss and decreased sense of smell, respectively. These subjective 153 sensations may occur at first and then improved by the time receiving TWSIT, 154 therefore few patients had smell dysfunction symptom and acceptable TWSIT score. 155

The patients possessing no smell symptom and satisfactory TWSIT score were 156 identified as no olfactory problem. 157

The odorants used for smell tests are culturally customized. A total of eight 159 odorants, including honey peach, passion fruit, cantaloupe, lemon, smoked plum, dysfunction, these symptoms were not presented differently, except for loss of smell 220 (69.2% vs. 0%, P-value=0.011; Table 2 ). 221

Similarly, there were no significant differences in the laboratory values, 222

including white blood count, neutrophil, lymphocyte, neutrophil to lymphocytes ratio, 223 creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, C-reactive 224 protein, creatine kinase, and lactate dehydrogenase, between the olfactory dysfunction 225 and non-dysfunction groups ( Table 2) . 226

To better evaluate the olfactory function objectively, TWSIT was introduced in 228 this study. According to the age-adjusted TWSIT score, the olfactory function of a 229 patient was divided into three groups, that is anosmia, hyposmia, and normosmia. The 230 median of TWSIT scores of the olfactory dysfunction group (n=13) was 38 (IQR: 31-231 43), which was significantly lower than that of the non-dysfunction group (n=6, 232 TWIST score 46; IQR: 44-46). Based on the scoring scheme, ten of the patients of the 233 olfactory dysfunction group were considered hyposmia, and their TWSIT scores 234 ranged from 13 to 42. Of the ten hyposmia patients, six suffered from subjective 235 anosmia and four without noticing this symptom. For the patient who got the lowest 236 TWSIT score (13 points), a paired TWSIT was performed 2 weeks after first testing, 237 and the score increased to 40 points, indicating that olfactory dysfunction had been 238 improved significantly. 239

As presented in Table 2 , thirteen of the COVID-19 patients (13/19, 68.4%) 240

were confirmed olfactory dysfunction, either subjectively or objectively detected. younger than those without this finding (Table 1 ). In general, older people had 251 degeneration of olfactory function. The TWSIT scores from patients in the olfactory 252 non-dysfunction group decreased with age ( Figure 1; solid line) . However, when the 253 loss of olfactory function was associated with SARS-CoV infections, younger patients 254 were likely to have a lower TWSIT score (Figure 1; dotted line) . had not been characterized. 13 In this study, the prevalence of olfactory dysfunction 271 (68.4%) in COVID-19 patients was higher than that of fever (57.9%) and cough 272 (42.1%). Seeing its sensitivity to detect COVID-19, it is suggested that the inclusion 273 of olfactory dysfunction in the screening criterion is feasible in the Taiwanese 274

Furthermore, the TWSIT provides an easy-to-use platform, and can therefore be 276 applied in the outpatient clinics. It is particularly useful for the identification of mild 277 to moderate COVID-19 patients. The odorants used for smell tests vary from nation to 278 nation. The familiarity of the odorants is influenced by the food, culture, and religious 279 habits of people. The UPSIT is regarded as a valid and accurate tool to identify 280 olfactory dysfunction in the western countries 11 , however, it had an increased false-281 positive rate when applied in Iran. 18 As a result, the odorant list of UPSIT needs to be 282 modified and validated before it can be used for the tested population. 283

We are the first to demonstrate that olfactory dysfunction was more frequently 284 present in the younger patients infected by COVID-19 (Table 2 and Figure 1 ). Yet the 285 underlying mechanism is not clarified. 19 It is known that, when activated by a 286 specific odorant, the neuronal receptor in the olfactory epithelium at the roof of the 287 nasal cavity transmits a signal along the axon of the olfactory nerve. Through the 288 convergence of axons in the olfactory bulbs connecting the primary sensory cortex 289 and the amygdala, the odor is produced. Aging is a factor of olfactory degeneration. 290

When the patient age increases, the integrity of olfactory epithelium and the size of 291 the olfactory bulb naturally decrease. 20 converting enzyme 2 receptor. 23 When the peripheral nervous system is affected, 307 patients present loss of smell, loss of taste, vision disturbance, or nerve pain. 24 All the 308 patients in this study had characteristics of mild to moderate COVID-19 cases and 309 they did not have severe neurologic problems except for anosmia. 310 COVID-19-associated olfactory dysfunction is likely reversible, and one study 311 demonstrated that the recovery rate reached 80%. 25 In this current study, the patient 312 with worst olfactory function had a TWSIT score of 13 initially and improved to a 313 score of 40 two weeks later. Repeated stimuli have been recommended to help the 314 regenerative capacity of olfactory function 16 , and through the anti-inflammatory 315 effects on olfactory receptors, corticosteroids have been reported to improve the 316 olfactory dysfunction. 21 Nevertheless, no standard regimen so far is formulated for 317 the treatment of post-infection olfactory dysfunction. All the COVID-19 patients with 318 olfactory dysfunction in this study received no specific treatment, and their hyposmia 319 symptom partially or entirely resolved two or more weeks later. 320

There were several limitations to this study. First, during March 25 to May 5, 322 2020, the number of confirmed COVID-19 patients in central Taiwan was limited. 323

Although the tested patients is small, the yielded data is important to apply for clinical 324 identification of COVID-19. Accompanying with the subjective smell complaints, this 325 portable olfactory test is easy-to-interpret via telecommunication and is likely to serve 326 as a screening test for early recognizing COVID-19 patients. Second, there was no 327 unified timing for preforming the TWSIT; some patients did this test early in the 328 disease process, and some in the recovery phase. Third, TWSIT is solitarily used in 329

In the study, anosmia or hyposmia is the most common symptom of COVID-19 332

patients. The patients with olfactory dysfunction were statistically younger than those 333 without such finding. In the flu season, olfactory dysfunction is presumably a potent 334 screening criterion for early detection of COVID-19 in the community and can be 335 quantified and qualified by TWSIT. By using the TWSIT, we could quantify the 336 severity score of COVID- 19 .3) 1 (7.7) 0 (0) * Comorbidities are including diabetes, heart disease and hepatitis in the patient without olfactory dysfunction patient and allergic rhinitis in the patient with olfactory dysfunction; there were no comorbidities of hypertension, airway disease, sinusitis, autoimmunity disease, or malignancy. to lymphocytes ratio, AST= aspartate aminotransferase, ALT= alanine aminotransferase, CK= creatine kinase, LDH= lactate dehydrogenase , TWSIT= Taiwan smell identification test * Upper respiratory infection symptoms comprised rhinorrhea, stuff nose and sore throat.

† Lower respiratory infection symptoms included cough, short of breath and chest tightness. ‡ Other symptoms contained headache, myalgia, and diarrhea but there were no abdominal pain, nausea/vomiting, or skin rash Figure1. The correlation between age and olfactory score of SARS-CoV-2-infected patients with or without olfactory dysfunction. The TWSIT scores from patients in the olfactory nondysfunction group likely decreased with age (solid line). For of olfactory dysfunction group, younger patients seemed to have a lower TWSIT score (Figure 1 ; dotted line).

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