key: cord-0900826-akm1h9gq
authors: Sheng, Wang-Huei; Liu, Wang-Da; Wang, Jann-Tay; Chang, Su-Yuan; Chang, Shan-Chwen
title: Dysosmia and dysgeusia in patients with COVID-19 in northern Taiwan
date: 2020-10-20
journal: J Formos Med Assoc
DOI: 10.1016/j.jfma.2020.10.003
sha: 300122a9c0e5131169e5b2f76b6fb991e55d42bb
doc_id: 900826
cord_uid: akm1h9gq

Background/Purpose To investigate the characteristics of dysosmia and dysgeusia among patients diagnosed with coronavirus disease 2019 (COVID-19) in Taiwan. Methods Prospective data collection between January 22, 2020 to May 7, 2020 of nucleic acid confirmed COVID-19 hospitalized patients in northern Taiwan by the Taiwan Centers for Disease Control were analyzed. Results Of 217 patients enrolled, 78 (35.9%) reported dysosmia (n = 73, 33.6%) and/or dysgeusia (n = 62, 28.6%). The median duration of COVID-19 associated symptom-onset to development of dysosmia and/or dysgeusia was <1 days (interquartile range [IQR], <1 to 6 days) and 53 of 78 (67.9%) patients developed dysosmia and/or dysgeusia as one of the initial symptoms of COVID-19. Of 59 closely monitored patients, 41 (69.5%) patients recovered within 3 weeks after symptoms onset and the median time to recovery was 12 days (IQR, 7 to 20 days). Only 6 of the 59 (10.2%) patients reported persistent dysosmia and/or dysgeusia before discharge from hospitals. Multivariate analysis showed that younger individuals (adjusted hazard ratio [AHR], 0.93 per one-year increase; 95% confidence interval [95% CI], 0.89-0.97; P = 0.001), women (AHR, 2.76; 95% CI, 1.05-7.25; P = 0.04) and travel to North America (AHR, 2.35; 95% CI, 1.05-5.26; P = 0.04) were the significant factors associated with dysosmia and/or dysgeusia. Conclusion Dysosmia and/or dysgeusia are common symptoms and clues for the diagnosis of COVID-19, particularly in the early stage of the disease. Physicians should be alerted to these symptoms to make timely diagnosis and management for COVID-19 to limit spread.

The coronavirus disease 2019 outbreak caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic on March 11, 2020 , by the World Health Organization. In order to prevent transmission of COVID-19, Taiwan government began onboard quarantine since December 31, 2019. Taiwan Centers for Disease Control (Taiwan CDC) laboratory set up a protocol to test SARS-CoV-2 and announced COVID-19 as a notifiable disease, to be reported to Taiwan CDC within 24 hours since January 15, 2020. The first case of SARS-CoV-2 infection in Taiwan was diagnosed on January 21, 2020. Since March 20, 2020, all returned travelers must undergo 14 days of quarantine upon their arrival to Taiwan.

By June 30, 2020, a total of 447 COVID-19 confirmed cases with a mortality rate of 1.6% had been identified in Taiwan 1 .

COVID-19 is characterized by a variety of clinical manifestations. Common symptoms among COVID-19 patients include fever, dry or productive cough, shortness of breath (dyspnea), muscle ache (myalgia), confusion, headache, sore throat, rhinorrhea, chest pain, diarrhea, nausea/vomiting, conjunctival congestion, nasal congestion, fatigue, and generalized malaise. 1 Fever, cough, and fatigue were the most common symptoms reportedly associated with COVID-19 during initial outbreaks in China. [2] [3] [4] [5] In those early reports from China, dysosmia (include anosmia and hyposmia) and dysgeusia (include ageusia and hypogeusia) were not considered important symptoms for COVID-19. 2 However, in the following epidemics in Europe, United States and South Korea, dysosmia and dysgeusia were frequently associated with SARS-CoV-2 infection. [6] [7] [8] [9] [10] [11] J o u r n a l P r e -p r o o f Acute smell and taste disorders are related to a wide range of upper respiratory tract viral infections. 12, 13 However, absent or diminished ability to smell or taste, resulting from a viral infection targeting the upper respiratory tract, could be easily neglected from history taking by the primary care physician. Transmission of COVID-19 could occur before and immediately after symptom onset. 14 Recognition of early signs, might be helpful for earlier diagnosis of COVID-19 and enable rapid quarantine and isolation of patients. Here, we analyzed the data collected by the Taiwan's CDC of laboratory-confirmed COVID-19 cases in northern Taiwan to describe the demographic characteristics, clinical manifestations and outcome of patients with and without dysosmia or dysgeusia.

J o u r n a l P r e -p r o o f

When Taiwan's CDC announced COVID-19 as a notifiable disease on January   15 , 2020, the reporting criteria included: fever (≧38℃) and respiratory symptoms, or cough with tachypnea or respiratory difficulty, or radiologically/pathologically diagnosed pneumonia as well as travel history to a COVID-19 outbreak area within 14 days of disease onset. 1 The reporting criteria incorporated rolling updates to include all relevant travel exposure or contact history, and a wider spectrum of clinical illnesses. For example, the reporting clinical criteria was modified as fever or any acute respiratory symptoms, include cough, chest pain, dyspnea, rhinorrhea and nasal stuff since January 25, 2020, and dysfunction of smell (dysosmia) or taste Three consecutive negative samples from respiratory specimens were required for deisolation. Patients fulfilling the criteria for de-isolation were discharged if there was no need for additional clinical care, and the decision of de-isolation was approved after discussion of the primary care physician with the regional commander of the Infectious Diseases Control Network, which has been established since 2003 by Taiwan CDC.

In this study, we collected the information of confirmed COVID-19 patients derived from 7,500,518 inhabitants-based in northern Taiwan, including Taipei City, New Taipei City, Keelung City and I-Lan County reported to Taiwan CDC during January 22, 2020 to May 7, 2020, accounting for nearly one-third of the total population in Taiwan. Information on clinical presentation, underlying diseases and travel history of patients were collected during case investigation. All information was reconfirmed by Taipei Regional Commander (S.C. Chang) before patients were deisolated. Laboratory results within 48 hours of admission were retrieved from medical records that were uploaded to the National Notifiable Disease Surveillance System. Based on the above information, the investigation team determined the clinical severity of each confirmed patient following the World Health Organization (WHO) interim guidance. 15 

The patients were divided into two groups based on the presence of dysosmia and/or dysgeusia (case group) or not (control group). Categorical variables, such as gender, travel history, clinical features, disease severity, treatment and outcomes, were compared using Pearson's chi-squared test. Continuous variables, such as age and duration of virus shedding, were compared using Mann-Whitney U test. Cox proportional hazards models was used to estimate the unadjusted and adjusted hazard ratios (aHRs) for development of smell or taste dysfunction. Factors with at least borderline significance (P < 0.1) in the univariate analysis were subjected to multivariate analysis. Kaplan-Meier survival curve for the evaluation of factors associated with dysosmia and/or dysgeusia was used among patients with or without J o u r n a l P r e -p r o o f pneumonia. All analyses were performed using Stata/SE software, Version 11.0 (https://www.stata.com).

Data collection and analysis of cases were determined by the Taiwan Ministry of Health and Welfare to be part of a continuing public health outbreak response and were thus considered exempt from institutional review board approval. (Fig. 3) suggested that patients without pneumonia had borderline significant higher proportion of dysosmia and/or dysgeusia than those with pneumonia (log-rank test, P = 0.085).

In this study, we report that dysosmia and/or dysgeusia manifest early in the disease process of COVID-19 in Taiwanese patients and these symptoms usually In our present study, we found that younger patients and women more commonly experienced dysosmia and/or dysgeusia than elderly and male patients. In an anonymous electronic survey of 145 confirmed COVID-19 patients and 157 patients with negative test results of SARS-CoV-2, smell or taste change, fever, and body ache were associated with COVID-19 patients, and shortness of breath and sore throat were associated with patients of negative test results (all P < 0.05). 17 Interestingly, the survey showed that 214 (72%) were female and the participants had a mean age of 39 J o u r n a l P r e -p r o o f years. 17 Biadsee et al. conducted a web-based questionnaire assessing initial clinical presentation of 140 confirmed COVID-19 patients. 18 The common symptoms included cough, weakness, myalgia, fever, headache, dysosmia, dysgeusia, sore throat, rhinorrhea and nasal congestion. Dysosmia and dysgeusia were reported in 38.3% and 32.8% of the patients, respectively. All symptoms were reported more frequently by female patients than male patients,. 18 Lee et al. prospectively collected data of cases of anosmia or ageusia via telephone interview among 3191 patients from South

Korea. 10 In all, 68.9% of patients with dysosmia and/or dysgeusia were female, compared with 31.1% were male (P = 0.01). The median age of cases with dysosmia and/or dysgeusia was also younger than those without (median age, 36.5 years versus 46.0 years, P <0.001). 10 19 Totally 885 (60.7%) and 822 (56.4%) had dysosmia and/or dysgeusia, respectively, with women being more often affected. Dysosmia and/or dysgeusia may have been noted even without nasal obstruction/rhinorrhea or before the initial symptoms of COVID-19.

Dysosmia and/or dysgeusia usually resolved within the first two weeks after COVID-19. 19 Lechien et al. reported 417 mild-to-moderate COVID-19 patients who were recruited from 12 European hospitals. 6 They found dysosmia and/or dysgeusia were more frequently reported in female patients than in male patients (P = 0.001). 6 In line with the above reports, our results suggest that dysosmia and/or dysgeusia were more common among females and young individuals.

Travel history to northern America was also one of the significant factors associated with dysosmia and/or dysgeusia in our study. Tsou et al. The pathophysiological mechanism that causes dysosmia and/or dysgeusia is still uncertain. Dysosmia and/or dysgeusia are related to a wide range of viral infections. 13 Infection of the upper respiratory tract can cause dysosmia and/or dysgeusia because of viral damage to the olfactory epithelium. 13, 24 However, traditional nasal cavity manifestations of upper respiratory viral infections (such as rhinovirus, influenza, and adenovirus), such as nasal congestion, rhinorrhea, post-nasal drip and nasal stuff have been reported not common in patients with COVID-19. 11 Coronaviruses were known to be neurotropic with invasive neural spread into the neuroepithelium and the olfactory bulb. [25] [26] [27] By taking biopsies of the olfactory epithelium from patients with J o u r n a l P r e -p r o o f confirmed COVID-19 compared with uninfected controls, elevated levels of the proinflammatory cytokine tumor necrosis factor α (TNF-α) were shown to be significantly increased in the olfactory epithelium of the COVID-19 group compared to the control group. 28 The ACE2 receptor, which is the main host cell receptor of SARS-CoV-2 for binding and penetrating cells, is widely expressed on epithelial cells of the nasal 29 and oral mucosa. 30 In conclusion, dysosmia and/or dysgeusia are pertinent clues for the diagnosis of COVID-19, particularly in the early stage of the disease. Particularly among patients with mild disease severity and few symptoms, the presence of dysosmia and/or dysgeusia may important to elicit for the diagnosis of COVID-19. We recommend adding these symptoms to the list of primary screening symptoms for COVID-19 to prevent viral spread in the early stage. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical characteristics of coronavirus disease 2019 in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Olfactory and gustatory dysfunctions as a clinical presentation of mild-tomoderate forms of the coronavirus disease (COVID-19): a multicenter European study

Selfreported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study

Sudden and complete olfactory loss function as a possible symptom of COVID-19

Olfactory and taste disorder: the first and only sign in a patient with SARS-CoV-2 pneumonia

Prevalence and duration of acute loss of smell or taste in COVID-19 patients

Smell and taste dysfunction in patients with COVID-19

Identification of viruses in patients with postviral olfactory dysfunction

Smell and taste disorders

Contact tracing assessment of COVID-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset

Clinical management of severe acute respiratory infection when COVID-19 is suspected. World Health Organization

Olfactory and oral manifestations of COVID-19: sex-related symptoms-a potential pathway to early diagnosis

Olfactory and taste disorders in COVID-19: a systematic review

Epidemiology of the first 100 cases of COVID-19 in Taiwan and its implications on outbreak control

Distinct viral clades of SARS-CoV-2: implications for modeling of viral spread

ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome

Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2

The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system

Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Neurologic manifestations of hospitalized patients with coronavirus disease

Proinflammatory cytokines in the olfactory mucosa result in COVID-19 induced anosmia

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

The authors would like to thank all participated physicians of Infectious Diseases Control Network who took care of the patients with COVID-19. The authors also appreciate staffs and medical officers of the Taipei