key: cord-304872-hnxmtbrf
authors: Lv, Hao; Zhang, Wei; Zhu, Zhanyong; Xiong, Qiutang; Xiang, Rong; Wang, Yingying; Shi, Wendan; Deng, Zhifeng; Xu, Yu
title: Prevalence and recovery time of olfactory and gustatory dysfunctions of hospitalized patients with COVID‑19 in Wuhan, China
date: 2020-09-17
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.09.039
sha: 
doc_id: 304872
cord_uid: hnxmtbrf

OBJECTIVES: To investigate olfactory and gustatory dysfunction in patients with coronavirus disease 2019 (COVID-19) in Wuhan using a telephone interview. METHODS: This retrospective telephone survey investigated 196 consecutive patients with COVID-19 discharged 3 months previously from two hospital in Wuhan, China. The characteristics of the patient's disease course and recovery time for olfactory and/or gustatory dysfunctions (OD and/or GD) were collected by telephone interview. Demographic data were collected from the patients’ medical records. RESULTS: A total of 196 patients with COVID-19 completed the study. The most prevalent general symptoms consisted of fever, cough, and fatigue. 19.9% of patients reported OD and/or GD. In 87.2% of these cases, OD or GD appeared after the general symptoms. Among the patients, 51.4% had a recovery time of more than 4 weeks for OD and/or GD. Patients with COVID-19 and OD and/or GD had significantly higher rates of cardiovascular disease than patients without OD and/or GD (p = 0.002). CONCLUSION: Recovery from chemosensory dysfunction (OD and/or GD) was slow, with over half of the patients taking more than 4 weeks to recover. Cardiovascular disease might be related to the development of olfactory or taste disorders in patients with COVID-19.

The COVID-19 pandemic is still spreading around the world at an exponential rate.

To date, this infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people worldwide and killed more than 450,000. Early in the pandemic, Chinese clinicians reported typical symptoms of the J o u r n a l P r e -p r o o f disease, such as fever, fatigue, cough, and dyspnea (Guan et al., 2020) . However, the spread of COVID-19 in the United States and Europe has revealed some atypical symptoms of the disease, such as olfactory and gustatory dysfunctions (OD and GD) Speth et al., 2020) . Few Chinese studies have focused on olfactory and gustatory dysfunction in patients with . To the best of our knowledge, only one study has described these two symptoms. In their study of neurological symptoms of COVID-19 infection, Mao et al. (2020) found that 5.6% of patients had hypogeusia and 5.2% had hyposmia, which were the most common peripheral nervous system symptoms, which was much lower than that reported from Europe and the United States. Two hypotheses might explain the low prevalence of OD and/ or GD reported in the Chinese study: First, the number of Chinese patients with COVID-19 who exhibit olfactory or gustatory disorders is indeed lower. Second, most early research in Wuhan was based on the hospital medical records, and patients' sense of smell or taste might have been ignored by doctors during their medical history inquiry and records for the relative scarcity of medical resources during the early outbreak in Wuhan. Furthermore, all previous studies were limited to the acute phase with a short follow-up period, which might not reflect the recovery regularity of olfactory and/or gustatory impairment in patients with COVID 19. In otolaryngology, olfactory and gustatory dysfunction following viral infection is not uncommon. Unfortunately, in China, there is no professional group of ENT physicians that has studied this condition.

As of now, the mechanism by which patients with COVID-19 develop OD and/ or GD is unclear. It has been hypothesized that the development of OD after SARS-CoV-2 J o u r n a l P r e -p r o o f infection may be related to direct damage to the olfactory bulb, to damage to olfactory receptor neurons in the olfactory epithelium, or both. And the ensuing change in taste may depend largely on olfactory impairment (Ralli et al., 2020) . Exploring the clinical features of these chemosensory disorders helps us to gain insight into the mechanisms behind them. Therefore, we decided to collect detailed information about the OD and/ or GD of patients with COVID-19 using telephone interviews.

The aim of this study was to investigate the occurrence and recovery time of olfactory and/or gustatory dysfunction in patients with COVID-19 infection who were discharged from non-intensive care units 3 months earlier in China.

we followed up 206 consecutive patients with COVID-19 discharged from two hospital in Wuhan, China (Renmin Hospital of Wuhan University and Wuchang mobile cabin hospital) between March 1 st and March 16 th , 2020. From the computerized database of these hospitals, we identified all adults hospitalized and diagnosed as having COVID-19 by reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from nasopharyngeal swabs. The exclusion criteria were as follows: Patients under 18 years of age, patients with a history of cognitive disorders, and patients with OD and/or GD known before the epidemic. Demographic data including gender, age, and patient comorbidities and general symptoms were collected from the electronic medical record system of these hospitals. Information about OD and/or GD of each patient, including the duration of the symptoms and the recovering J o u r n a l P r e -p r o o f time were obtained by telephone interview. Three trained otolaryngologists conducted telephone interviews with all participants using a standard questionnaire. All patients were then contacted by telephone up to three times to complete the study. We stopped the follow-up of the study on June, 20 th 2020. This study was approved by the ethics committee of Renmin Hospital of Wuhan University (No. WDRY2020-K148).

SPSS software, version 24.0 (IBM Corp, Armonk, NY, USA) was used to perform all statistical analyses. Data are presented as arithmetical mean values with the standard deviation (SD). The statistical significance of differences between data was evaluated using an independent sample t test. The chi-squared test was used to evaluate the constituent ratios in COVID-19 with OD and/or GD group and COVID-19 without OD and/or GD group. A level of significance of p < 0.05 was used.

206 patients were interviewed by telephone. 7 patients were excluded from the study because they could not be reached by phone three times. And 3 patients were unable to complete our questionnaire. So a total of 196 patients (95.1%) completed the survey.

The mean age of the patients was 50.6 ± 13.8 years. There were 108 females and 88 males. The most common comorbidities of patients were hypertension, diabetes, and cardiovascular disease. Table 1 shows the clinical and demographic characteristics of the patients. Patients with COVID-19 and OD and/or GD had significantly higher rates of cardiovascular disease than patients without OD and/or GD (p = 0.002). The two J o u r n a l P r e -p r o o f groups did not differ significantly in their general symptoms or other comorbidities (p > 0.05).

Of the 196 patients, 9.7% (39/196) reported smell and/or taste disorders. Among them, 41.0% (16/39) and 23.1% (9/39) reported smell or taste disorders, respectively.

In addition, 35.9% of patients (14/39) reported both smell and taste disorders ( Figure   1 ).

Five of the 39 patients (12.8%) reported olfactory or gustatory dysfunction as their first symptom of COVID-19 infection. The five patients stated that they exhibited typical symptoms, such as fever and cough, about 1 week after the onset of olfactory or gustatory dysfunction. Thirty-four patients (87.2%) began to experience olfactory or gustatory disturbances following the appearance of general symptoms of COVID-19 infection ( Figure 2 ). Among them, 85.3% of patients (29/34) reported chemosensory disorders (OD and/or GD) within 8 days of the onset of general symptoms ( Figure 2 ).

The median time to develop OD and/or GD after the onset of the typical symptoms was 3 days.

By the end of follow-up, 10.3% of patients (4/39) indicated that their olfactory and/or gustatory function had not returned to normal, while 89.7% of patients (35/39) reported that the sense of smell and/or taste function was restored. Figure 3 shows the recovery time pattern for the remaining 35 patients. Only 8.6% of patients (3/35), OD and/or GD recovered within 1 week of onset. It took more than 4 weeks for OD and/or GD to return J o u r n a l P r e -p r o o f to normal in 51.4% of patients (18/35). Two of the patients reported a recovery time of 2 months, which was the longest recovery time during our follow-up. Figure 4 demonstrates the relationship between recovery time of patients with COVID-19 with OD and/or GD and overall patient-reported clinical improvement. Recovery of the sense of smell and taste in most patients with COVID-19 correlated temporally with overall clinical improvement of the disease. Finally, we also compared the clinical characteristics of patients with a recovered sense of smell and/or taste and those who had not recovered their sense of smell and/or taste. There were no statistically significant differences in age, sex composition, or length of hospital stay between the two groups of patients (Table 2 ).

The spread of COVID-19 is now accelerating worldwide, putting enormous pressure on every country's epidemic prevention efforts. Studies have suggested OD and/or GD as a screening criterion to identify patients with mild symptoms. However, the epidemiological characteristics and pathogenesis of these chemosensory disorders remain unclear. Especially in China, there are few relevant studies. In this study, we performed subjective olfactory and gustatory evaluations in patients with COVID-19 via telephone interviews. In addition, we analyzed the relationship between other symptoms of COVID and chemosensory dysfunction using patients' electronic medical records and the telephone interviews.

In the current study, 8.2% (16/196) and 4.6% (9/196) of patients reported olfactory and taste disorders, respectively. The low rates of OD and/or GD in our study population J o u r n a l P r e -p r o o f are clearly contrary to those reported in European and American studies Speth et al., 2020; Chary et al., 2020) . In addition, a study from Korea showed that 15% of patients with COVID-19 had anosmia or ageusia, which was similar to our results ( Lee et al., 2020) . However, a recent study showed that 38% of patients with COVID-19 who self-reported as having an olfactory disorder showed normal in an objective olfactory test . Therefore, the prevalence of COVID-19related olfactory disorders might have been overestimated in studies based on subjective reports.

In our study, most of the patients had OD and/or GD following general symptoms such as fever, cough, and fatigue. The median time to onset of OD and/or GD after general symptoms was 3 days. This meant that chemosensory disorders usually appeared early in the course of COVID-19 infection. Notably, in 5 of the 39 patients with chemosensory disorders, OD and GD appeared before the other symptoms. In the context of the current pandemic, it is important for physicians to pay attention to patients who develop sudden OD and GD, which are important for the early detection and isolation of patients with COVID-19.

Similar to some previous studies Chary et al., 2020) , women appear to be more susceptible to OD or GD. In our cohort, 64.1% of patients with chemosensory disorders were female. However, Meini et al. (2020) showed that women are less likely to develop chemosensory disorders compared with men. Clearly, sex differences in patients with COVID-19 with OD or GD still require further study.

One of the biggest concerns for all ENT physicians and patients is the recovery time J o u r n a l P r e -p r o o f for OD and/or GD. In the present study, over half of the patients with chemosensory disorders recovered over 4 weeks. However, our results contradicted those previous studies. Klopfenstein et al. (2020) reported a mean duration of anosmia of 9 days, with a complete recovery occurring in almost all patients within 4 weeks. also reported that 72.6% of patients recovered their olfactory and gustatory functions completely within the first 8 days following resolution of the disease. In our study, all patients had complete recovery of overall disease symptoms within three weeks post-diagnosis. In contrast, more than half of the patients did not recover their olfactory or gustatory function during that time frame. Although our results are preliminary, we concluded that the recovery time for chemosensory disorders in patients with COVID-19 in the Wuhan area is slow.

We also sought to explore the differences in clinical characteristics between patients with a fully recovered sense of smell and/or taste and those with a partially recovered sense of smell and/or taste. However, there were no statistically significant differences in age, sex composition, or length of hospital stay between the two groups of patients.

Notably, all four patients who had not regained their sense of smell and/or taste by the end of follow-up were female.

The pathophysiological mechanisms by which SARS-CoV-2 infection causes OD or GD are unclear. A number of recent studies have explored the mechanisms that may lead to OD or GD. Zou et al. (2020) found that SARS-CoV-2 replicated particularly well in the nose, where a high viral load was detected shortly after the onset of symptoms. In addition, in the upper respiratory tract, nasal mucosal epithelial cells J o u r n a l P r e -p r o o f exhibited the highest expression of the SARS-CoV-2 receptor angiotensin I converting enzyme 2 (ACE2), which increased the chance of viruses invading these cells and causing OD (Sungnak et al., 2020) . Likewise, high expression of ACE2 has been found in the tongue and oral mucosa, which might contribute to GD (Xu et al., 2020) . Nasal inflammation and obstruction might cause OD and/or GD. However, Mercante et al. (2020) found that most patients with a reduced sense of smell or taste did not report nasal congestion. During the telephone follow-up, we also asked patients about their nasal symptoms, including nasal obstruction, rhinorrhea (anterior and posterior), and sneezing. Similarly, few patients indicated that they had any of these symptoms.

Apparently, there are other causes of OD and/or GD following COVID-19 infection.

The invasion of SARS-CoV-2 through peripheral olfactory neurons, resulting in damage to the central nervous system, was considered a possible mechanism for the development of OD (Conde et al., 2020). Brain magnetic resonance imaging of patients with COVID-19 with anosmia noted abnormalities of the olfactory bulb and olfactory nerve Aragão et al., 2020) . Previous research on SARS-CoV also supported this hypothesis. Netland et al. (2008) found that the virus can enter other areas of the brain through the olfactory bulb, creating rapid transmission across neurons.

In fact, many of the clinical symptoms of COVID-19 are suspected to be related to its nerve invasiveness. For example, a previous study showed that SARS-CoV-2 might cause respiratory failure in patients with COVID-19 by attacking the respiratory center in the medulla oblongata . The slow relief of OD and GD might be related to damage to the olfactory central nervous system.

Although the prevalence and prognosis of olfactory or gustatory disturbances in patients with COVID-19 varies worldwide, the mechanisms underlying them remain unclear. Some studies have shed some light on the mechanisms that underlie these differences. Forster et al. (2020) identified three major variants, named type A, B, and C in a phylogenetic network analysis of 160 SARS-CoV-2 genomes. They found that type A followed by type C was predominant in Europe and the United States, while type B was most common in East Asia. Phenotypic characteristics might differ between these variants, including those related to the prevalence of OD and GD. In addition, the affinity of the virus for certain tissues and individuals might partially explain the clinical differences between patients in different parts of the world. The expression level of ACE2, the receptor for SARS-CoV-2, in different tissues might be critical for the susceptibility, symptoms, and outcomes of COVID-19 infection. A previous study on SARS-CoV showed that certain human ACE2 variants show reduced binding to the SARS-CoV S protein (Li et al., 2005) . Similar to SARS, the spike protein (S protein) of SARS-CoV-2 is responsible for entry into the host cell (Wan et al., 2020) . By comparing 15 expression quantitative trait locus (eQTLs) variants of the ACE2 gene, the researchers found a large number of ACE2 polymorphisms and differences in expression levels between the European and Asian populations (Cao et al., 2020) .

We also compared the clinical characteristics of patients with COVID-19 with a chemosensory disorder and those without a chemosensory disorder. The results indicated a significantly higher incidence of cardiovascular disease in patients with COVID-19 with a chemosensory disorder than in patients with COVID-19 without a J o u r n a l P r e -p r o o f chemosensory disorder. Some studies have suggested that a decreased sense of smell is a predictor of cardiovascular disease development (Schubert et al., 2015; Siegel et al., 2019) . Despite the small number of cases in our study, we speculated that cardiovascular disease might be related to the development of olfactory or taste disorders in patients with COVID-19.

There are some limitations to our study. The main limitation of our study is its retrospective nature, which might have led to recall bias. However, in patients with COVID-19, olfactory or gustatory disturbances are relatively specific to other symptoms. In our telephone survey, the vast majority of patients were able to recall the onset and duration of the OD and/or GD. The lack of full objective methods to assess olfaction may be considered as another weakness. Considering the risk of crossinfection when performing objective tests, we decided to use a telephone interview in this study to learn about the patients' olfactory and gustatory functions. These shortcomings should be addressed in future research.

The prevalence of olfactory and gustatory disorders associated with SARS-CoV-2 infection in China is much lower than that in the United States and Europe. However, it is undeniable that OD and/or GD is an early and even the first symptom of COVID-19.

As such, they help screen and identify patients with atypical symptoms. Another characteristic of patients with COVID-19 in China is the long recovery time from OD and/or GD. Cardiovascular disease might be related to the development of olfactory or taste disorders in patients with COVID-19. However, because of the limited sample 

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.