key: cord-0988452-df8yxkl7 authors: Parente-Arias, Pablo; Barreira-Fernandez, Pilar; Quintana-Sanjuas, Ana; Patiño-Castiñeira, Berta title: Recovery rate and factors associated with smell and taste disruption in patients with coronavirus disease 2019 date: 2020-07-14 journal: Am J Otolaryngol DOI: 10.1016/j.amjoto.2020.102648 sha: 221a940b983e96e7b4668b2225f1eab8372920b3 doc_id: 988452 cord_uid: df8yxkl7 PURPOSE: To determine the occurrence of olfactory and gustatory disruptions in COVID-19 patients, their association with demographic and clinical features and prognosis. MATERIAL AND METHODS: This observational cohort study involved consecutively diagnosed COVID-19 patients tested between March the 3rd 2020 and March the 24th 2020, in a geographically defined cohort area. All COVID-19 patients were evaluated in a University Hospital. The primary outcome of interest is the prevalence of smell and taste alterations, factors associated and recovery rate. Univariate and multivariate analysis by logistic regression was performed to detect factors associated to these symptoms. RESULTS: 151 patients were included and 99 (65.3%) reported olfactory or gustatory symptoms. Olfactory dysfunction was reported by 75 patients (49.7%). Isolated anosmia was found in 2 patients (1.3%). Gustatory dysfunction was reported by 91 patients (60.3%). Factors associated with higher prevalence of smell dysfunction included age, sex, and comorbidities. The time to smell disruption development was significantly shorter in mild to moderate patients than in severe patients (p = 0.043). In 85.3% of patients with smell disruption, the symptom had been resolved in the first 2 months. 14.7% of patients remained symptomatic after 3 months of follow-up. CONCLUSIONS: Olfactory and gustatory dysfunction was common in COVID-19 patients. Smell disruption has high recovery rate and was associated with age, sex, and clinical severity. It may be beneficial to investigate the appearance of taste and/or smell disruptions in individual patients, with respect to diagnosis and prognosis. that was subsequently determined to be caused by a novel coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 . The disease it causes has been named coronavirus disease 2019 (COVID- 19) , and it has become a pandemic that has rapidly spread virtually worldwide. The virus is transmitted via oronasal cavities 2 through aerosols and droplets from both symptomatic and asymptomatic patients 3, 4 . The most common symptoms reported in China include fever, coughing, dyspnea, sputum production, myalgia, arthralgia, headache, and diarrhea. Otolaryngologic symptoms were less prevalent in those studies but included sore throat (7%-15%), nasal discharge (5%), nasal obstruction (5%), and anosmia and/or ageusia (5%) 5 . Smell and taste dysfunction have been reported by otolaryngologists in patients, sometimes as the sole symptoms present, and this has led to issue specific recommendations in this regard. Some evidence has emerged implicating both olfactory and gustatory disruptions as indicative clinical symptoms in COVID-19 patients outside China. The aims of the current study were to investigate and characterize the occurrence, duration and recovery of olfactory and gustatory disruptions in a geographically defined cohort of patients with laboratory-confirmed COVID-19 and investigate the relationships between these disruptions and demographic and clinical features. An observational cohort study involving consecutively diagnosed COVID-19 patients between March the 3 rd 2020 and March the 24 th 2020 in the province of Lugo (Spain) was performed. Inclusion criteria were age > 18 years and COVID-19 confirmed via reverse transcription polymerase chain reaction (RT-PCR). The exclusion criteria were inability to speak on the telephone, olfactory or gustatory dysfunction prior to the COVID-19 epidemic, and lack of informed consent. Insufficient cognitive skills to collaborate were also considered an exclusion criterion. Cognitive skills were assessed via interview (subjectively assessed by the evaluator) and from medical records. Initial telephone interviews were conducted between April the 1 st 2020 and April the 10 th 2020 by four researchers. Form April the 14 th 2020 to June 25 th 2020 researchers re-contacted patients who had reported persistence of symptoms during the first telephone interview, to assess whether they had recovered or were experiencing ongoing persistence. Electronic charts were reviewed during telephone interviews and all relevant clinical data were confirmed by the patient. The questionnaire included age, sex, date of clinical onset, date of testing, general clinical symptoms (fever, dry cough, dyspnea, diarrhea, myalgia, among others) and their dates of onset, presence of otolaryngologic symptoms (rhinorrhea, nasal obstruction, sore throat, otalgia, facial pain), and medical J o u r n a l P r e -p r o o f 7 history (specific otolaryngologic history, comorbidities, previous chronic treatment, current treatment). Based on potentially relevant laboratory test results, imaging, and clinical data obtained from electronic records, patients were classified in accordance with Wang et al. 6 , and assigned to a mild group (mild to moderate in Wang's classification) or to a severe group (severe and critical in Wang's classification). Questions pertaining to olfactory impairment were based on the Self-reported Mini Olfactory Questionnaire 7 , but were adapted to be applied to isolated patients. Ability to smell sanitary alcohol, bleach, perfume and coffee were assessed. Based on patients' answers they were assigned to a no symptoms group (no change in their ability to recognize usual smells), hyposmic group (who experienced changes in their sensitivity but that they still had maintained perception of strong odors), or anosmic group (unable to perceive any smells). Taste impairment was measured by means of relevant questions featured in the United States National Health and Nutrition Examination survey 8 . Based on the patients' answers they were assigned to a no symptoms group (no change in their ability to perceive taste), a dysgeusia group (alteration or distortion of their ability to taste), or an ageusia group (their ability to taste was reduced or abolished). Galicia Ethics Committee (Santiago de Compostela, Spain) approved the study protocol (Study Code: 2020-186), and informed consent was obtained from all patients. J o u r n a l P r e -p r o o f 8 Statistical analyses were performed using version 3.5.2 of the R programming language (R Project for Statistical Computing; R Foundation). Relationships between variables were assessed via the chi-square test. The Kaplan-Meier method was used to generate curves to estimate the timing of the emergence of symptoms, and curves derived from patients with mild disease were compared with curves derived from patients with severe disease via the log-rank test. Lastly, the comparative influences of different factors on disease's severity were investigated using logistic regression, associated odd-ratios, and 95% confidence intervals. The first 184 patients who tested positive in the first 1,007 PCR tests performed at Lugo were considered for inclusion in the study, but 33 were excluded based on the aforementioned criteria. Of these 33 patients, 9 had been intubated in the intensive care unit during the study, 7 were in the intensive care unit and their clinical circumstances rendered participation in the interview impossible, 7 had died, 4 were uncontactable, 3 had dementia, 2 were aged < 18 years, and 1 refused to participate. A total of 151 patients completed the study, 53 men and 98 women, and their mean age was 55.2 years (range 18-88 years). Thirty-five patients were included in the severe group because they fulfilled the requirements at some point during the evolution of their disease condition. Patient characteristics and comorbidities are summarized in Table 1 , and non-mutually exclusive general and otolaryngologic symptoms are presented in Table 2 . Of the 151 patients who completed the study, 99 (65.6%) reported olfactory or J o u r n a l P r e -p r o o f (Table 3) . Anosmia or hyposmia developed on the same day as the rest of the symptoms in 19/75 patients (25.3%). In the rest of the patients time from clinical onset to olfactory disruption varied from 1 day to 11 days (mean 4.4 ± 0.6 days). The time to anosmia or hyposmia development was significantly shorter in mild to moderate patients than in severe patients (p < 0.05; Figure 1 ). Although all patients reported improvement, in 11/75 (14.7%) patients the symptom remained at the final follow-up timepoint, which constituted durations ranging from 91 to 108 days (mean 100.5 ± 3.3 days). In those in whom the symptom had resolved by the final follow-up timepoint, it had lasted from 3 to 60 days (mean 17.7 ± 8.9 days), 55,2% of them in the first 12 days. Figure 2 . The present study adds evidence to the knowledge base pertaining to alterations in smell and taste and COVID 19, and, to our knowledge, it's the first study to find association between these symptoms and age, sex, disease severity, and comorbidities. The rate of olfactory and/or gustatory dysfunction found was 65.6% (49.7% olfactory and 60.3% gustatory), showing a recovery rate of 85.3% after, at least, 91 days, in the longest follow up reported. The prevalence of such symptoms varies markedly between studies, from 5.1% to 98.0% 9 . Several factors are involved in this variation. The most influential is the technique used to assess the presence of olfactory or gustatory disruption. Chart review studies were initially used by Vaira et al. 10 and Mao et al. 11 and reported prevalence of chemosensory dysfunction from 5,1% to 19.4%. Records-based investigations underestimate such symptoms because assessment was not included in previous clinical protocols. Self-reporting of symptoms via online questionnaires has been used by Lechien et al. 12 reporting 85.6% olfactory dysfunction and 88.0% gustatory dysfunction. Notably, however, self-reported olfactory acuity is reportedly inaccurate 13 . Some studies have assessed symptoms via oral interviews. Giacomelli et al. 14 In the present study, there were associations between these disruptions and age, sex, and disease severity. Age is known to be associated with olfactory loss 15 . All patients in the present study reported normal olfactory and gustatory function before COVID-19 onset, and disruption was based on differential acuity thereafter. Only one previous study has shown this 14 . Some evidence suggests that olfactory capacity is worse in men than in women at all ages 15, . In the COVID-19 patients in the current study, olfactory J o u r n a l P r e -p r o o f and gustatory disruptions were more common in women than in men, as it has been reported in other studies 12, 14 , but this was not found in objective testing studies 18 . It could mean that women can be aware of smell and taste alteration better than men. In our study we found an association between presence of comorbidities and clinical severity and smell disruptions. Patients with one or more comorbidities reported less smell and taste disruptions and the timing of presentation differed between severe and non-severe patients. Mild and moderate patients reported an earlier onset of olfactory dysfunction. This has not been reported in previous studies even if Yan et al 19 reported that anosmia was strongly and independently associated with outpatient care. The meaning of the observation is not clear. One proposed pathophysiological mechanism of anosmia involves a bigger local inflammatory response the first days of the infection, mediated by upregulated expression of angiotensin-converting enzyme 2 (ACE2), which increases the risk of coronavirus infection, resulting in greater olfactory dysfunction but protecting against lung injury, as it was proposed in smokers 20 . In the present study, smell and taste disruptions occurred at various points during disease progression. The existence of a common syndrome associated with COVID-19 infection termed isolated sudden onset anosmia has been proposed in some studies 21 . Notably, only 2 patients in the present study reported other non-olfactory and nongustatory symptoms. Probably, exhaustive interview with simultaneous access to clinical electronic data and close follow up allowed to identify other symptoms associated. In the present study, 85.3% patients experienced a total recovery of the smell in the first two months. Smell disruption improved in the remaining patents although continue after three months suggesting that recovery will be more difficult the longer the symptom lasts. Nevertheless, the sample was relatively small and geographically limited. The method used to assess olfactory and gustatory dysfunction is not the most accurate. Ideally, an electrophysiological method or sniffing test that can quantify smell and taste acuity and accurately distinguish between olfactory and gustatory symptoms would be used. Nevertheless, such methods require direct interaction between patients and researchers and are thus impractical in patients who are isolated at home or in hospital and may be unnecessary if dysfunction can be reliably established via other patient-based methods, irrespective of significance or effects on prognosis. Although it is the longest follow-up period published, whether the persistent olfactory or gustatory disruption reported by some patients at the last interview will be permanent remains to be determined. 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