key: cord-0841079-ut6aykfq
authors: Costa, Klinger V.T. da; Carnaúba, Aline Tenório Lins; Rocha, Katianne Wanderley; Andrade, Kelly Cristina Lyra de; Ferreira, Sonia M.S.; Menezes, Pedro de L.
title: Olfactory and taste disorders in COVID-19: a systematic review()()
date: 2020-06-09
journal: Braz J Otorhinolaryngol
DOI: 10.1016/j.bjorl.2020.05.008
sha: 22b4798e5ee4d384cf31fc757e2bf3595edfb36a
doc_id: 841079
cord_uid: ut6aykfq

INTRODUCTION: The SARS-CoV-2 virus causes COVID-19, and it is responsible for the largest pandemic since the 1918 H1N1 influenza outbreak. The classic symptoms of the disease have been well defined by the World Health Organization; however, olfactory/gustatory disorders have been reported in some studies, but there are still several missing points in the understanding and in the consensus about the clinical management of these cases. OBJECTIVE: To identify evidence in the scientific literature about olfactory/gustatory disorders, their clinical presentation, prevalence and possible specific treatments associated with COVID-19. METHODS: A systematic review of articles published up to April 25, 2020 was performed in Medline, Cochrane Clinical Trials, ScienceDirect, Lilacs, Scopus and Google Schoolar, OpenGrey.eu, DissOnline, The New York Academy of Medicine and Reasearch Gate. Inclusion criteria: (1) Studies on patients with COVID-19; (2) Records of COVID-19 signs/symptoms, and olfactory/gustatory functions. Exclusion criteria: (1) Studies on non-human coronavirus; (2) Review articles; (3) Experimental studies (in animals or in vitro); (4) Olfactory/gustatory disorders initiated prior to SARS-CoV-2 infection. The risk assessment of bias of the selected studies was performed using the Newcastle-Ottawa scale. RESULTS: Six articles from the 1788 records met the inclusion criteria and were analyzed. A total of 1457 patients of different ethnicities were assessed; of them, 885 (60.7%) and 822 (56.4%) had smell and taste disorders, respectively, with women being most often affected. There were olfactory/gustatory disorders even without nasal obstruction/rhinorrhea and beginning even before the signs/symptoms of COVID-19; the recovery of smell/taste, when it occurs, usually happened in the first two weeks after COVID-19 resolution. There is evidence that olfactory/gustatory disorders are strong predictors of infection by SARS-CoV-2, and it is possible to recommend patient isolation, as early as of the medical consultation, preventing the spread of the virus. No scientific evidence has been identified for effective treatments for any of the disorders. CONCLUSION: Olfactory/gustatory disorders may occur at varying intensities and prior to the general symptoms of COVID-19 and should be considered as part of the clinical features of COVID-19, even in mild cases. There is still no scientific evidence of specific treatments for such disorders in COVID-19 disease.

2) Registro dos sinais/sintomas da COVID-19 e das funções olfativo-gustativa. Foram critérios de exclusão: 1) Estudos sobre coronavírus não humano; 2) Artigos de revisão;

3) Estudos experimentais (em animais ou in vitro); 4) Distúrbios olfativos-gustativos iniciados previamente à infecção pelo SARS-CoV-2. A avaliação de risco de viés dos estudos selecionados foi feita por meio da escala de Newcastle-Ottawa.

Resultados: Seis artigos dos 1.788 registros foram selecionados. Um total de 1.457 pacientes de diversas etnias foi avaliado; destes, 885 (60,7%) apresentaram perda do olfato e 822 (56,4%) com perda do paladar, sendo as mulheres as mais afetadas. Os distúrbios olfativo-gustativos estiveram presentes mesmo sem obstrução nasal/rinorreia e com início mesmo antes dos sinais/sintomas clínicos da COVID-19; a recuperação do olfato/paladar, quando ocorre, geralmente se dá nas duas primeiras semanas após a resolução da doença . Há evidências que os distúrbios olfativogustativos sejam fortes preditores de infecção pelo SARS-CoV-2, podendo-se recomendar o isolamento do paciente, já a partir da consulta médica, para evitar a disseminação do vírus. Não foram identificadas evidências científicas para tratamentos eficazes para nenhum dos distúrbios.

Smell and taste are essential sensory functions both for good quality of life and for its preservation, by identifying several harmful odors and flavors. Viral Upper Respiratory Tract Infections (URTIs) can lead to Olfactory (OD) and Gustatory (GD) Disorders of varying degrees and duration, [1] which can also occur in 70% of cases caused by rhinovirus, influenza virus and parainfluenza, respiratory syncytial virus, adenovirus and the severe acute respiratory syndrome virus (SARS-CoV-2). [2] Coronavirus disease 2019 (COVID-19) became a viral pandemic that emerged from East Asia due to SARS-CoV-2. [3] In Brazil, the number of cases continues to increase, with more than 66,000 confirmed cases by the end of April 2020; [4] however, it is estimated that the number is even higher, as the number of diagnostic tests performed is still insufficient for the national demand.

In COVID-19, the most common otorhinolaryngological symptoms are coughing, sore throat and dyspnea; rhinorrhea and nasal congestion have also been found; however, there are reports of OD/GD [5, 6] and that they are present even before molecular confirmation of SARS-CoV-2 infection. [6, 7] These observations were made recently, in countries that started to perform molecular tests for COVID-19 more extensively, in which patients infected with SARS-CoV-2 reported severe OD and GD without rhinorrhea or nasal obstruction. In the beginning, COVID-19 was not suspected in some of these patients, as they did not have fever, cough or any other classic general signs/symptoms of COVID-19. The OD and GD in COVID-19 still show gaps in their understanding of both the clinical spectrum and the treatment to be proposed.

The advancement of knowledge on a specific topic can be facilitated through systematic reviews (SR), which make it possible to identify, analyze and synthesize the best scientific evidence for best clinical practices, especially in the face of new clinical scenarios such as the current COVID-19 pandemic, in that randomized controlled studies and precise recommendations for their management are not yet available. The objective of this SR is to identify evidence of current knowledge on olfactory-gustatory disorders about the clinical presentation, prevalence and possible specific treatments associated with COVID-19.

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

The creation of this Systematic Review (SR) aimed to answer the following question:

"What is the association of olfactory/gustatory disorders, including their clinical presentations and treatments, with COVID-19?", constructed with the help of the PICO strategy. This SR is in agreement with the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA)" checklist. [ York Academy of Medicine and Reasearch Gate. To prevent citation bias, there was no manual search for the included articles and specialists in the field were not contacted. [9] After the search, the references of each database were exported to the Mendeley ® program (https://www.mendeley.com/) aiming to identify all articles in duplicate, promote greater selection reliability and proceed to the eligibility criteria step. Clinical report of OD/GD with onset prior to the SARS-CoV-2 infection.

The search for the articles was carried out by two reviewers. The titles and abstracts of the retrieved articles were independently assessed by two researchers who were not blinded to the authors or the titles of journals. The full versions of the potentially eligible articles were retrieved for further evaluation and were carried out in three stages:

1. Identification and reading of titles in different electronic databases. Articles that clearly did not meet any of the inclusion or exclusion criteria were excluded.

2. Reading of the abstracts of the studies selected in the first phase. Likewise, articles that clearly did not meet any of the inclusion or exclusion criteria were excluded.

3. All studies that were not excluded in these first two stages were read in full for the selection of the ones that would be included in this Systematic Review (SR).

The main data for each article was fully collected and inserted into a database created in the Microsoft Office Excel 2010 ® software. There were no disagreements between the evaluators. A standard form for data storage was created based on the model adopted by Cochrane. [10] For a better presentation of the results, it was decided to consider the following variables of the selected articles: Title, author, study location, study design, sample size (N), patients' mean age and ethnicity, both the diagnostic method and the most prevalent general signs/symptoms and the severity of the clinical picture of COVID-19, methods used in the olfactory-gustatory evaluation and the prevalence of OD and GD. The outcomes sought in the studies were both the demographic data, prevalence and clinical expressions of OD/GD, as well as possible specific treatments for such disorders in patients diagnosed with COVID-19.

The risk of bias was assessed according to the recommendations in the manual and the Newcastle-Ottawa scale adapted for cross-sectional observational studies. [11] Study J o u r n a l P r e -p r o o f quality was independently assessed by two researchers and the divergences were evaluated by consensus. The maximum score to be achieved was 10 points and the items evaluated on the scale were: 1) Representativeness of the sample; 2) Sample size;

3) Characterization of the diagnosis; 4) Risk exposure assessment (risk factor); 5) Comparability, to investigate whether individuals in different groups of results are comparable, based on the study design or analysis, control of confounding factors; 6) Evaluation of results and 7) Statistical test (Table 1) .

After these evaluations, the selected studies were submitted to a statistical analysis to verify the possibility of building a meta-analysis. This analysis combines and summarizes the results of several studies, thus increasing the accuracy and power of evidence of the results.

In the first phase of this SR, 1,788 articles were found in six databases and none in the gray literature. After eliminating 1,023 studies in duplicate, 765 were selected for the reading of titles and abstracts. A total of 749 were excluded according to the established selection criteria (62 studies on non-human coronavirus, 301 due to lack of data on clinical aspects, 375 literature reviews and 11 experimental studies in vitro) and 16 articles were selected to be read in full. After the reading, 10 articles were excluded as they did not have data on smell/taste (Table 2) . Therefore, six full articles were included in the qualitative analysis ( Table 3 ). The entire article selection process is described in Figure 1 , which shows the Prisma flow diagram for inclusion.

The analysis of the quality of the included articles and, consequently, of the risk of bias, is shown in Table 4 . All included studies are characterized as observational and crosssectional studies. Moreover, in the final evaluation, all obtained a percentage of quality equal to or greater than 80% (8/10), and four of the six articles obtained the maximum score of 90% (9/10).

Only one of the studies carried out a census study, the other studies did not perform a random selection of patients, which compromises the representativeness of the samples, but took into account the sample size.

All studies were concerned with the participants' selection, defining the inclusion and exclusion criteria, in order to exclude factors that could influence the results found.

The size of the studied samples was adequate to the central limit theorem for all studies, and only two studies had samples smaller than 300 subjects.

The characterization of the diagnosis and the determination of exposure were very well described in all studies. All studies controlled at least one variable, allowing an efficient comparison among all studies.

The evaluation of the results was carried out in all studies through a specific report and the methods were described and validated in all studies.

Finally, all studies showed appropriate statistical tests, with description of the statistical tests, the levels of significance and the applications used.

It was not possible to perform a meta-analysis in this SR because the articles included had very different methodologies and measures resulting from the tests.

Regarding the overall characteristics of the included articles (Table 3) , the six studies were published in 2020, one in China, [12] one in Europe, [13] one in Iran, [14] two in the United States [15, 16] and one in the United Kingdom. [17] The Chinese study (Mao et al.) [12] retrospectively evaluated 214 patients from three hospitals in Wuhan;

the European study (Lechien et al.) [13] cross-sectionally evaluated 417 patients in a multicentric model; the Iranian study (Moein et al.) [14] studied 60 patients with COVID-19 and 60 subjects in the control group, matched for age and gender; the two North-American studies were carried out by the same group of researchers (Yan et al.) ; [15, 16] while the British study (Menni et al.) [17] evaluated, through a census study, 579 COVID-19 positive and 1123 COVID-19 negative patients. The demographic data, general symptoms and the prevalence of OD and GD in patients in the six studies are depicted in Table 5 .

In total, the six studies evaluated 1,457 patients (Table 3 ). In the study by Mao et al., [12] the sample consisted only of Chinese patients; in the study by Lechien et al., [13] most of the sample consisted of European patients; in the study by Moein et al., [14] all patients were Iranians; in the two studies by Yann et al., [15, 16] most patients were North-American; and in the study by Menni et al., [17] the ethnicity of the study participants was not recorded.

The exam used for diagnosing COVID-19 in the six studies was the RT-PCR (Real-Time Reverse-Transcription Polymerase Chain Reaction). Regarding the most prevalent overall signs/symptoms of COVID-19, there were differences between groups; fever was the most prevalent sign in the studies by Mao et al. [12] and by Moein et al.; [14] fatigue was the first symptom in the first study by Yan et al. [15] and of Menni et al.; [17] coughing was the first sign in the second study by Yan et al. [16] and in the study by Lechien et al. [13] (Table 5) .

Mao et al. [12] carried out the study at three hospitals designated for the care of patients with OD reported that the disorder started at the same time or immediately after the onset of the signs/symptoms of COVID-19. There were no detailed data on the type of gustatory disorder or specific treatments for OD/GD in the studied sample.

In their first study, Yan et al. [15] 

The current SR was designed to identify evidence in the scientific literature about both olfactory/gustatory disorders in relation to the clinical presentation, prevalence and possible specific treatments associated with COVID-19.

The six studies showed different prevalence rates for OD and GD. The study with the greatest divergence from the others regarding the prevalence of OD and GD was the Chinese study by Mao et al., [12] in which the prevalence of OD was 19 times lower than in the study by Moein et al. [14] and 14 times lower than in the study by Lechien et al. [13] These differences can be explained by two possibilities: 1) The study J o u r n a l P r e -p r o o f models, because while the Chinese study, with lower prevalence rates of OD and GD, was based only on data from medical records in which gustatory/olfactory complaints may have been neglected, while the other studies used tools aimed at assessing smell and taste; 2) Chinese patients, in fact, had few olfactory-gustatory complaints.

We observed that in the Chinese, Iranian and North-American studies, the mean age was older than in European studies; such divergence can be explained by the sample composition regarding the severity of COVID-19, since the Asian and North-American studies had patients with the severe form of the disease, more common in older patients and those with comorbidities, [19] [20] [21] [22] while in the European groups there were only mild to moderate cases.

The clinical behavior of OD and GD varied in several aspects: it was observed that anosmia was the most prevalent OD and its onset can occur even before the symptoms/signs of COVID-19. There is evidence that loss of smell may not only be a clinical marker for SARS-CoV-2 infection but can also help to stratify the degree of illness at the onset of infection. Considering the difficulties in terms of public health for the performance and acquisition of results in a timely manner by RT-PCR, the evaluation of these disorders in times of COVID-19 pandemic can be useful to guide immediate isolation, even before having access to the test result, favoring the prevention of the dissemination of the virus. A opposed to OD that occurs with other viral infections, OD in most patients with COVID-19 was not associated with nasal obstruction or rhinorrhea. OD recovery occurs, in most cases, within the first two weeks, while only 3.3% manage to recover their sense of smell/taste after this period and it is not yet known whether the others who persist with OD can recover their sense of smell in the long term. The olfactory neuroepithelium has considerable regenerative capacity, leading to spontaneous improvement of smell, at varying degrees, over time [23] if the stem cell layer is not markedly damaged. [24] [25] [26] Regarding the GD, detailed information was not found; however, the association of GDs with ODs was significant, and the recovery of taste depended on the recovery of the smell. have already been observed, [27] and can modify the biological behavior of the virus in relation to tissue affinity. [20] The Angiotensin-Converting Enzyme 2 (ACE2) acts as a receptor for SARS-CoV-2, especially in the olfactory bulb, [28] so that some of its variants observed in different ethnicities could reduce its ability to receive the virus S protein by modifying its susceptibility, symptoms and clinical outcomes; [29] there are relatively high expressions of ACE2 and transmembrane serine protease 2 (TMPRSS2) in the human olfactory epithelium; [30] the non-neuronal expression of ACE2/ TMPRSS2 may possibly make the olfactory epithelium a reservoir of viruses. [30] The expression of TMPRSS2 seems to be higher compared to that of ACE2 and occurs in both neurons and non-neuronal cells in the olfactory epithelium and with a mosaic pattern, suggesting that some olfactory neurons may be more vulnerable to viral infection. [31, 32] Regarding specific treatments, there was no evidence of specific drugs that were effective for the recovery of olfactory/gustatory functions. Nasal lavage was predominant in the studied groups. There is evidence that OD/GD are strong predictors of infection by SARS-CoV-2, and it is possible to recommend the isolation of the patient as of the medical consultation and still without the result of the laboratory test, to prevent the dissemination of the virus.

The recovery of smell/taste, when it occurs, usually does so within the first two weeks after the resolution of COVID-19. No scientific evidence has been identified for effective treatments for any of the disorders.

The studies have shown that both olfactory and gustatory disorders of varying intensities and in which onset occurred prior to the general symptoms of SARS-CoV-2 infection may occur, and such disorders should be considered as part of the symptoms that may be present, even in mild cases of COVID-19. There is still no scientific evidence of specific treatments for such disorders in COVID-19. Table 1 The Newcastle-Ottawa scale adapted for cross-sectional observational studies. 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 

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CoV-2 OR sars coronavirus OR coronavirus OR coronavirus infection OR coronavirus COVID-19 OR novel coronavirus) AND (COVID-19 clinical features OR olfactory disorders OR olfaction disorders OR taste disorders)

Science Direct (COVID-19 OR 2019-nCoV OR 2019 novel coronavirus pneumonia OR SARS-CoV OR SARS

CoV-2 OR sars coronavirus OR coronavirus OR coronavirus infection OR coronavirus COVID-19 OR novel coronavirus) AND (COVID-19 clinical features OR olfactory disorders OR olfaction disorders OR taste disorders) FILTERS: (YEAR 2019-2020)

SCOPUS (COVID-19 OR 2019-nCoV OR 2019 novel coronavirus pneumonia OR SARS-CoV OR SARS

CoV-2 OR sars coronavirus OR coronavirus OR coronavirus infection OR coronavirus COVID-19 OR novel coronavirus) AND (COVID-19 clinical features OR olfactory disorders OR olfaction disorders OR taste disorders)

COVID-19 OR 2019-nCoV OR 2019 novel coronavirus pneumonia OR SARS-CoV OR SARS

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The authors declare no conflicts of interest.