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Smell and Taste Dysfunction in Patients With COVID-19: A Systematic Review and Meta-analysis

      Abstract

      Objective

      To estimate the prevalence of olfactory and gustatory dysfunctions (OGDs) among patients infected with novel coronavirus disease 2019 (COVID-19).

      Methods

      A systematic review was conducted by searching MEDLINE, EMBASE, and the preprint server MedRxiv from their inception until May 11, 2020, using the terms anosmia or hyposmia or dysosmia or olfactory dysfunction or olfaction disorder or smell dysfunction or ageusia or hypogeusia or dysgeusia or taste dysfunction or gustatory dysfunction or neurological and COVID-19 or 2019 novel coronavirus or 2019-nCoV or SARS-CoV-2. The references of included studies were also manually screened. Only studies involving patients with diagnostic-confirmed COVID-19 infection were included. Random-effects meta-analysis was performed.

      Results

      Twenty-four studies with data from 8438 patients with test-confirmed COVID-19 infection from 13 countries were included. The pooled proportions of patients presenting with olfactory dysfunction and gustatory dysfunction were 41.0% (95% CI, 28.5% to 53.9%) and 38.2% (95% CI, 24.0% to 53.6%), respectively. Increasing mean age correlated with lower prevalence of olfactory (coefficient = −0.076; P=.02) and gustatory (coefficient = −0.073; P=.03) dysfunctions. There was a higher prevalence of olfactory dysfunctions with the use of objective measurements compared with self-reports (coefficient = 2.33; P=.01). No significant moderation of the prevalence of OGDs by sex was observed.

      Conclusion

      There is a high prevalence of OGDs among patients infected with COVID-19. Routine screening for these conditions could contribute to improved case detection in the ongoing COVID-19 pandemic. However, to better inform population screening measures, further studies are needed to establish causality.

      Abbreviations and Acronyms:

      AAO-HNS (American Academy of Otolaryngology–Head and Neck Surgery), CCCRC (Connecticut Chemosensory Clinical Research Center), COVID-19 (novel coronavirus disease 2019), NHANES (National Health and Nutrition Examination Survey), NR (not reported), OGD (olfactory and gustatory dysfunction), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), UPSIT (University of Pennsylvania Smell Identification Test)
      Novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an outbreak that emerged in China in December 2019, has rapidly evolved into a global pandemic.
      Worldometers. COVID-19 coronavirus pandemic. 2020.
      To contain the outbreak, effective screening, rapid diagnosis, and isolation of infected individuals are essential. These measures require sound understanding of the clinical presentation of the disease. Early observations in China revealed several nonspecific signs and symptoms related to COVID-19 infection, including fever, dry cough, dyspnea, myalgia, and anorexia.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Chen N.
      • Zhou M.
      • Dong X.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      Recently, an association between COVID-19 and olfactory and gustatory dysfunctions (OGDs) has been raised.
      • Lechien J.R.
      • Hopkins C.
      • Saussez S.
      Sniffing out the evidence; it's now time for public health bodies recognize the link between COVID-19 and smell and taste disturbance.
      In the United Kingdom, a surge in patients seeking medical advice for recent onset of self-diagnosed loss of sense of smell has been reported.
      • Hopkins C.
      • Surda P.
      • Kumar N.
      Presentation of new onset anosmia during the COVID-19 pandemic.
      Similarly, an outbreak of olfactory dysfunctions in Iran was observed.
      • Bagheri S.
      • Asghari A.
      • Farhadi M.
      • et al.
      Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak [preprint posted March 27, 2020]. MedRxiv.
      Furthermore, Walker et al
      • Walker A.
      • Hopkins C.
      • Surda P.
      The use of Google trends to investigate the loss of smell related searches during COVID-19 outbreak [published online ahead of print April 11, 2020]. Int Forum Allergy Rhinol.
      have noted an increase in Internet searches for smell-related information in several countries and hypothesize that smell dysfunction may be an under-recognized symptom of COVID-19 infection. Consequently, the British Association of Otorhinolaryngology
      ENTUK
      Loss of sense of smell as a marker of COVID-19 infection. 2020.
      and the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS)
      American Academy of Otolaryngology–Head And Neck Surgery
      AAO-HNS: Anosmia, hyposmia, and dysgeusia symptoms of coronavirus disease. 2020.
      proposed that symptoms of OGDs be added to the list of screening tools for possible COVID-19 infection. Nevertheless, the proportion and characteristics of patients infected with COVID-19 who experience OGDs are not thoroughly understood.
      Thus, we conducted a systematic review and meta-analysis to estimate the prevalence of OGDs among patients infected with COVID-19. We also examined the potential effects of factors such as age, sex, and assessment method on the prevalence of OGDs. At the time of commencing this review (May 3, 2020), no systematic review and meta-analysis on the topic had been published.

      Methods

      This systematic review follows the recommendations outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      and the Cochrane collaboration handbook
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019.
      (Supplemental Table 1, available online at http://www.mayoclinicproceedings.org). Given the urgent need for information to inform clinical decision making in the context of the COVID-19 pandemic, prior registration of the review protocol was not feasible.

       Database Search

      To identify appropriate studies for the review, searches were performed in MEDLINE, EMBASE, and the preprint server MedRxiv using the terms anosmia or hyposmia or dysosmia or olfactory dysfunction or olfaction disorder or smell dysfunction or ageusia or hypogeusia or dysgeusia or taste dysfunction or gustatory dysfunction or neurological and COVID-19 or 2019 novel coronavirus or 2019-nCoV or SARS-CoV-2 (Supplemental Table 2, available online at http://www.mayoclinicproceedings.org). The search was initially performed on May 3, 2020, and last updated on May 11, 2020. No language restrictions were applied. The reference lists of included studies were also hand-searched for additional articles.

       Study Selection and Evaluation

      Only studies with data for patients with test-confirmed COVID-19 status were eligible for inclusion. Moreover, because our objective was to estimate the prevalence of smell and taste dysfunctions separately, studies that reported a composite of smell and taste dysfunction without presenting individual data for each outcome were excluded. When studies from the same center recruiting patients during the same period were present, we selected the one with the larger sample size or more detailed information. Furthermore, we excluded case series involving fewer than 10 patients, as well as commentaries, editorials, and reviews.

       Quality Assessment

      The methodological quality of each study was assessed using a tool developed by Murad et al.
      • Murad M.H.
      • Sultan S.
      • Haffar S.
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.
      This tool involves 8 items under 4 domains: selection, ascertainment, causality, and reporting (Supplemental Table 3, available online at http://www.mayoclinicproceedings.org). Only items applicable to the studies included in the review were evaluated. Numeric scoring was not performed and an overall judgment about methodological quality of the included studies was made as per the questions deemed most critical in the specific clinical scenario.
      • Murad M.H.
      • Sultan S.
      • Haffar S.
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.

       Data Extraction and Analysis

      Data were extracted independently by 2 reviewers (A.A.A. and R.O.-A.), and any disagreements were resolved through consensus. For each study, first author name, country, participant mean age, proportion of females, and percentage with smell or taste disorders were extracted. If a study assessed OGDs based on patients’ self-report and objective measurements, we prioritized the data from the objective assessments.
      Analyses were conducted using Stata SE software, version 16 (StataCorp). Meta-analysis of prevalence was conducted using the STATA Metaprop command,
      • Nyaga V.N.
      • Arbyn M.
      • Aerts M.
      Metaprop: a Stata command to perform meta-analysis of binomial data.
      using the Freeman-Tukey double arcsine transformed proportions to account for variance instability.
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019.
      Owing to the anticipated between-study heterogeneity, a random-effects model was used. Between-study heterogeneity was quantified using the I2 statistic.
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019.
      An I2>50% was considered to represent substantial heterogeneity. Leave-1-out sensitivity analyses were performed to assess the stability of pooled estimates. Using the STATA Metareg command,
      • Harbord R.
      • Higgins J.
      Meta-regression in Stata.
      meta-regression was conducted to determine the influence of study mean age, proportion of females, assessment method (subjective vs objective), and region of study (Europe vs other) on the pooled prevalence. The syntax for the metaregression was “Metareg logitEventRate age [proportion of females] region [assessment method], wsse(logitEventSE),” where logitEventRate=log(p/(1 − p)) and logitEventSE=[sqrt(1/(p×Total) + 1/((1 − p)×Total))], and p indicates proportion and Total indicates sample size. A 2-tailed P<.05 was considered significant. Because our study relied on published literature, institutional ethical review was not required.

      Results

       Study Characteristics

      The searches in MEDLINE and EMBASE retrieved 341 citations. Following removal of duplicates and screening of titles and abstracts, 52 articles were selected for full-text evaluation. Fifteen articles were retained after full-text assessment. Nine additional studies were identified from the preprint server, resulting in 24 studies being included in the review (Figure 1).
      • Tostmann A.
      • Bradley J.
      • Bousema T.
      • et al.
      Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020.
      • Giacomelli A.
      • Pezzati L.
      • Conti F.
      • et al.
      Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study [published online ahead of print March 26, 2020]. Clin Infect Dis.
      • Bénézit F.
      • Le Turnier P.
      • Declerck C.
      • et al.
      Utility of hyposmia and hypogeusia for the diagnosis of COVID-19 [published online ahead of print April 15, 2020]. Lancet Infect Dis.
      • Klopfenstein T.
      • Kadiane-Oussou N.J.
      • Toko L.
      • et al.
      Features of anosmia in COVID-19 [published online ahead of print April 17, 2020]. Med Mal Infect.
      • Tomlins J.
      • Hamilton F.
      • Gunning S.
      • Sheehy C.
      • Moran E.
      • MacGowan A.
      Clinical features of 95 sequential hospitalised patients with novel coronavirus 2019 disease (COVID-19), the first UK cohort [published online ahead of print April 27, 2020]. J Infect.
      • Luers J.C.
      • Rokohl A.C.
      • Loreck N.
      • et al.
      Olfactory and gustatory dysfunction in coronavirus disease 19 (COVID-19) [published online ahead of print May 1, 2020]. Clin Infect Dis.
      • Yan C.H.
      • Faraji F.
      • Prajapati D.P.
      • Ostrander B.T.
      • DeConde A.S.
      Self-reported olfactory loss associates with outpatient clinical course in COVID-19 [published online ahead of print April 24, 2020]. Int Forum Allergy Rhinol.
      • Chico-García J.L.
      • Martínez-Poles J.
      • et al.
      Beltrán-Corbellini Á
      Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study [published online ahead of print April 22, 2020]. Eur J Neurol.
      • Moein S.T.
      • Hashemian S.M.R.
      • Mansourafshar B.
      • Khorram-Tousi A.
      • Tabarsi P.
      • Doty R.L.
      Smell dysfunction: a biomarker for COVID-19 [published online ahead of print April 17, 2020]. Int Forum Allergy Rhinol.
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China [published online ahead of print April 10, 2020]. JAMA Neurol.
      • Levinson R.
      • Elbaz M.
      • Ben-Ami R.
      • Shasha D.
      • Levinson T.
      • Choshen G.
      Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection [preprint posted April 14, 2020]. MedRxiv.
      • Fontanet A.
      • Tondeur L.
      • Madec Y.
      • et al.
      Cluster of COVID-19 in northern France: a retrospective closed cohort study [preprint posted April 23, 2020]. MedRxiv.
      • Vaira L.A.
      • Deiana G.
      • Fois A.G.
      • et al.
      Objective evaluation of anosmia and ageusia in COVID-19 patients: single-center experience on 72 cases.
      • Lechien J.R.
      • Chiesa-Estomba C.M.
      • Place S.
      • et al.
      Clinical and epidemiological characteristics of 1,420 European patients with mild-to-moderate coronavirus disease 2019 [published online ahead of print April 30, 2020]. J Intern Med.
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      • Lee Y.
      • Min P.
      • Lee S.
      • Kim S.W.
      Prevalence and duration of acute loss of smell or taste in COVID-19 patients.
      • Hornuss D.
      • Lange B.
      • Schröter N.
      • Rieg S.
      • Kern W.
      • Wagner D.
      Anosmia in COVID-19 patients [preprint posted May 3, 2020]. Medrxiv.
      • Just J.
      • Puth M.
      • Regenold F.
      • Weckbecker K.
      • Bleckwenn M.
      Distinguishing between COVID-19 and the common cold in a primary care setting - comparison of patients with positive and negative SARS-CoV-2 PCR results [preprint posted May 5, 2020]. MedRxiv.
      • Lechien J.
      • Cabaraux P.
      • Chiesa-Estomba C.
      • et al.
      Psychophysical olfactory findings of mild-to-moderate COVID-19 patients: preliminary report [preprint posted May 6, 2020]. MedRxiv.
      • Borobia A.
      • Carcas A.
      • Arnalich F.
      • et al.
      A cohort of patients with COVID-19 in a major teaching hospital in Europe [preprint posted May 6, 2020]. MedRxiv.
      • Cavagna L.
      • Bruno R.
      • Zanframundo G.
      • et al.
      Clinical presentation and evolution of COVID-19 in immunosuppressed patients. Preliminary evaluation in a North Italian cohort on calcineurin-inhibitors based therapy [preprint posted May 1, 2020]. MedRxiv. 2020.
      • Härter G.
      • Spinner C.
      • Roider J.
      • et al.
      COVID-19 in people living with human immunodeficiency virus: a case series of 33 patients [preprint posted May 1, 2020]. MedRxiv.
      • Allenbach Y.
      • Saadoun D.
      • Maalouf G.
      • et al.
      Multivariable prediction model of intensive care unit transfer and death: a French prospective cohort study of COVID-19 patients [preprint posted May 8, 2020]. MedRxiv.
      • Vaira L.A.
      • Salzano G.
      • Petrocelli M.
      • Deiana G.
      • Salzano F.A.
      • De Riu G.
      Validation of a self-administered olfactory and gustatory test for the remotely evaluation of COVID-19 patients in home quarantine [published online ahead of print May 1, 2020]. Head Neck.
      The included studies were from China (n=1),
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China [published online ahead of print April 10, 2020]. JAMA Neurol.
      the Netherlands (n=1),
      • Tostmann A.
      • Bradley J.
      • Bousema T.
      • et al.
      Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020.
      United Kingdom (n=1),
      • Tomlins J.
      • Hamilton F.
      • Gunning S.
      • Sheehy C.
      • Moran E.
      • MacGowan A.
      Clinical features of 95 sequential hospitalised patients with novel coronavirus 2019 disease (COVID-19), the first UK cohort [published online ahead of print April 27, 2020]. J Infect.
      Iran (n=1),
      • Moein S.T.
      • Hashemian S.M.R.
      • Mansourafshar B.
      • Khorram-Tousi A.
      • Tabarsi P.
      • Doty R.L.
      Smell dysfunction: a biomarker for COVID-19 [published online ahead of print April 17, 2020]. Int Forum Allergy Rhinol.
      Israel (n=1),
      • Levinson R.
      • Elbaz M.
      • Ben-Ami R.
      • Shasha D.
      • Levinson T.
      • Choshen G.
      Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection [preprint posted April 14, 2020]. MedRxiv.
      South Korea (n=1),
      • Lee Y.
      • Min P.
      • Lee S.
      • Kim S.W.
      Prevalence and duration of acute loss of smell or taste in COVID-19 patients.
      United States (n=2),
      • Yan C.H.
      • Faraji F.
      • Prajapati D.P.
      • Ostrander B.T.
      • DeConde A.S.
      Self-reported olfactory loss associates with outpatient clinical course in COVID-19 [published online ahead of print April 24, 2020]. Int Forum Allergy Rhinol.
      ,
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      France (n=4),
      • Bénézit F.
      • Le Turnier P.
      • Declerck C.
      • et al.
      Utility of hyposmia and hypogeusia for the diagnosis of COVID-19 [published online ahead of print April 15, 2020]. Lancet Infect Dis.
      ,
      • Klopfenstein T.
      • Kadiane-Oussou N.J.
      • Toko L.
      • et al.
      Features of anosmia in COVID-19 [published online ahead of print April 17, 2020]. Med Mal Infect.
      ,
      • Fontanet A.
      • Tondeur L.
      • Madec Y.
      • et al.
      Cluster of COVID-19 in northern France: a retrospective closed cohort study [preprint posted April 23, 2020]. MedRxiv.
      ,
      • Allenbach Y.
      • Saadoun D.
      • Maalouf G.
      • et al.
      Multivariable prediction model of intensive care unit transfer and death: a French prospective cohort study of COVID-19 patients [preprint posted May 8, 2020]. MedRxiv.
      Germany (n=4),
      • Luers J.C.
      • Rokohl A.C.
      • Loreck N.
      • et al.
      Olfactory and gustatory dysfunction in coronavirus disease 19 (COVID-19) [published online ahead of print May 1, 2020]. Clin Infect Dis.
      ,
      • Hornuss D.
      • Lange B.
      • Schröter N.
      • Rieg S.
      • Kern W.
      • Wagner D.
      Anosmia in COVID-19 patients [preprint posted May 3, 2020]. Medrxiv.
      ,
      • Just J.
      • Puth M.
      • Regenold F.
      • Weckbecker K.
      • Bleckwenn M.
      Distinguishing between COVID-19 and the common cold in a primary care setting - comparison of patients with positive and negative SARS-CoV-2 PCR results [preprint posted May 5, 2020]. MedRxiv.
      ,
      • Härter G.
      • Spinner C.
      • Roider J.
      • et al.
      COVID-19 in people living with human immunodeficiency virus: a case series of 33 patients [preprint posted May 1, 2020]. MedRxiv.
      Italy (n=4),
      • Giacomelli A.
      • Pezzati L.
      • Conti F.
      • et al.
      Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study [published online ahead of print March 26, 2020]. Clin Infect Dis.
      ,
      • Vaira L.A.
      • Deiana G.
      • Fois A.G.
      • et al.
      Objective evaluation of anosmia and ageusia in COVID-19 patients: single-center experience on 72 cases.
      ,
      • Cavagna L.
      • Bruno R.
      • Zanframundo G.
      • et al.
      Clinical presentation and evolution of COVID-19 in immunosuppressed patients. Preliminary evaluation in a North Italian cohort on calcineurin-inhibitors based therapy [preprint posted May 1, 2020]. MedRxiv. 2020.
      ,
      • Vaira L.A.
      • Salzano G.
      • Petrocelli M.
      • Deiana G.
      • Salzano F.A.
      • De Riu G.
      Validation of a self-administered olfactory and gustatory test for the remotely evaluation of COVID-19 patients in home quarantine [published online ahead of print May 1, 2020]. Head Neck.
      Spain (n=2),
      • Chico-García J.L.
      • Martínez-Poles J.
      • et al.
      Beltrán-Corbellini Á
      Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study [published online ahead of print April 22, 2020]. Eur J Neurol.
      ,
      • Borobia A.
      • Carcas A.
      • Arnalich F.
      • et al.
      A cohort of patients with COVID-19 in a major teaching hospital in Europe [preprint posted May 6, 2020]. MedRxiv.
      Belgium (n=1),
      • Lechien J.
      • Cabaraux P.
      • Chiesa-Estomba C.
      • et al.
      Psychophysical olfactory findings of mild-to-moderate COVID-19 patients: preliminary report [preprint posted May 6, 2020]. MedRxiv.
      and 1 multicountry study across Europe (France, Spain, Italy, Belgium, and Switzerland).
      • Lechien J.R.
      • Chiesa-Estomba C.M.
      • Place S.
      • et al.
      Clinical and epidemiological characteristics of 1,420 European patients with mild-to-moderate coronavirus disease 2019 [published online ahead of print April 30, 2020]. J Intern Med.
      The studies involved a total of 8438 patients. The reported mean age ranged from 34.0 to 77.0 years, and 58.7% (4785 of 8150; 20 studies) of the patients were females (Table).
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart of study selection process.
      TableCharacteristics of Included Studies
      Reference, yearCountriesOGD Assessment MethodSample SizeMean Age (y)Female (%)Olfactory Dysfunction, n (%)Gustatory Dysfunction, n (%)
      Tostmann et al,
      • Tostmann A.
      • Bradley J.
      • Bousema T.
      • et al.
      Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020.
      2020
      NetherlandsSelf-report (questionnaire)79NRNR37/79 (46.8)NR
      Giacomelli et al,
      • Giacomelli A.
      • Pezzati L.
      • Conti F.
      • et al.
      Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study [published online ahead of print March 26, 2020]. Clin Infect Dis.
      2020
      Italy (Milan)Self-report (interview)5960.032.214/59 (23.7)17/59 (28.8)
      Bénézit et al,
      • Bénézit F.
      • Le Turnier P.
      • Declerck C.
      • et al.
      Utility of hyposmia and hypogeusia for the diagnosis of COVID-19 [published online ahead of print April 15, 2020]. Lancet Infect Dis.
      2020
      France (Western)Self-report (questionnaire)68NRNR31/68 (45.6)42/68 (61.8)
      Klopfenstein et al,
      • Klopfenstein T.
      • Kadiane-Oussou N.J.
      • Toko L.
      • et al.
      Features of anosmia in COVID-19 [published online ahead of print April 17, 2020]. Med Mal Infect.
      2020
      France (Eastern)Self-report (medical files)114NRNR54/114 (47.4)NR
      Tomlins et al,
      • Tomlins J.
      • Hamilton F.
      • Gunning S.
      • Sheehy C.
      • Moran E.
      • MacGowan A.
      Clinical features of 95 sequential hospitalised patients with novel coronavirus 2019 disease (COVID-19), the first UK cohort [published online ahead of print April 27, 2020]. J Infect.
      2020
      UK (Bristol)Self-report (admission records)9575.0373/95 (3.2)NR
      Luers et al,
      • Luers J.C.
      • Rokohl A.C.
      • Loreck N.
      • et al.
      Olfactory and gustatory dysfunction in coronavirus disease 19 (COVID-19) [published online ahead of print May 1, 2020]. Clin Infect Dis.
      2020
      Germany (Cologne)Self-report (questionnaire)7238.043.153/72 (73.6)50/72 (6.4)
      Yan et al,
      • Yan C.H.
      • Faraji F.
      • Prajapati D.P.
      • Ostrander B.T.
      • DeConde A.S.
      Self-reported olfactory loss associates with outpatient clinical course in COVID-19 [published online ahead of print April 24, 2020]. Int Forum Allergy Rhinol.
      2020
      US (California)Self-report (medical files or telephone interview)Admitted = 26

      Ambulatory = 102
      Admitted = 53.5

      Ambulatory = 43.0
      Admitted = 65.4

      Ambulatory = 49.0
      Admitted = 7/26 (26.9)

      Ambulatory = 68/102 (66.7)
      Admitted = 6/26 (23.1)

      Ambulatory = 64/102 (62.7)
      Beltrán-Corbellini et al,
      • Chico-García J.L.
      • Martínez-Poles J.
      • et al.
      Beltrán-Corbellini Á
      Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study [published online ahead of print April 22, 2020]. Eur J Neurol.
      2020
      Spain (Madrid)Self-report (questionnaire)7961.639.225/79 (31.6)28/79 (35.4)
      Moein et al,
      • Moein S.T.
      • Hashemian S.M.R.
      • Mansourafshar B.
      • Khorram-Tousi A.
      • Tabarsi P.
      • Doty R.L.
      Smell dysfunction: a biomarker for COVID-19 [published online ahead of print April 17, 2020]. Int Forum Allergy Rhinol.
      2020
      IranObjective measurement (UPSIT microencapsulation test)6046.633.359/60 (98.3)NR
      Mao et al,
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China [published online ahead of print April 10, 2020]. JAMA Neurol.
      2020
      China (Wuhan)Self-report (interview)21452.759.311/214 (5.1)12/214 (5.6)
      Levinson et al,
      • Levinson R.
      • Elbaz M.
      • Ben-Ami R.
      • Shasha D.
      • Levinson T.
      • Choshen G.
      Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection [preprint posted April 14, 2020]. MedRxiv.
      2020
      Israel (Tel Aviv)Self-report (questionnaire)4234.045.214/42 (33.3)15/42 (35.7)
      Fontanet et al,
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      CCCRC = Connecticut Chemosensory Clinical Research Center; NHANES = National Health and Nutrition Examination Survey; NR = not reported; OGD = olfactory and gustatory dysfunction; UPSIT = University of Pennsylvania Smell Identification Test.
      The methodological assessment of the individual studies is presented in Supplemental Table 4 (available online at http://www.mayoclinicproceedings.org). Because our review included only patients with COVID-19 infection with diagnostic confirmation, bias from nonascertainment of exposure was minimized. However, very few studies had reported use of objective assessment of OGDs, with most relying on unvalidated questionnaires. Thus, studies may experience ascertainment bias. Most studies (20/24; 83%) did not explore other potential causes that may explain the outcome, and they could not establish with certainty that OGDs were absent before COVID-19 infection and therefore causality cannot be implied.

       Olfactory Dysfunctions

      Of the 24 studies that reported the prevalence of olfactory dysfunction, 21% (5/24) used objective assessments, whereas the rest (19/24; 79%) mainly relied on self-reports. The reported prevalence of olfactory dysfunction ranged from 3.2% to 98.3%, and the pooled prevalence was 41.0% (95% CI, 28.5% to 53.9%; I2=99.1%; Figure 2). A leave-1-out sensitivity analysis did not significantly change the results (point estimate ranged from 38.1% to 42.1%). The pooled prevalence tended to decrease with increasing mean age of study participants (coefficient = −0.076; 95% CI, −0.135 to −0.016; P=.02) and was higher when objective measurements were used compared with self-reports (coefficient = 2.33; 95% CI, 0.57 to 4.09; P=.01) but was not significantly moderated by sex (coefficient = −0.018; 95% CI, −0.062 to 0.026; P=.39) or study region (coefficient = 0.564; 95% CI, −0.818 to 1.946; P=.40). The variables included in the metaregression altogether explained 51.7% of the between-study variance relative to the prevalence of olfactory dysfunctions. There was no strong evidence of publication bias (funnel plot, Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org; Eggers test, P=.306).
      Figure thumbnail gr2
      Figure 2Forest plot of proportion of patients with novel coronavirus disease 2019 infection presenting with olfactory dysfunction. ES = proportion; n = number of patients with olfactory dysfunction; N = sample size.

       Gustatory Dysfunctions

      Fifteen studies involving 5649 patients reported the prevalence of gustatory dysfunctions. Among these, 13% (2/15) used objective assessments, whereas the rest (13/15; 87%) relied mainly on self-reports. The reported prevalence of gustatory dysfunctions ranged from 5.6% to 62.7%, and the pooled prevalence was 38.2% (95% CI, 24.0% to 53.6%; I2=98.8; Figure 3). A leave-1-out sensitivity analysis did not significantly change the results (point estimate ranged from 36.1% to 41.2%). The pooled prevalence tended to decrease with increasing mean age (coefficient = −0.073; 95% CI, −0.136 to −0.009; P=.03) and was slightly higher across European studies than studies from elsewhere (coefficient = 1.195; 95% CI, 0.118 to 2.272; P=.03). There was no significant moderation by sex (coefficient = −0.022; 95% CI, −0.066 to 0.022; P=.29) or assessment methods (coefficient = 0.439; 95% CI, −1.192 to 2.071; P=.56). The variables included in the metaregression altogether explained 47.9% of the between-study variance relative to the prevalence of gustatory dysfunctions. There was no strong evidence of publication bias (funnel plot, Supplemental Figure 2, available online at http://www.mayoclinicproceedings.org; Eggers test, P=.604).
      Figure thumbnail gr3
      Figure 3Forest plot of proportion of patients with novel coronavirus disease 2019 infection presenting with gustatory dysfunction. ES = proportion; n = number of patients with gustatory dysfunction; N = sample size.

      Discussion

      In this systematic review and meta-analysis, we found that about 41% and 38% of diagnostic-confirmed patients with COVID-19 infection presented with olfactory or gustatory dysfunctions, respectively. Increasing age correlated with lower prevalence of OGDs, whereas the use of objective assessment methods correlated with higher prevalence of olfactory dysfunction. No significant moderation of the prevalence of OGDs by sex was noted.
      The exact mechanisms underlying OGDs among patients with COVID-19 infection remain unclear. However, olfactory impairment after upper respiratory tract infection is a common occurrence in clinical settings. In particular, postviral olfactory dysfunction has been implicated in 40% of cases of anosmia in adults,
      • Welge-Lüssen A.
      • Wolfensberger M.
      Olfactory disorders following upper respiratory tract infections.
      with coronaviruses accounting for 10% to 15% of cases.
      • Hopkins C.
      • Surda P.
      • Kumar N.
      Presentation of new onset anosmia during the COVID-19 pandemic.
      Olfactory dysfunction in COVID-19 infection could be related to the involvement of the olfactory bulb or to peripheral damage of the olfactory receptor cells in the nasal neuroepithelium.
      • Ralli M.
      • Di Stadio A.
      • Greco A.
      • de Vincentiis M.
      • Polimeni A.
      Defining the burden of olfactory dysfunction in COVID-19 patients.
      This assertion is based on the potential neurotrophic features of SARS-CoV-2. In particular, it has been demonstrated in transgenic mice that after intranasal administration of SARS-CoV (which shares similarities with SARS-CoV-2), the virus could penetrate into the brain through the olfactory bulb, leading to rapid transneuronal spread.
      • Li K.
      • Wohlford-Lenane C.
      • Perlman S.
      • et al.
      Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4.
      It is also well recognized that alterations in the volume and composition of saliva can disturb taste sensation.
      • Matsuo R.
      Role of saliva in the maintenance of taste sensitivity.
      Previously, epithelial cells lining salivary gland ducts were found to be early target cells of SARS coronavirus infection in the upper respiratory tracts of rhesus macaques.
      • Liu L.
      • Wei Q.
      • Alvarez X.
      • et al.
      Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus Macaques.
      Phylogenetic similarities between SARS-CoV and SARS-CoV-2 mean that the latter could also alter gustatory sensation in affected patients.
      The few studies that have evaluated the clinical utility of OGDs in COVID-19 diagnosis have suggested their low sensitivity (23%-43%) and high specificity (93%-99%).
      • Bénézit F.
      • Le Turnier P.
      • Declerck C.
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      Utility of hyposmia and hypogeusia for the diagnosis of COVID-19 [published online ahead of print April 15, 2020]. Lancet Infect Dis.
      ,
      • Wee L.E.
      • Chan Y.F.Z.
      • Teo N.W.Y.
      • et al.
      The role of self-reported olfactory and gustatory dysfunction as a screening criterion for suspected COVID-19 [published online ahead of print April 24, 2020]. Eur Arch Otorhinolaryngol.
      Regardless, in one study, the sensitivity and specificity of OGDs were reported to be comparable to the sensitivity and specificity of a history of close contact with a confirmed COVID-19 case.
      • Wee L.E.
      • Chan Y.F.Z.
      • Teo N.W.Y.
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      The role of self-reported olfactory and gustatory dysfunction as a screening criterion for suspected COVID-19 [published online ahead of print April 24, 2020]. Eur Arch Otorhinolaryngol.
      An analysis of 237 entries from the AAO-HNS COVID-19 Anosmia Reporting Tool suggested that anosmia was noted in 73% of patients before the COVID-19 diagnosis and was the initial symptom in 26.6%.
      • Kaye R.
      • Chang C.W.D.
      • Kazahaya K.
      • Brereton J.
      • Denneny 3rd, J.C.
      COVID-19 anosmia reporting tool: initial findings [published online ahead of print April 28, 2020]. Otolaryngol Head Neck Surg.
      Yan et al
      • Yan C.H.
      • Faraji F.
      • Prajapati D.P.
      • Ostrander B.T.
      • DeConde A.S.
      Self-reported olfactory loss associates with outpatient clinical course in COVID-19 [published online ahead of print April 24, 2020]. Int Forum Allergy Rhinol.
      have also suggested that OGDs may be associated with a milder course of COVID-19 infection. This may also potentially explain the lower prevalence of OGDs with increasing mean age because older people are more likely to experience severe COVID-19 infection compared with younger individuals.
      • Liu K.
      • Chen Y.
      • Lin R.
      • Han K.
      Clinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients.
      Consequently, the potential higher burden of OGDs in patients with milder COVID-19 disease is concerning because such patients may be less likely to be tested but could continue to spread the virus. Thus, public education about symptoms of OGDs may be necessary, and patients experiencing such symptoms should be advised to self-isolate pending confirmatory testing.
      American Academy of Otolaryngology–Head And Neck Surgery
      AAO-HNS: Anosmia, hyposmia, and dysgeusia symptoms of coronavirus disease. 2020.
      It is not yet clear whether the COVID-19–related OGDs are transient or permanent. However, among 23 patients with COVID-19 infection with anosmia in Iran, 75% reported significant improvement over 2 weeks.
      • Just J.
      • Puth M.
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      Moreover, among 237 patients with anosmia on the AAO-HNS COVID-19 Anosmia Reporting platform, 27% reported improvement in symptoms, with the mean time to improvement being 7.2 days.
      • Kaye R.
      • Chang C.W.D.
      • Kazahaya K.
      • Brereton J.
      • Denneny 3rd, J.C.
      COVID-19 anosmia reporting tool: initial findings [published online ahead of print April 28, 2020]. Otolaryngol Head Neck Surg.
      Owing to the high occurrence of anosmia in COVID-19–positive individuals, the indiscriminate use of corticosteroids, particularly in the absence of known head trauma or allergic symptoms, should be discouraged because corticosteroids may escalate COVID-19 infection.
      • Lao W.P.
      • Imam S.A.
      • Nguyen S.A.
      Anosmia, hyposmia, and dysgeusia as indicators for positive SARS-CoV-2 infection [published online ahead of print April 17, 2020]. World J Otorhinolaryngol Head Neck Surg.
      Moreover, as more evidence evolves around COVID-19, further studies addressing therapeutic approaches to OGDs among infected patients will be needed.
      Our study has some key strengths. Although a recent meta-analysis by Tong et al
      • Tong J.Y.
      • Wong A.
      • Zhu D.
      • Fastenberg J.H.
      • Tham T.
      The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: a systematic review and meta-analysis [published online ahead of print May 5, 2020]. Otolaryngol Head Neck Surg.
      reported the pooled prevalence of olfactory and gustatory dysfunction among patients with COVID-19 infection as 52.73% (95% CI, 29.64% to 75.23%) and 43.93% (95% CI, 20.46% to 68.95%), respectively, their analysis was based on 10 studies and involved fewer than 1700 patients. Our study has provided pooled prevalence estimates of OGDs based on data from 24 studies involving more than 8400 patients with diagnostic-confirmed COVID-19 infection from 13 countries. Furthermore, our analysis provides new insights into the potential role of individual-level characteristics such as age and sex in the presentation of OGDs among patients with COVID-19 infection that were not explored in the study by Tong et al.
      • Tong J.Y.
      • Wong A.
      • Zhu D.
      • Fastenberg J.H.
      • Tham T.
      The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: a systematic review and meta-analysis [published online ahead of print May 5, 2020]. Otolaryngol Head Neck Surg.
      Despite the strengths of our study, the findings should be interpreted in light of some limitations. There was high statistical heterogeneity, which is largely attributable to the observational nature of the studies. Further investigations revealed that the heterogeneity was not entirely explained by differences in patients' age, proportion of females, region, or OGD assessment methods.
      From a methodological perspective, the design of most of the included studies preclude the confirmation of causality between COVID-19 and OGDs. Thus, to better inform population screening measures, further well-designed prospective studies using validated or objective measurement techniques are needed to establish causality. Most studies also recruited patients in European settings, which may affect the generalizability of our findings.
      Moreover, few studies used objective assessment methods for establishing the presence of OGDs, whereas most relied on self-reports. These may lead to bias in the ascertainment of OGDs. For example, it is possible for patients to confuse taste function and aroma sense perception,
      • Stevenson R.J.
      • Prescott J.
      • Boakes R.A.
      Confusing tastes and smells: how odours can influence the perception of sweet and sour tastes.
      but it was not clear from most studies whether this distinction had been made. In one study by Lechien et al
      • Lechien J.
      • Cabaraux P.
      • Chiesa-Estomba C.
      • et al.
      Psychophysical olfactory findings of mild-to-moderate COVID-19 patients: preliminary report [preprint posted May 6, 2020]. MedRxiv.
      that made this distinction, among 28 patients with COVID-19 infection, 86% experienced aroma disorders, whereas 60.7% experienced taste disorders. However, it was unclear what proportion of patients experienced both symptoms.
      • Lechien J.
      • Cabaraux P.
      • Chiesa-Estomba C.
      • et al.
      Psychophysical olfactory findings of mild-to-moderate COVID-19 patients: preliminary report [preprint posted May 6, 2020]. MedRxiv.
      Last, because the metaregression relied on study-level characteristics such as mean age and proportion of females, ecological fallacy cannot be entirely ruled out.
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019.
      ,
      • Kaufmann E.
      • Reips U.-D.
      • Maag Merki K.
      Avoiding methodological biases in meta-analysis: use of online versus offline individual participant data (IPD) in educational psychology.
      Thus, future studies adopting methods such as the use of individual participant data meta-analysis
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      • Kaufmann E.
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      • Maag Merki K.
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      may be essential toward confirming our findings.

      Conclusion

      This study found a high prevalence of OGDs among patients infected with COVID-19. Hence, the consideration of OGDs as part of the screening and diagnostic approaches for COVID-19 could help improve case detection and further curtail the spread of the virus. However, to better inform population screening measures, further well-designed studies are needed to establish causality between COVID-19 and the occurrence of OGDs.

      Supplemental Online Material

      Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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