Epidemiology Section DOI : 10.7860/JCDR/2021/45714.14565
Year : 2021 | Month : Feb | Volume : 15 | Issue : 02 Page : LE06 - LE16

Olfactory and Gustatory Symptoms of Coronavirus Disease 2019: A Systematic Review and Meta-analysis

Sivakumar Pradeep1, Kalpa Pandya2, Vinayak Kamath3, Sivakumar Vidhyadharan4, Naveen Hedne5

1 Junior Consultant, Department of Head and Neck Surgical Oncology, Apollo Proton Cancer Center, Chennai, Tamil Nadu, India.
2 Senior Lecturer, Department of Oral and Maxillofacial Surgery, Sri Ramachandra Dental College, Chennai, Tamil Nadu, India.
3 Lecturer, Department of Public Health Dentistry, Goa Dental College, Goa, India.
4 Consultant, Department of Head and Neck Surgical Oncology, Apollo Proton Cancer Center, Chennai, Tamil Nadu, India.
5 Senior Consultant, Department of Head and Neck Surgical Oncology, Apollo Proton Cancer Center, Chennai, Tamil Nadu, India.


NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR: Kalpa Pandya, 82/1, Second Street, F Block, Anna Nagar East, Chennai, Tamil Nadu, India.
E-mail: kalpa.pandya@gmail.com
Abstract

Introduction

There is increasing anecdotal evidence that olfactory and gustatory dysfunction may be associated with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).

Aim

The aim of this systematic review and meta-analysis was to find the association of olfactory and gustatory symptoms with Coronavirus Disease-19 (COVID-19) and estimate their pooled prevalence.

Materials and Methods

PubMed, Embase, EBSCO and Cochrane databases were searched for cross-divtional, cohort and case-control studies evaluating olfactory and gustatory symptoms in patients with COVID-19. The search terms included COVID-19, severe acute respiratory syndrome coronavirus-2, coronavirus, olfaction disorders, anosmia, hyposmia, dysgeusia and ageusia. Random effects model was used to calculate a pooled Odds Ratio (OR) and pooled prevalence.

Results

Total 14 studies were included in qualitative synthesis and 13 studies were incorporated in quantitative synthesis, involving 3,125 patients. The pooled OR was 15.59 reflecting that smell and taste disorders were strongly associated with COVID-19. The pooled prevalence of olfactory and gustatory dysfunction was 56% and 44%, respectively.

Conclusion

It can be concluded that there is a significant association between olfactory and gustatory symptoms and COVID-19. Majority of the studies support the use of these symptoms as screening tools for COVID-19.

Introduction

The Novel Coronavirus was first identified in Wuhan, China on 31st December 2019. It was named as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV) [1]. World Health Organisation (WHO) named the disease as Coronavirus Disease-2019 (COVID-19). On 11th March 2020, WHO declared COVID-19 as a pandemic [2]. As of 12th May 2020, there have been 4,013,728 confirmed cases and 278,993 deaths worldwide due to COVID-19 [3]. The SARS-CoV-2 Virus is known to transmit through close contact and respiratory droplets (droplets particles >5-10 microns in diameter) as well as aerosols of smaller size [4]. Till date, airborne transmission of SARS-CoV-2 has not been reported. However, WHO’s recent communication has stated that this form of transmission in small, poorly ventilated rooms cannot be ruled out [5]. The transmission is occurring at an exponential rate resulting in steep curves in many countries [6]. There has been significant transmission of virus from asymptomatic and paucisymptomatic individuals [7]. A meta-analysis including 3,600 patients from 43 studies has reported the most common symptoms of COVID-19 to be fever (83.3%), cough (60.3%) and fatigue (38%) [8]. According to a large series of 72,314 cases from the Chinese Center for Disease Control and Prevention (CDC), 80% of the cases presented with mild symptoms. Limited attention has been given to the mild symptoms that may present at the initial stage of infection and often may be the only clinical manifestation of the disease [9].

There is increasing anecdotal evidence that olfactory and gustatory dysfunction may be associated with SARS-CoV-2 and they may potentially be the early symptoms of the disease [10]. Smell and taste dysfunctions have been known to be associated with various other viral infections, such as rhinovirus, Epstein-Barr virus and certain other strains of coronavirus like Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). These viruses cause inflammation of nasal passages leading to rhinorrhoea, nasal obstruction and olfactory dysfunction [11,12]. Evidence suggests that unlike other viruses, olfactory dysfunction in COVID-19 may not present with co-existing rhinorrhoea and nasal obstruction [6].

Walker A et al., used Google trends to analyse the number of Google searches made, related to smell in multiple countries. They found a strong correlation between smell related searches and onset of COVID-19 infections, hypothesising that smell dysfunction may be an under-recognised symptom of COVID-19 [13]. In view of emerging evidence of smell and taste dysfunctions in COVID-19, the American Association of Otorhinolaryngology and Head and Neck Surgery has proposed to include anosmia, hyposmia and dysgeusia as screening tools for detection of COVID-19 [14].

A number of studies across the world have reported the prevalence of smell and taste dysfunctions such as anosmia, hyposmia, dysgeusia and ageusia in association with COVID-19 [6,15-29]. Few more have also established a strong association between smell and taste dysfunction and COVID-19 [23,30-32]. This systematic review and meta-analysis estimated the association of olfactory and gustatory dysfunctions with COVID-19 and their pooled prevalence across the studies [23]. To author’s knowledge, this is the first meta-analysis assessing the association of smell and taste dysfunction with COVID-19.

Materials and Methods

Protocol and registration: This systematic review and meta-analysis was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) guidelines. The protocol for this systematic review was designed and registered with PROSPERO (Registration Number- CRD42020181841) [33]. The review was conducted in May, 2020 and extended over a study period of two months.

Search strategy: The following databases were searched: PubMed, Embase, EBSCO and Cochrane Central Register of Controlled Trials (CENTRAL) database. The searches were supplemented by screening references of the included studies. Respective authors were also contacted for a few unclear data. The primary search period included all studies published until 1st May 2020, without language restrictions. The following strategy was used to search the MEDLINE database: [[“COVID-19”[All Fields] OR “COVID-2019”[All Fields] OR “severe acute respiratory syndrome coronavirus 2”[Supplementary Concept] OR “severe acute respiratory syndrome coronavirus 2”[All Fields] OR “2019-nCoV”[All Fields] OR “SARS-CoV-2”[All Fields] OR “2019nCoV”[All Fields] OR [[“Wuhan”[All Fields] AND [“coronavirus”[MeSH Terms] OR “coronavirus”[All Fields]]] AND [2019/12[PDAT] OR 2020[PDAT]]]] OR [“coronavirus”[MeSH Terms] OR “coronavirus”[All Fields]] OR [“severe acute respiratory syndrome coronavirus 2”[Supplementary Concept] OR “severe acute respiratory syndrome coronavirus 2”[All Fields] OR “sars cov 2”[All Fields]]] AND [[“olfaction disorders”[MeSH Terms] OR [“olfaction”[All Fields] AND “disorders”[All Fields]] OR “olfaction disorders”[All Fields] OR “anosmia”[All Fields]] OR hyposmia[All Fields] OR [“dysgeusia”[MeSH Terms] OR “dysgeusia”[All Fields]] OR [“ageusia”[MeSH Terms] OR “ageusia”[All Fields]] OR [“taste”[MeSH Terms] OR “taste”[All Fields]] OR [“smell”[MeSH Terms] OR “smell”[All Fields]] OR [“taste”[MeSH Terms] OR “taste”[All Fields] OR “gustation”[All Fields]]]. The search strategy for CENTRAL, EBSCO and EMBASE were similar to those used in the MEDLINE search.

Selection of studies: Reference management software (Zotero 5.0.85) was used to save all the potentially eligible studies. Two reviewers (KP and SP) independently screened the available searched studies for inclusion by reviewing the title and abstracts. Any disagreements amongst the two reviewers were resolved by involving a third reviewer. In cases where abstracts did not provide adequate or relevant information, full texts of papers were screened for eligibility. Following this, the full text of all included studies was retrieved and reviewed in detail. Excluded studies were stated with the reasons for their exclusion.

Selection criteria: All cross-sectional, cohort and case-control studies evaluating olfactory and gustatory symptoms in patients with COVID-19 were included. Studies published on or before 1st May 2020 were included. Case reports, case-series, narrative reviews and letters to the editor were excluded. Studies with insufficient data regarding olfactory and gustatory symptoms were excluded.

Data collection and synthesis of results: Two reviewers independently extracted relevant information. Tabulation of the following data was done in Microsoft Excel sheet: First author, publication date, study design, country, number of COVID-19 positive patients, mean or median age of patients, gender, total patients with olfactory dysfunction, total patients with gustatory dysfunction, patients with combined olfactory and gustatory dysfunctions (both), patients with olfactory or gustatory dysfunctions as presenting symptoms, patients with anosmia, hyposmia, ageusia, hypogeusia, dysgeusia, smell recovery time and any significant associations between the variables.

Assessment of study quality: The quality assessment tool by the National Institutes of Health (NIH) for observational studies and case-control was used to assess the quality of included studies [34]. Zero or 1 point was scored for each item according to the criteria and overall quality score was generated by adding the individual scores for each item. Based on the scores, the studies were classified as having good quality (≥7), fair quality (5-6) and poor quality (≤4). Good quality studies are deemed to have least risk of bias. Studies with fair quality have moderate amount of bias whereas poor quality studies have a significant risk of bias [35].

Statistical Analysis

The data was analysed using STATA 13.0 (StataCorp, College station, TX) and Revman version 5.3. Random effects model was used to calculate a pooled OR to determine the overall association between Olfactory and Taste Disorder (OTD) and COVID-19. Using random effects model, pooled prevalence of olfactory dysfunction, gustatory dysfunction, patients with both olfactory and gustatory dysfunction, and patients with some form of chemosensory dysfunction (taste and/or smell) were assessed. Apart from these, pooled prevalence of different types of smell and taste disturbances such as anosmia, hyposmia, ageusia and dysgeusia were calculated. Heterogeneity of the studies was calculated using I2 statistics (Higgins JPT et al.,) [36].

Results

Study selection: The records identified 140 articles by the application of the search strategy. After removing the duplicate search records, a total of 74 records were identified from the electronic searches [Table/Fig-1].

Study selection process illustrated by preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.

These search records were screened for title and abstracts. Three articles did not had an English translation of which one was in Danish, one in German and one in Greek. Fifty three records were excluded due to publication types like case reports (2), case series (2), editorials (5), short communications (1), excerpts from books (1), letter to editors (5), narrative reviews (6) and due to irrelevance to the topic (31). For the remaining 18 records, full text articles were searched for eligibility. Of these, four articles were excluded due to the following reasons: COVID-19 positivity was not confirmed in one study, one study included only anosmic patients leading to selection bias and full text was not available for two articles. Thus, 14 [6,16,17,21-23,27,30-32,37-40] studies were included in qualitative synthesis and 13 studies were incorporated in quantitative synthesis. Of these 11 were used to measure the pooled prevalence, and 5 [23,27,30-32] studies were used to establish an overall association by measuring pooled OR.

Study characteristics: Fourteen studies consisting of six cross-sectional surveys [6,16,17,37,39,40], three retrospective observational studies [21,22,38], five case-control studies [23,27,30-32] with a total of 3,125 patients included in the final review [Table/Fig-2] [6,16,17,21-23,27,30-32,37-40].

Table describing the study characteristics of the included studies [6,16,17, 21-23,27,30-32,37-40].

S. No.AuthorCountryAge (Years) Mean (SD)/MedianCOVID Positive casesMaleFemaleStudy designPatients with olfactory dysfunction (%)Patients with gustatory dysfunction (%)
1Giacomelli A et al., [16]ItalyMedian 60594019Cross-sectional survey14 (23.7)17 (28.8)
2Lechien JR et al., [6]Europe36.9 (11.4)417154263Cross-sectional survey357 (85.6)342 (82.01)
3Yan CH et al., [38]USA18-79592929Cross-sectional survey40 (67.8)42 (71.2)
4Klopfenstein T et al., [22]France47 (16)114Not reportedNot reportedRetrospective observational study54 (47)46 (85)
5Mao L et al., [21]China52.7 (15.5)21487127Retrospective observational study11 (5.1)12 (5.6)
6Moein ST et al., [23]Iran46.55 (12.17)604020Case-control study59 (98)14 (23.3)
7Benezit F et al., [27]FranceNot reported68Not reportedNot reportedCase-control study31 (45)42 (62)
8Vaira LA et al., [39]Italy49.2722745Cross-sectional86.147.2
9Spinato G et al., [40]United KingdomMedian 5620297105Cross-sectional surveyNot mentionedNot mentioned
10Lechein JR et al., [37]Europe39.17 (12.09)1420458962Cross-sectional997 (70.2)770 (54.2)
11Beltran- Corbellini A et al., [30]Spain61.6 (17.4)794831Case-control study25 (80.6)28 (90.3)
12Tostmann A et al., [31]NetherlandNot reported791971Case-control study37 (46.8)Not mentioned
13Wee LE et al., [32]SingaporeNot reported154Not reportedNot reportedCase-control studyNot mentionedNot mentioned
14Yan CH et al., [17]USA53.5: Admitted patients, 43: Ambulatory patients1286167Retrospective observational study75 (58.5)70 (54.6)

SD: Standard deviation


Assessment of the quality of the studies: The study quality was assessed using National Heart Lung and Blood Institute (NHLBI) quality assessment tool for observational studies by the NIH for the nine observational studies and the NHLBI tool for case-control studies was used for the five included case-control studies. The study qualities were good for nine studies, fair for four studies and poor for one study [Table/Fig-3].

Table describing the key findings, strengths and limitations of the studies [6,16,17,22-24,27,30-32,37-40].

S. No.Author/YearKey featuresAuthors conclusionStrengthsLimitationsStudy quality
1Giacomelli A et al., [16] March 2020

33.9% had at least one gustatory/olfactory disorder and 18.6% had both.

20.3% presented as initial symptoms.

Taste dysfunction was more as an initial symptom (91%)

Females had these symptoms more than males {52.6% versus 25%, p=0.036}.

Patients with at least one olfactory/gustatory symptom were younger than those without

Olfactory and gustatory dysfunction are frequent in patients with COVID-19.

It may precede the onset of more serious disease.

Patients with memory disorders were excluded

Not used a structured questionnaire

Subjective assessment

Since the study was done for hospitalised patients, patients with mild symptoms who does not need hospitalisation may be missed

Olfactory recovery not assessed

Fair
2Lechien JR et al., [6] April 2020

Patients with mild-to-moderate disease

85.6% had olfactory dysfunction

88.0% of patients had gustatory dysfunctions.

There was a significant association between both dysfunctions (p<0.001).

Olfactory dysfunction was a presenting symptom in 11.8% cases.

Quality of Life (QOL) scores were significantly lower in anosmia

Majority olfactory dysfunctions were without nasal obstruction or rhinorrhea.

Early olfactory recovery rate was 44.0%.

Females were significantly more affected by smell and taste dysfunctions than males (p=0.001).

In European COVID-19 patients, olfactory and gustatory dysfunctions were prevalent

The sudden anosmia/ageusia should be recognised as a symptom of COVID-19 disease.

Standard questionnaire

Included varied ethnicity

Mild to moderate cases included.

QOL assessed

Smell recovery assessed

Subjective assessment

Not included severe patients

May not be representative as physicians with anosmia voluntarily participated.

Good
3Yan CH et al., [38] April 2020

Anosmia and ageusia was reported in 68% and 71% patients, respectively (p<0.001).

Anosmia and ageusia was independently and strongly associated with Covid-19 (anosmia: adjusted Odds Ratio (aOR) 10.9, 95% CI: 5.08-23.5; ageusia: aOR 10.2 95% CI: 4.74-22.1)

74% of anosmia patients recovered in two weeks with overall recovery from illness.

22% reported anosmia as an initial symptom

Anosmia and ageusia were 10 times more common in Covid-19-positive patients

Olfactory and gustatory dysfunction was strongly associated with COVID-19.

Should be considered as a screening symptom

Most of these symptoms recovered with overall recovery from illness

10 point olfaction score was used.

Smell recovery assessed

Subjective assessment

Short sampling period

Only ambulatory patients with relatively mild COVID-19 infection were included

Moderate to severe patients admitted in the hospitals were not included

Patients with memory disorders were not excluded

Good
4Klopfenstein T et al., [22] April 2020

47% had anosmia.

Anosmia was associated with dysgeusia in 85% cases.

Patients with anosmia were younger with a female predominance

Anosmia started 4.4 {±1.9 (1-8)} days after onset of infection.

Mean duration of anosmia - 8.9 {±6.3 (1-21)} days.

80% patients recovered in 14 days & 98% patients recovered within 28 days.

Nearly half of

COVID-19 patients had anosmia and it is associated with dysgeusia in 85% cases.

Favourable outcome in 28 days.

Smell recovery assessed

Patients with memory disorders were excluded

Data was retrospectively collected from the file where mild patients may not be captured

Only taken hospitalised patients and ambulatory patients with these symptoms may be missed

Fair
5Villalba NL, et al., [24] April 2020

Neurologic symptoms was noted in 36.4% patients

These were common in patients with severe infection (45.5%)

Amongst the peripheral nervous symptom symptoms, Gustatory dysfunction seen in 5.6% of which 3 had severe infection and 9 had nonsevere infection

Olfactory dysfunction was seen in 5.1% patients of which 3 had severe infection and 8 had nonsevere infection

Neurologic symptoms are seen in a sizable proportion of COVID-19 patients.

Physicians should suspect COVID-19 as a differential diagnosis, if neurologic manifestations present

Categorised and included both severe and nonsevere infection patients

Data collected retrospectively collected where mild patients may not be captured

Included only hospitalised patients

Smell recovery not assessed

Poor
6Moein ST et al., [23] April 2020

98% patients had some form of olfactory dysfunction which was graded into anosmia, mild, moderate and severe microsmia

35% had either taste or smell loss

12% had only smell loss

7% had only taste loss

17% had combined smell and taste loss

Of 83% patients who had anosmia/severe microsmia, only 35% was aware of their smell dysfunction.

Objective assessment shows some degree of olfactory dysfunction and not always anosmia, is a major sign for COVID-19

Objective Olfactory testing may help in screening COVID-19 patients.

This is the only study using objective testing for olfactory function using The University of Pennsylvania Smell Identification Test (UPSIT)

Patients were graded based on severity

Matched controls used

Quantitative assessment not done for taste dysfunction.

Included only hospitalised patients

Smell recovery was not assessed

Fair
7Bénézit F et al., [27] April 2020

62% had hypogeusia

45% had hyposmia

43% had combined hyposmia and hypogeusia

Hyposmia and hypogeusia were strongly associated with COVID-19 diagnosis independently and together

These symptoms can be used for

Mass screening and initial diagnosis of COVID-19

Findings compared with COVID negative patients (with Influenza-Like Illness (ILI))

No objective assessment

No standard questionnaire

Smell recovery was not assessed.

Good
8Vaira LA et al., [39] April 2020

Smell: Olfactory threshold and odor discriminative ability assessed

Taste: Standardised test to test four primary tastes

73.6% have one or more of olfactory-gustatory disturbance

Most patients had mild-moderate olfactory and taste disorders (OTD)

Older patients more prone to taste disturbance (p<0.003)

OTD are common clinical findings in COVID-19

OTD occur in early stages of infection

If sudden and OTD not associated with rhinitis symptoms, COVID-19 to be suspected

Standardised objective tests used for taste and smell assessment

Smell recovery was tested

Studies relation of OTD with age and time of onset of clinical symptoms

Evaluation of OTD performed at 19.3 days from the onset of clinical symptomsFair
9Spinato G et al., [40] April 2020

64.4% reported one or more OTD

11.9% reported it as a presenting symptom

3% reported OTD as an isolated symptom

STD more common in women

Testing for COVID-19 and self-isolation to be considered in sudden onset of altered taste or smell

Standard questionnaire- Sino-nasal outcome test 22 (SNOT-22) used

Studied grades of OTD

Smell and taste dysfunction not distinguished

Objective testing not performed

Only mildly symptomatic cases included

Good
10Lechein JR et al., [37] April, 20

OTD more common in younger patients and in female patients

Anomsia-70.2% Dysgeusia-54.2% of 1420 patients

Anosmia persisted for 1 week in 37.5% of cured patients

Smell disturbance is a key under estimated symptom of mild to moderated COVID-19 patients

Multi-centre study with large sample size

Varied ethnicity

Age and sex association with COVID-19 assessed

Only mild-moderate cases

Young patients with few co-morbidities

No objective testing

Good
11Yan CH et al., [17] April, 20

Investigated association between smell loss and hospitalisation in COVID-19

Smell loss was strongly associated with COVID-19 which does not require hospitalisation (aOR 0.09 95% CI- 0.01-0.74) whereas positive findings on chest imaging was associated with hospitalisation

Anosmia may be related to a mild disease, not requiring hospitalisation

Included both mild and severe cases of COVID-19

No objective testing

Grades of smell dysfunction not assessed

Good
12Beltrán-Corbellini A et al., [30] April 20

Investigate new onset olfactory and taste disorders (OTD) in COVID-19 compared to ILI (controls)

39.2% of cases had OTD compared to 12.5% in controls.

Smell dysfunction-80%

Taste dysfunction-90.3%

Among COVID-19 patients, patients with OTD were younger than those without OTD

Mean duration of OTD- 7.5+/- 3.2 days. 40% recovered completely after 1 week.

OTD common in COVID-19 compared to Influenza-Like Illness (ILI)

Usually it is a presenting symptom and acute in onset

Case-control study

Assessed recovery

No objective testing

Good
13Tostmann A et al., [31] April 20

Healthcare workers with mild symptoms tested for COVID-19

Anosmia reported in 47% COVID positive and strongly associated with COVID-positivity OR=23.0; 95% confidence interval (CI): 8.2-64.8)

Predictive model based on these symptoms showed sensitivity: 91.2%; specificity: 55.6%

Authors propose self-isolation to patients with olfactory symptoms

Predictive model calculated

No objective testing done

Study subjects involved only those with mild symptoms

Good
14Wee LE et al., [32] April 20

COVID testing done for all suspected cases including those with the symptoms of OTD

22.7% patients COVID positive subjects had OTD

Odds ratio for OTD was higher for patients with COVID compared to those with other respiratory viruses (odds ratio, OR=10.14, 95% CI 2.37-43.49, p<0.001).

OTD as a self-reported symptom had a high specificity (98.7%) as a screening tool in an Asian cohort

Compared with COVID-negative cases with the same mild symptoms

No objective testing performed

Fair

Qualitative synthesis: A total of 14 studies were included in the qualitative synthesis. The key findings, strength and limitations of various studies have been summarised in [Table/Fig-3].

Quantitative synthesis (Meta-analysis): Association between smell and taste disorders and COVID-19: Five studies compared the smell and taste function of patients with COVID-19 with those who were COVID-19 negative. Smell and taste function was assessed through questionnaires for four of these studies [27,30-32] whereas by objective testing for one study [23]. The pooled OR was 15.59 (95% CI, 6.31-38.55) [Table/Fig-4].

Association of olfactory and gustatory symptoms with COVID-19.

This reflects that smell and taste disorders are strongly associated with COVID-19. The studies had moderate heterogeneity by I2 test (72%). On the funnel plot, the study by Moein ST et al., appeared to be well away from the central line indicating a publication bias [Table/Fig-5] [23].

Funnel plot depicting publication bias.

Prevalence of Olfactory and gustatory dysfunction: Olfactory dysfunction was reported by 12 studies. The pooled prevalence of olfactory dysfunction was 56% (95% CI 37-75) in the patients with COVID-19 [Table/Fig-6a]. The pooled prevalence for gustatory disturbance as reported by 11 studies was 44% (95% CI 28-62) [Table/Fig-6b]. A 32% of the patients reported both smell and taste disturbance (95% CI, 21-43) [Table/Fig-6c]. Nine studies reported data regarding OTD as presenting symptoms for which the prevalence was 9%. (95% CI, 3-17) [Table/Fig-6d]. Detailed statistical analyses are demonstrated in supplemental tables.

Forest plot illustrating pooled prevalence of olfactory dysfunction.

Forest plot illustrating pooled prevalence of gustatory dysfunction.

Forest plot illustrating pooled prevalence of both olfactory and gustatory dysfunction.

Forest plot illustrating pooled prevalence of olfactory and gustatory dysfunction as presenting symptoms.

Prevalence of different types of smell and taste dysfunctions: The estimated pooled prevalence of anosmia was 28% (95% CI, 10-50) in the patients with COVID-19. Hyposmia was reported in eight studies, the pooled prevalence for which was 27% (95% CI, 6-54). Eight studies reported ageusia with estimated pooled prevalence of 12% (95% CI, 1-33). Dysgeusia was reported by six studies with pooled prevalence of 8% (95% CI, 0-21) [Table/Fig-7a,b,c and d].

Forest plot depicting pooled prevalence of anosmia.

Forest plot depicting pooled prevalence of hyposmia.

Forest plot depicting pooled prevalence of ageusia.

Forest plot depicting pooled prevalence of dysgeusia.

Subgroup analysis: A high degree of heterogeneity was found across various studies. Studies were performed in different countries with wide ethnicity. A region-wise subgroup analysis was performed for olfactory and gustatory dysfunction. The prevalence ranged from 5% (China) to 98% (Asia). Pooled prevalence involving only the European countries was 56%, which was similar to the overall pooled prevalence [Table/Fig-8].

Subgroup analysis for prevalence of olfactory dysfunction based on geographical location.

Discussion

There is growing anecdotal evidence of sudden anosmia or hyposmia with or without other symptoms of COVID-19 infection [10]. This systematic review and meta-analysis involving 13 studies and 3,125 patients demonstrates a significant association between olfactory and gustatory dysfunction and COVID-19. It also demonstrates a high prevalence of these symptoms in patients with COVID-19.

Pooled OR across the five case-control studies was 15.59 showing that OTD were 15 times more common in patients with COVID-19 compared to those without. Lechien JR et al., found olfactory and gustatory symptoms show a significant correlation with each other [6]. Yan CH et al., showed that among all the symptoms, anosmia and ageusia displayed the strongest association with COVID-19 positivity and these symptoms were 10 times more common than those in COVID-19 negative individuals [17]. This reflects the importance of adding anosmia and ageusia as important components of screening symptoms for COVID-19.

The pooled prevalence of olfactory dysfunction was 56% while that of anosmia and hyposmia was 28% and 27%, respectively [6,16,17,22,27]. It is noteworthy that smell dysfunction in the studies ranged from as low as 5% (Mao L et al.,) to 98% (Moein ST et al.,) with the other authors reporting a smell dysfunction of 23.7%, 85.6%, 67.8%, 47% and 45% [6,16,17,21-23]. Mao L et al., (smell dysfunction-5%) have based their findings on electronic medical records which could have led to under-reporting of minor symptoms such as that related to olfaction [21]. Recent evidence suggests that Angiotensin Converting Enzyme 2 (ACE-2) receptor to which coronavirus binds, might have some diversity across the populations. This may in turn lead to its variable association with SARS-CoV-2. This difference may translate into the difference in symptoms and clinical outcomes of patients that is found among different ethnicities [6,41]. It is noteworthy that in COVID-19 disease, olfactory symptoms were seen without nasal obstruction or rhinorrhoea unlike other viral infections [42]. The aetiology of olfactory and gustatory symptoms in COVID-19 is elusive and various theories have been proposed for the same [32]. One of the proposed aetiology is the possible neuroinvasive potential of SARS-CoV-2 [43]. Trans-neural penetration of the SARS-CoV virus into the central nervous system through the olfactory bulb has been demonstrated in a mice model [44]. Significant neuronal death has been observed in brain due to rapid spread of SARS-CoV [6]. A similar neuroinvasive potential of the SARS-CoV-2 may have a major role not only in causing OTD but also in causing respiratory failure of patients with COVID-19 [45]. Another proposed mechanism is due to the binding of SARS-CoV-2 to Angiotensin converting enzyme 2 (ACE-2) receptors. Since the taste buds and olfactory epithelium also express ACE-2, SARS-CoV-2 may have a cytopathic effect resulting in these symptoms.

This meta-analysis found gustatory disturbance of 44% in COVID-19 patients. Some studies also reported the type of taste dysfunction as ageusia and dysgeusia, the pooled prevalence of which were 12% and 8%, respectively. In the systematic review, most of the studies reported gustatory dysfunction either in combination with smell dysfunction or in isolation [6,16,17,21-23,30,37,39]. Except for the basic taste types of sour, sweet, salty, umami and bitter, the rest of the gustatory flavours are attributed to the olfactory system. Thus in many cases, taste loss may be attributed to a loss of smell rather than an actual damage to the taste buds [23,46,47].

OTD was reported as presenting symptom with an estimated pooled prevalence of 9% across nine studies [6,16,17,22,23,27,30,39,40]. Since these symptoms have not been identified as screening symptoms by major health organisations, they may often get missed leading to underdiagnosis of COVID-19. Giacomelli A et al., noted taste alteration as an initial symptom before hospitalisation in 91% of the patients [16]. Moreover, a few studies also reported sudden onset anosmia with or without dysgeusia as an isolated symptom of COVID-19 in otherwise asymptomatic patients [19,24,48].

Olfactory disturbances showed a gender predilection towards females across a number of studies [6,16,17]. with the values being statistically significant in the study done by Lechien JR et al., and Giacomelli A et al., [6,16]. Lechien JR et al., have suggested that this could be due to a possible heightened inflammatory response in females compared to males, warranting further studies to investigate the gender susceptibility to anosmia [6,35].

Many studies assessed smell recovery within a time frame of one week to four weeks. Most studies reported that the smell loss was transient, with a variable recovery after two weeks [6,17,22]. Lechien JR et al., pointed out that smell recovery takes a longer time compared to the recovery of other symptoms [6]. The authors observed a wide amount of heterogeneity in the meta-analysis which is a common finding in most of the studies pertaining to COVID-19 [49]. A subgroup analysis was done based on the prevalence of these symptoms across different countries.

Limitation(s)

This systematic review has various limitations considering the paucity of data available related to olfactory and taste disturbances in COVID-19. Most of the studies included were cross-sectional studies, where the data was collected either retrospectively from medical records or through a survey, without a standard follow-up [16,21,22,27]. The data was mostly collected in the form of a questionnaire except for two studies by Moein ST et al., and Vaira LA et al., which involved an objective testing method [23,39]. Of the studies involving questionnaires, only Lechein JR et al., and Spinato G et al., used standard validated questionnaires [6,40]. Most of the data was collected through internet and phone calls, questioning its reliability. Moein ST et al., reported that of the 85% patients that reported ansomia or severe microsmia, only 35% were aware of their smell dysfunction [23]. From this, it can be inferred that a sizeable population may be unaware of their olfactory disturbances leading to a recall bias in questionnaire-based studies.

Conclusion(s)

Since most of the studies were based on self-reported symptoms, more studies with validated objective testing of olfactory and gustatory disturbances in larger sample size are required. It can be concluded that there is a significant association between olfactory and gustatory symptoms and COVID-19 disease. Majority of the studies support the use of these symptoms as screening tools for COVID-19. This could help in early diagnosis and to contain disease transmission, especially from otherwise asymptomatic cases. Considering the ongoing exponential spread of SARS-CoV-2, limited diagnostic tests and scarce health resources worldwide, the authors emphasise the use of olfactory and taste disturbance as early markers of the disease.

SD: Standard deviation

References

[1]Wu Z, McGoogan JM, Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention JAMA 2020 323(13):1239-42.10.1001/jama.2020.264832091533  [Google Scholar]  [CrossRef]  [PubMed]

[2]WHO Director-General’s opening remarks at the media briefing on COVID-19- 11 March 2020 [cited 2020 Apr 27]. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020  [Google Scholar]

[3]WHO COVID-19 Dashboard. World Health Organization c202. [cited 2020 Apr 27]. Available from: https://covid19.who.int/  [Google Scholar]

[4]Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia N Engl J Med 2020 382(13):1199-207.10.1056/NEJMoa200131631995857  [Google Scholar]  [CrossRef]  [PubMed]

[5]Transmission of SARS-CoV-2: implications for infection prevention precautions. World Health Organization c2021. [cited: 9 July 2020]. Availablef from-https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions  [Google Scholar]

[6]Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): A multicenter European study Eur Arch Otorhinolaryngol 2020 277(8):2251-61.10.1007/s00405-020-05965-132253535  [Google Scholar]  [CrossRef]  [PubMed]

[7]Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Presumed asymptomatic carrier transmission of COVID-19 JAMA 2020 323(14):1406-07.10.1001/jama.2020.256532083643  [Google Scholar]  [CrossRef]  [PubMed]

[8]Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis J Infect 2020 80(6):656-65.10.1016/j.jinf.2020.03.04132283155  [Google Scholar]  [CrossRef]  [PubMed]

[9]Lovato A, de Filippis C, Marioni G, Upper airway symptoms in coronavirus disease 2019 (COVID-19) Am J Otolaryngol 2020 41(3):10247410.1016/j.amjoto.2020.10247432278470  [Google Scholar]  [CrossRef]  [PubMed]

[10]kaye_covid-19_anosmia_reporting_tool_initial_findings.pdf. [cited 2020 Apr 27]. Available from: https://www.entnet.org/sites/default/files/uploads/kaye_covid-19_anosmia_reporting_tool_initial_findings.pdf  [Google Scholar]

[11]Suzuki M, Saito K, Min WP, Vladau C, Toida K, Itoh H, Identification of viruses in patients with postviral olfactory dysfunction Laryngoscope 2007 117(2):272-77.10.1097/01.mlg.0000249922.37381.1e17277621  [Google Scholar]  [CrossRef]  [PubMed]

[12]Van RD, Verdijk R, Kuiken T, The olfactory nerve: A shortcut for influenza and other viral diseases into the central nervous system J Pathol 2015 235(2):277-87.10.1002/path.446125294743  [Google Scholar]  [CrossRef]  [PubMed]

[13]Walker A, Hopkins C, Surda P, Use of Google Trends to investigate loss-of-smell-related searches during the COVID-19 outbreak Int Forum Allergy Rhinol 2020 10(7):839-47.10.1002/alr.2258032279437  [Google Scholar]  [CrossRef]  [PubMed]

[14]AAO-HNS: Anosmia, hyposmia and dysguesia symptoms of coronavirus disease. https://www.entnet.org/content/aao-hns-anosmia-hyposmia-and-dysgeusia-symptoms-coronavirus-disease  [Google Scholar]

[15]Vaira LA, Salzano G, Deiana G, De Riu G, Anosmia and Ageusia: Common findings in COVID-19 patients The Laryngoscope 2020 130(7):178710.1002/lary.2869232237238  [Google Scholar]  [CrossRef]  [PubMed]

[16]Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: A cross-sectional study Clin Infect Dis 2020 71(15):889-90.10.1093/cid/ciaa33032215618  [Google Scholar]  [CrossRef]  [PubMed]

[17]Yan CH, Faraji F, Prajapati DP, Boone CE, DeConde AS, Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms Int Forum Allergy Rhinol 2020 10(7):806-13.10.1002/alr.2257932279441  [Google Scholar]  [CrossRef]  [PubMed]

[18]Russell B, Moss C, Rigg A, Hopkins C, Papa S, Van Hemelrijck M, Anosmia and ageusia are emerging as symptoms in patients with COVID-19: What does the current evidence say? Ecancermedicalscience 2020 3(14):ed9810.3332/ecancer.2020.ed98  [Google Scholar]  [CrossRef]

[19]Gane SB, Kelly C, Hopkins C, Isolated sudden onset anosmia in COVID-19 infection. A novel syndrome? Rhinology 2020 58(3):299-301.10.4193/Rhin20.11432240279  [Google Scholar]  [CrossRef]  [PubMed]

[20]Gautier J-F, Ravussin Y, A New symptom of COVID-19: Loss of taste and smell Obes Silver Spring Md 2020 28(5):84810.1002/oby.2280932237199  [Google Scholar]  [CrossRef]  [PubMed]

[21]Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Neurologic manifestations of hospitalised patients with coronavirus disease 2019 in Wuhan, China JAMA Neurol 2020 77(6):683-90.10.1001/jamaneurol.2020.112732275288  [Google Scholar]  [CrossRef]  [PubMed]

[22]Klopfenstein T, Kadiane-Oussou NJ, Toko L, Royer PY, Lepiller Q, Gendrin V, Features of anosmia in COVID-19 Med Mal Infect 2020 50(5):436-39.10.1016/j.medmal.2020.04.00632305563  [Google Scholar]  [CrossRef]  [PubMed]

[23]Moein ST, Hashemian SMR, Mansourafshar B, Khorram-Tousi A, Tabarsi P, Doty RL, Smell dysfunction: A biomarker for COVID-19 Int Forum Allergy Rhinol 2020 10(8):944-50.10.1002/alr.2258732301284  [Google Scholar]  [CrossRef]  [PubMed]

[24]Villalba NL, Mao LY, Ortiz MBA, Sosa ZC, Chahbazian JB, Syrovatkova A, Anosmia and dysgeusia in the absence of other respiratory diseases: Should COVID-19 infection be considered? Eur J Case Rep Intern Med 2020 7(4):001641  [Google Scholar]

[25]Hopkins C, Surda P, Kumar N, Presentation of new onset anosmia during the COVID-19 pandemic Rhinology 2020 58(3):295-98.10.4193/Rhin20.11632277751  [Google Scholar]  [CrossRef]  [PubMed]

[26]Xydakis MS, Dehgani-Mobaraki P, Holbrook EH, Geisthoff UW, Bauer C, Hautefort C, Smell and taste dysfunction in patients with COVID-19 Lancet Infect Dis 2020 20(9):1015-16.10.1016/S1473-3099(20)30293-0  [Google Scholar]  [CrossRef]

[27]Bénézit F, Le Turnier P, Declerck C, Paillé C, Revest M, Dubée V, Utility of hyposmia and hypogeusia for the diagnosis of COVID-19 Lancet Infect Dis 2020 20(9):1014-15.10.1016/S1473-3099(20)30297-8  [Google Scholar]  [CrossRef]

[28]Ollarves-Carrero MF, Rodriguez-Morales AG, Bonilla-Aldana DK, Rodriguez-Morales AJ, Anosmia in a healthcare worker with COVID-19 in Madrid, Spain Travel Med Infect Dis 2020 35:10166610.1016/j.tmaid.2020.10166632298782  [Google Scholar]  [CrossRef]  [PubMed]

[29]Jang Y, Son H-J, Lee S, Lee EJ, Kim TH, Park SY, Olfactory and taste disorder: The first and only sign in a patient with SARS-CoV-2 pneumonia Infect Control Hosp Epidemiol 2020 41(9)10.1017/ice.2020.15132307026  [Google Scholar]  [CrossRef]  [PubMed]

[30]Beltrán-Corbellini Á, Chico-García JL, Martínez-Poles J, Rodríguez-Jorge F, Natera-Villalba E, Gómez-Corral J, Acute-onset smell and taste disorders in the context of Covid-19: A pilot multicenter PCR-based case-control study Eur J Neurol 2020 27(9):1738-41.10.1111/ene.1427332320508  [Google Scholar]  [CrossRef]  [PubMed]

[31]Tostmann A, Bradley J, Bousema T, Yiek W-K, Holwerda M, Bleeker-Rovers C, Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020 Eurosurveillance 2020 25(16):200050810.2807/1560-7917.ES.2020.25.16.200050832347200  [Google Scholar]  [CrossRef]  [PubMed]

[32]Wee LE, Chan YFZ, Teo NWY, Cherng BPZ, Thien SY, Wong HM, The role of self-reported olfactory and gustatory dysfunction as a screening criterion for suspected COVID-19 Eur Arch Otorhinolaryngol 2020 277:2389-90.Available from: https://doi.org/10.1007/s00405-020-05999-510.1007/s00405-020-05999-532328771  [Google Scholar]  [CrossRef]  [PubMed]

[33]Pradeep S, Pandya K, Nagappan N, Vidhyadharan S, Hedne N, A systematic review and meta-analysis on olfactory and gustatory symptoms of coronavirus disease (COVID-19). PROSPERO International prospective register of systematic reviews National Institute of Health Research 24 April 2020 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020181841  [Google Scholar]

[34]Study Quality Assessment Tools. National Heart, Lung, and Blood Institute (NHLBI) [Internet]. Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools[cited 2020 Apr 29]  [Google Scholar]

[35]Background: Development and Use of Study Quality Assessment Tools. National Heart, Lung, and Blood Institute (NHLBI) [Internet]. Available from: https://www.nhlbi.nih.gov/node/80102 [cited 2020 May 12]  [Google Scholar]

[36]Higgins JPT, Thompson SG, Deeks JJ, Altman DG, Measuring inconsistency in meta-analyses BMJ 2003 327(7414):557-60.10.1136/bmj.327.7414.55712958120  [Google Scholar]  [CrossRef]  [PubMed]

[37]Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P, Mat Q, Clinical and epidemiological characteristics of 1,420 european patients with mild-to-moderate coronavirus disease 2019 Journal of Internal Medicine 2020 288:335-44.10.1111/joim.1308932352202  [Google Scholar]  [CrossRef]  [PubMed]

[38]Yan CH, Faraji F, Prajapati DP, Ostrander BT, DeConde AS, Self-reported olfactory loss associates with outpatient clinical course in Covid-19 Int Forum Allergy Rhinol 2020 10(7):821-31.10.1002/alr.2259232329222  [Google Scholar]  [CrossRef]  [PubMed]

[39]Vaira LA, Deiana G, Fois AG, Pirina P, Madeddu G, De Vito A, Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases Head and Neck-Journal of the Sciences and Specialties of Head and Neck 2020 42(6):1252-58.10.1002/hed.2620432342566  [Google Scholar]  [CrossRef]  [PubMed]

[40]Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection JAMA [Internet] 2020 323(20):2089-90.10.1001/jama.2020.677132320008  [Google Scholar]  [CrossRef]  [PubMed]

[41]Li W, Zhang C, Sui J, Kuhn JH, Moore MJ, Luo S, Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2 EMBO J 2005 24(8):1634-43.10.1038/sj.emboj.760064015791205  [Google Scholar]  [CrossRef]  [PubMed]

[42]Vukkadala N, Qian ZJ, Holsinger FC, Patel ZM, Rosenthal E, COVID-19 and the otolaryngologist: Preliminary evidence-based review The Laryngoscope 2020 Mar 26 10.1002/lary.2867232219846  [Google Scholar]  [CrossRef]  [PubMed]

[43]Finsterer J, Stollberger C, Causes of hypogeusia/hyposmia in SARS-CoV2 infected patients J Med Virol 2020 92(10):1793-94.10.1002/jmv.2590332311107  [Google Scholar]  [CrossRef]  [PubMed]

[44]Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S, Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2 J Virol 2008 82(15):7264-75.10.1128/JVI.00737-0818495771  [Google Scholar]  [CrossRef]  [PubMed]

[45]Li YC, Bai WZ, Hashikawa T, The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients J Med Virol 2020 92(6):552-55.10.1002/jmv.2572832104915  [Google Scholar]  [CrossRef]  [PubMed]

[46]Deems DA, Doty RL, Settle RG, Moore-Gillon V, Shaman P, Mester AF, Smell and taste disorders, a study of 750 patients from the University of Pennsylvania smell and taste center Arch Otolaryngol Head Neck Surg 1991 117(5):519-28.10.1001/archotol.1991.018701700650152021470  [Google Scholar]  [CrossRef]  [PubMed]

[47]Burdach KJ, Doty RL, The effects of mouth movements, swallowing, and spitting on retronasal odor perception Physiol Behav 1987 41(4):353-56.10.1016/0031-9384(87)90400-8  [Google Scholar]  [CrossRef]

[48]Eliezer M, Hautefort C, Hamel AL, Verillaud B, Herman P, Houdart E, Sudden and complete olfactory loss of function as a possible symptom of COVID-19 JAMA Otolaryngol Head Neck Surg 2020 146(7):674-75.10.1001/jamaoto.2020.083232267483  [Google Scholar]  [CrossRef]  [PubMed]

[49]Etoom M, Alwardat S, Alwardat M, Issues for conducting meta-analyses in COVID-19. Commentary on “Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis’’ J Clin Virol Off Publ Pan Am Soc Clin Virol 2020 128:10438910.1016/j.jcv.2020.10438932387969  [Google Scholar]  [CrossRef]  [PubMed]