QJM: An International Journal of Medicine

Hawkes, Christopher H

doi: 10.1093/qjmed/hcaa326pmid: 33340323

Summary During the COVID-19 pandemic, it became clear that smell and taste (chemosensory) disturbance is very common in the early stages of disease. This article addresses (i) why COVID-19 specifically targets the modalities of smell and possibly taste and what is the mechanism, (ii) what is the frequency of smell and taste loss and (iii) what is the overall prognosis. It is suggested that mouth-breathers may be at particular risk of COVID-19. Symptom-based questionnaires are likely to under-estimate the prevalence of chemosensory impairment by as much as 50%. The prevalence of smell loss is so high that a person who has normal olfaction on formal testing is unlikely to be infected significantly with Cov-2. Furthermore, someone without symptoms who has an abnormal smell test could still be infected and liable to spread the disease. Brief, low-cost, olfactory tests are available that would permit a high throughput in field stations and airports. A normal result might obviate the need for a nasopharyngeal swab for the Cov-2 virus. Introduction On 20 March 2020, Claire Hopkins, President of the British Rhinological Society and Nirmal Kumar, President of ENT UK1 circulated a letter to fellow members that drew attention to the heightened incidence of isolated anosmia in their clinics. In normal circumstances, they would see around one case of post-viral anosmia per month whereas in the recent past this had increased to 4 per week and remarkably all were under 40 years old. They questioned whether new onset anosmia in relatively young people might be an early warning of COVID-19 infection and emphasized the presence of similar observations from China, South Korea and Iran. It is unusual for impairment of smell sense to be such a prominent symptom of upper respiratory viral infection. The majority of the latter are recognized in ear, nose and throat (ENT) units particularly as a symptom from middle-aged or elderly in the aftermath of upper respiratory infection (URT). Most individuals who experience URT such as the common cold, accept a degree of smell impairment that results typically from a blocked nose, but what is remarkable about COVID-19 is that its occurrence is often early, of acute onset, severe and only occasionally associated with a blocked nose.2,3 These thoughts have been given preliminary support from a study of 10 patients with proven COVID-19 infection compared to 10 people with an acute cold and 10 healthy controls.4 Using the extended version of Sniffin’ Sticks there were significant differences: those with COVID-19 infection scored lower than the acute cold group, with identification scores affected more than threshold or discrimination. Several questions arise: why should COVID-19 specifically target chemosensation (i.e. smell and taste) and what is the mechanism? What is the frequency of smell and taste loss and what is the overall prognosis? Why should COVID-19 specifically target the sense of smell and possibly taste? Preliminary information about the likely mode of nasal invasion is just emerging. The virus, SARS-CoV-2, (shortened here to Cov-2) that causes the illness, COVID-19, infects cells through interactions between its spike protein and the ACE2 protein on target cells (Figure 1). Figure 1. Open in new tabDownload slide Molecular structure of the SARS-Cov-2 virus to show how the virus can attach to a pneumocyte (alveolar cell) that lines the alveoli. Reproduced with permission from David Baker, Blizard Institute, Queen Mary, University of London. Figure 1. Open in new tabDownload slide Molecular structure of the SARS-Cov-2 virus to show how the virus can attach to a pneumocyte (alveolar cell) that lines the alveoli. Reproduced with permission from David Baker, Blizard Institute, Queen Mary, University of London. This interaction requires cleavage of the spike protein, likely by the cell surface protease, serine (TMPRSS2) and other proteases such as cathepsin B and L. It has been demonstrated that non-olfactory epithelial cells from the human upper airway express high levels of ACE2 and serine proteases5 as shown in Figure 2, a finding that implies they could act as a viral reservoir. Figure 2. Open in new tabDownload slide Simplified model for CoV-2-induced anosmia/hyposmia in COVID-19 based on results obtained from patients and animal models. Article from Open Access journal reproduced with permission from Bilinska and Butowt.6 Figure 2. Open in new tabDownload slide Simplified model for CoV-2-induced anosmia/hyposmia in COVID-19 based on results obtained from patients and animal models. Article from Open Access journal reproduced with permission from Bilinska and Butowt.6 According to Brann et al.,7 olfactory epithelial sustentacular cells, horizontal basal cells and Bowman’s gland cells express the receptors required for entry of CoV-2 but there is no ACE2 expression in mature olfactory receptor neurones. In essence, they propose that the anosmia of COVID-19 relates to primary infection of non-neuronal cell types and by implication, that smell loss is a consequence of local inflammation in and around the nasal neuro-epithelium. This concept has received preliminary confirmation from magnetic resonance imaging (MRI)-based studies that reveal congestion in the olfactory cleft—the area that houses olfactory neurones.8 Although these findings are plausible, it is possible, as the authors suggest, that other non-ACE2 dependent receptors may facilitate cellular entry of CoV-2. These observations are preliminary and it is still possible that CoV-2 may involve the olfactory bulb. Indeed MRI-based studies have shown oedema of the olfactory bulb9 (Figure 3) as well as more central changes, namely in the gyrus rectus10 and by computed tomography/positron emission tomography (CT/PET), in the orbitofrontal cortex.11 Figure 3. Open in new tabDownload slide Transient olfactory bulb oedema as shown in coronal 3D MRI T2-weighted imaging (1.5 T) during anosmia (day 7; C) compared to recovery (day 24; D). Olfactory bulb (ob; pink) displays transient volume and signal increase, olfactory cleft oedema (OC; brown), and focal left ethmoid (eth; green) sinusitis (*), and normal cranial fossa (grey line) and orbit (orb; yellow). Reproduced from Figure 1C and D with permission from Laurendon et al.9 Figure 3. Open in new tabDownload slide Transient olfactory bulb oedema as shown in coronal 3D MRI T2-weighted imaging (1.5 T) during anosmia (day 7; C) compared to recovery (day 24; D). Olfactory bulb (ob; pink) displays transient volume and signal increase, olfactory cleft oedema (OC; brown), and focal left ethmoid (eth; green) sinusitis (*), and normal cranial fossa (grey line) and orbit (orb; yellow). Reproduced from Figure 1C and D with permission from Laurendon et al.9 There is provisional evidence that ACE2 receptors are present in the tongue (Figure 4), particularly taste buds and to lesser degree in the lingual epithelium.12,13 Cov-2 can be isolated from saliva,14 thus there is a plausible mechanism for such infection to involve taste bud receptors. Less is known about ACE2 expression in the major taste nerves, namely the chorda tympani and glossopharyngeal nerves. Figure 4. Open in new tabDownload slide Bulk RNA-seq analysis of public datasets. Bar plot of ACE2 expression in normal tissues from FANTOM5 CAGE dataset, coloured by organs. Reproduced from Figure 1b with permission under Open Access from: Xu et al.14 Figure 4. Open in new tabDownload slide Bulk RNA-seq analysis of public datasets. Bar plot of ACE2 expression in normal tissues from FANTOM5 CAGE dataset, coloured by organs. Reproduced from Figure 1b with permission under Open Access from: Xu et al.14 What is the frequency of chemosensory loss? There have been numerous estimates worldwide, but with a few exceptions detailed below, most have been based on questionnaire surveys without objective measurement and several have not contained a control group. Samples have been varied: some are based predominantly on out-patients; others reliant on in-patients with testing at varying stages of illness. The largest investigation15,16 employed a smartphone-based app to retrieve symptomatic data on over 2 million people in UK and USA and found that in those reporting chemosensory impairment, 65% had a subsequent positive polymerase chain reaction (PCR) for COVID-19. When this was combined with fever, cough, fatigue and loss of appetite the correlation with PCR for Cov-2 was very high. Another large meta-analysis totalling 38 198 subjects17 documented an overall prevalence of smell impairment of 49% in Caucasians and 16.7% in Asians. Taste symptoms occurred in 51% Caucasians and 18% Asians. Other studies show wide estimates of prevalence—up to 70%18 with an approximately equal rate for smell or taste. Sometimes isolated impairment of smell or taste is documented as a presenting symptom. A study from San Diego, based on ambulatory individuals with influenza-like symptoms, noticed that subjective report of smell impairment was associated with a 10-fold lower risk of hospital admission for COVID-19.19 This finding is discussed further below. Surveys that have relied on patient reports are susceptible to multiple confounders including recall bias20 and a tendency to over-representation of female respondents.21 Even more importantly, less than 40% of individuals are actually aware of a proven olfactory defect.22 For subjective awareness, the defect needs to be bilateral and of at least moderate severity. Furthermore, smell loss and taste loss are very frequently confused. Most people who complain of impaired taste have reduced olfaction23 whereas it is unusual for someone with primary taste loss to complain of smell impairment. The mechanism of this phenomenon has not been satisfactorily explained. Patient reports of olfactory impairment are therefore intrinsically unreliable and will tend to under-estimate the true picture due to lack of awareness and confusion with taste. Furthermore, if taste is really affected in COVID-19 any such deficiency would inflate estimates of smell impairment where based on subjective reports. According to PubMed, at the time of writing (October 2020) there have been 14 articles worldwide where various objective olfactory measurements have been made (Table 1). Case numbers range by centre from 14 to 345 individuals. In nearly all instances, a confirmatory PCR test for Cov-2 has been undertaken. In only nine cases was there a control group and where present the PCR test is not stated in seven of these. Matching by age and gender was performed in just four instances. Subjective awareness of olfactory loss was indicated in 12 studies with a prevalence ranging from 28% to 86% (mean 54%). Some authors have used non-standard olfactory measurement, e.g. modified ethyl-alcohol threshold test24 or an in-house identification test of 10 odours25 neither containing details of control data. In one article, patients quarantined at home were instructed on how to make up their own smell and taste ingredients,26 despite the existence of readily available standardized commercial test kits for home use. The 4-odour Pocket Smell Identification Test used by one group27 or the 3-odour Quick Smell Identification Test (Q-SIT) employed by others28,29 are more appropriate for rapid screening in the clinic, rather than large research projects. For example, a score of 3/3 correct answers on the Q-SIT is likely to indicate normal olfaction30 but as emphasized by the authors, a value of 2/3 could represent either hyposmia or a normal result because of wide variance. Nonetheless, a score of 3/3 would help exclude anosmia where a low-cost, high-volume survey is required. The data from Iran31,32 have been criticized unfairly because many of the 40 odours used in the identification kit were allegedly unfamiliar to Iranians.33 However, the test used was in fact specifically modified to account for cultural differences.34 Table 1. Summary of articles where objective chemosensory testing was undertaken Reference and country of test Listed alphabetically by lead author . Type of tests . CASES Number, source, mean age/gender, Cov-2 PCR status. Time of testing . CONTROLS Number, source, mean age/gender COVID-19 PCR status. Time of testing . CASES Number aware of smell/or taste impairment . CASES Smell test results . CONTROLS Smell test results . CASES Taste test results . Altin37 Turkey 16 odour SST ID test In-house taste ID of sucrose, salt, vinegar and coffee. 81 in-patients. 40 female. Mean age: 54 years. All PCR positive. TOT not stated. 40 age/gender matched healthy controls. 19 female (47%). Mean age: 55 years. Source not stated. All PCR negative. TOT not stated. 50/81 (62%) Median score 6/16 Percent abnormal not stated Median score 10/16 Percent abnormal not stated 22/81 (27%) abnormal Bocksberger36 Germany 12 odour SST ID test Taste Strips Test 14 in-patients for smell tests. Taste test in 10. Mean age 46 years. 13 female. Cov-2 status not stated. TOT 4–23 days from symptom onset None 26/63 (41%) complained of loss of smell or taste 10/14 (71%) abnormal Not helped by nasal decongestant None All 10 patients were normal Calvo-Henriquez24 Spain Modified ethyl-alcohol threshold test 129 in- or out-patients. Mean age 55 years. 67 (52%) female. Severe cases excluded. All PCR positive. TOT not given 146 healthy hospital staff Mean age 55 years. 76 female. (52%). PCR: not stated. TOT not given Not stated Abnormal threshold Not supplied directly Not done Chung38 Hong Kong UPSIT and Butanol threshold test (BTT) 18 mildly infected in-patients. Mean age 28 years. 11 female (61%). All PCR positive. Median TOT: 14 days. 18 students or health-care workers. Mean age 31 years. 13 (72%) female. PCR not stated. TOT not stated 12/18 (67%) Abnormal BTT in 6/18 (33%). All 6 had abnormal UPSIT. Not given Not done Hintschich27 Germany Pocket Smell Test (four odours) Taste Strips Test Both self-administered 41 patients under home quarantine. All PCR positive. Median age 37 years. 28 (68%) female. TOT: 3 days after positive PCR. Median of 13 days after first symptoms 30 patients. Source: not stated. Median age 33 years. 22 (73%) female. All negative for IgG antibodies. TOT not stated. 25 (61%) for smell. 18 (44%) for taste 22 (54%) abnormal Where there was subjective loss of smell, abnormal in 18 (72%) Not stated Not significantly different from controls Hornuss35 Germany 12 odour SST ID test 45 in-patients. 20 female (44%). Median age 56 years. All PCR positive. Mean duration of symptoms/time of testing: 10 days. 45 asymptomatic in-patients or health-care workers. Median age 54 years. Gender not stated. PCR: not done. TOT not stated Smell: 22/45 (49%) 38/45 (84%) abnormal 12/45 (27%) abnormal Not done Le Bon39 Belgium Extended SST (threshold, discrimination and Identification to 16 odours). Taste Strips Test 72 out-patients. 49 (68%) female. Mean age 38.9 years. 25 PCR positive. 47 IgG antibody positive. TOT: mean of 37 days after symptom onset None Smell: 100% as self selected 27/72 (38%) abnormal Main effect on threshold scores. 45 normal (62%). None 5/72 (7%) abnormal. Lechien40 Belgium 16 odour SST ID test 46 out-patients with ‘initial sudden olfactory anosmia’. Mean age: 40.6 years. 46 female (59%) PCR positive in 42/46 when tested in <12 days from symptom onset None Smell: 35/41 (86%) had subjective loss as reported from earlier study 35/46 (76%) abnormal overall None Not done Lima28 Brazil Q-SIT. 3 odour ID test 57 out-patients. 31 females (54%). Mean age 41.4 years. All PCR positive. All but two had mild disease. Mean symptom duration: 4 days. Total: 36. Source not stated. Mean age: 37.2 years. 19 female (53%). PCR: not stated. TOT not stated Smell: 34/57 (60%). 20/23 (87%) abnormal in those with subjective smell loss. 11/34 (32%) abnormal in those without subjective smell loss. 4/36 (11%) abnormal Not done Moein31 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 60. All in-patients. 20 female (33%). Mean age: 46 years. All PCR positive. TOT: <14 days of symptom onset 60 healthy sex- and age-matched controls from prior study. PCR: not stated. Smell: 21/60 (35%) 59/60 (98%) abnormal Mean UPSIT score 21/40. 11/60 (18%) abnormal. Mean score 34/40 (normal) Not done Moein32 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 100 initial in-patients. Mean age 45 years. 33 females (33%). TOT: near end of acute disease phase. After symptom onset 82 retested at 1–4 weeks. 51 retested at 6–8 weeks. All PCR positive 51 healthy age- and sex-matched to 52 COVID patients from prior study. 19 female (37%). Mean age 45.4 years. PCR: not stated. Smell: 28/100 (28%) 96/100 (96%) abnormal on initial testing. Mean UPSIT score 22/40 Not stated. Not done Tsivgoulis29 Greece Q-SIT. 3 odour ID test Total: 22 in-patients. Mean age 55 years. 10 female (45%). TOT: mean of 12 days after hospital admission. All PCR positive 22 age- and sex-matched controls taken from movement disorders clinic. PCR: not stated. TOT not stated. Not stated 17/22 (77%) abnormal 8/22 (36%) abnormal Not done Vaira25 Sardinia CCCRC. In-house ID of 10 odours and butanol threshold. In-house taste identification for: salt, sugar, lemon and coffee solutions Total: 72 health personnel. 25 in-patients. Others out-patients. 45 female (62%). Mean age 49 years. TOT: mean 19 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 53/72 (74%). 60/72 (83%) abnormal for composite olfactory score (threshold and discrimination) None Abnormal: 35/72 (49%) Vaira26 Italian multicentre For quarantined patients: home self-administered and prepared odour discrimination test to six odour classes. Also used home self-administered and prepared solutions to four tastants. For in-patients: CCCRC Total 345 patients. 161 in quarantine (self-evaluated at home). 184 in-patients. 199 (58%) female. Mean age 49 years. TOT: mean 15 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 256 (74%) Overall percentages not supplied. From sequential graphs: around 70% abnormal for olfaction. 45% overall abnormal on taste test. None Abnormal in 190 cases (45%) Reference and country of test Listed alphabetically by lead author . Type of tests . CASES Number, source, mean age/gender, Cov-2 PCR status. Time of testing . CONTROLS Number, source, mean age/gender COVID-19 PCR status. Time of testing . CASES Number aware of smell/or taste impairment . CASES Smell test results . CONTROLS Smell test results . CASES Taste test results . Altin37 Turkey 16 odour SST ID test In-house taste ID of sucrose, salt, vinegar and coffee. 81 in-patients. 40 female. Mean age: 54 years. All PCR positive. TOT not stated. 40 age/gender matched healthy controls. 19 female (47%). Mean age: 55 years. Source not stated. All PCR negative. TOT not stated. 50/81 (62%) Median score 6/16 Percent abnormal not stated Median score 10/16 Percent abnormal not stated 22/81 (27%) abnormal Bocksberger36 Germany 12 odour SST ID test Taste Strips Test 14 in-patients for smell tests. Taste test in 10. Mean age 46 years. 13 female. Cov-2 status not stated. TOT 4–23 days from symptom onset None 26/63 (41%) complained of loss of smell or taste 10/14 (71%) abnormal Not helped by nasal decongestant None All 10 patients were normal Calvo-Henriquez24 Spain Modified ethyl-alcohol threshold test 129 in- or out-patients. Mean age 55 years. 67 (52%) female. Severe cases excluded. All PCR positive. TOT not given 146 healthy hospital staff Mean age 55 years. 76 female. (52%). PCR: not stated. TOT not given Not stated Abnormal threshold Not supplied directly Not done Chung38 Hong Kong UPSIT and Butanol threshold test (BTT) 18 mildly infected in-patients. Mean age 28 years. 11 female (61%). All PCR positive. Median TOT: 14 days. 18 students or health-care workers. Mean age 31 years. 13 (72%) female. PCR not stated. TOT not stated 12/18 (67%) Abnormal BTT in 6/18 (33%). All 6 had abnormal UPSIT. Not given Not done Hintschich27 Germany Pocket Smell Test (four odours) Taste Strips Test Both self-administered 41 patients under home quarantine. All PCR positive. Median age 37 years. 28 (68%) female. TOT: 3 days after positive PCR. Median of 13 days after first symptoms 30 patients. Source: not stated. Median age 33 years. 22 (73%) female. All negative for IgG antibodies. TOT not stated. 25 (61%) for smell. 18 (44%) for taste 22 (54%) abnormal Where there was subjective loss of smell, abnormal in 18 (72%) Not stated Not significantly different from controls Hornuss35 Germany 12 odour SST ID test 45 in-patients. 20 female (44%). Median age 56 years. All PCR positive. Mean duration of symptoms/time of testing: 10 days. 45 asymptomatic in-patients or health-care workers. Median age 54 years. Gender not stated. PCR: not done. TOT not stated Smell: 22/45 (49%) 38/45 (84%) abnormal 12/45 (27%) abnormal Not done Le Bon39 Belgium Extended SST (threshold, discrimination and Identification to 16 odours). Taste Strips Test 72 out-patients. 49 (68%) female. Mean age 38.9 years. 25 PCR positive. 47 IgG antibody positive. TOT: mean of 37 days after symptom onset None Smell: 100% as self selected 27/72 (38%) abnormal Main effect on threshold scores. 45 normal (62%). None 5/72 (7%) abnormal. Lechien40 Belgium 16 odour SST ID test 46 out-patients with ‘initial sudden olfactory anosmia’. Mean age: 40.6 years. 46 female (59%) PCR positive in 42/46 when tested in <12 days from symptom onset None Smell: 35/41 (86%) had subjective loss as reported from earlier study 35/46 (76%) abnormal overall None Not done Lima28 Brazil Q-SIT. 3 odour ID test 57 out-patients. 31 females (54%). Mean age 41.4 years. All PCR positive. All but two had mild disease. Mean symptom duration: 4 days. Total: 36. Source not stated. Mean age: 37.2 years. 19 female (53%). PCR: not stated. TOT not stated Smell: 34/57 (60%). 20/23 (87%) abnormal in those with subjective smell loss. 11/34 (32%) abnormal in those without subjective smell loss. 4/36 (11%) abnormal Not done Moein31 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 60. All in-patients. 20 female (33%). Mean age: 46 years. All PCR positive. TOT: <14 days of symptom onset 60 healthy sex- and age-matched controls from prior study. PCR: not stated. Smell: 21/60 (35%) 59/60 (98%) abnormal Mean UPSIT score 21/40. 11/60 (18%) abnormal. Mean score 34/40 (normal) Not done Moein32 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 100 initial in-patients. Mean age 45 years. 33 females (33%). TOT: near end of acute disease phase. After symptom onset 82 retested at 1–4 weeks. 51 retested at 6–8 weeks. All PCR positive 51 healthy age- and sex-matched to 52 COVID patients from prior study. 19 female (37%). Mean age 45.4 years. PCR: not stated. Smell: 28/100 (28%) 96/100 (96%) abnormal on initial testing. Mean UPSIT score 22/40 Not stated. Not done Tsivgoulis29 Greece Q-SIT. 3 odour ID test Total: 22 in-patients. Mean age 55 years. 10 female (45%). TOT: mean of 12 days after hospital admission. All PCR positive 22 age- and sex-matched controls taken from movement disorders clinic. PCR: not stated. TOT not stated. Not stated 17/22 (77%) abnormal 8/22 (36%) abnormal Not done Vaira25 Sardinia CCCRC. In-house ID of 10 odours and butanol threshold. In-house taste identification for: salt, sugar, lemon and coffee solutions Total: 72 health personnel. 25 in-patients. Others out-patients. 45 female (62%). Mean age 49 years. TOT: mean 19 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 53/72 (74%). 60/72 (83%) abnormal for composite olfactory score (threshold and discrimination) None Abnormal: 35/72 (49%) Vaira26 Italian multicentre For quarantined patients: home self-administered and prepared odour discrimination test to six odour classes. Also used home self-administered and prepared solutions to four tastants. For in-patients: CCCRC Total 345 patients. 161 in quarantine (self-evaluated at home). 184 in-patients. 199 (58%) female. Mean age 49 years. TOT: mean 15 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 256 (74%) Overall percentages not supplied. From sequential graphs: around 70% abnormal for olfaction. 45% overall abnormal on taste test. None Abnormal in 190 cases (45%) CCCRC, Connecticut Chemosensory Clinical Research Center Orthonasal Olfaction Test; PCR, polymerase chain reaction; ID, identification; Q-SIT, Quick Smell Identification Test; UPSIT, University of Pennsylvania Smell Identification Test; SST, Sniffin’ Sticks test; TOT, time of testing. The Taste Strips Test uses four tastants at four different concentrations. Open in new tab Table 1. Summary of articles where objective chemosensory testing was undertaken Reference and country of test Listed alphabetically by lead author . Type of tests . CASES Number, source, mean age/gender, Cov-2 PCR status. Time of testing . CONTROLS Number, source, mean age/gender COVID-19 PCR status. Time of testing . CASES Number aware of smell/or taste impairment . CASES Smell test results . CONTROLS Smell test results . CASES Taste test results . Altin37 Turkey 16 odour SST ID test In-house taste ID of sucrose, salt, vinegar and coffee. 81 in-patients. 40 female. Mean age: 54 years. All PCR positive. TOT not stated. 40 age/gender matched healthy controls. 19 female (47%). Mean age: 55 years. Source not stated. All PCR negative. TOT not stated. 50/81 (62%) Median score 6/16 Percent abnormal not stated Median score 10/16 Percent abnormal not stated 22/81 (27%) abnormal Bocksberger36 Germany 12 odour SST ID test Taste Strips Test 14 in-patients for smell tests. Taste test in 10. Mean age 46 years. 13 female. Cov-2 status not stated. TOT 4–23 days from symptom onset None 26/63 (41%) complained of loss of smell or taste 10/14 (71%) abnormal Not helped by nasal decongestant None All 10 patients were normal Calvo-Henriquez24 Spain Modified ethyl-alcohol threshold test 129 in- or out-patients. Mean age 55 years. 67 (52%) female. Severe cases excluded. All PCR positive. TOT not given 146 healthy hospital staff Mean age 55 years. 76 female. (52%). PCR: not stated. TOT not given Not stated Abnormal threshold Not supplied directly Not done Chung38 Hong Kong UPSIT and Butanol threshold test (BTT) 18 mildly infected in-patients. Mean age 28 years. 11 female (61%). All PCR positive. Median TOT: 14 days. 18 students or health-care workers. Mean age 31 years. 13 (72%) female. PCR not stated. TOT not stated 12/18 (67%) Abnormal BTT in 6/18 (33%). All 6 had abnormal UPSIT. Not given Not done Hintschich27 Germany Pocket Smell Test (four odours) Taste Strips Test Both self-administered 41 patients under home quarantine. All PCR positive. Median age 37 years. 28 (68%) female. TOT: 3 days after positive PCR. Median of 13 days after first symptoms 30 patients. Source: not stated. Median age 33 years. 22 (73%) female. All negative for IgG antibodies. TOT not stated. 25 (61%) for smell. 18 (44%) for taste 22 (54%) abnormal Where there was subjective loss of smell, abnormal in 18 (72%) Not stated Not significantly different from controls Hornuss35 Germany 12 odour SST ID test 45 in-patients. 20 female (44%). Median age 56 years. All PCR positive. Mean duration of symptoms/time of testing: 10 days. 45 asymptomatic in-patients or health-care workers. Median age 54 years. Gender not stated. PCR: not done. TOT not stated Smell: 22/45 (49%) 38/45 (84%) abnormal 12/45 (27%) abnormal Not done Le Bon39 Belgium Extended SST (threshold, discrimination and Identification to 16 odours). Taste Strips Test 72 out-patients. 49 (68%) female. Mean age 38.9 years. 25 PCR positive. 47 IgG antibody positive. TOT: mean of 37 days after symptom onset None Smell: 100% as self selected 27/72 (38%) abnormal Main effect on threshold scores. 45 normal (62%). None 5/72 (7%) abnormal. Lechien40 Belgium 16 odour SST ID test 46 out-patients with ‘initial sudden olfactory anosmia’. Mean age: 40.6 years. 46 female (59%) PCR positive in 42/46 when tested in <12 days from symptom onset None Smell: 35/41 (86%) had subjective loss as reported from earlier study 35/46 (76%) abnormal overall None Not done Lima28 Brazil Q-SIT. 3 odour ID test 57 out-patients. 31 females (54%). Mean age 41.4 years. All PCR positive. All but two had mild disease. Mean symptom duration: 4 days. Total: 36. Source not stated. Mean age: 37.2 years. 19 female (53%). PCR: not stated. TOT not stated Smell: 34/57 (60%). 20/23 (87%) abnormal in those with subjective smell loss. 11/34 (32%) abnormal in those without subjective smell loss. 4/36 (11%) abnormal Not done Moein31 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 60. All in-patients. 20 female (33%). Mean age: 46 years. All PCR positive. TOT: <14 days of symptom onset 60 healthy sex- and age-matched controls from prior study. PCR: not stated. Smell: 21/60 (35%) 59/60 (98%) abnormal Mean UPSIT score 21/40. 11/60 (18%) abnormal. Mean score 34/40 (normal) Not done Moein32 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 100 initial in-patients. Mean age 45 years. 33 females (33%). TOT: near end of acute disease phase. After symptom onset 82 retested at 1–4 weeks. 51 retested at 6–8 weeks. All PCR positive 51 healthy age- and sex-matched to 52 COVID patients from prior study. 19 female (37%). Mean age 45.4 years. PCR: not stated. Smell: 28/100 (28%) 96/100 (96%) abnormal on initial testing. Mean UPSIT score 22/40 Not stated. Not done Tsivgoulis29 Greece Q-SIT. 3 odour ID test Total: 22 in-patients. Mean age 55 years. 10 female (45%). TOT: mean of 12 days after hospital admission. All PCR positive 22 age- and sex-matched controls taken from movement disorders clinic. PCR: not stated. TOT not stated. Not stated 17/22 (77%) abnormal 8/22 (36%) abnormal Not done Vaira25 Sardinia CCCRC. In-house ID of 10 odours and butanol threshold. In-house taste identification for: salt, sugar, lemon and coffee solutions Total: 72 health personnel. 25 in-patients. Others out-patients. 45 female (62%). Mean age 49 years. TOT: mean 19 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 53/72 (74%). 60/72 (83%) abnormal for composite olfactory score (threshold and discrimination) None Abnormal: 35/72 (49%) Vaira26 Italian multicentre For quarantined patients: home self-administered and prepared odour discrimination test to six odour classes. Also used home self-administered and prepared solutions to four tastants. For in-patients: CCCRC Total 345 patients. 161 in quarantine (self-evaluated at home). 184 in-patients. 199 (58%) female. Mean age 49 years. TOT: mean 15 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 256 (74%) Overall percentages not supplied. From sequential graphs: around 70% abnormal for olfaction. 45% overall abnormal on taste test. None Abnormal in 190 cases (45%) Reference and country of test Listed alphabetically by lead author . Type of tests . CASES Number, source, mean age/gender, Cov-2 PCR status. Time of testing . CONTROLS Number, source, mean age/gender COVID-19 PCR status. Time of testing . CASES Number aware of smell/or taste impairment . CASES Smell test results . CONTROLS Smell test results . CASES Taste test results . Altin37 Turkey 16 odour SST ID test In-house taste ID of sucrose, salt, vinegar and coffee. 81 in-patients. 40 female. Mean age: 54 years. All PCR positive. TOT not stated. 40 age/gender matched healthy controls. 19 female (47%). Mean age: 55 years. Source not stated. All PCR negative. TOT not stated. 50/81 (62%) Median score 6/16 Percent abnormal not stated Median score 10/16 Percent abnormal not stated 22/81 (27%) abnormal Bocksberger36 Germany 12 odour SST ID test Taste Strips Test 14 in-patients for smell tests. Taste test in 10. Mean age 46 years. 13 female. Cov-2 status not stated. TOT 4–23 days from symptom onset None 26/63 (41%) complained of loss of smell or taste 10/14 (71%) abnormal Not helped by nasal decongestant None All 10 patients were normal Calvo-Henriquez24 Spain Modified ethyl-alcohol threshold test 129 in- or out-patients. Mean age 55 years. 67 (52%) female. Severe cases excluded. All PCR positive. TOT not given 146 healthy hospital staff Mean age 55 years. 76 female. (52%). PCR: not stated. TOT not given Not stated Abnormal threshold Not supplied directly Not done Chung38 Hong Kong UPSIT and Butanol threshold test (BTT) 18 mildly infected in-patients. Mean age 28 years. 11 female (61%). All PCR positive. Median TOT: 14 days. 18 students or health-care workers. Mean age 31 years. 13 (72%) female. PCR not stated. TOT not stated 12/18 (67%) Abnormal BTT in 6/18 (33%). All 6 had abnormal UPSIT. Not given Not done Hintschich27 Germany Pocket Smell Test (four odours) Taste Strips Test Both self-administered 41 patients under home quarantine. All PCR positive. Median age 37 years. 28 (68%) female. TOT: 3 days after positive PCR. Median of 13 days after first symptoms 30 patients. Source: not stated. Median age 33 years. 22 (73%) female. All negative for IgG antibodies. TOT not stated. 25 (61%) for smell. 18 (44%) for taste 22 (54%) abnormal Where there was subjective loss of smell, abnormal in 18 (72%) Not stated Not significantly different from controls Hornuss35 Germany 12 odour SST ID test 45 in-patients. 20 female (44%). Median age 56 years. All PCR positive. Mean duration of symptoms/time of testing: 10 days. 45 asymptomatic in-patients or health-care workers. Median age 54 years. Gender not stated. PCR: not done. TOT not stated Smell: 22/45 (49%) 38/45 (84%) abnormal 12/45 (27%) abnormal Not done Le Bon39 Belgium Extended SST (threshold, discrimination and Identification to 16 odours). Taste Strips Test 72 out-patients. 49 (68%) female. Mean age 38.9 years. 25 PCR positive. 47 IgG antibody positive. TOT: mean of 37 days after symptom onset None Smell: 100% as self selected 27/72 (38%) abnormal Main effect on threshold scores. 45 normal (62%). None 5/72 (7%) abnormal. Lechien40 Belgium 16 odour SST ID test 46 out-patients with ‘initial sudden olfactory anosmia’. Mean age: 40.6 years. 46 female (59%) PCR positive in 42/46 when tested in <12 days from symptom onset None Smell: 35/41 (86%) had subjective loss as reported from earlier study 35/46 (76%) abnormal overall None Not done Lima28 Brazil Q-SIT. 3 odour ID test 57 out-patients. 31 females (54%). Mean age 41.4 years. All PCR positive. All but two had mild disease. Mean symptom duration: 4 days. Total: 36. Source not stated. Mean age: 37.2 years. 19 female (53%). PCR: not stated. TOT not stated Smell: 34/57 (60%). 20/23 (87%) abnormal in those with subjective smell loss. 11/34 (32%) abnormal in those without subjective smell loss. 4/36 (11%) abnormal Not done Moein31 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 60. All in-patients. 20 female (33%). Mean age: 46 years. All PCR positive. TOT: <14 days of symptom onset 60 healthy sex- and age-matched controls from prior study. PCR: not stated. Smell: 21/60 (35%) 59/60 (98%) abnormal Mean UPSIT score 21/40. 11/60 (18%) abnormal. Mean score 34/40 (normal) Not done Moein32 Iran UPSIT. 40 odour ID test Revised Persian language version Total: 100 initial in-patients. Mean age 45 years. 33 females (33%). TOT: near end of acute disease phase. After symptom onset 82 retested at 1–4 weeks. 51 retested at 6–8 weeks. All PCR positive 51 healthy age- and sex-matched to 52 COVID patients from prior study. 19 female (37%). Mean age 45.4 years. PCR: not stated. Smell: 28/100 (28%) 96/100 (96%) abnormal on initial testing. Mean UPSIT score 22/40 Not stated. Not done Tsivgoulis29 Greece Q-SIT. 3 odour ID test Total: 22 in-patients. Mean age 55 years. 10 female (45%). TOT: mean of 12 days after hospital admission. All PCR positive 22 age- and sex-matched controls taken from movement disorders clinic. PCR: not stated. TOT not stated. Not stated 17/22 (77%) abnormal 8/22 (36%) abnormal Not done Vaira25 Sardinia CCCRC. In-house ID of 10 odours and butanol threshold. In-house taste identification for: salt, sugar, lemon and coffee solutions Total: 72 health personnel. 25 in-patients. Others out-patients. 45 female (62%). Mean age 49 years. TOT: mean 19 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 53/72 (74%). 60/72 (83%) abnormal for composite olfactory score (threshold and discrimination) None Abnormal: 35/72 (49%) Vaira26 Italian multicentre For quarantined patients: home self-administered and prepared odour discrimination test to six odour classes. Also used home self-administered and prepared solutions to four tastants. For in-patients: CCCRC Total 345 patients. 161 in quarantine (self-evaluated at home). 184 in-patients. 199 (58%) female. Mean age 49 years. TOT: mean 15 days from symptom onset. All PCR positive None Smell and/or taste symptoms in 256 (74%) Overall percentages not supplied. From sequential graphs: around 70% abnormal for olfaction. 45% overall abnormal on taste test. None Abnormal in 190 cases (45%) CCCRC, Connecticut Chemosensory Clinical Research Center Orthonasal Olfaction Test; PCR, polymerase chain reaction; ID, identification; Q-SIT, Quick Smell Identification Test; UPSIT, University of Pennsylvania Smell Identification Test; SST, Sniffin’ Sticks test; TOT, time of testing. The Taste Strips Test uses four tastants at four different concentrations. Open in new tab It is important to be aware of the time of olfactory assessment in calculating the prevalence of Cov-2 related smell impairment, whether based on questionnaires or psychophysical tests. Clearly, the closer to acute symptom onset, the more chance of an abnormal result. In four instances this information is not supplied. Where the time of testing is supplied, this ranges from 4 to 37 days. Taking into account the above reservations, there are just four more robust studies that have used standardized smell tests, have a control group, time of examining 14 days or less and adequate patient numbers, arbitrarily set at 45 or more.28,31,32,35 With this reservation, it may be inferred (i) that subjective awareness of smell impairment is highly variable, i.e. 28–49%, (ii) olfactory impairment on objective testing is present in 84–98%. (iii) in general, hospitalized patients who are assessed within 14 days of symptom onset have more abnormal smell tests (71–98%). The picture for out-patients is less clear. Compared to subjective patient reports, smell measurement will therefore uncover a further 40–50% of proven Cov-2 infected people, indicating that the olfactory defect is near universal. In practical terms, this means that an abnormal smell test may be present in someone with no symptoms and yet be capable of spreading the virus. Conversely, a normal standardized smell test such as the Sniffin’ Sticks or University of Pennsylvania Smell Identification Test (UPSIT) should help exclude the presence of COVID-19 and would be valuable for mass population screening. A less clear picture is available for the sense of taste. Only six studies report taste measurement (Table 1) and details of a control group are not given in four of these. Just three centres27,34,36 implemented a standardized measurement (taste strips) and documented a normal result in a total of 40 patients from two centres27,36 with an abnormal value from one unit34 (5/72; 7%). The other three25,26,37 used in-house tests and observed abnormalities ranging from 27% to 49%. No reliable conclusion can be drawn from these limited observations. Prognosis Some subjective patient reports describe recovery of olfaction in 2–6 weeks. This finding is exemplified by one article with serial longitudinal objective assessment.32 Return to normal was shown in nearly two-thirds (61%) within 8 weeks (Figure 5). At that point, 35% still had varying degrees of impairment although complete smell loss affected just 4%. Distortion of perceived smells (cacosmia) and smell hallucinations (phantosmia) are recognized in the established and disease recovery phase.40 Figure 5. Open in new tabDownload slide Proportion of patients with varying degrees of recovery according to COVID-19 symptom onset. All initial (n = 100) and follow-up (n = 82) scores are combined. Reproduced from Figure 4 with permission under Open Access from Moein et al.32 Figure 5. Open in new tabDownload slide Proportion of patients with varying degrees of recovery according to COVID-19 symptom onset. All initial (n = 100) and follow-up (n = 82) scores are combined. Reproduced from Figure 4 with permission under Open Access from Moein et al.32 The olfactory neuro-epithelium has considerable capacity for regeneration, provided the stem cell layer is not damaged.41 This process is unlikely to account for the rapid subjective recovery that in some instances appears complete in as little as 2 weeks (Figure 5). Such swift improvement is more in keeping with resolution of inflammation/oedema surrounding the nasal neuro-epithelium as shown on by MRI (Figure 3). There are insufficient reports relating to the prevalence and recovery of taste impairment. Potential risk for mouth-breathers There are multiple causes of mouth breathing. It relates usually to nasal obstruction from a displaced septum, congestion, polyps and a variety of developmental abnormalities of the nasal cavity including Down’s syndrome. In some it is just a bad habit. Most snorers breathe through the mouth and there is evidence that people with obstructive sleep apnoea are mouth-breathers.42 In the San Diego study of olfaction and COVID-19,19 it was speculated that milder cases of COVID-19 may present with severe anosmia and higher self-reporting, compared to the undetected or slight hyposmia associated with moderate to severe COVID-19 cases. If correct, this dichotomy may relate in part, to an individual’s pattern of inspiration. Thus, habitual nose-breathers would direct airborne virus into the nasal passages where there are multiple immune-based defence functions that serve as a primary mucosal immune barrier, e.g. the nasopharynx-associated lymphoid tissue43 (NALT) known collectively as Waldeyer’s ring. A mouth-breather would therefore bypass the nasal component, i.e. the adenoid and tubal tonsils and have to rely on the laryngeal and lingual tonsils. In theory, those who have had tonsillectomy or adenoidectomy might be more susceptible to subsequent viral infection although the consensus view is against this contention.44,45 A further defence mechanism favouring nose-breathers relates to increased synthesis of sino-nasal nitric oxide (NO) which is an integral and highly conserved part of the host immune response. It acts as a first-line of defence against micro-organisms and upregulates ciliary motility. At low concentration, NO acts as a signalling molecule that promotes growth and activity of immune cells. At high concentrations, it binds DNA, proteins and lipids, thereby inhibiting or killing target pathogens.46 In support of this in the clinical setting,47 six human volunteers were infected with human rhinovirus (HRV-16), a non-enveloped RNA virus. Elevated nitric oxide synthase mRNA was detected in nasal turbinate scrapings from infected individuals and increased levels of exhaled NO from the nose and lower airways. Others48 are exploring the possible benefits of inhaled nitric oxide in acute respiratory distress syndrome. Discussion Smell impairment occurs in COVID-19 probably by involvement of ACE2-expressing cells (particularly the sustentacular cells) in the nasal olfactory area rather than the olfactory neurones per se thus resulting in a local inflammatory response in the nasal cleft, thereby impairing olfactory transduction. Involvement of the olfactory bulb and its central connections may occur in more advanced cases. The value of subjective reports is severely limited by low sensitivity to an established smell defect and confusion with taste impairment. Objective testing suggests that there is smell loss in nearly all patients suffering from COVID-19. In theory, a mouth-breather would be more at risk of lung infection (and severe COVID-19) than a nose breather. Partial or complete smell recovery takes place in around two-thirds subjects over a period of 2–6 weeks. Hence, anosmia constitutes an important warning symptom and sign of infection by Cov-2 and has been highlighted in the UK public domain since June 2020. Olfactory testing elevates the detection rate of a defect by about 50%, i.e. from around 30–40% according to symptoms, to more than 90% where based on measurement. The importance of smell testing as opposed to smell questioning cannot be emphasized more strongly The prevalence of smell symptoms and signs is so high that a person who has normal olfaction on testing by procedures listed below, is unlikely to be infected with Cov-2 or if so, their viral load would be low and unlikely to result in transmission to others. Where resources are limited it is suggested that a rapid screening test of olfaction could be used in field stations or airports as a substitute for, or complementary to, nasal and throat swabs. False positives, i.e. anosmia may result from other rhinotropic viruses but these patients would require formal viral testing in any event. The risk of a false negative result is low with estimates ranging from 2% to 28%. If one excludes the small study of 41 patients that implemented a 4 odour test27 then the false negative rate drops to 2–16%. The position regarding taste impairment is less clear. Subjective complaint of dysgeusia is frequent but in most instances represents confusion with olfactory loss. Objective evaluation of taste impairment is complex and reviewed elsewhere.49 There are clearly some weaknesses in this analysis. Although 14 studies address COVID-19 and hyposmia, patient numbers are relatively small and the tests employed are varied, sometimes unorthodox. Some groups have no control group and do not state clearly the time of testing—or if so, the range in days is wide. Other investigations have been published without peer review or possibly submitted (and published) in haste, given the urgency of the current pandemic. Ethnic differences may account for some of the wide variation in results.17 Despite this, the conclusions based primarily on the four most thorough investigations, show a consistent relationship between smell impairment and COVID-19 and support the main messages in this paper. The way forward The following are suggested for future COVID-19 chemosensory research Smell measurement should be undertaken by centres with a proven track record of chemosensory research using internationally recognized tests Large numbers of cases at varying stages of disease and healthy controls should be collected in the community and hospital setting. The number required should be determined from power calculations based on the number of test odours used. Any of the following identification procedures would be suitable for large-scale studies at walk-in centres or airports: Sniffin’ Sticks, 12 odour version. This may be re-used multiple times within its shelf life. Given the potential risks of transmission, it would be best administered by a trained operator rather than the subjects themselves B-SIT (Brief Smell Identification Test). This is a ‘scratch and sniff’ procedure for single use only and comprises 12 odours. It is suitable for on-site or home completion NHANES-8. (US National Health and Nutrition Examination Survey). This is a low-cost 8 odour version similar in principle to the B-SIT. It is under evaluation for future field use. The above procedures could be undertaken in COVID-19 walk-in centres or airports as an inexpensive screening procedure. An initial large-scale trial would be required to assess the sensitivity of the chosen test. Based on current data, a normal result would likely avoid the need for nasal/throat swabs whereas an abnormal result would require formal virological analysis. Acknowledgements The author would like to acknowledge the help and advice in the preparation of this manuscript from: Professor R.L. Doty, Director, University of Pennsylvania Smell and Taste Center, Philadelphia, USA and Dr. Glenis Scadding, Consultant Physician in Allergy and Rhinology at the Royal National Throat, Nose and Ear Hospital, London UK. Abbreviations. Q-SIT (Quick Smell Identification Test), B-SIT (Brief Smell Identification Test), UPSIT (University of Pennsylvania Smell Identification Test) and the Pocket Smell Test are trademarks of Sensonics International, Haddon Heights, New Jersey, USA. Sniffin’ Sticks and Taste Strips are trademarks of Burghart Messtechnik GmbH, Wedel, Germany. Author contributions This article is the sole work of the author. Conflict of interest I receive an honorarium from Elsevier in respect of the Chief Editor duties for Multiple Sclerosis and Related Disorders. I receive royalties from Cambridge University Press for two books: Neurology of Olfaction by Hawkes C.H. and Doty R.L. 2009 and Smell and Taste Complaints, by Hawkes C.H. and Doty R.L. 2018. I receive royalties from Oxford University Press for Instant Neurological Diagnosis. Hawkes C.H., Sethi K. and Swift T.J. 2019 (second edition). References 1 Hopkins C , Kumar N. Loss of sense of smell as marker of COVID-19 infection. The Royal College of Surgeons of England: British Rhinological Society, 2020 . Cambridge University Press, The Edinburgh Building, Cambridge CB2 8RU, UK. 2 Lechien JR , Chiesa-Estomba MCM , Hans S , Barillari MM , Jouffe L , Saussez S. Loss of smell and taste in 2013 European patients with mild to moderate COVID-19 . Ann Int Med 2020 ; 173 : 672 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Beltrán‐Corbellini Á , Chico‐García JL , Martínez‐Poles J , Rodríguez‐Jorge F , Natera VE , Gómez CJ , et al. Acute‐onset smell and taste disorders in the context of COVID‐19: a pilot multicentre polymerase chain reaction based case–control study . Eur J Neurol 2020 ; 27 : 1738 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Huart C , Philpott C , Konstantinidis I , Altundag A , Trecca EM , Cassano M , et al. Comparison of COVID-19 and common cold chemosensory dysfunction . Rhinology 2020 ; 58 : 623 – 5 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 5 Sungnak W , Huang N , Bécavin C , Berg M , Queen R , Litvinukova M , et al. ; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes . Nat Med 2020 ; 26 : 681 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Bilinska K , Butowt R. Anosmia in COVID-19: a bumpy road to establishing a cellular mechanism . ACS Chem Neurosci 2020 ; 11 : 2152 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Brann D , Tsukahara T , Weinreb C , Logan DW , Datta SR. Non-neural expression of SARS-CoV-2 entry genes in the olfactory epithelium suggests mechanisms underlying anosmia in COVID-19 patients . Sci Adv 2020 ; 6 : eabc5801 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Eliezer M , Hamel AL , Houdart E , Herman P , Housset J , Jourdaine C , et al. Loss of smell in COVID-19 patients: MRI data reveals a transient edema of the olfactory clefts . Neurology 2020 ; 95 . Doi: 10.1212/WNL.0000000000010806. Google Scholar OpenURL Placeholder Text WorldCat 9 Laurendon T , Radulesco T , Mugnier J , Gérault M , Chagnaud C , El Ahmadi AA , et al. Bilateral transient olfactory bulb edema during COVID-19–related anosmia . Neurology 2020 ; 95 : 224 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Politi LS , Salsano E , Grimaldi M. Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (Covid-19) and anosmia . JAMA Neurol 2020 ; 77 : 1028 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Galougahi MK , Ghorbani J , Bakhshayeshkaram M , Naeini AS , Haseli S. Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report . Acad Radiol 2020 ; 27 : 892 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Shigemura N , Takai S , Hirose F , Yoshida R , Sanematsu K , Ninomiya Y. Expression of renin-angiotensin system components in the taste organ of mice . Nutrients 2019 ; 11 : 2251 . Google Scholar Crossref Search ADS WorldCat 13 Xu H , Zhong L , Deng J , Peng J , Dan H , Zeng X , et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa . Int J Oral Sci 2020 ; 12 : 1 – 5 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 14 Xu J , Li Y , Gan F , Du Y , Yao Y. Salivary glands: potential reservoirs for COVID-19 asymptomatic infection . J Dent Res 2020 ; 99 : 989 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Menni C , Valdes A , Freydin MB , Ganesh S , Moustafa JE , Visconti A , et al. Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection . Nat Med 2020 ; 26 : 1037 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Menni C , Valdes AM , Freidin MB , Sudre CH , Nguyen LH , Drew DA , et al. Real-time tracking of self-reported symptoms to predict potential COVID-19 . Nat Med 2020 ; 26 : 1037 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat 17 von Bartheld CS , Hagen MM , Butowt R. Prevalence of chemosensory dysfunction in COVID-19 patients: a systematic review and meta-analysis reveals significant ethnic differences . ACS Chem Neurosci 2020 ; 11 : 2944 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Tong JY , Wong A , Zhu D , Fastenberg JH , Tham T. The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: a systematic review and meta-analysis . Otolaryngol Head Neck Surg 2020 ; 163 : 3 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat 19 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 : 821 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Coughlin SS. Recall bias in epidemiologic studies . J Clin Epidemiol 1990 ; 43 : 87 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Wymer W. The implications of sex differences on volunteer preferences . Voluntas 2011 ; 22 : 831 – 51 . Google Scholar Crossref Search ADS WorldCat 22 Wehling E , Nordin S , Espeseth T , Reinvang I , Lundervold AJ. Unawareness of olfactory dysfunction and its association with cognitive functioning in middle aged and old adults . Arch Clin Neuropsychol 2011 ; 26 : 260 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Deems DA , Doty RL , Settle RG , Moore-Gillon V , Shaman P , Mester AF , et al. 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 : 519 – 28 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Calvo-Henriquez C , Maldonado-Alvarado B , Chiesa-Estomba C , Rivero-Fernández I , Sanz-Rodriguez M , Villarreal IM , et al. Ethyl alcohol threshold test: a fast, reliable and affordable olfactory assessment tool for COVID-19 patients . Eur Arch Otorhinolaryngol 2020 ; 277 : 2783 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Vaira LA , Deiana G , Fois AG , Pirina P , Madeddu G , De Vito A , et al. Objective evaluation of anosmia and ageusia in COVID‐19 patients: single‐center experience on 72 cases . Head Neck 2020 ; 42 : 1252 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Vaira LA , Hopkins C , Salzano G , Petrocelli M , Melis A , Cucurullo M , et al. Olfactory and gustatory function impairment in COVID‐19 patients: Italian objective multicenter‐study . Head Neck 2020 ; 42 : 1560 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Hintschich CA , Wenzel JJ , Hummel T , Hankir MK , Kühnel T , Vielsmeier V , et al. Psychophysical tests reveal impaired olfaction but preserved gustation in COVID‐19 patients . Int Forum Allergy Rhinol 2020 ; 10 : 1105 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Lima MA , Silva MT , Oliveira RV , Soares CN , Takano CL , Azevedo AE , et al. Smell dysfunction in COVID-19 patients: more than a yes-no question . J Neurol Sci 2020 ; 418 : 117107 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Tsivgoulis G , Fragkou PC , Delides A , Karofylakis E , Dimopoulou D , Sfikakis PP , et al. Quantitative evaluation of olfactory dysfunction in hospitalized patients with Coronavirus [2](COVID-19) . J Neurol 2020 ; 267 : 2193 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Jackman AH , Doty RL. Utility of a three‐item smell identification test in detecting olfactory dysfunction . Laryngoscope 2005 ; 115 : 2209 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Moein ST , Hashemian SM , Mansourafshar B , Khorram‐Tousi A , Tabarsi P , Doty RL. Smell dysfunction: a biomarker for COVID‐19 . Int Forum Allergy Rhinol 2020 ; 10 : 944 – 950 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Moein ST , Hashemian SM , Khorram-Tousi A , Tabarsi P , Doty RL. Prevalence and reversibility of smell dysfunction measured psychophysically in a cohort of COVID-19 patients . Int Forum Allergy Rhinol 2020 ; 10 : 1127 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Mariño-Sánchez F , Santamaría-Gadea A , de Los Santos G , Alobid I , Mullol J. Psychophysical olfactory testing in COVID-19: is smell function really impaired in nearly all patients? Int Forum Allergy Rhinol 2020 ; 10 : 951 – 2 . Google Scholar Crossref Search ADS PubMed WorldCat 34 Moein ST , Hashemian SM , Mansourafshar B , Khorram-Tousi A , Tabarsi P , Doty RL. Reply to: psychophysical olfactory testing in COVID-19: is smell function really impaired in nearly all patients? Int Forum Allergy Rhinol 2020 ; 10 : 953 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Hornuss D , Lange B , Schröter N , Rieg S , Kern WV , Wagner D. Anosmia in COVID-19 patients . Clin Microbiol Infect 2020 ; 26 : 1426 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Bocksberger S , Wagner W , Hummel T , Guggemos W , Seilmaier M , Hoelscher M , et al. Temporäre Hyposmie bei COVID-19-Patienten . HNO 2020 ; 68 : 440 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Altin F , Cingi C , Uzun T , Bal C. Olfactory and gustatory abnormalities in COVID-19 cases . Eur Arch Otorhinolaryngol 2020 ; 277 : 2775 – 81 . Google Scholar Crossref Search ADS PubMed WorldCat 38 Chung TW , Sridhar S , Zhang AJ , Chan KH , Li HL , Wong FK , et al. Olfactory dysfunction in COVID-19 patients: observational cohort study and systematic review . Open Forum Infect Dis 2020 ; 7 : ofaa199 . Google Scholar Crossref Search ADS PubMed WorldCat 39 Le Bon SD , Pisarski N , Verbeke J , Prunier L , Cavelier G , Thill MP , et al. Psychophysical evaluation of chemosensory functions 5 weeks after olfactory loss due to COVID-19: a prospective cohort study on 72 patients . Eur Arch Otorhinolaryngol 2020 ; 1 – 8 . Google Scholar OpenURL Placeholder Text WorldCat 40 Lechien JR , Cabaraux P , Chiesa-Estomba C , Khalife M , Plzak J , Hans S , et al. Objective olfactory testing in patients presenting with sudden onset olfactory dysfunction as the first manifestation of confirmed COVID-19 infection . Medrxiv . 2020 . Doi:10.1101/2020.04.15.20066472. Google Scholar OpenURL Placeholder Text WorldCat 41 London B , Nabet B , Fisher AR , White B , Sammel MD , Doty RL. Predictors of prognosis in patients with olfactory disturbance . Ann Neurol 2008 ; 63 : 159 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Koutsourelakis I , Keliris A , Minaritzoglou A , Zakynthinos S. Nasal steroids in snorers can decrease snoring frequency: a randomized placebo‐controlled crossover trial . J Sleep Res 2015 ; 24 : 160 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Tacchi L , Musharrafieh R , Larragoite ET , Crossey K , Erhardt EB , Martin SA , et al. Nasal immunity is an ancient arm of the mucosal immune system of vertebrates . Nat Commun 2014 ; 5 : 5205 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Bitar MA , Dowli A , Mourad M. The effect of tonsillectomy on the immune system: a systematic review and meta-analysis . Int J Pediatr Otorhinolaryngol 2015 ; 79 : 1184 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat 45 Altwairqi RG , Aljuaid SM , Alqahtani AS. Effect of tonsillectomy on humeral and cellular immunity: a systematic review of published studies from 2009 to 2019 . Eur Arch Otorhinolaryngol 2020 ; 277 : 1 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 46 Schairer DO , Chouake JS , Nosanchuk JD , Friedman AJ. The potential of nitric oxide releasing therapies as antimicrobial agents . Virulence 2012 ; 3 : 271 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 47 Sanders SP , Proud D , Permutt S , Siekierski ES , Yachechko R , Liu MC. Role of nasal nitric oxide in the resolution of experimental rhinovirus infection . J Allergy Clin Immunol 2004 ; 113 : 697 – 702 . Google Scholar Crossref Search ADS PubMed WorldCat 48 Harris NS , Strickland B. Inhaled Nitric Oxide Therapy for Emergency Room COVID-19 Patients. https://rally.partners.org/study/no_cov_ed?code=ca (October 2020, date last accessed). 49 Hawkes CH , Doty RL. Smell and Taste Disorders . Cambridge University Press , 2018 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC © The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: [email protected]