Author: Alessio Silva; Reviewer: Edda Cava
An increasing number of case series and reports on patients infected with COVID-19 presenting with acute olfactory/taste disorders (OTD) as the only symptom, or together with other symptoms, have been published.
The limitations in comparing such a large number of reports are the use of different tools to evaluate OTD, the differences in exclusion criteria, selection bias, and retrospective or prospective study design, the number of patients enrolled in the different studies, even if some are case-control (2, 6) studies.
The difference in the choice of the evaluation tool can explain the differences reported in the rate of OTD. Here is a list of tools, other than unvalidated questionnaires (6, 11-12) or retrospective analysis (1, 8), used: University of Pennsylvania Smell Identification Test (UPSIT) (2), Sino-nasal Outcome Test 22 (SNOT) (5), Total Nasal Symptom Score (TNSS) (10), Connecticut Chemosensory Clinical Research Center orthonasal olfaction test (CCCRC) (9).
Therefore, OTD were reported in high rates with large differences within studies: about 60-80% for olfactory disorders and 70-90% for taste disorders. Among the reported symptoms at least 45% reported complete anosmia and 45% ageusia, but when reported as partial dysfunction the rate of incidence increased among the reports up to 98% for olfactory dysfunctions (2). Concomitant nasal obstruction was frequently present in about 13% to half of the patients, as well as sneezing or rhinorrhoea.
Taking in account the presence of both OTD together rates reported were about 18.6% (12) up to 68% (10).
In a Chinese report (11), OTD were reported only in 5.05% of the sample, being COVID-19 positive a 22.7% of them.
OTDs were more frequent in females than in males (1, 5, 12) and in younger patients (1, 6). Moreover, being outpatient (8), therefore having possibly less severe disease presentation, makes the report of OTD more likely. Sometimes OTD are reported as the only COVID-19 symptom.
Mean duration reported for OTD was 7 to 9 ± 2 to 6 days, patients reported total/partial recovery within a month after the onset, suggesting OTD reversibility.
Conclusions: OTDs are frequent in patients with SARS-CoV-2 infection and may precede the clinical disease onset. Anosmia/hyposmia, unlinked to drug treatment, may serve as a marker inversely related to COVID-19 severity but also of the host’s innate immune response during the infection. Olfactory dysfunction and neurological symptoms support SARS-CoV-2 neurotropism, with a potentially higher risk of faster progression into acute respiratory failure. In the end, OTD seem less common in Chinese COVID-19 patients (only up to 5%) compared to European higher rates.
For a detailed study analysis, with a summary of each report (OTD definition, rates of OTD, tool used, limitations, recovery rates) and full bibliography please check the following sections.
Full Clinical Data
Corbellini et al. demonstrated that new-onset olfactory/taste disorder (OTD) is more frequent in COVID-19 patients (31, 39.2%) than influenza patients (5, 12.5%) comparing 79 cases/40 controls (influenza positive).
Evaluation type: From 23rd to 25th March 2020, questionnaire to COVID-19 patients admitted in two tertiary care centres of Madrid, Spain.
Exclusion criteria: dementia, low consciousness, previous OTD.
Time of onset: COVID-19 patients with OTD are significantly younger than those without (52.6 vs. 67.4). Among OTD+ COVID-19 patients, 22 (70.9%) recalled an acute onset and was an initial manifestation in 11 (35.5%).
Recovery: Mean duration of OTD was 7.5 ± 3.2 days; 12 patients (40%) manifested complete recovery after 7.4 ± 2.3 days of onset. Most patients (56.7%) reported total/partial recovery during data collection, suggesting OTD reversibility.
Study limitations: case-control design, poor comparison, use of a self-reported questionnaire restricted to hospitalized patients.
Conclusions: OTD assessment in anamnesis as a hint for COVID-19, supporting self-isolation.
Spinato et al.evaluated prevalence, intensity, and timing of OTD in patients with SARS-CoV-2 infections. 202 completed the survey.
Incidence: OTD was more frequent among 105 women (72.4%) than among 97 men (55.7%). OTD was reported by 130 patients (64.4%). Of those, 45 (34.6%) also reported blocked nose.
Evaluation type: From 19th to 22nd March 2020, telephonic Sino-nasal Outcome Test 22 to SARS-CoV-2 positive patients.
Time of onset: OTD occurred before other symptoms in 24 patients (11.9%), at the same time in 46 (22.8%) and after other symptoms in 54 (26.7%). OTD was the only symptom for 6 patients (3.0%).
Study limitations: self-reported data, limited and restricted sampling, severe patients not included.
Conclusions: testing and self-isolation of patients with new onset OTD.
Luers et al. performed a cross-sectional study in which two-thirds of COVID-19 European patients reported OTD, indicating its relevance in early diagnostics.
Incidence: 72 participants (41 males, 31 females, mean age of 38 ± 13 years). 44/72 patients (61%) had contact with individuals with confirmed COVID-19. Reduced olfaction occurred in 53 COVID-19 patients (74%) while reduced sense of taste in 50 patients (69%). 49 patients (68%) reported both symptoms. 1 patient (1%) had only reduced sense of taste. 4 patients (6%) had only reduced olfaction. Lots of patients had nasal congestion (54%), nasal sneezing (50%) and rhinorrhoea (53%).
Evaluation type: between 22nd and 28th March 2020, COVID-19 outpatients were retrospectively identified by the records of the University Hospital of Cologne, Germany. A standardized two-section questionnaire was performed 13 ± 3 days after the first symptom occurred and 7 ± 1 days after a positive COVID-19 test. Total Nasal Symptom Score (TNSS) was evaluated.
Exclusion criteria: past or current hospitalization caused by COVID-19 or other reasons.
Time of onset: OTD occurred on average 4 days after the first symptoms.
Conclusions: Commenting Mao L. et al., OTD seem less common in Chinese COVID-19 patients (only up to 5%) compared to European ones. The same conclusions are given by Finsterer et al.
Klopfenstein et al. conducted a retrospective observational study in the NFC hospital, stressing the clinical relevance of COVID-19-related anosmia.
Incidence: 114 COVID-19 patients, mean age was 47 (±16) years; 67% were females and 37% were hospitalized. 54/ 114 (47%) reported anosmia; it was the third symptom in 38% (22/52) of cases, never the first/second. 46 patients (85%) had dysgeusia, 15 (28%) presented with pneumonia. 16 patients (30%) had nasal obstruction. Diarrhoea was reported in more than 50% of cases, more frequently in patients with anosmia, like in the study of Lechien et al.
Evaluation type: Data required was collected from the medical files of COVID-19 PCR-confirmed patients with anosmia between 1st and 17th March 2020.
Exclusion criteria: pregnancy, children (<18 years), dementia.
Time of onset: Anosmia began 4.4 (±1.9) days after infection onset. The mean duration of anosmia was 8.9 (±6.3) days
Recovery: 98% of patients recovered from OTD within 28 days. Mean duration of anosmia: 9 days.
Study limitations: patients number
Conclusions: Anosmia is a frequent symptom in COVID-19 patients, who seem to be younger with a predominance of females. Lechien et al. reported anosmia in 86% (n=357/417) of their patients. This higher frequency may be explained by their population profile which were ambulatory cases (37 ± 11.4 years) for whom it is probably easier to relate functional symptoms than critical patients.
Moein et al. performed a case-control study assessing the magnitude and frequency of olfactory dysfunction of COVID-19 patients (PCR and CT imaging) hospitalized in the Masih Daneshvari Hospital, Tehran.
Incidence: 60 COVID-19 inpatients and 60 matched controls were evaluated. 59/60 (98%) patients exhibited some olfactory dysfunction. 35/60 patients (58%) were either anosmic (15/60; 25%) or severely microsmic (20/60; 33%); 16 exhibited moderate microsmia (16/60; 27%), 8 mild microsmia (8/60; 13%), and one normosmia (1/60; 2%).
Evaluation type: a validated 40-odorant test (University of Pennsylvania Smell Identification Test – UPSIT) was administered between 21st and 23rd March 2020 or 31st March and 5th April 2020. During the olfactory testing, all the subjects were inpatients in the recovery period of the disease, ready to be discharged within 4 days.
Study limitations: sampling at only one time-point.
Conclusions: decreased olfactory function, but not always anosmia, is a major marker for SARS-CoV-2, unlinked to drug treatment for the disease. Olfactory testing may help to identify COVID-19 patients.
Giacomelli et al. from the Infectious Disease Department of L. Sacco Hospital in Milan, Italy, performed a cross-sectional study in SARS-CoV-2 positive hospitalized patients of the prevalence of self-reported OTD.
Incidence: 59 patients included, 20 (33.9%) reported at least 1 OTD; 11 (18.6%) both. 12 patients (20.3%) presented the symptoms before hospital admission. Taste alterations were more frequently (91%) before hospitalization. OTDs were more frequent in females than in males. Patients with at least 1 OTD were younger than those without (56 years vs 66).
Evaluation type: on 19 March 2020 a questionnaire regarding OTD, type and time of onset was submitted through verbal interview.
Exclusion criteria: dementia, linguistic barrier, non-invasive ventilation.
Recovery: All reported the persistence of OTDs at the time of the interview.
Study limitations: impossibility to perform a questionnaire associated with validated tests (ie. UPSIT).
Conclusions: OTDs are frequent in patients with SARS-CoV-2 infection and may precede the clinical disease onset.
Ralli et al. commented on this study: olfactory dysfunction and neurological symptoms support SARS-CoV-2 neurotropism, with a potentially higher risk of faster progression into acute respiratory failure.
Also, Hjelmesæth et al. supported this study, reporting two SARS-CoV-2 infection cases with OTD but no typical respiratory symptoms of COVID-19.
Vaira et al. objectively tested olfactory and gustatory function in 72 COVID-19 patients treated at the Hospital of Sassari. The frequencies are higher than those reported by Giacomelli et al. but similar to Lechien et al.
Incidence: 53 (73.6%) patients reported chemosensitive disorders. 44 patients (61.1%) reported having or having had olfactory disorders (34 complete anosmia, 8 hyposmia 2 disosmia). During the CCCRC examination, 2 patients were completely anosmic (2.8%), 58 had variable hyposmia (80.6%), 12 (16.7%) exhibited normosmia. Moreover, 39 patients reported taste disorders (28 complete ageusia, 11 variable hypogeusia, 7 dysgeusia). With CCCRC ageusia was detected in 1 patient (1.4%), severe hypogeusia in 7 patients (9.7%), moderate hypogeusia in 11 patients (15.3%) and mild hypogeusia in 16 patients (22.2%). 37 patients (51.4%) had a normal gustatory function.
Evaluation type: Between March 31st and April 6th, 2020 olfactory function was assessed with the Connecticut Chemosensory Clinical Research Center orthonasal olfaction test (CCCRC).
Exclusion criteria: uncooperative patients, assisted ventilation, psychiatric/neurological disorders, previous surgery or radiotherapy in the oral and nasal cavities, pre-existing OTD, head trauma, allergic rhinitis, chronic rhinosinusitis.
Time of onset: ageusia/anosmia are early symptoms in COVID-19, generally occurring within the first 5 days of the clinical onset. In 13 patients (18.1%) OTD represented the first clinical manifestation of the disease.
Recovery: during the evaluation 35 cases (66%) reported a complete recovery of chemosensitive functions, which occurred in less than 5 days in 19 cases. OTD was persistent in 18 patients (34%).
Conclusions: OTD not associated with rhinitis symptoms as a diagnostic option for COVID-19 patients. OTD is typical of early infection and tends to disappear over time.
Wee et al. at the Singapore General Hospital stratified all patients reporting OTD to exclude COVID-19.
Incidence: 870 patients were included as suspected for COVID-19. 44/870 (5.05%) presented with OTD. 154/870 patients (17.9%) were COVID-19 positive. 35/154 (22.7%) had OTD; among them, 3 were anosmic without other symptoms.
Evaluation type: from 26 March–10 April 2020 a questionnaire was administered to all new admissions, to screen for self-reported OTD.
Conclusions: OTD had high specificity as a screening criterion for COVID-19 (98.7%), but lower sensitivity (22.7%).
Yan et al. performed a retrospective review of all COVID-19 patients to the UC San Diego Health System evaluating OTD to help stratify mild from moderate COVID-19 early in SARS-CoV-2 infection.
Incidence: 128 subjects were included with available smell and taste data.26/128 (20.1%) COVID-19 patients were admitted for management. They were less likely to report anosmia/hyposmia (26.9% vs 66.7%) and dysgeusia (23.1% vs 62.7%) than managed outpatients.
Evaluation type: between March 3 and April 8, 2020, comparison between self-reported sense of smell and taste to pre-morbid levels.
Recovery: SARS-CoV-2 may cause inflammation of the olfactory cleft. This would be consistent with relatively
rapid recovery of olfactory function in most patients.
Study limitations: self-reported anosmia/hyposmia, particularly in those COVID-19 positives.
Conclusions: anosmia/hyposmia may serve as a marker inversely related to COVID-19 severity but also of the host’s innate immune response during the infection.
Overall, professional organisations worldwide all agree in advising the screening for anosmia, including it as a symptom of COVID-19.
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