Can symptoms of anosmia and dysgeusia be diagnostic for COVID‐19?

Abstract Objective Olfactory and taste dysfunction (OTD) is a potential neurological manifestation of coronavirus‐2019 (COVID‐19). We aimed to investigate the diagnostic value of symptoms of anosmia and dysgeusia for COVID‐19. Methods A comprehensive electronic search was conducted using PubMed, MEDLINE, Scopus, Cochrane database, and Google Scholar from 1 June 2020 to 12 June 2020. All studies reporting symptoms of anosmia and dysgeusia in COVID‐19‐positive patients were included. A total of 23 studies were included in the systematic review. Results Symptoms of anosmia and dysgeusia were frequently reported by COVID‐19‐positive patients. Symptoms were more common in females and in younger patients. There was no direct association between the severity of COVID‐19 and the presence of symptoms. However, some evidence was found for a longer duration of these symptoms and increased severity of COVID‐19 infection in young patients. Conclusion OTD is commonly reported by COVID‐19 patients. Due to limited literature on the association between OTD and COVID‐19, it is currently not possible to conclude that these symptoms alone can be used to diagnose COVID‐19. However, the presence of OTD can potentially be used as a screening tool for COVID‐19 especially in young and female patients. Further research is required to establish the true diagnostic value of these symptoms and efficacy as screening tools for COVID‐19 patients.

August 2020, there have been > 21 million cases with > 700,000 deaths globally (World Health Organisation, 2019). Coronaviruses (CoV) belongs to the Coronavirinae subfamily and are known for their microscopic crown-like appearance (Chen, Liu, & Guo, 2020a;Ren et al., 2020). The COVID-19 pathogen is a human RNA virus and belongs to the β-CoVs in the CoV phylogenetic tree . Genome examinations reveal that the novel SARS-CoV-2 is 87.99% genetically similar to bats SARS-like coronavirus and genetically distant from the previously known SARS and MERS viruses (Lovato & Filippis, 2020;Ren et al., 2020). The virus is transmittable from person-to-person via respiratory droplets and has a basic reproductive number of approximately 1-3 (Flahault, 2020;Lovato & Filippis, 2020).
Studies report that COVID-19 patients can present with fever, dry cough, dyspnea, and fatigue Lovato & Filippis, 2020). In severe cases, the infection can cause viral pneumonia leading to severe acute respiratory distress syndrome or even death Lovato & Filippis, 2020). Symptoms of pharyngodynia, nasal congestion, and rhinorrhoea have also been reported in infected patients (Lovato & Filippis, 2020). Sense of smell is controlled by the olfactory cranial nerve (Cranial & Nerve). The European Rhinology society reported that a significant number of COVID-19 patients (20%-60%) appear to have loss of smell also known as anosmia (IMPORTANT INFO ON, 2020). Furthermore, reports from China, South Korea, and Italy also reported anosmia in COVID-19 patients (Entuk.org., 2020;Guan et al., 2020;Kang, Cho, Lee, Kim, & Park, 2020;Lee, Min, Lee, & Kim, 2020). In the UK, anosmia is classed as an official symptom for COVID-19 (Statement from the UK, 2020). Anosmia may be the first presenting symptom, preceding the occurrence of other COVID-19 symptoms such as cough and fever (Kang et al., 2020). Interestingly, changes in sense of taste also known as dysgeusia have also been reported in infected patients (Carrillo-Larco & Altez-Fernandez, 2020).
The presence of anosmia and dysgeusia may help neurologists and otolaryngologists identify patients with COVID-19 early, allowing prompt management and infection control procedures to be implemented. The current study aimed to systematically review the current literature on the clinical presentation of COVID-19, specifically focussing on the symptoms of anosmia and dysgeusia and their diagnostic value in COVID-19 patients.

| Electronic database search
A comprehensive literature search was conducted using PubMed, Medline, Scopus, Cochrane database, and Google Scholar using MeSH words including: "COVID-19," "Coronavirus 2019," "Anosmia," "Dysgeusia." The systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) (Moher, Liberati, Tetzlaff, & Altman, 2009). We examined articles and abstracts available in the English language.
Literature was screened for original data, and any related references were retrieved and checked manually for other relevant studies.

| Inclusion and exclusion criteria
Studies were included if the following criteria were met: (a) Articles were original reports, (b) studies included laboratory-confirmed COVID-19 patients, (c) studies reported details of clinical presentation, and (d) the reports were published in the English language.
Exclusion criteria included: (a) study design: case report, editorial, letter to the editor, or review; (b) studies reporting symptoms in children/infants.

| Data extraction
All studies were screened by two authors independently (KP and SI).
Any disagreements were resolved by discussion between the review team members. The extracted data were then cross-checked by another author (SAZ) to validate its accuracy. Included studies were analyzed to extract all available data and assure eligibility for all patients. Description data of patients including age, sex, clinical symptoms, underlying medical conditions, and outcomes were extracted and recorded for all studies.

| Methodological assessment of the studies
Quality Assessment of the included qualitative studies was conducted using the Newcastle-Ottawa Scale (Table 1) (Wells et al., 2020). The scale was devised specifically to allow quality assessment of the nonrandomized studies included in the systematic review. The scale allows assessment of bias using a star-based rating system with a maximum score of 9 indicating a low risk of bias and a minimum of 0 indicating the highest risk (Wells et al., 2020). Scores ≥ 7 generally represent a low risk of bias (Wells et al., 2020). The quality of included studies was rated by two of the authors (SAZ and SI).

| Statistical analysis
It was not possible to do pooled analysis due to high heterogeneity in study design and assessment.

| Retrieving studies
A search was started on 10 June 2020, and the last search was on 20 June 2020. A total of 150 articles were retrieved from different databases. After removing duplicates and screening titles and abstracts of studies, we identified 35 studies potentially relevant to the topic. The full text screening of the articles allowed exclusion of 12 studies that did not meet our inclusion criteria. The remaining 23 studies were considered to be eligible for our systematic review. Figure 1 shows a summary of the selection process and criteria.
Most studies were poor quality, with only 6 studies identified to be of good quality. There is high risk of reporting bias as most studies utilized self-report questionnaires. These questionnaires are subjective, and it may be possible that some patients exaggerated or over reported their symptoms. Confounders such as the presence of preexisting respiratory or otolaryngology disease were not universally accounted for.

| Prevalence of anosmia and dysgeusia
The prevalence of olfactory and taste dysfunction (OTD) in COVID-19 varies widely in the literature (Table 2). A large multicentre study from Europe reports over 85% of patients who have been confirmed positive for COVID-19 report OTD . This proportion remains consistently high in the absence of nasal obstruction   .
It is important to regard nasal obstruction as a possible explanation for OTD. Lechien et al. and Spinato et al. report a minority of patients with concomitant nasal obstruction, but this aspect is not widely accounted for in the literature (Lechien, Cabaraux, & Chiesa-Estomba et al., 2020b;Spinato et al., 2020). A consistent feature in the evidence base is that OTD is significantly more common in younger patients and those who are female. Lechien, Cabaraux, & Chiesa-Estomba et al., 2020b;Spinato et al., 2020;

| Other symptoms
In most studies that reported olfactory or gustatory dysfunction, a range of other symptoms such as fever, cough, headache, fatigue, and arthralgia/myalgia were also reported (Table 3

| Severity
There is significant variability in the reported severity of symptoms (

| Recovery
As seen with severity, there is marked variability in the recovery from the OTD (Table 2
The presence of anosmia and dysgeusia could help neurologists and otolaryngologists identify COVID-19 cases early, allowing prompt treatment and reduction in infection transmission. It is possible that symptoms of anosmia and dysgeusia can be used as an effective screening tool and aid diagnosis of COVID-19. Zayet et al. suggest that the positive predictive value (PPV) for anosmia is 77%, dysgeusia 77% and a combination of anosmia plus dysgeusia 83% for a positive SARS-CoV-2 real time-polymerase chain reaction (RT-PCR) test on a nasopharyngeal sample . However, a key limitation of Zayet et al.'s study is that although RT-PCR on a nasopharyngeal sample is specific for COVID-19, it has a sensitivity of 56%-83% and may be an inaccurate test to diagnose COVID-19 (AAO-HNS: Anosmia, Hyposmia; Kokkinakis, Selby, Favrat, Genton, & Cornuz, 2020). Therefore, some patients with anosmia and dysgeusia that tested negative for COVID-19 may be infected with the disease. Further research is required to confidently determine the utility of OTD dysfunction as an effective screening tool for COVID-19 infection.
Furthermore, the human coronavirus 229E has been isolated in nasal discharge from a patient with postviral olfactory dysfunction (Suzuki et al., 2007). It has been proposed that SARS-CoV-2 gains entry into the central nervous systems via several different ways (Ahmed et al., 2020). One of the proposed mechanisms is dissemination and spread from the cribriform plate which is in close contact to the olfactory bulb; this mechanism is postulated to be the underlying cause of olfactory dysfunction in patients (Baig, Khaleeq, Ali, & Syeda, 2020).
Furthermore, the general presence of the virus in the circulation can lead to systematic dissemination, allowing the virus to enter the cerebral circulation (Ahmed et al., 2020). The brain has been reported to express ACE2 receptors mainly on glial cells, neurons, and brain vasculature, making these cells susceptible to attacks by the SAR-CoV-2 (Ahmed et al., 2020;Turner, Hiscox, & Hooper, 2004).
It is well-established that SARS-CoV-2 can exploit the angiotensinconverting enzyme 2 (ACE2) receptor to gain entry into the cells (Ahmed et al., 2020). Viral interaction with the expression of the ACE2 receptor in neurones can result in significant damage to the neurones without substantial association inflammation previously observed with SARS-CoV infection (Ahmed et al., 2020;Netland et al., 2008;Wrapp et al., 2020). Therefore, it can be postulated that SARS-CoV-2 can cause neuronal damage via the ACE2 receptor leading to OTD (Figure 2) (Ahmed et al., 2020). Binding of the virus to the ACE2 receptors may cause endothelial dysfunction and also lead to serious consequences such as cerebral hemorrhage via unknown mechanisms (Ahmed et al., 2020). Another mechanism by which the neurotropic SARs-CoV-2 can disseminate through the central nervous system is by anterograde and retrograde transport with the aid of motor proteins such as kinesins and dynein via sensory and motor nerve endings, the afferent nerve endings from the vagus nerve from the lungs are especially implicated (Ahmed et al., 2020;Li, Bai, & Hashikawa, 2020;Swanson & McGavern, 2015). Through this mechanism, SARS-CoV-2 could potentially cause gustatory dysfunction. Besides, other ways in which SARS-CoV-2 can cause neurological damage leading to OTD is through a surge of inflammatory cytokines leading to cytokine storm syndrome (Ahmed et al., 2020;Wan, Yi et al., 2020).

| Limitations
Our review, only focussed on COVID-19-positive patients, however, these symptoms may also be present in patients that were COVID-19-negative. Therefore, to fully establish the diagnostic value of

| IMPLI C ATI ON S FOR FURTHER RE S E ARCH
Currently, the literature on COVID-19 and OTD is limited and is mainly confined to reports of self-reported symptoms. Further studies with large cohort sizes and global collaborations with an objective assessment of OTD are required to fully establish the merit of these symptoms in the diagnosis of COVID-19. OTD can also be present in non-COVID-19 patients (Kosugi et al., 2020). Kosugi et al. reported OTD in patients which subsequently tested negative for COVID-19 (Kosugi et al., 2020). Future studies with larger cohort sizes comparing the difference in duration and prevalence of OTD in COVID-19-positive patients compared to non-COVID-19 patients would help elucidate the true diagnostic value of these symptoms in COVID-19. OTD tends to significantly affect patients who are female and from younger age groups; however, the reasons are unknown.
Furthermore, there is uncertainty regarding the utility of these symptoms as a predictor of severe COVID-19 infection. Therefore, further research is required to clarify the association between OTD and the severity of COVID-19 infection. The pathophysiology of OTD in COVID-19 remains to be determined.

| CON CLUS ION
Clinical examination of the olfactory nerve is often neglected in routine clinical practice. The COVID-19 pandemic has highlighted the importance of this much forgotten cranial nerve. COVID-19 patients frequently report symptoms of anosmia and dysgeusia, and therefore, these symptoms should raise a high index of suspicion for COVID-19 infection especially in young and female patients. The presence of these symptoms alongside objective clinical assessment would help to make a diagnosis. Further research is warranted as currently both the performance of these symptoms as predictors of COVID-19 infection and their diagnostic value is uncertain.

D I SCLOS U R E S
All authors have no conflicts of interest to declare.

PE E R R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.1839.