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.
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.
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.
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.
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).
It was not possible to do pooled analysis due to high heterogeneity in study design and assessment.
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.
All 23 studies included were relevant for the review topic. (Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, & Kumar, 2020; Iravani et al., 2020; Kaye, Chang, Kazahaya, Brereton, & Denneny, 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Lee et al., 2020; Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Vaira, Salzano, Deiana, & De Riu, 2020; Wee et al., 2020; Yan, Faraji, Prajapati, Ostrander, & DeConde, 2020) There were no randomized control trials, and studies were mainly retrospective (20) or prospective (3) case-series, case-control, cohort, cross-sectional studies (Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Iravani et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Lee et al., 2020; Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Vaira, Hopkins, Salzano et al., 2020; Vaira, Salzano, Deiana, & De Riu, 2020; Wee et al., 2020; Yan et al., 2020) . Quality of the studies included in the review was assessed using the Newcastle-Ottawa Scale (Table 1) (Wells et al., 2020) . A "good" quality score required 3 or 4 stars in selection, 1 or 2 stars in comparability, and 2 or 3 stars in outcomes (Wells et al., 2020) . A "fair" quality score required 2 stars in selection, 1 or 2 stars in comparability, and 2 or 3 stars in outcomes (Wells et al., 2020) . A "poor" quality score reflected 0 or 1 star(s) in selection, or 0 stars in comparability, or 0 or 1 star(s) in outcomes (Wells et al., 2020) .
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.
We included results from 12,314 patients in this review (Table 2) ( Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Iravani et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Patients with initial sudden olfactory anosmia (ISOA) were separated into two groups based on duration of greater or less than 12 days. They were swabbed for COVID−19 and completed psychophysical olfactory evaluation.
Complete cohort evaluation was limited by travel restriction but overall in the group with symptoms less than 12 days: 87.5% were positive for COVID−19 Retrospective ( Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Wee et al., 2020; Yan et al., 2020) . Patient demographics were not reported by all studies but in those that had, most patients were male with the age of the patients ranging from 32 to 60 years (Beltrán-Corbellini et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Yan et al., 2020) The presence of comorbidities especially cardiovascular disease, cerebrovascular disease, and diabetes mellitus has been associated with increased risk of COVID-19 infection and increased severity of the infection. Comorbidities were also not reported by most studies, but in those that had, hypertension (4.7%-28.3%) was the most common disease found in COVID-19 patients. Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Yan et al., 2020) .
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; 
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 
There is significant variability in the reported severity of symptoms ( 
As seen with severity, there is marked variability in the recovery from the OTD (Table 2 
A large COVID-19 case series published by the Chinese Centre of Disease Control and prevention reported that among a total of 72, 314 COVID-19 cases, a total of 22% of patients were identified as suspected cases and 15% were clinically diagnosed based on clinical symptoms (Wu & McGoogan, 2020) . The most common symptoms were reported to be fever and cough, with no detailed description of any other symptoms (Wu & McGoogan, 2020) . Increasing evidence shows that symptoms of anosmia and dysgeusia are related to COVID-19 (Lovato & Filippis, 2020; Zayet et al., 2020 Anosmia and dysgeusia were frequently reported in patients who tested positive for COVID-19 (Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Iravani et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Lee et al., 2020; Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Wee et al., 2020; Yan et al., 2020) High prevalence of these symptoms was reported in both studies with an objective assessment of taste and smell and self-reported symptom questionnaires (Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Iravani et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Lee et al., 2020; Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Wee et al., 2020; Yan et al., 2020) OTD was found to be significantly higher in females and in younger patients (Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Iravani et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Lee et al., 2020; Levinson et al., 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Wee et al., 2020; Yan et al., 2020) . Indeed, neurological manifestations of COVID-19 such as Guillain-Barré syndrome (GBS) in young people are of great concern (Ahmed et al., 2020). However, so far only a few cases of COVID-19 associated with GBS have been reported (Webb, Wallace, & Martin-Lopez, 2020) . GBS can rarely present with taste dysfunction (Kogan, Mednick, & Dolgovina, 2011) . Although currently there is no literature on the prevalence of OTD in COVID-19positive patients with GBS, we speculate that increased prevalence of taste dysfunction in GBS patients may raise the suspicion of the infection. Postviral anosmia has been reported to account for 40% of the anosmia cases and one of the leading causes of anosmia in adults (Hummel et al., 2017) . There is variability in OTD dysfunction among patients, and its association with the severity of COVID-19 infection is currently uncertain. However, a significant correlation between the duration of olfactory and gustatory symptoms and severe COVID-19 infection has been reported . Therefore, hospitalized patients especially younger patients with OTD should be monitored carefully. In terms of other COVID-19 symptoms, fever and cough were the most common, which is consistent with already published medical literature Carignan et al., 2020; Giacomelli et al., 2020; Iravani et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Lee et al., 2020; Lovato & Filippis, 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Wee et al., 2020; Yan et al., 2020) .
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.
Anosmia associated with COVID-19 has been well documented by the literature (Beltrán-Corbellini et al., 2020; Bénézit et al., 2020; Boscolo-Rizzo et al., 2020; Carignan et al., 2020; Giacomelli et al., 2020; Hopkins, Surda, Whitehead, et al., 2020; Iravani et al., 2020; Kaye et al., 2020; Klopfenstein et al., 2020; Kosugi et al., 2020; Lechien, Cabaraux, & Chiesa-Estomba et al., 2020a , 2020b Levinson et al., 2020; Lovato & Filippis, 2020; Mao et al., 2020; Moein et al., 2020; Spinato et al., 2020; Wee et al., 2020; Whitcroft & Hummel, 2020; Yan et al., 2020) Netland et al. reported that SARS-CoV can cause neuronal death in mice by invading the brain via the nose, which is close to the olfactory epithelium (Netland, Meyerholz, Moore, Cassell, & Perlman, 2008) .
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) .
Possible mechanism of interaction between SARs-CoV-2 and the cranial nerves. SARS-CoV-2 can potentially interact with the cranial nerves (olfactory, vagus, facial, and glossopharyngeal) via the angiotensin-converting enzyme receptor-2 (ACE2) leading to olfactory taste dysfunction. SARS-CoV-2 can also cause damage to the peripheral nerves leading to several other neurological manifestations. Angiotensin-converting enzyme 2; ACE2, Original Illustration created using BioRender 
& Rouhani, 2020; Toscano et al., 2020; Virani et al., 2020; Wan, Xiang et al., 2020; Wan, Cao, Fang, Wang, & Huang, 2020; Wang, Hu et al., 2020; Wang, Yang, Li, Wen, & Zhang, 2020; Yang et al., 2020; Ye, Ren, & Lv, 2020; Zhao, Shen, Zhou, Liu, & Chen, 2020; Zhou et al., 2020 
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 
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.
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.
All authors have no conflicts of interest to declare. 
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.1839.
Amer Harky https://orcid.org/0000-0001-5507-5841 