Gustatory Dysfunction as an Early Symptom in COVID-19 Screening.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from Wuhan, China in December 2019 leads to the present coronavirus disease 2019 (COVID-19) pandemic. The various symptoms identified for COVID-19 are fever, dry cough, sore throat, dyspnea, fatigue, myalgia, and headache. Olfactory and gustatory dysfunctions are emerging as a new symptom more in the European patients. Taste disturbances are common in various oral and systemic diseases. Varying severity and onset of taste disturbances are reported in COVID-19 positive patients in this pandemic. But a sudden onset of taste disturbances without an established and recognized cause should raise suspicion of COVID-19. This article will analyze the various studies focusing on taste disturbances as a reliable early symptom for COVID-19 screening.

Currently the identified symptoms of coronavirus disease 2019 (COVID-19) are fever, dry cough, sore throat, dyspnea, fatigue, myalgia, and headache. Olfactory and gustatory dysfunctions are emerging as a new symptom. Gustatory dysfunctions are taste disturbances varying between hypogeusia, dysgeusia, phantogeusia, and ageusia.[1] They may occur in many situations related to nerve damage, autoimmune disease, malignancy, radiotherapy, inflammation, hormone imbalance, psychologic problems, ageing, etc.[2] Taste loss was also reported often to occur in viral upper respiratory infections and following an influenza-like illness.[3,4] It is noted that many studies in this pandemic showed the association of disturbances in smell and taste with COVID-19.[5]

The American academy of Otolaryngology-Head and Neck Surgery recommends that anosmia, hyposmia, or dysgeusia raises COVID-19 suspicion and also the British Association of Otorhinolaryngology recommends that the olfactory and gustatory disturbance symptoms (chemosensitive disorders) can be included as primary screening symptoms.[6] The Center for Disease Control and Prevention also added the symptom of new loss of smell or taste occurring in 2 to 14 days after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure in their symptoms list.[7] World Health Organization added these symptoms as less common for COVID-19.[8] This article analyzes the various studies reporting these new symptoms, focusing on taste disturbances as a reliable early symptom for COVID-19 screening.

POSSIBLE MECHANISMS OF TASTE DYSFUNCTION IN COVID-19

The molecular mechanisms leading to the gustatory dysfunctions in COVID-19 are still unclear. But it is suggested that angiotensin-converting enzyme-2 (ACE2) receptor expressing cells may act as target cells for SARS-CoV-2 entry.[9] The results from single cell RNA-seq profiles shows that the ACE2 is expressed in the epithelial cells of the oral cavity and is higher in the tongue epithelium than that of buccal and gingival tissues.[10] This indicates that oral cavity being a high risk route of SARS-CoV-2 entry and involvement of tongue epithelium may contribute to taste disturbances.

Another common possibility is the simultaneous presence of olfactory disturbances which prevents the taste sensation, because of the intimate functional correlation between these 2 chemosensory systems.[11] However, isolated taste dysfunctions are reported in COVID-19 which shows other mechanisms are involved. Coronaviruses are known to be neurotropic and neuroinvasive. This might lead to alteration in smell or taste sensation through the cranial nerves, but still lacks enough evidence.[12] We hope that prospective histopathologic analysis from COVID-19 autopsies will give us the understanding of pathogenesis of these chemosensitive disorders.

PREVALENCE OF TASTE DISTURBANCES IN COVID-19

One of the initial study from China by Mao et al, analyzed the neurologic manifestations in SARS-CoV-2 infected 214 patients and reported ageusia in 5.6% of patients.[13] In contrary to this, the first European clinical series showed a high frequency of chemosensitive disorders ranging between 19.4% and 88%. They also found that the gustatory changes were frequent in the initial stages of the infection and in paucisymptomatic patients.[14-16]

Giacomelli et al collected data on olfactory and taste dysfunctions, and their type and time of onset respective to hospital admission from 59 COVID-19 hospitalized patients by a questionnaire interview. Out of these, 33.9% patients reported either a taste or odor disorder and 18.6% had both. Symptoms before hospitalization was present in 20.3% patients and 13.5% patients experienced during the hospital stay. Taste disturbances were present in 91% before hospitalization, whereas after hospitalization the symptoms appeared with equal frequency. Females (52.6%) reported symptoms more frequently than males (25%).[17]

A multicentric study was conducted by Vaira et al in Italy on 300 COVID-19 positive patients and reported that 80% patients commonly had chemosensitive disorders typically 2 days after the onset of the fever in the early stages of the disease. Interestingly, 15.3% patients manifested only temporary smell and/or taste alterations. In 67.5% of patients, there is spontaneous regression of these symptoms in few days. They reported that those patients who had the chemosensitive disorders for more than 10 days, had 2.4 times greater risk of developing a severe pulmonary damage.[18] This implies that chemosensitive disorders can be used to predict the severity of the disease to a certain level.

Spinato et al surveyed positive and mild symptomatic SARS-CoV-2 outpatients in Italy and found that 64.4% had some degree of taste or smell alterations. The timing of the onset of this symptom was analyzed and found that 11.9% had it before other symptoms, 22.8% had along with other symptoms, 26.7% had afterwards, and 3% had it as their only symptom. Women (72.4%) presented more frequently with an altered sense of smell or taste than men (55.7%).[19]

An European multicentric study was conducted by Lechien et al in hospitals from Belgium, France, Spain, and Italy. Clinical features data were collected through a questionnaire from 417 mild to moderate test-confirmed COVID-19 patients. 16 The questionnaire was based on the smell and taste component of the National Health and Nutrition Examination Survey.[20] Gustatory disorders were found in 88.0% of patients out of which 78.9% had hypogeusia and 21.1% had distorted ability to taste flavors. There was a significant association between olfactory and gustatory disorders (P < 0.001). The chemosensitive disorders were constant in 72.8% and fluctuated in 23.4% of patients over the days. Among the recovered patients, who had residual chemosensitive disorders: isolated smell disorder was in 53.9%, isolated taste disorder in 22.5% and both in 23.6%. In this study also, females were more affected by these symptoms than males. There was no significant association between the comorbidities and the presence of these symptoms.[16]

Most studies were based on subjective evaluation of the patients. The first study to objectively evaluate these symptoms was conducted extensively by Vaira et al on 72 COVID-19 positive patients in the University Hospital of Sassari, Italy.[21] The patients were requested to provide the timeline of the onset, duration and the regression of the chemosensitive symptoms. About 73.6% of patients reported chemosensory dysfunctions during the course of the infection. Gustatory function was evaluated by the ability to identify sweet, salt, sour, and bitter tastes. The most affected sensitivities were those for sweet and sour with no clear predominance to a specific taste. Taste scoring was carried out and found as normal in 51.4%, mild hypogeusia in 22.2%, moderate hypogeusia in 15.3%, severe hypogeusia in 9.7%, and ageusia in 1.4% of patients. Isolated taste and smell disorders were reported in 12.5% and 14.4% of patients, respectively, and both in 41.7% of patients. Complete recovery of chemosensitive symptoms was reported in 66% of patients, in which 54.3% recovered in <5 days and 45.7% in >5 days, meanwhile 34% had persistence of smell and taste alterations. Infact, 18.1% of this series presented smell and taste alterations as the first clinical manifestation of the disease. This implies that clinicians should suspect SARS-CoV-2 infection in the differential diagnosis of such nonspecific chemosensory dysfunction.

Also, it is noted that anosmia, with or without dysgeusia, manifests either early in the disease process or in patients with mild or no constitutional symptoms.[17] Still, it is commented that more evidence is needed to establish these chemosensitive changes as COVID-19 symptoms.[22]

VARIATIONS IN THE PREVALENCE OF TASTE DISTURBANCES

Gustatory dysfunctions are reported more in European studies and there is absence of such symptom in Asian studies. This might be due to the lack of assessment of these symptom or the Chinese patients really had insignificant taste disorders. This high regional variation might be due to the mutations of surface proteins (spike-S-protein and nucleocapsid-N protein) in SARS-Cov-2 or due to the ACE2 polymorphisms and ACE2 expression levels between Asian and European populations.[23,24] There is also a high susceptibility of females to develop these chemosensitive symptoms than males. This gender-related differences would be related to the variation in the inflammatory reaction process.[25]

CONCLUSION

Gustatory dysfunction symptoms are more prevalent symptoms in European COVID-19 patients as part of the chemosensory dysfunction. The sudden onset of taste disorders without any oral or systemic cause needs to be recognized by the physicians, oral-maxillofacial surgeons, craniofacial surgeons, and otorhinolaryngologists as an important suspicion for COVID-19. The relationship between the duration of the gustatory symptoms and the severity of COVID-19 disease might be associated with the viral load in the oral cavity. Future studies correlating the symptomatic condition to the viral loads from the swabs or saliva will help to verify this hypothesis. Thus, the available studies clearly show that the gustatory functions may be impaired in COVID-19 patients and would be a reliable early symptom which could be used for screening, testing and for self-isolation in this pandemic keeping in mind the regional variations.