Olfactory Dysfunction in COVID-19 Patients: Comparison
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Smell and taste dysfunction are frequently reported by SARS-CoV-2 positive patients. The degree of olfactory and gustatory dysfunction varies from a very mild reduction to their complete loss.

  • COVID-19
  • smell
  • olfactory disfunction
  • dentistry

1. Introduction

COVID-19 is caused by SARS-CoV-2, a virus that is part of the coronaviridae family, just like SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus, 2003) and MERS-Cov (Middle East Respiratory Syndrome Coronavirus, 2012) [2][1]. 
Ever since the outbreak of the infection, in addition to pneumonia, several symptoms have been associated with COVID-19. While some patients display relevant symptoms, others are completely asymptomatic or might present mild symptoms (paucisymptomatic). Asymptomatic subjects can also be responsible for secondary infections, although at a lower degree compared to symptomatic subjects [3][2]. Screening procedures put in place to reduce contacts between healthy and infected people and limit transmission, often fail to recognize asymptomatic and pre-symptomatic individuals and also individuals that present very mild symptoms (sub-clinical cases) [6][3]. Studies have shown that children present milder symptoms compared to adults; nonetheless, they are potential carriers and may transmit the infection [7][4].
Olfactory and gustatory dysfunction generally appear around the third or fourth day after the onset of symptoms; in some cases, they even precede other symptoms [9,10][5][6]. Studies performed to determine the incidence of anosmia and dysgeusia report heterogeneous results, ranging from 5% to 88% [8,11,12][7][8][9]. The most common method used to investigate the incidence of smell and taste alterations is the administration of questionnaires to patients who have tested positive for COVID-19 [13][10]. Other authors have collected data from patients’ records. Very few studies have employed objective olfactory tests to assess the presence of olfactory dysfunction [14][11]. As the correlation between subjective smell perception and the results of the olfactory tests can be low or even absent [15][12], relying only on patients’ reports on olfactory and gustatory dysfunctions may lead to biased results and underestimation of the real incidence of these symptoms in COVID-19 patients, also taking into consideration the fact that not all patients that present with olfactory dysfunction exhibit total anosmia. Some of them only exhibit a partial loss of smell, which, if very mild, may go unnoticed. Furthermore, only through objective measurements is it possible to quantify the loss of smell and monitor its recovery [14][11]. There is very little data in the literature regarding the duration of olfactory and gustatory dysfunction. Some authors report full recovery within a month from the onset of symptoms in the majority of patients, while a small percentage of patients exhibit partial recovery or no recovery [15,16,17][12][13][14].

2. Discussion

In a study conducted by Lechien et al. on a sample of 417 COVID-19 cases, OD appeared as the first symptom in 11.8% of all cases [10][6]. Kaye et al. report some very interesting data collected through the COVID-19 Anosmia Reporting Tool for Clinicians, a platform established by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) in order to gather data regarding olfactory symptoms. The authors analyzed the data of the first 237 entries in the platform. They report olfactory dysfunction as the first COVID-19 symptom in 27% of patients; OD was the reason the COVID-19 test was recommended in 40% of all cases [23][15]. These results indicate that, if recent onset of loss of smell and taste is reported by patients, they should be considered suspect COVID–19 cases and testing should be recommended. OD and GD are not represented only by complete loss of smell and/or taste; these alterations may present themselves at different degrees, separately or concomitantly with each other and in some cases, they may be subtle and undetectable by the patient [24][16]. Studies performed to determine the prevalence of OD and GD in COVID-19 patients report a wide range of results. There appears to be a notable difference between results based on patients’ self-reported OD questionnaires and results that are based on objective measurement methods of olfactory performance [14,25][11][17]. A meta-analysis conducted by Pang et al. which included 19 published studies, concluded that, although not statistically significant, the prevalence of OD detected through olfactory tests was higher than the one assessed through self-reported questionnaires [24][16]. The authors suggest that patients may not notice smell reduction when it is very mild, especially if there are other more severe respiratory symptoms overshadowing it. Moein et al. conducted a case-control study, in which COVID-19 positive subjects and healthy subjects underwent olfactory assessment using a validated objective test. The data they collected show a significant difference in test scoring between COVID-19 patients and healthy subjects. More than half of COVID-19 subjects presented with severe hyposmia or anosmia, while the rest of the group showed mild to moderate hyposmia. Interestingly, only 35% of the subjects had noticed and reported olfactory dysfunction [26][18]. Other authors that also have employed objective olfactory testing methods conclude that the prevalence of smell dysfunction is higher than the one based on patients’ reports [17][14]; furthermore, as reported by Vaira et al., there may be a residual olfactory deficiency even in patients that report full recovery [17][14]. These conclusions are in line with the results of the present study. Little has been published regarding the duration and recovery of olfactory and gustatory alterations. Beltrán-Corbellini et al. conducted a study on 79 COVID-19 patients and 40 controls. COVID-19 patients reported smell and test disorders lasting on average 7.5 days. Almost half of the patients recruited for their study recovered fully after 7.4 days. In some patients, smell and tasted disorders resolved after 9 days; no patient-reported persistence of OD and GD. However, the results were based on questionnaires to which the patients had to answer [27][19]. A multicenter study conducted by Vaira et al. concluded that severe OD and GD lasted on average 10 days; after the tenth day, smell and taste improved significantly. Almost 70% of the study group presented smell and taste disorders even 25–30 days after the onset of symptoms, but the disorders were represented by mild hyposmia and hypogeusia. The authors encountered, through objective measurement methods, mild to moderate hyposmia in almost 70% of patients that had reported full resolution of OD. They also reported residual hypogeusia in almost 30% of these patients [28][20]. Another smaller study showed an OD improvement after two weeks from the diagnosis [29][21]. Yan et al. conducted a cross-sectional study involving 1480 patients that presented symptoms similar to influenza. Out of 59 COVID-19 positive patients that responded to the survey, 40 patients reported olfactory dysfunction and 42 patients reported gustatory dysfunction. A total of 72% of patients that reported olfactory dysfunction experienced improvement 1 to 4 weeks after the onset of symptoms. Most patients reported improvement of the sense of taste contemporarily [30][22]. Otte et al. evaluated a group of 80 patients who had reported olfactory impairment, 8 weeks after the olfactory symptoms appeared. The authors found that almost half of the participants (45.1%) still showed to be hyposmic after 8 weeks. Not all the hyposmic subjects, although were aware of the persistence of the olfactory symptom [31][23]. Iannuzzi et al. evaluated 30 COVID-19 positive patients at 25 days after their COVID-19 diagnosis and at 1 month after the first evaluation, when patients no longer tested positive for the virus. The results of the Sniffin’ Sticks Test showed that there was a significant improvement from the first to the second evaluation, especially in Threshold and Discrimination values. At the first evaluation 53.3% of subjects showed to be hyposmic, while only 26.7% showed to be hyposmic at the second evaluation [32][24]. In general, authors conclude that smell and taste disorders resolve when other COVID-19 symptoms start to disappear; however, most studies employ subjective methods to assess the presence of OD and GD and their recovery. The results we obtained from our study demonstrate that, in some patients, recovery can be very slow and olfactory dysfunction may be present even months after its onset. Patients may be unaware of it, especially if the dysfunction is mild. It is necessary to underline that it is not possible to exclude that the hyposmic patients of the present study could have been suffering of olfactory loss before the pandemic and could be unaware of it. Nevertheless, the incidence of hyposmia in the general population is about 15% [33][25]. Furthermore, the subjects enrolled for this study were quite young and their history excluded other major causes of olfactory loss, a part COVID-19 infection. All in all, it seems difficult that these patients did not suffer from a mild post-viral olfactory dysfunction due to COVID-19 infection. Efforts have been made to explain the pathophysiology of OD and GD by different authors. Rhinorrhea and nasal obstruction are not plausible pathophysiological hypotheses for explaining smell alterations, as OD is often seen in patients who do not present these symptoms [34][26]. Spike glycoprotein is a membrane protein that allows the virus to enter the cells of the host. The virus targets the respiratory system; it invades and replicates within the alveolar cells in the lungs and results in respiratory symptoms [1][27]. Similar to other coronaviruses, SARS-CoV-2 not only attacks the respiratory system but also causes disease to the gastrointestinal system, nervous system, etc. To be able to enter the cells, the novel coronavirus binds angiotensin converting enzyme 2 (ACE-2), which is an enzyme that regulates blood pressure by inhibiting the angiotensin-renin-aldosterone pathways. ACE-2 is widely distributed in the cell membranes of many organs and there is a high density of ACE-2 in the nasal and oral mucosa. The link between the spike protein and ACE-2 receptors is aided by a protease present in the surface of the target cell called TMPRSS2 [35][28]. One suggested hypothesis on the pathophysiology of anosmia and/or dysgeusia regards the direct damage SARS-CoV-2 may cause to the olfactory receptors present in the nasal mucosa and the gustatory receptors present in the tongue [35,36][28][29]. Olfactory and gustatory receptors bind the smell and taste molecules. The inflammation caused by the binding of the virus with the ACE-2 receptors could directly affect the activity of the receptors, thus impairing the sense of smell and taste. Furthermore, it would also reduce their availability for odorants and tastants. The ACE-2 receptors are widely distributed in the nasal mucosa and the tongue; they are also present in the epithelium of salivary glands [37][30]. Another advanced hypothesis regarding anosmia and dysgeusia regards the ability of the virus to cause direct damage to the olfactory neurons and neurons responsible for the sense of taste, particularly the chorda tympani which can be reached by the virus through the eustachian tube [38][31]. This hypothesis, however, seems unlikely given the fact that in most anosmia cases, patients recover their sense of smell within 1–2 weeks, which is a shorter time than the one required for neuronal repair [38][31]. Recent data provided by experiments on mice have shown that the virus does not cause direct damage to the neurons, as they do not express ACE-2 receptors. Instead, the virus most likely alters the function of the olfactory epithelium by damaging the sustentacular cells and Bowman cells [35][28]. The olfactory epithelium contains the cells which provide metabolic support to olfactory neurons and present similar levels of ACE-2 receptors to those of the respiratory tract. The damage caused to the epithelium decreases the trophic support that it provides to the neurons, thus causing alterations of the sense of smell [39][32]. The results of the present study together with those of a previous one [15][12], showing mainly an involvement of T, seem to confirm that OD in COVID-19 patients has an end-organ failure pathogenesis [40][33]. Olfactory and gustatory dysfunctions, especially if long-lasting, may impair the patients’ quality of life. However, as mentioned above, most patients recover spontaneously in a short period of time. The prescription of corticosteroid sprays to patients is not supported by the current literature because it does not seem to improve olfaction [41][34].

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