Self-reported olfactory and gustatory dysfunctions in COVID-19 patients: a 1-year follow-up study in Foggia district, Italy

From the earliest stages of the coronavirus disease 19 (COVID-19) pandemic, in March 2020, the American Academy of Otolaryngology—Head and Neck Surgery proposed including anosmia and dysgeusia to the list of screening tools for possible COVID-19 infection [1]. In April 2020, the Centers for Disease Control and Prevention added ‘‘new loss of taste or smell’’ to the list of symptoms that may appear 2 to 14 days after exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. As of December 3^rd, 2020, the European Centre for Disease Prevention and Control included the “sudden onset of anosmia, ageusia or dysgeusia” among the clinical criteria of the new case definition for COVID-19 [3].

To date, several studies have documented a high prevalence of olfactory and gustatory dysfunctions in COVID-19. These sensory dysfunctions represent specific and sometimes early-onset symptoms, which differentiate SARS-CoV-2 infection from other acute respiratory diseases, mainly in paucisymptomatic patients [4‐12].

The pathophysiological mechanism through which SARS-CoV-2 causes sensory dysfunctions of various severity has not been fully clarified yet. It is well known that SARS-CoV-2 infects alveolar epithelial cells by directly binding the Angiotensin-Converting Enzyme 2 (ACE2) cell receptors, thereby decreasing their expression and protective function. ACE2 receptors are expressed by cells of the gut, kidney, heart, and oral mucosa. In particular, they are highly expressed in the tongue compared with other areas of the oral cavity (vestibular and gingival), suggesting a peculiar vulnerability of the oral mucosa to COVID-19 infection [13]. Furthermore, anosmia could be ascribed to the involvement of the central nervous system and damage of the nasal epithelium. Indeed, a potential neuroinvasiveness of coronaviruses through the olfactory nerve pathway or the peripheral trigeminal endings has been described [6, 14]. Accordingly, SARS-CoV-2 RNA has been isolated in the cerebrospinal fluid [6, 15]. More recently, in patients who have recovered from COVID-19, neuroimaging has revealed localized inflammation in intracranial olfactory structures with alterations of primary olfactory neurons putatively leading to a persistent impairment [16]. Gupta et al. [17] suggested that loss of smell in SARS-CoV-2 infection is probably due to the susceptibility of a subgroup of cells (i.e., sustentacular cells, Bowman’s cells, and olfactory stem cells) to virus entry, rather than to the direct impairment of the olfactory sensory neurons. Sustentacular cells, Bowman’s cells and olfactory stem cells do not have a sensory function but play a crucial role in the maintenance of the olfactory organ and its homeostasis. Recent evidence from combined investigations of COVID-19-associated olfactory dysfunction in humans and experimentally-infected animals suggests that multiple cell types of the olfactory neuroepithelium are infected during the acute phase and that protracted viral infection and inflammation in the olfactory neuroepithelium may account for prolonged anosmia [18, 19].

In most cases, olfactory and gustatory dysfunctions resolve naturally and completely in the short term. However, several studies have demonstrated that moderate-to-severe olfactory or gustatory disturbances persist in a significant proportion of patients even months after the clinical onset of COVID-19 [20‐29]. This observation is in agreement with the long-term sequelae referred to as “Long COVID”, which includes smell/taste disorders and chronic fatigue, among a variety of symptoms [30].

In this context, limited studies on the duration of olfactory and gustatory dysfunctions are available to date, and they predominantly document the mid-term evolution of these symptoms. Indeed, only a few studies have exceeded a 6-month follow-up and investigated the recovery of olfactory and gustatory dysfunctions beyond this period providing long-term information [21‐23, 27, 28]. Nevertheless, considering the large number of people affected worldwide by COVID-19, the definition of duration and persistence of olfactory and gustatory disorders deserve to be addressed because of their potential impact on the quality of life [31].

This study aimed to characterize the long-term evolution of self-reported olfactory and gustatory dysfunctions in COVID-19 cases with previous paucisymptomatic-to-mild clinical presentation, estimating their persistence and recovery rate one year after the diagnosis.

From March 1st to June 16th, 2020, a total of 1175 COVID-19 confirmed cases were notified in the Foggia district, of which 653 (mean age: 42.9 ± 17.9 years, median age: 45 years, IQR 44–47 years; 53.9% females) were home-quarantined. Clinical presentation of COVID-19 was classified as paucisymptomatic in 55.6% (n = 363) of cases and mild in 19.1% (n = 125) of cases; 165 (25.3%) cases were classified as asymptomatic (Fig. 1, Table 1). The mean estimated incubation period was 9.6 ± 9.8 days (median: 7 days, IQR 3–13.5 days). As of June 16th, 2020, 94.5% (n = 617) of cases were fully recovered with complete viral clearance (mean time to viral clearance: 28 ± 11.9 days; median: 25 days, IQR 18–38 days).

Olfactory and gustatory dysfunctions are widely reported by COVID-19 patients [4‐12] and are emerging as one of the most frequent long-term sequelae of SARS-CoV-2 infection [21‐29]. Although chemosensory disorders recover spontaneously in the short-term period in most cases [25, 36, 37], a significant portion of SARS-CoV-2 infected patients continues to suffer from persisting symptoms long after having recovered from the acute illness [30, 38, 39]. The persistence of these symptoms after recovery commonly lasts for 2–3 weeks but may sometimes exceed 6 months. Therefore, the long-term persistence (i.e., six months after clinical onset) of such symptoms deserves to be assessed and investigated. Additionally, considering the large number of people affected by COVID-19 worldwide and the negative impact of anosmia and ageusia on the quality of life [31, 40‐43], it is important to quantify the extent and duration of these symptoms to develop effective interventions able to manage the disorders in subjects with SARS-CoV-2 infection.

Our study was conducted on a cohort of confirmed SARS-CoV-2 positive patients with paucisymptomatic or mild disease who did not require hospitalization and were managed by the community healthcare system. At baseline, olfactory or gustatory dysfunctions were present in more than 40% of cases, in agreement with several studies [44‐46] and meta-analyses [47, 48]. A higher prevalence of anosmia and dysgeusia symptoms have been reported in studies that included severe cases requiring hospitalization (74.9 and 81.3% of cases, respectively) [12, 49] or healthcare professionals [12].

We performed a prospective evaluation of patients with self-reported gustatory and olfactory dysfunctions. Of the 201 participants included in our study, 178 agreed to participate in the follow-up phase, and only 23 withdrew. Although the majority of the participants (approximately 7 out of 10) in the follow-up reported complete resolution of the olfactory and gustatory disorders after 12 months, a substantial proportion of cases (approximately 3 out of 10) was still complaining of these symptoms. This proportion is remarkable, mainly because our data refer to a population with mild COVID-19. Few other studies comparable to ours in terms of sample size, demographic or clinical characteristics, adherence rates to the follow-up phase, have exceeded a 6-month follow-up and have investigated the recovery of olfactory and gustatory functions beyond this period [21‐23, 27, 28]. Of these, only two [22, 27] had a larger sample size at baseline and included a higher number of participants in the follow-up phase.

Most available studies used online questionnaires or telephone interviews for the follow-up phase to collect general and specific clinical information on chemosensory disorders. As opposed to other studies [27, 28], we did not conduct intermediate follow-up surveys. However, we collected data on the persistence and evolution of chemosensory dysfunctions through specific questions (persistence/recovery). These specific questions were administered together with the SNOT-22 test which, in turn, represents a validated subjective method to explore their severity [34, 35].

The rate of persistence of self-reported olfactory and gustatory dysfunctions observed in our study (29.8%) falls within the range reported by available studies (16 to 48%). In particular, Nguyen et al. [23] found that the persistence rate of chemosensory disorders was 24% at 7 months, Nehme et al. [27] reported 16.8% from 7 to 9 months, and Biadsee et al. [21] observed that smell and taste dysfunctions persist respectively in 48% and 38.5% of patients after a mean follow-up of 229 days. Boscolo-Rizzo et al. [22], whose study was similar to ours in design and length of follow-up, estimated that the prevalence of self-reported COVID-19 associated chemosensory dysfunctions was 21.3% at 12 months, roughly in line with our result. Only Renaud et al. [28], who used an objective measurement, described a higher rate of smell recovery (96.1%) at one year.

The reason for the differences between the studies are still unclear and might be of various nature. Primarily, the estimated prevalence may be affected by the methodology used for the data collection. Indeed, it has been proven that the proportion of sensory dysfunctions is affected by the detection instruments, being higher with the use of objective measurements [48, 50]. On the contrary, the assessment of chemosensory dysfunctions based on anamnestic data may fail to detect a considerable proportion of cases [7].

Two very recent case–control studies have evaluated the persistence of smell and taste disorders at least one year after the onset of COVID-19 using psychophysical tests [51, 52]. More specifically, Boscolo-Rizzo et al. estimated that, overall, 58% of cases vs. 18% of controls had an olfactory or gustatory dysfunction, while 33% of cases self-reported a persistently altered sense of smell or taste at the time of the psychophysical evaluation [51]. Vaira et al. found that 26.5% of cases vs. 3.5% of controls had olfactory dysfunction on psychophysical tests, while 25.9% of patients self-reported some form of persistent olfactory loss, suggesting that qualitative and quantitative disturbances of smell may have similar clinical implications on the quality of life [52].

We did not find any baseline demographic or clinical predictive factors for the persistence of symptoms. Interestingly, the occurrence of the syndrome defined “Long COVID” has been reported independently of the severity of the acute phase, being present also in patients with a mild disease [30, 38, 39].

The recovery time is putatively dependent on the underlying pathophysiological mechanisms of sensory dysfunctions. These mechanisms were not investigated in our study but can hopefully be clarified with further purposely designed researches. In our analysis, patients were also asked to estimate the approximate duration of their symptoms. It emerged that a complete recovery of smell and taste tended to occur mostly in the first month after the acute phase of COVID-19. This is in agreement with Nguyen et al. [23], who documented the recovery of the sense of smell and taste mainly during the first 6 weeks after onset using a retrospective questionnaire, and with Nehme et al. [27], who performed an interim interview at 30–45 days after COVID-19 diagnosis.

Olfactory and gustatory dysfunctions are generally considered less disabling and life-threatening than other sensory impairments. Thus, they may not receive adequate medical attention despite their impact on quality of life, especially if prolonged over months. However, olfactory and gustatory deprivations of various cause have been documented as disruptive on daily activities already before the spread of SARS-CoV-2 [31, 40], and their negative impact has been recently confirmed by properly designed studies [41‐43]. It is apparent that COVID-19 patients with loss of smell and taste experience a reduced quality of life related to those situations or functions in which the chemical senses play a significant role. Furthermore, they also present with higher levels of psychological distress. In particular, the presence of chemosensory dysfunctions is positively correlated to anxiety and depression, which are attributable to a sense of frustration as the patient often struggles to be fully understood [43].

Our study has some limitations. The self-reported assessment of the severity of symptoms and the retrospective investigation of their persistence within the 12-months follow-up period could be inaccurate due to a recall bias. Moreover, we did not record any possible pharmacological or rehabilitative intervention that could potentially affect the evolution of the olfactory and gustatory dysfunctions during the study period. As previously discussed, another possible limitation lies in the fact that, in our study, chemosensory dysfunctions were not assessed using objective examinations, such as psychophysical and electrophysiological tests, but only on a subjective basis. Therefore, underreporting of chemosensory dysfunctions cannot be excluded. However, in the perspective of a clinical approach taking into account the quality of life, a subjective evaluation may be more significant than an objective assessment of the disorders. Moreover, due to the absence of a control group, our findings could have been biased by the underlying prevalence of chemosensory dysfunctions in the general population [53, 54]. Also the inclusion of only patients with paucisymptomatic-to-mild COVID-19 may have influenced both the prevalence of sensory disorders and the characteristics or the timing of their evolution. Finally, the possibility of spontaneous recoveries of a post-viral olfactory loss even beyond one year from the onset cannot be excluded [55].

Olfactory and gustatory dysfunctions persist in a substantial portion of patients with previous paucisymptomatic-to-mild clinical COVID-19 up to 12 months after disease onset. As SARS-CoV-2 infection may be associated with long-term smell and/or taste loss that may significantly impact the quality of life, there is a need for a better understanding of the extent and duration of these symptoms. In addition, a better understanding of the physiological mechanisms driving the recovery is required to facilitate the development of effective preventive and therapeutic strategies.