Presence of gustatory and olfactory dysfunction in the time of the COVID-19 pandemic

The novel COVID-19 coronavirus infection currently causing a global pandemic may present on a spectrum from asymptomatic to severe infection affecting almost every possible organ system [1]. A more severe course of disease, with rapid deterioration and acute respiratory distress syndrome (ARDS) or even fatal outcomes were reported especially among older people or those with comorbidities [2]. The current literature estimated a mean incubation period of three to 5 days [3, 4]. In symptomatic patients, the clinical manifestations of the disease usually started after less than 1 week [4]. However, as the virus effectively replicates in the upper respiratory tract and infected individuals produce a considerable amount of virus during a prodrome period, the infection may be spread early and index persons may be unrecognized for several days [2]. As a second wave of COVID-19 is ongoing, epidemiological studies are important in order to characterize symptoms, comorbidities, age and even country specific characteristics of the disease in order to identify infected patients as early as possible [4]. We therefore report our single center study on COVID-19 and share our detailed analysis on patient-reported symptoms, co-morbidities, and course of disease.

Current evidence indicates that the clinical features of olfactory and gustatory dysfunction (OGD) might be far more prevalent in the European population than in the Asian population [10, 11], raising questions for possible new mutations [12], different expression of the angiotensin-converting enzyme 2 (ACE2)-entry receptor in different populations and different organs [13‐15]. Neurons and glial cells express the ACE2 receptor offering a binding spot for the virus and subsequent neurological, olfactory, and gustatory dysfunction [16].

Niklassen et al. [17] assessed OGD in a total of 111 COVID-19 positive tested individuals at three different time intervals with the help of Sniffin’ Sticks and taste sprays/strips. The study indicated that during the acute infection with SARS-CoV-2, 21% of patients displayed anosmia and 49% hyposmia, in contrast 26% showed various degrees of gustatory dysfunction. The same tests were used in a study conducted by Huart et al. [18] distinguishing possible differences in the pathophysiology of OGD in acute cold and COVID-19 patients. A comparison of OGD was made between COVID-19 infected individuals, acute cold patients in the pre- COVID-19 era, and healthy controls. Similarly, like in the study conducted by Niklassen et al. [17], Huart et al. [18] showed that patients infected with COVID-19 have worse global, sweet and bitter gustatory scores (p = 0,0015; p = 0,026 and p = 0,001), suggesting a possible involvement of central olfactory structures and therefore a neuroinvasive nature of SARS-CoV-2. However, a definitive generalization of these results is due to a small cohort not possible.

Although the beforementioned studies stipulate a principal link between COVID-19 and OGD, no study can reliably compare the degree of existing OGD in patients before and after a SARS-CoV-2 infection. A high prevalence of OGD was also found in diverse studies [11, 19, 20], e.g., a multicenter European study [21] in which almost 90% of COVID-19 patients reported olfactory and gustatory dysfunction. Lechien et al. [21] assessed the impact of COVID-19 on olfactory and gustatory dysfunction by using a short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS) and the smell and taste component of the National Health and Nutrition Examination Survey. Similarly, Luers et al. [22] used a standardized 2-section questionnaire consisting of demographic data and the total nasal symptom score (TNSS) evaluating for nasal congestion, sneezing, nasal itching, and rhinorrhea. The study indicated a significant relationship between the presence of reduced olfaction and a reduced sense of taste (P < .001). Furthermore, recent studies suggested that the presence of self-reported olfactory and gustatory dysfunction had a high specificity as a screening criterion for COVID-19 [23] (98.7, 95% CI 97.6–99.4%) and correlated with a milder course of infection [24]. Similarly, our study indicated a significantly higher prevalence of olfactory (58.1%) and gustatory dysfunction (62.8%) (each p <  0.0001) and significantly longer median duration of olfactory disturbance (p = 0.0010) compared to SARS-CoV-2 negative tested patients.

Nevertheless, more than 20% of SARS-CoV-2 negative tested individuals in our study reported OGD. This may be critical to proceedings in diagnosis and treatment of COVID-19 as currently no recommendation on how to proceed with SARS-CoV-2 negative tested individuals is available. Although robust data are lacking one could assume that these individuals displaying severe olfactory and gustatory dysfunction as loss of smell and taste may have a higher chance of false negative tests as OGD was reported to serve as a potential predictor of infection [25‐28].

In light of the increased awareness of OGD as a symptom of COVID-19 created by mainstream media, potential contributory factors like other diseases, medication- or allergies have to be taken into closer consideration. In addition, the general prevalence of olfactory and gustatory impairment is not well established.

Medications like acetaminophen and ibuprofen can cause olfactory and gustatory dysfunction although these side effects are reported rarely [29] and are especially more prevalent in older patients in conjunction with the use of other medication for chronic conditions [30]. Other viral infections might also be associated with olfactory and gustatory dysfunction [31]. The influenza virus is known to cause hyposmia and hypogeusia [32], but recent epidemiological data from Germany indicates that the influenza virus was virtually non-existent in April and subsequent months [33]. Additionally, we included questions assessing concomitant use of anti-inflammatory medication as the onset of taste or smell dysfunction could coincide with the introduction of a new drug or drug combination [5]. Patients infected with COVID-19 tended to use more anti-inflammatory medication compared to COVID-19 negative tested individuals with statistical difference in the use of acetaminophen (p = 0.0025) and metamizole (p = 0.0039). Therefore, our study indicates that use of concomitant medication may have a contributory effect in patients tested positive for SARS-CoV-2 reporting OGD, as a statistical significance in the mean number of taste disturbances was evident in the SARS-CoV-2 positive tested subgroup (μ in changes of taste 0.8 versus 0.3; p <  0.0001). In addition, pre-existing olfactory and gustatory dysfunction are possibly more likely in older male patients [5, 30], in patients with upper airway inflammation (allergic rhinitis, rhinosinusitis) [34] or in patients with neurodegenerative disorders [35]. Our analysis indicated that OGD was more commonly recognized as a symptom in the younger population. More females displayed symptoms of gustatory dysfunction (29.8%, p = 0.0041) and olfactory dysfunction (22.9%, p = 0.0174) compared to man. Additionally, the simultaneous occurrence of OGD was more prevalent in females (33.08%) than males (23.96%) with statistical significance in younger patients.

Our data indicates that a statistical difference in the number of pre-existing diseases was present in COVID-19 negative tested patients with OGD (p = 0. 0314). Similarly, COVID-19 positive tested patients had more pre-existent diseases with statistical significance in kidney disease (p = 0.0004,) which potentially could contribute to the presence of OGD [9, 36]. Other possible causes for altered olfaction and gustation include upper airway inflammation (e.g allergic rhinitis, chronic rhinosinusitis with or without nasal polyps) [34, 37]. Allergic rhinitis is a common, underdiagnosed disorder which can affect people of all ages and is associated with symptoms like pruritis, rhinorrhea and nasal congestion [6, 38]. Recent research indicates that over the last 20 years, a significant rise in the total number of weed pollen sensitization, especially in younger patients took place in Germany [39]. Our study indicates that patients tested negative for COVID-19 who displayed OGD more commonly reported allergy-like features like rhinorrhea (72%, p = 0.0001) and ocular pruritus (39%, p = 0.0164) compared to negative tested patients without OGD (p = 0.0001), indicating a possible allergic component which could coincide with the COVID-19 pandemic.

We acknowledge several limitations to our study. First, our study contains a relatively small amount of COVID-19 positive tested individuals. Furthermore, no psychophysical evaluation of smell and taste was conducted. Recent studies [40] indicate that an olfactory disorder in COVID-19 patients is much more prevalent than those detected by questionnaires and use of objective methods are useful tools to discriminate between these patients. That would imply that the self-reported OGD of more than 20% in our SARS-CoV-2 negative tested individuals are severely underestimated. So the correlation between OGD and different disease processes remains to be further enlightened. One can speculate about the different etiologies for OGD, but this study indicates that the global COVID-19 pandemic and our findings in COVID-19 negative-tested individuals merit deeper investigation in these disturbances in the future.

Overall, when characterizing the course of COVID-19 disease in Germany, the most common symptoms among individuals who tested positive for COVID-19 were fatigue, headache, and cough. Additionally, olfactory and gustatory dysfunction were also reported by many COVID-19 negative individuals who more commonly reported allergy-like features like rhinorrhea (72%, p = 0.0001) and ocular pruritus (39%, p = 0.0164) indicating a possible allergic component that could coincide with the COVID-19 pandemic.

More females displayed symptoms of gustatory dysfunction (29.8%, p = 0.0041) and olfactory dysfunction (22.9%, p = 0.0174) compared to males. Thus, bringing early COVID-19 tests to the populations at risk must be a main focus for the upcoming months.