Post-COVID-19 patients suffer from chemosensory, trigeminal and salivary dysfunctions

doi:10.21203/rs.3.rs-3395187/v1

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Post-COVID-19 patients suffer from chemosensory, trigeminal and salivary dysfunctions

https://doi.org/10.21203/rs.3.rs-3395187/v1

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Journal Publication

published 11 Feb, 2024

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Recent literature indicates that post-COVID-19 patients suffer from a plethora of complications, including chemosensory dysfunction. However, little is known about salivary dysfunction in these patients and little attention is given to understand the interactions between chemosensory, trigeminal and salivary dysfunctions in post-COVID-19 patients. The aims of this study were (i) to investigate the prevalence and combinations of chemosensory, trigeminal and salivary dysfunctions, (ii) to identify the odorants/tastants that are compromised, and (iii) to explore possible associations in post-COVID-19 patients. One hundred patients and 76 pre-COVID, healthy controls were included in this cross-sectional, case-controlled study. Participants’ smell, taste, trigeminal, and salivary functions were assessed. Significantly higher prevalence was found in patients for parosmia (80%), hyposmia (48%), anosmia (40%), dysgeusia (34%), complete ageusia (3%), specific ageusia (27%), dysesthesia (11%) and dry mouth (18%) compared to controls (0% in all above except 11.8% in hyposmia). Bitter taste was the most prevalent specific ageusia (66.7%) and coffee was the most common distorted smell (56.4%). Eight different combinations of dysfunctions were observed where combination of olfactory and gustatory dysfunction was the most common (45%). These findings indicate that post-COVID-19 patients experience a range of chemosensory, trigeminal and salivary disturbances, occurring in various combinations.

Health sciences/Diseases

Health sciences/Diseases/Oral diseases

Post-COVID-19

long COVID

parosmia

burning mouth

dry mouth

taste

smell

The COVID-19 pandemic is one of the most dramatic global health crises in recent history, presenting unparalleled challenges to societies all over the world. Caused by the novel coronavirus SARS-CoV-2, this infectious disease has spread rapidly affecting millions of individuals and causing substantial morbidity and mortality^1,2. As of August 2023, there have been almost 1.5 million confirmed cases of COVID-19 in Norway and over 768 million worldwide¹. COVID-19 seems to manifest from mild to severe forms, while some individuals remain asymptomatic³. The most common symptoms include fever, dry cough, fatigue, shortness of breath, sore throat, headache, myalgia, chills⁴ and loss of smell and taste^− 5–7. Sudden loss of smell and taste is known to be the most discriminative symptom of COVID-19 infection^5–8.

Most COVID-19 patients experience spontaneous recovery within weeks⁹ while others have persisting symptoms¹⁰. Patients having long lasting symptoms after COVID-19 infection are called post-COVID-19 patients. They are characterized by a history of probable or confirmed SARS CoV-2 infection, symptoms persisting more than three months after COVID-19 infection, with a duration of at least two months, that cannot be explained by another diagnosis. Moreover, symptoms may fluctuate or relapse over time and may persist from the initial illness, or new onset following initial recovery¹¹. Other names for post-COVID-19 are long-COVID and long-haul COVID. These patients present a varied spectrum of symptoms including smell and taste dysfunction¹².

Angiotensin-converting enzyme 2 (ACE2) is identified as entry protein for SARS-CoV-2 virus into human cells¹³ and is expressed in the olfactory mucosa¹⁴, gustatory cells¹⁵, oral epithelial cells¹⁶ and in the salivary glands¹⁷. Reduced expression of ACE2 due to SARS-CoV-2 infection¹⁸ could be the reason behind disturbances in smell, taste¹⁵, chemesthesis and might lead to reduced salivary secretory rate. To our knowledge, no studies have explored the effect of SARS-CoV-2 on salivary function in post-COVID-19 patients.

Olfaction, gustation and chemesthesis are three independent modalities that together provide the perception of flavor^19,20. The sense of smell is mediated through the olfactory receptor cells located in the nasal epithelium and innervated by the olfactory nerve²¹. The sense of taste is mediated through the gustatory receptor cells found in the taste buds in the oral cavity^22–24. Taste buds are innervated by three cranial nerves: the facial nerve, the glossopharyngeal nerve and the vagus nerve²⁵. The sensation provided by the sensory fibers of the trigeminal nerve is called chemesthesis, which can detect temperature, touch, pain and irritation. Multimodal interaction between smell, taste and chemesthesis contributes to the overall flavor perception^19,20. Moreover, saliva plays an important role in dissolving solid foods and facilitating the binding of taste stimuli to adequate taste receptor cells²⁶.

Taste loss can be difficult to differentiate from smell loss based on self-reporting alone due to the sense of smell being a large part of the flavor perception⁷. It is, therefore, important to supplement self-report with measured testing. Chemosensory dysfunctions can be reliably divided into two main categories: quantitative and qualitative. The quantitative dysfunctions describe either complete loss (anosmia, ageusia) or reduced perception (hyposmia, hypogeusia) of smell and taste, respectively^27,28. On the other hand, qualitative dysfunctions reflect distortion of smell (parosmia, phantosmia) and taste (dysgeusia)^27,28. Trigeminal dysfunction is broadly categorized into abnormal sensation without any pain (paresthesia)²⁹, or a painful, abnormal sensation with or without stimuli (dysesthesia)^30,31. Dry mouth includes a subjective feeling of dry mouth (xerostomia) and a condition of low saliva secretory flow determined by sialometry (hyposalivation)³².

The most explored dysfunction is parosmia, which has been found to be highly prevalent in post-COVID-19 patients^33–35. Other conditions like hyposmia, hypogeusia³⁶ and dysgeusia³⁷ have also been reported in patients recovering from COVID-19. No studies, as far as we know, have explored the prevalence of ageusia/specific ageusia and xerostomia in post-COVID-19 patients. Importantly, it is necessary to elucidate the occurrence of smell, taste, trigeminal and salivary dysfunctions in the same cohort as the multimodal interactions between them play a vital role in food intake. Consequences of altered smell, and taste could be compromised nutritional intake, reduced quality of life and psychological distress³⁵. Reduced salivation²⁶ and oral burning sensation³⁶ may add further negative impact.

The aims of the present study, therefore, were (i) to investigate the prevalence and combination of chemosensory, trigeminal, and salivary dysfunction in post-COVID-19 patients (ii) to identify the tastants and odorants that are compromised due to COVID-19 infection and (iii) to explore possible associations between the chemosensory, trigeminal, and salivary dysfunctions.

Study design and participants

This cross-sectional, case-controlled study was conducted at the Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo (UiO) in Norway between October 2020 and June 2023. Patients from all around Norway are referred to us for treatment of persisting smell, taste and trigeminal dysfunction. “Clinic of Smell, Taste and Oral Pain” has newly been established at the Faculty of Dentistry, dedicated specifically to accommodate post-COVID-19 patients. Information about our services was provided through Facebook, newspaper articles, radio programs, national news channel on television and clinical workshop and seminar for ENT-surgeons, neurologists, dentists and family doctors. One hundred post-COVID-19 patients were consecutively recruited for this study among referred patients. Seventy-six pre-COVID, healthy controls were used to ascertain that controls were not asymptomatic COVID-19 patients. These pre-pandemic controls had undergone the same assessments as the post-COVID-19 patients and were enrolled in previous studies from the Faculty of Dentistry, UiO^38,39. The exclusion criteria for controls were oral dryness, and presence of chronic diseases or medications that could affect smell, taste, trigeminal and salivary functions. The study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics (REK 2021/274615) and performed in compliance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants. The participants were instructed to refrain from eating, drinking, and smoking one hour prior to examination. The assessments of olfaction, gustation, trigeminal, and salivary function were carried out according to a preset protocol.

The Oslo COVID-19 questionnaire

Participants’ medical history was obtained through standard health forms used at University Clinic at the Faculty of Dentistry. Thereafter, post-COVID-19 patients completed a questionnaire designed specifically for this study, called the Oslo COVID-19 questionnaire (Supplement). This questionnaire contained both binary, multiple choice and open-ended questions. In section 1, patients reported their age, gender, occupational status, and use of tobacco. In section 2, information about COVID-19 infection was obtained; date of diagnosis, mode of confirmation of diagnosis (PCR test, home test, antibody test or clinical symptoms), and course of illness (mild, moderate or severe). Finally, time for onset of loss of smell and taste, burning sensation and oral dryness was recorded (number of days before or after the confirmation of COVID-19 infection). Aetiology of chemosensory, trigeminal and salivary dysfunctions was recorded (other viral or bacterial infections, menopause, trauma in head and neck region, head and neck surgery, dental surgery). Section 3 was dedicated to more specific questions about parosmia, dysgeusia, dysesthesia, and xerostomia described below.

Olfactory assessment

Participants were asked to score their smell perception on a linear visual analogue scale (VAS) from 0 to 10 before olfactory testing, where 0 indicated no smell perception and 10 very good smell perception. Score 5 was chosen as the cut-off point and scores 0-4.9 indicated low, 5-8.9 moderate, and 9–10 very good perception of smell, respectively. Quantitative olfactory function is broadly categorized into anosmia (complete loss of smell), hyposmia (reduced ability to smell) and normosmia (normal sense of smell)²⁷. Sniffin` Sticks test (Burghart Messtechnik GmbH, Holm, Germany) consisting of 12 felt-tip odor pens were used for non-lateralized psychophysical testing of olfactory function. The participants were informed about the procedure before the test started. The responses were recorded as 1 = correct or 0 = incorrect and summarized (score range 0– 12). A normative classification⁴⁰ was used to categorize participants into anosmic (score 0–5), hyposmic (score 6–9) and normosmic (score 10–12).

Gustatory assessment

Participants were asked to score their taste perception on a VAS from 0 to 10 before gustatory testing, where 0 indicated no taste perception and 10 very good taste perception. Score 5 was chosen as the cut-off point where scores 0-4.9 indicated low, 5-8.9 moderate, and 9–10 very good perception of taste, respectively.

Quantitative gustatory function is categorized into ageusia (complete loss of taste), hypogeusia (partial loss of taste), normogeusia (normal sense of taste)²⁸ and specific ageusia (complete loss of one or more taste qualities, but not all). Gustatory function was measured by Taste Strips (Burghart Messtechnik GmbH, Holm, Germany) impregnated with solutions in four different concentrations of four different taste qualities: sweet, sour, salty and bitter. The responses were recorded as 1 = correct or 0 = incorrect and summarized (score range 0–16). Participants were classified into ageusic (score 0), hypogeusic (score 1–9) and normogeusic (score 10–16) by a normative classification⁴¹. Participants were considered to have a specific ageusia if they were unable to detect all four different concentrations of one tastant.

Assessment of parosmia, dysgeusia, dysesthesia and xerostomia

The categorization of parosmia was based on results from the questionnaire, where participants had no parosmia (score 0) or parosmia (score 1). Further, they were asked to describe how often they experienced parosmia: constantly, daily, sometimes, during meals, in between meals, or only when in contact with odorant. They were also asked to report which smells that were distorted in a list of 35 odors, as well as describe the character of the distortion.

Similarly, absence or presence of dysgeusia was as follows: no dysgeusia (score 0) and dysgeusia (score 1). Participants reported how often they experienced dysgeusia (constantly, daily, sometimes, periodically, during meals, in between meals) and described the form of dysgeusia (metallic, rotten, bitter, harsh, other).

Dysesthesia was categorized as no dysesthesia (score 0), and dysesthesia (score 1). Participants reported how often they experienced dysesthesia (constantly, daily, sometimes, periodically, during meals, in between meals), described where in the mouth they experienced dysesthesia (whole tongue, anterior tongue, lips, palate, buccal mucosa, other), and mentioned food items that enhanced dysesthesia (spicy, sweet, sour, salty, bitter).

Xerostomia was categorized according to participants’ self-reported perception of no dry mouth (score 0) and dry mouth (score 1). Participants reported whether symptoms of xerostomia started before or after COVID-19 infection, and open-ended questions where the patients could describe their experience of oral dryness. Finally, they were asked to report whether there were food items that they had to refrain from because of parosmia, dysgeusia, dysesthesia or xerostomia.

Statistical analyses

The statistical analyses were performed using SPSS (SPSS Statistics 28.0, IBM, Armonk, NY, USA). The results from descriptive analyses were presented as percentages, histograms and median/interquartile range (IQR)/range. Chi-square (χ²) or Fisher’s exact test were used to compare categorical variables and determine dependency between variables. The non-parametric test, Mann-Whitney U, was used to describe median differences between the groups in case of non-normal distribution. Pearson’s correlation coefficient (r) test was used to measure the strength and direction of linear relationships between pairs. Statistical significance was considered at p < 0.05.

Participant characteristics

The characteristics of post-COVID-19 patients and controls are presented in Table 1. No significant differences between patients and controls were found regarding age, gender and tobacco use. Post-COVID-19 patients had a significantly higher number of other chronic conditions and used significantly more medications compared to controls. Most of the patients experienced a mild or moderate course of COVID-19, and only one of the patients reported a severe course involving hospitalization.

Table 1. Participant characteristics.

Post-COVID-19 patients

(n = 100)

Controls

(n = 76)

p-values

Age (years)

Mean (range)

41.7 (18 – 73)

41.8 (18 – 79)

Gender % (n)

Female

Male

68.0 (68)

32.0 (32)

73.7 (56)

26.3 (20)

Chronic conditions % (n)

Yes

Allergy

Heart disease

Endocrinological disorders

Auto-immune disorders

Neurological disorders

Psychiatric disorders

Renal disease

Cancer (prostate)

Other

40.0 (40)

60.0 (60)

24.0 (24)

9.0 (9)

8.0 (8)

12.0 (12)

5.0 (5)

1.0 (1)

8.0 (8)

10.5 (8)

89.5 (68)

18.4 (14)

2.6 (2)

1.3 (1)

˂ 0.001

Number of medications

Mean ± SD

0.8 ± 1.0

0.4 ± 0.8

˂ 0.01

Tobacco use % (n)

Smoking

Use of snuff

6.0 (6)

11.0 (11)

2.6 (2)

7.9 (6)

Time since COVID-19 diagnosis (months)

Mean (range)

12.4 (2 – 39)

Severity of COVID-19 disease

Mild

Moderate

Severe

46.0 (46)

52.0 (52)

1.0 (1)

Mann-Whitney U test, Chi-square, Fisher’s exact test, NS = Not significant.

Assessment of olfactory and gustatory functions

The onset of chemosensory loss was about 5 days after the COVID-19 infection in 87% of the patients. These patients reported that they experienced complete chemosensory loss that occurred abruptly. Complete loss of the sense of smell only was reported in 9% of the patients, while 81% reported complete loss of smell and taste, and the remaining 10% could not report the time of onset of their chemosensory loss. The Mann-Whitney U test showed that the self-reported smell score (median (IQR), range) was significantly lower in the patient group (3.0 (1.0-5.0), 0.0-10.0) compared to the control group (8.0 (7.0-10.0), 4.0-10.0), Figure 1A. Also, the self-reported taste score (median (IQR), range) was significantly lower in the patient group (4.5 (2.0-6.0), 0.0-10.0) compared to the control group (8.0 (8.0-9.7, 4.0-10.0), Figure 1B. Median scores for self-reported smell and taste in the patient group were below the cut-off point (5.0) indicating low sense of smell and taste.

Figure 1. Boxplots illustrating A) self-reported smell score and B) self-reported taste score, in post-COVID-19 patients and controls. ***p < 0,001. The circles in the figure represent outliers.

The results from Sniffin’ Sticks test and Taste Strips test are presented in Figure 2. The Fisher’s exact test showed that the prevalences of anosmia (40%) and hyposmia (48%) were significantly higher among post-COVID-19 patients compared to controls (anosmia (0%), hyposmia (11.8%)). In addition, the prevalences of ageusia (3%), specific ageusia (27%) and hypogeusia (16%) were significantly higher among post-COVID-19 patients compared to controls (ageusia (0%), specific ageusia (0%), hypogeusia (17.1%)).

Pearson’s correlation coefficient test showed significant positive moderate correlations between (i) self-reported smell score and the measured Sniffin’ Sticks score (r =0.5, p < 0.001), and (ii) self-reported smell score and self-reported taste score (r = 0.6, p < 0.001) in patients. No significant correlations were found between self-reported taste score and the measured Taste Strips score.

Figure 2. Histogram illustrating A) smell diagnosis and B) taste diagnosis, in post-COVID-19 patients and controls. ***p < 0.001.

Assessment of self-reported parosmia, dysgeusia, dysesthesia and xerostomia

Fisher’s exact test showed a significantly higher prevalence of parosmia (80% vs 0%, p < 0.001), dysgeusia (34% vs 0%, p < 0.001), dysesthesia (11% vs 0%, p < 0.01) and xerostomia (18% vs 0%, p < 0.001) among post-COVID-19 patients compared to controls, Figure 3.

Figure 3. Histogram illustrating self-reported parosmia, dysgeusia, dysesthesia and xerostomia in post-COVID-19 patients.

The results from the follow-up questions regarding a) how often the dysfunctions were experienced and b) whether they were related to meals, are presented in Table 2. There were some missing data in the follow-up questions regarding parosmia, dysgeusia, dysesthesia and xerostomia.

Table 2. Dysfunction characteristics of post-COVID-19 patients with parosmia, dysgeusia and dysesthesia.

Parosmia (n=80)

% (n)

Dysgeusia (n=34)

% (n)

Dysesthesia (n=11)

% (n)

How often?

Constantly

Daily

Sometimes

In contact with odorants

Periodically

Missing data

42.5 (34)

13.7 (11)

18.7 (15)

3.7 (3)

7.5 (6)

17.6 (6)

14.7 (5)

32.3 (11)

8.8 (3)

26.4 (9)

18.1 (2)

45.4 (5)

18.1 (2)

Related to meals?

During meals

In between meals

Missing data

81.2 (65)

3.7 (3)

15.0 (12)

14.7 (5)

32.3 (11)

52.9 (18)

9.0 (1)

27.2 (3)

63.6 (7)

Description of dysgeusia

Metallic

Rotten

Harsh

Salty

Bitter

Other

55.8 (19)

17.6 (6)

2.9 (1)

20.5 (7)

8.8 (3)

Burning sensation

Anterior tongue

Whole tongue

Lateral tongue

Palate

Throat

Lips

Buccal mucosa

Other

45.4 (5)

18.1 (2)

9.0 (1)

27.2 (3)

18.1(2)

9.0 (1)

Chi-square test of independence showed a significant positive dependence between dysgeusia and xerostomia (χ² = 4.5, p ˂ 0.05).

Combinations of dysfunctions

A combination of olfactory and gustatory dysfunction was the most prevalent complaint (45%), followed by isolated olfactory dysfunction (30%) in post-COVID-19 patients. Other combinations of dysfunctions found were: olfactory, gustatory and salivary dysfunction (9%), olfactory and salivary dysfunction (5%), olfactory, gustatory and trigeminal dysfunction (4.0%), olfactory, gustatory, trigeminal and salivary dysfunction (4%), olfactory and trigeminal dysfunction (2%) and gustatory, trigeminal and salivary dysfunction (1%), Figure 4.

Figure 4: Pie chart showing distribution of patients with different combinations of dysfunctions.

Assessment of compromised taste qualities

Among patients with specific ageusia, 66.7% had bitter taste ageusia, 37% had salt taste ageusia, 33.3% had sour taste ageusia and 3.7% had sweet taste ageusia. Moreover, specific ageusia was observed for one taste quality in 66.7%, two taste qualities in 26% and three taste qualities in 7.4% of the post-COVID-19 patients.

Assessment of compromised odors

The onset of parosmia was 4.6 ± 1.9 (mean ± SD) months after the COVID-19 infection. Patients reported that many food items, detergent products, hygiene articles and body odors had the same distorted smell. This smell was described as a very characteristic smell experienced as unpleasant, unfamiliar and indescribable. Some of the patients’ descriptions of this smell were: “bonfire”, “chemical smell”, “sewage”, “smoke”, “burnt rubber”, “burnt plastic”, “rotten”, “fried liver”, “old sesame oil”, “unclean ice in the freezer” “dead badger” and “COVID-smell”. An overview of odors experienced as parosmic is shown in Table 3.

Table 3. Percentage of distorted odorants in post-COVID-19 patients with parosmia.

Categories of odorants

Post-COVID-19 patients with parosmia

(n = 80)

Drinks and beverages

Coffee

Coke

Orange juice

Wine

Milk

Cold drink

Beer

% (n)

56.4 (44)

42.3 (33)

39.7 (31)

37,2 (29)

30.8 (24)

29.5 (23)

28.3 (22)

Fruits and vegetables

Bell Pepper

Garlic

Onion

Cucumber

Celery

Tomato

Banana

Potatoes

46.2 (36)

44.9 (35)

41.0 (32)

39.7 (31)

30.8 (24)

28.2 (22)

25.6 (20)

21.8 (17)

Meat, fish and egg

Egg

Meat

Chicken

Ham

Bacon

Fish

47.4 (37)

44.9 (35)

37.2 (29)

34.6 (27)

33.3 (26)

26.9 (21)

Other food items

Chocolate

Nuts

Bread

29.5 (23)

28.2 (22)

23.1 (18)

Hygiene articles

Shampoo/Conditioner

Toothpaste

Soap

Deodorant

47.4 (37)

44.9 (35)

28.2 (22)

Detergents

Dishwasher soap

Detergent powder

41.0 (32)

38.5 (30)

Own body odors

Feces

Urine

Sweat

44.9 (35)

41.0 (32)

32.1 (25)

Others body odor

Partner

Children

26.9 (21)

23.1 (18)

The major findings in the present study were that (i) various combinations of dysfunctions were observed, (ii) in addition to smell, taste and trigeminal dysfunction, xerostomia was also frequently reported, (iii) all taste qualities were compromised, bitter taste ageusia being the most prevalent, and (iv) most of the odors in the milieu around us were found to be severely distorted.

In this study, eight different combinations of dysfunctions were found, smell and taste dysfunction being the most prevalent, followed by isolated smell dysfunction. These findings are consistent with other studies that also have reported olfactory, gustatory and trigeminal dysfunctions among COVID-19 patients^{33,35,36,42,43}. However, to our knowledge, no other studies have explored the possibility of salivary dysfunction in post-COVID-19 patients. Novel findings from this study showed that nearly one-fifth of post-COVID-19 patients complained of xerostomia. The ACE2 positive cells are known to be sensitive to SARS-CoV-2 virus infection, and it has been suggested that low expression of ACE2 due to infection is associated with increased inflammation and disease¹⁸. One study has shown that the ACE2-expressing epithelial cells within the salivary gland ducts are among the first to be targeted by the SARS-CoV virus¹⁷. It is plausible to hypothesize that this is similar for the close related SARS-CoV-2 virus and therefore could be the reason behind salivary dysfunction in post- COVID-19 patients. Adequate salivary secretion is important for chewing, swallowing, nutritional intake and maintenance of a healthy oral environment^26,44,45. It is, therefore, important to examine salivary function in patients recovering from COVID-19.

The patients in this study reported sudden smell and taste loss, shortly after COVID-19 infection. No considerable association was found between the patients’ self-reported taste function and their measured taste function. Many patients believed that their sense of taste was compromised, while it was their sense of smell that was compromised. This underscores the patients’ challenge of distinguishing between the sense of smell and the sense of taste, and the importance of examining the two senses separately. While occurrence of parosmia in post-COVID-19 patients has previously been explored^33,46, there is apparently no literature available describing different types of specific ageusia in this patient group. The sense of taste is more protected compared to the sense of smell, partly because the taste cells are innervated by three different cranial nerves. The sense of smell, on the other hand, is more vulnerable being innervated by only one cranial nerve. Therefore, taste dysfunction is not as commonly seen as smell dysfunction in other patients with such dysfunctions. However, in post-COVID-19 patients, both quantitative and qualitative taste dysfunctions were observed. Ageusia and specific ageusia, which are rare conditions, were found in almost one-third of the patients in this study. Similarly, dysgeusia, a qualitative disorder, was found in one-third of the patients. Novel findings from this study revealed that two-third of the patients with specific ageusia had no taste sensation for bitter taste, about two-fifth had no sensation for salty taste, and one-third had no sensation for sour taste. Only one patient reported no sensation for sweet taste. Loss of perception of bitter taste may have serious implications as bitter taste warns about ingestion of potentially harmful, toxic, or poisonous chemical substances⁴⁷. Perception of salt and sour taste helps maintain water and electrolyte equilibrium in humans. Inability to detect salt and sour taste may lead to overconsumption of these tastants subsequently leading to health problems. These findings suggest that taste receptor cells for bitter, salt and sour taste were compromised among our patients. According to current literature, bitter, sweet and umami taste is mediated through Type II taste cells⁴⁸ and sour taste is mediated through Type III taste cells⁴⁹. Interestingly, in the present study, sweet taste was not as impaired as the bitter taste although both sweet and bitter taste receptors are found in the same subtype of taste receptor cells. This suggests that sweet receptors may have been protected, compared to bitter taste receptors in this post-COVID-19 cohort. In the future, more molecular biological studies are needed to fully understand how SARS-CoV-2 affects the different taste receptor cells.

Parosmia and dysgeusia were common findings in this study. Four out of five patients complained of parosmia, in line with other studies^33,50. These reports are consistent with the theory that parosmia is believed to be a part of the recovery process in patients with impaired olfactory function^46,51. All patients reported the distorted smell and taste to be of an unappealing character. Many odors of food items like meat, egg, fruits and vegetables, dairy products, spices and beverages were severely distorted, and were more pronounced related to meals among most of the post-COVID-19 patients. While occurrence of parosmia in COVID-19 patients has been largely explored, little is published about different types of dysgeusia that also exists in this patient group. This study demonstrates that dysgeusia and dysesthesia are quite prevalent conditions in post-COVID-19 patients more than a year since debut of infection. This study stands out in exploring parosmia, dysgeusia and dysesthesia related to meals among post-COVID-19 patients. While parosmia was more pronounced related to meals, dysgeusia and dysesthesia were more pronounced “in between meals”, suggesting that patients could be suffering throughout the day. Parosmia has been suggested to affect the patients’ nutritional intake³⁵. However, a combination of distorted smell and taste, burning sensation in the oral cavity and oral dryness may cause a lot more despair in the patients and affect nutritional status, emotional health and quality of life. Therefore, special attention should be given to simultaneously examine all the different functions of the oral cavity rather than exploring them separately. A multidisciplinary mindset is crucial for appropriate diagnostics and for providing patients with relevant treatment. This is the only study, that we know of, which elucidates the impaired functions of smell, taste, chemesthesis and xerostomia in post-COVID-19 patients.

Trigeminal dysfunction and xerostomia were always found in combination with smell and/or taste dysfunction in this group. These patients were referred to the Faculty of Dentistry because of altered smell and taste function primarily, so the prevalence of dysesthesia and xerostomia related to post-COVID-19 could be even higher. Public awareness regarding dysesthesia and xerostomia related to post-COVID-19 should be increased to assure adequate treatment for this patient group.

One of the limitations of this study was that historic controls were used instead of controls specifically recruited for this project. Given the notable prevalence of asymptomatic COVID-19 cases³, it was found necessary to use controls from a period preceding the COVID-19 era, ensuring their non-exposure to the SARS-CoV-2 virus and its potential imprints. Quantitative olfactory function was measured using the Sniffin’ Sticks, 12-pen identification test. While the use of the Threshold, Discrimination, and Identification (TDI) test of Sniffin’ Sticks would have given more precise evaluations, TDI test could not be executed due to time limitations. Some patients experienced their sense of smell to be weak, even though they managed to identify most of the odors in the test, suggesting poor Threshold score and high Identification score. This illustrates one of the limitations in the present study; solely using the identification test for olfactory function measurement, does not take into account the patient’s threshold value and discrimination ability. Furthermore, it is worth noting that some of the odors present in the 16-pen identification test of Sniffin' Sticks were unfamiliar for our patients and, therefore, could produce false negative outcomes. Similar findings have also been reported in the Danish population⁵². Notably, the 12-pen test does not include these less familiar odors such as turpentine and sauerkraut. Salivary secretory flow rate was not measured in this study because of limited resources. It would have been valuable to explore whether SARS-CoV-2 virus affected the secretory flow rate of stimulated and/or unstimulated whole saliva. More studies are, therefore, needed to fully understand the extent of salivary dysfunction in post-COVID-19 patients.

In conclusion, the present study showed that post-COVID-19 patients suffer from many different combinations of chemosensory and oral dysfunctions. Not only odorants, but also tastants were found to be distorted, which may affect the patients’ oral health-related quality of life. Oral dryness and burning sensation in the oral cavity were also found to be associated with post-COVID-19-patients. More research is needed to explore the extent of these dysfunctions in post-COVID-19 patients.

Acknowledgements:

The authors express their sincere gratitude to all the post-COVID-19 patients and controls who participated in this study. We further express thanks to all the staff members at the Faculty of Dentistry involved in this study for their support. We are grateful to professor Alix Young for overseeing the forward and backward translation of Oslo COVID-19 questionnaire and professor Gianpaolo Scalia Tomba for overseeing the statistical analyses in this study. Gratitude is also due to dental students Heerthana Kulendran and Emilie Aabel for their assistance in this study. We are grateful for external grants from the University of Oslo: Life Science and Stiftelsen til Tannlegevitenskapens Fremme.

Data availability:

Request for materials should be addressed to the corresponding author, Å.R.

Author Contributions:

Study design and concept: Preet Bano Singh (P.B.S.)

Patients and control recruitment: Preet Bano Singh (P.B.S.), Janicke Liaaen Jensen (J.L.J.)

Clinical data collection: Preet Bano Singh (P.B.S.), Åsmund Rogn (Å.R.)

Analysis interpretation of data: Preet Bano Singh (P.B.S.), Åsmund Rogn (Å.R.), Janicke Liaaen Jensen (J.L.J.), Per Ole Iversen (P.O.I.)

Statistical analysis: Preet Bano Singh (P.B.S.), Åsmund Rogn (Å.R.)

Preparation of figures: Åsmund Rogn (Å.R.), Preet Bano Singh (P.B.S.)

Writing the manuscript: Preet Bano Singh (P.B.S.), Åsmund Rogn (Å.R.), Janicke Liaaen Jensen (J.L.J.), Per Ole Iversen (P.O.I.)

Supervision: Preet Bano Singh (P.B.S.)

Additional information:

The authors declare no conflict of interest.

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No competing interests reported.

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Post-COVID-19 patients suffer from chemosensory, trigeminal and salivary dysfunctions

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Abstract

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Introduction

Methods

Study design and participants

The Oslo COVID-19 questionnaire

Olfactory assessment

Gustatory assessment

Assessment of parosmia, dysgeusia, dysesthesia and xerostomia

Statistical analyses

Results

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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