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\begin{document}

\title{Functional and Morphological Disorders of Taste and Olfaction in
COVID-19-Patients}



\author[1]{Pavlos Pavlidis}%
\author[2]{Gregor Schittek}%
\author[3]{Evangelia Fouka}%
\author[4]{Efstathios Spyridonidis}%
\author[5]{Haralampos Gouveris}%
\affil[1]{General Hospital of Thessaloniki G Papanikolaou}%
\affil[2]{Medical University of Graz}%
\affil[3]{General Hospital of Thessaloniki G Papanikolaou Pulmonology Department NHS}%
\affil[4]{General Hospital Veria}%
\affil[5]{Johannes Gutenberg University Hospital Mainz}%


\vspace{-1em}



  
  \date{March 14, 2025}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives: To test the prevalence and evolution of acute olfactory and
gustatory functional impairment and of their morphologic correlates in
COVID-19 patients who require hospitalization due to COVID-19-related
respiratory conditions. Key-words: COVID-19, taste, olfaction,
electrogustometry, contact endoscopy Design: Electrogustometric (EGM) -
thresholds at the tongue area supplied by the chorda tympani, at the
soft palate and at the vallate papillae area were recorded bilaterally.
Olfaction was examined by Sniffin' sticks. The patients' nasal and oral
mucosa (fungiform papillae, fpap) were examined by contact endoscopy.
Setting: Tertiary referral medical centre. Patients: 53 consecutive
hospitalized patients (23 males, 30 females, age 42,54 \selectlanguage{ngerman}± 10, 95 yrs)
with RT-PCR-confirmed COVID-19 diagnosis were included. Patients have
been examined twice: just after hospital discharge and 4-6 weeks later.
Main outcome measures: EGM-thresholds and taste strips,
Schniffin-Sticks, Contact-Endoscopyesults: EGM-thresholds in patients
were significantly higher at both instances than those of healthy
subjects. EGM-thresholds at the second measurement were significantly
lower than those at the first measurement. Accordingly, patient-reported
gustatory outcomes were improved at the second measurement. The same
pattern has been found using Sniffin' sticks. Significant alterations in
form and vascularization of fPap have been detected in patients,
especially at the first instance. Conclusions: COVID-19 affects both
gustatory and olfactory functions. It also affects in parallel the
structure and vascularization of both nasal and oral mucosa, although
the nasal mucosa to a much less, non-significant, extent. Our findings
suggest that COVID-19 may cause a mild to profound neuropathy of
multiple cranial nerves.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Functional and Morphological Disorders of Taste and Olfaction in
COVID-19-Patients}

\textbf{Taste and Olfaction in COVID-19-Patients}

Abstract

\textbf{Objectives:} To test the prevalence and evolution of acute
olfactory and gustatory functional impairment and of their morphologic
correlates in COVID-19 patients who require hospitalization due to
COVID-19-related respiratory conditions.

\textbf{Design:} Electrogustometric (EGM) - thresholds at the tongue
area supplied by the chorda tympani, at the soft palate and at the
vallate papillae area were recorded bilaterally. Olfaction was examined
by Sniffin' sticks. The patients' nasal and oral mucosa (fungiform
papillae, fpap) were examined by contact endoscopy.

\textbf{Setting:} Tertiary referral medical centre.

\textbf{Patients:} 53 consecutive hospitalized patients (23 males, 30
females, age 42,54 \selectlanguage{ngerman}± 10, 95 yrs) with RT-PCR-confirmed COVID-19
diagnosis were included. Patients have been examined twice: just after
hospital discharge and 4-6 weeks later.

\textbf{Main outcome measures:} EGM-thresholds and taste strips,
Schniffin-Sticks, Contact-Endoscopy\textbf{esults:} EGM-thresholds in
patients were significantly higher at both instances than those of
healthy subjects. EGM-thresholds at the second measurement were
significantly lower than those at the first measurement. Accordingly,
patient-reported gustatory outcomes were improved at the second
measurement. The same pattern has been found using Sniffin' sticks.
Significant alterations in form and vascularization of fPap have been
detected in patients, especially at the first instance.

\textbf{Conclusions:} COVID-19 affects both gustatory and olfactory
functions. It also affects in parallel the structure and vascularization
of both nasal and oral mucosa, although the nasal mucosa to a much less,
non-significant, extent. Our findings suggest that COVID-19 may cause a
mild to profound neuropathy of multiple cranial nerves.

\textbf{Key-words:} COVID-19, taste, olfaction, electrogustometry,
contact endoscopy

\textbf{Key-points:}

\begin{itemize}
\tightlist
\item
  COVID-19 affects both gustatory and olfactory functions.
\item
  SARS-coronavirus affects more than one cranial nerves, namely the
  chorda tympani, the glossopharyngeal and the trigeminal nerves.
\item
  It seems to disturb not only the peripheral receptors related to the
  chemical senses, but also the regeneration of their peripheral nerve
  fibers.
\item
  The majority of the patients reports an improvement of taste and
  odour-disturbances within 4 weeks.
\item
  The functional improvement of taste acuity does not correlate directly
  to the morphology (including the vascularization) of fPap.
\end{itemize}

\textbf{1 INTRODUCTION}

Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 evolved to a
pandemic {[}1,2{]}. There are reports of early olfactory and/or
gustatory dysfunction even before molecular confirmation of SARS-CoV-2
infection {[}1-7{]}. Smell and taste complaints in COVID-19 appear to
have somehow different features compared to those related to other
viruses {[}8-10{]}.

The primary hypothesis of this study was that COVID-19-infection causes
a functional deterioration of gustatory function, as measured by EGM, at
the regions supplied by the trigeminal, facial and glossopharyngeal
nerves. Secondary hypotheses of our study were: a. that COVID-infection
causes structural alterations of the taste buds, more specifically of
the fungiform papillae, b. that COVID-infection induces a functional
olfactory decline, c. that COVID-infection causes structural alterations
of the nasal mucosa, d. that structural and functional changes regarding
olfaction and taste correlate and e. that the above structural and
functional changes improve with time, more specifically 4 to 6 weeks
after hospital discharge.

\textbf{2 MATERIALS AND METHODS}

\emph{2.1 Study design}

This was a prospective controlled longitudinal study conducted in a
tertiary general hospital setting. Patients, who had been tested
positive for SARS-CoV-2 on PCR-test and were hospitalized were asked to
participate in our study. 84 COVID-patients, hospitalized for severe
COVID-19 were initially screened for inclusion in this study. After
application of the above inclusion and exclusion criteria, 53 (23 males,
30 females, 42,54 ± 10, 95 yrs.; patients-group) were found appropriate
for inclusion and were asked to participate in this study. The study
protocol was reviewed and approved by the Institutional Review Board
(Nr21-06022021).

Patients have been examined twice: 7 - 10 days after discharge and again
4-6 weeks later. Patients' findings were also compared to those of 53
healthy volunteers (23 males, 30 females, 42,90 ± 10,64 yrs; healthy
subjects-group), which served as controls. The study protocol was in
agreement with the STARD 2015 guidelines.

\textbf{2.2 Outcome measures}

\emph{2.2.1Electrogustometry}

We have evaluated taste acuity with electrogustometry (EGM). Electrical
stimuli were delivered using an electrogustometer (TR-06, Rion Co,
Tokio, Japan) with a single, flat, circular stainless steel stimulus
probe (5mm in diameter).

All subjects were instructed not to drink or eat for at least an hour
before the beginning of the testing session. A 500-ms electric stimulus
was applied, beginning at -6 dB and increasing up to +34 dB (3-400 \selectlanguage{greek}μΑ\selectlanguage{english})
in 2dB-steps {[}12,13,15{]}. Thresholds were measured randomly on both
sides of the tongue to avoid any possible bias. All six areas were
tested with the same stimulus duration before proceeding with the
application of a stimulus of different duration. The subject was kept
unaware of whether the current was applied (blind test) as previously
reported {[}11,12{]}. A two-alternative forced-choice initially
ascending single-staircase detection was employed using a two-down,
one-up rule {[}11,12{]}.

\emph{2.2.2 Contact endoscopy}

Contact endoscopy exams (for the evaluation of the nasal and oral
mucosa) were all performed with a contact endoscope (Karl Storz, 7215AA,
0\selectlanguage{ngerman}°, 23 cm long, 4 mm in diameter; Tuttlingen, Germany) as an outpatient
procedure. A contact endoscope (CE) was connected to a 150W xenon light
source, a video camera, and an SVHS video recorder (Olympus, nCare
medical recorder). Subsequently, the tip of the endoscope was gently put
in contact with the mucosa (nasal-Locus Kiesselbachii-, or oral) and the
mucosa was examined under 60x- and 150x- magnification, by adjusting the
zoom switch on the endoscope. All findings were recorded digitally. The
digital images were evaluated for blood flow dynamics, overall mucosal
morphology, and density of the sub-epithelial vessels {[}11-14{]}.

The form of the fungiform papillae was classified to one of four types
in increasing order of damage as following: \textbf{type 1} ,
(egg-shaped or long ellipse type -- without surface thickness),
\textbf{type 2}(slight thicker surface compared to type 1), \textbf{type
3} (thick and irregular surface) and \textbf{type 4} (remarkably flat
and atrophic surface). Due to their very light staining, fungiform
papillae could be readily distinguished from filiform papillae, which
stained dark {[}11,12,14{]}.

The classification of the blood vessels' morphology at the tip of
anterior tongue apex was performed according to a classification by
Negoro et al. {[}14{]}. Five types of vessels' morphology, classified in
increasing order of morphologic alterations were found,
namely\textbf{type A} (clear loop and wooden branch shape), \textbf{type
B}(unclear loop and wooden branch shape), \textbf{type C} (elongated
blood vessels), \textbf{type D} (granular shape or dotted shape)
and\textbf{type E} (unclear blood vessels).

Nonetheless, based on previous published experience and studies on
description of the morphology and vascularization of the oral mucosa, a
modification of Negoro's classification for the outline of the
vascularization of nasal mucosa showed quite reproducible findings and
therefore has been used {[}14,15{]}. According to this modified
classification, there are five morphological types of nasal mucosa
vascularization, which have been already described thoroughly above
(Figure 1).

After carefully suctioning of the secretions, the anterior part of the
nasal cavity was stained with methylene blue 1\%. Then the mucosa was
gently touched with the tip of the contact endoscope.

\emph{2.2.3 Sniffin' Sticks Test}

For odor presentation, the cap was removed from the pen and the pen's
tip was brought in front of the patient's nose and thoroughly moved from
left to right nostril and backwards for 3s. Individual scores can be
related to standard values for (a) normosmia (normal olfactory
function), (b) hyposmia (impaired olfactory function) or (c) functional
anosmia (residual or absent olfactory function) {[}16{]}.

It was the patient's condition in most of the case (fatigue, exhaustion)
which prevented us from applying the detailed TDI-battery.

\textbf{2.3 Statistical analysis}

Data were analyzed with IBM SPSS Statistics for Windows version 25.0
(IBM Corp.,Armonk, NY, USA). The null hypothesis was that no statistical
difference in vascularization-patterns in both oral and nasal mucosa
existed between the two groups. The results of Sniffin' sticks have also
been compared. For statistical analysis, if an EGM-threshold could not
be measured at all, then it was assigned a numerical value of 36 dB. To
examine if our results were normally distributed, we applied a
quantile-quantile plot (QQ plot), which proved that the distribution was
not normal. As a result, non-parametric tests were applied. The level of
statistical significance was set at p \textless{} 0.05. On each
occasion, the findings between two groups were compared by using
Kruskal-Wallis and Mann-Whitney tests. The Bonferroni correction was
applied when necessary. Tukey's multiple comparison was used to detect
differences significant at the 0.05-level in mean thresholds for both
groups.

\textbf{3 RESULTS}

\textbf{3.1 Patient-reported outcomes}

The patients have been asked to report on their subjective smell-related
complaints or experiences prior to the Sniffin' Sticks-test. On the
first examination, on the day of hospital discharge, 30 patients
reported anosmia and 23 hyposmia (without being able to specify any
specific odorant at all). Regarding patient-reported gustatory outcomes,
18 patients reported ageusia, 22 hypogeusia and 3 of them phantogeusia
(an often metallic or salty taste in the mouth for which no external
stimulus can be found), the rest 10 reported a normogeusia. On the
second examination, 4-6 weeks later, fourteen participants reported
normosmia, seven reported anosmia, and 32 hyposmia. Additionally, 22 of
them reported hypogeusia, 4 patients reported dysgeusia and 8 ageusia.
Interestingly 6 of them reported allogeusia. The rest 13 reported no
taste alterations. The results are depicted in \textbf{Table 1.}

\emph{3.2 EGM-thresholds}

We have found a significant difference between the measurements of the
EGM-thresholds (both 1st and the 2\textsuperscript{nd} measurement) and
those of the healthy subjects. The values on the second measurement were
clearly lower (i.e. better) than those on the first occasion.

The mean numerical values of EGM-thresholds for both groups are depicted
on \textbf{Table 1} . The statistical differences between them are
depicted on \textbf{Table 2} .

The statistical difference between the values at the
1\textsuperscript{st} measurement and those of the healthy subject was
p=0.001 for all six loci.

The p- values, estimated between the EGM-Thresholds recorded on the
2\textsuperscript{nd} measurement and the control-patients-groupre
depicted on \textbf{Table 3} .

\emph{3.3 Structural changes related to the fungiform papillae}

In comparison to the findings of the healthy subjects, changes in both
structure and vascularization of fPap have been detected. It is
interesting that the parameters of fPap (vascularization and form) seem
to have in some patients a tendency to deteriorate after the end of the
treatment (in 2 males: from 3/D to 4/A and 4/B). Findings of both
measurements, as those of the healthy subjects are presented in Table 4.
As it can be appreciated in this Table, despite the remarkable
improvement in the EGM-thresholds in all six oral anatomic areas, the
changes in form and vascularization of fPap are not completely
synchronized.

\textbf{3.4 Correlation between EGM-thresholds and morphology and
vascularization of fPap.}

We have used the Spearman-test to calculate any correlation between the
EGM-thresholds and the morphology and vascularization of fPap. The null
hypothesis was that there is no correlation between the above parameters
for all measurements of the study.

On the 1st measurement we have found a correlation coefficient (r)
between the EGM-thresholds and the morphology, equal to 0.31. This
correlation was significantly increased at the second exam (r = 0.5).
Our findings indicate, that the functional improvement of taste acuity
does not correlate directly to the morphology (including the
vascularization) of fPap. Concerning the vascularization and the
EGM-Thresholds, we have found a correlation coefficient (r) on the first
measurement equal to 0. 56. This correlation was found increased by the
second measurement (r=0.74) This indicates that the vascularization of
fPap is not directly correlated to the morphology of the fPap.

\emph{3.5 Sniffin' Sticks and patient-reported olfactory outcomes}

The use of the Sniffin' sticks showed anosmia in the majority of the
patients (n=39, 14 males, 25 females) on the first examination. Hyposmia
was found in the remaining 14 patients (6 males, 8 females) on the first
examination. The average of the right answers was 2,84. On the second
exam, we have found that 4 patients had normosmia (3 males, 1 female),
17 had hyposmia (6 males, 11 females), but 32 still had anosmia (12
males, 20 females). The average of the correct answers was 6,62.

Comparing the results of the first measurement in the patients' group to
those of the healthy subjects, a significant statistical difference
(p=0.0024) was found. The difference between the results of the second
measurement and those of healthy controls was less, at the p =
0.02-level. The average of the correct answers by the Schniffin-Stick's
Test was 11,62.

\emph{3.6 Contact endoscopy and nasal mucosa}

Contact endoscopy allowed direct visualization of the superficial cell
layers of the epithelium previously stained with methylene blue. This
was the case in both examinations in patients-group and in healthy
subjects-group.

By using contact endoscopy, we managed to observe the condition of the
microvascular network correlated to any possible damage of the nasal
mucosa. More specifically, on the first evaluation of patients-group, 6
patients had a type A microvascular network pattern, 35 had a type B
pattern (granular or dotted shape) and 12 patients a type C pattern. On
the second exam of patients-group, 15 patients had an A type, 32
exhibited a B type and 6 of them had a C type. In the control group, 38
healthy subjects showed a type B, 10 of them had an A type and the rest
5 had a type C pattern. No septal defect was observed in any subject of
the study groups.

Although it is not quite clear, whether SARS-coronavirus directly
affects the shape of vessels in the nasal mucosa, it is worth mentioning
that the vessels in patients on the second examination and those of the
healthy subjects tended to exhibit similar patterns in absolute numbers.

\textbf{4 DISCUSSION}

We show that COVID-19 impairs the epithelial structure and
vascularization of both nasal and oral mucosa, although the nasal mucosa
seems to be altered to a less extent than the oral mucosa is. We suggest
that COVID-19 may cause multiple cranial neuropathies of quite varying
degree (i.e. mild to profound) involving the nerves responsible for the
innervation of fPap and the transmission of the chemical stimuli. Most
patients reported a concomitant loss of smell and taste, and fewer
patients reported only loss of either smell or taste {[}15,17{]}. 65.71
\% of the patients reported a total recovery of both taste and olfaction
within 4 weeks after the discharge from the hospital, and 74.29 \% had
recovered within 6 weeks after hospital discharge (both olfactory and
gustatory function). However, the reported recovery time (median: 17
days) was not as short as reported in previous studies, probably because
the hospitalized patients included in our study had more severe disease
{[}17{]}.

A significant study limitation is the lack of objective data on taste
and olfaction in the study participants before hospitalization and even
before the infection. Although all participants reported no history of
gustatory or olfactory disorder in the past, any objective measurements
to compare are missing. Another limitation is the lack of subjective
methods for the evaluation of gustatory function. In our study
electrogustometry was preferred, because of its reliability and the
ability to take repeated results on the same loci. It should be
mentioned that the control group was not measured twice, as these
subjects remained healthy throughout the study the study, without
corresponding pneumonia or any other medication.

The nasal cavity plays an important role in COVID-19 infection; it is
probably the major entry point for SARS-CoV-2 and the site of intense
viral replication {[}17,18{]}. SARS-CoV-2 seems to have its own
mechanisms of aggression to the olfactory neuroepithelium, with a
greater predilection for neural structures' involvement over the nasal
mucosa {[}19{]}. Subjective olfactory dysfunction in COVID-19 patients
has been extensively reported in a number of studies {[}1,4,8-9{]}.

The exact mechanisms underlying olfactory and gustatory disorders among
patients with COVID-19 infection remain unclear. SARS-C0V-2 seems to
enter the central nervous system (CNS) via the olfactory or trigeminal
route. Initially, the CNS infection or inflammation could be mild and
cause olfactory damage {[}23-25{]}. However, olfactory impairment after
upper respiratory tract infection is a common occurrence in clinical
settings {[}21-24{]}. Another hypothesis is that COVID-19 infection
could be related to the involvement of the olfactory bulb or to
peripheral damage of the olfactory receptor cells in the nasal
neuroepithelium. This assumption is based on the potential neurotrophic
features of SARS-CoV-2 {[}17,18{]}.

The role of innervation in the regeneration of the fungiform papillae
has been extensively studied. The impact of denervation on fungiform
taste buds appears to be less severe than on circumvallate; while the
former are reduced in number, many albeit smaller taste buds remain
{[}21,24{]}. Differentiated taste buds disappear or are reduced in
density in denervated taste epithelium. Progenitor taste cells also
require the trophic and / or electrical signals provided by the afferent
taste nerve fibres, in order to continue to provide immature taste cells
to the taste buds {[}24,25{]}.

\textbf{5 CONCLUSIONS}

Our findings suggest that SARS-coronavirus affects more than one cranial
nerves, namely the chorda tympani, the glossopharyngeal and the
trigeminal nerves. It also seems to disturb not only the peripheral
receptors related to the chemical senses, but also the regeneration of
their peripheral nerve fibers.

\textbf{Figures and Tables}

\textbf{Figure 1.} The modified Negoro's Classification, there are 5
morphological types of nasal mucosa vascularization, which have been
already described thoroughly in text.

\textbf{Table 1} . The means of EGM-thresholds for both groups are
depicted in this table. The threshold of the right side of the soft
palate is \textbf{threshold A (A in Table)} , the one of the vallate
papillae is \textbf{threshold B (B in Table)} and the right side of the
tongue apex \textbf{threshold C (C in Table)} . The corresponding
thresholds of the left side of the tongue are \textbf{threshold D (D in
Table)} , \textbf{threshold E (E in Table)} and \textbf{threshold F} (F
for the left side of the soft palate in Table). The reader can also find
information about smell dysfunction and its recovery.

\textbf{Table 2.} The statistical differences between the
1\textsuperscript{st} and 2nd measurement in patients' Group . The
statistical difference between the values of the 1st measurement and
those of the healthy subject is p=0.001 for all six loci.

\textbf{Table 3.} The p- values, estimated between the EGM-thresholds
recorded in patients-group by the 2nd measurement and the control-group
(healthy subjects-group). There is an improvement of taste acuity by the
COVID- the patients.

\textbf{Table 4.} It is interesting that the parameters of fPap
(vascularization and form) seem to have in some patients a deteriorating
tension after the end of the treatment (2 men, from 3/D to 4/A and 4/B).
Despite the remarkable improvement in the EGM-thresholds in all 6
anatomic areas, the form and vascularization of fPap do not follow in
parallel.

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\end{enumerate}

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