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\begin{document}

\title{Objective Olfactory Evaluation of Self-reported Loss of Smell in
a Case Series of 86 COVID-19 Patients}



\author[1]{Jerome R. Lechien, MD, PhD, MS}%
\affil[1]{Universite de Mons}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective : To investigate olfactory dysfunction (OD) in patients with
mild COVID-19 through patient-reported outcome questionnaires and
objective psychophysical testing.

Methods : COVID-19 patients with self-reported sudden-onset OD were
recruited. Epidemiological and clinical data were collected. Nasal
complaints were evaluated with the sino-nasal outcome-22 (SNOT-22).
Subjective olfactory and gustatory status was evaluated with the
National Health and Nutrition Examination Survey (NHNES). Objective OD
was evaluated using psychophysical tests.

Results : Eighty-six patients completed the study. The most common
symptoms were fatigue (72.9\%), headache (60.0\%), nasal obstruction
(58.6\%) and postnasal drip (48.6\%). Total loss of smell was
self-reported by 61.4\% of patients. Objective olfactory~testings
identified 41 anosmic (47.7\%), 12 hyposmic (14.0\%), and 33 normosmic
(38.3\%) patients. There was no correlation between the objective test
results and subjective reports of nasal obstruction or postnasal drip.

Conclusion : A significant proportion of COVID-19 patients reporting OD
do not have OD on objective testing.%
\end{abstract}%



\sloppy


Jerome R. Lechien, MD, PhD, MS\textsuperscript{1-4}, Pierre Cabaraux
MD\textsuperscript{1-5}, Carlos M. Chiesa-Estomba MD,
MS\textsuperscript{1,6}, Mohamad Khalife MD\textsuperscript{1,7},
St\selectlanguage{ngerman}éphane Hans, MD, PhD, MS\textsuperscript{1,3}, Christian
Calvo-Henriquez, MD\textsuperscript{1,8}, Delphine Martiny, PharmD,
PhD\textsuperscript{9}, Fabrice Journe, PhD\textsuperscript{1,2}, Leigh
Sowerby, MD, MHM, FRCSC\textsuperscript{1,10}, Sven Saussez, MD,
PhD\textsuperscript{2,4,7}

\textbf{Institutions:}

\begin{enumerate}
\tightlist
\item
  COVID-19 Task Force of the Young-Otolaryngologists of the
  International Federations of Oto-rhino-laryngological Societies
  (YO-IFOS).
\item
  Department of Human Anatomy and Experimental Oncology, Faculty of
  Medicine, UMONS Research Institute for Health Sciences and Technology,
  University of Mons (UMons), Mons, Belgium
\item
  Department of Otolaryngology-Head \& Neck Surgery, Foch Hospital,
  School of Medicine, UFR Simone Veil, Université Versailles
  Saint-Quentin-en-Yvelines (Paris Saclay University), Paris, France.
\item
  Department of Otorhinolaryngology and Head and Neck Surgery, CHU de
  Bruxelles, CHU Saint-Pierre, School of Medicine, Université Libre de
  Bruxelles, Brussels, Belgium.
\item
  Department of Neurology, CHU de Charleroi, Charleroi, Belgium.
\item
  Department of Otorhinolaryngology-Head \& Neck Surgery, Hospital
  Universitario Donostia, San Sebastian, Spain.
\item
  Department of Head and neck Surgery, EpiCURA Hospital, Hornu, Belgium.
\item
  Department of otolaryngology-Hospital Complex of Santiago de
  Compostela, Santiago de Compostela, Spain.
\item
  Department of Microbiology, Laboratoire Hospitalier Universitaire de
  Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels,
  Belgium; Faculté de Médecine et Pharmacie, Université de Mons (UMONS),
  Mons, Belgium.
\item
  Department of Otolaryngology - Head and Neck Surgery, University of
  Western Ontario, London, Ontario, Canada.
\end{enumerate}

\textbf{Running title} : Coronavirus and Olfaction.

\textbf{Key words} : COVID-19; anosmia; olfaction; olfactory; smell;
evaluation; taste; coronavirus.

\textbf{Author contribution:}

\emph{Study concept and design:} Lechien, Cabaraux, Chiesa,
Calvo-Henriquez, Saussez, Hans, Khalife.

\emph{Acquisition, analysis, or interpretation of data} : Cabaraux,
Lechien, Saussez, Journe, Khalife, Martiny, Sowerby.

\emph{Drafting of the manuscript:} Lechien, Saussez, Sowerby.

\emph{Critical revision of the manuscript for important intellectual
content:} Sowerby, Saussez, Chiesa, Calvo-Henriquez, Hans, Journe,
Khalife, Carabaux.

\textbf{Correspondence to} :

Dr. Jay R. Lechien, M.D., Ph.D., M.S.

Department of Otorhinolaryngology and Head and Neck Surgery, Foch
Hospital, School of Medicine, UFR Simone Veil, Université Versailles
Saint-Quentin-en-Yvelines (Paris Saclay University), Paris, France.

Email: Jerome.Lechien@umons.ac.be

Telephone: +32 65 37 35 84

\textbf{Abstract} :

\textbf{Objective} : To investigate olfactory dysfunction (OD) in
patients with mild COVID-19 through patient-reported outcome
questionnaires and objective psychophysical testing.

\textbf{Methods} : COVID-19 patients with self-reported sudden-onset OD
were recruited. Epidemiological and clinical data were collected. Nasal
complaints were evaluated with the sino-nasal outcome-22 (SNOT-22).
Subjective olfactory and gustatory status was evaluated with the
National Health and Nutrition Examination Survey (NHNES). Objective OD
was evaluated using psychophysical tests.

\textbf{Results} : Eighty-six patients completed the study. The most
common symptoms were fatigue (72.9\%), headache (60.0\%), nasal
obstruction (58.6\%) and postnasal drip (48.6\%). Total loss of smell
was self-reported by 61.4\% of patients. Objective olfactory~testings
identified 41 anosmic (47.7\%), 12 hyposmic (14.0\%), and 33 normosmic
(38.3\%) patients. There was no correlation between the objective test
results and subjective reports of nasal obstruction or postnasal drip.

\textbf{Conclusion} : A significant proportion of COVID-19 patients
reporting OD do not have OD on objective testing.

\textbf{Introduction:}

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic in
Europe, many otolaryngologists have reported patients with a sudden loss
of smell.\textsuperscript{1,2} Olfactory dysfunction is rapidly becoming
a key symptom of COVID-19, with more than 66\% of patients in Europe and
U.S reporting some degree of hyposmia.\textsuperscript{1,3-6} The loss
of smell has been reported to occur before (11.8\%), after (65.4\%) or
at the same time (22.8\%) as the onset of other general or
otolaryngological symptoms.\textsuperscript{1} Knowledge around the
relationship between olfactory dysfunction and COVID-19 is rapidly
evolving. Recently, Yan \emph{et al} . shown that anosmia seems to be
associated with a milder clinical course in patients with
COVID-19.\textsuperscript{6} Moein \emph{et al} . suggested that 98\% of
60 Iranian COVID-19 patients exhibited some olfactory dysfunction on
objective testing; only 35\% of these patients were aware of
hyposmia/anosmia before testing.\textsuperscript{7} The nuances around
olfaction in COVID-19 appear to be associated with different clinical
parameters than other symptoms, and, consequently, warrant further
investigation.

The objective of this study was to investigate the olfactory dysfunction
of COVID-19 patients with subjective validated patient-reported outcome
questionnaires and objective psychophysical testing.

\textbf{Methods:}

The study protocol was approved by the ethics committee of the Jules
Bordet Institute (Central Ethics Committee, IJB-0M011-3137). Patients
were invited to participate and informed consent was obtained once
inclusion criteria were met.

\emph{Setting}

Adult patients with confirmed COVID-19 and self-reported sudden-onset
olfactory dysfunction were recruited through a public call from the
Department of Anatomy of the University of Mons (Mons, Belgium). To be
included, patients had to be not currently hospitalized
(mild-to-moderate patients). The diagnosis of COVID-19 infection was
based on the WHO interim guidance and symptoms of disease {[}8{]}.
Individuals with self-reported sudden olfactory dysfunction and a
clinical history suggestive of COVID-19 were invited to participate. A
nasopharyngeal swab was performed to identify severe acute respiratory
coronavirus-2 (SARS-CoV-2) via reverse transcription polymerase chain
reaction (RT-PCR) for patient with symptom duration\textless{}14 days.
In case of negative RT-PCR, serology for IgG and IgM to SARS-CoV-2 was
realized. For patients with symptom duration \selectlanguage{english}[?]14 days, physicians
performed serology (Figure 1). Only patients with a RT-PCR positive test
or with positive IgG or IgM were included. Patients with a history of
olfactory dysfunction before the pandemic, history of nasal surgery,
chronic rhinosinusitis, head \& neck trauma, or degenerative
neurological disease were excluded from the study.

\emph{COVID-19 diagnosis}

The RT-PCR was performed by an experienced microbiologist (D.M.) in the
LHUB-ULB laboratory of Brussels (Laboratoire Hospitalier Universitaire
de Bruxelles, Belgium). Viral RNA extraction was performed by m2000
mSample Preparation SystemDNA Kit (Abbott) using 1000\selectlanguage{greek}µ\selectlanguage{english}l manually lysed
sample (700\selectlanguage{greek}µ\selectlanguage{english}l sample + 800\selectlanguage{greek}µ\selectlanguage{english}l lysis buffer from kit) eluted in 90\selectlanguage{greek}µ\selectlanguage{english}l
elution buffer. A~qRT-PCR~internal control was added at each extraction.
qRT-PCR was performed using 10\selectlanguage{greek}µ\selectlanguage{english}l of extracted sample in the
RealStar\selectlanguage{ngerman}\textsuperscript{®}SARS-CoV-2 RT-PCR Kit from Altona-diagnostics
with a cut-off set at 40 cycle threshold (Ct).

Patients with a negative RT-PCR benefited from a serological test
(Zentech, University of Liege Lab, Liege, Belgium) to determine whether
or not they have been exposed to SARS-Cov-2.

\emph{Epidemiological \& Clinical outcomes}

To minimize the risk of exposure for study personnel, the clinical and
epidemiological characteristics of patients were electronically
collected via an online questionnaire developed with Professional Survey
Monkey® (San Mateo, California, USA). Demographic data including gender,
age and ethnicity, as well as patient comorbidities and medications were
collected.

\emph{General and Otolaryngological Symptoms}

The following general and ear, nose, and throat symptoms were collected
and rated (from 0=no symptom to 4=severe symptom): cough, chest pain,
dyspnea, headache, fever, fatigue, loss of appetite, myalgia,
arthralgia, nausea, vomiting, diarrhea, excessive sticky sputum, skin
manifestations (urticaria), conjunctivitis, nasal obstruction, postnasal
drip, rhinorrhea, sore throat, facial pain, ear pain, dysphagia,
dysphonia and dysgeusia. Dysgeusia was defined as the impairment of
salty, sweet, bitter and sour.

\emph{Patient-reported outcome questionnaires}

The impact of COVID-19 on sinonasal symptoms was evaluated through the
French version of the sino-nasal outcome test-22
(SNOT-22),\textsuperscript{9} a validated patient-reported outcome
questionnaire from the original U.S. 20-item
version.\textsuperscript{10}

The impact of olfactory dysfunction on quality of life was assessed
through the short version of the Questionnaire of Olfactory
Disorders-Negative Statements (sQOD-NS).\textsuperscript{11} sQOD-NS is
a 7-item patient-reported outcome questionnaire. Patients rated the item
proposition from 0 (agree) to 3 (disagree) with total score ranging from
0 (significant impact of olfactory dysfunction on QoL) to 21 (no impact
on QoL). Authors used sQOD-NS for its ease of completion.

The olfactory and gustatory questions were based on the smell and taste
component of the National Health and Nutrition Examination Survey
(NHNES).\textsuperscript{12} NHNES is a population survey that
continuously monitors the health of adult citizens in the U.S. through a
nationally representative sample of 5,000 persons on a yearly
basis.\textsuperscript{12} The questions have been selected to
characterize the variation, timing and associated-symptoms of both
olfactory and gustatory dysfunction.

\emph{Psychophysical Olfactory Evaluation}

The psychophysical olfactory evaluations were performed using the
identification sniffin' sticks test (Medisense, Groningen, The
Netherlands), which is a validated objective test of olfactory
dysfunction.\textsuperscript{13} A total of 16 scents were presented via
a pen device to patients for 3 seconds followed by a forced choice from
4 given options with a total possible score of 16 points. According to
the results, patients were classified as normosmic (score between
12-16), hyposmic (score between 9-11) or anosmic (score 8 or below).

\emph{Statistical Analyses}

Statistical analyses were performed using the Statistical Package for
the Social Sciences for Windows (SPSS version 22,0; IBM Corp, Armonk,
NY, USA). The relationship between clinical and olfactory outcomes was
analyzed through non-parametric test using Spearman correlation for
scale data, Khi2 test for ordinal data and Mann-Whitney or
Kruskal-Wallis test for categorized data. We investigated all potential
associations between nasal complaints (nasal obstruction, rhinorrhea,
postnasal drip) and the occurrence of olfactory disorder (sniffin'stick
test). A level of significance of p\textless{}0.05 was used.

\textbf{Results:}

A total of 86 patients were eligible and completed the study (Figure 1).
There were 56 females (65.1\%) and 30 males (34.9\%). The mean age was
42 ± 12 years. The majority of patients were Caucasian. Reflux, asthma
and allergic rhinitis were the most common comorbidities (Table 1).
Non-smokers accounted for 90\% of the cohort.

\emph{Clinical outcomes based on the general questionnaire.}

The most common general symptoms developed over the clinical course were
fatigue (72.9\%), headache (60.0\%), cough (48.6\%) and myalgia (42.9\%)
(Table 2). Fever, defined as a body temperature \textgreater{}38C°, was
only reported by 8.6\% of patients. Asthenia was the most commonly
reported severe general symptom. The most common otolaryngological
symptoms were nasal obstruction (58.6\%), postnasal drip (48.6\%), and
dysgeusia (47.1\%). Dysgeusia was considered the most severe
otolaryngological symptom by half of the surveyed patients (Table 3).

\emph{Patient Reported Outcome Questionnaire of Olfactory \& Gustatory
Function}

According to the NHNES questions, 61.4\% of patients described their
olfactory disorder as total loss of smell at the onset of the disease,
while the remainder reported partial loss. Cacosmia and phantosmia
occurred in 34\% and 20\% patients, respectively. The mean scores of
SNOT-22 and sQOD-NS are reported in Table 4.

Regarding gustatory dysfunction, 51\% of patients reported taste
disorders with abnormal sensations of salty, sweet, bitter and sour. The
aroma perception was completely or partly lost in 42\% and 32\%,
respectively, while 12\% reported distortion of aroma.

\emph{Psychophysical Olfactory Evaluations}

The mean score of Sniffin' Stick testing was 9 ± 4. Among the 86
patients, 41 (48\%) and 12 (14\%) patients were anosmic and hyposmic,
respectively. A total of 33 (38\%) patients who reported loss of smell
were objectively normosmic. In the anosmic group, 26 (78.8\%) patients
reported total loss of smell. In the second group, 8 hyposmic
individuals (88.9\%) reported total loss of smell (Table 5).

The mean durations of olfactory dysfunction at the time of the
evaluations were 17 ± 11 days and 18 ± 11 days for anosmic and hyposmic
patients, respectively. The mean duration of olfactory dysfunction of
normosmic patients was 17 ± 11 days (Table 5).

Eleven patients realized sniffin'stick test twice (one week apart).
Among these 11 patients, 9 were anosmic, 1 hyposmic and 1 normosmic at
the first evaluation. From the first to the second visit (1 week later),
the sniffin'stick test values improved in 5 patients (1 became hyposmic
and 4 normosmic individuals) of the 9 anosmic patients of the first
visit.

\emph{Subgroup Analysis \& Relationship between Outcomes}

The nasal obstruction was not significantly associated with the
development of olfactory dysfunction. Among the anosmic group, 60.1\% of
patients did not suffer from nasal obstruction (Table 5). There was no
significant association between the results of the sniffin' stick tests
and the occurrence/severity of the following complaints: nasal
obstruction and postnasal drip.

\textbf{Discussion:}

The involvement of COVID-19 in the development of olfactory and
gustatory dysfunctions seems obvious. However, the characterization of
the pathophysiological mechanisms underlying the olfactory dysfunction
remains challenging regarding the risk of contamination. In this study,
we have performed both subjective and objective olfactory evaluations in
COVID-19 patients through online patient-reported outcome questionnaires
and individual objective psychophysical testings. Interestingly, 38\% of
patients with self-reported olfactory dysfunction had normal olfactory
testing at the sniffin'stick test.

The mismatch between the self-reported loss of smell and the anosmia
regarding psychophysical testings has already been suggested in a recent
Italian study where a few COVID-19 patients, who self-reported loss of
smell, were objectively anosmic.\textsuperscript{14} Thus, the
prevalence of olfactory dysfunction related to COVID-19 would be
overestimated in the epidemiological studies where the loss of smell was
based on subjective reports.

Another important finding of this study is the non-significant
relationship between symptoms of nasal inflammation and objective
olfactory dysfunction. In most cases of olfactory dysfunction occurring
in viral infections, the olfactory disorder is related to the
inflammatory reaction of the mucosa, leading to nasal obstruction,
rhinorrhea and postnasal drip. In some cases, the olfactory dysfunction
appeared to be related to other mechanisms, such as a neural spread of
the virus into the neuroepithelium and the olfactory bulb. In 2007,
Suzuki \emph{et al} . demonstrated that coronavirus may be detected in
the nasal discharge of patients with olfactory
dysfunction.\textsuperscript{15} In this study, some patients had normal
acoustic rhinometry, suggesting that nasal inflammation and related
obstruction were not the only etiological factors underlying the
olfactory dysfunction in viral infection. Netland \emph{et al} .
demonstrated on transgenic mice expressing the SARS-CoV receptor (human
angiotensinconverting enzyme 2) that SARS-CoV may enter the brain
through the olfactory bulb, leading to rapid transneuronal
spread.\textsuperscript{16} The neurotropism of the COVID-19 is not new
and would be associated with other symptoms and findings. For example,
the virus spread into the central nervous system is currently suspected
to play a key role in respiratory failure through an effect on the
medullary cardiorespiratory center.\textsuperscript{17} Similarly, the
existence of different patterns of gustatory and olfactory recoveries
would be explained by selective neurological
impairments.\textsuperscript{1} In other words, and suggested by the
aroma and gustatory outcomes, the loss of taste would be not a
retro-olfactory disorder in some patients. Future experimental and
clinical studies are needed to better understand the pathophysiological
mechanisms underlying the development of olfactory and gustatory
dysfunctions. These studies would associate patient-reported outcome
questionnaires, psychophysical olfactory evaluations, fiberoptic
examinations, and imaging or neurophysiological assessments.

The main limitation of the present study is the heterogeneity between
patients about the duration of the olfactory dysfunction. However, it is
complicated to recruit patients at the first day of the olfactory
disorder for many reasons. First, many patients have other troublesome
symptoms (e.g. fatigue, myalgia, arthralgia), which may limit the
realization of the tests. Second, the recruitment of patients at the
first day of the olfactory dysfunction involved a continuous
communication to recruit these patients. In practice, it is complicated
to communicate with the general public every day for a scientific study.
The lack of full objective methods to assess olfaction may be considered
as another weakness. In this study, we decided to use the Identification
sniffin'sticks test (16 items) for practical and ethical reasons. This
test may be performed quickly, which is important to reduce the risk of
potential contamination of caregivers.

\textbf{Conclusion:}

Only 62\% of COVID-19 patients with self-reported olfactory dysfunction
have anosmia or hyposmia on objective psychophysical olfactory
evaluation. Interestingly, the majority of those with confirmed
objective olfactory dysfunction did not have nasal inflammatory
symptoms, supporting the need of future clinical and experimental
studies to clarify the pathophysiological mechanisms underlying the
development of anosmia in COVID-19.

\textbf{Funding} : FRMH Funding.

\textbf{Conflict of interest statement} : The authors have no conflicts
of interest

\textbf{Acknowledgments:} -.

\textbf{References:}

1. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and
gustatory dysfunctions as a clinical presentation of mild-to-moderate
forms of the coronavirus disease (COVID-19): a multicenter European
study. \emph{Eur Arch Otorhinolaryngol} . 2020. doi:
10.1007/s00405-020-05965-1.~ 2. Hopkins C, Surda P, Kumar N.
Presentation of new onset~anosmia~during the COVID-19 pandemic.
\emph{Rhinology} . 2020. doi: 10.4193/Rhin20.116.

3. Lechien JR, Chiesa-Estomba CM, Place S, et al (in press). Clinical
and Epidemiological Characteristics of 1,420 European Patients with
mild-to-moderate Coronavirus Disease 2019. In press, \emph{J Int Med} .
2020

4. Kaye R, Chang DW, Kazahaya K, Brereton J, Denneny III JC. COVID-19
Anosmia Reporting Tool: Initial Findings. Accepted for publication
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5. Beltrán-Corbellini Á, Chico-García JL, Martínez-Poles J, et al.
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6. Yan CH, Faraji F, Prajapati DP, Ostrander BT, DeConde AS.
Self-reported olfactory loss associates with outpatient clinical course
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10.1002/alr.22592.

7. Moein ST, Hashemian SMR, Mansourafshar B, Khorram-Tousi A, Tabarsi P,
Doty RL. Smell dysfunction: a biomarker for~COVID-19. \emph{Int Forum
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8. World Health Organization. Clinical management of severe acute
respiratory infection when novel coronavirus (2019- nCoV) infection is
suspected: interim guidance. January 28, 2020
https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-novel-cov.pdf

9. de Dorlodot C, Horoi M, Lefebvre P, Collet S, Bertrand B, Eloy
P,~Poirrier~AL. French adaptation and validation of the~sino-nasal
outcome test-22: a prospective cohort study on quality of life among 422
subjects. \emph{Clin Otolaryngol} . 2015; 40(1):29-35. doi:
10.1111/coa.12315.

10. Piccirillo JF, Merritt MG Jr, Richards ML. Psychometric and
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11. Mattos JL, Edwards C, Schlosser RJ, Hyer M, Mace JC, Smith TL, Soler
ZM. A~brief~version~of
the~questionnaire~of~olfactory~disorders~in~patients~with~chronic~rhinosinusitis.\emph{Int
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12. Bhattacharyya N, Kepnes LJ. Contemporary assessment of the
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13. Hummel, T., Kobal, G., Gudziol, H. et al. Normative data for the
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14. Vaira~LA, Deiana G, Fois AG, et al. Objective evaluation of anosmia
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15. Suzuki~M, Saito K, Min WP, Vladau C, Toida K, Itoh H, Murakami S.
Identification of viruses in patients with postviral olfactory
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16. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S.

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\textbf{Table 1: Epidemiological Characteristics of Patients.}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Characteristic & All patients\tabularnewline
\midrule
\endhead
& (N=86)\tabularnewline
Age &\tabularnewline
Mean (SD) -- yo & 41.7 \selectlanguage{ngerman}± 11.8\tabularnewline
Gender (N - \%) &\tabularnewline
Female & 56 (65.1)\tabularnewline
Male & 30 (34.9)\tabularnewline
Ethnicity (N - \%) &\tabularnewline
Caucasian & 84 (97.7)\tabularnewline
North African & 2 (2.3)\tabularnewline
Addictions (N - \%) &\tabularnewline
Non-smoker & 77 (89.5)\tabularnewline
Mild smoker (1-10 cigarettes daily) & 7 (8.1)\tabularnewline
Moderate smoker (11-20 cigarettes daily) & 1 (1.2)\tabularnewline
Heavy smoker (\textgreater{}20 cigarettes daily) & 1
(1.2)\tabularnewline
Allergic patients & 16 (18.6)\tabularnewline
Comorbidities &\tabularnewline
GERD & 9 (10.5)\tabularnewline
Asthma & 5 (5.8)\tabularnewline
Allergic rhinitis & 5 (5.8)\tabularnewline
Hypertension & 4 (4.7)\tabularnewline
Hypothyroidism & 3 (3.5)\tabularnewline
Psoriasis & 2 (2.4)\tabularnewline
Depression & 2 (2.3)\tabularnewline
Sarcoidosis & 1 (1.2)\tabularnewline
Hemochromatosis & 1 (1.2)\tabularnewline
Obstructive apnea syndrome & 1 (1.2)\tabularnewline
Autoimmune disease & 0 (0)\tabularnewline
Diabetes & 0 (0)\tabularnewline
Renal failure & 0 (0)\tabularnewline
Hepatic insufficiency & 0 (0)\tabularnewline
Respiratory insufficiency & 0 (0)\tabularnewline
Heart problems & 0 (0)\tabularnewline
Neurological diseases & 0 (0)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1 footnotes} : The mean PCR cycle number inversely
reflects the viral load, According to the threshold of our Lab, 29
patients were positive for COVID-19 10 days (mean) after the initial
diagnosis. Abbreviations: GERD=gastroesophageal reflux disease;
SD=standard deviation.

\textbf{Table 2: Severity of General Symptoms developed over the
Clinical Course of the Disease (Percent of patients).}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{General Symptoms} & 0= No & 1=Very Mild & 2=Mild or & 3=Moderate
& 4=Severe\tabularnewline
\midrule
\endhead
& Problem & Problem & Slight Problem & Problem & Problem\tabularnewline
Fever & 64 (91.4) & 5 (7.1) & 1 (1.4) & 0 (0) & 0 (0)\tabularnewline
Cough & 36 (51.4) & 18 (25.7) & 12 (17.1) & 4 (5.7) & 0
(0)\tabularnewline
Chest pain & 57 (81.4) & 6 (8.6) & 5 (7.1) & 1 (1.4) & 1
(1.4)\tabularnewline
Loss of appetite & 43 (61.4) & 10 (14.3) & 8 (11.4) & 5 (7.1) & 4
(5.7)\tabularnewline
Sticky Sputum & 52 (73.4) & 11 (15.7) & 4 (5.7) & 1 (1.4) & 2
(2.9)\tabularnewline
Arthralgia & 48 (68.6) & 8 (11.4) & 5 (7.1) & 7 (10.0) & 2
(2.9)\tabularnewline
Myalgia & 40 (57.1) & 19 (27.1) & 3 (4.3) & 6 (8.6) & 2
(2.9)\tabularnewline
Diarrhea & 48 (68.9) & 15 (21.4) & 4 (5.7) & 2 (2.9) & 1
(1.4)\tabularnewline
Abdominal pain & 58 (82.9) & 8 (11.4) & 4 (5.7) & 0 (0) & 0
(0)\tabularnewline
Nausea/vomitting & 61 (87.1) & 7 (10.0) & 2 (2.9) & 0 (0) & 0
(0)\tabularnewline
Headache & 28 (40.0) & 17 (24.3) & 14 (20.0) & 10 (14.3) & 1
(1.4)\tabularnewline
Asthenia & 19 (27.1) & 17 (24.3) & 14 (20.0) & 13 (18.6) & 7
(10.0)\tabularnewline
Urticaria & 61 (87.1) & 3 (4.3) & 4 (5.7) & 1 (1.4) & 1
(1.4)\tabularnewline
Conjonctivitis & 52 (74.3) & 12 (17.1) & 2 (2.9) & 3 (4.3) & 1
(1.4)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2 footnotes} : The symptoms severity was assessed with a
4-point scale (from no problem (0) to Severe problem (4)). The symptom
data were available for 70 patients. The rest of the patients fulfilled
the patient-reported outcome questionnaire a few days after the
sniffin'stick tests, which may bias the analysis. The data of these
patients were not considered in this table.

\textbf{Table 3: Severity of Ear, Nose, and Throat Symptoms developed
over the Clinical Course of the Disease (Percent of patients).}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Ear, nose \& throat} & 0= No & 1=Very Mild & 2=Mild or &
3=Moderate & 4=Severe\tabularnewline
\midrule
\endhead
\textbf{Symptoms} & Problem & Problem & Slight Problem & Problem &
Problem\tabularnewline
Nasal obstruction & 29 (38.6) & 23 (32.9) & 12 (17.1) & 5 (7.1) & 1
(1.4)\tabularnewline
Rhinorrhea & 37 (50.0) & 19 (27.1) & 12 (17.1) & 2 (2.9) & 0
(0)\tabularnewline
Postnasal drip & 36 (48.6) & 17 (24.3) & 12 (17.1) & 5 (7.1) & 0
(0)\tabularnewline
Throat pain & 52 (72.9) & 12 (17.1) & 3 (4.3) & 3 (4.3) & 0
(0)\tabularnewline
Facial pain & 55 (77.1) & 7 (10.0) & 7 (10.0) & 1 (1.4) & 0
(0)\tabularnewline
Ear pain & 47 (65.7) & 19 (27.1) & 2 (2.9) & 2 (2.9) & 0
(0)\tabularnewline
Dysphagia & 63 (88.6) & 2 (2.9) & 4 (5.7) & 1 (1.4) & 0
(0)\tabularnewline
Dyspnea & 52 (72.9) & 12 (17.1) & 3 (4.3) & 3 (4.3) & 0
(0)\tabularnewline
Dysphonia & 53 (75.7) & 12 (17.1) & 2 (2.9) & 2 (2.9) & 1
(1.4)\tabularnewline
Dysgeusia & 37 (52.9) & 4 (5.7) & 1 (1.4) & 7 (10.0) & 21
(30.0)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3 footnotes} : The symptoms severity was assessed with a
4-point scale (from no problem (0) to Severe problem (4)). The symptom
data were available for 70 patients. The rest of the patients fulfilled
the patient-reported outcome questionnaire a few days after the
sniffin'stick tests, which may bias the analysis. The data of these
patients were not considered in this table.

\textbf{Table 4: Sino-nasal Complaints of Patients with Olfactory
Dysfunction.}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
SNOT-22 items & Mean \selectlanguage{ngerman}± (SD)\tabularnewline
\midrule
\endhead
Need to blow nose & 1.7 \selectlanguage{ngerman}± 1.3\tabularnewline
Nasal blockage & 1.1 \selectlanguage{ngerman}± 1.1\tabularnewline
Sneezing & 1.6 \selectlanguage{ngerman}± 1.4\tabularnewline
Runny nose & 1.6 \selectlanguage{ngerman}± 1.3\tabularnewline
Cough & 1.3 \selectlanguage{ngerman}± 1.4\tabularnewline
Post-nasal discharge & 0.7 \selectlanguage{ngerman}± 1.0\tabularnewline
Thick nasal discharge & 0.6 \selectlanguage{ngerman}± 1.1\tabularnewline
Ear fullness & 0.6 \selectlanguage{ngerman}± 1.1\tabularnewline
Dizziness & 0.7 \selectlanguage{ngerman}± 1.1\tabularnewline
Ear pain & 0.6 \selectlanguage{ngerman}± 1.0\tabularnewline
Facial pain/pressure & 0.9 \selectlanguage{ngerman}± 1.3\tabularnewline
Decreased sense of smell/taste & 1.2 \selectlanguage{ngerman}± 1.6\tabularnewline
Difficulty falling asleep & 1.6 \selectlanguage{ngerman}± 1.7\tabularnewline
Wake up at night & 1.8 \selectlanguage{ngerman}± 1.7\tabularnewline
Lack of a good night's sleep & 2.1 \selectlanguage{ngerman}± 1.7\tabularnewline
Wake up tired & 2.4 \selectlanguage{ngerman}± 1.6\tabularnewline
Fatigue & 1.9 \selectlanguage{ngerman}± 1.5\tabularnewline
Reduced productivity & 1.8 \selectlanguage{ngerman}± 1.6\tabularnewline
Reduced concentration & 1.7 \selectlanguage{ngerman}± 1.6\tabularnewline
Frusated/restless/irritable & 1.6 \selectlanguage{ngerman}± 1.5\tabularnewline
Sad & 4.2 \selectlanguage{ngerman}± 1.3\tabularnewline
Embarrassed & 1.8 \selectlanguage{ngerman}± 1.4\tabularnewline
SNOT-22 total score & 33.3 \selectlanguage{ngerman}± 19.0\tabularnewline
Short version QOD-NS items &\tabularnewline
Changes in my sense of smell isolate me socially. & 2.0 \selectlanguage{ngerman}±
0.9\tabularnewline
The problems with my sense of smell have a negative impact on my daily
social activities & 1.8 \selectlanguage{ngerman}± 0.9\tabularnewline
The problems with my sense of smell make me more irritable & 1.7 \selectlanguage{ngerman}±
1.0\tabularnewline
Because of the problems with my sense of smell, I eat out less & 1.4 \selectlanguage{ngerman}±
1.2\tabularnewline
Because of the problems with my sense of smell, I eat less than before
(loss of appetite) & 1.3 \selectlanguage{ngerman}± 1.1\tabularnewline
Because of the problems with my sense of smell, I have to make more
effort to relax & 2.0 \selectlanguage{ngerman}± 0.8\tabularnewline
I'm afraid I'll never be able to get used to the problems with my sense
of smell. & 1.1 \selectlanguage{ngerman}± 1.0\tabularnewline
Short version QOD-NOS total score & 10.3 \selectlanguage{ngerman}± 5.7\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 4 footnotes} : Abbreviations: QOD-NS= short version of
Questionnaire of Olfactory Disorders-Negative Statements; SNOT-22=
sinonasal outcome test-22.

\textbf{Table 5: Characteristics of Anosmic, Normosmic and Hyposmic
Patients} .\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& \textbf{Anosmic (N=41)} & \textbf{Hyposmia (N=12)} & \textbf{Normosmia
(N=33)} & p-value & Test\tabularnewline
\midrule
\endhead
Age -- (Mean, SD) & 40 \selectlanguage{ngerman}± 12 & 39 \selectlanguage{ngerman}± 13 & 45 \selectlanguage{ngerman}± 11 & NS & KW\tabularnewline
Sex (M/F) & 15/36 & 3/0 & 12/21 & NS & Khi2\tabularnewline
Tabacco (yes/no) & 5/36 & 2/10 & 2/31 & NS & Khi2\tabularnewline
Comorbidities (yes/no) & & & & &\tabularnewline
Hypertension & 0 & 2 & 2 & 0.027 & Khi2\tabularnewline
Rhinitis & 1 & 2 & 2 & NS & Khi2\tabularnewline
Reflux & 4 & 1 & 4 & NS & Khi2\tabularnewline
Asthma & 2 & 2 & 1 & NS & Khi2\tabularnewline
\emph{SNOT-22 (Mean, SD)} & 33 \selectlanguage{ngerman}± 16 & 43 \selectlanguage{ngerman}± 20 & 34 \selectlanguage{ngerman}± 19 & NS &
KW\tabularnewline
Nasal obstruction (yes/no/NC) & 13/20/8 & 7/2/3 & 18/10/5 & NS &
Khi2\tabularnewline
Self-reported Total loss of smell (N/\%) & 26 (78.8) & 8 (88.9) & 18
(64.3) & NS &\tabularnewline
Duration of Anosmia (Mean, SD - days) & 17 \selectlanguage{ngerman}± 11 & 18 \selectlanguage{ngerman}± 11 & 17 \selectlanguage{ngerman}± 10 & NS
& KW\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 5 footnotes} : All 86 patients performed Sniffin'Stick
tests. However, only 70 patients completed the two questionnaires
(general and SNOT-22) the same day of the olfactory test. The patient
questionnaires, which were fulfilled after the olfactory dysfunction,
were not considered regarding the risk of bias (NC in the table).
Abbreviations: M/F = male/female; NC = not considered; SD=standard
deviation.

\par\null

\textbf{Figure 1: Chart flow}~

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-(1)/Figure-1-(1)}
\caption{{Abbreviations: NHNES: National Health and Nutrition Examination Survey;
SNOT-22: Sinonasal outcome tool-22; sQOD-NS: short version of
Questionnaire of Olfactory Disorders-Negative Statements.
{\label{675959}}%
}}
\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

