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\begin{document}

\title{Prolonged Olfactory Dysfunction in the COVID-19 Era; Etiological
Analysis in a Single-centered Cohort}



\author[1]{hiroko kawai}%
\author[1]{kousuke hashimoto}%
\author[1]{yuichi teranishi}%
\author[1]{yuu nakagama}%
\author[1]{yasutoshi kido}%
\author[1]{kishiko sunami}%
\affil[1]{Osaka Metropolitan University Graduate School of Medicine School of Medicine}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Key Points: ? COVID-19 often cause prolonged olfactory dysfunction. ?
This study evaluated the relative burden of the COVID-19-related disease
in a single-centered cohort of POD patients. ? COVID-19-related POD was
diagnosed serologically. ? In the COVID-19 era, the local burden of POD
increased two-fold. ? It is important to use pleiotropic approach and
robust measures, when we assess OD.%
\end{abstract}%



\sloppy


\textbf{Key Points:}

\begin{itemize}
\tightlist
\item
  COVID-19 often cause prolonged olfactory dysfunction.
\item
  This study evaluated the relative burden of the COVID-19-related
  disease in a single-centered cohort of POD patients.
\item
  COVID-19-related POD was diagnosed serologically.
\item
  In the COVID-19 era, the local burden of POD increased two-fold.
\item
  It is important to use pleiotropic approach and robust measures, when
  we assess OD.
\end{itemize}

\textbf{Introduction:}

Among other etiologies, such as the airway obstruction and neural
disorders, viral illnesses have always been the most common cause of
prolonged olfactory dysfunction (POD). The emerging coronavirus disease
2019 (COVID-19), which is now increasingly recognized to be accompanied
by an impairment in odor sensation, may have contributed to an increase
in the overall prevalence of POD, but to what extent is unknown. While
once thought to have a good prognosis, recent reports on long-term
follow-up data estimate that a significant proportion of patients with
the COVID-19-related odor sensation impairment, ranging from 1\% to
48\%\textsuperscript{1,2}, develop POD. In this study, we evaluated the
relative burden of the COVID-19-related disease in a single-centered
cohort consisting of patients with POD of previously undetermined
etiology. The clinical characteristics of COVID-19-related POD were
compared with those of POD from other etiologies.

\textbf{Methods:}

This study was cross-sectional study, and took place at ``Blind for
review''.

Participants of the study were 16 people (11 of 16 were women, 69\%),
with a median age of 42 years (interquartile range 15--83),
self-reporting of prolonged (lasting more than four weeks) impairment in
odor sensation, and visiting the outpatient clinic at ``Blind for
review'' from December 2020 to January 2022. Clinical data from their
medical records were collected, including symptoms, laboratory
variables, endoscopy and CT findings, and final diagnosis. The outcome
was the pattern and severity of odor sensation impairment. The following
methods were used to assess the outcome qualitatively and
quantitatively. (i) Participant completed the Self-Administered Odor
Questionnaire (SAOQ), which was developed by the Japan Rhinology Society
to assess an individual's ability to identify 20 different odorants. The
percentage of correct answers indicated the degree of
impairment\textsuperscript{3}. (ii) The Open Essence (OE) smell
identification card assessed an individual's ability to identify 12
different odorants familiar to the Japanese population. The number of
correct answers reflected the severity of impairment\textsuperscript{4}.
(iii) Intravenous olfactometry (IO) measures the latency in recognizing
the garlic-like odor and the duration of its perception, following an
injection of thiamine propyl-disulfide. The worst score was used for
analysis of participants who were assessed longitudinally at multiple
time points. This study was approved by the institutional review board
of ``Blind for review''. All participants have given their informed
consent to participate.

Participants were assessed for the etiology of their POD. They were
tested for anti-SARS-CoV-2 antibodies using the Elecsys Anti-SARS-CoV-2
assay (Roche, Basel, Switzerland). One participant with a
``high-negative'' result was further tested with the Architect
SARS-CoV-2 IgG and IgG II Quant (Abbott, Chicago, Illinois, USA)
immunoassays, targeting nucleocapsid and spike proteins, respectively.
In the absence of a SARS-CoV-2 vaccination, the participant had
``positive'' results on both confirmatory immunoassays and was thus
classified as having a positive serology. Participants with positive
serology against SARS-CoV-2 were diagnosed with COVID-19-related POD. CT
was used to diagnose paranasal sinus abnormalities. Non-SARS-CoV-2
post-viral POD was defined as a persistent impairment in odor sensation
after recovery from acute rhinitis. Participants with POD were otherwise
classified as ``idiopathic.''

The Strengthening the Reporting of OBservation studies in Epidemiology
statement was used to report the findings.

\textbf{Results:}

Surprisingly, 9 of 16 (56\%) of our cohort were serologically diagnosed
with COVID-19-related POD. Other causes of POD included eosinophilic
sinusitis (1), non-SARS-CoV-2 post-viral (2), and idiopathic (4).
COVID-19-related POD patients were more likely to expwrience gustatory
dysfunction than other miscellaneous PODs (6 of 9, 67\% vs. 2 of 7,
29\%). Despite not reaching statistical significance due to the limited
sample size of the study, the degree of POD assessed by all three
presented methods showed a trend toward increased severity for
COVID-19-related disease (Table). When the patterns of impairment in OE
odor discrimination were evaluated odorant by odorant, patients with
COVID-19 were more frequently non-recognizable of menthol (4 of 8, 50\%
vs. 2 of 7, 29\%).

\textbf{Discussions:}

In the contemporary COVID-19 era, the local burden of POD increased a
surprising two-fold. Thus, COVID-19-related POD has indeed caused a
non-negligible threat to the quality of life of the affected, as well as
the Japanese public health system. Surprisingly, 5 of 7 COVID-19
patients lacked an acute diagnosis and were later diagnosed
serologically. This may reflect the local situation in Japan, which once
faced a severe shortage of molecular diagnostics. Comparisons to
preceding findings from the UK, also indicated that seroprevalence of
the COVID-19-related impairment in the odor
sensation\textsuperscript{5}had relied on subjective assessment of
impairment lacking quantitative data. Our findings confirmed the
previously reported magnitude of an increase in the disease burden, by
further using robust indices of both qualitative and quantitative
features (SAOQ, OE, IO).

The intranasal trigeminal system, like the gustatory system, is now
recognized as a frequent neuronal target of the
SARS-CoV-2\textsuperscript{6}. OE, which is widely used in Japan,
contains menthol as one of the 12 odorants and allows for the screening
of any coexisting intranasal trigeminal dysfunction. In line with
previous research, non-recognition of the cooling sensation in menthol,
which is an expression of trigeminal dysfunction, rather than olfactory
dysfunction, was more commonly observed in our cohort of patients with
COVID-19-related POD. However, some participants reported a subjective
improvement in their POD during interviews, despite inconsistent
unimprovement in the OE scoring. This could be due to the patient's
difficulty in distinguishing trigeminal sensation from olfaction. Thus,
assessing POD in the clinic must use pleiotropic approaches and robust
measures. The prognostic value of differentiating the POD etiologies in
the era of COVID-19 shall be studied further in the future.

\textbf{Data Availability Statement:}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{References:}

{[}1{]} Alberto P, Davide M, Vittorio R, et al. Olfactory and gustatory
outcomes in COVID-19: A prospective evaluation in nonhospitalized
subjects. Otolaryngol Head Neck Surg. 2020 Dec;163(6):1144-1149.

{[}2{]} Ameen B, Or D, Zeev O, et al. Eight-month follow-up of olfactory
and gustatory dysfunctions in recovered COVID-19 patients. Am J
Otolaryngol. 2021 Jul-Aug;42(4): 103065.

{[}3{]} Hironori T, Kenzo T, Hideki O, Keijiro F, Takashi D, Masafumi S.
Clinical availability of a self-administered odor questionnaire for
patients with olfactory disorders. Auris Nasus Larynx. 2011
Feb;38(1):65-72.

{[}4{]} Kohei N, Masayoshi K, Hitomi O, Tetsu T, Masako K, Kazuhiko T.
Clinical usefulness of smell identification test card: Open Essence.
Nihon Jibiinkoka Gakkai Kaiho. 2010 Sep;113(9):751-757.

{[}5{]} Janine M, Jessica M, Nyaladzi B, et al. Seroprevalence of
SARS-CoV-2 antibodies in people with an acute loss in their sense of
smell and/or taste in a community-based population in London UK: An
observational cohort study. PLos Med. 2020 Oct;17(10):e1003358.

{[}6{]} Green BG. Surveying chemosensory dysfunction in COVID-19. Chem
Senses. 2020 Sep;45(7):509-511.

\textbf{Hosted file}

\verb`OD table_new.docx`  available at \url{https://authorea.com/users/499927/articles/580879-prolonged-olfactory-dysfunction-in-the-covid-19-era-etiological-analysis-in-a-single-centered-cohort}

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\end{document}

