Psychological Impact and Clinical Correlates of Olfactory Dysfunction in Post- COVID-19 and Non-COVID-19 Patients: A Comparative Study

Psychological Impact and Clinical Correlates of Olfactory Dysfunction in Post- COVID-19 and Non-COVID-19 Patients: A Comparative Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Psychological Impact and Clinical Correlates of Olfactory Dysfunction in Post- COVID-19 and Non-COVID-19 Patients: A Comparative Study Jae Hyun Yoo, Tae-Suk Kim, Ji Sun Kim, Seung Hoon Lee, Min Young Seo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4617956/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 13 You are reading this latest preprint version Abstract Olfactory dysfunction (OD) has been reported in individuals who have recovered from COVID-19. Those with OD after COVID-19 (COVID-19 group) exhibited more severe psychiatric symptoms than those with OD from other etiologies (non-COVID-19 group). This study aimed to investigate the differences in psychological symptoms and related clinical factors between the two groups. Fifty-two participants (26 COVID-19 group; 26 non-COVID-19 group) were recruited. Both objective and subjective olfactory function were assessed. Symptoms of depression, anxiety, and perceived stress were measured using self-report scales. There were no significant differences in objective and subjective olfactory function or psychological symptoms between the groups, except for age and the short version of the Questionnaire of Olfactory Disorders-negative statements (sQOD-NS). The sQOD-NS score was negatively correlated with the duration of OD only in the COVID-19 group. Both groups showed significant correlations between the sQOD-NS and the Patient Health Questionnaire-9 (PHQ-9) scores. Mediation analysis showed that the duration of OD indirectly affected PHQ-9 scores via sQOD-NS in the entire sample and particularly in the COVID-19 group. The findings suggest that subjective distress from OD may mediate the relationship between duration of OD and depressive symptoms in COVID-19 patients, highlighting the need for targeted psychiatric interventions after COVID-19. Biological sciences/Neuroscience Health sciences/Medical research Health sciences/Signs and symptoms Olfaction Disorders COVID-19 Depressive Disorder Anxiety Disorders Psychological distress Figures Figure 1 Figure 2 Figure 3 Introduction Olfactory dysfunction (OD) refers to a range of conditions involving impaired sense of smell, including anosmia (complete loss of smell) and hyposmia (reduced ability to smell). 1 OD can occur due to a variety of causes, including rhinosinusitis with or without nasal polyps, post viral infections, head trauma, toxic material exposure, and congenital disorders. 2,3 In recent years, the prevalent of OD has been increased due to the COVID-19 pandemic, with many patients experiencing a decrease in their sense of smell following infection. 4,5 The prevalence of OD following COVID-19 pandemic has been reported to range from approximately 10–55%, depending on race. 6 COVID-19 related OD often appears on the third day following infection and goes away entirely in 4–6 weeks. But these changes can last longer than four months in 27% of cases 7 and up to a year in 21.3% of cases. 8 According to Yom-Tov et al., COVID-19 patients with OD had a 30% higher incidence of depression and suicidal ideation than those without OD. 9 A online survey conducted by Coelho et al. on 322 OD subjects following COVID-19 infection also found that symptoms depression were present in 43% of participants. 10 Additionally, COVID-19 patients with OD reported higher anxiety levels. 11 These results suggested a correlation between neuropsychiatric symptoms and OD, and the pivotal role of COVID-19 infection in long term mental health outcome. Previous studies have proposed several hypothesized mechanisms for the development of neuropsychiatric symptoms in COVID-19 related OD. It has been demonstrated that SARS-CoV-2 can cause damage to the central nervous system. 12,13 Postmortem examination of brain tissues from patients with COVID-19 revealed the presence of neuroinflammation, microglia activation, and neuronal death. 14,15 Neuroinflammation can persist long after the acute phase of the disease, sometimes referred to as long COVID. 16 According to Stefanou et al., over one-third of patients experienced brain fog, cognitive dysfunction, changes in gustation and smell, and psychiatric manifestations like mood disorders as long COVID symptoms. 13 This phenomenon is thought to be likely caused by persistent systemic inflammation and the existence of viral RNA in the brains of COVID-19 patients after an extended length of time. 17 In the psychosocial perspectives, OD can cause problems in various emotional aspects of human life. The inability to smell can lead to a loss of pleasure from activities that were once enjoyed, such as eating and socializing, and this can cause significant psychological distress to the affected person. 18,19 Several lines of evidence demonstrate a significant association between OD and depression, anxiety, and feelings of isolation, which can further exacerbate one's quality of life (QoL). 19–21 In a study long COVID, distortion of smell was more prevalent in young people, and negative QoL were more common in people with a post-COVID-19 infection than in other post-infection cases. 22 Therefore, OD following COVID-19 also can elicit profound negative impact on psychological well-being and require clinical attention. However, it is not yet clear why the prevalence of psychological symptoms is higher in patients with COVID-19-related OD compared to OD due to other etiologies, such as chronic entorhinal inflammation or trauma. To date, no studies have been conducted to compare the stress level, symptoms of depression and anxiety followed by OD related with COVID-19 infection and that resulted from other etiologies. Furthermore, clinical factors that influence mood symptoms in the long COVID population remain poorly understood. In this study, we aimed to compare the olfactory function and emotional state of two groups: those who experienced OD due to COVID-19 infection and those who experienced long-term olfactory loss due to chronic entorhinal disease. Additionally, we investigated the potential associations among the duration of OD, subjective distress, and mood symptoms such as depression and anxiety using mediation analyses. Results The demographics of the patients are presented in Table 1 . The mean age of the participants was approximately 44 years old, with the COVID-19 group being significantly younger than the non-COVID-19 group. Among the 52 participants with subjective olfactory loss approximately 71% were confirmed to have OD according to psychophysical test results. The subjective and objective olfactory parameters did not differ significantly between the COVID-19 and non-COVID-19 groups except QOD-NS total score (11.08 ± 5.05 vs 7.81 ± 5.47, p = .030). Based on the cut-off of each psychological measure, 38.5% of the participants were considered to have depressive symptoms (20/52), and 21.2% of participants were considered to have moderate to severe anxiety (11/52). Furthermore, 78.8% of participants were considered to have moderate to severe perceived stress (41/52). Table 1 Demographics of the participants. QOD, Questionnaire of Olfactory Disorders; VAS, visual analog scale; sQOD-NS, short version of QOD-negative statements; YOF, YSK olfactory function; PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder 7-item scale; PSS-10, Perceived Stress Scale Total (n = 52) COVID-19 (n = 26) Non-COVID-19 (n = 26) P value Age (year-old) 44.21 ± 18.24 39.23 ± 16.12 49.19 ± 19.16 .048 Sex (male) 27 14 13 .781 sQOD-NS total score 9.44 ± 5.47 11.08 ± 5.05 7.81 ± 5.47 .030 QOD-VAS total score 32.31 ± 11.33 31.85 ± 9.64 32.77 ± 12.97 .772 YOF total score 15.91 ± 7.47 16.99 ± 7.00 14.84 ± 7.90 .303 Patients with objective OD (n) 37 19 18 .760 PHQ-9 score 8.23 ± 6.77 7.27 ± 6.10 9.19 ± 7.37 .310 GAD-7 score 5.24 ± 5.61 3.79 ± 5.13 6.64 ± 5.80 .076 PSS-10 18.04 ± 6.48 17.58 ± 7.53 18.46 ± 5.44 .637 Among 38 subjects, duration of OD did not differ significantly between the COVID-19 and the non-COVID-19 group (3.83 ± 3.22 vs. 3.34 ± 2.97, p = .625). According to correlation analysis about various olfactory function and psychologic parameters, the sQOD-NS was negatively correlated with duration of OD with marginal significance (Table 2 ). The correlation analysis between duration of OD and PHQ-9, GAD-7 or PSS-10 did not reach significance. In contrast, sQOD-NS demonstrated a significant correlation with PHQ-9 and GAD-7. The QOD-VAS also exhibited a moderate to high correlation with PHQ-9 and GAD-7, and low correlation with PSS-10. However, the total YOF score showed negligible or no correlation with the psychologic parameters. In the COVID-19 group, a significant negative correlation was observed between the duration of OD and sQOD-NS (Fig. 1 A). In contrast, no such correlation was found in the non-COVID-19 group. The sQOD-NS and PHQ-9 exhibited a significant correlation in both groups (Fig. 1 B), whereas the correlation between sQOD-NS and GAD-7 did not reached the level of significance (Fig. 1 C). Table 2 Spearman’s correlation matrix of olfactory function and psychological variables (n = 38) Variables 1 2 3 4 5 6 7 8 1 Age 1 2 Duration of OD .011 1 3 sQOD-NS − .107 − .318 † 1 4 QOD-VAS .064 .123 − .567 ** 1 5 YOF, total − .205 − .242 − .149 .242 1 6 PHQ-9 .032 − .107 − .539 ** .715 ** .179 1 7 GAD-7 .035 − .242 − .471 ** .644 ** .136 .838 ** 1 8 PSS-10 .093 − .131 − .160 .461 ** .260 .372 * .488 ** 1 † p = .051; * p < .05; **p < .01 OD, olfactory dysfunction; QOD, Questionnaire of Olfactory Disorders; VAS, visual analog scale; sQOD-NS, short version of QOD-negative statements; YOF, YSK olfactory function; PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder 7-item scale; PSS-10, Perceived Stress Scale A mediation model with sQOD-NS as the mediator showed a significant indirect effect (Fig. 2 A; effect size, 0.47; 95% Bootstrap CI [0.10, 1.04]) of duration of OD on PHQ-9 in the whole subject. In the COVID-19 group (n = 20), mediation effects were observed between duration of OD and PHQ-9 score through the sQOD-NS (Fig. 2 B; effect size, 0.30; 95% Bootstrap CI [0.00, 0.92]). However, there was no significant indirect effect of duration of OD on PHQ-9 mediated by the sQOD-NS (Fig. 2 C; effect size, 0.68; 95% Bootstrap CI [-0.24, 1.68]) in the non-COVID-19 group. In the whole subject, an indirect effect of sQOD-NS was also significant in the mediation model using GAD-7 as a dependent variable (Fig. 3 ; effect size, 0.38; 95% Bootstrap CI [0.09, 0.88]). However, no significance of sQOD-NS as a mediator was found in the subgroup analyses the COVID-19 (effect size, 0.23; 95% Bootstrap CI [-0.14, 0.83]) and non-COVID-19 groups (effect size, 0.47; 95% Bootstrap CI [-0.15, 1.24]). Discussion The purpose of the current study was to determine any differences in psychological symptoms between people with post-COVID-19-related OD and non-COVID-19 cases. The comparison of both groups did not demonstrate significant differences in clinical characteristics and symptoms of depression, anxiety and perceived stress, except age and sQOD-NS score. In the COVID-19 group, the sQOD-NS score was found to have a significant negative correlation with the duration of OD whereas the non-COVID-19 group was not. Additionally, significant correlation results between sQOD-NS and PHQ-9 were found in both groups. The mediation analysis demonstrated a significant indirect effect of the duration of OD on PHQ-9 scores via the sQOD-NS scores in the whole subjects and in the COVID-19 group, respectively. The existing literature has identified significant associations between OD and mood symptoms. 9–11,23 The causes of OD were diverse, encompassing a range of conditions, including those related to the SARS-CoV-2 infection, entorhinal diseases, and trauma. However, it is not yet known whether the mechanism of psychological symptoms differs between people who have experienced an OD following COVID-19 and those who have not. To the best of our knowledge, this is the first study to demonstrate that the relevant clinical factors associated with psychological symptoms after the onset of OD may be varied by its etiology. In this study, approximately 70% of patients who reported subjective OD were diagnosed with actual olfactory impairment through psychophysical tests. These inconsistencies between subjective and objective olfactory test results have been reported in a previous study. 24 Compared to the non-COVID-19 group, the COVID-19 group had younger age, and reported less subjective distress (sQOD-NS). In addition, there was no significant difference between groups, in terms of depression, anxiety and stress as well as duration of OD. The present findings differ from those of Stankevice and colleagues, 22 who found that people infected with SARS-CoV-2 had a greater complaint rate for distorted sensation but had a lower prevalence of olfactory abnormalities. The sample size and participant characteristics may have an impact on these findings. On the other hand, the correlation results for sQOD-NS scores demonstrated disparate patterns between groups. In the COVID-19 group, sQOD-NS scores had significant correlation with PHQ-9 scores as well as duration of OD, while non-COVID-19 group did not. These findings demonstrated that despite having less subjective distress, the COVID-19 group displayed a clear pattern of correlation in response to the length of OD and a moderate impact on the severity of depression. However, we could not find signficant correlation between duration of OD and depressive symptoms. Current results are in line with earlier research showing that the depressive symptom was significantly correlated with solely COVID-19 related OD. 25 Furthermore, Liu et al. also reported that QOD-NS score was a strong predictor of the depressive symptom in OD patients, while duration of OD was not. 25 This is also consistent with our findings. In the mediation analyses, there was an significant indirect mediation effect of between duration of OD and PHQ-9 in the entire subject, and also in the COVID-19 group. In contrast, the direct effect of duration of OD on PHQ-9 was not sigificant, had opposite effects to indirect pathway. This pattern of coefficients might indicate a suppressor effect of sQOD-NS. This particular mediational path suggest that, the participants with high sQOD-NS would not have long-term reduction of depressive symptoms. Patients with COVID-19 may have expected that once they had recovered from the symptoms of infection, they would also recover from the resulting loss of smell. However, in some patients, recovery can be markedly delayed, with OD persisting for months or longer after its onset. 26 This discrepancy may influence subjective distress and result in the emergence of additional psychological symptoms. In contrast, this mediating effect was not evident for the non-COVID-19 group, because OD may be a chronic and predictable course of underlying disease in this group. In this study, approximately 70% of patients who reported subjective olfactory impairment were diagnosed with actual olfactory impairment through psychophysical tests. However, the results of this study indicated that subjective olfactory impairment, rather than objective finding is significantly correlated with depressive symptoms among COVID-19 patients. This finding aligns with earlier studies suggesting that the subjectivity of sensory perception might be a crucial factor, potentially even surpassing the significance of the perceptual problem in the groups with post-COVID-19 OD. 27 This highlighted the importance of assessment of mental health problems in individuals with subjective OD after COVID-19 infection. This study has several limitations. First, the study employed self-report scales to assess depression, anxiety, and stress in the participants. However, expert interviews for checking current and past mental illness were not conducted. This raises the possibility that some participants may have had pre-existing mental health issues prior to the onset of OD. Second, this study only focused on patients who visited the hospital with subjective symptoms of OD and did not include an analysis of the population without OD. This may result in a sampling bias. Finally, the mediation analysis was based on patients who clearly recalled the duration of the OD. Some participants were unable to recall the exact time point of their OD, then excluded from the analysis. Therefore, it is recommended that future studies should include a larger number of participants and collect comprehensive data, including the duration of OD and various factors that may influence the mental health outcome. Conclusion In conclusion, we could find a substantial indirect influence of OD duration on PHQ-9 scores via sQOD-NS scores in the COVID-19 group, even though there were no discernible differences between the levels of anxiety, depression, or perceived stress compared with non-COVID-19 group. The results of this study indicate that high subjective distress from OD, even after recovery from COVID-19 symptoms, might have a negative impact on mental health outcomes. Accordingly, it is imperative that we need to endeavor to proactively identify and address subjective distress from patients with OD after COVID-19, adopting an assertive approach to treatment, with the objective of fostering long-term mental health outcomes. Materials and Methods Study population This retrospective cohort study included 52 patients who presented with subjective olfactory dysfunction and visited our tertiary hospital between January 2022 and August 2023. Patients who had already been diagnosed with psychiatric diseases or had other underlying neurological diseases were excluded from this study. Diagnosis of COVID-19 was confirmed by SARS-CoV-2 real-time reverse transcription polymerase chain reaction (RT-PCR) using respiratory samples. And the COVID-19 associated olfactory dysfunction was determined based on the patient's statements. If the patient reported that previously not having any smell-related issues and the onset of olfactory dysfunction after and linked it to their COVID-19 diagnosis, it was regarded as COVID-19-associated olfactory dysfunction (COVID-19 group). In patients with OD which not associated with COVID-19 (non-COVID-19 group), the causes of OD included head trauma (n = 5), brain hemorrhage (n = 1), post-SARS-CoV-2 mRNA vaccination (n = 2), post-upper respiratory infection (n = 2), chronic rhinosinusitis (n = 2), iatrogenic causes (n = 1, anterior skull base surgery for olfactory groove meningioma), and unknown etiologies (n = 13). All participants completed subjective and objective evaluations of their olfaction, and a psychological assessment was conducted using various questionnaires. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of our tertiary Hospital (2023AS0087). Written Informed consent was acquired from all study participants. Evaluation of olfaction We evaluated subjective olfactory function using the Korean version of the Questionnaire of Olfactory Disorders (QOD). 28 Among the subdomains of the QOD questionnaire, we used the QOD-visual analog scale (QOD-VAS) and the short version of QOD-negative statements (sQOD-NS). The Korean version of QOD-VAS comprises five questions with an 11-point scale (0–10), and a higher score indicates poor subjective olfactory function. On the other hand, the Korean version of sQOD-NS consists of seven questions with a 4-point scale (0–3), and a higher score indicates better subjective olfactory function. Objective olfactory function was evaluated using psychophysiological YSK olfactory function (YOF) test. 29 The YOF test consists of three subtests for threshold (T), discrimination (D), and identification (I) using Korean familiar odorants. The YOF subtests had a core range of 1–12 for the threshold test, 0–12 for the discrimination and identification tests, and 1–36 for the total TDI score. The diagnostic cutoff for the YOF test was established as ≤ 14.5 for anosmia and ≤ 21.0 for hyposmia. 29 Evaluation of psychological distress. Various psychological assessments were performed using Korean version of the Patient Health Questionnaire-9 (PHQ-9) for evaluation of depressive mood, Generalized Anxiety Disorder 7-item scale (GAD-7) for evaluation of anxiety and Perceived Stress Scale (PSS-10) for stress level assessment. The PHQ-9 is a self-report questionnaire that was designed for use in primary care settings to efficiently establish psychiatric diagnoses based on DSM-IV criteria. 30 It is composed of 9 items, and respondents are asked to select the degree of their symptoms on a scale of 0 to 3 for each item. The scores are then added up to give a total score out of 27, with a cut-off point of 10 used to indicate the presence of depressive symptoms. The GAD-7 is a self-rated assessment that was developed by Spitzer et al. to screen for generalized anxiety disorder in primary care populations. 31 The GAD-7 is composed of 7 items, and respondents are asked to select the degree of their symptoms on a scale of 0 to 3 for each item with a cut-off point of 9 used to screening for anxiety. 31 The PSS-10 is a self-rated assessment developed by Cohen et al. to assess an individual's overall perception and interpretation of stress experienced during the past month, rather than specific stressful events. 32 The PSS-10 is composed of 10 items, and respondents are asked to select the degree of their symptoms using 5-point Likert scale (0–4). The PSS-10 is not intended for diagnostic purposes, and thus, there is no universally accepted cut-off score for interpreting PSS-10 scores for each item. However, Swaminathan et al. have previously proposed criteria for classifying the degree of perceived stress in patients according to the following standards: low perceived stress (0–13), moderate perceived stress ( 14 – 26 ), and high perceived stress (27–40). Therefore, the present researchers classified the level of stress in patients according to these criteria. Statistics Statistical analysis was conducted using the Statistical Package for the Social Sciences version 21 (IBM Corporation, Armonk, NY, USA). The χ 2 test was used to compare categorical variables, and the independent T test was used to compare continuous variables between patient groups based on their experience of olfactory impairment. Furthermore, Spearman’s correlation coefficient was used to assess the relationship between olfactory assessment and psychological parameters. The magnitude of the correlation coefficient (Spearman’s rho) was interpreted using Hinkle’s suggestion (very high: 0.9 to 1.00; high: 0.7 to 0.9; moderate: 0.5 to 0.7; low: 0.3 to 0.5; negligible correlation: 0 to 0.3). In addition, we examined the relationship between duration of OD, sQOD-NS and mood symptoms (depression, and anxiety), which showed significant correlation findings with each other. Individuals who were unable to recall the duration of OD were excluded from further analysis, resulting in a total of 38 participants (20 in the COVID-19 group and 18 in the non-COVID-19 group) being included in the mediation analysis. We postulated that longer duration of OD may increase the severity of mood symptoms (direct effect), and sQOD-NS may serve as a mediating factor between duration of OD and mood symptoms (indirect effect). We performed mediation analyses using the SPSS PROCESS macro 33 with model 4 (single mediator model). The validity of mediation model was examined in three groups: the whole participant, the COVID-19 group, and the non-COVID-19 group. Using bootstrapping, 95% bias-corrected bootstrap confidence intervals [CI] for the indirect effects based on 5,000 bootstrap resamples were calculated. Declarations Competing interests The authors have no potential conflicts of interest to disclose. Author Contribution J.H.Y. and M.Y.S. analyzed the data and wrote the paper. T-S.K. and S.H.L. designed the study and wrote the paper. J.H.Y. and M.Y.S. collected the data. J.S.K., T-S.K. and M.Y.S. reviewed and revised the paper. Acknowledgement This study was supported by Korean University Ansan Hospital Grant (O2310621). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C0619). 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L., Kroenke, K. & Williams, J. B. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 282, 1737–1744, doi: 10.1001/jama.282.18.1737 (1999). Spitzer, R. L., Kroenke, K., Williams, J. B. & Lowe, B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 166, 1092–1097, doi: 10.1001/archinte.166.10.1092 (2006). Cohen, S. Perceived stress in a probability sample of the United States. (1988). Hayes, A. F. PROCESS: A versatile computational tool for observed variable mediation, moderation, and conditional process modeling. Retrieved from http://www.afhayes.com/public/process2012.pdf PROCESS . https://doi.org/978-1-60918-230-4 (2012). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 10 Feb, 2025 Reviews received at journal 30 Jan, 2025 Reviewers agreed at journal 28 Jan, 2025 Reviewers agreed at journal 21 Dec, 2024 Reviews received at journal 16 Dec, 2024 Reviewers agreed at journal 12 Dec, 2024 Reviews received at journal 26 Aug, 2024 Reviewers agreed at journal 14 Aug, 2024 Reviewers invited by journal 27 Jul, 2024 Editor assigned by journal 27 Jul, 2024 Editor invited by journal 25 Jun, 2024 Submission checks completed at journal 24 Jun, 2024 First submitted to journal 21 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4617956","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":326404829,"identity":"84613cf8-db91-4794-9bf4-839d2a4d2fa4","order_by":0,"name":"Jae Hyun Yoo","email":"","orcid":"","institution":"The Catholic University of Korea","correspondingAuthor":false,"prefix":"","firstName":"Jae","middleName":"Hyun","lastName":"Yoo","suffix":""},{"id":326404830,"identity":"1fb12514-b7ec-488f-bcde-f23bc74e90e0","order_by":1,"name":"Tae-Suk Kim","email":"","orcid":"","institution":"The Catholic University of Korea","correspondingAuthor":false,"prefix":"","firstName":"Tae-Suk","middleName":"","lastName":"Kim","suffix":""},{"id":326404833,"identity":"2637624c-4011-450c-a809-8f4dd531f166","order_by":2,"name":"Ji Sun Kim","email":"","orcid":"","institution":"Soonchunhyang University Cheonan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ji","middleName":"Sun","lastName":"Kim","suffix":""},{"id":326404835,"identity":"d6011bbb-c056-453f-ad34-c7063bb71e1a","order_by":3,"name":"Seung Hoon Lee","email":"","orcid":"","institution":"Korea University College of Medicine, Korea University Ansan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seung","middleName":"Hoon","lastName":"Lee","suffix":""},{"id":326404838,"identity":"a0e65689-3e54-4ec3-8a22-b806b51cb923","order_by":4,"name":"Min Young Seo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDACCSBOALOYD4C4MqRoYQNREjzEaYEAHgMwSVAH/+zmZx8e/LGR020/8/nVjRoLHgb2w0c34LXkzjHjGYltacZmZ3K3WeccAzqMJy3tBj4tBhIJxgyJDYcTtx3I3WacwwbUIsFjRkBL+meGhD//E7edf/PMOOcfUVpyjBkS2A4kbruRw/w4t40ILRI3cooZEtuSjc1uPDNjzu2T4GEj5Bf+GembGX/8sZMzO5/8+HPOtzo5fvbDx/BqQQZs4DhiI1Y5CDB/IEX1KBgFo2AUjBwAABPeR4eZqC5VAAAAAElFTkSuQmCC","orcid":"","institution":"Korea University College of Medicine, Korea University Ansan Hospital","correspondingAuthor":true,"prefix":"","firstName":"Min","middleName":"Young","lastName":"Seo","suffix":""}],"badges":[],"createdAt":"2024-06-21 14:23:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4617956/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4617956/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-07953-z","type":"published","date":"2025-07-01T15:58:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60625618,"identity":"d6739d4e-9cb5-4d8d-af82-a8048de6ca38","added_by":"auto","created_at":"2024-07-18 22:25:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":210860,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between sQOD-NS scores, and clinical and psychological variables in subjects with olfactory dysfunction (OD).\u003c/p\u003e\n\u003cp\u003eA scatter plot between (A) sQOD-NS and duration of OD, (B) sQOD-NS and PHQ-9 total score, and (C) sQOD-NS and GAD-7 total score\u003c/p\u003e","description":"","filename":"Figure1SMYOD1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4617956/v1/9047910f070227aa01508ede.jpg"},{"id":60625609,"identity":"e8054c44-eb28-48f2-8de5-ffa17c4c167f","added_by":"auto","created_at":"2024-07-18 22:25:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":294957,"visible":true,"origin":"","legend":"\u003cp\u003eStandardized regression coefficients for the sQOD-NS-mediated association between the duration of olfactory dysfunction and PHQ-9 total score\u003c/p\u003e\n\u003cp\u003e(A) Entire subjects (n=38), (B) COVID-19 group (20 subjects), (C) Non-COVID-19 group (18 subjects) Notes: *p \u0026lt; .05, **p \u0026lt; .01, ***p \u0026lt; .001, \u003csup\u003e† \u003c/sup\u003ep =.054,\u0026nbsp; ; All presented effects are unstandardized; Path a is effect of duration of OD on mediators; Path b is effect of mediators on PHQ-9; Path c’ is direct effect of duration of OD on PHQ-9; Path c is total effect of OD on PHQ-9\u003c/p\u003e","description":"","filename":"Figure2SMYOD1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4617956/v1/68ff7d6f6ec2e63ea850c922.jpg"},{"id":60625607,"identity":"e6d9c582-b6a4-49ba-a629-2daf53229331","added_by":"auto","created_at":"2024-07-18 22:25:14","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":71524,"visible":true,"origin":"","legend":"\u003cp\u003eStandardized regression coefficients for the sQOD-NS-mediated association between the duration of olfactory dysfunction and GAD-7 total score \u0026nbsp;in the entire subject (n=38)\u003c/p\u003e\n\u003cp\u003eNotes: *p \u0026lt; .05, **p \u0026lt; .01; All presented effects are unstandardized; Path a is effect of duration of OD on mediators; Path b is effect of mediators on GAD-7; Path c’ is direct effect of duration of OD on GAD-7; Path c is total effect of OD on GAD-7\u003c/p\u003e","description":"","filename":"Figure3SMYOD1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4617956/v1/59de5d39d19013fd46cf8b15.jpg"},{"id":86179132,"identity":"f9af4e07-0765-42c6-8c4c-1609f1a7a26e","added_by":"auto","created_at":"2025-07-07 16:16:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1173955,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4617956/v1/8c6d0f37-5ee3-46ff-930b-ccc988081403.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Psychological Impact and Clinical Correlates of Olfactory Dysfunction in Post- COVID-19 and Non-COVID-19 Patients: A Comparative Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOlfactory dysfunction (OD) refers to a range of conditions involving impaired sense of smell, including anosmia (complete loss of smell) and hyposmia (reduced ability to smell).\u003csup\u003e1\u003c/sup\u003e OD can occur due to a variety of causes, including rhinosinusitis with or without nasal polyps, post viral infections, head trauma, toxic material exposure, and congenital disorders.\u003csup\u003e2,3\u003c/sup\u003e In recent years, the prevalent of OD has been increased due to the COVID-19 pandemic, with many patients experiencing a decrease in their sense of smell following infection.\u003csup\u003e4,5\u003c/sup\u003e The prevalence of OD following COVID-19 pandemic has been reported to range from approximately 10\u0026ndash;55%, depending on race.\u003csup\u003e6\u003c/sup\u003e COVID-19 related OD often appears on the third day following infection and goes away entirely in 4\u0026ndash;6 weeks. But these changes can last longer than four months in 27% of cases\u003csup\u003e7\u003c/sup\u003e and up to a year in 21.3% of cases.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAccording to Yom-Tov et al., COVID-19 patients with OD had a 30% higher incidence of depression and suicidal ideation than those without OD.\u003csup\u003e9\u003c/sup\u003e A online survey conducted by Coelho et al. on 322 OD subjects following COVID-19 infection also found that symptoms depression were present in 43% of participants.\u003csup\u003e10\u003c/sup\u003e Additionally, COVID-19 patients with OD reported higher anxiety levels.\u003csup\u003e11\u003c/sup\u003e These results suggested a correlation between neuropsychiatric symptoms and OD, and the pivotal role of COVID-19 infection in long term mental health outcome.\u003c/p\u003e \u003cp\u003ePrevious studies have proposed several hypothesized mechanisms for the development of neuropsychiatric symptoms in COVID-19 related OD. It has been demonstrated that SARS-CoV-2 can cause damage to the central nervous system.\u003csup\u003e12,13\u003c/sup\u003e Postmortem examination of brain tissues from patients with COVID-19 revealed the presence of neuroinflammation, microglia activation, and neuronal death.\u003csup\u003e14,15\u003c/sup\u003e Neuroinflammation can persist long after the acute phase of the disease, sometimes referred to as long COVID.\u003csup\u003e16\u003c/sup\u003e According to Stefanou et al., over one-third of patients experienced brain fog, cognitive dysfunction, changes in gustation and smell, and psychiatric manifestations like mood disorders as long COVID symptoms.\u003csup\u003e13\u003c/sup\u003e This phenomenon is thought to be likely caused by persistent systemic inflammation and the existence of viral RNA in the brains of COVID-19 patients after an extended length of time.\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the psychosocial perspectives, OD can cause problems in various emotional aspects of human life. The inability to smell can lead to a loss of pleasure from activities that were once enjoyed, such as eating and socializing, and this can cause significant psychological distress to the affected person.\u003csup\u003e18,19\u003c/sup\u003e Several lines of evidence demonstrate a significant association between OD and depression, anxiety, and feelings of isolation, which can further exacerbate one's quality of life (QoL).\u003csup\u003e19\u0026ndash;21\u003c/sup\u003e In a study long COVID, distortion of smell was more prevalent in young people, and negative QoL were more common in people with a post-COVID-19 infection than in other post-infection cases.\u003csup\u003e22\u003c/sup\u003e Therefore, OD following COVID-19 also can elicit profound negative impact on psychological well-being and require clinical attention.\u003c/p\u003e \u003cp\u003eHowever, it is not yet clear why the prevalence of psychological symptoms is higher in patients with COVID-19-related OD compared to OD due to other etiologies, such as chronic entorhinal inflammation or trauma. To date, no studies have been conducted to compare the stress level, symptoms of depression and anxiety followed by OD related with COVID-19 infection and that resulted from other etiologies. Furthermore, clinical factors that influence mood symptoms in the long COVID population remain poorly understood.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to compare the olfactory function and emotional state of two groups: those who experienced OD due to COVID-19 infection and those who experienced long-term olfactory loss due to chronic entorhinal disease. Additionally, we investigated the potential associations among the duration of OD, subjective distress, and mood symptoms such as depression and anxiety using mediation analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe demographics of the patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of the participants was approximately 44 years old, with the COVID-19 group being significantly younger than the non-COVID-19 group. Among the 52 participants with subjective olfactory loss approximately 71% were confirmed to have OD according to psychophysical test results. The subjective and objective olfactory parameters did not differ significantly between the COVID-19 and non-COVID-19 groups except QOD-NS total score (11.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.05 vs 7.81\u0026thinsp;\u0026plusmn;\u0026thinsp;5.47, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.030). Based on the cut-off of each psychological measure, 38.5% of the participants were considered to have depressive symptoms (20/52), and 21.2% of participants were considered to have moderate to severe anxiety (11/52). Furthermore, 78.8% of participants were considered to have moderate to severe perceived stress (41/52).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographics of the participants. QOD, Questionnaire of Olfactory Disorders; VAS, visual analog scale; sQOD-NS, short version of QOD-negative statements; YOF, YSK olfactory function; PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder 7-item scale; PSS-10, Perceived Stress Scale\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCOVID-19\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-COVID-19\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (year-old)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e44.21\u0026thinsp;\u0026plusmn;\u0026thinsp;18.24\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e39.23\u0026thinsp;\u0026plusmn;\u0026thinsp;16.12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e49.19\u0026thinsp;\u0026plusmn;\u0026thinsp;19.16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e.048\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.781\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003esQOD-NS total score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e9.44\u0026thinsp;\u0026plusmn;\u0026thinsp;5.47\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e11.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e7.81\u0026thinsp;\u0026plusmn;\u0026thinsp;5.47\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e.030\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQOD-VAS total score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.31\u0026thinsp;\u0026plusmn;\u0026thinsp;11.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.85\u0026thinsp;\u0026plusmn;\u0026thinsp;9.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.77\u0026thinsp;\u0026plusmn;\u0026thinsp;12.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.772\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYOF total score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.91\u0026thinsp;\u0026plusmn;\u0026thinsp;7.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.99\u0026thinsp;\u0026plusmn;\u0026thinsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.84\u0026thinsp;\u0026plusmn;\u0026thinsp;7.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.303\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with objective OD (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.760\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePHQ-9 score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.23\u0026thinsp;\u0026plusmn;\u0026thinsp;6.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.27\u0026thinsp;\u0026plusmn;\u0026thinsp;6.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.19\u0026thinsp;\u0026plusmn;\u0026thinsp;7.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.310\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGAD-7 score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.24\u0026thinsp;\u0026plusmn;\u0026thinsp;5.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.79\u0026thinsp;\u0026plusmn;\u0026thinsp;5.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.64\u0026thinsp;\u0026plusmn;\u0026thinsp;5.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSS-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.04\u0026thinsp;\u0026plusmn;\u0026thinsp;6.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.58\u0026thinsp;\u0026plusmn;\u0026thinsp;7.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.46\u0026thinsp;\u0026plusmn;\u0026thinsp;5.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.637\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong 38 subjects, duration of OD did not differ significantly between the COVID-19 and the non-COVID-19 group (3.83\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22 vs. 3.34\u0026thinsp;\u0026plusmn;\u0026thinsp;2.97, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.625). According to correlation analysis about various olfactory function and psychologic parameters, the sQOD-NS was negatively correlated with duration of OD with marginal significance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The correlation analysis between duration of OD and PHQ-9, GAD-7 or PSS-10 did not reach significance. In contrast, sQOD-NS demonstrated a significant correlation with PHQ-9 and GAD-7. The QOD-VAS also exhibited a moderate to high correlation with PHQ-9 and GAD-7, and low correlation with PSS-10. However, the total YOF score showed negligible or no correlation with the psychologic parameters. In the COVID-19 group, a significant negative correlation was observed between the duration of OD and sQOD-NS (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). In contrast, no such correlation was found in the non-COVID-19 group. The sQOD-NS and PHQ-9 exhibited a significant correlation in both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), whereas the correlation between sQOD-NS and GAD-7 did not reached the level of significance (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpearman\u0026rsquo;s correlation matrix of olfactory function and psychological variables (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDuration of OD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esQOD-NS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.318\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQOD-VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.567\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYOF, total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePHQ-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.539\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.715\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGAD-7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.471\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.644\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.838\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePSS-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.461\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.372\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e.488\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u0026dagger; p\u0026thinsp;=\u0026thinsp;.051; * p\u0026thinsp;\u0026lt;\u0026thinsp;.05; **p\u0026thinsp;\u0026lt;\u0026thinsp;.01\u003c/p\u003e \u003cp\u003eOD, olfactory dysfunction; QOD, Questionnaire of Olfactory Disorders; VAS, visual analog scale; sQOD-NS, short version of QOD-negative statements; YOF, YSK olfactory function; PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder 7-item scale; PSS-10, Perceived Stress Scale\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA mediation model with sQOD-NS as the mediator showed a significant indirect effect (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA; effect size, 0.47; 95% Bootstrap CI [0.10, 1.04]) of duration of OD on PHQ-9 in the whole subject. In the COVID-19 group (n\u0026thinsp;=\u0026thinsp;20), mediation effects were observed between duration of OD and PHQ-9 score through the sQOD-NS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB; effect size, 0.30; 95% Bootstrap CI [0.00, 0.92]). However, there was no significant indirect effect of duration of OD on PHQ-9 mediated by the sQOD-NS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC; effect size, 0.68; 95% Bootstrap CI [-0.24, 1.68]) in the non-COVID-19 group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the whole subject, an indirect effect of sQOD-NS was also significant in the mediation model using GAD-7 as a dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; effect size, 0.38; 95% Bootstrap CI [0.09, 0.88]). However, no significance of sQOD-NS as a mediator was found in the subgroup analyses the COVID-19 (effect size, 0.23; 95% Bootstrap CI [-0.14, 0.83]) and non-COVID-19 groups (effect size, 0.47; 95% Bootstrap CI [-0.15, 1.24]).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe purpose of the current study was to determine any differences in psychological symptoms between people with post-COVID-19-related OD and non-COVID-19 cases. The comparison of both groups did not demonstrate significant differences in clinical characteristics and symptoms of depression, anxiety and perceived stress, except age and sQOD-NS score. In the COVID-19 group, the sQOD-NS score was found to have a significant negative correlation with the duration of OD whereas the non-COVID-19 group was not. Additionally, significant correlation results between sQOD-NS and PHQ-9 were found in both groups. The mediation analysis demonstrated a significant indirect effect of the duration of OD on PHQ-9 scores via the sQOD-NS scores in the whole subjects and in the COVID-19 group, respectively.\u003c/p\u003e \u003cp\u003eThe existing literature has identified significant associations between OD and mood symptoms.\u003csup\u003e9\u0026ndash;11,23\u003c/sup\u003e The causes of OD were diverse, encompassing a range of conditions, including those related to the SARS-CoV-2 infection, entorhinal diseases, and trauma. However, it is not yet known whether the mechanism of psychological symptoms differs between people who have experienced an OD following COVID-19 and those who have not. To the best of our knowledge, this is the first study to demonstrate that the relevant clinical factors associated with psychological symptoms after the onset of OD may be varied by its etiology.\u003c/p\u003e \u003cp\u003eIn this study, approximately 70% of patients who reported subjective OD were diagnosed with actual olfactory impairment through psychophysical tests. These inconsistencies between subjective and objective olfactory test results have been reported in a previous study.\u003csup\u003e24\u003c/sup\u003e Compared to the non-COVID-19 group, the COVID-19 group had younger age, and reported less subjective distress (sQOD-NS). In addition, there was no significant difference between groups, in terms of depression, anxiety and stress as well as duration of OD. The present findings differ from those of Stankevice and colleagues,\u003csup\u003e22\u003c/sup\u003e who found that people infected with SARS-CoV-2 had a greater complaint rate for distorted sensation but had a lower prevalence of olfactory abnormalities. The sample size and participant characteristics may have an impact on these findings.\u003c/p\u003e \u003cp\u003eOn the other hand, the correlation results for sQOD-NS scores demonstrated disparate patterns between groups. In the COVID-19 group, sQOD-NS scores had significant correlation with PHQ-9 scores as well as duration of OD, while non-COVID-19 group did not. These findings demonstrated that despite having less subjective distress, the COVID-19 group displayed a clear pattern of correlation in response to the length of OD and a moderate impact on the severity of depression. However, we could not find signficant correlation between duration of OD and depressive symptoms. Current results are in line with earlier research showing that the depressive symptom was significantly correlated with solely COVID-19 related OD.\u003csup\u003e25\u003c/sup\u003e Furthermore, Liu et al. also reported that QOD-NS score was a strong predictor of the depressive symptom in OD patients, while duration of OD was not.\u003csup\u003e25\u003c/sup\u003e This is also consistent with our findings.\u003c/p\u003e \u003cp\u003eIn the mediation analyses, there was an significant indirect mediation effect of between duration of OD and PHQ-9 in the entire subject, and also in the COVID-19 group. In contrast, the direct effect of duration of OD on PHQ-9 was not sigificant, had opposite effects to indirect pathway. This pattern of coefficients might indicate a suppressor effect of sQOD-NS. This particular mediational path suggest that, the participants with high sQOD-NS would not have long-term reduction of depressive symptoms. Patients with COVID-19 may have expected that once they had recovered from the symptoms of infection, they would also recover from the resulting loss of smell. However, in some patients, recovery can be markedly delayed, with OD persisting for months or longer after its onset.\u003csup\u003e26\u003c/sup\u003e This discrepancy may influence subjective distress and result in the emergence of additional psychological symptoms. In contrast, this mediating effect was not evident for the non-COVID-19 group, because OD may be a chronic and predictable course of underlying disease in this group.\u003c/p\u003e \u003cp\u003eIn this study, approximately 70% of patients who reported subjective olfactory impairment were diagnosed with actual olfactory impairment through psychophysical tests. However, the results of this study indicated that subjective olfactory impairment, rather than objective finding is significantly correlated with depressive symptoms among COVID-19 patients. This finding aligns with earlier studies suggesting that the subjectivity of sensory perception might be a crucial factor, potentially even surpassing the significance of the perceptual problem in the groups with post-COVID-19 OD.\u003csup\u003e27\u003c/sup\u003e This highlighted the importance of assessment of mental health problems in individuals with subjective OD after COVID-19 infection.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the study employed self-report scales to assess depression, anxiety, and stress in the participants. However, expert interviews for checking current and past mental illness were not conducted. This raises the possibility that some participants may have had pre-existing mental health issues prior to the onset of OD. Second, this study only focused on patients who visited the hospital with subjective symptoms of OD and did not include an analysis of the population without OD. This may result in a sampling bias. Finally, the mediation analysis was based on patients who clearly recalled the duration of the OD. Some participants were unable to recall the exact time point of their OD, then excluded from the analysis. Therefore, it is recommended that future studies should include a larger number of participants and collect comprehensive data, including the duration of OD and various factors that may influence the mental health outcome.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, we could find a substantial indirect influence of OD duration on PHQ-9 scores via sQOD-NS scores in the COVID-19 group, even though there were no discernible differences between the levels of anxiety, depression, or perceived stress compared with non-COVID-19 group. The results of this study indicate that high subjective distress from OD, even after recovery from COVID-19 symptoms, might have a negative impact on mental health outcomes. Accordingly, it is imperative that we need to endeavor to proactively identify and address subjective distress from patients with OD after COVID-19, adopting an assertive approach to treatment, with the objective of fostering long-term mental health outcomes.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study included 52 patients who presented with subjective olfactory dysfunction and visited our tertiary hospital between January 2022 and August 2023. Patients who had already been diagnosed with psychiatric diseases or had other underlying neurological diseases were excluded from this study. Diagnosis of COVID-19 was confirmed by SARS-CoV-2 real-time reverse transcription polymerase chain reaction (RT-PCR) using respiratory samples. And the COVID-19 associated olfactory dysfunction was determined based on the patient's statements. If the patient reported that previously not having any smell-related issues and the onset of olfactory dysfunction after and linked it to their COVID-19 diagnosis, it was regarded as COVID-19-associated olfactory dysfunction (COVID-19 group). In patients with OD which not associated with COVID-19 (non-COVID-19 group), the causes of OD included head trauma (n\u0026thinsp;=\u0026thinsp;5), brain hemorrhage (n\u0026thinsp;=\u0026thinsp;1), post-SARS-CoV-2 mRNA vaccination (n\u0026thinsp;=\u0026thinsp;2), post-upper respiratory infection (n\u0026thinsp;=\u0026thinsp;2), chronic rhinosinusitis (n\u0026thinsp;=\u0026thinsp;2), iatrogenic causes (n\u0026thinsp;=\u0026thinsp;1, anterior skull base surgery for olfactory groove meningioma), and unknown etiologies (n\u0026thinsp;=\u0026thinsp;13). All participants completed subjective and objective evaluations of their olfaction, and a psychological assessment was conducted using various questionnaires. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of our tertiary Hospital (2023AS0087). Written Informed consent was acquired from all study participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of olfaction\u003c/h2\u003e \u003cp\u003eWe evaluated subjective olfactory function using the Korean version of the Questionnaire of Olfactory Disorders (QOD).\u003csup\u003e28\u003c/sup\u003e Among the subdomains of the QOD questionnaire, we used the QOD-visual analog scale (QOD-VAS) and the short version of QOD-negative statements (sQOD-NS). The Korean version of QOD-VAS comprises five questions with an 11-point scale (0\u0026ndash;10), and a higher score indicates poor subjective olfactory function. On the other hand, the Korean version of sQOD-NS consists of seven questions with a 4-point scale (0\u0026ndash;3), and a higher score indicates better subjective olfactory function. Objective olfactory function was evaluated using psychophysiological YSK olfactory function (YOF) test.\u003csup\u003e29\u003c/sup\u003e The YOF test consists of three subtests for threshold (T), discrimination (D), and identification (I) using Korean familiar odorants. The YOF subtests had a core range of 1\u0026ndash;12 for the threshold test, 0\u0026ndash;12 for the discrimination and identification tests, and 1\u0026ndash;36 for the total TDI score. The diagnostic cutoff for the YOF test was established as \u0026le;\u0026thinsp;14.5 for anosmia and \u0026le;\u0026thinsp;21.0 for hyposmia.\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eEvaluation of psychological distress.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eVarious psychological assessments were performed using Korean version of the Patient Health Questionnaire-9 (PHQ-9) for evaluation of depressive mood, Generalized Anxiety Disorder 7-item scale (GAD-7) for evaluation of anxiety and Perceived Stress Scale (PSS-10) for stress level assessment.\u003c/p\u003e \u003cp\u003eThe PHQ-9 is a self-report questionnaire that was designed for use in primary care settings to efficiently establish psychiatric diagnoses based on DSM-IV criteria.\u003csup\u003e30\u003c/sup\u003e It is composed of 9 items, and respondents are asked to select the degree of their symptoms on a scale of 0 to 3 for each item. The scores are then added up to give a total score out of 27, with a cut-off point of 10 used to indicate the presence of depressive symptoms.\u003c/p\u003e \u003cp\u003eThe GAD-7 is a self-rated assessment that was developed by Spitzer et al. to screen for generalized anxiety disorder in primary care populations.\u003csup\u003e31\u003c/sup\u003e The GAD-7 is composed of 7 items, and respondents are asked to select the degree of their symptoms on a scale of 0 to 3 for each item with a cut-off point of 9 used to screening for anxiety.\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe PSS-10 is a self-rated assessment developed by Cohen et al. to assess an individual's overall perception and interpretation of stress experienced during the past month, rather than specific stressful events.\u003csup\u003e32\u003c/sup\u003e The PSS-10 is composed of 10 items, and respondents are asked to select the degree of their symptoms using 5-point Likert scale (0\u0026ndash;4). The PSS-10 is not intended for diagnostic purposes, and thus, there is no universally accepted cut-off score for interpreting PSS-10 scores for each item. However, Swaminathan et al. have previously proposed criteria for classifying the degree of perceived stress in patients according to the following standards: low perceived stress (0\u0026ndash;13), moderate perceived stress (\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and high perceived stress (27\u0026ndash;40). Therefore, the present researchers classified the level of stress in patients according to these criteria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted using the Statistical Package for the Social Sciences version 21 (IBM Corporation, Armonk, NY, USA). The χ\u003csup\u003e2\u003c/sup\u003e test was used to compare categorical variables, and the independent T test was used to compare continuous variables between patient groups based on their experience of olfactory impairment. Furthermore, Spearman\u0026rsquo;s correlation coefficient was used to assess the relationship between olfactory assessment and psychological parameters. The magnitude of the correlation coefficient (Spearman\u0026rsquo;s rho) was interpreted using Hinkle\u0026rsquo;s suggestion (very high: 0.9 to 1.00; high: 0.7 to 0.9; moderate: 0.5 to 0.7; low: 0.3 to 0.5; negligible correlation: 0 to 0.3).\u003c/p\u003e \u003cp\u003eIn addition, we examined the relationship between duration of OD, sQOD-NS and mood symptoms (depression, and anxiety), which showed significant correlation findings with each other. Individuals who were unable to recall the duration of OD were excluded from further analysis, resulting in a total of 38 participants (20 in the COVID-19 group and 18 in the non-COVID-19 group) being included in the mediation analysis.\u003c/p\u003e \u003cp\u003eWe postulated that longer duration of OD may increase the severity of mood symptoms (direct effect), and sQOD-NS may serve as a mediating factor between duration of OD and mood symptoms (indirect effect). We performed mediation analyses using the SPSS PROCESS macro\u003csup\u003e33\u003c/sup\u003e with model 4 (single mediator model). The validity of mediation model was examined in three groups: the whole participant, the COVID-19 group, and the non-COVID-19 group. Using bootstrapping, 95% bias-corrected bootstrap confidence intervals [CI] for the indirect effects based on 5,000 bootstrap resamples were calculated.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors have no potential conflicts of interest to disclose.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.H.Y. and M.Y.S. analyzed the data and wrote the paper. T-S.K. and S.H.L. designed the study and wrote the paper. J.H.Y. and M.Y.S. collected the data. J.S.K., T-S.K. and M.Y.S. reviewed and revised the paper.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003eThis study was supported by Korean University Ansan Hospital Grant (O2310621). This research was also supported by a grant of the Korea Health Technology R\u0026amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health \u0026amp; Welfare, Republic of Korea (grant number: HI22C0619).\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to information that could compromise the privacy of research participants but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHummel, T. \u003cem\u003eet al.\u003c/em\u003e Olfactory Dysfunction: Etiology, Diagnosis, and Treatment. 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Retrieved from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.afhayes.com/public/process2012.pdf PROCESS\u003c/span\u003e\u003cspan address=\"http://www.afhayes.com/public/process2012.pdf PROCESS\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. https://doi.org/978-1-60918-230-4 (2012).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Olfaction Disorders, COVID-19, Depressive Disorder, Anxiety Disorders, Psychological distress","lastPublishedDoi":"10.21203/rs.3.rs-4617956/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4617956/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOlfactory dysfunction (OD) has been reported in individuals who have recovered from COVID-19. Those with OD after COVID-19 (COVID-19 group) exhibited more severe psychiatric symptoms than those with OD from other etiologies (non-COVID-19 group). This study aimed to investigate the differences in psychological symptoms and related clinical factors between the two groups.\u003c/p\u003e \u003cp\u003eFifty-two participants (26 COVID-19 group; 26 non-COVID-19 group) were recruited. Both objective and subjective olfactory function were assessed. Symptoms of depression, anxiety, and perceived stress were measured using self-report scales.\u003c/p\u003e \u003cp\u003eThere were no significant differences in objective and subjective olfactory function or psychological symptoms between the groups, except for age and the short version of the Questionnaire of Olfactory Disorders-negative statements (sQOD-NS). The sQOD-NS score was negatively correlated with the duration of OD only in the COVID-19 group. Both groups showed significant correlations between the sQOD-NS and the Patient Health Questionnaire-9 (PHQ-9) scores. Mediation analysis showed that the duration of OD indirectly affected PHQ-9 scores via sQOD-NS in the entire sample and particularly in the COVID-19 group.\u003c/p\u003e \u003cp\u003eThe findings suggest that subjective distress from OD may mediate the relationship between duration of OD and depressive symptoms in COVID-19 patients, highlighting the need for targeted psychiatric interventions after COVID-19.\u003c/p\u003e","manuscriptTitle":"Psychological Impact and Clinical Correlates of Olfactory Dysfunction in Post- COVID-19 and Non-COVID-19 Patients: A Comparative Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 22:25:08","doi":"10.21203/rs.3.rs-4617956/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-10T07:08:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-30T17:21:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"265610162039861357414145969116846552248","date":"2025-01-28T18:05:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296903586055021759612536878477934046819","date":"2024-12-21T10:16:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-16T14:16:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63794345471963848169193804299055041657","date":"2024-12-12T22:16:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-26T17:58:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"45662758089429648225056922801675080467","date":"2024-08-14T07:35:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-27T11:39:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-27T11:38:21+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-25T12:17:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-24T11:48:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-21T14:22:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f6135672-cb48-4c85-91ec-6b0598bdd2f7","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34540466,"name":"Biological sciences/Neuroscience"},{"id":34540467,"name":"Health sciences/Medical research"},{"id":34540468,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-07-07T16:05:29+00:00","versionOfRecord":{"articleIdentity":"rs-4617956","link":"https://doi.org/10.1038/s41598-025-07953-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-01 15:58:12","publishedOnDateReadable":"July 1st, 2025"},"versionCreatedAt":"2024-07-18 22:25:08","video":"","vorDoi":"10.1038/s41598-025-07953-z","vorDoiUrl":"https://doi.org/10.1038/s41598-025-07953-z","workflowStages":[]},"version":"v1","identity":"rs-4617956","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4617956","identity":"rs-4617956","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}