2025 JORL-HNS临床实践指南：嗅觉功能障碍的管理（概要）

ARTICLE INFO

Keywords: Clinical practice guideline Olfactory dysfunction Important clinical issue Clinical question Evidence Recommendation

ABSTRACT

The aim of the 'Summary of Japanese Clinical Practice Guidelines 2025 for the Management of Olfactory Dysfunction is to review the latest evidence regarding olfactory dysfunction and to present the current standard approaches for diagnosis and treatment. For the present guidelines, the Clinical Practice Guideline Committee, which is composed of otorhinolaryngologists, neurologists and oncologists with extensive experience treating patients with olfactory dysfunction, was formed by the Japanese Rhinologic Society. The Committee revised and updated the 'Clinical Practice Guidelines for the Management of Olfactory Dysfunction 2019 Edition'. Following a public comment period, the guidelines underwent external evaluation through peer review by the Scientific Committee of the Japanese Society of Otorhinolaryngology-Head and Neck Surgery. A total of 16 clinical questions consisting of three categories (diagnosis, treatment, and neurodegenerative diseases associated with

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dementia), are comprehensively described. These evidence-based recommendations were compiled with the consensus of the Guideline Committee.

1. Guideline objects

The pathophysiology of olfactory dysfunction (OD) is still unknown in many respects, and diagnostic and therapeutic methods have not yet been fully established, which often leads to difficulties in daily practice. For this reason, the Japanese Rhinologic Society (hereinafter referred to as 'the JRS') published the Clinical Practice Guidelines for the Management of Olfactory Dysfunction (the first edition) in Japanese version in 2017 followed by English version as secondary publication in 2019 [1]. The first edition of the guideline provides an overview of OD, including definition, classification, epidemiology, age-related changes, diagnosis, and pathophysiology of each causative disease, as well as eight clinical questions (CQs) to evaluate the evidence. Following the publication of these guidelines, the treatment of OD has become standardized in clinical practice in Japan.

Several years have passed since the first edition of the guideline was published. For these years, the number of patients with an intractable chronic rhinosinusitis (CRS), eosinophilic chronic rhinosinusitis (ECRS), has increased, and new concept of OD caused by coronavirus disease 2019 (COVID-19) have emerged. In terms of treatment, biologics for type 2 inflammation and olfactory training (OT) for sensorineural and central OD have also emerged and developed. Therefore, in the present guideline as second edition in English version, duplication with the first edition was avoided as much as possible, new conditions that have emerged or been clarified were described, the clinical questions (CQs) were reorganized from the first edition, and level of evidence and strength of recommendations including more recent papers were determined [2]. We referred to the suggestions in the 'Minds Clinical Practice Guideline Development Manual 2020'.

The aim of the 'Summary of Japanese Clinical Practice Guidelines 2025 for the Management of Olfactory Dysfunction' is to review the latest evidence regarding olfactory dysfunction and to present the current standard approaches for diagnosis and treatment.

2. Users

The target clinician for this guideline is anyone who engages in the medical management of OD.

3. Subjects and diseases covered

The target subjects for this guideline are adults and children with a diagnosis of OD. All causative diseases of OD were taken into account in the guidelines, especially ECRS, allergic rhinitis, upper respiratory viral infection, COVID-19, trauma, and neurodegenerative diseases and dementia.

4. Responsibilities of society

The description and contents of these guidelines are the responsibility of the JRS. However, the responsibility for the treatment results should be attributed to the treatment of medical personnel, and the JRS shall not be held responsible.

5. Committee

Members of the subcommittee of the Japanese Clinical Practice Guideline for the management of OD (hereinafter referred to as ‘the Guideline Committee’) are composed of otorhinolaryngologists in the JRS and physicians (neurologists and oncologist).

6. Literature review process

The Guideline Committee raised 16 clinical questions (CQs) regarding the management of OD. To develop the strength of recommendation based on level of evidence for these CQs, systematic reviews (SR) were performed by 14th to 25th authors. The specific procedure for the literature search was as follows.

The committee members selected keywords and major papers related to the CQs. The main search domain terms included smell disorder, olfactory dysfunction, olfactory loss, olfactory disturbance, olfactory impairments, olfaction disorder, smell disorder, anosmia, cacosmia, and dysosmia. The Committee requested the staff of the Japan Library Association, a nonprofit organization, to create a search formula based thereon the keywords. The databases search targeted were papers published in The Cochrane Library, PubMed, and Igaku Chuo Zasshi Web (the Japan Medical Abstracts Society website) from October 2014 to the end of September 2022. Among the reference materials for the CQs, those included in the 2017 edition as reference materials and judged necessary were adopted for this edition. Consequently, the overall period covered by this edition was from April 1990 to September 2022 (the first edition covered from April 1990 to September 2014 and the present second edition covered from October 2014 to September 2022). The SR teams scrutinized and conducted a comprehensive literature search and selected those considered important. Hand searches were conducted for each CQ by two members of SR and one committee member.

7. Criteria for determining quality of evidence and strength of recommendation

First, we evaluated the evidence level (1 to 5) of each paper included in the draft recommendations for each CQ, based on the Oxford Levels of Evidence [3] (Table 1). The criteria for the inclusion of each paper for each CQ were level 4 or higher. Based on evidence level of papers included, we comprehensively summarized the quality of evidence (A to D), in accordance with the labeling method proposed by the American Academy of Pediatrics (AAP) (AAP Steering Committee on Quality Improvement and Management, AAP SCQIM) [4] (Table 2). Finally, we determined the strength of recommendation (Table 3), based on the current state of research on OD and discussion within the Guideline Committee. The level of recommendation was determined as ‘strongly recommended’, ‘recommended’, ‘optional’, or ‘not recommended’, focusing on the quality of evidence and the balance of benefits and harms to patients.

Table 1

Evidence level of each paper.

|Level|Diagnosis|Treatment / Prevention / Etiology| |---|---|---| |1|SR of cross-sectional studies with consistently applied control standards and blinding|SR of RCTs or N-of-1 trials| |2|Individual cross-sectional studies with consistently applied controls standards and blinding|Randomized trials, observational studies with dramatic effects| |3|Cohort studies, randomized trials|Non-randomized controlled cohort studies or follow-up studies| |4|Case series studies, case-control studies, low-quality prognostic cohort studies, Case series studies, case-control studies|Case series studies, case-control studies|

RCT: Randomized controlled trial, SR: Systematic review.

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Table 2

Summarized quality of evidence.

|grade|Research quality| |---|---| |A|Well-designed RCT| |B|RCT or diagnostic study with limitations, highly consistent evidence obtained from observational studies| |C|Observational studies (case-control studies, cohort studies)| |D|Expert opinion, case reports, Reasoning from first principles|

RCT: Randomized controlled trial.

Table 3

Strength of recommendation.

|Strongly Recommended|Strong evidence (A) exists, and the benefits outweigh the harms. Sufficient (moderate) evidence (B) exists, and the benefits far outweigh the harms. Weak evidence (C) exists, and the benefits clearly far outweigh the harms.| |---|---| |Recommended|Sufficient (moderate) evidence (B) exists, and the benefits far outweigh the harms. Weak evidence (C) exists, and the benefits of outweigh the harms. Weak evidence (C) exists, and the benefits far outweigh the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the harms. Weak evidence (C) exists, and the benefits of through the|

Based on Minds 2020, the quality of evidence and the grade of recommendation were determined using the original Delphi method, as in the first edition. A committee member was assigned to each CQ, and each member individually evaluated the results. The results were then presented to all 13 committee members, who voted to determine the consensus vote rate. For recommendations that did not achieve a 100% consensus rate, the committee members made a final decision by consensus, taking into account the opinion of the director in charge. While we strive to maintain objectivity and transparency in determining the strength of recommendation, we cannot guarantee complete accuracy for all content.

8. Process and reviews for producing the guidelines

After the draft for submission was completed, public comments were accepted on the website of the JRS from April 30, 2024 to May 31, 2024, and revisions were made to the draft according to the feedback. Subsequently, the draft was peer reviewed by Scientific Committee of the Japanese Society of Otorhinolaryngology-Head and Neck Surgery as an external evaluation, and revision version was made in response to those comments. After making the corrections, the second edition guideline was published on the website of the JRS in January 2025. These guidelines will be enacted with the approval of the Society and will be revised sequentially according to progress in medical treatment in the future. The procedure for revision for the third edition will involve creating a draft by the committee and enacting it with the approval of the Society.

9. Important clinical issues

(1) Diagnosis of OD

The diagnosis of OD is essentially divided into diagnosis of cause and severity of impairment. The main causes of OD are classified as sinonasal diseases such as rhinosinusitis, common cold due to upper respiratory viral infection, trauma, and

neurodegenerative diseases. Endoscopy can be performed by otorhinolaryngologists, but its effectiveness in diagnosing the presence or absence of OD and the severity of OD is not clear. There is also no clear consensus on the means and effectiveness of diagnostic imaging. Olfactory tests are necessary to determine the severity of OD, but their prevalence is low, and there is no test available at all medical institutions, which makes it difficult to diagnose and treat patients with OD in Japan.

(2) Treatment of OD

Given the rising incidence of ECRS, there is an urgent need to evaluate the direct impact of emerging biologic therapies on ol-factory outcomes, particularly as they offer alternatives to cortic-costeroids (glucocorticoid, hereinafter referred to as 'steroids'). Despite growing interest in OT for sensorineural and central OD, robust and comprehensive evidence remains insufficient. Notably, the effectiveness of treatment in patients with post-viral OD, COVID-19-related OD, and post-traumatic OD, continues to be uncertain.

(3) OD and neurodegenerative diseases associated with dementia

OD has been pointed out as an early symptom of dementia and is considered one of the risk factors for dementia. It is critically needed to differentiate between age-related OD and OD as a precursor symptom of dementia. In addition, the direct efficacy of dementia treatment on OD has not been clarified.

10. Clinical practice algorithm for OD

The overall flow of current clinical practice, diagnosis, and treatment algorithm for OD are shown in Figs. 1, 2, and 3.

Collaboration with specialists in other medical fields is important for diagnosis of causative OD. When congenital OD is suspected, consultation with pediatricians, endocrinologists, urologists, and obstetricians/gynecologists is recommended in order to diagnose the presence of complications such as malformations and gonadal dysfunction. When neurodegenerative diseases or intracranial diseases are suspected, consultation with a neurologist is recommended. For patients with phantosmia (spontaneous unpleasant odor perception), an electroencephalogram (EEG) should be performed for differential diagnosis of epilepsy. Treatments are listed in no particular order. The most appropriate treatment for the underlying cause of OD should be selected based on the individual case.

11. Clinical questions (CQ) and recommendations

A total of 16 CQs consisting of 3 categories (diagnosis, treatment, and management of OD associated with neurodegenerative diseases), are described in total. All CQs and their quality of evidence, strength of recommendation, and consensus rate are shown in Table 4. Herein es- sentials of the CQs are described.

CQ1 Diagnosis of OD

CQ1–1: Is a medical interview effective for assessing the presence and severity of OD?

Recommendation: Medical history-taking is of paramount importance for the clinical evaluation of OD. Determining the onset and potential triggers of symptoms is essential because clinical history often provides critical diagnostic clues. Moreover, assessing symptom severity is crucial for estimating the overall severity of a condition. Therefore, thorough interviews with patients are strongly recommended.

(Strength of Recommendation: Strongly recommended, Quality of Evidence: C, Consensus Rate: 92 %)

Evidence Summary

Systematic reviews addressing the effectiveness of interviews in estimating the presence [5–14] and severity [15–29] of OD were included, and all the studies were cross-sectional (Level 4).

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![graph TD\n A1[Other tests] --> A2[Gustatory test, psychology test Mini-Mental State Examination(MMSE)]\n A2 --> A3[Flavor or gustatory disorder Central OD]\n A4[Imaging tests] --> A5[Sinonasal CT Head MRI]\n A5 --> A6[Causative diseases]\n A7[Olfaction tests] --> A8[T&T olfactometer Intravenous olfactory test]\n A8 --> A9[Severity of quantitative OD]\n A10[Endoscopic tests] --> A11[rigid or flexible fiberscope]\n A11 --> A12[Nasal polyps]\n A13[Interview] --> A14[Triggers? Duration? Parosmia? Taste disorder? VAS, SAQ]\n A14 --> A15[Estimation of causes and severity Qualitative or quantitative?]\n](1/parseimages/figure0f7fd6943e514b7c9173d73095b993ed_0_2.png) Fig. 1. Diagnostic procedures for OD.

![graph TD\n A1[Birth with a sense of smell] --> A2[Preceding upper respiratory symptoms]\n A1 --> A3[Congenital]\n A3 --> A4[Sinonasal lesions]\n A3 --> A7[History of trauma]\n A4 --> A5[Sinonasal diseases]\n A4 --> A6[Viral infection including COVID-19]\n A7 --> A8[Trauma]\n A7 --> A9[History of drugs/addiction]\n A9 --> A10[Drug-induced]\n A9 --> A11[Neurological findings(neurologists)]\n A11 --> A12[Neurodegenerative diseases]\n A11 --> A13[Idiopathic]\n](1/parseimages/figureadfb8bbe4e394c7a81aef3c3240b07a5_0_4.png) Fig. 2. Flow chart of presuming the causes through interview and visual examination.

![graph TD\n A1[Interview Examination Насаl endoscope Sinonasal CT Head MRI Offraction test] --> A2[Consultation Otorhinolaryngology Internal medicine Neurology Neurosurgery Pediatrics Urology Gynecology]\n A2 --> A3[CRS Allergic rhinitis Sinonasal tumor PVOD / COVID-19 Trauma Drug addiction Neurodegeneration Congenital Idiopathic]\n A3 --> A4[Steroids, Biologics, Surgery(ESS) Steroids Multidisciplinary treatment Olfactory training, traditional Japanese herbal medicine Olfactory training, Zinc Removal of causative drugs Olfactory training Counseling Dealing with disabilities]\n](1/parseimages/figureabf68c6e6d3d44dabfc935cf1f43fa12_0_6.png) Fig. 3. Diagnosis and treatment algorithm for diseases causing OD.

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Table 4

Clinical questions.

|1. Diagnosis of OD|Strength of Recommendation|Quality of Evidence|Evidence $Level^{1}$|Consensus Rate| |---|---|---|---|---| |CQ1-1|Is a medical interview effective for assessing the presence and severity of OD?|Strongly recommended|C|92 % (12/13)| |CQ1-2|Is nasal endoscopy effective for diagnosing OD due to chronic rhinosinusitis?|Strongly recommended|C|92 % (12/13)| |CQ1-3|Are imaging studies effective for diagnosing post-traumatic OD?|Strongly recommended|B|100 %| |CQ1-4|Is intravenous olfactory test effective for determining prognosis?|Recommended|C|4| |2. Treatment of OD||Strength of Recommendation|Quality of Evidence|Evidence Rate| |CQ2-1|Eosinophilic chronic rhinosinusitis (ECRS)|||| |CQ2-1-1|Is pharmacotherapy effective for OD due to ECRS?|Strongly recommended|A|2| |CQ2-1-2|Is surgery effective for OD due to ECRS?|Recommended|B|100 %| |CQ2-2|Allergic rhinitis|||| |CQ2-2-1|Is pharmacotherapy effective for OD due to allergic rhinitis?|Recommended|B|2| |CQ2-3|Post-viral OD|||| |CQ2-3-1|Is olfactory training effective for post-viral OD?|Strongly recommended|B|2| |CQ2-3-2|Is pharmacotherapy effective for post-viral OD?|Recommended|B|92 % (12/13)| |CQ2-4|COVID-19|||| |CQ2-4-1|Is olfactory training effective for OD due to COVID-19?|Optional|C|85 % (11/13)| |CQ2-4-2|Is pharmacotherapy effective for OD due to COVID-19?|Optional|C|1| |CQ2-5|Post-traumatic OD|||| |CQ2-5-1|Is olfactory training effective for post-traumatic OD?|Strongly recommended|B|92 % (12/13)| |CQ2-5-2|Is pharmacotherapy effective due to post-traumatic OD?|Recommended|B|85 % (11/13)| |3. OD and neurodegenerative diseases associated with dementia||Strength of Recommendation|Quality of Evidence|Evidence Level| |CQ3-1|Is olfactory test effective for diagnosing neurodegenerative diseases with dementia?|Strongly recommended|B|92 % (12/13)| |CQ3-2|Is olfactory training effective for OD associated with neurodegenerative diseases?|Optional|C|1| |CQ3-3|Are dementia medications and antiparkinsonian drugs effective for OD associated with neurodegenerative diseases?|Optional|C|3| ||||||

* The highest evidence level among the papers cited in the guidelines was presented.

For estimating the presence of OD, a study based on the National Health and Nutrition Examination Survey (NHANES) involving more than 3000 participants reported 73.7 % agreement between subjective reports and objective olfactory tests; however, underestimation was more frequent in those aged ≥ 65 years [1]. Several other studies have demonstrated discrepancies in older adults, patients with dementia [6–8], and patients with COVID-19-related OD [9,10]. These findings suggest that reliance solely on interviews may lead to missed diagnoses or underestimation of OD [11–14].

For estimating the severity of OD, the Self-Administered Odor Questionnaire (SAOQ) demonstrated significant correlations with the visual analog scale (VAS) and T&T olfactometer results in 405 healthy volunteers and 539 patients with OD [15]. Similarly, in 2273 patients attending an outpatient olfactory clinic, scores from an odor-related questionnaire correlated with the Butanol Threshold Test (BTT) and Cross-Cultural Smell Identification Test (CCSIT) scores [16]. Comparable correlations have been reported in other studies [17–21], and such associations have also been observed in OD associated with chronic rhinosinusitis [22,23] and trauma [24]. However, no significant correlations have been found in a subset of healthy adults [25], children [26], and older adults with dementia [27]. In COVID-19-related OD, the

results have remained inconsistent [28,29].

It is important to conduct comprehensive medical interviews to estimate the underlying disease and severity of OD, while considering the possibility of underestimating OD and discrepancies between subjective symptoms and actual olfactory function.

CQ1-2: Is nasal endoscopy effective for diagnosing OD due to chronic rhinosinusitis?

Recommendation: Use of nasal endoscopy is strongly recommended for the diagnosis of OD due to chronic rhinosinusitis (CRS). Endoscopy should be complemented by a thorough medical history and imaging studies to ensure accurate differential diagnosis as the etiology of OD is diverse.

(Strength of Recommendation: Strongly recommended, Quality of Evidence: C, Consensus Rate: 92 %)

Evidence Summary

One paper on the diagnostic rate of conductive OD using anterior rhinoscopy, endoscopy, and computed tomography (CT) [30] and four papers that enabled comparison of endoscopic findings and olfactory test results [23,31–33] were adopted (Table 5).

Comparison of anterior rhinoscopy, nasal endoscopy, and CT [30]:

Table 5

Correlation between endoscopic examination and olfactory test in CRS.

|Reference|n|Endoscopy|Olfactory test|TDI|Result|Evidence Level| |---|---|---|---|---|---|---| |30|57|Observation|UPSIT|I|Diagnostic rate (anterior rhinoscopy and endoscopy): 91 %|4| |23|40|Lund-Kennedy score|CCCRCT|TI|Negative correlation between L-K and CCCRC (r = -0.39, p = 0.01)|4| |31|38|Olfactory Cleft Endoscopy Score|Sniffin' Sticks|TDI|Negative correlation between OCES and TDI (Sniffin' Sticks) (β = -1.13, p < 0.0001)|3| |32|40|Lund-Kennedy score|Iran SIT|I|Negative correlation between L-K and Iran-SIT (r = -0.362, p = 0.021)|4| |33|154|Lund-Kennedy score|Sniffin' Sticks|TDI|Negative correlation between L-K and TDI (Sniffin' Sticks) (r = -0.47, p < 0.001)|4| |||Lildhold score|||Negative correlation between Lildholdt and TDI (Sniffin' Sticks) (r = -0.35, p < 0.001)||

Quality of evidence was summarized as grade C in accordance with consensus rate of 92 %.

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Among 57 patients with conductive olfactory loss, only 40% (23 cases) were detected via anterior rhinoscopy, while 91% (52 cases) were diagnosed via nasal endoscopy. The remaining 9% (5 cases) required CT for diagnosis. Correlation studies between endoscopic findings and olfactory function [23,31-33]: Most studies used the Lund-Kennedy score to evaluate endoscopic findings and compared these with olfactory test results (threshold and suprathreshold tests). All studies reported significant correlations, indicating that endoscopic findings can predict OD in CRS.

CQ1-3: Are imaging studies effective for diagnosing post-traumatic OD?

Recommendation: Imaging studies are effective in diagnosing post-traumatic OD, and their implementation is strongly recommended. In particular, the MRI to confirm structural damage to the central olfactory system is especially important.

(Strength of Recommendation: Strongly recommended, Quality of Evidence: B, Consensus Rate: 100 %)

Evidence Summary

A total of 140 papers related to post-traumatic OD and imaging were initially identified. Among these, 13 studies were selected based on their description of the relationship between imaging findings and OD diagnosis, olfactory structures, central olfactory responses, results of olfactory testing, comparisons with functional assessments, and prognostic outcomes.

In 118 patients with moderate head trauma and post-traumatic OD confirmed via testing, CT and MRI scans successfully detected skull fractures, cerebral edema, or hemorrhagic lesions (Level 3) [49]. MRI abnormalities were found in 88 % of 25 patients, particularly in the olfactory bulbs, tracts, and inferior frontal lobes (Level 3) [35]. The extent of damage observed on MRI significantly correlated with olfactory function. In a comparative study of 41 head trauma patients and 23 controls, 62 % showed a correlation between the degree of OD and damage to the olfactory bulb and left temporal lobe (Level 3) [36]. In another randomized study involving 42 patients assigned to an olfactory OT group and a non-treatment group, MRI findings of brain damage significantly correlated with olfactory function (Level 2) [37]. A comparison between 26 patients and 21 healthy controls demonstrated that olfactory bulb volume was significantly reduced in the patient group, and that central olfactory damage was found in patients without olfactory evoked potentials (Level 2) [38]. In a study of 52 patients, those who showed improvement after OT (n = 16) had significantly larger olfactory bulb volumes than those who did not (n = 36), indicating a possible relationship between bulb size and functional recovery (Level 3) [39]. Morphological changes in the olfactory bulls were identified in 13 patients (Level 3) [40]. In 143 patients with post-traumatic OD, there was an association between the locations of injuries in the 27 olfactory-related brain regions identified by MRI and olfactory impairment or parosmia. Patients with anosmia often had lesions in the right olfactory bulb, while patients with parosmia tended to show damage in the left frontal lobe (Level 3) [41]. These injury sites were also shown to correlate with olfactory test results [42]. In another study of 17 patients with hyposmia and 19 with anosmia, MRI showed primary lesions in the olfactory bulb, orbitofrontal cortex, and temporal pole, with significantly more frequent damage in anosmic patients (Level 3) [42]. Functional MRI studies comparing patients and controls showed that activation of the frontal operculum and anterior insula in response to olfactory stimulation correlated positively with olfactory function (Level 2) [43]. In another study, patients with post-traumatic anosmia showed decreased activation in both primary and secondary olfactory cortices and the limbic system compared to healthy controls (Level 2) [44]. MRI findings were also effective in confirming lesions in 172 patients with clearly identifiable post-traumatic OD, and such abnormalities were useful for prognosis prediction (Level 3) [45]. Furthermore, in a randomized controlled trial involving 25 patients, significant improvement in central olfactory-related structures was identified on MRI in the group

that underwent OT, compared to the control group (Level 2) [46].

Q1-4: Is intravenous olfactory test effective for determining prognosis?

Recommendation: Intravenous olfactory test (commonly known as the Alinamin® test) is recommended for prognostic evaluation of olfactory function in postoperative patients undergoing endoscopic sinus surgery (ESS) for CRS and in patients with mild to moderate post-viral OD, as the efficacy has been reported.

(Strength of Recommendation: Recommended, Quality of Evidence: C, Consensus Rate: 100 %)

Evidence Summary

In another retrospective study focusing on patients with ECRS who underwent ESS, the presence of odor perception in the preoperative Alinamin® test was found to be a prognostic indicator of olfactory improvement at 3 months postoperatively, as assessed by the T&T olfactometer (Level 4) [47]. Furthermore, in a retrospective analysis of bilateral CRS cases with OD treated with bilateral ESS, a prolonged latency time in the preoperative intravenous olfactory test was associated with poorer subjective olfactory improvement postoperatively (Level 4) [48]. In a retrospective study of patients with post-infectious OD who were treated with traditional Japanese herbal medicines (tokishakuyakusan or ninjin'yoito), prolonged latency time in the Alinamin® test prior to treatment was a negative prognostic factor for subjective olfactory improvement among patients who perceived odor during the test (Level 4) [49]. Conversely, in another retrospective study on patients with anosmia due to post-infectious OD, the presence or absence of odor perception in the pre-treatment Alinamin® test did not correlate with olfactory improvement after D/AD and other treatment using intranasal betamethasone (Rinderon®) and traditional Japanese herbal medicines (tokishakuyakusan or ninjin'yoito), as evaluated by the T&T olfactometer (Level 4) [50].

CQ2 Treatment of OD

Eosinophilic Chronic Rhinosinusitis (CQ2-1)

CQ2–1–1: is pharmacotherapy effective for OD due to ECRS?

Recommendation: Interanasal steroid sprays, oral steroids, and dupilumab are strongly recommended. The efficacy of omalizumab has been reported, but consideration of insurance coverage is necessary. Evidence supporting the efficacy of benralizumab and mepolizumab is currently insufficient. Nasal irrigation with saline containing dissolved steroids following endoscopic sinus surgery (ESS) is not considered effective.

(Strength of Recommendation: Strongly recommended, Quality of Evidence: A, Consensus Rate: 100 %)

Evidence Summary

(1) Steroids

Strength of Recommendation: Recommended, Quality of Evidence: B

[Topical]

In a randomized, double-blind, placebo-controlled trial involving CRSwNP patients, administration of mometasone furoate nasal spray at 200 µg/day for 16 weeks significantly improved olfactory scores compared to placebo, with a trend toward improved mean olfactory threshold based on the BTT (Level 2) [51]. In another randomized, double-blind, placebo-controlled trial involving CRSwNP patients, both groups receiving fluticase nasal drops at doses of 400 µg twice-daily and once-daily, respectively, showed significant improvement in the University of Pennsylvania Smell Identification Test (UPSIT) after 12 weeks of treatment compared to the placebo group (Level 2) [52]. In a randomized, double-blind, placebo-controlled trial involving CRSwNP patients who underwent ESS, both the group in which an absorbable gelatin dressing containing saline was placed in the olfactory cleft and the group receiving a dressing containing triamcinolone showed significant improvement in olfactory function assessed using the BTT at 8 weeks postoperatively. The group treated with triamcinolone showed greater improvement (Level 2) [53]. Topical nasal steroid spray is not

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approved for CRS treatment in Japan at the time of guideline development.

[Systemic]

In a prospective, randomized, non-blined study involving CRSwNP patients, the combination therapy of oral dexamethasone (0.1 mg/kg/ day for 7 days) and budesonide nasal spray for 12 weeks demonstrated significantly greater improvement in Sniffin' Sticks scores and olfactory VAS scores at 2, 12, and 24 weeks compared to budesonide nasal spray monotherapy (Level 2) [5-4]. Another prospective study involving CRSwNP patients found that preoperative oral administration of prenisolone (starting at 40 mg/day, tapered by 5 mg every 2 days) significantly improved Sniffin' Sticks scores following endoscopic sinus surgery (Level 3) [55].

(2) Biologics

[Dupilumab]

Strength of Recommendation: Strongly recommended, Quality of Evidence: A

In placebo-controlled RCTs (SINUS-24 and SINUS-52) involving patients with severe CRSwNP, dupilumab significantly improved UPSIT and olfactory scores at both 24 and 52 weeks compared to placebo (Level 2) [56]. Subgroup analysis of SINUS-52 demonstrated that dupilumab significantly improved UPSIT at 24 and 52 weeks compared to placebo regardless of the severity of ECRS (Level 2) [57]. Additional group analyses of SINUS-24 and SINUS-52 revealed that olfactory scores improved significantly from day 3 after dupilumab administration compared to placebo, and UPSIT showed significant improvement at 2 weeks. Moreover, improvements in olfactory scores and UPSIT were observed regardless of surgical history, asthma, or aspirin intolerance (Level 2) [58]. Another placebo-controlled, randomized, double-blind trial involving CRSwNP patients found that the dupilumab group showed significant improvement in UPSIT at 16 weeks compared to placebo (Level 2) [59].

[Omalizumab]

Strength of Recommendation: Optional (Recommended if insurance coverage is not considered), Quality of Evidence: B

In placebo-controlled RCTs (POLYP1 and POLYP2) involving CRSwNP patients, omalizumab significantly improved UPSIT and ol-factory scores at week 24 compared to placebo (Level 2) [60]. In sub-group analysis, patients with blood eosinophil counts ≥300 cells/µL, those with asthma, aspirin intolerance, or no history of surgery showed significantly greater improvement in UPSIT scores at 24 weeks in the omalizumab group compared to the placebo group (Level 2) [61]. Omalizumab is not approved for CRS treatment in Japan at the time of guideline development.

[Benralizumab]

Strength of Recommendation: Optional, Quality of Evidence: B

In a placebo-controlled RCT involving patients with severe CRSSwNP, benralizumab significantly improved UPSIT from baseline at 20 weeks, but did not differ significantly from placebo (Level 2) [62]. In another RCT (OSTRO) involving patients with severe CRSSwNP, benralizumab significantly improved olfactory scores at weeks 40 and 56, although no significant improvement in UPSIT was observed (Level 2) [63]. Benralizumab is not approved for CRS treatment in Japan at the time of guideline development.

[Mepolizumab]

Strength of Recommendation: Optional, Quality of Evidence: B

In the SYNAPSE trial, mepolizumab significantly improved olfactory VAS scores at 52 weeks compared to placebo, but did not significantly improve UPSIT (Level 2) [64].

(3) Nasal Irrigation (Saline with Dissolved Steroids)

Strength of recommendation: Not recommended, Quality of Evidence: B

In a prospective, randomized, single-blind trial involving CRSwNP patients who underwent endoscopic sinus surgery, the change from baseline in UPSIT scores after postoperative nasal irrigation was compared between a group using saline alone and a group using saline

plus budesonide; no significant improvement was observed (Level 2) [65].

CQ2-1-2: Is surgery effective for OD due to ECRS?

Recommendation: ESS has been reported to be effective and is therefore recommended.

(Strength of Recommendation: Recommended, Quality of Evidence: B, Consensus Rate: 100 %)

Evidence Summary

In the systematic review (SR) related to this CQ, studies were excluded if the target population with ECRS was unclear, if surgery was performed on patients with nasal polyps without mention of CRS, if the study included other diseases besides CRSSwNP, or if olfactory testing was not performed. A prospective, randomized, single-blind trial involving CRSwNP patients undergoing ESS showed that the group in which polyps in the olfactory cleft were removed had a significant improvement in UPSIT scores at 6 months postoperatively compared to preoperative values. Furthermore, the clinical smell improvement at 6 months postoperatively was significantly better compared to the group in which olfactory cleft polyps were not removed (Level 2) [66]. Additionally, in a non-randomized trial involving CRSwNP patients, the group treated with fluticason propionate nasal spray 400 µg twice daily after ESS showed significantly greater improvement in the Connecticut Chemosensory Clinical Research Center Test (CCRCT) scores at 2 months postoperatively compared to the group receiving fluticasone propionate nasal spray alone. The improvement rate was 60 % in the surgery group versus 20 % in the medication-only group (Level 3) [67].

Allergic Rhinitis (CQ2-2)

$CQ2-2-1$: Is pharmacotherapy effective for OD due to allergic rhinitis?

Recommendation: Topical nasal steroid spray and immunotherapy in medical therapy of OD caused by allergic rhinitis are recommended.

(Strength of Recommendation: Recommended, Quality of Evidence:

B, Consensus Rate: 85 %

Evidence Summary

(1) Topical nasal steroid spray

Ten patients with allergic rhinitis received topical nasal steroid spray for 4 weeks. OD was improved, although Sniffin' Sticks was performed before and after treatment (Level 2) [68]. OD significantly improved at 1 and 3 months after topical nasal steroid spray treatment in 47 perennial allergic rhinitis patients (Level 2) [69]. Topical nasal steroid spray significantly improved OD in patients in whom olfactory function is correlated with area of nasal cavity (Level 3) [70]. Topical nasal steroid spray for seasonal allergic rhinitis significantly improved olfactory function in CCCRCT but not Sniffin' Sticks (Level 2) [71]. There is also a report that topical nasal steroid spray for 2 weeks significantly improved olfactory threshold, but not identification, with Sniffin' Sticks (Level 2) [72]. There was no significant difference of subjective olfactory symptom after topal nasal steroid therapy between allergic rhinitis group and non-allergic rhinitis group (Level 2) [73]. Topical nasal steroid spray for 2 weeks in pollen season significantly improved inflammation in the olfactory cleft, although it did not increase UPSIT score (Level 2) [74].

(2) Immunotherapy

OD estimated by Sniffin' Sticks was significantly improved in 145 allergic rhinitis patients who received sublingual immunotherapy (Level 2) [75].

Post-viral OD (excluding COVID-19) (CQ2-3)

CQ2-3-1: Is olfactory training effective for post-viral OD?

Recommendation: Olfactory training (OT) is strongly recommended as numerous studies have examined the effect of OT using odorants on PVOD and its efficacy has been reported with a moderate level of evidence.

(Strength of Recommendation: Strongly recommended, Quality of evidence.

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Evidence: B, Consensus Rate: 100 %)

Evidence Summary

A total of 10 papers regarding OT were included in the systematic review (SR) for this clinical question (CQ). Animal studies have shown that olfactory stimulation promotes the survival of olfactory receptor neurons and granule cells in the olfactory bulb, and induces improved synaptic efficiency. In a study involving 56 patients with OD, including 35 with post-viral OD, subjects were divided into two groups: one received OT using four types of odors (synthetic rose, eucalyptus, lemon, clove) twice daily for 12 weeks, while the other received no training. Sniffin's Sticks olfactory tests conducted before and after the training period showed significant improvement in olfactory scores in the training group (Level 3) [76]. A study in Korea using a different set of odorants also demonstrated significant improvements in threshold, identification, and total scores in the Sniffin's Sticks Korean version after 12 weeks in the training group compared to the non-training group (Level 3) [77]. Another report indicated significant improvement in TDI scores in Sniffin's Sticks after four months of training in 16 patients with post-viral OD (Level 4) [78]. A 32-week training program in 39 patients resulted in improved TDI scores in 79 % of the patients (Level 3) [79]. Additionally, a study reported greater improvement with 56-week training compared to 16-week training (Level 3) [80]. A multicenter randomized crossover study in Germany found that training with high-concentration odorants led to greater TDI score improvements than low-concentration odorant training (Level 2) [81]. On the other hand, one report found no effect from limiting the concentration or cost of essential oils used in training, as evaluated by the UPSIT (Level 2) [82].

Regarding the types of odors used in training, when comparing groups that underwent training using two types of odor sets, there was no significant difference in the improvement of Sniffin' Sticks TDI scores between the groups (Level 2) [83]. There is also a report (Level 3) that using a total of 12 types of odorants over 9 months by changing the odorant set every 3 months showed a higher improvement effect on the Sniffin' Sticks TDI score [84].

Regarding efficacy, there is a report (Level 4) that indicates effectiveness in improving discrimination and identification abilities compared to improvements in thresholds in evaluations using Sniffin' Sticks [85].

Q2-3-2: Is pharmacotherapy effective for post-viral OD?

Recommendation: There are exploratory single-arm studies and randomized controlled trials (RCTs) involving both systemic and topical drug administration. Although some drugs have shown efficacy, the number of the studies are few and results are somewhat inconsistent. Traditional Japanese herbal medicines have shown improvement rates in RCTs with few side effects and are therefore recommended. Other medications are only supported by exploratory studies, are not covered by insurance, or lack high-quality clinical trials, and are not recommended currently.

(Strength of Recommendation: Recommended, Quality of Evidence: B, Consensus Rate: 92 %)

Evidence Summary

Fifteen papers related to pharmacotherapy were included in the SR.

(1) Traditional Japanese Herbal Medicine

Tokishakuyakusan has been reported in animal studies to increase neurotrophic factors in the olfactory bulb and promote regeneration of olfactory receptor neurons. A multicenter, open-label randomized controlled trial (RCT) conducted in Japan compared tokishakuyakusan and mecobalamin. Using the T&T olfactometer based on criteria by the JRS for olfactory improvement [1], the improvement rate after 24 weeks was 56 % in the tokishakuyakusan group and 59 % in the mecobalamin group (Level 2) [86].

(2) Valproic Acid

Valproic acid has been shown in animal studies to promote the proliferation and differentiation of basal cells in the olfactory epithelium. In an open-label exploratory study, 11 patients with post-viral OD.

received 400 mg/day of oral valproic acid for 24 weeks. The improvement rate using the T&T olfactometer was 77.8 %, which was higher than the 47.3 % six-month improvement rate observed in previous studies using tokishakuyakusan (Level 3) [87].

(3) Vitamin A

Vitamin A has been shown in animal studies to promote functional recovery after experimentally induced olfactory damage. In a double-blind, placebo-controlled randomized trial, patients were administered 10,000 IU/day of vitamin A for three months and assessed approximately five months later using Sniffin' Sticks. No significant difference was observed between the treatment and control groups (Level 1) [88]. However, in a study where OT was combined with 10,000 IU/day of intranasal vitamin A (in head-down position) for two months, the group receiving both treatments showed significantly greater improvement in threshold and discrimination scores compared to the group of OT alone (Level 4) [99].

(4) Theophylline

Theophylline is a non-specific phosphodiesterase inhibitor known to increase intracellular cAMP and enhance neuronal excitability. In an open-label study, 200–800 mg/day of theophylline was administered for 2–8 months to 312 patients with OD, including 97 with post-viral olfactory loss. Improvement in olfactory function was observed in 50.3% of cases based on threshold and identification tests using four types of odorants (Level 4) [90]. Similarly, in a study where pentoxifylline, another phosphodiesterase inhibitor, was used to treat acute sensorineal hearing loss, improvements in olfactory thresholds assessed by Sniffin' Sticks were also reported (Level 4) [91]. Conversely, in a double-blind, placebo-controlled RCT involving 22 patients with post-viral OD, no significant difference in UPSIT scores was observed between groups receiving intranasal theophylline solution and saline for six weeks (Level 1) [92].

(5) Citric Acid

Citric acid has been reported to activate olfactory signal transduction by chelating calcium in nasal mucus and lowering its concentration. In a study involving 49 patients with post-viral OD, one nostril was administered citric acid solution and the other saline using a head-down position, followed by separate olfactory testing of each nostril. Significant improvement was observed in threshold and identification scores on the citric acid side (Level 4) [93]. However, when the same administration was repeated daily for two weeks, no significant difference was found in TDI scores between nostrils (Level 4) [94].

(6) Steroids

In a study involving patients with CRS and post-viral OD, systemic steroid therapy significantly improved the recognition threshold in the former group but not in the latter. However, some post-viral OD patients showed improvement in thresholds after steroid treatment, suggesting that steroids may be effective during the reversible acute injury phase of the olfactory mucosa (Level 4) [95]. In another study, both local and systemic steroids were administered. While local administration showed no significant effect, systemic steroid therapy led to significant improvements in TDI scores (Sniffin' Sticks) in the post-viral OD group (Level 4) [96].

(7) Omega-3 Fatty Acids

Omega-3 fatty acids possess anti-inflammatory properties and have been reported to promote axonal regeneration. In a pilot study involving 58 patients with post-viral OD, patients underwent either OT alone or in combination with oral omega-3 supplementation. After approximately 3 months, those in the omega-3 group showed greater improvement in TDI scores (Level 2) [97].

(8) Zinc Preparations

Zinc is a trace element involved in enzyme activity, especially enzymes related to cell proliferation, and is considered important for maintaining the function of sensory organs such as the olfactory and gustatory systems. Zinc preparations have long been used to treat olfactory and taste disorders; however, past studies have not clearly demonstrated their efficacy for post-viral OD. One report divided

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patients into three groups (zinc sulfate only, zinc sulfate + steroid nasal spray + vitamin B complex, and steroid nasal spray + vitamin B complex) and found no significant difference in olfactory function (measured by T&T olfactometer) among the groups (Level 4) [98].

(9) Alpha-Lipoic Acid

Alpha-lipoic acid, used for treating diabetic neuropathy, is known to increase neurotrophic factor expression and improve neural conduction velocity and microcirculation. In a preliminary study, 23 patients with post-viral OD received 600 mg/day of alpha-lipoic acid for 4-5 months. Results showed improvement in 61 %, no change in 30 %, and worsening in 9 % (Level 4) [99]. However, a subsequent placebo-controlled double-blind trial did not demonstrate a significant difference (Level 4).

(10) Minocycline

Minocycline is known to inhibit neuronal cell death and has shown neuroprotective effects in neurodegenerative diseases, cerebral ischemia, and traumatic brain injury. Animal studies have also reported its protective effects on olfactory neurons. In a double-blind, placebo-controlled RCT, 100 mg/day of minocycline was administered for 3 weeks, and olfactory tests (Sniffin' Sticks) were conducted 7 months later. There was no significant difference in TDI scores between the treatment and control groups (Level 1) [100].

Coronavirus Disease 2019 (COVID-19) (CQ2-4)

CQ2-4-1: Is olfactory training effective for OD due to COVID-19?

Recommendation: OT using odorants has been reported to be effective with a moderate or higher level of evidence. It is currently considered an optional treatment, due to the limited number of studies.

(Strength of Recommendation: Optional, Quality of Evidence: C, Consensus Rate: 85 %)

Evidence Summary

Four papers by SR were adopted. Effectiveness of OT for post-viral OD has been reported. In a study of 43 patients with COVID-19-related OD lasting over four weeks, participants were divided to an OT group and a control group. While both groups showed improvement in Sniffin' Sticks test scores, the training group showed statistically significant improvement after 12 weeks (Level 1) [101]. In patients with symptoms lasting over six weeks, a six-month OT program significantly improved olfactory thresholds on Sniffin' Sticks (Level 3) [102]. Another study divided patients into two groups trained with 4 vs. 8 odorants for 3 months. Both groups showed significant improvement in UPSIT scores, with no significant difference based on the number of odorants (Level 3) [103]. Regarding parosmia which is a common symptom in COVID-19-related OD, a 36-week OT program with changing 4 odorants every 12 weeks led to significant improvements in odor discrimination in Sniffin' Sticks test or parosmia scores compared to a control group at 24 to 36 weeks (Level 1) [104].

CQ2-4-2: Is pharmacotherapy effective for OD due to COVID-19?

Recommendation: Although some single-arm exploratory studies and randomized controlled trials (RCTs) have reported effectiveness of certain systemic or topical medications, the number of studies is limited and results are inconsistent. Therefore, pharmacological treatment is currently considered optional.

(Strength of Recommendation: Optional, Quality of Evidence: C, Consensus Rate: 100 %)

Evidence Summary

Eighteen papers were adopted.

(1) Steroids

[Topical]

Contradictory results have been reported. Patients with a 6-month pre-infection use of mometasone nasal spray in allergic rhinitis

showed low scores in SNOT-22 including nasal symptoms as rhinorrhea, stuffy nose, or OD, without worsening COVID-19-related OD regardless of suffering durations (Level 3) [105]. An RCT reported significant improvement of subjective olfaction as well as the scores of UPSIT modified for Irians in the group using mometasone spray added to OT compared with OT alone group (Level 1) [106]. Another RCT comparing mometasone vs. saline spray, both UPSIT scores and subjective olfaction improved significantly in 77 patients with suffering durations of longer than 2 weeks (Level 1) [107].

However, there are several RCTs showing no significant difference attributable to steroid use despite improvement in both groups. Those include a study evaluating subjective symptoms after steroid nasal irrigation as early treatment of OD in COVID-19 [108], meta-analyses of 5 RCT reports subjective symptoms and scores in UPSIT or Sniffin' Sticks in topical steroid application compared with control (Level 1) [109], a study of 70 patients with suffering duration of longer than 4 weeks in topical steroid application compared with control (Level 1) [110], a study of 100 patients evaluating subjective symptoms by topical steroid application with OT compared with OT alone regardless of suffering durations (Level 1) [111], and a study of 276 patients in acute phases evaluating subjective symptoms divided to topical steroid or saline application for longer than one month (Level 1) [112].

[Systemic]

Systemic steroids are used in treating COVID-19 pneumonia even in patients with OD. In a retrospective study of 750 hospitalized patients, 208 had subjective OD. Milder patients had a higher incidence, and those treated with systemic steroids had better outcomes (Level 3). One RCT of 18 patients with over 30 days of symptoms using prednisone with increasing dose from 1mg/kg/day in 15 days and betamethasone spray showed significant improvement compared with control group with assessment using CCCRCT (Level 1) [113]. Another study of 115 patients using prednisone for 10 days at 40mg/day, however, found no significant benefit using Sniffin' Sticks (Level 1) [114].

(2) Other treatment

[Topical]

Platelet-rich Plasma (PRP) is known to accelerate proliferation of neurons through anti-inflammatory effects and increasing growth factors. In 30 patients with over 6 months of symptoms, one-time 1 ml of PRP injection to olfactory clefts under local anesthesia significantly improved Sniffin' Sticks scores and symptoms compared to 26 controls (Level 3) [115].

Calcium-Chelating Agents are capable of maintaining reactivity of olfactory receptor neurons with inhibition of adaptation on keeping low Calcium concentration. Nasal administration of nitrotriacetic acid sodium salt [116] or tetra sodium pyrophosphate (TSPP) [117] as Calcium-chelating agents 3 times daily for 30 days to patients suffering over 14 or 90 days significantly decreased nasal calcium levels and improved Sniffin' Sticks scores in about 60 patients compared with control group (Level 1).

[Systemic]

Palmitoylethanolamide and Luteolin (PEA-LUT) is reported to have anti-inflammatory and neuroprotective effects as a commercial diet supplement. In 185 patients with over six months of symptoms, PEA-LUT combined with OT improved Sniffin' Sticks scores compared with control group (Level 1) [118]. Another study reported improvement in both OD and central nervous symptoms such as brain fog on patients with olfaction over 6 months resistant to other therapies (Level 3) [119].

Zinc is involved in recognition of viruses on induction of immune reaction against viral infection as well as modulation in differentiation, proliferation and maturation of cells. Zinc supply had effects on lower airway infection because Zn deficiency induces various pathological conditions. In 105 patients with OD due to COVID-19, subjective improvement was significantly faster with zinc supplementation despite

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no difference in serum zinc levels compared with control group (Level 1) [120].

Traditional Japanese herbal medicines, like kakkontokasenyhuïin and others have effects on upper airway infection as rhinosinusitis or pharyngitis. Among 87 patients, these traditional Japanese herbal medicines were effective based on multivariate analysis of self-rated olfactory function compared with 35 control patients (Level 3) [121].

Post-traumatic OD (CQ2-5)

CQ2-5-1: Is olfactory training effective for post-traumatic OD?

Recommendation: Olfactory training (OT) for patients with post-traumatic OD is strongly recommended as the efficacy is reported with high level of evidence.

(Strength of Recommendation: Strongly recommended, Quality of Evidence: B, Consensus Rate: 92 %)

Evidence Summary

In a prospective randomized controlled trial, a 12-week OT program utilizing six distinct odors resulted in a 62 % improvement rate in ol-factory identification, as assessed by the BAST-24, compared to 38 % in the control group (Level 2) [37]. In a prospective randomized controlled trial in patients with post-traumatic OD who showed no improvement after several weeks of oral steroid therapy and one month of zinc sup-plementation, the OT group demonstrated a significant improvement in ol-factory threshold, as measured by the phenyl ethyl alcohol threshold test, at three months compared to baseline (Level 2) [122]. Similarly, OT using phenyl ethyl alcohol resulted in a significantly higher improvement rate on the phenyl ethyl alcohol threshold test at six months compared to the control group (Level 2) [123]. In another prospective randomized controlled trial, patients underwent 16 weeks of OT and were randomly assigned to one of three groups: a control group (no training), a Classical OT group (using four fixed odors), and a Modified OT group (sequential exposure to four sets of four different odors). The Classical OT group showed a significantly higher post-treatment TDI score on the Sniffin' Sticks test compared to the control group. The Modified OT group demonstrated a significantly higher identification score than the control group (Level 2) [46]. In a study involving patients with post-traumatic OD with a mean duration of 62 months after injury, a 10-day course of oral steroid therapy followed by three months of OT using four types of odors led to an improvement in the mean TDI score from 14.4 to 20.8 on the Sniffin' Sticks test (Level 4) [124].

CQ2-5-2: Is pharmacotherapy effective due to post-traumatic OD?

Recommendation: For the treatment of post-traumatic OD, zinc preparations are recommended, while steroid therapy may be considered as a treatment option. The use of vitamin A is not recommended.

(Strength of Recommendation: Recommended, Quality of Evidence: B, Consensus Rate: 85 %)

Evidence Summary

(1) Zinc preparations

A prospective randomized controlled trial compared the efficacy of four treatments in 145 patients with post-traumatic OD: zinc gluconate with prednisolone (Group 1), zinc gluconate alone (Group 2), prednisolone alone (Group 3), and no medication (Group 4). Recovery rates, assessed using PEA threshold testing over a 6-month period, were significantly higher in Group 1 (28.2 %) and Group 2 (25.7 %) compared to the control group (2.7 %) (Level 2) [125]. In another prospective, non-randomized, non-controlled study, 95 patients with post-traumatic OD received one of the following treatments: zinc sulfate alone; a combination of zinc sulfate, topical steroids, and systemic vitamin B complex; or topical steroids and systemic vitamin B complex without

zinc. Patients treated with zinc sulfate showed a significantly greater improvement in subjective symptoms, assessed using a 7-point scale, compared to those who received topical steroids and systemic vitamin B complex alone (Level 3) [98].

(2) Steroids

In a prospective, single-arm study involving 116 patients with post-traumatic OD, systemic prednisolone was administered at 60 mg/day for 3 days, followed by tapering every 3 days over a total duration of 15 days. Improvement in olfactory threshold was observed in 19 patients (Level 4) [126]. In a retrospective case series, 12 patients with post-viral OD received topical intranasal betamethasone drops. Objective improvement, as assessed by both the T&T olfactometer and intravenous olfactory tests, was observed in only one patient. In contrast, among five patients who received systemic oral prednisolone, three demonstrated measurable improvement on both olfactory tests (Level 4) [127].

(3) Vitamin A

In a double-blind, placebo-controlled trial, 52 patients with OD, including 19 with post-traumatic OD, received 10,000 IU of vitamin A per day for three months. Olfactory function was evaluated using the Sniffin' Sticks test five months after the initial assessment, and no statistically significant improvement in TDI scores was observed (Level 1) [88]. In an uncontrolled, non-blinded retrospective study, adjunctive intranasal administration of 10,000 IU of vitamin A per day in combination with OT was suggested to be effective in the treatment of post-infectious OD; however, no such benefit was observed in patients with post-traumatic OD (Level 4) [89].

CQ3 OD and neurodegenerative diseases associated with dementia

CQ3–1: Is olfactory test effective for diagnosing neurodegenerative diseases with dementia?

Recommendation: Neurodegenerative diseases with dementia (Alzheimer's disease, AD; Parkinson's disease, PD; and dementia with Lewy bodies, DLB) are often associated with OD at the early stage of their onset. Therefore, olfactory tests are effective for the diagnosis of neurodegenerative diseases and are strongly recommended.

(Strength of Recommendation: Strongly recommended, Quality of Evidence: B, Consensus Rate: 92 %)

Evidence Summary

1) OD occurs at a high frequency in patients with neurodegenerative diseases associated with dementia.

The incidence of OD was compared using the Odor Perception and Semantics Battery. The groups included 14 patients with AD, 8 with semantic dementia (SD), 11 with frontotemporal dementia (FTD), 7 with corticobasal degeneration (CBD), and 20 healthy individuals. Odor discrimination was examined by determining whether the two types of odor they smelled were similar; odor identification was examined by smelling the odor and selecting one of the four odor illustrations. Both odor discrimination and identification were impaired in patients with AD. For patients with SD, odor discrimination was preserved, but odor identification was severely impaired. Odor identification was slightly impaired in patients with FTD and CBD (Level 4) [128].

2) The olfactory test is effective in the diagnosis of PD.

The brief smell identification test (B-SIT), which uses 12 smells out of 40 included in the University of Pennsylvania Smell Identification Test (UPSIT), was conducted in 166 patients with PD, revealing that 82 % of them had an impaired sense of smell. In the group of olfactory hypes- theiaz corresponding to the bottom 20 % of the B-SIT score, olfactory hypesetia was associated with severe cases of PD, as indicated by the Hoehn & Yahr (H&Y) severity classification, the motor assessment of the unified Parkinson's disease rating scale (UPDRS) motor function rating

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scale (part 3), the Freezing of Gait questionnaire (FOG-Q), levodopa equivalent dose of anti-PD drugs, and speed of disease progression (Level 4) [129]. Analogous diseases that can cause Parkinsonism include multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A card-type odor identification test (Open Essence® [OE]), consisting of 12 types of odors, was conducted in 98 patients with PD aged 50 years or older, 32 patients with MSA, 17 patients with PSP, and 96 healthy individuals. The group of PD showed a significant decline in OE score compared to the other groups, while the groups of MSA and PSP showed a mild decrease in OE score. When setting the cutoff value of the OE score to 6 according to the -receiver operating characteristic curve, the group of PD was differentiated from the healthy group with a sensitivity of 84.7 % and a specificity of 85.4 %. The discrimination of the groups of MSA and PSP from the healthy group was possible with a sensitivity of 60.2 % and a specificity of 77.6 % when setting the cutoff value as 4. In discriminating PD from its analogous diseases, the group of PD showed the highest percentage of undetectable odors among 12 odors and significantly lower percentages of correct responses to perfume, oranges, and curry odors compared to the other groups. In the groups of PD and MSA, OE scores ≤4 were associated with significantly lower mini-mental state examination (MMSE) scores (Level 4) [130].

3) PD with OD was associated with a higher incidence of dementia.

UPSIT and various kinds of neuropsychological assessments were performed at the first visit and 4 years later in 487 patients with early PD (postural reflex and gait disturbance, 43 patients; tremor dominant, 406 patients; indeterminate, 38 patients) and 197 healthy individuals. The PD group had significantly poorer UPSIT and Montreal cognitive assessment (MoCA) scores; only the tremor-dominant form of the disease showed significant correlations between UPSIT scores and both H&Y severity classification and MDS-UPDRS (MDS-sponsored UPDRS revision) part 1 (mental moods) and part 3 (motor function) scores. The group of tremor-dominant PD with OD had worse motor and non-motor function scores at 4 years than the group without OD (Level 3) [131]. Patients with newly diagnosed Parkinsonism (125 with PD, 14 with MSA, and 16 with PSP) were followed up for a maximum of 10 years using B-SIT, UPDRS, H&Y severity classification, and MMSE. OD with a B-SIT score <9 was observed at baseline diagnosis in 73 % of these patients, and 42 of these patients (46 %) developed dementia during follow-up. However, seven patients (21 %) with a normal sense of smell at the first examination developed dementia during follow-up. Additionally, one of 22 patients with normal olfaction and cognitive function at baseline developed dementia. The presence of OD at diagnosis increased the incidence of dementia, regardless of age, sex, motor deficits, and cognitive status (Level 3) [132].

4) Mild cognitive impairment (MCI) is also associated with OD.

In total, 1430 cognitively normal individuals between the ages of 70 and 89 years were followed up for an average of 3.5 years using B-SIT and various cognitive function tests. During the study period, 250 people developed MCI, and 64 of 221 patients with MCI who could be followed developed dementia. The incidence of MCI decreased with higher B-SIT scores in cognitively normal individuals and patients with MCI. Olfactory test may be useful in the predictable screening for the development of amnesic MCI and progression from amnesic MCI to AD (Level 3) [133]. Follow-up evaluation was performed at 2 and 4 years in 757 subjects without dementia (non-MCI, 498; amnesic MCI, 130; and non-amnesic MCI, 129) aged 65 years or older, using UPSIT and various neuropsychological batteries. During the course of the study, 101 individuals developed AD dementia. Olfaction was better in the order of non-MCI, non-amnesic MCI, and amnesic MCI, both at first visit and follow-up visits, and a lower initial UPSIT score was strongly correlated with the transition to dementia (Level 3) [134]. OE was performed in 220 patients with MCI whose MMSE scores were between 24 and 30 (a 30

perfect score of 40); they were divided into a group with severe olfactory impairment (OE score ≤4, 36 patients) and the remaining group. Multivariate logistic regression analysis matched for age, sex, and education showed that the group with severe olfactory impairment had decreases in verbal and visual memories, attention/executive function, and processing speed (Level 4) [135]. A 20-year prospective cohort study of olfactory and cognitive functions was conducted in 5021 older individuals, excluding those with dementia. Of 574 participants (11 %) with initial Sniffin Sticks scores ≤ 6 (a perfect score of 12), 204 developed MCI during the study period, indicating a 1.56-fold higher incidence of MCI than in the control group without OD. One hundred thirty-seven patients with OD transitioned from MCI to AD. The incidence rate of AD was 1.46-fold higher than that of the control group (Level 3) [136]. The Sniffin Sticks test and various cognitive function tests were performed in 1782 older subjects (345 with MCI and 1437 controls), excluding those with dementia. The group with MCI had poorer ability to identify smells. After adjusting for age, sex, and education, a low olfactory score was found to be an independent influential factor related to MCI (Level 4) [137]. Three hundred eighty elderly subjects without dementia were followed up for a maximum of 15 years using B-SIT, a battery of 21 cognitive function tests, and magnetic resonance imaging (MRI) scan. Anosmia (defined as an initial B-SIT score <6), reduced sense of smell (defined as a score of 6–10), and normal olfactory were observed in 29 (7.6 %), 213 (56.1 %), and 138 individuals (36.3 %), respectively. The group of OD had lower initial score cognitive function, faster cognitive decline during the follow-up period, and reduced volumes of the hippocampus, intra-olfactory cortex, and middle temporal cortex on MRI (Level 3) [138]. A total of 2906 subjects aged 57 to 85 years, excluding those with dementia, underwent a smell identification test using five different smells in Sniffin Sticks and a short portable mental status questionnaire (SPMSQ). After 5 years, 4.1 % of them developed dementia, defined as an SPMSQ score <8, 47 % of which had an OD with a score ≤ 3 (a perfect score of 5) on the initial olfactory test, indicating more than twice the incidence of dementia in the group of normal olaction. No cognitive impairment was observed at 5 years, with a specificity of 79 % for individuals without OD on the initial test. OD is a predictor of dementia even for cognitively sound older individuals (Level 3) [139].

5) Combining OD with other non-motor disorders and results of biochemical and imaging tests may increase the diagnostic rate of neurodegenerative diseases.

The cognitive function test (MoCA), olfactory test (Chinese version of UPSIT), motor deficits assessment (MDS-UPDRS part 3), and constipation (a non-motor impairment) were evaluated in 107 patients without dementia within 5 years after diagnosis of PD. An OD is defined as UPSIT score of less than 19 (a perfect score of 40), and 57 patients fell in this group. The group of OD showed significantly lower MoCA scores and significantly higher UPDRS part 3 scores than those in the group of non-olfactory disability, indicating that OD is associated with cognitive decline and motor deficits. In the group of OD, although the incidence of concomitant grade 3 severe constipation was significantly high, constipation was not correlated with cognitive function (Level 4) [140]. When 237 patients with AD-type cognitive impairment (99 with probable AD dementia, 62 with MCI, and 76 with subjective cognitive decline [SCD]) were compared with 217 patients with Lewy body-related cognitive impairment (33 with PD dementia, 15 with DLB, 83 with PD-MCI, 16 with prodromal DLB, and 70 with PD-SCD) as the control group. The group of Lewy body-related cognitive impairment showed more severe OD than the group of AD-type cognitive impairment in the smell identification test (cross-cultural smell identification test, in which patients smelled 12 different odor cards and chose one of four options). However, there was no difference between the two groups in the dementia subgroups. In both groups, the worse the cognitive function, the

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worse the olfactory function. In the AD-type cognitive impairment group, reduced olfactory function was correlated with reduced cortical thickness (particularly in the right parahippocampal cortex) on MRI imaging, and in the Lewy body-related cognitive impairment group, it was correlated with abnormalities in white matter including subcortical areas of orbitofrontal and frontoparietal cortex (Level 4) [141]. In a case-control study conducted over approximately 28 years using a mailed questionnaire among male healthcare professionals between the ages of 40 and 75 years, 120 patients with PD were compared with 6479 non-PD patients as controls. Olfactory function was poorer in the PD group than in the control group. During the follow-up period, 29.3% of patients with PD and 1.1 % of controls exhibited concomitant three symptoms (constipation, REM sleep behavior disorder, and decreased sense of small detected by B-SIT). The combination of the three symptoms increased the odds ratio to 160-fold in the group of PD, suggesting that it is effective for the diagnosis of early PD before the onset of motor symptoms (Level 3) [142]. The group of hyposmia (n = 185) and the group of normal olfaction (n = 95) were followed up using UPSIT and dopamine transporter (DAT) single photon emission computed tomography. All 19 patients who developed PD after the 4-year-follow-up belonged to the hyposmia group. This included 14 of 21 patients (67 %) with reduced DAT (<65 % of age-appropriate values), 2 of 22 patients (9 %) with mildly reduced DAT (65 %-80 % of age-appropriate values), and 3 of 109 patients (2.8 %) with normal DAT. The combination of decreased olfactory and decreased DAT identified a high-risk group for PD (Level 3) [143]. A total of 423 previously untreated patients with PD were followed up for a maximum of 3 years using UPSIT, MoCA, MDS-UPDRS, and assessment of non-motor symptoms. OD was present in 90.8 % of participants, and lower baseline olfactory scores were associated with more severe longitudinal deterioration in non-motor symptoms, verbal memory, and executive function. Eighty-seven percent of those with severely decreased olfaction and cerebrospinal fluid AP1–42 tau protein concentrations transitioned from normal cognitive function to MCI. Therefore, the combination of decreased olfactory perception and decreased AP levels predicted the development of MCI (Level 3) [144].

CQ3-2: Is olfactory training effective for OD associated with neurodegenerative diseases?

Recommendation: OT may have the potential to improve olfactory function in patients with mild cognitive impairment (MCI), while does not demonstrate a significant improvement in patients with Alzheimer's disease and Parkinson's disease. It remains an optional treatment.

(Strength of Recommendation: Optional, Quality of Evidence: C, Consensus Rate: 92 %)

Evidence Summary

In a prospective RCT including 37 patients with MCI, participants were assigned to either the olfactory stimulation group (mean age 71.4 years) or the placebo group (mean age 70.3 years). The participants in the olfactory stimulation underwent training by smelling four labeled scent vials for 20 s each morning and evening for four consecutive months. The intervention group received bottles containing 1 mL each of rose, lemon, and clove essential oils, while the placebo group received bottles containing no scent. Olfactory function was evaluated using the Sniffin' Sticks test with 16 different odors, along with cognitive function assessments including the MMSE, Wechsler Memory Scale, Boston Naming Test, and Trail-Making Test. Additionally, MRI imaging was used to assess olfactory bulb volume and cortical thickness. The results showed that the olfactory stimulation group had a significant improvement in discrimination scores ($F = 6.24, p = 0.018$). While there were no changes in olfactory bulb and hippocampal volumes, significant increases were observed in the thickness of the bilateral hippocampal cortex (CA2/3DG and CA1) and the medial temporal lobe cortex. No

significant differences in cognitive function were found between the two groups (Level 1) [145].

In a prospective single-blind RCT involving 33 patients with MCI, the participants were assigned to either the olfactory stimulation group or the placebo group. Both groups underwent training by smelling four scented vials for 15 s each morning and evening for four consecutive months. The intervention group received bottles containing 1 mL each of rose, eucalyptus, lemon, and clove essential oils, while the placebo group received bottles contained no scent, following the same procedure. Olfactory function was evaluated using the Sniffin' Sticks test, along with assessments of cognitive function and the Beck Depression Inventory. No significant improvements were observed in olfactory function, cognitive function, or depression scales in either group, and no significant differences were found between the groups (Level 2) [146]. In a small-scale, forward-looking randomized study involving Japanese patients with MCI and AD, the use of fir essential oil and aromathery bath salts did not demonstrate improvements in olfactory function as measured by the Odor Stick Identification Test for Japanese (OSIT-J) (Level 3) [147].

In a study involving patients with MCI and moderate AD, participants were divided into an olfactory stimulation group (9 patients) that are engaged in a task of selecting matching images while smelling 2 to 3 types of essential oils and a placebo group (9 patients). The study found no significant differences in the Sniffin' Sticks test, MMSE, Loewenstein Occupational Therapy Cognitive Assessment, or Geriatric Depression Scale between the two groups. In the placebo group, the levels of Aβ 1-42 increased after 12 weeks, while the olfactory stimulation group showed no changes in Aβ 1-42 concentration or plasma tau levels, with significantly lower levels of Aβ 1-42 compared to the placebo group (Level 3) [148].

In a case-control study involving patients with PD having normal MMSE scores, participants were divided into an olfactory stimulation group (34 patients), a non-stimulated group (20 patients), and a control group (20 healthy individuals). The Sniffin' Sticks identification test was administered twice on the same day with a two-hour break between assessments. In the olfactory stimulation group, training was conducted after the first test, using a card displaying the scents' names while participants smelled them. To evaluate the long-term effects of the training, eight participants who correctly identified three or more scents were tested with the Sniffin' Sticks approximately one month later. At baseline, the PD group demonstrated significant reductions in both detection and identification scores on the olfactory test compared to the healthy control group. In PD patients, the olfactory stimulation group showed higher identification scores than the non-stimulated group during the second olfactory test, indicating an immediate effect. Additionally, the identification scores did not decrease during the third olfactory test conducted one month later. This study is believed to reflect the memory of the scents used in the OT (Level 4) [149].

CQ3-3: Are dementia medications and antiparkinsonian drugs effective for OD associated with neurodegenerative diseases?

Recommendation: The efficacy of antiparkinsonian drugs for OD in patients with PD has not been established, but the monoamine oxidase B inhibitor (rasagine) may improve olfactory function in patients with early PD. Additionally, deep brain stimulation (DBS) of the hypothalamus in PD may improve olfactory function due to its acute effect at the onset. There are currently no studies on the effectiveness of dementia medications for OD in patients with AD. It remains an option.

(Strength of Recommendation: Optional, Quality of Evidence: C, Consensus Rate: 100 %)

Evidence Summary

In a group of patients with relatively mild PD (Hoehn & Yahr stages I or II), a comparison was made between 20 patients taking PD

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medications, including levodopa, amantadine, bromocriptine, and anticholinergics (with an average disease duration of 7 years), and 20 patients who were not taking these (with an average duration of 2.6 years). No significant difference was found in the UPSIT scores between the two groups (Level 4) [150]. In a study involving PD patients, 17 individuals taking rasagiline, an MAO-B inhibitor were compared to 17 individuals not taking the medication in terms of olfactory function, using the Sniffin' Sticks test, at baseline and again after 120 days. No statistically significant differences were observed between the two groups (Level 3) [151]. In a cross-sectional study involving 224 PD patients, there were no significant differences in olfactory function between the rasagiline group (74 patients) and the non-rasagiline group (150 patients). However, in early PD patients with a disease duration of less than 5 years, the rasagiline group demonstrated better discrimination scores. This suggests that rasagiline may have the potential to improve olfactory information processing abilities in early PD (Level 3) [152].

There has been research on the effects of DBS of the hypothalamus on olfactory function in PD patients. DBS involves the insertion of stimulating electrodes into the brain, which deliver programmed stimulation from a neurostimulator implanted subcutaneously in the upper chest, with the aim of improving symptoms. Studies with a small number of cases have not yielded consistent results. In a study of 15 PD patients, no changes in olfactory function were observed 12 months after the initiation of DBS when the stimulation was turned off. However, during stimulation, improvements in motor function were noted, along with enhanced discrimination abilities for five odors (acetic acid, amyl acetate (banana scent), mint, floral fragrance, and methyl indole) (Level 4) [153]. On the other hand, with DBS, the Sniffin' Sticks scores showed that 6 out of 15 patients improved, 5 remained unchanged, and 4 worsened, with no statistically significantly significant overall improvement [154]. In another study involving 10 PD patients, the UPSIT scores deteriorated three months after the initiation of DBS (Level 4) [155]. In a study involving a large number of cases, a total of 39 patients showed improvement in all components of the Sniffin' Sticks test three months after the initiation of DBS [156]. Similarly, another study with 65 patients also reported improvement (Level 4) [157].

Funding

Funding for paper preparation and literature searches were provided by the Japanese Rhinologic Society (JRS).

Authors' disclosure and potential conflict of interest

The following financial conflict of interests are shown as organizations and companies that have provided non-personal financial interests related to the content of this guideline to members of the guideline creation committee. Tsuzuki K. received lecture fees from Sanofi K.K. (2021 and Meiji Seika Pharma Co., Ltd. (2021), and research funds from Sanofi K.K. (2021). Takeno S. received lecture fees from Sanofi K.K. (2020-2022) and Mitsubishi Tanabe Corporation (2021). Miwa T. received lecture fees from Sanofi K.K. (2020 and 2022). Iijima M. received lecture fees from Eisai Co., Ltd. (2021), Ono Pharmaceutical Co., Ltd. (2021), and Takeda Pharmaceutical Co., Ltd. (2020 and 2022). Kondo K. received lecture fees from Sanofi K.K. (2020-2022) and Mitsubishi Tanabe Corporation (2020-2022). Motoo Y. has received lecture fees from Tsumura Corporation (2020-2022). Mori E received lecture fees from Sanofi K.K. (2022).

Author contributions

Contributor Tsuzuki K., as the chair of the Guideline Committee, was

responsible for organization and coordination of the creation of the guidelines. Tsuzuki K. (1st author) through Suzuki M. (13th author) were responsible for summarization and the draft recommendations. Horii S. (14th author) through Umeda-Kameyama Y. (25th author) were responsible for the systematic review and vetted the papers. Tanaka H (26th author) handled the formatting and management of the text. Haruna S. (22th author) as president of the JRS, and Takeno S. and Miwa T. (28th and 29th authors), as executive directors of the JRS, supervised the creation of the guidelines. All authors have final approval of the version to be published.

Acknowledgments

We deeply thank Ms. Tomomi Kojima, a staff member of the Japan Medical Library Association, a nonprofit organization, for assistance in the literature search. We deeply thank Professor Takeo Nakayama at the Department of Health Informatics, Kyoto University School of Public Health, for their advice during the development of these guidelines.

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