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Clinical practice guidelines for the management of olfactory dysfunction — Secondary publication

  • Takaki Miwa
    Correspondence
    Corresponding author at: Department of Otorhinolaryngology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
    Affiliations
    Department of Otorhinolaryngology, Kanazawa Medical University, Japan
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    Katsuhisa Ikeda
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    Affiliations
    Department of Otorhinolaryngology, Juntendo University, Japan
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    Takuya Ishibashi
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    Affiliations
    Department of Otorhinolaryngology, Head and Neck Surgery, Hiroshima University, Japan
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    Masayoshi Kobayashi
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    Department of Otorhinolaryngology–Head and Neck Surgery, Mie University, Japan
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    Kenji Kondo
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    1 Authors from K.I.b to K.T.i contributed equally to this work.
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    Department of Otorhinolaryngology, The University of Tokyo, Japan
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    Yoshinori Matsuwaki
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    Matsuwaki Clinic Shinagawa, Japan
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    Takao Ogawa
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    Department of Otorhinolaryngology, Shiga University of Medical Science, Japan
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    Hideaki Shiga
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    Department of Otorhinolaryngology, Kanazawa Medical University, Japan
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    Motohiko Suzuki
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    Department of Otorhinolaryngology, Nagoya City University, Japan
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    Kenzo Tsuzuki
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    1 Authors from K.I.b to K.T.i contributed equally to this work.
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    Department of Otolaryngology–Head and Neck Surgery, Hyogo College of Medicine, Japan
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  • Atsuko Furuta
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    Department of Otorhinolaryngology, Nippon Medical School Tama Nagayama Hospital, Japan
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  • Yoshiharu Motoo
    Affiliations
    Department of Medical Oncology, Kanazawa Medical University, Japan
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  • Shigeharu Fujieda
    Affiliations
    Division of Otorhinolaryngology Head and Neck Surgery, Department of Sensory and Locomotor Medicine, University of Fukui, Japan
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  • Yuichi Kurono
    Affiliations
    Department of Otolaryngology, Head and Neck Surgery, Kagoshima University, Japan
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    1 Authors from K.I.b to K.T.i contributed equally to this work.
Open AccessPublished:May 07, 2019DOI:https://doi.org/10.1016/j.anl.2019.04.002

      Abstract

      Objective

      To provide an evidence-based recommendation for the management of olfactory dysfunction in accordance with the consensus reached by the Subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction in the Japanese Rhinologic Society.

      Methods

      Seven clinical questions (CQs) regarding the management of olfactory dysfunction were formulated by the subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction. We searched the literature published between April 1990 and September 2014 using PubMed, the Cochrane Library, and Ichushi Web databases. The main search terms were “smell disorder,” “olfactory dysfunction,” “olfactory loss,” “olfactory disturbance,” “olfactory impairments,” “olfaction disorder,” “smell disorder,” “anosmia,” “cacosmia,” and “dysosmia.” Based on the results of the literature review and the expert opinion of the Subcommittee, 4 levels of recommendation, from A—strongly recommended to D—not recommended, were adopted for the management of olfactory dysfunction.

      Results

      Both oral and locally administered corticosteroids have been strongly recommended for patients with olfactory dysfunction due to chronic rhinosinusitis. Nasal steroid spray and antihistamine drugs have been moderately recommended for patients with allergic rhinitis. Although no drugs have been deemed to be truly effective for post-viral olfactory dysfunction by randomized-controlled trials (RCTs) or placebo-controlled trials, olfactory training using odorants has been reported to be effective for improving olfactory function. There is considerable evidence that olfactory testing is useful for differential diagnosis, prediction of disease progression, and early detection of cognitive decline in neurodegenerative diseases.

      Conclusion

      The Clinical Practice Guideline has developed recommendations for the management of various aspects of olfactory dysfunction.

      Keywords

      1. Introduction

      Olfaction is an important sensation for daily life. Not only is olfaction linked to the pleasure experienced during eating, but it is also essential for avoiding dangerous situations, such as fire and eating spoiled food. Therefore, olfactory dysfunction not only reduces the quality of life, but can also be life-threatening [
      • Miwa T.
      • Furukawa M.
      • Tsukatani T.
      • Costanzo R.M.
      • DiNardo L.J.
      • Reiter E.R.
      Impact of olfactory impairment on quality of life and disability.
      ,
      • Santos D.V.
      • Reiter E.R.
      • DiNardo L.J.
      • Costanzo R.M.
      Hazardous events associated with impaired olfactory function.
      ]. Recent work has reported that olfactory dysfunction is associated with neurodegenerative diseases, such as Alzheimer’s disease and other cognitive disorders, as well as movement diseases, such as Parkinson’s disease [
      • Nordin S.
      • Murphy C.
      Impaired sensory and cognitive olfactory function in questionable Alzheimer’s disease.
      ,
      • Suzuki Y.
      • Yamamoto S.
      • Umegaki H.
      • Onishi J.
      • Mogi N.
      • Fujishiro H.
      • et al.
      Smell identification test as an indicator for cognitive impairment in Alzheimer’s disease.
      ,
      • Ansari K.A.
      • Johnson A.
      Olfactory function in patients with Parkinson’s disease.
      ,
      • Ross G.W.
      • Petrovitch H.
      • Abbott R.D.
      • Tanner C.M.
      • Popper J.
      • Masaki K.
      • et al.
      Association of olfactory dysfunction with risk for future Parkinson’s  disease.
      ]. Although previous surveys have reported that the prevalence of olfactory dysfunction was 1–4% [
      • Wysocki C.J.
      • Gilbert A.N.
      National geographic smell survey: effects of age are heterogenous.
      ,
      • Hoffman H.J.
      • Ishii E.K.
      • Macturk R.H.
      Age-related changes in the prevalence of smell/taste problems among the United States adult population. Results of the 1994 disability supplement to the National Health Interview Survey (NHIS).
      ,
      • Murphy C.
      • Schubert C.
      • Cruickshanks K.J.
      • Klein B.E.
      • Klein R.
      • Nondahl D.M.
      Prevalence of olfactory impairment in older adults.
      ,
      • Schubert C.R.
      • Cruickshanks K.J.
      • Fischer M.E.
      • Huang G.H.
      • Klein B.E.
      • Klein R.
      • et al.
      Olfactory impairment in an adult population: the Beaver Dam Offspring Study.
      ], more recent reports have demonstrated that more than 20% of the population suffer from olfactory dysfunction [
      • Rawal S.
      • Hoffman H.J.
      • Bainbridge K.E.
      • Huedo-Medina T.B.
      • Duffy V.B.
      Prevalence and risk factors of self-reported smell and taste alterations: results from the 2011-2012 US National Health and Nutrition Examination Survey (NHANES).
      ]. Therefore, it is important to establish and disseminate guidelines for the diagnosis and treatment of olfactory dysfunction.
      Olfactory dysfunction is etiologically divided into three categories as follows: conductive dysfunction (e.g., airborne dysfunction caused by sinusitis and nasal allergy), sensorineural dysfunction (e.g., degeneration of the olfactory epithelium and nerves caused by viral infection and drug-induced impairment), and central dysfunction (e.g., disorder of the central nervous system caused by head injury, neurodegenerative diseases, and congenital anomalies) [
      • Hummel T.
      • Whitcroft K.L.
      • Andrews P.
      • Altundag A.
      • Cinghi C.
      • Costanzo R.M.
      • et al.
      Position paper on olfactory dysfunction.
      ]. Since these different pathophysiological mechanisms require different treatments, appropriate and individual diagnoses are essential. Although many reviews and textbooks about olfactory dysfunction have already been published [
      • Cowart B.J.
      • Young I.M.
      • Feldman R.S.
      • Lowry L.D.
      Clinical disorders of smell and taste.
      ,
      • Doty R.L.
      Olfaction.
      ], no clinical practice guidelines for the diagnosis and treatment of olfactory dysfunction have been published.
      On this basis, the Japanese Rhinologic Society (JRS) developed the Subcommittee of the Japanese Clinical Practice Guideline for the management of olfactory dysfunction. This clinical practice guideline reports the evidence-based recommendations for managing olfactory dysfunction in accordance with the consensus reached by the Subcommittee.
      It should be emphasized that the recommendations for the clinical practice guidelines are not yet standard in terms of medical care and legal grounds, and that treatment should be decided based on individual clinical situations [
      • Hurwitz B.
      Legal and political considerations of clinical practice guidelines.
      ].

      2. Users and subjects

      The target clinician for this guideline is anyone who engages in the medical management of olfactory dysfunction. The target subjects for this guideline are adults and children with a diagnosis of olfactory dysfunction.

      3. Literature search and evidence collection

      The subcommittee of the Japanese Clinical Practice Guideline for the management of olfactory dysfunction raised 7 clinical questions (CQs) regarding the management of olfactory dysfunction.
      To develop recommendations for these CQs, systematic reviews were performed. All members of the subcommittee of the Japanese Clinical Practice Guideline for the management of olfactory dysfunction, and a professional information specialist from the Japanese Medical Library Association, a non-profit corporation, cooperatively retrieved documents from 15th Oct. 2014 through to 16th Oct. 2014 by using an explicit search strategy. We searched for clinical practice guidelines, systematic reviews, RCTs, and comparative studies published between April 1990 and September 2014 using the PubMed, Cochrane Library, and Ichushi Web (the Japan Medical Abstracts Society website) databases. The main search terms were “smell disorder,” “olfactory dysfunction,” “olfactory loss,” “olfactory disturbance,” “olfactory impairments,” “olfaction disorder,” “smell disorder,” “anosmia,” “cacosmia,” and “dysosmia.”

      4. Critical appraisal of the evidence

      Members of the subcommittee of the Japanese Clinical Practice Guideline for the management of olfactory dysfunction reviewed the extracted articles detailed above. Two people were assigned for each CQ and they selected relevant articles to each CQ and collected relevant information. The subcommittee then assessed and summarized the information, and after achieving a consensus, coded the findings. The recommendation levels defined by the Medical Information Distribution Service (Minds), described below, were used to evaluate the efficacy of the treatment/examination in each CQ.
      A: strong scientific evidence, and implementation of the treatment is strongly recommended;
      B: scientific evidence, and recommended implementation of the treatment is moderate;
      C: no scientific evidence, but implementation of the treatment is weakly recommended;
      D: evidence suggests ineffectiveness or harm, and implementation of the treatment is not recommended.

      5. Reviews before the release of the guideline

      The draft guideline was externally evaluated and reviewed by both the JRS and the Oto-Rhino-Laryngological Society of Japan. After making corrections according to feedback, the published guideline received public comments on the JRS website.

      6. Standard olfactory testing in Japan

      T&T olfactometer and intravenous olfactory tests have been used in Japan as an evaluation for patients with olfactory dysfunction. Because these tests are less well known in other countries, their methods and referent values will be introduced briefly.
      T&T olfactometer is composed of five odors (β-phenylethyl alcohol, methyl cyclopentenolone, isovaleric acid, γ-undecalactone, and skatole; Table 1) and seven or eight graded series of concentrations (Fig. 1: Daiichi Yakuhin Sangyo, Tokyo, Japan). The odor detection threshold and odor recognition threshold are recorded on the olfactogram as shown in Fig. 2. The normal odor recognition threshold score of each nostril is 1.0 or less. The severity of olfactory dysfunction was categorized according to the mean T&T recognition thresholds, and patients were diagnosed with anosmia when the T&T recognition thresholds were 5.6 or greater (Table 2). The improvement in the T&T odor recognition threshold was judged according to the criteria of the Japanese Rhinologic Society (Table 3). Intravenous injection of thiamine Propyldisulfide (Alinamin) induces the sensation of a garlic-like odor, and Alinamin injection is widely used as one of the subjective olfactory tests in Japan. The mean of latency time and duration time in healthy volunteers are 8 s and 70 s, respectively. Nonresponders in the Alinamin test have been previously shown to have poor prognosis in the recovery of olfactory acuity.
      Table 1Words expressing qualities of standard odors.
      ItemCompound nameCharacter of odors
      Aβ-Phenylethyl alcoholOdor of rose, light sweet odor
      BMethyl cyclopentenoloneBurnt odor, caramel odor
      CIsovaleric acidPutrid odor, sweaty odor, odor of long-worn socks
      Dγ-UndecalactoneCanned peach odor, heavy sweet odor
      ESkatoleOdor of vegetable garbage, oral odor, aversive odor
      Table 2The severity of olfactory dysfunction determined by average T&T odor recognition thresholds for five odors.
      Recognition thresholdSeverity of olfactory dysfunction
      ≤ 1.0Normal
      1.1–2.5Mild hyposmia
      2.6–4.0Moderate hyposmia
      4.1–5.5Severe hyposmia
      ≥ 5.6Anosmia
      Table 3Changes in patient odor recognition threshold according to criteria of the Japanese Rhinologic Society using a T&T olfactometer.
      CategoryAverage recognition threshold changes after treatment
      CuredPatient odor recognition threshold achieved of ≤ 2.0
      ImprovedPatient odor recognition threshold decreased by ≥1.0 from pre-treatment condition
      WorsenedPatient odor recognition threshold increased by ≥1.0 from pre-treatment condition
      No changeAll other cases

      7. Clinical questions and recommendations

      7.1 CQ1: Is medical therapy effective in treating olfactory dysfunction caused by chronic rhinosinusitis?

      Tabled 1
      Grade of recommendation: A

      7.1.1 Local treatment of corticosteroids

      Randomized, double-blinded, placebo-controlled trials of the efficacy of mometasone nasal spray in patients with nasal polyps have shown that olfactory scores improved significantly with mometasone compared to placebo after 1 month of treatment [
      • Small C.B.
      • Hernandez J.
      • Reyes A.
      • Schenkel E.
      • Damiano A.
      • Stryszak P.
      • et al.
      Efficacy and safety of mometasone furoate nasal spray in nasal polyposis.
      ,
      • Stjärne P.
      • Mösges R.
      • Jorissen M.
      • Passàli D.
      • Bellussi L.
      • Staudinger H.
      • et al.
      A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis.
      ]. The adverse events included epistaxis and upper respiratory tract infection, none of which were serious. A prospective study reported that treatment with steroid nasal drops in the supine position with the head tilted back in patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) improved the odor threshold and identification scores on the Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test [
      • Mott A.E.
      • Cain W.S.
      • Lafreniere D.
      • Leonard G.
      • Gent J.F.
      • Frank M.E.
      Topical corticosteroid treatment of anosmia associated with nasal and sinus disease.
      ]. Application of gelatin dressing combined with triamcinolone (10 mg/mL) at the olfactory cleft after endoscopic sinus surgery (ESS) has been reported to significantly improve threshold scores on the CCCRC test compared to those in a control group (gelatin dressing with saline) [
      • Bardaranfar M.H.
      • Ranjbar Z.
      • Dadgarnia M.H.
      • Atighechi S.
      • Mirvakili A.
      • Behniafard N.
      • et al.
      The effect of an absorbable gelatin dressing impregnated with triamcinolone within the olfactory cleft on polypoid rhinosinusitis smell disorders.
      ]. A prospective study in patients with CRSwNP compared the effects of fluticasone nasal spray for 8 weeks after ESS (surgical group) and fluticasone nasal spray alone for 8 weeks (medical group); olfactory awareness scores and threshold and identification scores on the CCCRC test were significantly improved at 8 and 12 weeks after treatment in the medical group, albeit not as markedly as in the surgical group [
      • Baradaranfar M.H.
      • Ahmadi Z.S.
      • Dadgarnia M.H.
      • Bemanian M.H.
      • Atighechi S.
      • Karimi G.
      • et al.
      Comparison of the effect of endoscopic sinus surgery versus medical therapy on olfaction in nasal polyposis.
      ]. A randomized, double-blinded comparative study compared the effects of an oral leukotriene inhibitor and beclomethasone nasal spray on nasal symptoms after nasal endoscopic surgery [
      • Mostafa B.E.
      • Abdel Hay H.
      • Mohammed H.E.
      • Yamani M.
      Role of leukotriene inhibitors in the postoperative management of nasal polyps.
      ]. At 1 year, symptom scores were improved in all patients. Improvements in nasal itching, post-nasal discharge, and headache were more marked in the leukotriene inhibitor group than in the fluticasone spray group, and improvements in olfactory dysfunction and nasal obstruction was more marked in the beclomethasone spray group.

      7.1.2 Oral corticosteroids administration

      The efficacy of oral prednisolone in patients who do not improve with local treatment [
      • Ikeda K.
      • Sakurada T.
      • Suzaki Y.
      • Takasaka T.
      Efficacy of systemic corticosteroid treatment for anosmia with nasal and paranasal sinus disease.
      ,
      • Heilmann S.
      • Huettenbrink K.B.
      • Hummel T.
      Local andsystemic administration of corticosteroids in the treatment of olfactory loss.
      ] and the usefulness of combined local treatment and oral prednisolone [
      • Vaidyanathan S.
      • Barnes M.
      • Williamson P.
      • Hopkinson P.
      • Donnan P.T.
      • Lipworth B.
      Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial.
      ,
      • Alobid I.
      • Benitez P.
      • Cardelus S.
      • de Borja Callejas F.
      • Lehrer-Coriat E.
      • Pujols L.
      • et al.
      Oral plus nasal corticosteroids improve smell, nasal congestion, and inflammation in sino-nasal polyposis.
      ] have been reported. Oral prednisolone (40–60 mg/day for 10–14 days) has been reported to improve the mean olfactory recognition threshold in 83% of patients who did not respond to local treatments with betamethasone or beclomethasone [
      • Ikeda K.
      • Sakurada T.
      • Suzaki Y.
      • Takasaka T.
      Efficacy of systemic corticosteroid treatment for anosmia with nasal and paranasal sinus disease.
      ]. Furthermore, some patients have been reported to experience an exacerbation of symptoms when oral prednisolone was discontinued, which indicates the need for oral steroids in maintaining improved olfaction [
      • Ikeda K.
      • Sakurada T.
      • Suzaki Y.
      • Takasaka T.
      Efficacy of systemic corticosteroid treatment for anosmia with nasal and paranasal sinus disease.
      ]. In another study, odor identification function (Sniffin’ Sticks test) did not improve with mometasone nasal spray (1–3 months) but improved significantly with oral prednisolone (starting at 40 mg/day with a gradual dose reduction, 21 days) [
      • Heilmann S.
      • Huettenbrink K.B.
      • Hummel T.
      Local andsystemic administration of corticosteroids in the treatment of olfactory loss.
      ]. A randomized, double-blinded, placebo-controlled trial in patients with CRSwNP showed that olfactory visual analogue scale (VAS) scores were significantly improved in the oral prednisolone group (25 mg/day for 2 weeks) compared to the placebo group, and that this improvement in olfactory function could be subsequently maintained with fluticasone nasal spray (26 weeks) [
      • Vaidyanathan S.
      • Barnes M.
      • Williamson P.
      • Hopkinson P.
      • Donnan P.T.
      • Lipworth B.
      Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial.
      ]. One randomized controlled study was conducted to assess the effects of oral prednisolone (30 mg/day for 4 days, with gradual dose reduction by 5 mg/day every other day, for a total of 2 weeks) in patients with CRSwNP [
      • Alobid I.
      • Benitez P.
      • Cardelus S.
      • de Borja Callejas F.
      • Lehrer-Coriat E.
      • Pujols L.
      • et al.
      Oral plus nasal corticosteroids improve smell, nasal congestion, and inflammation in sino-nasal polyposis.
      ]. The treatment group showed significant improvements in olfactory test scores (Barcelona Small Test 24) and better maintenance of olfactory function with subsequent budesonide local treatment (12 weeks), compared to the control group.
      Based on these reports, both local and oral steroids can be considered effective in treating olfactory dysfunction. Appropriate combinations of steroids and surgery appear to be even more effective than the administration of steroids or surgery alone.

      7.1.3 Macrolides

      Some reports have examined the use of erythromycin, clarithromycin, and roxithromycin for treating olfactory dysfunction caused by CRS. A randomized, placebo-controlled, double-blinded study of roxithromycin (150 mg/day for 3 weeks) in patients with CRS did not show any significant improvement in threshold and discrimination scores on the Sniffin’ Sticks test after treatment [
      • Wallwork B.
      • Coman W.
      • Mackay-Sim A.
      • Greiff L.
      • Cervin A.
      A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis.
      ]. Evidence for the direct effects of macrolide therapy on olfactory dysfunction appears to be insufficient.

      7.1.4 Omalizumab

      A randomized, double-blinded, placebo-controlled trial of omalizumab (anti-immunoglobulin (Ig)E antibody) was conducted in patients with CRSwNP presenting with bronchial asthma [
      • Gevaert P.
      • Calus L.
      • Van Zele T.
      • Blomme K.
      • De Ruyck N.
      • Bauters W.
      • et al.
      Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.
      ]. Omalizumab administered subcutaneously for 16 weeks (8 times every 2 weeks or 4 times a month based on serum total IgE concentration and body weight at the pre-treatment baseline) significantly improved the olfactory awareness score (loss of sense of smell) compared to the placebo group.

      7.2 CQ2: Is endoscopic sinus surgery effective in treating olfactory dysfunction caused by chronic rhinosinusitis?

      Tabled 1
      Grade of recommendation: B
      A prospective study was conducted to compare the effects of a steroidal nasal spray after ESS (surgery group) and a steroidal nasal spray alone (conservative treatment group) [
      • Baradaranfar M.H.
      • Ahmadi Z.S.
      • Dadgarnia M.H.
      • Bemanian M.H.
      • Atighechi S.
      • Karimi G.
      • et al.
      Comparison of the effect of endoscopic sinus surgery versus medical therapy on olfaction in nasal polyposis.
      ]. Patients were matched by age, smoking history, and severity of obstruction. Both groups showed improvements in olfaction, although the remission rate was significantly greater in the surgery group (60%) compared to the conservative treatment group (20%). Most other reports have described observational studies with an olfactory dysfunction improvement ratio of 70% after surgery [
      • Bardaranfar M.H.
      • Ranjbar Z.
      • Dadgarnia M.H.
      • Atighechi S.
      • Mirvakili A.
      • Behniafard N.
      • et al.
      The effect of an absorbable gelatin dressing impregnated with triamcinolone within the olfactory cleft on polypoid rhinosinusitis smell disorders.
      ,
      • Baradaranfar M.H.
      • Ahmadi Z.S.
      • Dadgarnia M.H.
      • Bemanian M.H.
      • Atighechi S.
      • Karimi G.
      • et al.
      Comparison of the effect of endoscopic sinus surgery versus medical therapy on olfaction in nasal polyposis.
      ,
      • Katotomichelakis M.
      • Simopoulos E.
      • Tripsianis G.
      • Prokopakis E.
      • Danielides G.
      • Velegrakis S.G.
      • et al.
      Improvement of olfactory function for quality of life recovery.
      ,
      • Simopoulos E.
      • Katotomichelakis M.
      • Gouveris H.
      • Tripsianis G.
      • Livaditis M.
      • Danielides V.
      Olfaction-associated quality of life in chronic rhinosinusitis: adaptation and validation of an olfaction-specific questionnaire.
      ,
      • Jiang R.S.
      • Lu F.J.
      • Liang K.L.
      • Shiao J.Y.
      • Su M.C.
      • Hsin C.H.
      • et al.
      Olfactory function in patients with chronic rhinosinusitis before and after functional endoscopic sinus surgery.
      ,
      • Briner H.R.
      • Jones N.
      • Simmen D.
      Olfaction after endoscopic sinus surgery: long-term results.
      ,
      • Busaba N.Y.
      The impact of a patient’s age on the clinical presentation of inflammatory paranasal sinus disease.
      ,
      • Delank K.W.
      • Stoll W.
      Olfactory function after functional endoscopic sinus surgery for chronic sinusitis.
      ,
      • Downey L.L.
      • Jacobs J.B.
      • Lebowitz R.A.
      Anosmia and chronic sinus disease.
      ,
      • Katotomichelakis M.
      • Gouveris H.
      • Tripsianis G.
      • Simopoulou M.
      • Papathanassiou J.
      • Danielides V.
      Biometric predictive models for the evaluation of olfactory recovery after endoscopic sinus surgery in patients with nasal polyposis.
      ,
      • Oka H.
      • Tsuzuki K.
      • Takebayashi H.
      • Kojima Y.
      • Daimon T.
      • Sakagami M.
      Olfactory changes after endoscopic sinus surgery in patients with chronic rhinosinusitis.
      ,
      • Perry B.F.
      • Kountakis S.E.
      Subjective improvement of olfactory function after endoscopic sinus surgery for chronic rhinosinusitis.
      ,
      • Saedi B.
      • Sadeghi M.
      • Yazdani N.
      • Afshari A.
      Effectiveness of FESS in smell improvement of sinusitis patients.
      ,
      • Shin S.H.
      • Park J.Y.
      • Sohn J.H.
      Clinical value of olfactory function tests after endoscopic sinus surgery: a short-term result.
      ,
      • Soler Z.M.
      • Sauer D.A.
      • Mace J.C.
      • Smith T.L.
      Ethmoid histopathology does not predict olfactory outcomes after endoscopic sinus surgery.
      ]. Of the 21 articles that examined the improvement ratio, 20 articles reported that surgery is effective for olfactory dysfunction, and only one article reported surgery as ineffective, with an improvement ratio of only 5.7% [
      • Jiang R.S.
      • Lu F.J.
      • Liang K.L.
      • Shiao J.Y.
      • Su M.C.
      • Hsin C.H.
      • et al.
      Olfactory function in patients with chronic rhinosinusitis before and after functional endoscopic sinus surgery.
      ]. However, even that article showed a significant improvement in symptom and threshold scores after surgery.
      Some factors associated with poor prognosis of surgical treatment and subsequent post-operative treatment in CRS to improve olfactory dysfunction include the following: male sex, older age (≥60 or ≥51 years old), long duration of olfactory dysfunction, high circulating eosinophil count, complications (aspirin-induced asthma, bronchial asthma, and eosinophilic otitis media), history of sinus surgery, computed tomography score, absence of response to intravenous olfaction test, nasal polyps, post-operative recurrence of nasal polyps, smoking, degree of olfactory dysfunction, and low income [
      • Simopoulos E.
      • Katotomichelakis M.
      • Gouveris H.
      • Tripsianis G.
      • Livaditis M.
      • Danielides V.
      Olfaction-associated quality of life in chronic rhinosinusitis: adaptation and validation of an olfaction-specific questionnaire.
      ,
      • Busaba N.Y.
      The impact of a patient’s age on the clinical presentation of inflammatory paranasal sinus disease.
      ,
      • Saedi B.
      • Sadeghi M.
      • Yazdani N.
      • Afshari A.
      Effectiveness of FESS in smell improvement of sinusitis patients.
      ,
      • Shin S.H.
      • Park J.Y.
      • Sohn J.H.
      Clinical value of olfactory function tests after endoscopic sinus surgery: a short-term result.
      ].

      7.3 CQ3: Is medical therapy effective in olfactory dysfunction caused by allergic rhinitis?

      Tabled 1
      Grade of recommendation: B

      7.3.1 Nasal steroid spray

      Nasal steroid spray may improve olfactory function through inhibition of inflammation in the olfactory cleft [
      • Sivam A.
      • Jeswani S.
      • Reder L.
      • Wang J.
      • DeTineo M.
      • Taxy J.
      • et al.
      Olfactory cleft inflammation is present in seasonal allergic rhinitis and is reduced with intranasal steroids.
      ], because there is a possibility that eosinophilia in the olfactory mucosa induces olfactory dysfunction [
      • Ozaki S.
      • Toida K.
      • Suzuki M.
      • Nakamura Y.
      • Ohno N.
      • Ohashi T.
      • et al.
      Impaired olfactory function in mice with allergic rhinitis.
      ]. In a randomized, placebo-controlled, double-blinded, crossover study, budesonide nasal spray significantly improved the olfactory detection threshold [
      • Hilberg O.
      Effect of terfenadine and budesonide on nasal symptoms, olfaction, and nasal airway patency following allergen challenge.
      ]. Another double-blinded, randomized study also demonstrated that mometasone furoate significantly improved odor identification, although olfactory detection did not change [
      • Meltzer E.O.
      • Jalowayski A.A.
      • Orgel H.A.
      • Harris A.G.
      Subjective and objective assessments in patients with seasonal allergic rhinitis: effects of therapy with mometasone furoate nasal spray.
      ]. On the other hand, Stuck et al. conducted a randomized double-blinded trial, and showed that the olfactory detection threshold, but not odor identification, was improved by using a nasal steroid spray [
      • Stuck B.A.
      • Blum A.
      • Hagner A.E.
      • Hummel T.
      • Klimek L.
      • Hörmann K.
      Mometasone furoate nasal spray improves olfactory performance in seasonal allergic rhinitis.
      ].

      7.3.2 Antihistamines

      A randomized double-blinded trial also demonstrated that antihistamine drugs significantly improved VAS scores of olfactory dysfunction [
      • Guilemany J.M.
      • García-Piñero A.
      • Alobid I.
      • Cardelús S.
      • Centellas S.
      • Bartra J.
      • et al.
      Persistent allergic rhinitis has a moderate impact on the sense of smell, depending on both nasal congestion and inflammation.
      ]. In another randomized double-blinded trial, VAS scores of olfactory function were significantly improved with antihistamine drug treatment, but anosmia did not improve [
      • Kalpaklioglu A.F.
      • Kavut A.B.
      Comparison of azelastine versus triamcinolone nasal spray in allergic and nonallergic rhinitis.
      ].

      7.4 CQ4: Is medical therapy effective in treating post-viral olfactory dysfunction?

      Tabled 1
      Grade of recommendation: C
      Since post-viral olfactory dysfunction (PVOD) is a sensorineural olfactory dysfunction its recovery should require the regeneration of the olfactory epithelium/neural pathway. In Japan, several kinds of drugs, such as zinc sulfate, Kampo medicine, oral and intranasal steroids, vitamins, and adenosine triphosphate (ATP) have been used for the clinical treatment of PVOD. There were double-blind, randomized, placebo-controlled trials to test the efficacy of several drugs on PVOD, but none of the studies demonstrated statistically significant therapeutic effects. On the other hand, olfactory training using odorants has been reported to be effective in improving olfactory function in PVOD [
      • Hummel T.
      • Rissom K.
      • Reden J.
      • Hähner A.
      • Weidenbecher M.
      • Hüttenbrink K.B.
      Effects of olfactory training in patients with olfactory loss.
      ].
      One important point to be considered is that previous studies examining the effects of medication on PVOD enrolled many patients with long-lasting olfactory dysfunction after onset. Therefore, information about whether such medication is effective for the treatment of PVOD soon after its onset is still limited. Another point to be considered is that PVOD shows some natural recovery [
      • Reden J.
      • Mueller A.
      • Mueller C.
      • Konstantinidis I.
      • Frasnelli J.
      • Landis B.N.
      • et al.
      Recovery of olfactory function following closed head injury or infections of the upper respiratory tract.
      ,
      • Duncan H.J.
      • Seiden A.M.
      Long-term follow-up of olfactory loss secondary to head trauma and upper respiratory tract infection.
      ]. Therefore, placebo-controlled studies are necessary to accurately evaluate the effect of drugs on PVOD.

      7.4.1 Zinc

      Zinc is a trace metal involved in enzyme activity, especially those involved in cell proliferation. Therefore, zinc has been considered essential to maintain the function of olfactory and taste organs in which the sensory cells are constantly regenerated. Zinc sulfate has long been used to treat olfactory and taste dysfunction, but there is no clear evidence about the effects of zinc on PVOD. In one double-blinded study, Zinc administration did not improve PVOD vs. a placebo group [
      • Henkin R.I.
      A double-blind study of the effects of zinc sulfate on taste and smell dysfunction.
      ]. In a study by Aiba et al. 184 patients with PVOD were divided into three groups, as follows: (1) a group treated with zinc sulfate, (2) a group treated with a combination of intranasal steroid, vitamin B, and zinc sulfate, and (3) a group treated with a combination of intranasal steroids and vitamin B. There was no significant between-group difference in the improvement in olfactory function [
      • Aiba T.
      • Sugiura M.
      • Mori J.
      • Matsumoto K.
      • Tomiyama K.
      • Okuda F.
      • et al.
      Effect of zinc sulfate on sensoryneural olfactory disorder.
      ]. In another study, measured the serum concentration of zinc in patients with PVOD before the start of the treatment [
      • Furuta A.
      • Shino M.
      • Uchida J.
      • Yokomori K.
      • Suzuki E.
      • Suzaki H.
      The evaluation of serum zinc levels in patients with olfactory disturbance.
      ]. The authors reported that, in about half of the patients, the zinc concentration was within a normal range, while in the other half, it was below the normal range. The normal range group exhibited a greater improvement of olfactory function than did the low concentration group; within the low concentration group, patients treated with zinc exhibited a tendency for olfactory function to improve to a greater extent than those without zinc treatment.

      7.4.2 Kampo medicines

      The treatment of PVOD with tokishakuyakusan, a traditional Japanese medicine, greatly improved in olfactory function than that seen with intranasal steroid treatment [
      • Miwa T.
      Sensorineural olfactory dysfunction.
      ]. Tokishakuyakusan has been shown to promote the production of neurotrophic factors and has been used as a supplementary medication for Alzheimer’s disease [
      • Harada H.
      The effects of toki-shyakuyaku-San on alzheimer’s disease.
      ]. Two other Kampo medicines, ninjin’yoeito and kamikihito, have also been used for the treatment of PVOD [
      • Harada H.
      The effects of toki-shyakuyaku-San on alzheimer’s disease.
      ]. The administration with treated tokishakuyakusan or ninjin’yoeito to patients with PVOD who had not responded to intranasal steroids, improved 43% and 36% of patients, respectively [
      • Uchida J.
      • Furuta A.
      • Suzaki H.
      Kampo treatment on the cases of olfactory dysfunction.
      ].

      7.4.3 α-lipoic acid

      After α-lipoic acid (600 mg/day) for 4.5 months were orally administrated to 23 patients with PVOD, the olfactory threshold, discrimination, and identification were evaluated. They found an improvement in the olfactory test score in 61% of patients, no change in 30%, and a worsening in 9% [
      • Hummel T.
      • Heilmann S.
      • Hüttenbrink K.B.
      Lipoic acid in the treatment of smell dysfunction following viral infection of the upper respiratory tract.
      ]. However, their subsequent double-blinded study did not confirm these results [
      • Welge-Lussen A.
      • Wolfensberger M.
      Olfactory disorders following upper respiratory tract infections.
      ].

      7.4.4 Vitamin A

      In a double-blinded, randomized, placebo-controlled trial by Reden et al. [
      • Reden J.
      • Lill K.
      • Zahnert T.
      • Haehner A.
      • Hummel T.
      Olfactory function in patients with postinfections and posttraumatic smell disorders before and after treatment with vitamin A: a double-blind, placebo-controlled, randomized clinical trial.
      ], patients with PVOD received either vitamin A (10,000 U/day) or a placebo for 3 months. Olfactory function was evaluated using the Sniffin’ Stick test, which was administered 5 months after the start of treatment. No significant between-group differences in the outcomes were found.

      7.4.5 Minocycline

      In a double-blinded, randomized, placebo-controlled trial, patients with PVOD received either minocycline (100 mg/day) or placebo for 3 weeks [
      • Reden J.
      • Herting B.
      • Lill K.
      • Kern R.
      • Hummel T.
      Treatment of postinfectious olfactory disorders with minocycline: a double-blind, placebo-controlled study.
      ]. The olfactory tests were performed before and 7 months after the treatment. There were no significant between-group differences in patient outcomes.

      7.4.6 Theophylline

      Theophylline is a non-specific phosphodiesterase inhibitor and increases intracellular cAMP concentrations in neurons. In an open-label trial with 312 patients, including 97 patients with PVOD; after the administration of theophylline (200–800 mg/day), 50.3% of the patients with PVOD reported subjective improvement in olfaction [
      • Henkin R.I.
      • Velicu I.
      • Schmidt L.
      An open-label controlled trial of theophylline for treatment of patients with hyposmia.
      ]. Administration of pentoxifylline, another phosphodiesterase inhibitor, resulted in improvements in the olfactory threshold test in patients with sudden sensorineural hearing loss [
      • Gudziol V.
      • Hummel T.
      Effects of pentoxifylline on olfactory sensitivity: a postmarketing surveillance study.
      ].

      7.4.7 Steroids

      After systemically administration of steroids to patients with CRS or PVOD, Patients with CRS showed significant improvements in olfactory recognition, while patients with PVOD did not [
      • Ikeda K.
      • Sakurada T.
      • Suzaki Y.
      • Takasaka T.
      Efficacy of systemic corticosteroid treatment for anosmia with nasal and paranasal sinus disease.
      ]. However, the authors reported that some patients with PVOD did respond to the steroid treatment and showed an improvement in olfactory recognition, which suggests that steroids may be effective for acute, reversible stages of olfactory mucosal injury. Another group also administered steroids either systemically or intranasally in patients with PVOD [
      • Heilmann S.
      • Huettenbrink K.B.
      • Hummel T.
      Local and systemic administration of corticosteroids in the treatment of olfactory  loss.
      ]. There was no significant effect in the intranasal treatment group, while there was a significant improvement of olfactory scores after systemic steroid administration.

      7.4.8 Olfactory training

      Fifty-six patients with olfactory dysfunction, including 35 patients with PVOD were divided into two groups, as follows: patients in the olfactory training group performed olfactory training using four odorants (rose, eucalyptus, lemon, clove) twice a day for 12 weeks, and the control group did not perform such training [
      • Hummel T.
      • Rissom K.
      • Reden J.
      • Hähner A.
      • Weidenbecher M.
      • Hüttenbrink K.B.
      Effects of olfactory training in patients with olfactory loss.
      ]. The olfactory function of the two groups was evaluated using the Sniffin’ Sticks olfactory test. The olfactory training group showed greater improvements in test scores than the control group [
      • Hummel T.
      • Rissom K.
      • Reden J.
      • Hähner A.
      • Weidenbecher M.
      • Hüttenbrink K.B.
      Effects of olfactory training in patients with olfactory loss.
      ]. The impact of an 8-month period of olfactory training was examined in patients with PVOD (n = 16). The patients exposed themselves to four different odors twice a day, and olfactory function was evaluated at baseline and again at 4 and 8 months after the start of training. Olfactory function was significantly improved at 4 months [
      • Fleiner F.
      • Lau L.
      • Göktas Ö
      Active olfactory training for the treatment of smelling disorders.
      ]. Thirty-nine patients with PVOD exposed themselves to suprathreshold concentrations of four odors over 32 weeks; overall, 31 patients (79%) showed an increased olfactory score at 32 weeks [
      • Geißler K.
      • Reimann H.
      • Gudziol H.
      • Bitter T.
      • Guntinas-Lichius O.
      Olfactory training for patients with olfactory loss after upper respiratory tract infections.
      ]. A recent randomized, single-blind, controlled, multicenter crossover study in Germany including 174 patients with PVOD demonstrated that olfactory training for 18 weeks improved olfactory function, and the use of odors at higher concentrations is beneficial to such improvements [
      • Damm M.
      • Pikart L.K.
      • Reimann H.
      • Burkert S.
      • Göktas Ö
      • Haxel B.
      • et al.
      Olfactory training is helpful in postinfectious olfactory loss: a randomized, controlled, multicenter study.
      ].

      7.5 CQ 5: Are there any effective treatments for post-traumatic olfactory dysfunction?

      Tabled 1
      Grade of recommendation: C
      In Japan, prescriptions of Kampo medicines, zinc or vitamin preparations, topical or systemic steroids, and adenosine triphosphate are used to treat post-traumatic olfactory dysfunction. However, the efficacy of these medicines has not been supported by any studies with high levels of evidence, such as randomized-controlled trials. Several reports have indicated that olfactory training is effective in restoring olfactory function [
      • Konstantinidis I.
      • Tsakiropoulou E.
      • Bekiaridou P.
      • Kazantzidou C.
      • Constantinidis J.
      Use of olfactory training in post-traumatic and postinfectious olfactory dysfunction.
      ].
      Post-traumatic dysfunction has the potential to recover spontaneously, and it is unclear to what degree spontaneous recovery affects the improvement rate. In order to fully investigate the efficacy of a medication, it is necessary to conduct randomized-controlled trials and evaluate therapeutic interventions at an early stage after injury.

      7.5.1 Kampo medicine

      Tokishakuyakusan treatment improved olfactory test scores (using T&T olfactometry) in 41.7% of patients with post-traumatic olfactory dysfunction [
      • Miwa T.
      • Tsukatani T.
      • Ikeno S.
      • Furukawa M.
      The effectiveness of Toki-syakuyaku-san for the olfactory disturbed patients.
      ]. In another study, 7 patients with post-traumatic olfactory dysfunction were treated with kamikihito; 1 patient recovered, 5 patients improved, and 1 patient showed no change [
      • Shiga H.
      Post-traumatic olfactory impairment.
      ].

      7.5.2 Zinc

      Ninety-five patients with post-traumatic olfactory dysfunction were divided into three groups based on the method of treatment as follows: zinc sulfate only, combination of zinc sulfate and the usual therapy (topical corticosteroids and systemic vitamin B complex), or the usual therapy. Patients who were administered zinc sulfate demonstrated significantly higher improvement rates than those who received the usual therapy [
      • Aiba T.
      • Sugiura M.
      • Mori J.
      • Matsumoto K.
      • Tomiyama K.
      • Okuda F.
      • et al.
      Effect of zinc sulfate on sensoryneural olfactory disorder.
      ]. In another study, 22 patients with post-traumatic olfactory dysfunction were treated with zinc sulfate, tokishakuyakusan, and vitamin B12 complex; 5 patients recovered, 5 patients improved, 10 patients showed no change, and 2 patients showed an exacerbation of symptoms [
      • Kitano M.
      • Kobayashi M.
      • Miyamura T.
      • Takeuchi K.
      Prognosticators for the olfactory dysfunction by head injury.
      ].

      7.5.3 Steroids

      Some case studies have reported the efficacy of topical or systemic steroids. A total of 108 patients with post-traumatic olfactory dysfunction were treated with topical steroids, and the improvement rate was 25% [
      • Mori J.
      • Aiba T.
      • Sugiura M.
      • Matsumoto K.
      • Tomiyama K.
      • Okuda F.
      • et al.
      Clinical study of olfactory disturbance.
      ]. In another, 12 patients with post-traumatic olfactory dysfunction were treated with topical betamethasone; 1 out of 12 patients showed an improvement in the olfactory test score. Five patients were also treated with topical dexamethasone, and 3 out of the 5 patients showed an improvement [
      • Ikeda K.
      • Sakurada T.
      • Takasaka T.
      • Okitsu T.
      • Yoshida S.
      Anosmia following head trauma:preliminary study of steroid treatment.
      ]. In another study, 116 patients with post-traumatic olfactory dysfunction were treated with systemic prednisolone (15 mg × QID for 3 days, tapered every 3 days), and the olfactory threshold improved in 19 patients [
      • Jiang R.S.
      • Wu S.H.
      • Liang K.L.
      • Shiao J.Y.
      • Hsin C.H.
      • Su M.C.
      Steroid treatment of posttraumatic  anosmia.
      ]. Patients with post-traumatic olfactory dysfunction were treated with topical betamethasone, and the improvement rate was 28.6%. In this report, the improvement rate between patients who were administered steroids and those administered tokishakuyakusan was compared, but no significant differences were observed [
      • Miwa T.
      Sensorineural olfactory dysfunction.
      ].

      7.5.4 Vitamin A

      In a double-blinded, placebo-controlled study, vitamin A at a dose of 10,000 IU per day was administered to 52 patients with olfactory loss, including 19 patients with post-traumatic olfactory loss, for 3 months. No significant improvement, as evaluated by the olfactory test scores (the Sniffin’ Sticks test) was observed 5 months after the initial test [
      • Reden J.
      • Lill K.
      • Zahnert T.
      • Haehner A.
      • Hummel T.
      Olfactory function in patients with postinfections and posttraumatic smell disorders before and after treatment with vitamin A: a double-blind, placebo-controlled, randomized clinical trial.
      ].

      7.5.5 Olfactory training

      A prospective study with 38 patients with post-traumatic olfactory dysfunction was performed to investigate the effect of olfactory training [
      • Konstantinidis I.
      • Tsakiropoulou E.
      • Bekiaridou P.
      • Kazantzidou C.
      • Constantinidis J.
      Use of olfactory training in post-traumatic and postinfectious olfactory dysfunction.
      ]. The training group underwent olfactory training for 5 min twice daily using the following four odorants: phenylethyl alcohol (rose), eucalyptol (eucalyptus), citronellal (lemon), and eugenol (cloves). Compared to the control group, the training group had significantly higher olfactory function scores, as measured by the Sniffin’ Sticks test at 16 weeks. The improvement rates of both groups were 33% and 13%, respectively.

      7.6 CQ 6: Can olfactory dysfunction contribute to the prediction of early diagnosis of neurodegenerative diseases?

      Tabled 1
      Grade of recommendation: A
      There is considerable evidence that olfactory testing is useful in differential diagnosis, prediction of disease progression, and early detection of cognitive loss in neurodegenerative diseases. Objective olfactory dysfunction is an early sign and common symptom of Parkinson’s disease, and olfactory deficits may precede clinical motor signs. For example, some asymptomatic relatives of patients with Parkinson’s disease have been found to exhibit olfactory dysfunction that can predict the future development of Parkinson’s disease [
      • Ponsen M.M.
      • Stoffers D.
      • Booij J.
      • van Eck-Smit B.L.
      • Wolters E.C.h.
      • Berendse H.W.
      Idiopathic hyposmia as a preclinical sign of Parkinson’s disease.
      ]. Indeed, olfactory dysfunctions are considered as biomarkers of a preclinical diagnosis of Parkinson’s disease and for its differentiation from other forms of parkinsonism [
      • Shah M.
      • Muhammed N.
      • Findley L.J.
      • Hawkes C.H.
      Olfactory tests in the diagnosis of essential tremor.
      ,
      • Deeb J.
      • Shah M.
      • Muhammed N.
      • Gunasekera R.
      • Gannon K.
      • Findley L.J.
      • et al.
      A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson’s disease.
      ,
      • Iijima M.
      • Kobayakawa T.
      • Saito S.
      • Osawa M.
      • Tsutsumi Y.
      • Hashimoto S.
      • et al.
      Differences in odor identification among clinical subtypes of Parkinson’s disease.
      ,
      • Kim J.S.
      • Youn J.
      • Shin H.
      • Cho J.W.
      Nonmotor symptoms in drug-induced parkinsonism and drug-naive Parkinson disease.
      ]. Severe hyposmia is a prominent clinical feature that predicts the subsequent development of Parkinson’s disease [
      • Haehner A.
      • Hummel T.
      • Hummel C.
      • Sommer U.
      • Junghanns S.
      • Reichmann H.
      Olfactory loss may be a first sign of idiopathic Parkinson’s disease.
      ,
      • Baba T.
      • Kikuchi A.
      • Hirayama K.
      • Nishio Y.
      • Hosokai Y.
      • Kanno S.
      • et al.
      Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson’s disease: a 3 year longitudinal study.
      ,
      • Ponsen M.M.
      • Stoffers D.
      • Wolters E.C.
      • Wolters E.C.
      • Booij J.
      • Berendse H.W.
      Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson’s disease.
      ]. Olfactory testing may therefore be a useful screening tool to detect those at high risk for the development of Parkinson’s disease in later life [
      • Haehner A.
      • Hummel T.
      • Hummel C.
      • Sommer U.
      • Junghanns S.
      • Reichmann H.
      Olfactory loss may be a first sign of idiopathic Parkinson’s disease.
      ,
      • Ross G.W.
      • Petrovitch H.
      • Abbott R.D.
      • Tanner C.M.
      • Popper J.
      • Masaki K.
      • et al.
      Association of olfactory dysfunction with risk for future Parkinson’s disease.
      ]. Idiopathic hyposmia in relatives of patients with Parkinson’s disease is also associated with an increased risk of developing clinical Parkinson’s disease [
      • Ponsen M.M.
      • Stoffers D.
      • Wolters E.C.
      • Wolters E.C.
      • Booij J.
      • Berendse H.W.
      Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson’s disease.
      ,
      • Berendse H.W.
      • Booij J.
      • Francot C.M.
      • Bergmans P.L.
      • Hijman R.
      • Stoof J.C.
      • et al.
      Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell.
      ]. In another study, enlarged substantia nigra hyperechogenicity was the most frequent baseline sign in individuals developing Parkinson’s disease compared to healthy controls, followed by the occurrence of mild parkinsonian signs and hyposmia [
      • Lerche S.
      • Seppi K.
      • Behnke S.
      • Liepelt-Scarfone I.
      • Godau J.
      • Mahlknecht P.
      • et al.
      Risk factors and prodromal markers and the development of Parkinson’s disease.
      ]. Olfactory deficits in Parkinson’s disease are not stationary by the time the motor phase is entered but continue to progress over time. The olfactory deficits in Parkinson’s disease have also been found to correlate with both motor and non-motor features [
      • Berendse H.W.
      • Roos D.S.
      • Raijmakers P.
      • Doty R.L.
      Motor and non-motor correlates of olfactory dysfunction in Parkinson’s disease.
      ,
      • Stephenson R.
      • Houghton D.
      • Sundarararjan S.
      • Doty R.L.
      • Stern M.
      • Xie S.X.
      • et al.
      Odor identification deficits are associated with increased risk of neuropsychiatric complications in patients with Parkinson’s disease.
      ]. Another study found that early Parkinson’s disease is associated with frequent and severe olfactory deficits that are correlated with disease severity, symptom duration, and single photon emission computed tomography [
      • Deeb J.
      • Shah M.
      • Muhammed N.
      • Gunasekera R.
      • Gannon K.
      • Findley L.J.
      • et al.
      A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson’s disease.
      ]. Therefore, hyposmia may be useful as a marker of disease progression, at least in the early disease stages.
      Among older persons without cognitive impairment, difficulty in identifying odors has been found to predict subsequent development of mild cognitive impairment in Alzheimer’s disease [
      • Wilson R.S.
      • Schneider J.A.
      • Arnold S.E.
      • Tang Y.
      • Boyle P.A.
      • Bennett D.A.
      Olfactory identification and incidence of mild cognitive impairment in older age.
      ]. In patients with mild cognitive impairment, olfactory identification deficits, particularly with a lack of awareness of olfactory deficits, may have clinical utility as an early diagnostic marker for Alzheimer’s disease [
      • Devanand D.P.
      • Michaels-Marston K.S.
      • Liu X.
      • Pelton G.H.
      • Padilla M.
      • Marder K.
      • et al.
      Olfactory deficits in patients with mild cognitive impairment predict Alzheimer’s disease at follow-up.
      ].

      7.7 CQ7: Are steroids effective in the treatment of olfactory dysfunction? 

      Tabled 1
      Grade of recommendation: B
      A short course of systemic steroids should be prescribed for olfactory dysfunction due to CRSwNP. Topical steroids should be prescribed for olfactory dysfunction due to allergic rhinitis and CRSwNP. The long-term use of high-dose topical steroids should be considered as a risk for pituitary-adrenal suppression. There is limited evidence for the use of steroids in the treatment of olfactory dysfunction caused by other etiologies, such as post-infectious, post-traumatic, and idiopathic olfactory dysfunction.
      One systematic review [
      • Martinez-Deversa P.
      • Patiar S.
      Oral steroids for nasal polyps.
      ] and two randomized placebo-controlled double-blinded trials [
      • Vaidyanathan S.
      • Barnes M.
      • Williamson P.
      • Hopkinson P.
      • Donnan P.T.
      • Lipworth B.
      Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial.
      ,
      • Alobid I.
      • Benitez P.
      • Cardelus S.
      • de Borja Callejas F.
      • Lehrer-Coriat E.
      • Pujols L.
      • et al.
      Oral plus nasal corticosteroids improve smell, nasal congestion, and inflammation in sino-nasal polyposis.
      ] demonstrated that olfactory test scores significantly improved after treatment with oral steroids in patients with CRSwNP. In these studies, oral prednisolone or prednisone was administered at a dose of 15 mg–50 mg, which was gradually tapered over a period of 2–3 weeks. The frequency of adverse events was low. However, in one study, suppression of the pituitary/adrenal system and a decrease in bone metabolism occurred transiently during steroid administration [
      • Martinez-Deversa P.
      • Patiar S.
      Oral steroids for nasal polyps.
      ]. Thus, evidence for the efficacy of oral steroids for olfactory dysfunction is limited to short-term administration, and no long-term administration studies on their efficacy and safety have yet been conducted.
      Three randomized controlled trials have reported that nasal spray steroids improve olfactory test scores of patients with olfactory dysfunction due to allergic rhinitis [
      • Meltzer E.O.
      • Jalowayski A.A.
      • Orgel H.A.
      • Harris A.G.
      Subjective and objective assessments in patients with seasonal allergic rhinitis: effects of therapy with mometasone furoate nasal spray.
      ,
      • Stuck B.A.
      • Blum A.
      • Hagner A.E.
      • Hummel T.
      • Klimek L.
      • Hörmann K.
      Mometasone furoate nasal spray improves olfactory performance in seasonal allergic rhinitis.
      ,
      • Kalpaklioglu A.F.
      • Kavut A.B.
      Comparison of azelastine versus triamcinolone nasal spray in allergic and nonallergic rhinitis.
      ], and two randomized controlled trials have demonstrated that nasal spray steroids can improve subjective olfactory symptoms in patients with olfactory dysfunction due to CRSwNP [
      • Small C.B.
      • Hernandez J.
      • Reyes A.
      • Schenkel E.
      • Damiano A.
      • Stryszak P.
      • et al.
      Efficacy and safety of mometasone furoate nasal spray in nasal polyposis.
      ,
      • Stjärne P.
      • Mösges R.
      • Jorissen M.
      • Passàli D.
      • Bellussi L.
      • Staudinger H.
      • et al.
      A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis.
      ]. There were no serious adverse events due to nasal spray steroids, and no suppression of the pituitary/adrenal system. Nasal spray steroids are recommended as a remedy for olfactory dysfunction secondary to sinonasal disease. A high dose of topical steroids, 0.1% betamethasone nasal drops, has been used in Japan for patients with olfactory dysfunction. However, it has been reported that pituitary-adrenal suppression occurred in 61–68% of patients with olfactory dysfunction due to the use of steroid nasal drops for more than two months [
      • Kobayashi M.
      • Imanishi Y.
      • Ishikawa M.
      • Nishida K.
      • Adachi M.
      • Oishi M.
      • et al.
      Safety and usefulness of the long-term intranasal topical treatment with steroids for olfactory dysfunction.
      ,
      • Makino N.
      • Ohta Y.
      • Ishikawa T.
      • Ichimura K.
      Systemic effects of intranasal steroid drops in patients with dysosmia.
      ]. That said, in these studies, adrenal cortisol production recovered about one month after stopping steroid treatment.
      Regarding olfactory dysfunction caused by other etiologies, including post-infectious, post-traumatic, and idiopathic olfactory dysfunction, there is limited evidence for the efficacy of steroid treatment. In a randomized controlled trial of patients with post-infectious and idiopathic olfactory dysfunction, nasal spray steroids did not improve olfactory test scores [
      • Blomqvist E.H.
      • Lundblad L.
      • Bergstedt H.
      • Stjärne P.
      Placebo-controlled, randomized, double-blind study evaluating the efficacy of fluticasone propionate nasal spray for the treatment of patients with hyposmia/anosmia.
      ]. In three case studies [
      • Heilmann S.
      • Huettenbrink K.B.
      • Hummel T.
      Local and systemic administration of corticosteroids in the treatment of olfactory loss.
      ,
      • Schriever V.A.
      • Merkonidis C.
      • Gupta N.
      • Hummel C.
      • Hummel T.
      Treatment of smell loss with systemic methylprednisolone.
      ,
      • Jiang R.S.
      • Wu S.H.
      • Liang K.L.
      • Shiao J.Y.
      • Hsin C.H.
      • Su M.C.
      Steroid treatment of posttraumatic anosmia.
      ], oral steroids resulted in an improvement in olfactory test scores. However, these studies did not use control groups for comparison. It is therefore difficult to determine whether the recovery of olfaction was due to spontaneous recovery or the effect of treatment.

      Disclosure statement

      This study was funded by The Japanese Rhinologic Society (JRS). The JRS is an independent academic organization that receives no sponsorship or funding from specific organizations or businesses. Furthermore, the JRS received no funding for the preparation of the present guidelines from any businesses, which includes businesses representing the pharmaceutical industry.

      Conflicts of interest

      The authors report no conflicts of interest. Members of the committee with a conflict of interest were excluded from the drafting of any part of the guideline to which the conflict of interest is applicable. Companies that provided non-personal financial conflicts of interest to members of the Committee of the Clinical Practice Guideline during the production of this guideline are listed as follows:
      Ajinomoto Co., Inc., MSD K.K., Tsumura & Co., GlaxoSmithKline K.K., Sanofi K.K., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Co.

      Acknowledgments

      We 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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