Olfaction in allergic rhinitis: A systematic review

Current perspectives

Olfaction in allergic rhinitis: A systematic review Boris A. Stuck, MD,a and Thomas Hummel, MDb

Essen and Dresden, Germany

Olfactory dysfunction is a key symptom in patients with allergic rhinitis (AR). Despite the implications for quality of life, relatively few articles have tested olfactory function in their investigations. The current systematic review aimed to investigate the following 2 questions: (1) What does AR do to human olfaction? (2) How effective is the treatment of AR in restoring the sense of smell? A comprehensive literature search was performed, and human studies of any design were included. A total of 420 articles were identified, and 36 articles were considered relevant. Data indicate that the frequency of olfactory dysfunction increases with the duration of the disorder, and most studies report a frequency in the range of 20% to 40%. Although olfactory dysfunction does not appear to be very severe in patients with AR, its presence seems to increase with the severity of the disease. There is very limited evidence that antihistamines improve olfactory function. In addition, there is limited evidence that topical steroids improve the sense of smell, especially in patients with seasonal AR. This is also the case for specific immunotherapy. However, many questions remain unanswered because randomized controlled trials are infrequent and only a few studies rely on quantitative measurement of olfactory function. (J Allergy Clin Immunol 2015;nnn:nnn-nnn.) Key words: Allergy, rhinitis, smell, olfaction, hyposmia, anosmia

Olfactory dysfunction is a key symptom in patients with allergic rhinitis (AR). It is likely due to both a mechanical component (ie, blockage of the nasal airways through mucosal congestion) and an inflammatory component1,2; see Doty and Mishra3 for a review. In addition, olfactory function is a key contributor to quality of life; its loss is accompanied by the decreased enjoyment of food and drink, a decrease in social competence, and an increased risk for other factors, including food poisoning.4,5 Although relatively large numbers of patients have AR and as a consequence, could exhibit olfactory dysfunction, there remains a lack of studies examining olfactory function in AR-related investigations.

From athe Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Essen, and bthe Smell and Taste Clinic, Department of Otorhinolaryngology, Head and Neck Surgery, TU Dresden. Disclosure of potential conflict of interest: B. A. Stuck has received research support from MedaPharm GmbH. T. Hummel declares that he has no relevant conflicts of interest. Received for publication March 19, 2015; revised August 3, 2015; accepted for publication August 10, 2015. Corresponding author: Boris A. Stuck, MD, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. E-mail: [email protected]. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.08.003

Abbreviations used AR: Allergic rhinitis Mesh: Medical subject heading OD: Odor discrimination OI: Odor identification OT: Odor threshold RCT: Randomized controlled trial Tiab: Title/abstract UPSIT: University of Pennsylvania Smell Identification Test VAS: Visual analog scale

Although instruments that measure olfactory dysfunction have been developed and are commercially available (eg, Doty et al6 and Hummel et al7), most studies report qualitative ratings by patients. This limits the quality of the data, with most patients typically having trouble rating their olfactory function8 because nasal patency and olfactory function are often difficult to distinguish. Therefore throughout this article a distinction will be made between ‘‘rated’’ olfactory function and assessment of olfactory function by using quantitative methods (‘‘measured’’ olfactory function), including tests for odor thresholds (OTs) or odor identification (OI). If not otherwise specified, rated olfactory function will be discussed because this has been more widely administered in comparison with measured olfactory function. The present structured review aimed to investigate the following 2 questions: (1) What does AR do to human olfaction? (2) How effective is the treatment of AR in reducing olfactory dysfunction?

METHODS A comprehensive literature search was performed in August 2014 with the help of a professional librarian specialized in medical database reviews. All human studies published in English or German were included. The search strategy was adjusted to the database in use and was specified as follows (Medical subject heading [Mesh]/mh, title/abstract [tiab], title [ti], and abstract [ab]): PubMed (no date restriction): (‘‘Rhinitis, Allergic, Perennial’’ [Mesh] or ‘‘Rhinitis, Allergic, Seasonal’’ [Mesh] or Allergic rhiniti* [tiab] or Nasal allerg* [tiab] or Nose allerg* [tiab] or Pollen allerg* [tiab] or Pollinosis [tiab] or Pollinoses [tiab] or Hay fever [tiab] or hayfever [tiab]) AND (‘‘Olfaction Disorders’’ [Mesh] or ‘‘Olfactory Mucosa’’ [Mesh] or ‘‘Smell’’ [Mesh] or olfact* [tiab] or odor* [tiab] or smell [tiab] or taste [tiab] or Cacosmia* [tiab] or Dysosmia* [tiab] or Paraosmia* [tiab] or Anosmia* [tiab] or Hyposmia* [tiab]) AND (English [lang] or German [lang]) NOT (animals [Mesh] not humans [Mesh]). Web of Science Core Collection (since 1987, limits: English or German): TS 5 ([‘‘Allergic rhiniti*’’ or ‘‘Nasal allerg*’’ or ‘‘Nose allerg*’’ or ‘‘Pollen allerg*’’ or ‘‘Pollinosis’’ or ‘‘Pollinoses’’ or ‘‘Hay fever’’ or ‘‘Hayfever’’] AND [‘‘olfact*’’ or ‘‘odor*’’ or ‘‘smell’’ or ‘‘taste’’ or ‘‘Cacosmia*’’ or ‘‘Dysosmia*’’ or ‘‘Paraosmia*’’ or ‘‘Anosmia*’’ or ‘‘Hyposmia*’’]). The Cochrane Library (no date restriction): ([mh ‘‘Rhinitis, Allergic, Perennial’’] or [mh ‘‘Rhinitis, Allergic, Seasonal’’] or [‘‘Allergic rhiniti*’’ or 1

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‘‘Nasal allerg*’’ or ‘‘Nose allerg*’’ or ‘‘Pollen allerg*’’ or ‘‘Pollinosis’’ or ‘‘Pollinoses’’ or ‘‘Hay fever’’ or ‘‘Hayfever’’]: ti,ab) AND ([mh ‘‘Olfaction Disorders’’] or [mh ‘‘Olfactory Mucosa’’] or [mh ‘‘Smell’’] or ‘‘olfact*’’ or ‘‘odor*’’ or ‘‘smell’’ or ‘‘taste’’ or ‘‘Cacosmia*’’ or ‘‘Dysosmia*’’ or ‘‘Paraosmia*’’ or ‘‘Anosmia*’’ or ‘‘Hyposmia*’’: ti,ab). Study design was not an exclusion factor. The initial electronic search was conducted by a medical librarian, as stated above, and the results were screened independently by the 2 authors of this review based on title, abstract, and key words, if available. Articles were considered relevant if one of the 2 authors rated them accordingly. Relevant articles were then evaluated based on the full-text version independently by the 2 authors. Again, articles were considered relevant if one of the 2 authors rated them accordingly based on the full-text version.

RESULTS Search results After eliminating duplicate findings, 420 articles were identified by using the search criteria described above. In the initial evaluation 74 articles were considered relevant for this review, leading to exclusion of 346 articles based on the title, abstract, and key words. After evaluation of the full-text version, 38 articles were additionally excluded. The 38 articles were excluded as follows. Seven articles were meeting abstracts,9-15 and 1 was published in French.16 Four articles investigating different therapeutic approaches did not address olfactory function as an outcome parameter but only mentioned smell or taste under potential adverse events.17-20 Six articles included patients with AR and non-AR and did not provide a separate analysis for the subgroup of patients with AR.21-26 Two articles were excluded because they only assessed the immediate effects of an allergic challenge, therefore providing little clinical information.27,28 One article consisted of a meeting abstract of work in progress without sufficient data.29 In addition, 1 search result was incomplete but turned out to be a duplicate finding, whereas 5 review articles did not provide new data with regard to olfactory function in patients with AR.3,30-33 The data from 1 article34 were included in a later publication, and the latter was used for this review. One article was only a case report,35 another was an animal study,36 and 6 others did not report data that would have been useful for this review.37-42 Lastly, 2 review articles that were initially considered relevant were not included in the analysis. One of the articles addressed medical treatment of olfactory dysfunction resulting from various underlying pathologies,43 and the other article reviewed olfactory function in a different form of rhinitis.44 Neither articles provided relevant data or articles not already identified in the current initial literature search. After the aforementioned exclusions, 36 articles were selected for final analysis (Fig 1). EFFECT OF AR ON OLFACTION Numerous studies indicate that olfaction is affected by inflammatory causes1,2; see Doty and Mishra3 for a review. The frequency and severity of olfactory dysfunction in patients with AR were examined. In the present review the term olfactory dysfunction is used to describe a reduced sense of smell based on patient self-report or quantitative measures. The terms hyposmia and anosmia are restricted to corresponding results of quantitative tests. The most frequently used quantitative tests mentioned in this review are characterized in Table I.6,7,45-47

FIG 1. Flowchart showing search results for the systematic review.

What is the frequency of olfactory dysfunction in patients with AR? A study by Cowart et al48 indicated that in 91 patients with AR, 23% exhibited ‘‘measured’’ smell loss. Binder et al49 showed that 92 (31%) of 293 patients with self-reported symptoms for a period of less than 10 years reported smell impairment. In comparison, 56 (43%) of 130 patients from the same study with allergic symptoms for more than 10 years exhibited olfactory dysfunction. These data indicate that the frequency of olfactory dysfunction increases with the duration of the disorder, although there are no concrete longitudinal data available. Meltzer et al50 observed that OTs were within the normal range in 90% of 121 patients with seasonal AR. Chaiyasate et al51 found that 36% of 434 patients with AR reported smell dysfunction, Di Lorenzo et al52 found that 24% of 1017 patients with AR reported olfactory dysfunction, and Jareoncharsri et al53 observed that 11% of 83 patients with AR reported a disturbance in their sense of smell. In a larger sample (n 5 770) Binder et al49 found that 41% of patients with perennial AR and 26% of patients with seasonal AR reported smell dysfunction. Guss et al54 showed, although in a much smaller group of patients with AR, that 48% of 31 patients had measured olfactory dysfunction. Work by Sivam et al55 showed that measured olfactory function was normal in 2 of 16, mild-to-moderate dysfunctional in 12 of 16, and anosmic in 2 of 16 patients during the allergy season. Altogether, the data suggest that, depending on the group studied, olfactory dysfunction could occur with a frequency ranging from 10% to 88% (mode range, 20% to 40%). The wide range might be explained by differences in study design, definition, and assessment of olfactory dysfunction and the type of AR studied (see below).

How severe is olfactory dysfunction in patients with AR? Guilemany et al56 observed in 49 patients and 60 control subjects that AR had an overall moderate effect on measured olfactory function. Becker et al57 showed in 72 patients that measured olfactory dysfunction in patients with AR is present but not severe. Additionally, in that study patients with seasonal or persistent AR scored in the normal range on average. Similarly, Olsson et al58 reported in a study including 10,670 subjects that the prevalence of reduced olfactory function in patients with

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TABLE I. Glossary of olfactory tests Name of test

References

What is tested

Barcelona Smell Test

45

OI task (4-AFC) for 24 odors. Subjects are asked whether they perceive an odor, whether they can name the odor, and whether they can name the odor from a list of 4 descriptors (4-AFC). The final score is built on the subjects’ answers to all 3 questions. Odors are presented in glass jars.

CCCRC test

46

The test includes assessment of cued OI plus a threshold test (based on the method of ascending limits, using a 2-AFC task) for butanol odor. For threshold measurements, odors are presented in squeeze bottles; OI odors are presented in salt dispensers or glass bottles. This test includes, in its extended form, 3 tests: thresholds for butanol or phenyl ethyl alcohol odor (based on a staircase model with 7 turning points, 3-AFC task), an OD task for 16 odors (based on a 3-AFC task), and an OI task (4-AFC) for 16 odors. Often, only the OI part of the Sniffin’ Sticks test is used. Odors are presented in felt-tip pen–like odor dispensers.

Sniffin’ Sticks

UPSIT

7, 47

6

OI task (4-AFC) for 40 odors. Odors are presented within a ‘‘Scratch and Sniff’’ paradigm, with microencapsulated odors on paper being released by scratching the surface with a pencil.

AFC, Alternative force choice; CCCRC, Connecticut Chemosensory Clinical Research Center.

self-reported allergic rhinoconjunctivitis symptoms (frequency of olfactory dysfunction, 10.9% from time to time and 2.2% often) was similar to the prevalence in healthy subjects (frequency of olfactory dysfunction, 9.0% from time to time and 1.9% often). In contrast, in the group with unique self-reported nonallergic nasal symptoms (eg, recurrent sneezing, itching, and nasal blockage in the absence of asthma, allergic eye symptoms, hay fever or any other AR, chronic bronchitis, or emphysema), the prevalence of reduced olfactory sensitivity was 3 to 4 times as high as that in the healthy group (23.5% from time to time and 8.4% often). However, the study groups were defined based on self-reported symptoms and medical history only, so that selfreported nonallergic symptoms might, at least in part, also reflect undiagnosed AR. As already mentioned above, Guss et al54 showed in a small group of 31 patients with AR that 48% had measured olfactory dysfunction. However, none of their patients exhibited anosmia, indicating that olfactory dysfunction was not severe. Also, in a small group of 20 patients and 18 control subjects, Mann et al59 reported significantly increased OTs without qualifying that in terms of the presence of hyposmia or anosmia. Results from Apter et al60,61 in 1995 (n 5 64) and 1999 (n 5 60) indicate that measured olfactory dysfunction in patients with AR is less severe than that found in patients with chronic rhinosinusitis. This is supported by work from Cowart et al48 in 91 patients. Their data showed that a much higher percentage of patients with associated rhinosinusitis (43%) reported smell dysfunction compared with only patients with AR without rhinosinusitis (14%). Rhee et al62 observed in 2305 subjects that the frequency of reported olfactory dysfunction increases with the severity of AR based on the Allergic Rhinitis and its Impact on Asthma guidelines.63 In fact, in patients with intermittent mild AR, 4.7% of the patients reported olfactory dysfunction. In contrast, in patients with persistent moderate-to-severe AR, 23% reported smell dysfunction (intermittent mild vs healthy, 4.7%; intermittent moderate/severe vs healthy, 19%; persistent mild/healthy, 8.0%; and persistent moderate/severe vs healthy, 23.4%). Because moderate-to-severe AR can be diagnosed when symptoms are ‘‘troublesome’’ based on the Allergic Rhinitis and its Impact on Asthma guidelines, smell dysfunction might not only be related to more severe symptoms but can also be the reason why patients rate the disease as severe.

Thus olfactory dysfunction does not appear to be very severe in patients with AR; however, the presence of olfactory dysfunction seems to increase with the severity of the disease.

Differences between persistent/perennial AR and seasonal AR In patients with seasonal AR, measured olfactory deficits are more pronounced in season compared with out of season, as has been found in 47 patients versus 66 control subjects.64 In addition, Klimek65 observed in a small sample that patients with seasonal AR (n 5 17) in comparison with control subjects (n 5 12) had normal measured olfactory function before the season and exhibited a significant decrease of measured olfactory function after onset of season. This decrease was equivalent to that seen with medium-grade hyposmia.65 Conversely, Becker et al57 did not see a significant difference between 16 patients with perennial and 23 patients with seasonal AR for measured olfactory function, although in a larger sample (n 5 770) Binder et al49 found that 41% of patients with perennial AR and 26% of patients with seasonal AR reported smell dysfunction. In their investigation of OTs in 240 patients, Rydzewski et al66 found that in patients with seasonal AR, approximately 10% exhibited hyposmia, with none of these showing anosmia; in contrast, in patients with perennial AR, 8% had hyposmia, and another 20% exhibited anosmia. The study by Khanna and Shah67 reported that ‘‘sneezers and runners’’ were less severely affected (14% loss of smell) than ‘‘blockers’’ (36%) based on self-reports of 114 patients. These data indicate that the frequency and severity of olfactory dysfunction increase in patients with persistent/perennial AR compared with patients with seasonal AR. Further details regarding studies assessing the effects of allergy on olfactory function are presented in Table II.6,7,45-62,64-69 ANTIALLERGIC THERAPY AND ITS EFFECT ON OLFACTION Various therapeutic approaches for the treatment of AR and related complaints have been investigated with regard to their effect on olfaction. However, studies primarily looking at the effect on olfaction are rare. Nevertheless, therapeutic approaches

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TABLE II. Characteristics of the studies assessing the effects of allergy on olfactory function Author

Year

Age

Study design

62 patients

Mean, approximately 47 y

Retrospective cohort study

1999

60 patients

Mean, approximately 50 y

Cohort study

Becker et al57

2012

72 patients

Mean, 33 y; range, 16-69 y

Cohort study

Binder et al49

1982

770 patients

Age range, <10 to >60 y

Cohort study

Chaiyasate et al51

2009

434 patients

Mean, approximately 36 y

Retrospective cohort study

Cowart et al48

1993

91 patients

8-56 y; mean, 30 y

Cohort study

Di Lorenzo et al52 Guilemany et al56

2011 2009

1,017 patients 49 patients, 60 control subjects

Mean, 33 y 21-56 y

Cohort study Cohort study

Guss et al54

2009

31 patients

Mean, 39 y (18-76 y)

Cohort study

Jareoncharsri et al53 Khanna and Shah67

1999 2005

83 patients 114 patients

11-68 y 18-50 y

Cohort study Cohort study

Klimek65

1998

17 patients; 12 control subjects

21-43 y

Cohort study

Mann et al59

2002

20 patients vs 18 control subjects

Mean, 27 y

Cohort study

Meltzer et al50

1998

121 patients

12-65 y

RCT

Moll et al64

1998

47 patients vs 66 control subjects

16-60 y

Cohort study

Olsson et al58

2003

10,670 subjects

19-80 y

Cohort study

Rhee et al62

2014

2,305 subjects (1,140 male, 1,165 female)

10-83 y; mean, 40 y

Cohort study

Rydzewski et al66

2000

240 patients

7-79 y

Cohort study

Sivam et al55

2010

17 patients

23-52 y; mean, 39 y

RCT

60

Apter et al

1995

Apter et al61

Subjects (no.)

CCCRC, Connecticut Chemosensory Clinical Research Center; CRS, chronic rhinosinusitis; EMB, evidence-based medicine (level of evidence according to the Oxford Centre for Evidence-based Medicine); RCT, randomized controlled trial; TDI, threshold, discrimination, and identification.

from studies investigating the effects on olfactory function are as follows: oral and topical antihistamines, topical steroids, surgery for the reduction of the inferior nasal turbinate in nasal obstruction caused by AR, specific immunotherapy, and various

other therapeutic approaches. However, only half of the studies are based on quantitative tests, which reduces the significance of the data. There is also a lack of studies regarding the effects of systemic steroids on olfactory function in patients with AR.

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TABLE II. (Continued) Type of rhinitis

Outcome parameter

Effect

EBM

Both seasonal and perennial AR

CCCRC test (OT plus OI)46

Mean olfactory score for 28 AR group patients indicated moderate hyposmia, and that of 34 subjects with polyps, CRS, or both indicates anosmia

2b

Not provided

CCCRC test (OT plus OI)46 Sniffin Sticks TDI test7,47

Only patients with olfactory dysfunction; patients with AR with decreased olfactory function but significantly less than in patients with CRS with and without polyposis Control subjects better than patients with perennial and those with seasonal AR (mean TDI, 40.0 for control subjects, 33.4 for patients with seasonal AR, 31.5 for patients with perennial AR; no difference between those with perennial and those with seasonal AR)

1b

45.5% perennial, 33.5% seasonal, 21% mixed

Self-reported

Not provided

Self-reported

Ninety-two (31%) of 293 patients with symptoms for <10 y reported smell impairment; 1b 56 (43%) of 130 patients with symptoms for >10 y; 41% of patients with perennial AR and 26% of patients with seasonal AR reported smell loss. Thirty-six percent of patients reported smell dysfunction. 2b

51 patients with perennial AR, 40 patients with seasonal AR

OT

Not provided

Self-reported

Twenty-three percent of patients exhibited smell loss; 43% of patients with associated rhinosinusitis reported smell dysfunction, only 14% of patients with AR without rhinosinusitis reported olfactory impairment. Twenty-four percent of patients reported olfactory dysfunction.

Persistent AR

Barcelona Smell Test-24 (OI45) UPSIT6

Patients scored significantly worse than control subjects; overall moderate effect of AR on olfactory function. Forty-eight percent with olfactory dysfunction and no one with anosmia

1b

Self-reported Self-reported

Smell disturbance in 10.8% Group divided into ‘‘sneezers and runners’’ (14% loss of smell) and ‘‘blockers’’ (36%)

1b

23 patients with seasonal AR; 16 patients with perennial AR; 33 control subjects

AR without sinusitis; time of testing not provided (seasonal/ nonseasonal) Perennial Seasonal and perennial

46

1b

1b

1b 1b

Seasonal; tested before and CCCRC test (OT, OI) during the season Unclear; also not mentioned Elsberg blast whether tested inside or outside olfactometer68 (OT) the season

Before season, all patients had normal smell function; significant decrease during days 3, 7, 14, and 21 after onset of season (equivalent to medium-grade hyposmia). Significant increase of OTs

2b

Seasonal; tested during season

OT normal in 90% of patients

1b

Mite allergies worse than in control subjects in terms of OT, OD, and OI tests; preseasonal pollen allergies had similar results as control subjects but lower values in OTs; preseasonal pollen allergies were better than mite allergies in OT, OD, and OI; intraseasonally pollen allergies decreased for OT and OD compared with before season; under pollen exposure (mite allergies vs pollen allergies), mite allergies had better OT and OI, but OD results were better for the patients with pollen allergy.

1b

Prevalence of reduced olfactory sense in the group of self-reported allergic rhinoconjunctivitis symptoms (10.9% from time to time and 2.2% often) was similar to that in the healthy group (9.0% and 1.9%). In contrast, in the group with selfreported nonallergic nasal symptoms, the prevalence of reduced olfactory sense was 3-4 times as high as that in the healthy group (23.5% and 8.4%). Odds ratio for higher risk of olfactory dysfunction 5 4.88; frequency of olfactory dysfunction increases with severity of AR (intermittent mild vs healthy: 4.7%; intermittent moderate/severe vs healthy: 19%; persistent mild/healthy: 8.0%; persistent moderate/severe vs healthy: 23.4%)

1b

Estimated from Fig 2: in patients with perennial, AR 20% anosmia plus 8% hyposmia; in patients with seasonal AR, 10% hyposmia and no anosmia

2b

Two anosmic, 12 mild-to-moderate olfactory dysfunction, 2 normal

1b

Mite allergies; pollen allergies during and outside season

CCCRC test (OT and OI)46 Modified CCCRC test (with OT, OD, and OI)

Subjects with self-reported allergic Self-ratings of rhinoconjunctivitis; subjects with olfactory function self-reported nonallergic nasal symptoms; control subjects Patients with atopy and AR

Questionnaire for olfactory dysfunction69

136 patients with perennial AR; OT68 41 patients with seasonal AR; 119 asthmatic patients; 19 patients with Quincke edema/ allergic stomatitis Not provided; tested within season 40-Item UPSIT6

Antihistamines Five relevant studies assessing the effects of antihistamines on olfaction in patients with AR were detected. Four of these were randomized controlled trials: 1 placebo-controlled trial, 1 trial comparing the effects of an oral with a topical antihistamine, and

1b

1b

2 trials comparing the effects of a topical antihistamine with a topical steroid. In 1997, the effects of azelastine nasal spray were assessed in a subpopulation of 211 children aged less than 13 years from 2 postmarketing drug surveillance programs.70 Children were

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TABLE III. Characteristics of the studies assessing the effects of antihistamines on olfactory function Author 72

Gambardella

Guilemany et al71 Kalpaklioglu and Kavut73

Wober et al70

Year

Subjects (no.)

1993

30

Age

Median, 31 y (18-55 y)

Study design

RCT

Type of rhinitis

Outcome parameter

Treatment

Seasonal

Loratadine tablets vs azelastine nasal spray 2012 27 Mean, RCT Persistent Levocetirizine 31.9 6 2 y (5 mg by mouth) vs placebo 2010 62 (azelastine Mean, RCT Not Azelastine nasal subgroup) 32.44 6 12.17 y provided spray vs (azelastine triamcinolone subgroup) nasal spray 1997 211 (children) <13 y Drug Seasonal and Azelastine nasal surveillance perennial spray program

Effect

Symptom score No difference between the 2 treatment arms Barcelona Smell Superior to Placebo Test-24 and only for the VAS VAS after 7 d Symptom score No treatment effect on anosmia and no difference between the 2 treatment arms Symptom score Increased no. of symptom-free patients (smell loss)

EBM

1b

1b

1b

4

EMB, Evidence-based medicine (level of evidence according to the Oxford Centre for Evidence-based Medicine); RCT, randomized controlled trial.

TABLE IV. Characteristics of the studies assessing the effects of topical steroids on olfactory function Author

Year

Subjects (no.)

Age

Study design

Type of rhinitis

Golding-Wood 1996 et al74

25

Median, 41 y (16-64 y)

Case Persistent series

Higaki et al76

75

20-66 y

RCT

2012

Kalpaklioglu 2010 70 33.76 6 12.87 y RCT and Kavut73 (triamcinolone (triamcinolone group) group) Meltzer et al50 1998

121

12-65 y

RCT

Sivam et al55

2010

17

18-59 y

RCT

Stuck et al75

2003

24

27.3 6 4.9 y

RCT

Seasonal

Treatment

Beclomethasone drops

Mometasone nasal spray (early intervention vs postonset intervention) vs placebo Not Azelastine nasal provided spray vs triamcinolone nasal spray Seasonal Mometasone nasal spray vs placebo Seasonal Mometasone nasal spray vs placebo

Seasonal

Outcome parameter

UPSIT and VAS

Questionnaire

Symptom score

CCCRC

Effect

EBM

Improvement in subgroup 4 of patients with initial subjective olfactory impairment No difference between 1b groups

No treatment effect on anosmia and no difference between the 2 treatment arms Improvement in OI

ChemosensoryImprovement in specific qualitychemosensory-specific of-life score and quality of life but not UPSIT UPSIT Mometasone nasal Sniffin’ Sticks Improvement in butanol spray vs placebo threshold

1b

1b 1b

1b

CCCRC, Connecticut Chemosensory Clinical Research Centre; EMB, evidence-based medicine (level of evidence according to the Oxford Centre for Evidence-based Medicine); RCT, randomized controlled trial.

treated for 2 (seasonal AR) or 4 (perennial AR) weeks depending on the underlying disease and received 1 puff per nostril twice daily in the majority of the cases. A significant reduction after treatment was reported for all symptoms in both groups, although a separate analysis for the smell-reduction symptom score was not provided in the article. However, the number of children free of olfactory symptoms increased from 72.1% before to 94.6% after treatment. A separate analysis for seasonal and perennial AR was not provided. Guilemany et al71 performed a randomized, placebo-controlled trial with 27 patients with persistent AR and subjective loss of smell. Patients received either 5 mg of levocetirizine or placebo for 30 days, and olfactory function was assessed with a visual analog scale (VAS), as well as with the Barcelona Smell Test-24. Olfactory function improved during treatment, but a

statistically significant difference between levocetirizine and placebo could only be demonstrated for the subjective assessment after 7 days of treatment but not after 30 days and not for the Barcelona Smell Test-24. After 7 days, nasal nitric oxide levels correlated with ratings of olfactory function, and therefore the authors concluded that improvement in the sense of smell with levocetirizine could be related to an improvement in nasal inflammation rather than nasal obstruction. Gambardella72 compared the effects of loratadine tablets (10 mg once daily) with azelastine nasal spray (0.14 mg per nostril twice daily) in a randomized, double-blind, doubledummy study in 30 patients with seasonal AR in which participants rated olfactory loss by using a 4-point scale. Here smell loss was rated as ‘‘mild’’ at baseline and as ‘‘no symptoms’’ after 6 weeks of treatment (data derived from the figures as no

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TABLE V. Characteristics of the studies assessing the effects of immunotherapy on olfactory function Year

Subjects (no.)

2009

142

Katotomichelakis 2013 et al80

36

Author 78

Chang et al

Mun et al79

2013

153

Radcliff et al77

1996

36

Tansuker et al81

2014

12

Age

Mean, 16.3 y; range, 5-71 y Not provided for the subgroup of patients with AR 18.6 6 1.67 y (subgroup with escalation regimen); 22.6 6 1.64 y (subgroup without escalation regimen) Mean, 37.8 y (range, 16-66 y [active placebo]); mean, 39.9 y (range, 19-55 y [placeboactive]) 30.67 6 8.51 y

Study design

Type of rhinitis

Effect

EBM

Case Persistent (house SLIT Symptom score series dust mite) Case Not provided Not provided Sniffin’ Sticks and series questionnaire

Improvement after treatment Improvement after treatment

4

Case Persistent (house SLIT (with Symptom score series dust mite) or without escalation regimen)

Improvement after treatment

4

RCT

Seasonal

Case Not provided series

Treatment

Outcome parameter

4

SCIT

Symptom score

Superior to placebo 1b

SCIT

Sniffin’ Stick

Improvement after treatment

4

EMB, Evidence-based medicine (level of evidence according to the Oxford Centre for Evidence-based Medicine); RCT, randomized controlled trial; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy.

mean values and SDs are provided). No significant differences were observed between the 2 drug regimens during the study period. In a randomized parallel-group design Kalpaklioglu and Kavut73 compared the effects of azelastine versus triamcinolone nasal spray in patients with AR (n 5 69) and non-AR (n 5 63). Olfactory function was assessed with a symptom score after 2 weeks of treatment. A statistically significant treatment effect on ‘‘anosmia’’ could not be detected for the allergic or nonallergic group, and there was also no difference between the 2 treatment arms. However, the extent of olfactory impairment at baseline was not provided. The characteristics of these studies are presented in Table III.70-73 In summary, there is very limited evidence that antihistamines improve olfactory function in the doses tested. Furthermore, in studies documenting an improvement in olfaction, the effects were relatively weak.

Topical steroids In 1996, Golding-Wood et al74 treated 25 patients with perennial AR with an intranasal application of beclomethasone drops in a prospective nonrandomized study. In the subgroup of patients with a subjective impairment in their sense of smell at baseline (n 5 15), a statistically significant improvement could be detected in the University of Pennsylvania Smell Identification Test (UPSIT) and in rated assessment of olfactory function (VAS), whereas no such improvements were seen in the subjectively nonimpaired group. Four randomized, placebo-controlled trials were performed assessing the effects of the topical nasal steroid mometasone nasal spray on olfactory function in patients with seasonal AR. Meltzer et al50 provided the first trial in 1998, assessing the effects of a 2-week treatment in 41 subjects. Mometasone was superior to placebo in terms of rated improvement in nasal symptoms and various parameters of nasal inflammation. Olfactory function

was assessed with the test of the Connecticut Chemosensory Clinical Research Centre showing a statistically significant improvement for OI but not for butanol OTs. In 2003, Stuck et al75 investigated the therapeutic effects of a 2-week course of mometasone in 24 patients regardless of pre-existing subjective olfactory impairment. Olfactory function was assessed with the Sniffin’ Sticks Test. After treatment with mometasone, participants became more sensitive to butanol in the threshold test compared with placebo, although there was no such effect for OI or odor discrimination (OD). The third study was performed by Sivam et al55 in 2010. Seventeen patients with seasonal AR and subjective olfactory impairment were treated for 2 weeks, and olfactory function and mucosal inflammation were assessed before and after treatment. Both nasal symptoms and nasal inflammation improved compared with placebo, as did chemosensory-specific quality of life. OI as assessed with the UPSIT but did not improve, and there was no statistically significant difference between the 2 groups. In the most recent trial Higaki et al76 investigated the effects of a 12-week course of mometasone (early intervention) or placebo or 4 weeks of placebo followed by 8 weeks of mometasone (postonset treatment) during the pollen season. Although an exacerbation in nasal symptoms was documented in relation to the start of the season in the placebo and postonset groups, no such increase was seen in the early intervention group. Interestingly, olfactory function, as assessed with a selfadministered questionnaire, was similar in the 3 groups, although no detailed data were provided in the article. The study by Kalpaklioglu and Kavut73 comparing antihistamines with topical steroids has already been described above. Study characteristics are presented in Table IV.50,55,73-76 In summary, although study results are conflicting, there is evidence, however limited, that topical steroids improve specific measures of olfactory function, especially in patients with seasonal AR.

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Specific immunotherapy In an early study by Radcliff et al77 in 1996, the effects of specific immunotherapy were assessed in a randomized, double-blind, placebo-controlled trial in 36 patients with perennial AR against various allergens. A so-called low-dose immunotherapy was initiated based on the maximum intradermally tolerated dose using individually prepared multiallergen injections. An active treatment period of 2 weeks was compared with a placebo treatment of the same duration and a washout period of 2 weeks, according to randomization. Significant symptom relief was documented in favor of active treatment based on nasal symptom scores. One nasal symptom assessed was ‘‘anosmia,’’ which was graded on a 4-point scale (nil to severe). Compared with placebo, the effect of the active treatment was statistically significantly greater and resulted in a reduction of approximately 1 point during treatment. Clinically, however, the study is difficult to evaluate because the treatment protocol differs substantially from the immunotherapy protocols currently in use. Conversely, from 2009, 5 additional studies were published with more current immunotherapy protocols. In 2009, Chang et al78 treated 142 patients with persistent AR sensitized to house dust mites with sublingual immunotherapy for at least 6 months. Despite a high dropout rate of 31%, the symptoms of AR as assessed with a questionnaire improved after immunotherapy with statistical significance, including the symptom of olfactory disturbance. In 2013, an observational study was published from the same institution comparing 2 regimens of sublingual immunotherapy for house dust mite allergy in terms of safety and efficacy.79 In this trial olfactory symptoms that were self-assessed with the help of the same symptom score significantly improved again after immunotherapy in both groups. However, neither study had a control group, and olfactory function was not measured or otherwise assessed with validated tests. In 2013, Katotomichelakis et al80 presented the results of a prospective trial investigating treatment effects in patients with olfactory dysfunction resulting from chronic rhinosinusitis or AR (n 5 36). Compared with a control group with no olfactory dysfunction, the pretreatment olfactory function was inferior in both patient groups based on the Sniffin’ Sticks Test (OI, OD, and OT), as well as the Questionnaire of Olfactory Deficits. After treatment, significant improvement was documented for measured olfactory function, as well as the results of the questionnaire in both groups. Olfactory function became normal. However, interpretation of the results is difficult because there was no untreated (allergic) control group during the timeline of the study except the nonallergic normosmic control group at baseline, and there was no information provided with regard to the kind of sensitization or treatment regimen applied. The most recent study was published by Tansuker et al81 in 2014. Olfactory function was assessed with the help of the Sniffin’ Sticks Test (OI, OD, and OT) in 12 patients receiving subcutaneous specific immunotherapy for AR not further specified. Measured olfactory function improved moderately after immunotherapy; however, a statistically significant improvement could only be demonstrated for the identification subtest. The limited information regarding the type of AR and treatment regimen used and the small number of subjects limit the significance of

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the study. The characteristics of this and the other studies described above are presented in Table V.77-81 To summarize, the evidence suggests that specific immunotherapy improves olfactory function in patients with AR; however, it is limited by study design.

Surgical treatment of nasal obstruction Two articles evaluated the effects of surgical treatment for reduction of the inferior nasal turbinate refractory to standard medical treatment in patients with nasal obstruction caused by AR. In 2006, Ikeda et al82 investigated the effects of a procedure named ‘‘functional inferior turbinosurgery’’ on various symptoms of AR, including olfactory function. From the 56 patients included in this prospective noncontrolled case series, 8 complained about anosmia, and 4 of those patients reported improvement after surgery. In another case series from 2011, the effects of radiofrequency surgery of the inferior turbinate was assessed in 47 patients, 15 of them complaining of hyposmia.83 Ratings of smell function with a VAS improved significantly after surgery. Because of the design limits (uncontrolled case series and lack of standardized tests for olfactory function), the effects of turbinate surgery on olfactory function in patients with AR cannot be assessed reliably.

Other treatment strategies Lee et al84 investigated the effects of nasal application of diclofenac eye drops in patients with perennial AR in a double-blind randomized study in a small number of subjects. They could not demonstrate a positive effect on any of the outcome measures, including olfactory function assessed by using the UPSIT. In 2007, Hu and Li85 applied far infrared therapy to 31 patients with AR of various origins in a noncontrolled case series. Smell impairment was classified with a symptom score and showed a trend for improvement, with a statistically significant difference after the final treatment only. However, the baseline symptom score for smell impairment was very low (between ‘‘no’’ and ‘‘mild’’ impairment).

DISCUSSION Effect of AR on olfaction Although olfactory dysfunction is a key symptom of AR, surprisingly few studies have investigated this symptom. Even fewer studies have measured olfactory function despite the availability of various reliable and valid olfactory tests (eg, UPSIT or the Sniffin’ Sticks Test). The fact that patients with nasal dysfunction are known to mistake changes in airflow for changes in olfactory function (eg, Landis et al8) might question the reliability of qualitative measurements. Regardless of these limitations, the currently reviewed literature suggests the following major conclusions. First, olfactory dysfunction has been shown to occur with a frequency of approximately 10% to 88%, with most studies reporting in the range of 20% to 40%. However, this is variable between groups.

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Second, the frequency of olfactory dysfunction increases with the duration of the disorder. Third, olfactory dysfunction does not appear to be very severe in patients with AR. However, the presence of olfactory dysfunction seems to increase with disease severity. Fourth, the frequency and severity of olfactory dysfunction are higher in patients with perennial or persistent AR compared with those with seasonal AR.

Antiallergic therapy and its effect on olfaction The effects of antiallergic therapy on olfactory function are difficult to evaluate. For most interventions, the number of studies published and the methodology used are insufficient to reliably assess olfactory-specific therapeutic effects. A meaningful assessment is limited to antihistamines, topical steroids, and immunotherapy. Although the number of studies available for these 3 treatment strategies is higher, significant limitations remain. First, in general, there are not enough studies with regard to persistent AR. The majority of studies were published with patients with seasonal AR only. Second, olfactory function is often not quantitatively assessed with validated tests but is evaluated by using symptom scores, VASs, or other forms of questionnaires only. Third, in those cases in which quantitative tests are used, the substantial differences in methodologies of the tests complicates the comparison of results. Fourth, the number of subjects included in the randomized controlled trials is often too small to assess the significance of the effects on olfactory function. Finally, olfactory function is a secondary outcome measure in the majority of trials, and patients are often not preselected for olfactory dysfunction. This means that a significant proportion of patients included in the trials are normosmic or do not have olfactory dysfunction. This in turn weakens the potential to see effects of antiallergic treatment on olfaction. Olfactory dysfunction in the context of AR is typically described in 2 ways, either as conductive or sensorineural. Conductive olfactory dysfunction implies, similar to conductive hearing loss, that odors do not reach the olfactory receptor neurons because of a mechanical block, such as congested mucosa or increased mucus secretion creating a mucosal barrier. In contrast, sensorineural loss indicates a situation in which the olfactory receptor neurons or the olfactory bulbs are affected such that there is a decrease in olfactory function. In patients with AR, probably both causes are at work56; in fact, they are difficult to detangle. On the one hand, mucosal congestion is a significant part of AR symptoms.86 In addition, inflammatory mediators released at an epithelial level have been shown to be related to olfactory dysfunction1,32; there is also speculation that mucosal inflammatory mediators might affect function at the level of the olfactory bulb.43 Thus olfactory dysfunction within the context of AR is best described as olfactory dysfunction caused by inflammation, which involves both conductive and sensorineural components. CONCLUSIONS Olfactory dysfunction is frequently experienced by patients with AR and, in combination with decreased nasal patency, decreases quality of life. Frequency and severity increase with

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symptom severity and disease duration. Accordingly, olfactory dysfunction is more pronounced in patients with perennial/ persistent AR than in those with seasonal AR. Antiallergic and anti-inflammatory therapy both appear to be effective in patients with AR, at least as topical steroids, immunotherapy, and to a certain extent, antihistamines are concerned. Nevertheless, many questions remain unanswered, especially because there are very few randomized trials that quantitatively measure olfactory function. In contrast to symptoms usually assessed in AR studies, olfactory function can be relatively easily measured and quantified in a cost-effective manner and should be included in future AR-related therapeutic trials. Future studies are needed to enable counseling of patients with olfactory dysfunction caused by AR. We thank Mr Volker Braun, Mannheim, Germany, for his assistance in the literature search, and we deeply appreciate the editorial help of Waku Maboshe, Cardiff, United Kingdom. REFERENCES 1. Klimek L, Eggers G. Olfactory dysfunction in allergic rhinitis is related to nasal eosinophilic inflammation. J Allergy Clin Immunol 1997;100:158-64. 2. Seiden AM, Litwin A, Smith DV. Olfactory deficits in allergic rhinitis. Chem Senses 1989;14:746-7. 3. Doty RL, Mishra A. Olfaction and its alteration by nasal obstruction, rhinitis, and rhinosinusitis. Laryngoscope 2001;111:409-23. 4. Croy I, Nordin S, Hummel T. Olfactory disorders and quality of life—an updated review. Chem Senses 2014;39:185-94. 5. Stevenson RJ. An initial evaluation of the functions of human olfaction. Chem Senses 2010;35:3-20. 6. Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32:489-502. 7. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. Sniffin’ sticks’: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 1997;22:39-52. 8. Landis BN, Hummel T, Hugentobler M, Giger R, Lacroix JS. Ratings of overall olfactory function. Chem Senses 2003;28:691-4. 9. Bende M, Hinriksdottir I, Murphy C. Olfactory threshold in allergic rhinitis. Chem Senses 1995;20:99. 10. Eggers G, Klimek L. Der Einfluß der Hyposensibilisierungstherapie auf das Riechverm€ogen bei saisonaler Rhinitis allergica. Allergologie 1997;20:526-7. 11. Guilemany J, Garcia-Pinero A, Alobid I, Cardelus S, Centellas S, Bartra J, et al. Persistent allergic rhinitis induces a moderate loss of the sense of smell. Allergy 2008;63(suppl 88):72-3. 12. Klimek L, Glowania A, Stuck B, H€ormann K, Pfaar O. Olfactory function in seasonal allergic rhinitis can be improved by allergen-specific immunotherapy. Allergy 2011;66(suppl 94):632. 13. Pinto JM, Jeswani S, Reder L, Wang J, Perez R, DeTineo M, et al. Olfactory cleft inflammation is present in seasonal allergic rhinitis and improves with intranasal steroids. J Allergy Clin Immunol 2008;121(suppl):S277. 14. Shariat M, Moin M, Pourpak Z, Sharifi L, Khalesi M, Movahedi M, et al. The smell dysfunction in allergic rhinitis and its impacts on quality of life. Allergy 2012;67(suppl 96):492-3. 15. Tsakiropoulou E, Konstantinidis I, Constantinidis J. Allergic rhinitis as a risk factor of olfactory dysfunction: outcome from a smell and taste clinic. Allergy 2011; 66(suppl 94):353. 16. Haguenauer JP. Controlled study of sodium cromoglycate and beclomethasone dipropionate in the local treatment of chronic aperiodic rhinitis. Revue Francaise d’Allergologie et d’Immunologie Clinique 1981;21:167-9. 17. Baccioglu Kavut A, Kalpaklioglu F. Efficacy and safety of once daily triamcinolone acetonide aqueous nasal spray in adults with non-allergic and allergic rhinitis. Allergol Immunopathol (Madr) 2013;41:374-80. 18. Lin HC, Lin PW, Friedman M, Chang HW, Su YY, Chen YJ, et al. Long-term results of radiofrequency turbinoplasty for allergic rhinitis refractory to medical therapy. Arch Otolaryngol Head Neck Surg 2010;136:892-5. 19. Said SA, McHembe MD, Chalya PL, Rambau P, Gilyoma JM. Allergic rhinitis and its associated co-morbidities at Bugando Medical Centre in Northwestern Tanzania; a prospective review of 190 cases. BMC Ear Nose Throat Disord 2012;12:13.

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