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Risk factors for olfactory dysfunction in chronic rhinosinusitis
Auris Nasus Larynx 40 (2013) 465–469
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Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Risk factors for olfactory dysfunction in chronic rhinosinusitis§ Eri Mori a,b,c,*, Yoshinori Matsuwaki a, Chieko Mitsuyama a, Tetsushi Okushi a,d, Tsuneya Nakajima d, Hiroshi Moriyama a a
Department of Otorhinolaryngology, Jikei University, School of Medicine, Tokyo, Japan Department of Otorhinolaryngology, St. Luke’s International Hospital, Tokyo, Japan c Department of Otorhinolaryngology, Ota General Hospital, Kanagawa, Japan d Department of Otorhinolaryngology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 October 2012 Accepted 11 January 2013 Available online 16 February 2013
Objective: Although risk factors for olfactory dysfunction in patients with chronic rhinosinusitis (CRS) have been examined, most studies did not distinguish between classified eosinophilic chronic rhinosinusitis (ECRS) and noneosinophilic chronic rhinosinusitis (NECRS). The incidence of eosinophilic disease in Japan differs from that in the West. Thus, when olfaction in CRS is investigated, ECRS and NECRS should be examined separately. In the present study, we examined the clinical characteristics associated with olfactory dysfunction in Japanese patients with ECRS and NECRS enrolled in a large multicenter, prospective cohort study. Methods: Olfactory examination results, demographic data, clinical factors, and comorbidity data were analyzed for 418 patients with CRS at 3 tertiary care centers. We used T&T olfactometry, intravenous olfactory test (the Alinamin test) and Likert scale to assess subjects’ olfactory function. Data were analyzed with univariate and multivariate analyses. Results: Olfactory dysfunction was more severe and more prevalent in ECRS than in NECRS. We found that olfactory cleft polyps (odds ratio [OR], 3.24), ethmoid opacification (OR, 2.64), asthma (OR, 2.29), current smoking (OR, 1.74) and age 50 years (OR, 1.66) were associated with olfactory dysfunction in CRS. Ethmoid opacification (OR, 3.09) and olfactory cleft polyps (OR, 3.05) were associated with olfactory dysfunction in NECRS. Olfactory cleft polyps (OR, 3.98), current smoking (OR, 2.67), IgE 400 IU/ml (OR, 2.65), ethmoid opacification (OR, 2.51), and asthma (OR, 2.34) were associated with olfactory dysfunction in ECRS. Conclusions: Olfactory dysfunction was more severe and prevalent in ECRS than in NECRS. Physician should pay attention to these clinical findings to diagnose olfactory dysfunction, especially in ECRS, and should provide appropriate explanation, guidance, and care. In addition, smokers should be advised to stop smoking to help prevent olfactory dysfunction. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Olfactory dysfunction Chronic rhinosinusitis Eosinophilic rhinosinusitis Noneosinophilic rhinosinusitis Risk factor
1. Introduction Olfactory function is an essential sensory function in animals and is deeply involved in appetite, motivation, and libido. Patients with anosmia often feel isolated and emotionally impaired [1], and their quality of life is decreased [2]. However, many people are unaware of olfactory dysfunction [3], because information can be obtained via the other senses. There is also a general lack of awareness regarding the problem of olfactory dysfunction, even on
§ This article was presented at the 2010 International Symposium on Infection and Allergy of Nose held in Geneva, Switzerland, from June 20th to 24th, 2010. * Corresponding author at: Department of Otorhinolaryngology, St. Luke’s International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan. Tel.: +81 3 3541 5151; fax: +81 3 3544 0649. E-mail addresses: [email protected], [email protected] (E. Mori).
0385-8146/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.anl.2012.12.005
the part of clinicians. Olfactory dysfunction may not directly cause systemic problems, but if left untreated, harmful effects may manifest in regard to nutrition, reproductive activity, and even survival. Little data are available regarding olfactory dysfunction in Japan, but 40–50% of cases of olfactory dysfunction are caused by chronic rhinosinusitis (CRS) [4,5]. In the West, approximately 90% of patients with nasal polyps show a mixed cellular infiltrate with prominent eosinophilia [6]. Tissue eosinophilia [7,8] and local increases in IgE levels [9] are hallmarks of nasal polyps and are thought to be risk factors for disease recurrence. In Japan, eosinophilic chronic rhinosinusitis (ECRS) has recently been classified and induces severe olfactory dysfunction even at an early stage [10,11]. However, the incidence of eosinophilic disease in Japan is lower than in the West, but the incidence of noneosinophilic chronic rhinosinusitis (NECRS) is much higher
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in Japan [11]. Thus, when olfaction in CRS, ECRS, and NECRS are investigated, they should be considered distinct entities. Age, nasal polyposis, smoking, and asthma are considered risk factors for olfactory dysfunction in patients with CRS [12]. However, the risk factors and severity remain unclear for ECRS and NECRS. In the present study, we examined the clinical characteristics associated with olfactory dysfunction in Japanese patients with ECRS and NECRS enrolled in a large multicenter, prospective cohort study.
chronic lung disease, smoking habits, and nasal surgery [20]. Allergic rhinitis was diagnosed on the basis of a blood examination finding of allergen-specific IgE. Patients were considered to have asthma if they reported a history of wheezing or a diagnosis of asthma or both without a significant smoking history or a history of chronic lung disease other than asthma. 2.4. Computed tomography findings and endoscopic findings
2. Materials and methods 2.1. Study population We performed a multicenter prospective cohort study of 621 patients who underwent endoscopic sinus surgery (ESS) from April 2007 through March 2008 at the Department of Otorhinolaryngology, The Jikei University School of Medicine, Ota General Hospital, or Tokyo Dental College Ichikawa General Hospital. Of these patients, 418 (67.3%) for whom preoperative olfactory data were available were included in the analyses. The Ethics Committee of The Jikei University School of Medicine approved the study protocol. Cases of CRS were diagnosed in accordance with the criteria of the Task Force of the American Academy of Otolaryngology-Head and Neck Surgery [13]. Patients were excluded from this study if they had undergone ESS with an external approach, had a follow-up period of less than 1 month, or had a tumor, allergic fungal rhinosinusitis, odontogenic sinusitis, fungal disease, or mucocele.
The extent of sinus disease identified with computed tomography (CT) was quantified with the Lund-Mackay scoring system [21]. We used the total score for bilateral anterior and posterior ethmoid sinus opacification. The bilateral olfactory clefts were endoscopically evaluated for nasal polyps using a scale of 0–3 (0 is no polyps, 1 is edema, 2 is polyps, and 3 is polyposis). 2.5. Sinus mucosal or polyp eosinophils At the time of ESS, sinus mucosal or polyp tissue was removed and subjected to pathologic examination using hematoxylin–eosin staining. All specimens were examined microscopically in a blinded fashion, and the number of eosinophils was counted per high-power field (HPF, 400, 0.238 mm2). For each specimen, eosinophils were counted in the 3 HPFs containing the largest numbers of eosinophils, and the mean number of mucosal or polyp eosinophils per HPF was calculated.
2.2. Olfactory examination and symptoms of patients 2.6. Diagnosis of ECRS and NECRS T&T olfactometry (Takasago Industry, Tokyo, Japan) [14] and an intravenous olfactory test (Alinamin1 test, Takeda Pharmaceutical Co. Ltd., Osaka, Japan) are the most commonly used olfactory examinations in Japan. For T&T olfactometry, a Jet Stream Olfactometer (Nagashima Medical Instruments Co., Ltd., Tokyo, Japan), with modified injection procedures, was used [15]. To reduce the laboratory technicians’ workload and to analyze more patients with olfactory dysfunction, we simplified the test to include 3 types of odorants: b-phenyl ethyl alcohol (odorant A), cyclotene (odorant B), and isovaleric acid (odorant C), as previously described [16]. The detection and recognition thresholds were determined for each odorant, and the recognition thresholds of the 3 odorants were averaged to evaluate olfactory acuity [16]. A recognition threshold of 2 to 1 is defined as ‘‘normosmia,’’ 1.1–2.5 as ‘‘mild hyposmia,’’ 2.6–4.0 as ‘‘moderate hyposmia,’’ 4.1–5.5 as ‘‘severe hyposmia’’ and 5.6–5.8 as ‘‘anosmia,’’ in accordance with the Japanese Olfactory Test Committee criteria [17]. Alinamin1 is a thiol derivative of vitamin B1 and smells like garlic. The latent time is measured as the interval from the start of injection until recognition of the garlic smell, and the duration is recorded as the interval from recognition until the disappearance of the garlic smell [18]. In healthy subjects, the latent time is 7–9 s, and the duration is 1–2 min. Patients who do not respond to the Alinamin1 test have a poor prognosis for the recovery of olfactory acuity [18]. For each patient, the severity of olfactory dysfunction, nasal obstruction, nasal discharge, and postnasal drip was assessed with a 7-point Likert scale [19] in which 0 is none, 2 is mild, 4 is moderate, and 6 is very severe. 2.3. Asthma, allergic rhinitis, smoking and operative history Patients were asked specific questions regarding their history of wheezing and asthma, use of asthma medications, history of
Diagnoses of CRS were made in accordance with the criteria of Meltzer et al. [22]. The diagnostic criteria for ECRS were: (1) CRS with nasal polyps and (2) mucosal eosinophilia of 120/HPF or more or eosinophilic mucin or both [7]. The diagnostic criteria for NECRS were: (1) CRS with nasal polyps or CRS without nasal polyps and (2) mucosal eosinophilia less than 120/HPF and no eosinophilic mucin. 2.7. Statistical analyses Analyses were performed with SPSS v 11.0 statistical software (SPSS, Chicago, IL). Individual correlations between ECRS and NECRS were analyzed with the t-test (for normal distributed data), the Mann–Whitney U-test (for not normal distributed data), or the chi-square test. Multivariate logistic regression models were constructed to compare the characteristics of patients with CRS and patients with CRS plus olfactory dysfunction. The first model examined variables associated with CRS, the second model examined variables associated with NECRS, and the third model examined variables associated with ECRS. As dependent variables, the results of T&T olfactometry (4.1 for 1, and <4.1 for 0) were used. Independent variables were sex, age, peripheral eosinophil count, total IgE level, ethmoid opacification, olfactory cleft polyps, percent of predicted vital capacity (%VC), the percent predicted forced expiratory volume in 1 s (%FEV1.0), history of previous surgery, allergic rhinitis, asthma, past smoking, current smoking, and Brinkman index. Patients were divided by age into 2 groups – 50 and <50 years – on the basis of the cut-off point from 40 to 75 years old that would provide the highest accuracy on multivariate analysis. Patients were also divided into 2 groups on the basis of IgE level – 400 and <400 IU/ml – on the basis of the cut-off point from 100 to 700 IU/ml that would provide the highest accuracy on multivariate analysis.
E. Mori et al. / Auris Nasus Larynx 40 (2013) 465–469
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Table 1 Comparison of risk factors between NECRS and ECRS.
Patients (female:male) Age (years) Peripheral eosinophil (count/ml) Total IgE (IU/ml) CT ethmoid opacification Polyps of olfactory cleft Spirometry, %VC Spirometry, %FEV Previous surgery (%) Allergic rhinitis (%) Asthma (%) Past smoking (%) Current smoking (%) Brinkmann index
All patients
NECRS
ECRS
p-Value
418 (126:292) 47.9 14.9 342.7 294.2 243.6 406.9 4.2694 3.00 1.98 2.36 112.9 17.3 94.6 17.3 70 (16.7) 281 (67.2) 88 (21.0) 101 (24.1) 121 (28.9) 259.8 439
228 (71:157) 48.4 15.5 184.1 109.7 189.0 372.6 3.43 2.88 1.18 1.99 112.6 18.0 77.8 12.0 38 (16.7) 135 (59.2) 22 (9.6) 46 (20.1) 74 (32.5) 288.8 478
190 (55:135) 47.4 14.6 533.1 331.4 308.0 437.4 5.25 2.83 2.95 2.41 113.4 16.5 114.4 539.1 32 (16.8) 146 (76.8) 66 (34.7) 55 (29.0) 47 (24.7) 221 384
0.569 0.519 0.000 0.000 0.000 0.000 0.937 0.059 0.962 0.000 0.000 0.047 0.065 0.386
3. Results 3.1. Characteristics of patients, comparison between NECRS and ECRS Table 1 summarizes the demographic and clinical characteristics of patients with CRS, NECRS, or ECRS. The mean peripheral eosinophil count, total IgE level, and degree of total ethmoid opacification of patients with ECRS were significantly greater than those in patients with NECRS. Allergic rhinitis, asthma, and a past smoking history were more common in patients with ECRS than in patients with NECRS. However, there were no statistically significant differences in regards to sex, age, %VC, %FEV, previous surgery, current smoking history, or Brinkman index. 3.2. Comparison of symptoms between NECRS and ECRS Fig. 1 compares NECRS and ECRS in terms of the severity of the assessed symptoms. The mean (SD) severity scores for olfactory dysfunction, nasal obstruction, and nasal discharge in ECRS (3.75 0.16, 4.08 0.12, and 2.74 0.12) were significantly greater than those in NECRS (2.65 0.15, 3.19 0.12, and 2.40 0.13) (Fig. 1a–c). However, there was no statistically significant difference in the severity of postnasal drip (Fig. 1d). 3.3. Comparison of olfactory examination results between ECRS and NECRS Fig. 2 shows the olfactory examination results in patients with NECRS or ECRS. Of patients with ECRS, 49.2% (91 of 185 patients) had a Likert scale score of 5, which was a significantly greater
percentage than for patients with NECRS (42.4%, 67 of 158 patients; Fig. 2a). Of patients with ECRS, 47.0% (77 of 164) had an Alinamin1 test duration of 60 s or more, which was a significantly greater percentage than for patients with NECRS (29.8%, 67 of 225; Fig. 2b). Furthermore, of patients with ECRS, 55.3% (105 of 190 patients) had a T&T score of 4.1, which was significantly greater percentage than for patients with NECRS (36.4%, 83 of 228 patients; Fig. 2c). The mean (SD) latent time of the Alinamin1 test in patients with ECRS (21.0 1.74 s) was significantly longer than in patients with NECRS (16.0 0.61 s). The mean duration of the Alinamin1 test in patients with ECRS (75.1 4.53 s) was significantly shorter than that in patients with NECR (88.1 4.00 s). The mean T&T olfactometry score in patients with ECRS (3.92 1.98) was significantly greater than that in patients with NECRS (3.17 1.87). 3.4. Multivariate regression analysis Patients with olfactory cleft polyps (odds ratio [OR], 3.24), ethmoid opacification (OR, 2.64), asthma (OR, 2.29), or current smoking (OR, 1.74) or who were 50 years or older (OR, 1.66) were at significantly greater risk of CRS than were patients without olfactory cleft polyps, without ethmoid opacification, without asthma, or without current smoking habit or who were younger than 50 years (Table 2, Model 1). Patients with ethmoid opacification (OR, 3.09) or olfactory cleft polyps (OR, 3.05) were at significantly greater risk of NECRS than were patients without these features (Table 2, Model 2). Patients with olfactory cleft polyps (OR, 3.98), a current smoking habit (OR 2.67), IgE 400 IU/
Fig. 1. (a–d) Comparison of symptoms between noneosinophilic rhinosinusitis (NECRS) and eosinophilic rhinosinusitis (ECRS). The individual symptoms between ECRS and NECRS were analyzed with the Mann–Whitney U-test; n = 418, *p < 0.01. The vertical axis is the ‘Severity Score’: 0 = none, 2 = mild, 4 = moderate, and 6 = very severe.
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E. Mori et al. / Auris Nasus Larynx 40 (2013) 465–469 Table 2 Odds ratio for each variable in CRS, NECRS, and ECRS. Model Model 1 CRS patients
(n = 418)
Model 2 NECRS patients (n = 228)
Model 3 ECRS patients (n = 190)
Fig. 2. Comparison of olfactory test scores between NECRS and ECRS: (a) Likert scale score of 5 or <5. The percentage of patients with a Likert scale score of 5 or more was significantly greater for ECRS than for NECRS. (b) Intravenous olfactory test, duration of 60 s or <60 s. The percentage of patients with a duration of 60 s or more was significantly greater for ECRS than for NECRS. (c) T&T olfactometry score of 4.1 or <4.1. The percentage of patients with a T&T olfactometry score of 4.1 or higher was significantly greater for ECRS than for NECRS. Individuals were analyzed with the chi-square test; n = 418, *p < 0.01.
ml (OR, 2.65), ethmoid opacification (OR, 2.51), or asthma (OR, 2.34) were at significantly greater risk of ECRS than were patients without these characteristics (Table 2, Model 3). 4. Discussion The present study is, to the best of our knowledge, the first to examine the clinical characteristics associated with olfactory dysfunction in Japanese patients with ECRS and NECRS enrolled in a large multicenter, prospective cohort study. We found, on the basis of 3 different olfactory examinations, that olfactory dysfunction was more severe and more prevalent in patients with ECRS than in patients with NECRS. These findings suggest that eosinophils may act as important effectors of olfaction. Eosinophilia is a hallmark of nasal polyps, is thought to be a risk factor for disease recurrence [7,8], and is thought to play a major role in the pathogenesis of CRS [23,24]. Patients with CRS who have high infiltration of activated eosinophils, i.e., ECRS, significantly had severe olfactory dysfunction [25]. Our comparison of ECRS and NECRS showed that the degree of CT ethmoid opacification and the frequency of olfactory cleft polyps were greater in ECRS than in NECRS. This finding suggests that ECRS causes mixed olfactory dysfunction. Mixed olfactory
Risk factor
Odds ratio
95% CI
p-Value
Polyps of olfactory cleft Ethmoid opacification (0–8) Comorbid with asthma Current smoking Age 50 years
3.24
1.93–5.46
0.000
2.64
1.54–4.52
0.000
2.29 1.74 1.66
1.27–4.14 1.04–2.91 1.04–2.65
0.006 0.034 0.032
Ethmoid opacification (0–8) Polyps of olfactory cleft
3.09
1.58–6.04
0.001
3.05
1.53–6.07
0.001
Polyps of olfactory cleft Current smoking IgE 400 IU/ml Ethmoid opacification (0–8) Asthma
3.98 2.67 2.65 2.51
1.67–9.48 1.17–6.11 1.12–6.23 1.06–5.96
0.002 0.019 0.026 0.036
2.34
1.10–4.95
0.026
dysfunction is caused by a mechanical blockage of the upper nasal airway by polyps, inflammatory damage of the neuroepithelium and alterations of the olfactory mucosal membrane. Peripheral eosinophil levels and total IgE levels were higher in ECRS than in NECRS. However, when multivariate logistic regression models were constructed, peripheral eosinophil levels did not help predict olfactory dysfunction in patients with CRS. Local eosinophilia correlated with peripheral eosinophilia [7,11]. Neither ethmoid eosinophil levels nor basement-membrane thickening is an independent predictor of olfactory dysfunction in CRS [26]. Local eosinophils were measured from nasal polyps, which usually arose from the ethmoid sinus. If the eosinophilia of olfactory mucosa were added to factors, the results might have been different. Further study is needed at this point. When we examined ECRS, we identified olfactory cleft polyps, current smoking, serum IgE 400 IU/ml, ethmoid opacification, and asthma as independent risk factors for olfactory dysfunction. IgE, which was not found to be a risk factor for olfactory dysfunction in all types of CRS, was identified as a risk factor for olfactory dysfunction in ECRS. IgE, a key inflammatory process mediator in allergic rhinitis and asthma, has been implicated in CRS. Serum levels of IgE correlate with the severity of mucosal disease assessed with CT [27]. In our study, IgE 400 IU/ml was associated with severe olfactory dysfunction in ECRS. For patients with CRS, treatment with a monoclonal antibody against IgE (omalizumab) improves olfaction [28]. IgE is an attractive target for therapeutic intervention for CRS, especially for ECRS. Olfactory function changes with age [29]. Thus, it is not surprising that olfactory function is decreased in patients with CRS who are 50 years or older. Older rats show increased proapoptotic gene expression in the olfactory epithelium and increased cell death of olfactory receptor neurons [30,31]. Furthermore, olfactory dysfunction in patients with CRS involves inflammatory changes within the olfactory mucosa and altered airflow to the olfactory cleft [32]. Older patients with CRS are affected by both inflammation and age-related changes. Smoking is also associated with olfactory dysfunction. Olfactory function is negatively correlated with the cumulative smoking dose and the time since the last cigarette [33]. Olfactory membrane biopsies in patients with CRS show a greater frequency of squamous metaplasia in smoking patients than in nonsmoking patients [34]. In the present study, past smoking was not identified
E. Mori et al. / Auris Nasus Larynx 40 (2013) 465–469
as a causative factor of olfactory dysfunction, suggesting that olfactory dysfunction due to smoking is a reversible change and that smoking cessation may prevent severe olfactory dysfunction. Therefore, smokers should be advised to stop smoking to help prevent olfactory dysfunction. We found that asthma was a risk factor for olfactory dysfunction in all patients with CRS and in patients with ECRS. The association between CRS and asthma has long been appreciated [35]. High prevalences both of abnormal sinus mucosa in patients with asthma and of asthma in patients with CRS have been reported [36,37]. Patients with asthma and CRS can be considered to have systemic inflammation in the upper and lower respiratory tracts (the ‘‘one air way one disease’’ theory) which would cause olfactory dysfunction [38]. Comorbid and severity of asthma are associated with nasal blockage, nasal secretion, aching sinuses, and reduced smell [39]. In NECRS, we identified only ethmoid opacification and olfactory cleft polyps as independent risk factors for olfactory dysfunction. These 2 factors were also found to be risk factors for ECRS and for any type of CRS. Repeated inflammation over a long period of time can damage the olfactory epithelium and cause mixed olfactory dysfunction [40]. ESS, which removes nasal polyposis and opens the ethmoid sinus, improves both sense of smell and olfactory thresholds in patients with nasal polyposis [41]. Olfactory dysfunction was more severe and more prevalent in ECRS than in NECRS, and the risk factors for olfactory dysfunction differed between them. Thus, when olfaction in CRS is investigated, ECRS and NECRS should be examined separately. Physicians should pay attention to these clinical findings to diagnose olfactory dysfunction, especially in ECRS, and should also provide appropriate explanation, guidance, and care. Conflict of interest There is no financial and material support for this research. Conflict of interest is none. References [1] Bra¨merson A, Nordin S, Bende M. Clinical experience with patients with olfactory complaints, and their quality of life. Acta Otolaryngol 2007;127:167–74. [2] Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Impact of olfactory impairment on quality of life and disability. Arch Otolaryngol Head Neck Surg 2001;127:497–503. [3] Landis BN, Konnerth CG, Hummel T. A study on the frequency of olfactory dysfunction. Laryngoscope 2004;114:1764–9. [4] Egawa M. Olfactory disturbance caused by chronic sinusitis. Nippon Jibiinkoka Gakkai Kaiho 1995;98. 843-584 [in Japanese]. [5] Mori E, Matsuwaki Y, Mitsuyama C, Yamazaki M, Okushi T, Moriyama H. Comparison of open essence scent identification test card and conventional olfaction tests. Nippon Jibiinkoka Gakkai Kaiho 2011;114:917–23 [in Japanese]. [6] Meltzer EO, Hamilos DL. Rhinosinusitis diagnosis and management for the clinician: a synopsis of recent consensus guidelines Mayo Clinic proceedings. Mayo Clin 2011;86:427–43. [7] Matsuwaki Y, Okushi T, Asaka D, Mori E, Nakajima T, Yoshida T, et al. Chronic rhinosinusitis: risk factors for the recurrence of chronic rhinosinusitis based on 5-year follow-up after endoscopic sinus surgery. Int Arch Allergy Immunol 2008;146:77–81. [8] Nakayama T, Yoshikawa M, Asaka D, Okushi T, Matsuwaki Y, Otori N, et al. Mucosal eosinophilia and recurrence of nasal polyps – new classification of chronic rhinosinusitis. Rhinology 2011;49:392–6. [9] Bachert C, Gevaert P, Holtappels G, Johansson SGO, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 2011;107:607–14. [10] Nakayama T, Asaka D, Yoshikawa M, Okushi T, Matsuwaki Y, Otori N, et al. Identification of chronic rhinosinusitis phenotypes using cluster analysis. Am J Rhinol 2012;26:172–6.
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Risk factors for olfactory dysfunction in chronic rhinosinusitis§ Eri Mori a,b,c,*, Yoshinori Matsuwaki a, Chieko Mitsuyama a, Tetsushi Okushi a,d, Tsuneya Nakajima d, Hiroshi Moriyama a a
Department of Otorhinolaryngology, Jikei University, School of Medicine, Tokyo, Japan Department of Otorhinolaryngology, St. Luke’s International Hospital, Tokyo, Japan c Department of Otorhinolaryngology, Ota General Hospital, Kanagawa, Japan d Department of Otorhinolaryngology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 October 2012 Accepted 11 January 2013 Available online 16 February 2013
Objective: Although risk factors for olfactory dysfunction in patients with chronic rhinosinusitis (CRS) have been examined, most studies did not distinguish between classified eosinophilic chronic rhinosinusitis (ECRS) and noneosinophilic chronic rhinosinusitis (NECRS). The incidence of eosinophilic disease in Japan differs from that in the West. Thus, when olfaction in CRS is investigated, ECRS and NECRS should be examined separately. In the present study, we examined the clinical characteristics associated with olfactory dysfunction in Japanese patients with ECRS and NECRS enrolled in a large multicenter, prospective cohort study. Methods: Olfactory examination results, demographic data, clinical factors, and comorbidity data were analyzed for 418 patients with CRS at 3 tertiary care centers. We used T&T olfactometry, intravenous olfactory test (the Alinamin test) and Likert scale to assess subjects’ olfactory function. Data were analyzed with univariate and multivariate analyses. Results: Olfactory dysfunction was more severe and more prevalent in ECRS than in NECRS. We found that olfactory cleft polyps (odds ratio [OR], 3.24), ethmoid opacification (OR, 2.64), asthma (OR, 2.29), current smoking (OR, 1.74) and age 50 years (OR, 1.66) were associated with olfactory dysfunction in CRS. Ethmoid opacification (OR, 3.09) and olfactory cleft polyps (OR, 3.05) were associated with olfactory dysfunction in NECRS. Olfactory cleft polyps (OR, 3.98), current smoking (OR, 2.67), IgE 400 IU/ml (OR, 2.65), ethmoid opacification (OR, 2.51), and asthma (OR, 2.34) were associated with olfactory dysfunction in ECRS. Conclusions: Olfactory dysfunction was more severe and prevalent in ECRS than in NECRS. Physician should pay attention to these clinical findings to diagnose olfactory dysfunction, especially in ECRS, and should provide appropriate explanation, guidance, and care. In addition, smokers should be advised to stop smoking to help prevent olfactory dysfunction. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Olfactory dysfunction Chronic rhinosinusitis Eosinophilic rhinosinusitis Noneosinophilic rhinosinusitis Risk factor
1. Introduction Olfactory function is an essential sensory function in animals and is deeply involved in appetite, motivation, and libido. Patients with anosmia often feel isolated and emotionally impaired [1], and their quality of life is decreased [2]. However, many people are unaware of olfactory dysfunction [3], because information can be obtained via the other senses. There is also a general lack of awareness regarding the problem of olfactory dysfunction, even on
§ This article was presented at the 2010 International Symposium on Infection and Allergy of Nose held in Geneva, Switzerland, from June 20th to 24th, 2010. * Corresponding author at: Department of Otorhinolaryngology, St. Luke’s International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan. Tel.: +81 3 3541 5151; fax: +81 3 3544 0649. E-mail addresses: [email protected], [email protected] (E. Mori).
0385-8146/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.anl.2012.12.005
the part of clinicians. Olfactory dysfunction may not directly cause systemic problems, but if left untreated, harmful effects may manifest in regard to nutrition, reproductive activity, and even survival. Little data are available regarding olfactory dysfunction in Japan, but 40–50% of cases of olfactory dysfunction are caused by chronic rhinosinusitis (CRS) [4,5]. In the West, approximately 90% of patients with nasal polyps show a mixed cellular infiltrate with prominent eosinophilia [6]. Tissue eosinophilia [7,8] and local increases in IgE levels [9] are hallmarks of nasal polyps and are thought to be risk factors for disease recurrence. In Japan, eosinophilic chronic rhinosinusitis (ECRS) has recently been classified and induces severe olfactory dysfunction even at an early stage [10,11]. However, the incidence of eosinophilic disease in Japan is lower than in the West, but the incidence of noneosinophilic chronic rhinosinusitis (NECRS) is much higher
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in Japan [11]. Thus, when olfaction in CRS, ECRS, and NECRS are investigated, they should be considered distinct entities. Age, nasal polyposis, smoking, and asthma are considered risk factors for olfactory dysfunction in patients with CRS [12]. However, the risk factors and severity remain unclear for ECRS and NECRS. In the present study, we examined the clinical characteristics associated with olfactory dysfunction in Japanese patients with ECRS and NECRS enrolled in a large multicenter, prospective cohort study.
chronic lung disease, smoking habits, and nasal surgery [20]. Allergic rhinitis was diagnosed on the basis of a blood examination finding of allergen-specific IgE. Patients were considered to have asthma if they reported a history of wheezing or a diagnosis of asthma or both without a significant smoking history or a history of chronic lung disease other than asthma. 2.4. Computed tomography findings and endoscopic findings
2. Materials and methods 2.1. Study population We performed a multicenter prospective cohort study of 621 patients who underwent endoscopic sinus surgery (ESS) from April 2007 through March 2008 at the Department of Otorhinolaryngology, The Jikei University School of Medicine, Ota General Hospital, or Tokyo Dental College Ichikawa General Hospital. Of these patients, 418 (67.3%) for whom preoperative olfactory data were available were included in the analyses. The Ethics Committee of The Jikei University School of Medicine approved the study protocol. Cases of CRS were diagnosed in accordance with the criteria of the Task Force of the American Academy of Otolaryngology-Head and Neck Surgery [13]. Patients were excluded from this study if they had undergone ESS with an external approach, had a follow-up period of less than 1 month, or had a tumor, allergic fungal rhinosinusitis, odontogenic sinusitis, fungal disease, or mucocele.
The extent of sinus disease identified with computed tomography (CT) was quantified with the Lund-Mackay scoring system [21]. We used the total score for bilateral anterior and posterior ethmoid sinus opacification. The bilateral olfactory clefts were endoscopically evaluated for nasal polyps using a scale of 0–3 (0 is no polyps, 1 is edema, 2 is polyps, and 3 is polyposis). 2.5. Sinus mucosal or polyp eosinophils At the time of ESS, sinus mucosal or polyp tissue was removed and subjected to pathologic examination using hematoxylin–eosin staining. All specimens were examined microscopically in a blinded fashion, and the number of eosinophils was counted per high-power field (HPF, 400, 0.238 mm2). For each specimen, eosinophils were counted in the 3 HPFs containing the largest numbers of eosinophils, and the mean number of mucosal or polyp eosinophils per HPF was calculated.
2.2. Olfactory examination and symptoms of patients 2.6. Diagnosis of ECRS and NECRS T&T olfactometry (Takasago Industry, Tokyo, Japan) [14] and an intravenous olfactory test (Alinamin1 test, Takeda Pharmaceutical Co. Ltd., Osaka, Japan) are the most commonly used olfactory examinations in Japan. For T&T olfactometry, a Jet Stream Olfactometer (Nagashima Medical Instruments Co., Ltd., Tokyo, Japan), with modified injection procedures, was used [15]. To reduce the laboratory technicians’ workload and to analyze more patients with olfactory dysfunction, we simplified the test to include 3 types of odorants: b-phenyl ethyl alcohol (odorant A), cyclotene (odorant B), and isovaleric acid (odorant C), as previously described [16]. The detection and recognition thresholds were determined for each odorant, and the recognition thresholds of the 3 odorants were averaged to evaluate olfactory acuity [16]. A recognition threshold of 2 to 1 is defined as ‘‘normosmia,’’ 1.1–2.5 as ‘‘mild hyposmia,’’ 2.6–4.0 as ‘‘moderate hyposmia,’’ 4.1–5.5 as ‘‘severe hyposmia’’ and 5.6–5.8 as ‘‘anosmia,’’ in accordance with the Japanese Olfactory Test Committee criteria [17]. Alinamin1 is a thiol derivative of vitamin B1 and smells like garlic. The latent time is measured as the interval from the start of injection until recognition of the garlic smell, and the duration is recorded as the interval from recognition until the disappearance of the garlic smell [18]. In healthy subjects, the latent time is 7–9 s, and the duration is 1–2 min. Patients who do not respond to the Alinamin1 test have a poor prognosis for the recovery of olfactory acuity [18]. For each patient, the severity of olfactory dysfunction, nasal obstruction, nasal discharge, and postnasal drip was assessed with a 7-point Likert scale [19] in which 0 is none, 2 is mild, 4 is moderate, and 6 is very severe. 2.3. Asthma, allergic rhinitis, smoking and operative history Patients were asked specific questions regarding their history of wheezing and asthma, use of asthma medications, history of
Diagnoses of CRS were made in accordance with the criteria of Meltzer et al. [22]. The diagnostic criteria for ECRS were: (1) CRS with nasal polyps and (2) mucosal eosinophilia of 120/HPF or more or eosinophilic mucin or both [7]. The diagnostic criteria for NECRS were: (1) CRS with nasal polyps or CRS without nasal polyps and (2) mucosal eosinophilia less than 120/HPF and no eosinophilic mucin. 2.7. Statistical analyses Analyses were performed with SPSS v 11.0 statistical software (SPSS, Chicago, IL). Individual correlations between ECRS and NECRS were analyzed with the t-test (for normal distributed data), the Mann–Whitney U-test (for not normal distributed data), or the chi-square test. Multivariate logistic regression models were constructed to compare the characteristics of patients with CRS and patients with CRS plus olfactory dysfunction. The first model examined variables associated with CRS, the second model examined variables associated with NECRS, and the third model examined variables associated with ECRS. As dependent variables, the results of T&T olfactometry (4.1 for 1, and <4.1 for 0) were used. Independent variables were sex, age, peripheral eosinophil count, total IgE level, ethmoid opacification, olfactory cleft polyps, percent of predicted vital capacity (%VC), the percent predicted forced expiratory volume in 1 s (%FEV1.0), history of previous surgery, allergic rhinitis, asthma, past smoking, current smoking, and Brinkman index. Patients were divided by age into 2 groups – 50 and <50 years – on the basis of the cut-off point from 40 to 75 years old that would provide the highest accuracy on multivariate analysis. Patients were also divided into 2 groups on the basis of IgE level – 400 and <400 IU/ml – on the basis of the cut-off point from 100 to 700 IU/ml that would provide the highest accuracy on multivariate analysis.
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Table 1 Comparison of risk factors between NECRS and ECRS.
Patients (female:male) Age (years) Peripheral eosinophil (count/ml) Total IgE (IU/ml) CT ethmoid opacification Polyps of olfactory cleft Spirometry, %VC Spirometry, %FEV Previous surgery (%) Allergic rhinitis (%) Asthma (%) Past smoking (%) Current smoking (%) Brinkmann index
All patients
NECRS
ECRS
p-Value
418 (126:292) 47.9 14.9 342.7 294.2 243.6 406.9 4.2694 3.00 1.98 2.36 112.9 17.3 94.6 17.3 70 (16.7) 281 (67.2) 88 (21.0) 101 (24.1) 121 (28.9) 259.8 439
228 (71:157) 48.4 15.5 184.1 109.7 189.0 372.6 3.43 2.88 1.18 1.99 112.6 18.0 77.8 12.0 38 (16.7) 135 (59.2) 22 (9.6) 46 (20.1) 74 (32.5) 288.8 478
190 (55:135) 47.4 14.6 533.1 331.4 308.0 437.4 5.25 2.83 2.95 2.41 113.4 16.5 114.4 539.1 32 (16.8) 146 (76.8) 66 (34.7) 55 (29.0) 47 (24.7) 221 384
0.569 0.519 0.000 0.000 0.000 0.000 0.937 0.059 0.962 0.000 0.000 0.047 0.065 0.386
3. Results 3.1. Characteristics of patients, comparison between NECRS and ECRS Table 1 summarizes the demographic and clinical characteristics of patients with CRS, NECRS, or ECRS. The mean peripheral eosinophil count, total IgE level, and degree of total ethmoid opacification of patients with ECRS were significantly greater than those in patients with NECRS. Allergic rhinitis, asthma, and a past smoking history were more common in patients with ECRS than in patients with NECRS. However, there were no statistically significant differences in regards to sex, age, %VC, %FEV, previous surgery, current smoking history, or Brinkman index. 3.2. Comparison of symptoms between NECRS and ECRS Fig. 1 compares NECRS and ECRS in terms of the severity of the assessed symptoms. The mean (SD) severity scores for olfactory dysfunction, nasal obstruction, and nasal discharge in ECRS (3.75 0.16, 4.08 0.12, and 2.74 0.12) were significantly greater than those in NECRS (2.65 0.15, 3.19 0.12, and 2.40 0.13) (Fig. 1a–c). However, there was no statistically significant difference in the severity of postnasal drip (Fig. 1d). 3.3. Comparison of olfactory examination results between ECRS and NECRS Fig. 2 shows the olfactory examination results in patients with NECRS or ECRS. Of patients with ECRS, 49.2% (91 of 185 patients) had a Likert scale score of 5, which was a significantly greater
percentage than for patients with NECRS (42.4%, 67 of 158 patients; Fig. 2a). Of patients with ECRS, 47.0% (77 of 164) had an Alinamin1 test duration of 60 s or more, which was a significantly greater percentage than for patients with NECRS (29.8%, 67 of 225; Fig. 2b). Furthermore, of patients with ECRS, 55.3% (105 of 190 patients) had a T&T score of 4.1, which was significantly greater percentage than for patients with NECRS (36.4%, 83 of 228 patients; Fig. 2c). The mean (SD) latent time of the Alinamin1 test in patients with ECRS (21.0 1.74 s) was significantly longer than in patients with NECRS (16.0 0.61 s). The mean duration of the Alinamin1 test in patients with ECRS (75.1 4.53 s) was significantly shorter than that in patients with NECR (88.1 4.00 s). The mean T&T olfactometry score in patients with ECRS (3.92 1.98) was significantly greater than that in patients with NECRS (3.17 1.87). 3.4. Multivariate regression analysis Patients with olfactory cleft polyps (odds ratio [OR], 3.24), ethmoid opacification (OR, 2.64), asthma (OR, 2.29), or current smoking (OR, 1.74) or who were 50 years or older (OR, 1.66) were at significantly greater risk of CRS than were patients without olfactory cleft polyps, without ethmoid opacification, without asthma, or without current smoking habit or who were younger than 50 years (Table 2, Model 1). Patients with ethmoid opacification (OR, 3.09) or olfactory cleft polyps (OR, 3.05) were at significantly greater risk of NECRS than were patients without these features (Table 2, Model 2). Patients with olfactory cleft polyps (OR, 3.98), a current smoking habit (OR 2.67), IgE 400 IU/
Fig. 1. (a–d) Comparison of symptoms between noneosinophilic rhinosinusitis (NECRS) and eosinophilic rhinosinusitis (ECRS). The individual symptoms between ECRS and NECRS were analyzed with the Mann–Whitney U-test; n = 418, *p < 0.01. The vertical axis is the ‘Severity Score’: 0 = none, 2 = mild, 4 = moderate, and 6 = very severe.
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E. Mori et al. / Auris Nasus Larynx 40 (2013) 465–469 Table 2 Odds ratio for each variable in CRS, NECRS, and ECRS. Model Model 1 CRS patients
(n = 418)
Model 2 NECRS patients (n = 228)
Model 3 ECRS patients (n = 190)
Fig. 2. Comparison of olfactory test scores between NECRS and ECRS: (a) Likert scale score of 5 or <5. The percentage of patients with a Likert scale score of 5 or more was significantly greater for ECRS than for NECRS. (b) Intravenous olfactory test, duration of 60 s or <60 s. The percentage of patients with a duration of 60 s or more was significantly greater for ECRS than for NECRS. (c) T&T olfactometry score of 4.1 or <4.1. The percentage of patients with a T&T olfactometry score of 4.1 or higher was significantly greater for ECRS than for NECRS. Individuals were analyzed with the chi-square test; n = 418, *p < 0.01.
ml (OR, 2.65), ethmoid opacification (OR, 2.51), or asthma (OR, 2.34) were at significantly greater risk of ECRS than were patients without these characteristics (Table 2, Model 3). 4. Discussion The present study is, to the best of our knowledge, the first to examine the clinical characteristics associated with olfactory dysfunction in Japanese patients with ECRS and NECRS enrolled in a large multicenter, prospective cohort study. We found, on the basis of 3 different olfactory examinations, that olfactory dysfunction was more severe and more prevalent in patients with ECRS than in patients with NECRS. These findings suggest that eosinophils may act as important effectors of olfaction. Eosinophilia is a hallmark of nasal polyps, is thought to be a risk factor for disease recurrence [7,8], and is thought to play a major role in the pathogenesis of CRS [23,24]. Patients with CRS who have high infiltration of activated eosinophils, i.e., ECRS, significantly had severe olfactory dysfunction [25]. Our comparison of ECRS and NECRS showed that the degree of CT ethmoid opacification and the frequency of olfactory cleft polyps were greater in ECRS than in NECRS. This finding suggests that ECRS causes mixed olfactory dysfunction. Mixed olfactory
Risk factor
Odds ratio
95% CI
p-Value
Polyps of olfactory cleft Ethmoid opacification (0–8) Comorbid with asthma Current smoking Age 50 years
3.24
1.93–5.46
0.000
2.64
1.54–4.52
0.000
2.29 1.74 1.66
1.27–4.14 1.04–2.91 1.04–2.65
0.006 0.034 0.032
Ethmoid opacification (0–8) Polyps of olfactory cleft
3.09
1.58–6.04
0.001
3.05
1.53–6.07
0.001
Polyps of olfactory cleft Current smoking IgE 400 IU/ml Ethmoid opacification (0–8) Asthma
3.98 2.67 2.65 2.51
1.67–9.48 1.17–6.11 1.12–6.23 1.06–5.96
0.002 0.019 0.026 0.036
2.34
1.10–4.95
0.026
dysfunction is caused by a mechanical blockage of the upper nasal airway by polyps, inflammatory damage of the neuroepithelium and alterations of the olfactory mucosal membrane. Peripheral eosinophil levels and total IgE levels were higher in ECRS than in NECRS. However, when multivariate logistic regression models were constructed, peripheral eosinophil levels did not help predict olfactory dysfunction in patients with CRS. Local eosinophilia correlated with peripheral eosinophilia [7,11]. Neither ethmoid eosinophil levels nor basement-membrane thickening is an independent predictor of olfactory dysfunction in CRS [26]. Local eosinophils were measured from nasal polyps, which usually arose from the ethmoid sinus. If the eosinophilia of olfactory mucosa were added to factors, the results might have been different. Further study is needed at this point. When we examined ECRS, we identified olfactory cleft polyps, current smoking, serum IgE 400 IU/ml, ethmoid opacification, and asthma as independent risk factors for olfactory dysfunction. IgE, which was not found to be a risk factor for olfactory dysfunction in all types of CRS, was identified as a risk factor for olfactory dysfunction in ECRS. IgE, a key inflammatory process mediator in allergic rhinitis and asthma, has been implicated in CRS. Serum levels of IgE correlate with the severity of mucosal disease assessed with CT [27]. In our study, IgE 400 IU/ml was associated with severe olfactory dysfunction in ECRS. For patients with CRS, treatment with a monoclonal antibody against IgE (omalizumab) improves olfaction [28]. IgE is an attractive target for therapeutic intervention for CRS, especially for ECRS. Olfactory function changes with age [29]. Thus, it is not surprising that olfactory function is decreased in patients with CRS who are 50 years or older. Older rats show increased proapoptotic gene expression in the olfactory epithelium and increased cell death of olfactory receptor neurons [30,31]. Furthermore, olfactory dysfunction in patients with CRS involves inflammatory changes within the olfactory mucosa and altered airflow to the olfactory cleft [32]. Older patients with CRS are affected by both inflammation and age-related changes. Smoking is also associated with olfactory dysfunction. Olfactory function is negatively correlated with the cumulative smoking dose and the time since the last cigarette [33]. Olfactory membrane biopsies in patients with CRS show a greater frequency of squamous metaplasia in smoking patients than in nonsmoking patients [34]. In the present study, past smoking was not identified
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as a causative factor of olfactory dysfunction, suggesting that olfactory dysfunction due to smoking is a reversible change and that smoking cessation may prevent severe olfactory dysfunction. Therefore, smokers should be advised to stop smoking to help prevent olfactory dysfunction. We found that asthma was a risk factor for olfactory dysfunction in all patients with CRS and in patients with ECRS. The association between CRS and asthma has long been appreciated [35]. High prevalences both of abnormal sinus mucosa in patients with asthma and of asthma in patients with CRS have been reported [36,37]. Patients with asthma and CRS can be considered to have systemic inflammation in the upper and lower respiratory tracts (the ‘‘one air way one disease’’ theory) which would cause olfactory dysfunction [38]. Comorbid and severity of asthma are associated with nasal blockage, nasal secretion, aching sinuses, and reduced smell [39]. In NECRS, we identified only ethmoid opacification and olfactory cleft polyps as independent risk factors for olfactory dysfunction. These 2 factors were also found to be risk factors for ECRS and for any type of CRS. Repeated inflammation over a long period of time can damage the olfactory epithelium and cause mixed olfactory dysfunction [40]. ESS, which removes nasal polyposis and opens the ethmoid sinus, improves both sense of smell and olfactory thresholds in patients with nasal polyposis [41]. Olfactory dysfunction was more severe and more prevalent in ECRS than in NECRS, and the risk factors for olfactory dysfunction differed between them. Thus, when olfaction in CRS is investigated, ECRS and NECRS should be examined separately. Physicians should pay attention to these clinical findings to diagnose olfactory dysfunction, especially in ECRS, and should also provide appropriate explanation, guidance, and care. Conflict of interest There is no financial and material support for this research. Conflict of interest is none. References [1] Bra¨merson A, Nordin S, Bende M. Clinical experience with patients with olfactory complaints, and their quality of life. Acta Otolaryngol 2007;127:167–74. [2] Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Impact of olfactory impairment on quality of life and disability. Arch Otolaryngol Head Neck Surg 2001;127:497–503. [3] Landis BN, Konnerth CG, Hummel T. A study on the frequency of olfactory dysfunction. Laryngoscope 2004;114:1764–9. [4] Egawa M. Olfactory disturbance caused by chronic sinusitis. Nippon Jibiinkoka Gakkai Kaiho 1995;98. 843-584 [in Japanese]. [5] Mori E, Matsuwaki Y, Mitsuyama C, Yamazaki M, Okushi T, Moriyama H. Comparison of open essence scent identification test card and conventional olfaction tests. Nippon Jibiinkoka Gakkai Kaiho 2011;114:917–23 [in Japanese]. [6] Meltzer EO, Hamilos DL. Rhinosinusitis diagnosis and management for the clinician: a synopsis of recent consensus guidelines Mayo Clinic proceedings. Mayo Clin 2011;86:427–43. [7] Matsuwaki Y, Okushi T, Asaka D, Mori E, Nakajima T, Yoshida T, et al. Chronic rhinosinusitis: risk factors for the recurrence of chronic rhinosinusitis based on 5-year follow-up after endoscopic sinus surgery. Int Arch Allergy Immunol 2008;146:77–81. [8] Nakayama T, Yoshikawa M, Asaka D, Okushi T, Matsuwaki Y, Otori N, et al. Mucosal eosinophilia and recurrence of nasal polyps – new classification of chronic rhinosinusitis. Rhinology 2011;49:392–6. [9] Bachert C, Gevaert P, Holtappels G, Johansson SGO, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 2011;107:607–14. [10] Nakayama T, Asaka D, Yoshikawa M, Okushi T, Matsuwaki Y, Otori N, et al. Identification of chronic rhinosinusitis phenotypes using cluster analysis. Am J Rhinol 2012;26:172–6.
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