Approximately 5% of the general population are considered to be anosmic, and an additional 15% are considered to be hyposmic [1]. Upper respiratory infections (URIs) are among the most frequent causes of olfactory dysfunction [2-4]. To date, there is no validated pharmacotherapy for post-URI olfactory dysfunction, although attempts have been made to establish treatment modalities through trials involving systemic and topical steroids [5,6]. Furthermore, repeated short-term exposure to odorants so-called olfactory training (OT), vitamin B [7], caroverine [8], alpha-lipoic acid [9], minocycline [10], and acupuncture [11] appears to be effective in improving olfaction.

Hummel, et al. [12] determined that OT for ＞12 weeks increased olfactory function in 28% of participants. They used eucalyptus, clove, lemon, and rose as odorants in their study. In a recent randomized study, the same authors extended the duration of OT from 12 to 18 weeks, and they obtained results similar to those obtained in the original study [1].

However, in Korea, patients cannot recognize the odors of eucalyptus and clove, considering that Asians, particularly Koreans, are not familiar with these substances. In fact, some Koreans have never seen or smelt these plants. Therefore, the results of OT using plants grown in the West, such as clove, may not be as good as those of OT using Korean plants as odorants for Korean patients with olfactory dysfunction. Based on the hypothesis that the use of familiar odors may improve the results of OT, we designed the present study using Korean odorants for OT in a cohort of Korean patients with olfactory dysfunction.

Among the 88 patients who were initially enrolled, 82 completed the BTT, CCSIT, VAS, NOSE, SNOT-20, and BDI. Six patients were exclude due to uncompleted the olfactory test or questionares. The mean baseline BDI score was 6.7 for these patients, which indicated mild depression. The mean baseline VAS scores for nasal obstruction, sneezing, snoring, headache, facial pain, and olfactory dysfunction were 2.4, 3.0, 3.0, 2.1, 1.18, and 6.7, respectively.

After the first visit, 56 patients were lost to follow-up, and 26 patients remained at the 3-month follow-up. Of these 26 patients, 16 patients did not continue their OT. The remaining 10 patients were included in our study. All 10 patients reported an impaired sense of smell and taste. Nine of the 10 patients exhibited improved olfaction after OT (Fig. 1). BTT and CCSIT scores increased for four patients (patients 1, 3, 5, and 10) after 3 months of OT, while a subjective improvement in olfactory function was observed in the remaining five patients (patients 2, 4, 6, 7, and 8) at the 3- or 6-month follow-up (Table 1). Patient 1 showed a 3-point increase in BTT score and no change in CCSIT score. Patient 3 showed a 4-point increase in BTT score and a 1-point increase in CCSIT score. Patient 5 showed a 1-point increase in BTT score and a 1-point increase in CCSIT score. Patient 10 showed an 8-point increase in BTT score and a 2-point increase in CCSIT score. One patient (patient 9) tested her olfaction after 3 months and exhibited no subjective improvements. In fact, her BTT score decreased by 3 points. Nine patients reported changes in olfaction and the perception of smells over the duration of OT. In detail, patient 2 reported alleviation of his depressive state after 3 months of OT, and that his perception of shampoo smell had changed after 6 months of OT. Patient 3 reported an increased sense of smell after 3 months of OT, although he could not distinguish different smells at that time. Patient 4 reported that he could only smell briefly after 3 months of OT. Patient 5 reported that his perception of a toilet smell was wrong after 3 months of OT, but that this was rectified after 6 months of OT. Patient 10 perceived the smell of cucumber as a fishy smell after 3 months of OT. We were unable to fully analyze the VAS, NOSE, SNOT-20, and BDI scores after 3 and 6 months because the patients did not completely answer all of the questions.

In the present study, we evaluated the effects of OT using Korean odorants in Korean patients with post-URI olfactory dysfunction and found that most of the included patients exhibited an improvement in their olfactory function after OT.

Recent studies have shown that olfactory disorders occur at a much higher rate than previously assumed [12]. Hendriks [16] reported a 35% recovery rate over approximately 12 months. Reden, et al. [17] reported that 32% of patients exhibited significant improvement after a mean interval of 14 months. Heilmann, et al. [18] showed that 35% of patients exhibited a marked increase in olfactory function over an average period of four months. However, regardless of how long it may take to olfactory recovery, olfactory loss has been shown to have a severe impact on the quality of life in some patients [19]. Despite the fact that numerous studies have shown a regenerative ability for olfactory receptor neurons, few treatment options have been proven effective for post-URI dysosmia; One of the most common causes of dysosmia [20,21]. Numerous therapeutic strategies have been proposed, such as the use of strychnine, zinc, theophylline, lipoic acid, and caroverine [3,8,9,22-27]. Although the effectiveness of most of these regimens is far from clear, the usefulness of corticosteroids in sensorineural dysfunction-related olfactory loss is established. This is supported by the observation that systemic steroids are helpful in sensorineural dysfunction-related olfactory loss. However, some patients cannot use oral steroids because of systemic complications. In particular, the long-term use of steroids can result in more severe complications such as stroke, heart disease, and diabetes [5].

Of late, OT has been shown to improve olfactory function in humans [28-30]. A recent systematic review and meta-analysis suggested that OT may be an effective intervention for patients with olfactory dysfunction [31]. Most other studies have reported positive outcomes of OT with regard to olfaction, without significant adverse effects.

Repeated exposure of healthy individuals to odorants was shown to significantly increase olfactory sensitivity, improve the recovery of patients with post-viral olfactory loss [32]. The results of the OT meta-analysis were consistent with the reported results of individual studies, primarily with regard to an improvement in the Threshold-Discrimination-Identification (TDI) score.

In the present study, we derived four important and unique findings compared with the findings of recent studies. First, nine of 10 patients who received OT for a long duration showed an improvement in olfaction. This rate is higher than that in other studies [32], probably because our Korean odorants were more effective for Korean patients, compared to the scents of eucalyptus, clove, lemon, and rose, which were designed for Western patients [1,12]. A biased odor selection maight be a limitation. The four odorants chosen by Hummel, et al. [12] were within the four odor categories claimed by Henning and Der [33] in his workon the ‘odor prism.’ Among our odor selection (pine, cinnamon, lemon, and peppermint), flowery axis is lacking. Also, pine and lemmon are same axis. However, we selected those odors because the use of familiar smells in OT might be more effective than that of unfamiliar smells and could aid patients in better identification.

Second, the patients reported changes in olfaction and the perception of smells during the duration of OT. These findings may be a result of differences in the mechanisms underlying an improvement in the olfactory threshold and olfactory identification, although the level at which these changes occurred, e.g., olfactory receptors, synapses, or central nerves, remains unclear.

Three of the 10 patients showed an improvement of ＞3 points in their BTT score, and the improvement in the CCSIT score came later than that in the BTT score. These findings suggest that the olfactory threshold may improve faster than olfactory identification when olfactory nerves are regenerated. In other words, the progress of regeneration probably differs between the olfactory threshold and olfactory identification [34].

The olfactory system exhibits extraordinary plasticity because of mechanisms that have been extensively investigated at the cognitive as well as the cellular level [35,36]. The mechanisms of neural plasticity in the olfactory system are interesting, because olfactory loss is among the first symptoms of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease [37,38]. In addition, there is a loss of, or at least a decrease in, olfactory function in many neurological conditions [39]. Therefore, neural plasticity with regard to olfactory loss may have widespread implications for brain function. However, the mechanisms underlying the neural plasticity of the olfactory system are still under investigation [38]. It is known that sensory loss often entails functional and structural modifications in the central nervous system [40,41]. An understanding of the extent and mechanisms of plasticity in the olfactory system might provide insight into the brain mechanisms underlying recovery and reorganization [38]. These findings suggest that OT may induce extensive reorganizational processes in more than just the olfactory areas, i.e., OT may strengthen cognitive function beyond olfactory perception. In addition to the central effects of OT manifesting as network changes, there was a statistically significant improvement in the odor detection threshold in other studies [42,43].

Third, our results indicated the need for changes in conventional olfactory testing methods. We found that two patients complained of serious olfactory dysfunction that caused them great inconvenience after URI. However, their BTT and CCSIT scores were 8 and 9, which fall within the normal range. On the other hand, patient 2 had BTT and CCSIT scores of 5, which indicates abnormal olfactory function, although he led a comfortable life without any problems. This suggests that the findings of tests indicating normosmia and hyposmia may not correspond to the clinical findings of olfactory dysfunction. Accordingly, more appropriate tests and criteria are desirable for grading olfactory dysfunction.

Fourth, 7 patients who experienced olfactory dysfunction for 2-3 months after URI showed no improvement after oral steroid therapy in the present study. However, after 3 months of OT, all seven patients exhibited improved olfaction, as indicated by their BTT and CCSIT scores and a subjective improvement in symptoms. This demonstrates the effectiveness of OT. However, we do not believe that OT can serve as a replacement for oral steroid therapy, because according to our experience and the results of other studies, oral steroids are effective in the recovery of olfaction [5]. However, it was reported that two-thirds of patients who received local corticosteroids experienced little or no improvement in olfactory function, particular with regard to long-term changes [5]. We believe that an effective and definite alternative is required for the management of olfactory dysfunction, and OT can be that alternative treatment as assistant to steroid therapy.

The present study was limited in that it had a small sample size and high rate of drop-out. However, we treated 13 anosmic patients with oral steroid without OT in our clinic. Only one patient recovered his olfaction. And a single doctor followed up all patients from diagnosis through treatment over a 2-year period, and also analyzed all their data. Therefore, we believe that the data is accurate and robust. Moreover, all patients were consistently educated throughout the study period. This is necessary to encourage patients to persist with OT, and continuous interaction between doctors and patients, as well as appropriate patient education are important for successful OT. Maintenance of a diary, for example, may aid in increasing long-term compliance with training.

Future studies should investigate the long-term effects of OT to shed light on its impact on higher olfactory function, which may require a longer training period for recovery, considering the recovery of basic sensory perception is required for the regeneration of higher function. In addition, future studies can present a detailed description of changes in the brain during OT using functional MRI. A study has already documented olfactory bulb assessments using MRI; the results showed that the olfactory bulb volume was significantly larger after OT [44]. However, the sample size was small in that study. Mammalian models can also be used for such experiments, although it is difficult to create models of olfactory dysfunction and correctly measure olfaction in such models. However, this is an area of research that we plan to focus on. In addition, we are hoping to design tools for the direct visualization of nerve regeneration in the near future.

In conclusion, OT is a cost-effective and noninvasive treatment option for olfactory dysfunction. However, we cannot conclude that it is suitable as a sole treatment. Instead, the findings of our study and previous studies suggest that OT is an effective long-term ancillary treatment for oral steroid therapy, without the complications associated with steroid therapy. Furthermore, odorants should be customized according to the individual patient’s characteristics, including race, environment, and residence. Odorants familiar to the patient should be used for effective OT, and the development of such odorants is an essential clinical task.