Olfactory disorder is a commonly found upper respiratory condition; its prevalence stands at around 5% for the general population, and up to 24.5% in the population aged 50 years and over [1]. Olfactory disorder increases the risk of accidents as the patient cannot smell gas or food. It may also adversely affect the patient’s dietary and psychological life [2,3]. Despite these adverse effects on the patient’s quality of life, due to the lack of awareness on its seriousness, olfactory disorder is often ignored and left undiagnosed. The cause of olfactory disorder varies, from upper respiratory infection, paranasal sinus diseases, trauma, and congenital anomaly, each requiring different prognosis and treatment [4].

Coronavirus disease (COVID-19) is an acute respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease rapidly spread across the world after the first confirmed case was reported in December 2019, and the World Health Organization declared a global pandemic in March 2020. The most common early symptoms of COVID-19 include fever, cough, throat pain, breathing difficulty, and headache [5]. However, some COVID-19 patients only experienced olfactory disorder, and up to 47.85% of COVID-19 patients were found to have olfactory disorder [6]. In response, the American Academy of Otolaryngology and Head and Neck Surgery proposed adding olfactory disorder to the list of distinguishing symptoms of COVID-19 [7]. In fact, a study found that people who confirmed positive in the reverse-transcription polymerase chain reaction test were 6.74 times more likely to experience olfactory disorder than the control group [8], and the degree of recent smell dysfunction in an individual with an upper respiratory symptom was reported as the most reliable COVID-19 predictor [9].

Many researchers proposed theories about the mechanism of olfactory disorder caused by COVID-19. However, none of them have been clearly substantiated. A histopathologic examination of a COVID-19 patient’s olfactory epithelium indicated an increase in proinflammatory cytokine, leukocyte infiltration, atrophic nasal mucosa, and marked destruction of olfactory epithelium [10-12]. It is unclear whether these symptoms were directly caused by the virus, or mediated by the damage to non-neuronal cells. The uncertainty about the cause of COVID-19–induced olfactory disorder makes the disease difficult to treat. However, it can be said with certainty that SARS-CoV-2 is one of the many viruses that may cause inflammation in the nasal cavity, and COVID-19–induced olfactory disorder can be classified as post-infectious olfactory dysfunction (PIOD) among many causes of olfactory disorder.

Olfactory training utilizes neuroplasticity to lower the olfactory threshold through repeated exposure to aromas. Hummel et al. (2009) [13] proposed an olfactory training method involving exposure to four aromas. Since then, many researchers confirmed the effectiveness of the method for patients and health individuals alike. Olfactory training is one of the most attractive treatment options for olfactory disorder, as it causes little side effect and can be performed by patients themselves at low costs. In addition, olfactory disorder serves as an evidence-based treatment option for PIOD, for which treatment has not been clearly identified [14,15]. It has taken on greater influence during the COVID-19 pandemic.

This review explores the relevant literature to outline the mechanism and effect of olfactory disorder, and describe the role and effect of olfactory training for COVID-19–induced olfactory disorder in this pandemic age.

Olfactory epithelium is plastic, which means the functions of damaged olfactory epithelium can be restored through neurogenesis. Before the 1980s, it was a widely held opinion that adults do not produce new nerve cells. However, multiple studies using adult rodents found nerve generation in the olfactory bulb [16,17]. Some researchers reported functional and structural changes in olfactory nerves caused by aromatic stimulus. They found that simple exposure to aroma causes changes in the activity of rodents’ olfactory mucosa, thereby lowering the threshold for the aromas that stimulated it [18,19]. In addition, the number of aroma-specific sensory nerve cells increased in olfactory-trained mice, as well as the size of the glomerulus in the olfactory bulb [20]. A 2004 study using human subjects reported that repeated exposure to androstenone lowered the androstenone threshold in both those who can detect odor and those who cannot [21]. The findings indicate the plasticity of the olfactory system, and serve as the evidentiary foundation of olfactory training currently performed on people with olfactory disorders.

Some studies confirmed changes in the olfactory nerves, while others used functional magnetic resonance imaging (fMRI) to verify the involvement of brain regions in the olfactory training mechanism. A study reported that continued exposure to a specific odor increases the reaction of the piriform cortex and the orbitofrontal cortex [22]. Another study compared the fMRI results of olfactory disorder patients before and after a twelve-week olfactory training program, which showed the restoration of functional connection in the non-olfactory areas of the brain, which were disorderly connected before the training [23]. In a study where healthy individuals went through olfactory training for only one of their nostrils, the participants showed significant volume increase in both olfactory bulbs [24]. These findings led some researchers infer a top-down process from the brain to olfactory nerves. These and other researchers reported that various stages of the olfactory training system are involved in olfactory training, and it is difficult to explain the changes brought on by olfactory training with a single theory about its mechanism. A large number of issues still remain to be explained through lab studies.

Many studies reported the positive effect of olfactory training on COVID-19–induced olfactory disorder. In order to qualitatively and quantitatively analyze the degree of the effect and identify clinical evidence of the effect, this study searched for academic articles on the effect of olfactory training for meta-analysis.

Medications currently prescribed for PIOD patients include local and systemic glucocorticoid, alpha lipoic acid, and caroverin [30,31]. The effect of nasal steroid spray on the olfactory function of COVID-19 patients can be explained through a large-scale randomized controlled trial [26,32]. Kasiri et al. [28] suggested that, compared with the olfactory training-only option, the combination of olfactory training and the mometasone furoate nasal spray is more effective in improving the olfactory function of COVID-19 patients with anosmia. On the other hand, Abdelrahman Ahmed analyzed 50 patients complaining of post–COVID-19 olfactory dysfunction by dividing them into the training-only group and the mometasone furoate nasal spray group, and failed to find significant difference in olfactory function in the third week. As such, Abdelalim et al. [26] reported that the nasal steroid spray does not hold advantage over olfactory training in the treatment of post–COVID-19 olfactory disorder. The same conclusion was reported by Rashid et al. [32], who conducted a placebo-controlled trial with 356 COVID-19 and olfactory disorder patients. The patients were divided into two groups: a group of 138 patients who applied betamethasone nasal spray, and another group of 138 patients who applied saline nasal spray. The study failed to identify significant difference between the two groups after 30 days.

Vaira et al. [12] and Le Bon et al. [33] recently conducted small-scale studies that analyzed the clinical benefits of adding oral steroid and nasal steroid spray to olfactory training for COVID-19 patients with olfactory disorder. In Vaira et al.’s study [12], 9 patients who experienced olfactory disorder for 30 days or longer used oral and nasal steroid during their olfactory training, while the control group only went through olfactory training. The findings showed that the patients treated with nasal and oral corticosteroid reported significantly improved olfactory scores than the control group on Day 20 and 40 [12]. Le Bon et al. [33] treated 9 COVID-19 patients with one month or longer olfactory dysfunction with oral steroid and olfactory training, while the control group (18 patients with olfactory disorder for an average 5 weeks) only received olfactory training. The findings indicated a higher level of olfactory score improvement in the group treated with oral steroid. However, while both Vaira et al. [12] and Le Bon et al. [33] found significant difference in identification scores after a month of treatment, the difference was no longer significant after two months. The findings suggest that glucocorticoid accelerates the recovery of olfactory function by accelerating the elevation to the normal threshold and reducing the occurrence of parosmia. However, the group treated with two-month training and systemic steroid or the group with training and nasal steroid did not significantly differ from the training-only group in terms of the percentage of patients who recovered normal olfactory function. This finding requires long-term tracking. The fast recovery reported by the oral steroid group appears to be related with the effect of corticosteroid to accelerate epithelium regeneration and reduce inflammation on the olfactory mucosa. The use of oral corticosteroid for post–COVID-19 olfactory disorder has sparked controversies over the possibility of exacerbation caused by immunosuppression, delayed elimination of the virus, and other side effects. Patients using oral steroids reported adverse side effects such as insomnia, headache, and high blood pressure, of which prevalence rates were similar to those reported by other researchers. The use of oral corticosteroid in COVID-19–related olfactory disorder patients requires further studies [27,34].

Despite some discrepancies among the studies included in the analysis, a number of recent meta-analysis studies have shown the benefits of olfactory training for patients with olfactory disorders from various causes [35,36]. In addition, numerous studies found that olfactory training is more effective for disorder caused by PIOD than olfactory disorders from other causes [15,37-41]. In a systemic review, Harless and Liang [30] failed to find any evidence for the use of drug as the sole treatment for olfactory disorder, which highlights the use of non-drug options such as olfactory training. In a meta-analysis, minimal clinically important difference in threshold discrimination identification (TDI) scores of PIOD patients treated with olfactory training was almost three times higher than that of control group [42]. According to the study, PIOD patients showed reduced metabolism in the olfactory center of their brains, and olfactory training induces changes in the functional connection in olfactory senses, somatic senses, and the integrated pathways [43,44]. The effectiveness of drug treatment has not been proven to an extent that justifies it as a treatment option for PIOD, which supports the increased interest in olfactory training as a treatment option.

COVID-19–induced olfactory disorder can be classified as PIOD, and olfactory disorder is known to improve the olfactory function of COVID-19 patients. The relevant studies need optimization and standardization to account for slight differences in their training protocols. Given the findings on the improvement of olfactory function in patients treated with systemic and/or nasal steroid relative to the training-only group, the benefits of steroid for patients with COVID-19–related olfactory disorder have not been substantiated, and requires further studies.

Olfactory training must be considered as a treatment option for olfactory dysfunction in PIOD and COVID-19 patients. The training should be preceded by otorhinolaryngologic examination to identify other causes, and accompany an appropriate olfactory test to determine the exact degree of olfactory dysfunction and assess the effect of olfactory training.