Olfactory disorder was an important clinical manifestation of CRSwNP. European and American scholars have statistically shown that about 14% and 10% of CRS patients have progressive olfactory dysfunction, respectively (1, 12). Although olfactory disorder was not fatal, it could seriously lower the quality of life and result in loss of appetite, malnutrition, immunity dysfunction, and even food poisoning due to accidental consumption of spoiled food (13, 14). Studies had shown that the most common clinical symptom of eCRSwNP was olfactory disorder (15, 16), and ECRSwNP was usually resistant to drug therapy and surgical treatment and was prone to relapse after treatment. Therefore, eCRSwNP, an important category of refractory rhinosinusitis (17), had become the annoying bottleneck in the treatment of eosinophilic nasal polyps with functional endoscopic sinus surgery. To date, researchers had developed a variety of diagnostic approaches for eCRSwNP, such as blood routine tests, radiologic examinations, and tissue histopathology. Nevertheless, all these methods were invasive or need to wait for a long time to get the reports. Therefore, it was important to diagnose eCRSwNP by recognizing the first noticed primary complaints.
A total of 298 patients with CRSwNP were prospectively analyzed in our study, and the clinical characteristics of eCRSwNP and non-eCRSwNP were collected and described. Using the characteristics of the patients' clinical symptoms, we explored the initial diagnostic tendency. In our study, most CRSwNP patients were aged between forty and fifty years with a male dominance. Patients with eCRSwNP had a familiar history of asthma, and the findings were consistent with those in many previous studies (18-20). In addition, the CT manifestation of eCRSwNP was the centralization of polyps and edema mucosa in the ethmoid sinus and olfactory cleft region, while the non-eCRSwNP was predominantly observed in the maxillary sinus. Our findings were similar to those in previous studies, which showed that the ethmoid and the maxillary sinus were predominantly involved in eCRSwNPs and non-eCRSwNPs, respectively (8, 21, 22). Notably, eCRSwNP patients complained mostly about olfactory dysfunction in the early days; non-eCRSwNP patients commonly presented with nasal congestion with olfactory sensation worsening over time. Therefore, olfactory dysfunction might be the most important clinical symptom in eCRSwNP and non-eCRSwNP patients.
Regarding physiology and pathophysiology of olfactory function, the first step in olfaction was to diffuse the odors to the olfactory epithelium located on the cribriform plate, the upper part of the nasal septum, and the middle and superior turbinate, which were called the olfactory area. Odors were dissolved in the mucus layer and then activated the olfactory receptors (14). Each odor can be recognized by an olfactory receptor through a complex code to help distinguish millions of odors. After processing, the olfactory information was integrated into the olfactory bulb and then transmitted to the limbic system (sentiment), to the hippocampus (memory), and finally to the olfactory cortex (23). Olfactory disorders were associated with complicated fusions of a variety of triggers and involved not only physical obstructions of odors conduction, especially in the olfactory area (24), but also immunologic and chemical effects. Polyps in eCRSwNP were usually bilaterally involved in lesions, mostly in the ethmoid sinus, ostiomeatal complex, and olfactory area, where the olfactory epithelium was richly distributed. The polyps and edema of mucosa mechanically blocked the transmission of odors to the olfactory area (15, 25). The immunologic effect of eCRSwNP mainly involved type 2 inflammation due to nasal polyps or edema and was associated with production of IL-3, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, and eotaxin and up-regulation of adhesion molecules, thereby leading to ecclasis and degeneration of the olfactory epithelium until falling-down of olfactory function (26, 27). Moreover, neurotoxic mediators, known as eosinophilic derived neurotoxins, which were released by eosinophils, can damage the olfactory nerve (28), impede the transmission of odors to the mucus and epithelium, and impair regeneration of neurons. As one of the four main proteins (major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophilic cationic protein [ECP]) in the eosinophils (29), ECP played a devastating role by activating infiltration of the eosinophilic inflammatory cells in the neuroepithelium. In vitro studies had found that ECP gradually increased after exposure to pollen, and the increase was associated with the progression of hyposmia. Nevertheless, ECP can slower the frequency of nasal ciliary movement, even in the epithelial cells (30). All these complicated factors made the sensory receptor fragile to the pathologic stimuli (25, 27).
In our study, patients with eCRSwNP had more severe olfactory disorders than those with non-eCRSwNP. The number and severity of symptoms were significantly higher in eCRSwNP patients than in non-eCRSwNP patients. By multiple regression analysis, we found that the high eosinophilic level in the peripheral blood was an independent risk factor for olfactory dysfunction in CRSwNP patients. The higher the eosinophil level, the more severe the olfactory dysfunction would be. Haruna et al. reported that olfactory dysfunction was more significant when there were a large number of eosinophils in the ethmoid sinus mucosa than when there were a small number of eosinophils in the tissue (15). Mori et al. observed that eosinophilic CRS patients had more severe olfactory dysfunction than non-eosinophilic CRS patients, and smoking was a risk factor for olfactory dysfunction (31). Therefore, it was believed that patients with eCRSwNP were more likely to suffer from loss of smell, probably due to the high eosinophilic level. Furthermore, the ROC curves, with 5.75 as the cutoff value, revealed the significance of olfactory dysfunction in clinical symptoms. All above, if the VAS score of olfactory disorders was beyond 5.75, the patient probably had eCRSwNP, and the symptomatic marker for olfactory dysfunction would be practical and instructive.
The analysis of the risk factors found that olfactory disorders were correlated with the eosinophilic levels, but not with the disease duration, in eCRSwNP patients. In contrast, olfactory disorders were related to the disease duration in non-eCRSwNP patients. The longer the duration, the more severe the hyposmia. Further, stratified analysis of the disease duration showed that when the disease duration was less than 10 years, patients with eCRSwNP had more apparent olfactory disorders, while patients with non-eCRSwNP mainly had nasal congestion. However, when the disease duration was more than 10 years, the symptoms of olfactory disorders became confusing in both groups. These findings indicated that with the progression of the disease, olfactory dysfunction became more significant in non-eCRSwNP patients, probably because the reduplicate stimulation destroyed the epithelium in the context of chronic inflammation (28, 30).
There were some limitations in the present study. First, the sample size was limited so that the disease duration could not be further subdivided, thus probably decreasing the accuracy of the predictive analysis. Further studies with a large sample size were needed to identify an accurate time boundary for better distinguishing between eCRSwNP and non-eCRSwNP. Second, the subjective judgment of VAS scores was used for the diagnosis of olfactory disorder; thus, other objective methods (such as the Sniffin’ Sticks test) should be applied to increase the accuracy of diagnosis in future studies. Third, the diagnostic criteria used in this study were based on the blood eosinophilia and were mainly used to distinguish eosinophilia-dominant from non-eosinophilia-dominant. Therefore, a relatively broad standard would be more appropriate to define the two types in clinical practice and to help diagnose the olfactory disorders.