Comparative analyses of post-infectious olfactory dysfunction between COVID-19 and non-COVID-19 cases – Scientific Reports

The emergence of COVID-19 has highlighted the importance of PIOD. In our analysis of 169 patients with PIOD, clear differences were identified between those with COVID-19 and those with other viral infections. Patients in the COVID group were younger, tended to be males, and had parosmia compared to those in the non-COVID group. More strikingly, the initial olfactory function tests revealed that the COVID group’s TDI, D, and I scores were significantly higher than those in the non-COVID group. Interestingly, although both groups demonstrated improvements in olfactory function, the nature of recovery differed. Specifically, the COVID group significantly enhanced the odor detection threshold, while the non-COVID group primarily improved odor identification. These differences in the olfactory function test results provide clues to explain the potentially unique mechanism of olfactory impairment linked to COVID-19. Our findings underscore the diverse manifestations of PIOD and suggest differences in treatment outcomes according to the cause of PIOD.

In line with the previous literature¹¹, patients with PIOD were predominantly female in the present study. Additionally, the female-to-male ratio observed in our study was similar to the results of a meta-analysis of C19OD¹². The non-COVID group was older than the COVID group, and the non-COVID group had a significantly higher proportion of women, especially middle-aged women, consistent with previous studies^11,13. A study comparing non-COVID PIOD and C19OD populations found significant differences in age, sex, and symptom duration¹⁰. Our study showed a consistent trend in age and symptom duration, and an opposite trend concerning sex. Although the prevalence of OD generally increases with age^14,15, C19OD is more common in younger demographics¹⁶. As younger individuals experience a more significant decline in olfactory function, the subsequent discomfort can lead to a perceivable decrease in their quality of life¹⁷. This may prompt them to seek medical services more frequently than ever. The younger age in the COVID group compared to the non-COVID group may be explained by several factors. First, the high incidence of COVID-19 in young individuals may have led to a high incidence of C19OD at younger ages. Second, the mechanisms underlying PIOD may differ between COVID-19 and other viral infections. If the downregulation of genes related to olfactory signal transduction by immune responses is more evident in COVID-19 than in other viral infections, C19OD may be more prevalent in younger individuals exhibiting robust immune responses compared to non-COVID-19-associated PIOD. Further research is required to elucidate the mechanisms underlying the younger age of patients with C19OD.

The vast number of COVID-19 cases during the pandemic has allowed us to conduct extensive research on initial symptoms, recovery rates, and persistence. According to a previous meta-analysis, approximately 78% of patients recover their sense of smell within a month of SARS-CoV-2 infection and 86% within two months³. In contrast, objective evaluations reveal a higher OD diagnosis rate than subjective evaluations¹². Paradoxically, OD defined by an objective identification score appears to recover faster than that defined by a subjective evaluation¹⁸. Considering the findings from previous studies and our own study, we hypothesized that there would be a subsequent enhancement in the odor detection threshold after improving odor identification among patients with COVID-19. This anticipated progression may be related to the pathogenesis of COVID-19.

The underlying mechanisms of PIOD, especially C19OD, were elucidated following the COVID-19 outbreak. The prevalence of PIOD, particularly between March and May, is speculated to be associated with influenza and parainfluenza type 3 viruses¹³. The influenza A virus is classified into 16 hemagglutinin and nine neuraminidase antigenic subtypes. Hemagglutinin plays a crucial role in neurotropism. H5N1 exhibits rapid central nervous system (CNS) transmission, whereas H1N1 primarily affects the olfactory epithelium, suggesting different patterns and severities according to the subtype^19,20. Although the parainfluenza virus does not typically invade the CNS, it has been observed to infect olfactory sensory neurons and surrounding cells in the olfactory epithelium and bulb⁵, potentially impacting the sense of smell²¹.

Additionally, viruses such as herpes simplex virus, cytomegalovirus, and respiratory syncytial virus have been demonstrated to potentially infect both the olfactory epithelium and olfactory sensory neurons, as confirmed in animal models⁵. In the context of COVID-19, sustentacular cells^8,9 predominantly expressing angiotensin-converting enzyme 2 receptors and transmembrane serine protease 2, which are crucial for SARS-CoV-2 viral entry, are the primary targets for infection, whereas olfactory sensory neurons are less affected. While it has been suggested that the CNS may also be susceptible to COVID-19, the rapid recovery suggests that this is unlikely. Furthermore, no definite association has been established between OD and CNS-related symptoms²². Although the mechanisms are still unclear, it has been suggested that death of infected supporting cells in the olfactory epithelium leads to retraction of the cilia on olfactory receptor neurons, possibly because of the lack of support cell-derived glucose in the mucus²³. Additionally, host immune responses following COVID-19 may downregulate genes involved in olfactory signal transduction. Additionally, it has been hypothesized that the odor threshold score reflects peripheral function more accurately than odor discrimination and identification scores²⁴. Considering the relatively preserved scores for discrimination and identification in comparison with the threshold scores in the COVID group, we hypothesized that impairment in peripheral function due to neuropraxia during acute COVID-19²⁵ initially leads to a decrease in all three scores. Then, the discrimination and identification scores rapidly recover³. In contrast, PIOD caused by non-COVID viruses damaging the olfactory epithelium, olfactory sensory neurons, or even the CNS may elicit significant reductions in discrimination and identification scores, with slow recovery. Although the link between OD and neurodegenerative diseases has increasingly been suggested²⁶, the impact of PIOD or COVID-associated PIOD on the development of neurodegenerative diseases, or vice versa, remains unclear. Further research is needed to investigate the potential for an increased incidence of neurodegenerative diseases following the onset of PIOD, as well as the possibility that preceding cognitive function decline may increase the incidence of PIOD.

In our study, we found no significant difference in olfactory function based on the presence of parosmia or phantosmia among the COVID group, in line with the previous study²⁷. Additionally, PIOD patients with parosmia, particularly in the non-COVID group, paradoxically exhibited a lesser improvement in TDI scores than those without parosmia. One study reported that parosmia was associated with lower rates of subjective complete recovery²⁸. This observation and our results contradict a previous study suggesting an enhanced recovery of identification and discrimination scores in the presence of parosmia²⁴. Given the lower prevalence of parosmia and lower TDI scores in the non-COVID group in our study, it can be assumed that parosmia is an indicator of the late stages of recovery rather than a predictor of recovery outcomes.

OT is the primary and most effective intervention for patients with PIOD, including those with C19OD^17,29. However, no significant improvement in olfactory function was observed following treatment with OT alone. A significant difference was observed only in the group that received combined therapy with OT, OCS, and INCS. Given that follow-up test outcomes could be influenced by factors such as patient sex, underlying cause, initial olfactory test scores, and definition of recovery or improvement, it is essential to continuously evaluate patient-reported outcome measures, such as the visual analog scale or Questionnaire for Olfactory Disorders (QOD), to measure subjective recovery³⁰.

This study has some limitations. First, although OT was provided to all the patients, steroid use (OCS or INCS) was considered at the physicians’ discretion. Second, an olfactory questionnaire was not administered after treatment to assess the presence of qualitative OD or quality of life. Third, there is a possibility that some COVID-19 patients may have been classified as non-COVID due to false-negative test results. Fourth, we could not obtain information regarding the severity of COVID-19. Whether the degree of OD is affected by the severity of COVID-19 in patients with C19OD needs to be addressed in future studies. Fifth, there was a low rate of follow-up examinations owing to the retrospective nature of this study. There is a possibility of selection bias in that patients who benefited from treatment or, conversely, those still exhibiting symptoms even after treatment, may be overrepresented. Therefore, future prospective studies are required to verify our results.

In conclusion, we comprehensively compared the clinical characteristics and treatment outcomes of patients with PIOD based on the causative virus, explicitly distinguishing between COVID-19 and non-COVID-19 cases. The patients with C19OD were younger and had a higher prevalence of parosmia. These patients exhibited higher scores for odor discrimination and identification than patients with non-COVID-associated OD. Improvement in the odor detection threshold can be anticipated in patients with C19OD following treatment, whereas patients with non-COVID-associated OD can expect an increase in the identification score. These data provide novel insights into the current understanding of PIOD, including C19OD, and will help guide prognosis and establish treatment strategies.