Loss of smell is a key symptom of the coronavirus disease 2019, which may be isolated symptom or associated with other general and otolaryngological symptoms. The majority of studies that investigated OD in COVID-19 included mild patients,2,4,7,11−13 which raised the issue of the specificity and the predictive value of OD on the severity of the infection.
In this study, we observed that both self-reported and objective ODs were more prevalent in mild patients compared with individuals presenting moderate-to-critical COVID-19. Vaira et al. recently observed that anosmia and hyposmia accounted for 70% of COVID-19 mild-to-moderate patients.5 However, they only observed a trend of significant differences between severe and mild forms regarding the objective olfactory disorder. In the study of Moein et al. 60 COVID-19 hospitalized and home-managed patients benefited from objective olfactory evaluations.14 Using a different anosmia definition (microsmia), the authors reported a prevalence of objective OD in 98% of patients. Although a low number of hospitalized patients (N = 6), the study findings support a higher prevalence of OD in mild patients (45%) compared with severe patients (10%).14 The comparison with these two studies is however limited because authors did not classify the patients according to the WHO classification and they used different olfactory tests.
The main hypothesis underlying the higher prevalence of anosmia in mild COVID-19 would consist of differences in the immune response to the infection in mild and moderate-to-critical patients. In this hypothesis, patients with mild COVID-19 could have a better local immunological response through a higher production of IgA, which could limit the virus spread into the organism. The limited virus spread in the host body could therefore be associated with a mild clinical form of the disease. Due to the local inflammatory reaction and the well-demonstrated olfactory cell expression of Angiontensin Coverting Enzyme-2 (ACE2) and TMPRSS2,15,16 the patients with mild disease could have stronger impairment of olfactory cells. In addition, we observed that severe and critical patients had a significantly higher level of IgG than mild patients, which may corroborate some findings of the literature.17 However, this hypothesis requires additional studies involving immunological sera, saliva, and nasal secretion analyses.
According to our analysis, young patients could have a higher rate of anosmia compared with elderly individuals. Similar findings have been reported in the study of Speth et al. who investigated self-reported OD in 103 COVID-19 patients.18 Although a significant p-value, we need to remain cautious in the interpretation of this results for two reasons. On the one hand, the association is significant but exhibited a low correlation coefficient (rs=0.246).
The high prevalence of OD in COVID-19 patients supports the need for primary care, ear, nose, and throat (ENT) and neurology physicians to be able to counsel patients regarding the likelihood of recovery, and to identify those at risk of persistent OD, such that therapeutic strategies can be targeted appropriately. Considering both subjective and objective data, we may suggest that the 60-day recovery rate ranges from 75–85%. Interestingly, we may identify several profiles of OD severity because over a third of patients reported smell recovery within the 14 days following the development of OD, while one third did not recover within the 45 days. Typically, OD occurring as part of the common cold is related to nasal congestion, rhinorrhea, olfactory cleft edema and lasts 2–3 weeks. The high prevalence of nasal symptoms could partly explain the occurrence of short OD in some patients who rapidly recovered olfaction once the nasal symptoms disappeared. However, for patients with mid-to-long term or persistent OD, the pathophysiological mechanisms underlying the development of OD could be more complex. According to recent findings,15,19 the OD could be additionally associated with injury of the olfactory neuroepithelial and a virus spread into the olfactory bulb where sustentorial cells and; in some patients, stem neurons express ACE2 and TMPRSS2. Because the expression of ACE2 and TMPRSS2 varies between individuals,20 the long duration of OD in some patients could be due to higher protein expression and more extensive injuries of the olfactory cells. The neurogenesis of the olfactory cells is possible but may take several months.21 The neural hypothesis of OD related to COVID-19 infection is supported by the lack of significant association between olfactory evaluation results and nasal complaints. Moreover, post-viral anosmia was observed in some infections related to viruses of the Coronaviridae family.22
In sum, the mechanisms underlying the OD development could associate olfactory cleft congestion in short-term anosmic patients, injury of the olfactory neuroepithelium and virus spread into the olfactory bulb in mid-to-long terms anosmic patients. Future studies are needed to confirm these hypotheses.
The present study has several strengths and limitations. The main strength is the high number of included patients, which allows to confirm the higher prevalence of OD in mild over moderate-to-critical patients. The data collected in this large cohort allowed us to evaluate the 2-month subjective and objective recovery rate of smell sense. The main limitations are the lack of clinical olfactory examination or imaging at the onset of the disease to assess the olfactory cleft and the olfactory bulb. These observations could provide useful information to better understand the pathophysiological mechanisms underlying the development of anosmia. However, performing nasal fiberoptic examination during the pandemic was prohibited. Moreover, the taste evaluations reported low rates of taste dysfunction in hospitalized patients. Many severe-to-critical patients had nasogastric feeding tube, which, additionally to the delay to assess taste function, may bias the assessment of taste dysfunction. Another limitation is related to the delay (2 to 3 weeks) between the OD onset and the realization of the olfactory evaluations. This delay was particularly long in hospitalized patients who had to be able to undergo olfactory evaluations. Although this possibility is not supported by patient-reported symptoms, the delay between the onset of symptoms and the objective olfactory testing may underestimate the incidence of olfactory dysfunction.