Discussion:
The involvement of COVID-19 in the development of olfactory and gustatory dysfunctions seems obvious. However, the characterization of the pathophysiological mechanisms underlying the olfactory dysfunction remains challenging regarding the risk of contamination. In this study, we have performed both subjective and objective olfactory evaluations in COVID-19 patients through online patient-reported outcome questionnaires and individual objective psychophysical testings. Interestingly, 38% of patients with self-reported olfactory dysfunction had normal olfactory testing at the sniffin’stick test.
The mismatch between the self-reported loss of smell and the anosmia regarding psychophysical testings has already been suggested in a recent Italian study where a few COVID-19 patients, who self-reported loss of smell, were objectively anosmic.14 Thus, the prevalence of olfactory dysfunction related to COVID-19 would be overestimated in the epidemiological studies where the loss of smell was based on subjective reports.
Another important finding of this study is the non-significant relationship between symptoms of nasal inflammation and objective olfactory dysfunction. In most cases of olfactory dysfunction occurring in viral infections, the olfactory disorder is related to the inflammatory reaction of the mucosa, leading to nasal obstruction, rhinorrhea and postnasal drip. In some cases, the olfactory dysfunction appeared to be related to other mechanisms, such as a neural spread of the virus into the neuroepithelium and the olfactory bulb. In 2007, Suzuki et al . demonstrated that coronavirus may be detected in the nasal discharge of patients with olfactory dysfunction.15 In this study, some patients had normal acoustic rhinometry, suggesting that nasal inflammation and related obstruction were not the only etiological factors underlying the olfactory dysfunction in viral infection. Netland et al . demonstrated on transgenic mice expressing the SARS-CoV receptor (human angiotensinconverting enzyme 2) that SARS-CoV may enter the brain through the olfactory bulb, leading to rapid transneuronal spread.16 The neurotropism of the COVID-19 is not new and would be associated with other symptoms and findings. For example, the virus spread into the central nervous system is currently suspected to play a key role in respiratory failure through an effect on the medullary cardiorespiratory center.17 Similarly, the existence of different patterns of gustatory and olfactory recoveries would be explained by selective neurological impairments.1 In other words, and suggested by the aroma and gustatory outcomes, the loss of taste would be not a retro-olfactory disorder in some patients. Future experimental and clinical studies are needed to better understand the pathophysiological mechanisms underlying the development of olfactory and gustatory dysfunctions. These studies would associate patient-reported outcome questionnaires, psychophysical olfactory evaluations, fiberoptic examinations, and imaging or neurophysiological assessments.
The main limitation of the present study is the heterogeneity between patients about the duration of the olfactory dysfunction. However, it is complicated to recruit patients at the first day of the olfactory disorder for many reasons. First, many patients have other troublesome symptoms (e.g. fatigue, myalgia, arthralgia), which may limit the realization of the tests. Second, the recruitment of patients at the first day of the olfactory dysfunction involved a continuous communication to recruit these patients. In practice, it is complicated to communicate with the general public every day for a scientific study. The lack of full objective methods to assess olfaction may be considered as another weakness. In this study, we decided to use the Identification sniffin’sticks test (16 items) for practical and ethical reasons. This test may be performed quickly, which is important to reduce the risk of potential contamination of caregivers.