Abstract
Based on observations described in our letter, we can draw the following conclusions: (1) anosmia must imperatively be added to the list of specific symptoms of COVID-19 infection, (2) anosmia can serve as a free and specific diagnostic tool for developing countries currently affected by the pandemic, (3) the mechanisms of COVID-19 anosmia seem not to directly involve nasal obstruction but rather seem to be related to damage the olfactory neuroepithelium.
From the earliest days of the COVID-19 pandemic, many otolaryngologists and infectious disease clinicians described an extremely high number of cases of sudden anosmia with or without other symptoms. In this context, we carried out the first prospective study aiming to assess all symptoms presented by COVID-19+ patients. This first study included 417 patients with mild or moderate form of reverse transcription-polymerase chain reaction (RT-PC)R+ COVID-19 infection. We showed that 86% of patients had a smell disorder and 88% had a taste disorder. 1 We confirmed in a clinical series of 1420 patients with mild to moderate RT-PCR+ COVID-19 infection that the 2 most common symptoms were headache (70.03%) and anosmia (70.02%). 2 Interestingly, we observed that anosmia could be the first symptom of the disease in 12% of the cases and even that initial anosmia could be the only symptom. We therefore wanted to know whether these patients with a sudden and initial anosmia were infected with COVID-19. Thus, in a prospective clinical series of 78 patients with initial sudden anosmia observed for a maximum of 12 days, we demonstrated that 87.5% of these patients were RT-PCR+ for COVID-19. 3 Based on our psychophysical olfactory evaluation using sniffing tests, we demonstrated that approximately 50% of patients remained anosmic at 15 days and that 24% had recovered a normal sense of smell. We also wanted to know whether nasal obstruction could explain the majority of these smell disorders, mechanism traditionally proposed to mainly explain anosmia in relation to the seasonal flu. Our statistical analysis tend to show that nasal obstruction would not involve to explain our objectively anosmic patients. 1 In addition, in our patient population with initial and sudden anosmia, we observed that 44% would not develop any other ear, nose, and throat (ENT) symptom. This finding reinforces the idea that anosmia induced by COVID-19 infection was most probably linked to damage to the neuroepithelium rich in ACE2 receptor (especially stem cells). 4 In this regard, Gupta et al performed a bioinformatic analysis of single-cell expression profiles underscored selective expression of angiotensin-converting enzyme 2 (ACE2) in a subset of horizontal basal cells and sustentacular cells of the olfactory mucosa in humans. They evaluated the expression of ACE2 transcript in 3906 olfactory mucosa originated single cells from the recent report by Durante et al and suggested that loss of smell in the infected patients is most unlikely due to the direct impairment of the olfactory sensory neurons; in particular the sustentacular cells and the horizontal basal cells are the potential cell types that are highly susceptible to viral entry. 5 Moreover, multiple non-neuronal cell types present in the olfactory epithelium express 2 host receptors, ACE2 and TMPRSS2 proteases, that facilitate SARS-CoV-2 binding, replication, and accumulation (Butowt and Bilinska). 6 Recently, we compared the epidemiological and clinical data obtained from 5740 patients who responded to our survey. Of these, 1420 patients were RT-PCR COVID-19+, 3740 were diagnosed as infected on the basis of World Health Organization symptoms by the general practitioner and 485 by the clinician. Again, we observed in these 5740 patients that anosmia (initial or not) was the most frequent symptom. In addition, our Bayesian analysis confirms that there is no direct correlation with nasal obstruction. Finally, the analysis of comorbidities showed that the most significant negative association was that encountered between hypertension and anosmia (P < .001). This correlation reinforces our hypothesis that the anosmia of COVID-19 patients does not seem to be directly related to nasal obstruction. Indeed, cardiovascular diseases may augment inefficient ACE2 levels, increasing available substrate for SARS-CoV-2 infection within certain organs such as the lung and heart. Moreover, increased ACE2 levels are seen in multiple cardiovascular conditions and related comorbidities such as diabetes and hypertension. 7 However, we are the first to observe such a negative correlation between hypertension and COVID-19 anosmia. This very significant correlation between hypertension and anosmia therefore constitutes a new indirect argument supporting our hypothesis that COVID-19 anosmia is linked to direct damage to neuroepithelial stem cells.
All these observations allow us to draw the following conclusions: (1) anosmia must imperatively be added to the list of specific symptoms of COVID-19 infection, (2) anosmia can serve as a free and specific diagnostic tool for developing countries currently affected by the pandemic, (3) the mechanisms of COVID-19 anosmia seem not to directly involve nasal obstruction but rather seem to be related to damage to the olfactory neuroepithelium.
