Discussion:
The recent study of home-managed COVID-19 patients resulted in the identification of an otolaryngological picture of the disease, which could particularly concern mild COVID-19 forms.10,11Among the common otolaryngological symptoms, olfactory and gustatory dysfunctions were reported in many studies conducted around the world12-14 and are currently considered as prognostic factor for lower severity of COVID-19.15 However, to date, a few studies have investigated the prevalence of sense disorders regarding the severity of the infection, as defined by WHO criteria.
In this large cross-sectional study, we observed different clinical pictures depending on the severity of the disease. Mild disease might concern more frequently young patients who usually have otolaryngological symptoms including OD, GD and AD, while elderly patients have a higher risk to develop moderate to critical COVID-19, which are both characterized by general symptoms (e.g. cough, dyspnea, anorexia, nausea) and fewer otolaryngological disorders. In other words, the development of OD, GD and, to a lesser extend, AD may be considered as good prognostic outcomes of COVID-19 because less associated with moderate and severe-to-critical forms of the disease. Similar findings have been suggested in a recent cohort study of 949 patients who did not benefit from objective olfactory evaluations.15
The association between mild COVID-19 form and the development of OD is not yet elucidated. We suspect that the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into the olfactory neuroepithelium and the olfactory bulb may lead to the development of local immunological reaction, which limits the spread of the virus in the host but leads to injuries of the neuroepithelium and olfactory bulb. This neurological hypothesis is supported by recent studies that identified injuries and edema of the olfactory cleft16and abnormalities of olfactory bulb on the magnetic resonance imaging.17 Moreover, SARS-CoV-2 was identified in brain and olfactory bulb of non-survivors in a cadaveric study.18 According to our data and the literature, the presence of otolaryngological symptoms and related OD could be a sign of a local inflammatory reaction, which could limit the virus spread into the host. The lack of association between SNOT-22 items and total score and the development of OD support the neurological process and not the OD related to nasal obstruction, which is frequently observed in usual viral infections such as common cold. Patients with subjective OD would have higher proportions of GD and AD. Although we used NHNES questionnaire, which is validated, it is possible that many patients with isolated OD had ‘flavor disorder’ and, therefore, confused OD, GD and AD. For this reason, it is important to conduct future studies using psychophysical olfactory assessments and gustometry so as to establish the potential association between these sense disorders.
In addition to the age and the disease severity, many conditions were found to be associated with the development of OD, GD or AD. In our study, diabetes was associated with the development of GD and there was a trend of association with Sniffin’Stick test results. The association between diabetes and the development of OD is well-known and supported by a recent meta-analysis.19 Similar findings were observed in patients with GD, confirming the potential role of diabetes in the development of sense disorders.20 In this study, we found that patients with hypertension had a lower proportion of subjective OD and AD compared with those without hypertension. The role of hypertension and the potential intake of angiotensin converting enzyme inhibitors in the development of OD, GD and AD was not extensively studied because only one report argued that COVID-19 patients with hypertension could have a significantly lower risk of OD compared with those without hypertension.21 In the same vein, the association between tobacco, COVID-19 and AD is still unclear and requires future investigations using objective measurements of sense functions.
The occurrence of gender-related differences in COVID-19 presentation and clinical course has already been suspected in recent investigations and confirmed in the present study.22,23 Due to chromosomal, hormonal and inflammatory differences, females could have a better prognosis of the disease, a higher proportion of mild and moderate forms, and, therefore, a higher proportion of OD.10,22,23 Moreover, we observed higher proportions of OD, GD, cacosmia and AD in females compared with males, supporting the existence of gender differences in the host response to the viral infection. This hypothesis has to be confirmed in future studies using objective methods of olfactory and gustatory evaluations.
The main strength of this study is the high number of patients and the use of standardized patient-reported outcome questionnaire. Moreover, to the best of our knowledge, this study is the first investigation that reported subjective and objective OD according to the WHO clinical state of COVID-19 patients. Through our collected data, we have identified clinical outcomes associated with the development of subjective or objective OD, GD or AD. The relevance of some of these factors was confirmed in a subset of patients benefiting from psychophysical olfactory evaluations.
The main weakness of the study is the delay between the onset of the OD and the subjective and objective assessments. However, in practice, it was difficult to perform olfactory evaluations at the onset of the OD because the health situation limited us in the realization of our evaluations in mild patients, who were home-managed according to European government decisions, and moderate-to-critical (hospitalized) patients who required intensive cares. In addition, we were unable to perform olfactory cleft examination through nasal fibroscopy regarding the health recommendations of the majority of European hospitals. The delayed inclusion of severe-to-critical survivors in the study and the lack of inclusion of dead patients who early died is another potential inclusion bias which did not allow us to draw a clear conclusion about the prevalence of OD, GD and AD in severe-to-critical COVID-19 patients.