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.