Persistent olfactory complaints after COVID-19: a new interpretation of the psychophysical olfactory scores*

Background: Sudden olfactory loss is a major symptom of SARS-CoV-2 infection and has a negative impact on daily life quality. Almost 80% of disorders regress spontaneously. No precise characterization of the mediumand long-term olfactory symptoms has been carried out yet, apart from self-assessments. The main objective of this work was to characterize persistent smell disorders in this population. Methodology: Consecutive patients consulting to the ENT department with post-Covid19 olfactory loss were included. The clinical examination included an analog scale for the self-assessment of olfactory recovery), a nasofibroscopy, the Sniffin’ Stick Test and the short version of the Questionnaire of olfactory disorders. Results: Among the 34 patients included, based on the Sniffin’ Sticks Test, 29.4% (n=10) could be classified as normosmic, 55.9% (n=19) as hyposmic and 14.7% (n=5) as functional anosmic). Only olfactory identification impairment was significantly correlated with olfactory complaint and daily anxiety and annoyance related to lack of olfaction recovery. This identification disorder seemed to worsen over time. Conclusions: It is crucial to assess odor identification disorders in case of persistent olfactory complaints after COVID-19. It is fundamental to target this disorder, as it does not improve spontaneously and negatively impact quality of life.

A patient with anosmia and loss of taste would be 6 times more likely to be infected with COVID-19 (8) , which in this specific case, would more frequently be a "mild" form that doesn't require hospitalization (2) .
The long-term anosmia can cause an alteration in the quality of life and psychiatric disorders such as depression (15,16) , anxiety, anorexia (17) and its nutritional consequences (18) , social interaction disorders (19,20) and cognitive impairment (19,21,22) . So, the diagnosis of olfactory disorders and their management is essential.
Spontaneous olfactory recovery between the first and third year after loss is observed in 32 to 66% (23) of other post-viral olfactory loss, not related to COVID-19 (23) . The early recovery rate (at 2 months) of post-viral olfactory loss post-COVID-19 is approximately 44% to 79% (of which 73% of patients recover within 8 days) (2,23,24) . So, spontaneous olfactory recovery rate is better in of post-COVID-19 olfactory loss that in other post-viral olfactory loss such as Rhinovirus, Influenza, Respiratory syncytial virus or other Coronavirii. However, post-COVID-19 olfactory disorders appears to persist after 6 months in 60% (25) of patients (including 50% hyposmia and 10% anosmia with sometimes parosmia (26) ).
The principal aim of this study was to analyse the characteristics of persistent olfactory disorders post-COVID-19. The secondary aim was to measure their effects on olfaction-related quality of life.

Population
The study was approved by the institutional review board of the Nice University Hospital (CNIL number: 412). This study is part of a large work registered under a ClinicalTrials.gov number (ID: NCT04799977). Since March 2020, we retroprospectively recruited at ENT department of Nice University Hospital all patients infected by COVID-19 with persistent olfactory disorders from two to nine months. Patients where self-referred or referred by colleagues, general practitioners or advised by the infectiology department that managed all COVID-19 declared patients (city guidelines). Patients had either an olfactory complaint for over 6 weeks and a molecular-proven SARS-CoV-2 diagnosis or a CT-proven SARS-CoV-2 diagnosis secondarily confirmed by serology. The patients' demographic data and clinical characteristics were recorded. Nasofibroscopy was performed to evaluate state and nasal cavity patency. The clinical examination included a visual analogue scale (VAS) for the subjective assessment of olfactory recovery (ranging from 0% to 100%), an objective evaluation of olfactory loss using Sniffin' Sticks Test® (27)(28)(29) and the completion of a short version of Questionnaire of Olfactory Disorders (Short-QOD-NS) (30) .

Nasofibroscopy
Using a flexible endoscope and a high-definition camera, a nasofibroscopy was performed without local anesthesia (to avoid transient olfactive disorders) in order to assess the permeability of the olfactory cleft (presence of polyps, surgical adhesions, tumor or mucus was being sought).
Odor thresholds were determined for N-butanol (BUT), using a three-alternative forced choice task. Three sticks were presented to the patient in an alternating order, one containing the odorant, the other two containing solvents only. The subject's task was to find out which of the three pens smelled of the odorant. The odor discrimination test was performed using 16 triplets of odorants sticks. Subjects were presented with three sticks, two containing the same odorant, and one a different odorant. Through a forced choice, the patient's task was to identify the stick that smelled differently. For odor identification, 16 odorant sticks were presented once, separated by an interval of at least 20 seconds to prevent olfactory desensitization. Each stick presentation was accompanied by a written list containing the correct odorant and 3 semantic distractors. Results from the three tests, odor threshold (T), odor discrimination (D), and odor identification (I) were summed up to a composite score, the socalled "TDI-score. "

Olfactory quality of life
The olfactory quality of life was assessed using the Short-QOD-NS which is based on the Questionnaire of Olfactory Disorders (QOD) related to the consequences of an olfactory and taste loss such as the pleasure of sharing a meal, of creating social interactions or even of creating close bonds with others (35) . The original version was divided into 52 items regarding negative and positive social consequences of olfactory loss (36) . The "negative consequences" subdomain of QOD (QOD-NS (37) ) has been shown to be more correlated with the results of psychophysical olfactory tests (Sniffin 'sticks tests) (38) . So, shorter versions have been developed to be more suitable for daily clinical practice (30,39,40) . These shorter versions increase the response rate and reduce the patient's mental load when completing the questionnaire (30) . The QOD-NS is a validated test (41) which includes 17 questions with answers go from 0 to 3 for a total score of 0 to 51 (51 meaning there is no disorder). Finally, Mattos et al. (30) developed an even shorter version (Short-QOD-NS) with the 7 most relevant questions with the different aspects such as social aspect (n = 3), eating (n = 2), anxiety (n = 1) and annoyance (n = 1) following an olfactory loss. We have decided to use this version for this study, with score ranging from 0 to 21 (21 meaning there is no disorder).

Statistical analysis
Data are presented as mean (SD) for quantitative variables and as frequency and percentage for qualitative variables. In order to investigate correlations between subjective reports (VAS), objective disorders in the different dimension (threshold detection, T; odor discrimination, D; odor identification I), and Short-QOD-NS, we performed bivariate correlation analyses. As data were not normally distributed (as suggested by Kolmogorov-Smirnov test), non-parametric Spearman's correlations were employed.

Loss of smell and taste
Descriptive analyses for the loss of smell and taste are reported in Table 2. The day of consultation, patients reported to have recovered 37±27% of their olfaction (ranging from 0% to 90%).  Short-QOD-NS =Short version of Questionnaire of Olfactory Disorders (30) performance (rho (32) = -0.24, p= 0.177).

Links between olfactory disorders and quality of life
Descriptive analyses of the Short-QOD-NS are reported in Table   2. Spearman's correlations revealed that the global Short- Stick test (14) .
Subdomain Sniffin' Stick test analyses employing recent normative data (33) highlights a predominant disorder on the identification (I) of the odorant, which is more important than the odor discrimination (D) or the detection threshold (T). Also, normosmic patients (TDI> 30.75) (33) had more altered scores in odor identification (I) than in detection (T). The results of this study raise the question of an unrecognized central involvement of olfaction, compatible with an olfactory agnosia type (34,42) . Indeed, Whitcroft et al. (42) have shown that the impairment of odor identification compared to the impairment of threshold detection, was more frequently found in central damage sequelae of neuronal lesions of infectious, traumatic or degenerative origin.
On the contrary, it has been shown that the isolated impairment of detection is mainly the consequence of sinonasal pathologies (42) . These sinonasal symptoms (43,44)  with ACE2 facilitated by TMPRSS2 (45)(46)(47)(48) . Indeed, more and more reports suggest the penetration of SARS-CoV-2 into the central nervous system (49,50) through the olfactory cleft through the olfactory epithelium, and more particularly through sustentacular and / or trans-cribriform sheath cells (47,51,52) , through a rupture of the blood-brain barrier (53,54) or by trans-axonal feedback (50,55) within the peripheral nerves coming from the respiratory tree (Vagus nerve). Finally, previous SARS-CoV-1 studies results (56) and the olfactory identification impairment found in neurodegenerative diseases, raised questions about the pathophysiological similarities and consequences of SARS-CoV-2 cells and the mechanisms involved in the origin of neurodegenerative diseases (57) .
This study did not show any significant correlation between the olfactory disorder duration and the severity of the olfactory impairment. However, we observed a non-significative tendency for identification disorders to increase over time, rather than to reduce. This pattern has to be confirmed using longitudinal data. If this observation will be confirmed by other authors, two hypotheses can be put forward. The first is an early progressive deafferentation (58) of central olfactory projections, which negatively influences the cognitive performance of these patients.
In this way, Lu et al. (59) found an alteration in cerebral trophicity on MRI at the level of the olfactory cortex, the hippocampus, the Insula, the left Rolandic operculum, the Heschl gyrus, left and right cingulate about 3 months from the end of COVID-19 symptoms. The second is the emergence of new variants of SARS-CoV-2 in which the Spike S1 protein is said to have an increasing affinity in vivo with ACE2. This physiopathological mechanism described by Butowt et al. (60,61) is thought to have its origin in a mutation of an aspartic acid to glycine at position 614 of the code for the Spike S1 protein (D614G). This mutation, associated with a genetic and geographic polymorphism of ACE2 (62) , could potentially cause an increase in the prevalence of olfactory damage, specifically in Europe (61) .
In addition, this study shows an isolated taste disorders (sweet, salty, sour, bitter and umami) in 3.3% of cases. This is in line with the results of Hopkins et al. (25) , that found 2.8% of persistent taste disturbances 6 months after COVID-19 infection. Taste loss can be explained by the tantalizing effect of ACE2 involvement on the taste buds (63) , which remains the main receptor targeted Olfaction assessment is most important as olfaction impairments can be the cause of domestic accidents (gas, burning smell) (17) , can testify the emergence of psychological (19) , psychiatric (15,16,19) , or eating disorders (64,65) , as well as loss of taste pleasure (66) and social isolation for fear of one's own body odor, or even eating spoiled or undercooked food.
Smell loss will therefore cause a significant deterioration in the quality of life (35,39,67) , especially since the loss occurs before the age of 30 (67) . In ENT studies, 22-item Sinonasal Outcome Test (SNOT-22) (68) is commonly used for quality-of-life assessment but is not focused on smell and taste impairment. QOD and specifically QOD-NS (37,40,67,69) is rather used for this specific olfaction assessment. However, QOD-NS 17-item questionnaire length can be a problem in clinical and scientific research as patients' mental burden can be important. In order to improve efficiency and the quality of collected data, Mattos et al. (30)  for patients regarding the lack of smell recovery. In a previous study, Lechien et al. (62) already showed, at about 10 days of the onset of symptoms of COVID-19, a degradation of Short-QOD-NS, which is more significant in anosmic patients and predominant in their daily worry about habituation to this disorder.
Their results showed a deterioration in the overall quality of an olfactory life with the duration of olfactory deprivation (62) .
Despite these interesting results, this study suffers from some

Conclusion
This work analyzes long term olfactory disorders occurring after

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