Olfactory Training and Visual Stimulation Assisted by a Web-Application for Patients With Persistent Olfactory Dysfunction After SARS-CoV-2 Infection

Introduction We aimed to quantify the benet of olfactory training and visual stimulation assisted by a dedicated web application for patients who experienced olfactory dysfunction for ≥ 1 month after Sars-Cov-2 infection and compared it with published cohorts of spontaneous recoveries. Materials and Methods We performed a prospective observational study. Participants performed olfactory training and visual stimulation assisted by a dedicated web-application. Improvement was dened as a 2-point increase on a 10-point, self-assessed olfactory visual analogue scale. Results


Introduction
Persistent olfactory dysfunction is a signi cant complication of SARS-CoV-2 infection. Olfactory training involving aromatic oils has been recommended in this situation to improve olfactory recovery after a positive randomized trial in post-infectious olfactory loss, but quantitative and comparative data after SARS-CoV-2 infection are missing. [1,2] We aimed to assess the dynamic and the bene t of olfactory training assisted by a dedicated webapplication and compared results to previous studies of spontaneous recovery without training.

Materials And Methods
We performed an observational, real-life, data-based study on a cohort of patients who experienced at least 1 month of persistent olfactory dysfunction induced by SARS-CoV-2 infection between January 30 and June 18, 2021. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline and was approved by the French National Health Data Institute, which reviews the ethical conduct of human subject's research, data con dentiality, and safety.
To participate, individuals were required to connect to the free covidanosmia.eu web-application and provide electronic agreement. Gradation of symptoms were obtained through questionnaires at baseline and weekly by the application as well as toxicity. Details of the inclusion criteria and results of interim analysis performed after a mean olfactory training time of at least 28 days with the rst 548 patients were previously published. [3] Participants exposed themselves twice daily to odors from 4 highconcentration oils and visual stimulation assisted by the dedicated web-application. Improvement was de ned as a 2-point increase on a 10-point, subjective self-assessed olfactory visual analogue scale. Comparison of recovery was done with previous published cohorts of post viral (SARS-CoV-2 or other virus) patients with persistent olfactory dysfunction having training or not. [2,4,5] Categorical variables were summarized using frequencies and percentages and Chi-square test was employed to make comparison. The level of statistical signi cance was 5% for all statistical tests. To analyze predictive factors of assessment, logistic regression was used to calculate odds ratios, which were presented with CIs set at 95%. All statistical analyses were conducted with SAS (Statistical Analysis System), version 9.3 (SAS Institute Incorporated).
All experiments were performed in accordance with relevant guidelines and regulations. This study was approved by the French National Health-Data Institute, which reviews ethical conduct of human subject research, data con dentiality, and safety. All methods were carried out in accordance with relevant guidelines and regulations, other than (STROBE) guidelines.

Informed consent
was obtained from all subjects and/or their legal guardian(s).

Results
On June 18, 2021, 10084 users downloaded the web-application and 1155 patients were assessable for primary outcome assessment with a mean olfactory training duration of 30 days. The mean age was 40.3 (min 18, max 85). The mean baseline, self-assessed olfactory score was 1.9 (SD 1.7), and this increased to 4.8 (SD 2.7) after a mean olfactory training time of 30 days. The rate of patients achieving olfactory dysfunction improvement was 75.7% (311/411) with at least 30 days training. Olfactory recovery increased dramatically from 1-day to 4 weeks training and was further asymptotic between 70% and 77% from 8weeks training. Figure 2 Improvement was observed in patients who trained 4 weeks and 4 to 8 weeks in 63.0% (58/92) and 72.9% (137/188) respectively, whereas in historical cohorts of patients with Sars-Cov-2 or other infection's persistent olfactory dysfunction, a spontaneous improvement was observed in 7% to 43% without training or using low concentration oils respectively (p<.001). Figure 3 The duration of the training was associated with better outcomes (p<.001) and no other predictive factors were highlighted in univariate analysis. Table 2   Table 2. Logistic regression analysis for determining the predictive factors of olfactory function improvement (ie, an increase of ≥2 points on the olfactory scale).
The bene t of 30-days or more olfactory training was observed regardless of the duration of the olfactory dysfunction: 73.7% (140/190) of patients having 1-month to 2.9 months olfactory dysfunction duration and 77.1% (165/214) in 3-months to 1-year dysfunction (p=.82) as well as the mean improvement of olfactory function on olfactory scale. Figure 4 Discussion This study is the largest that prospectively assess the bene t of olfactory training for patients who experience persistent olfactory dysfunction after SARS-CoV-2 infection.
Olfactory training and visual stimulation assisted by a dedicated web application was associated with accelerated improvement in olfaction as compared with spontaneous recovery in SARS-CoV-2 or other virus persistent olfactory dysfunction reported in literature (73% of patients with high concentration oils' training vs 43% with low concentration oils' training vs 7-27% without training. [2,4,5]. The maximal duration of training appeared to be 8 weeks as improvement rate became asymptotic from 8-weeks. The mean improvement in self-assessed olfactory scale scores was similar regardless of the anteriority of the olfactory dysfunction and training duration was associated with probability of recovery. No other predictive factors were highlighted such as parosmia, taste loss, gender… As only subjective assessment was performed in our study, we probably underestimated the rate of improvement as Renaud M and al recently reported that participants tend to underappreciate the return of normosmia in subjective assessment versus objective measures. [6] So our results could be higher after objective assessment of recovery by physician using sni ng tests.
The limitation of our study is the lack of a direct comparison with a placebo group, but as olfactory training is recommended, it is not ethical to perform a new randomized trial. Another limitation is the different scales and methods used in other studies reporting olfactory function improvement.

Conclusion
Olfactory training and visual stimulation assisted by a dedicated web application seems to accelerate olfactive improvement in persistent olfactory dysfunction following SARS-CoV-2 infection, especially after 30 days of olfactory training. Maximal duration of training appears to be 8 weeks.
Declarations Figure 1 Flowchart of the study