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

BACKGROUND: Persistent olfactory dysfunction is a significant complication of SARS-CoV-2 infection. Olfactory training involving aromatic oils has been recommended to improve olfactory recovery, but quantitative data are missing. OBJECTIVE: We aimed to quantify the benefit of olfactory training and visual stimulation assisted by a dedicated web application for patients who experienced olfactory dysfunction for ≥1 month. 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 between January 30 and March 26, 2021. An analysis was performed after a mean olfactory training time of 4 weeks, and at least 500 patients were assessable for primary outcome assessment. Participants exposed themselves twice daily to odors from 4 high-concentration oils and visual stimulation assisted by a dedicated web application. Improvement was defined as a 2-point increase on a 10-point, self-assessed olfactory visual analogue scale. RESULTS: In total, 548 patients were assessable for primary outcome assessment. The mean baseline, self-assessed olfactory score was 1.9 (SD 1.7), and this increased to 4.6 (SD 2.8) after a mean olfactory training time of 27.7 days (SD 17.2). Olfactory training was associated with at least a 2-point increase in 64.2% (352/548) of patients. The rate of patients' olfactory improvement was higher for patients who trained for more than 28 days than that rate for patients who trained for less than 28 days (73.3% vs 59%; P=.002). The time to olfactory improvement was 8 days faster for patients with hyposmia compared to the time to improvement for patients with anosmia (P<.001). This benefit was observed regardless of the duration of the olfactory dysfunction. CONCLUSIONS: Olfactory training and visual stimulation assisted by a dedicated web application was associated with significant improvement in olfaction, especially after 28 days of olfactory training.

Association of Olfactory Training With Neural Connectivity in Adults With Postviral Olfactory Dysfunction.

Importance: Viral upper respiratory tract infections are a major cause of olfactory loss. Olfactory training (OT) is a promising intervention for smell restoration; however, a mechanistic understanding of the changes in neural plasticity induced by OT is absent. Objective: To evaluate functional brain connectivity in adults with postviral olfactory dysfunction (PVOD) before and after OT using resting-state functional magnetic resonance imaging. Design, Setting, and Participants: This prospective cohort study, conducted from September 1, 2017, to November 30, 2019, recruited adults with clinically diagnosed or self-reported PVOD of 3 months or longer. Baseline olfaction was measured using the University of Pennsylvania Smell Identification Test (UPSIT) and the Sniffin' Sticks test. Analysis was performed between December 1, 2020, and July 1, 2020. Interventions: Participants completed 12 weeks of OT using 4 essential oils: rose, eucalyptus, lemon, and clove. The resting-state functional magnetic resonance imaging measurements were obtained before and after intervention. Main Outcome and Measures: The primary outcome measure was the change in functional brain connectivity before and after OT. Secondary outcome measures included changes in UPSIT and Sniffin' Sticks test scores, as well as patient-reported changes in treatment response as measured by subjective changes in smell and quality-of-life measures. Results: A total of 16 participants with PVOD (11 female [69%] and 14 White [88%]; mean [SD] age, 60.0 [10.5] years; median duration of smell loss, 12 months [range, 3-240 months]) and 20 control participants (15 [75%] female; 17 [85%] White; mean [SD] age, 55.0 [9.2] years; median UPSIT score, 37 [range, 34-39]) completed the study. At baseline, participants had increased connectivity within the visual cortex when compared with normosmic control participants, a connection that subsequently decreased after OT. Furthermore, 4 other network connectivity values were observed to change after OT, including an increase in connectivity between the left parietal occipital junction, a region of interest associated with olfactory processing, and the cerebellum. Conclusions and Relevance: The use of OT is associated with connectivity changes within the visual cortex. This case-control cohort study suggests that there is a visual connection to smell that has not been previously explored with OT and that further studies examining the efficacy of a bimodal visual and OT program are needed.

Smell disorders in COVID-19 patients: role of olfactory training: A protocol for systematic review and meta-analysis.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) spread around the world, a surge of evidence suggests that smell disorders are common symptoms in COVID-19 infection. This dysfunction may cause loss of appetite, malnutrition, poisoning, and depression. Obviously, the impairment has a strong impact on the quality of life. Therefore, there is an urgent need to identify effective treatments. Various therapies have been studied to treat smell disorders after infection, and olfactory training (OT) is considered a promising treatment option. Assessing the effectiveness and safety of olfactory training for COVID-19 patients with smell disorders is the main purpose of this systematic review protocol. METHODS: PubMed, EMBASE, MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, ClinicalTrials.gov trials registry, and Chinese Clinical Trial Registry will be searched from January 2019 to January 2021. A combination of subject words and free text words will be applied in the searches. The language is limited to Chinese and English. The complete process will include study selection, data extraction, risk of bias assessment, and meta-analyses. Endnote X9.3 will be used to manage data screening. The statistical analysis will be completed by Review Manager V.5.3 (Cochrane Collaboration) or Stata V.16.0 software. RESULTS: This proposed study will assess the effectiveness and safety of OT for COVID-19 patients with smell disorders. CONCLUSION: The conclusion of this study will provide evidence to prove the effectiveness and safety of olfactory training for COVID-19 patients with smell disorders. ETHICS AND DISSEMINATION: This protocol will not evaluate individual patient information or infringe patient rights and therefore does not require ethical approval. REGISTRATION: PEROSPERO CRD42020218009.

COVID-19: Recovery from Chemosensory Dysfunction. A Multicentre study on Smell and Taste.

OBJECTIVE/HYPOTHESIS: With the COVID-19 pandemic, chemosensory dysfunction are among the most prevalent symptoms. Most reports are subjective evaluations, which have been suggested to be unreliable. The objective is to test chemosensory dysfunction and recovery based on extensive psychophysical tests in COVID-19 during the course of the disease. STUDY DESIGN: Prospective cohort study. METHODS: A total of 111 patients from four centers participated in the study. All tested positive for SARS-COV-2 with RT-PCR. They were tested within 3 days of diagnosis and 28 to 169 days after infection. Testing included extensive olfactory testing with the Sniffin' Sticks test for threshold, discrimination and identification abilities, and with the Taste Sprays and Taste Strips for gustatory function for quasi-threshold and taste identification abilities. RESULTS: There was a significant difference in olfactory function during and after infection. During infection 21% were anosmic, 49% hyposmic, and 30% normosmic. After infection only 1% were anosmic, 26% hyposmic, and 73% normosmic. For gustatory function, there was a difference for all taste qualities, but significantly in sour, bitter, and total score. Twenty-six percent had gustatory dysfunction during infection and 6.5% had gustatory dysfunction after infection. Combining all tests 22% had combined olfactory and gustatory dysfunction during infection. After infection no patients had combined dysfunction. CONCLUSIONS: Chemosensory dysfunction is very common in COVID-19, either as isolated smell or taste dysfunction or a combined dysfunction. Most people regain their chemosensory function within the first 28 days, but a quarter of the patients show persisting dysfunction, which should be referred to specialist smell and taste clinics for rehabilitation of chemosensory function. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1095-1100, 2021.

Parosmia is Associated with Relevant Olfactory Recovery After Olfactory Training.

OBJECTIVE/HYPOTHESIS: This study aims to determine the association between parosmia and clinically relevant recovery of olfactory function in patients with post-infectious olfactory dysfunction (PIOD) receiving olfactory training. STUDY DESIGN: Retrospective cohort study. METHODS: This was a retrospective cohort study of patients with PIOD that received olfactory training. Adult patients with the major complaint of quantitative smell loss were recruited and treated at several ENT clinics in German between 2008 and 2018. The outcome was based on the association between smell-loss related factors (including parosmia and phantosmia) and clinically relevant changes in overall and subdimension olfactory function of threshold, discrimination, and identification using binary logistic regression analysis. RESULTS: A total of 153 participants with PIOD were included. Clinically relevant improvements in overall olfactory function were more likely in those that had lower baseline olfactory function. Relevant improvements in discrimination function were more likely in those that had lower baseline olfactory function and those that had parosmia at the initial visit. Similarly, relevant improvements in odor identification were more likely in those that had a lower baseline olfactory function and in those who had parosmia at the first visit. Clinically significant improvements in odor threshold were more likely in those who were older in age. CONCLUSIONS: This study demonstrated that the presence of parosmia is associated with clinically relevant recovery in olfactory discrimination and identification function in patients with PIOD receiving olfactory training. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:618-623, 2021.

Prolonged complaints of chemosensory loss after COVID-19.

INTRODUCTION: Chemosensory loss is a common symptom of coronavirus disease 2019 (COVID-19) and has been associated with a milder clinical course in younger patients. Whereas several studies have confirmed this association, knowledge about the improvement and recovery of olfactory and gustatory loss is lacking. The aim of this study was to investigate the temporal dynamics of improvement and recovery from sudden olfactory and gustatory loss in patients with confirmed and suspected COVID-19. METHODS: Subjective chemosensory function, symptoms of COVID-19, COVID-19 tests results, demographics and medical history were collected through a questionnaire. RESULTS: Among the 109 study participants, 95 had a combined olfactory and gustatory loss, five participants had isolated olfactory loss and nine participants has isolated taste loss. The mean age of participants was 39.4 years and 25% of participants were under the age of 30 years. Young age was not associated with a higher recovery rate. After a mean time of > 30 days since the chemosensory loss, participants reported relatively low recovery and improvement rates. For participants with olfactory loss, only 44% had fully recovered, whereas 28% had not yet experienced any improvement of symptoms. After gustatory loss, 50% had fully recovered, whereas 20% had not yet experienced any improvement. Olfactory and gustatory deficits were predominantly quantitative and mainly included complete loss of both olfactory and gustatory function. CONCLUSIONS: Chemosensory loss was frequent in young individuals and persisted beyond a month after symptom onset, often without any improvement during this time. FUNDING: The author wishes to acknowledge research salary funding from Arla Foods (Viby, Denmark) and the Central Region Denmark. The sponsors had no say, roles or responsibilities in relation to the study, including (but not limited to) the study design, data collection, management and analysis. TRIAL REGISTRATION: not relevant.

A primer on viral-associated olfactory loss in the era of COVID-19.

Early reports have suggested that smell loss may be an early symptom associated with the pandemic known as coronavirus disease 2019 (COVID-19). The possibility that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might cause olfactory dysfunction is certainly plausible. Patients presenting to specialized smell clinics are commonly diagnosed with upper respiratory infection (URI)-associated olfactory loss and most are presumed to be viral related. In acute phases of infection, it is common to experience some smell loss as a result of nasal inflammation, mucosal edema, and obstruction of airflow into the olfactory cleft. In most cases, these episodes of smell loss are self-limiting and coincide with resolution of URI symptoms. However, in some cases the smell loss persists for months to years and this is presumed to occur through a more direct olfactory insult by the virus. It remains too early to know whether infection with SARS-CoV-2 causes persistent olfactory dysfunction. However, given the scale of this pandemic, if SARS-CoV-2 does cause chronic olfactory loss in even a small portion of those infected, then the overall population prevalence could be quite large. This review provides a brief, practical overview of viral-associated olfactory loss, realizing that evidence related to COVID-19 will likely not be clear for some time. Our goal is to highlight the existence and importance of this condition and provide information geared for both providers and patients. Practical suggestions regarding evaluation and treatment will be provided, realizing that there may be constraints on medical resources and the nature of this pandemic remains dynamic.

Effectiveness of olfactory training on different severities of posttraumatic loss of smell.

OBJECTIVE/HYPOTHESIS: A common, lasting condition from traumatic brain injury is impairment to smell. In patients with olfactory impairment, recent meta-analyses have demonstrated that olfactory training consistently improves higher-order functions, such as odor identification. The focus of this work was to assess effects of olfactory training (OT) in posttraumatic olfactory loss patients through several metrics including psychophysical, olfactory bulb (OB) volume, and functional magnetic resonance imaging. STUDY DESIGN: Prospective cohort study. METHODS: Sniffin' Sticks were used to classify two patient groups (anosmic [N = 23] and hyposmic [N = 14]) and measure changes after OT. Additionally patients were asked the intensity, valence, and uncued identification of odors presented (coffee and peach) within the magnetic resonance imaging scanner before and after olfactory training. Olfactory training was performed twice daily with a four-odor training set for 24 weeks, and sets were replaced halfway through the entire training session (~12 weeks). RESULTS: Patients had an increase in test scores (threshold and identification) and in-scanner intensity ratings and identification. Anosmic patients showed improved olfactory thresholds to 2-phenylethanol, increased intensity ratings, and activation in the right superior frontal gyrus (SFG) to odors after OT. Hyposmic patients were able to identify odors better after training. This behavior was mirrored with increased, ipsilateral activations in semantic processing areas such as Broca's area, left angular gyrus, and left SFG. CONCLUSIONS: Taken together, along with neither patient group showing changes in OB volumes, OT improves olfactory performance in patients with posttraumatic olfactory loss and seems to be driven, at least in part, by top-down processes (central) rather than bottom-up (peripheral). LEVELS OF EVIDENCE: 2 Laryngoscope, 129:1737-1743, 2019.

[Efficacy and associated factors of olfactory training in the treatment of olfactory dysfunction].

Objective: To explore the clinical effects and the influence factors of olfactory training in the treatment of olfactory dysfunction. Methods: A total of 86 patients with olfactory dysfunction (49 post-infectious and 37 post-traumatic) in Beijing Anzhen Hospital during Dec 2016 to May 2017 were recruited in this prospective study. The clinical data of patients were analyzed, including gender, age, body mass index (BMI), course of disease, smoking history, drinking history, diabetes history, hypertension history, hyperlipidemia history, and anxiety visual analogue score (VAS). All patients were treated with olfactory training for 16 weeks, and all of them underwent Sniffin' Sticks olfactory test before and after treatment, which was evaluated by composite threshold-discrimination-identification score (TDI). SPSS 23.0 software, paired t test and univariate and multivariate Logistic regression analysis were used to analyze the data. Results: Eighty patients received treatment, including 46 post-infectious olfactory dysfunction and 34 post-traumatic olfactory dysfunction. After olfactory training, the total scores of TDI increased with statistically significant (18.3±8.6 vs 13.6±7.4, t=-6.158, P<0.05). The overall efficacy was 40% (32/80). The effective rate were 45.7% (21/46) in post-infectious olfactory dysfunction and 32.4% (11/34) in post-traumatic olfactory dysfunction respectively, with no statistically significant difference (χ(2)=1.441, P=0.230). Logistic regression analysis showed that the course of disease was an influence factor in the clinical curative effect (OR=0.881, 95%CI: 0.799-0.973, P=0.012). In patients with less than a year of olfactory dysfunction, the olfactory function improved obviously with the efficiency of 50.9% (29/57). Conclusion: Sixteen weeks of olfactory training provides a significant therapeutic effect on the post-infectious and post-traumatic olfactory dysfunction, and the olfactory training can achieve better therapeutic effects at the early stage.

Entrenamiento olfatorio: revisión de literatura / Olfactory training: review of literature

RESUMEN La disfunción olfatoria es una patología frecuente que trae consigo una disminución importante en la calidad de vida de los pacientes y que incluso conlleva una mortalidad aumentada respecto a la población general. Sin embargo, es una condición subdiagnosticada, ya sea por desconocimiento de los profesionales o por falta de un método diagnóstico adecuado. A la fecha no existe un tratamiento efectivo para estos pacientes y generalmente se les deja sin tratar. Una alternativa para este gran problema es el entrenamiento olfatorio, tratamiento propuesto recientemente con resultados promisorios.

ABSTRACT Olfactory dysfunction is a frequent pathology associated with an important decrease in the quality of life of patients and an increased mortality respect to the general population. However, it is an underdiagnosed condition, either due to lack of knowledge of the professionals or due to the lack of an adequate diagnostic method. To date there is no effective treatment for these patients and they are usually left untreated. An alternative to this problem is olfactory training, a treatment recently proposed with promising results.

Olfactory training changes electrophysiological responses at the level of the olfactory epithelium.

BACKGROUND: Olfactory training (OT) has been shown to increase olfactory performance in healthy subjects and patients with post-traumatic or post-infectious olfactory loss. Morphological correlates such as olfactory bulb volume increase and gray matter changes suggest central changes in olfactory brain areas following olfactory exposure. Some evidence from animal studies indicates peripheral changes upon OT whereas no such data exist in humans. This study explores the question whether changes in olfaction following OT are associated with alterations of the electro-olfactogram (EOG) derived from the olfactory epithelium. METHODOLOGY: We compared electrophysiological EOG responses to a pleasant, rose-like odor (phenylethyl alcohol, PEA) and to an unpleasant odor (rotten eggs, H2S) in patients and controls. EOG were recorded in smell impaired patients before and after OT for a period of 4-6 months. RESULTS: EOG recordings following PEA and H2S stimulation were significantly more often obtained in controls than in patients. OT was associated with a significantly higher number of EOG recordings. CONCLUSIONS: OT is associated with an increase in EOG responses implicating stimulus-induced plasticity to start at the level of the olfactory epithelium.

Budesonide irrigation with olfactory training improves outcomes compared with olfactory training alone in patients with olfactory loss.

BACKGROUND: Olfactory training (OT) helps many patients with olfactory loss, but unfortunately it is ineffective for a significant number of patients. Budesonide irrigations are widely used to help patients with paranasal sinus inflammation, but have never been tested as a treatment for olfactory loss. We sought to examine the effect of adding budesonide irrigation to olfactory training on patients with olfactory loss without any visible sign of sinonasal inflammation. METHODS: In this randomized, controlled trial, 138 patients with olfactory loss and without any visible sign of sinonasal inflammation were randomized to either OT with saline irrigations or OT with budesonide irrigations. The University of Pennsylvania Smell Identification Test (UPSIT) was administered at the beginning of the study and at 6 months. RESULTS: A total of 133 patients completed the study. Forty-seven patients (35.3%) had a clinically significant change in UPSIT score. Among those in the budesonide irrigation + olfactory therapy group, 43.9% improved, compared with 26.9% in the saline irrigation + olfactory therapy group (p = 0.039); this corresponds to an odds ratio of 3.93 (95% confidence interval, 1.20-12.88) in a fully adjusted model (p = 0.024). Younger age and shorter duration of olfactory loss were also significant predictors of improvement. CONCLUSION: Adding budesonide irrigation to olfactory training significantly improved olfactory ability compared with olfactory training plus saline irrigation.

Olfactory Training in Post-Traumatic Smell Impairment: Mild Improvement in Threshold Performances: Results from a Randomized Controlled Trial.

Traumatic Brain Injury (TBI) can be associated with partial or total smell loss. Recent studies have suggested that olfactory outcome can be positively modulated after olfactory training (OT). This study's aim was to investigate OT's potential role in smell recovery after TBI-induced olfactory loss. A prospective, randomized, and controlled study was developed. Patients with TBI-induced olfactory dysfunction (n = 42) were randomized into an experimental group with OT and a control group without (nOT). OT was performed twice daily with a six odor training set during 12 weeks. Olfactory loss was assessed using subjective olfactometry (Barcelona Smell Test [BAST] 24), a visual analogue scale (VAS), and n-butanol threshold (n-BTt) at baseline at 4, 12, and 24 weeks. Additionally, patients underwent MRI of the olfactory brain and olfactory bulbs (OB). Based on the MRI results, an overall score (0-16) was developed to associate the structural neurological damage with olfactory outcomes. The primary outcome was the change in olfactory measurements (VAS and BAST-24) between baseline and 12 weeks. The secondary outcome was the association of the MRI score with olfactory outcomes at baseline, and the impact on quality of life (QoL). After 12 weeks of training, OT patients showed a significant improvement in n-BTt (0.6 ± 1.7 OT vs. -0.6 ± 1.8 nOT, p < 0.05), but not in the smell VAS and BAST-24 scores. Olfactory outcomes (VAS, BAST-24, and n-BTt) were significantly associated with MRI structural findings (p < 0.001), but not with the OB volume or olfactory sulcus length. The present study suggests that 12 weeks of OT mildly improves the olfactory threshold in TBI, whereas the overall MRI score may be used as an imaging marker of olfactory dysfunction and disease severity in TBI patients.

A questionnaire to assess olfactory rehabilitation for laryngectomized patients (Provox voice prosthesis users) in Japan.

OBJECTIVE: We used a questionnaire to investigate olfactory function and the present state of olfactory rehabilitation for laryngectomized patients in Japan. METHODS: This study was conducted using a questionnaire survey. We mailed questionnaires to 190 members of a Japanese laryngectomized patient group (the nonprofit organization YOUSAY-KAI). The survey queried the following items: (1) basic information (age, sex, alaryngeal speech method, etc.); (2) questions about olfactory rehabilitation, such as the individual's experience of olfactory rehabilitation, the number of days from laryngectomy to the start of olfactory rehabilitation, and the location of rehabilitation (i.e., hospital or patient association); (3) free comments; and (4) the self-administered Odor Questionnaire (SAOQ). RESULTS: We received 121/190 questionnaires by the submission deadline. Of these, 105 questionnaires were valid. All 105 responders used the Provox voice prosthesis as the alaryngeal speech method. Only 4.7% (5/105) of the patients received olfactory rehabilitation in hospitals. Many comments in the free comment column included demands for olfactory rehabilitation such as "I want to know where we can have olfactory rehabilitation" and "I want to have rehabilitation if olfaction recovers." The SAOQ score was significantly higher in the rehabilitation group (mean, 42.5%) compared to the nonrehabilitation group (mean, 22.1%) (p<0.05). There was no correlation between the SAOQ score and the number of days from laryngectomy to the start of rehabilitation (r=0.08, p=0.76)． CONCLUSION: Patient demand for olfactory rehabilitation is strong, but this therapy is not widely offered to laryngectomized patients in Japan. Notably, the SAOQ scores showed that olfactory rehabilitation may have an effect, even if it is initiated after laryngectomy. We believe that when patients choose voice prosthesis for speech, their olfaction deteriorates unless they undergo olfactory rehabilitation separately from speech rehabilitation. It is therefore necessary to administer olfactory rehabilitation for laryngectomized patients who have never received olfactory rehabilitation, as well as for patients scheduled to undergo laryngectomy.

"I really hope it comes back" - Olfactory impairment following traumatic brain injury: A longitudinal study.

BACKGROUND: Olfactory impairment (OI) can present in up to 66% of all individuals following traumatic brain injury (TBI) and can have significant implications for everyday life. OBJECTIVE: To investigate the predictive factors, natural progression and consequences of OI following TBI in individuals 12 months post injury. METHODS: In this prospective longitudinal study, 37 adults (28 males, 9 females), mean age 42.3 years (SD 19.4), with predominately severe TBI (mean length of posttraumatic amnesia (PTA) 28.6 days, SD 22.6) were assessed using the University of Pennsylvania Smell Identification Test (UPSIT). Each participant also participated in an open ended interview to allow exploration of their experience of having OI. RESULTS: Thirty (83.33%) of the participants demonstrated persisting OI at 12 months. Nineteen of these participants demonstrated no change in their OI severity category and 4 produced a poorer performance. Thirteen participants (36.11%) demonstrated some recovery with 6 of these performing within the 'normal' range for age andgender. CONCLUSIONS: OI is an enduring impairment for a substantial proportion of individuals who experience it following severe TBI. It impacts a range of everyday activities, regardless of its severity, and requires comprehensive management during rehabilitation.

Effects of olfactory training: a meta-analysis.

The neural plasticity of the olfactory system offers possibilities of treatment in terms of stimulation of the sense of smell, and different studies have suggested effectiveness of smell training, i.e., daily exposition to certain odors. To obtain reliable and precise estimates of overall treatment benefit on the olfactory function, we meta-analyzed the effects of smell training reported in 13 previous studies. We analyzed the smell training effectiveness across three different olfactory abilities, smell identification, discrimination and threshold for odor detection. We found a significant, positive effect of olfactory training for all olfactory abilities, with large effects of training on identification, discrimination and TDI-score and small-to-moderate effect in the case of threshold for odor detection. Interestingly, the pattern of results differed across Sniffin Sticks subtests depending on the origin of participants smell disorder, and the smell training duration influenced its effectiveness in the case of identification and the TDI score. Although the exact mechanism of olfactory recovery following the smell training still requires further investigation, our meta-analysis showed that such training should be considered an addition or alternative to existing smell treatment methods.