Alpha-lipoic acid does not improve olfactory training results in olfactory loss due to COVID-19: a double-blind randomized trial.

OBJECTIVES: Olfactory loss is a recognized long-term dysfunction after Coronavirus Disease 2019 (COVID-19) infection. This investigation aimed to assess the effect of alpha-lipoic acid as an adjuvant treatment of olfactory training on the improvement of smell loss in post-COVID-19 patients. METHODS: This randomized controlled trial included 128 adult outpatients who had persistent smell loss for more than 3-months after COVID-19 infection. The participants were randomly allocated into two groups: the intervention treatment group, which received alpha-lipoic acid associated to olfactory training, and comparison treatment group, which received placebo pills associated to olfactory training. The participants were followed-up for 12-weeks. Olfactory dysfunction was assessed in terms of Visual Analog Scale (VAS), and the Connecticut Chemosensory Clinical Research Center (CCCRC) test for the Brazilian population. RESULTS: A total of 100 participants completed the follow-up period and were analyzed in this study. Both groups have improved CCCRC score (p = 0.000), olfactory threshold (p = 0.000), identification score (p = 0.000) and VAS score (p = 0.000) after 12-weeks follow-up. No significant differences were determined between the intervention and comparison treatment groups in CCCRC score (p = 0.63), olfactory threshold (p = 0.50), identification score (p = 0.96) and VAS score (p = 0.97). In all these criteria, comparison treatment group went slightly worse. At the endpoint of the study, the frequency of anosmia reduced to 2% in the intervention treatment group and to 7.8% in the comparison treatment group. Also, 16.8% of the intervention group' subjects, and 15.7% of comparison treatment group's patients reached normosmia. CONCLUSIONS: Overall, there was a strongly significant difference in olfactory function between baseline and endpoint for both groups. However, based on the lack of significant difference between the intervention treatment and the comparison treatment groups in terms of olfactory changes, our study appoints that the alpha-lipoic acid is not better than olfactory training alone to treat olfactory loss after COVID-19. LEVEL OF EVIDENCE: Level 2.

Omega-3 Fatty Acid Supplementation for the Treatment of Persistent COVID-Related Olfactory Dysfunction.

OBJECTIVE: To evaluate the efficacy of omega-3 fatty acid (O3FA) supplementation in the treatment of COVID-related olfactory dysfunction (OD). METHODS: Patients with laboratory-confirmed or clinically-suspected COVID-19 infection and new-onset OD from August 2020 to November 2021 were prospectively recruited. Patients with quantitative OD, defined as a brief smell identification test (BSIT) score of 9 or less, were eligible for study inclusion. The experimental group received 2 g of O3FA supplementation, while the control group received an identical placebo to be taken daily for 6 weeks. The primary outcome was a change in BSIT score between the initial and 6-week follow-up tests. RESULTS: One hundred and seventeen patients were included in the analysis, including 57 patients in the O3FA group and 60 in the placebo group. O3FA group patients demonstrated a mean BSIT improvement of 1.12 ± 1.99 compared to 0.68 ± 1.86 in the placebo group (p = 0.221). Seventy-seven patients, 42 within the O3FA group and 35 in the placebo group, completed a follow-up BSIT survey at an average of 717.8 days from study onset. At long-term follow-up, there was an average BSIT score improvement of 1.72 within the O3FA group compared to 1.76 within the placebo group (p = 0.948). CONCLUSION: Among patients with persistent COVID-related OD, our study showed no clear evidence of relative short-term or long-term olfactory recovery among patients receiving high doses of O3FA supplementation.

The Effect of Chinese Herbal Medicine on Traumatic Anosmia: A Prospective, Randomized Clinical Trial.

OBJECTIVE: Chinese herbal medicine (CHM) has been implemented as a form of treatment for olfactory dysfunction. In this study, we aimed to use a tailored Guizhi decoction for the treatment of traumatic olfactory dysfunction. METHODS: Patients who had lost olfactory function after experiencing head trauma and whose olfactory function was anosmic were selected. The eligible patients were randomly assigned to two groups. In the CHM group, a tailored Guizhi decoction was prescribed, with patients also undergoing olfactory training (OT). In the OT group, patients performed OT only. The olfactory function of each patient was evaluated by both the phenyl ethyl alcohol (PEA) odor detection threshold test and the traditional Chinese version of the University of Pennsylvania Smell Identification Test (TC-UPSIT), at both 3 and 6 months after the completion of treatment. RESULTS: A total of 38 patients in the CHM group and 40 in the OT group completed the study. The TC-UPSIT scores of patients slightly rose after treatment in both the CHM and OT groups. Nevertheless, there were no significant differences in TC-UPSIT scores before and after treatment in both groups. However, the PEA thresholds improved significantly in both CHM and OT groups (p = 0.005 and 0.016, respectively). Of note, there were no significant differences in threshold or identification scores between the CHM and OT groups. CONCLUSION: Our results show that adding a tailored Guizhi decoction to OT conferred a limited benefit to the olfactory function of patients experiencing traumatic anosmia. LEVEL OF EVIDENCE: 2 Laryngoscope, 133:1473-1479, 2023.

Therapeutic options of post-COVID-19 related olfactory dysfunction: a systematic review and meta-analysis.

BACKGROUND: Olfactory dysfunction is a typical post-COVID-19 presentation, affecting patients' quality of life. There are currently multiple treatment options in this group of patients such as oral and intranasal corticosteroids, olfactory training, oral vitamin-mineral supplementation, amongst others. This meta-analysis aims to consolidate existing evidence for current therapies in patients with persistent olfactory dysfunction related to COVID-19 infection and evaluate the possible role of corticosteroid add-on therapy in olfactory training. METHODOLOGY: A systematic review and meta-analysis to study current treatments/interventions for olfactory dysfunction in post-COVID-19 infection were conducted. Data were pooled for the meta-analysis. The outcomes include subjective or objective olfactory assessment major and minor adverse reactions. RESULTS: Eleven studies (1414 participants) were included in this review, with six studies (916 participants) then assessed for the meta-analysis. Combined treatment of intranasal corticosteroid (INCS) with olfactory training (OT) has no benefit over OT monotherapy from both a VAS score improvement and identification component of Sniffin' Sticks test standpoint. In addition, there were no differences in improvement of TDI score between combined oral corticosteroid (OCS) with OT therapy compared to OT alone. Olfactory function was, however, significantly improved after OT. CONCLUSION: There were no significant differences in the improvement of olfactory scores in combination INCS+OT or OCS+OT therapies compared to OT monotherapy. However, there is improvement in olfactory function after OT.

GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Shufeng Jiedu capsule ameliorates olfactory dysfunction via the AMPK/mTOR autophagy pathway in a mouse model of allergic rhinitis.

BACKGROUND: Shufeng Jiedu capsule (SFJDC) has been widely used as a conventional Chinese pharmaceutical agent for various upper respiratory infections, including acute lung injury, acute respiratory distress syndrome and allergic rhinitis (AR). However, its mechanism in AR remains unclear. PURPOSE: The present study aimed to decipher the antiallergic inflammatory effect of SFJDC in an AR model with olfactory dysfunction. Specifically, we wanted to explore whether SFJDC can improve the olfactory abnormality in AR mice and reduce the levels of inflammatory factors in the olfactory epithelium (OE) and olfactory bulb (OB). METHODS: To address the above issues, we constructed an AR model using C57BL/6 mice, which were sensitised and challenged with ovalbumin (OVA) by intraperitoneal injection. SFJDC (0.045 or 0.18 g/kg) was delivered by gavage administration 1 h prior to the intraperitoneal injection of OVA. The control mice received saline alone. Then, the animals were assessed according to the presence of nasal symptoms and nasal inflammation, and a buried food test was used to evaluate olfactory function. The levels of proteins involved in the AMPK/mTOR autophagy pathway in the OE and OB were investigated by western blotting and fluorescence staining. RESULTS: After OVA induction of AR and drug administration, we found that SFJDC significantly ameliorated the nasal symptoms and allergic inflammatory reaction of the nasal mucosa superior to cetirizine. A behavioural test indicated that the mice with AR had olfactory dysfunction, and SFJDC can ameliorate this behavior deficiency. Meanwhile, SFJDC clearly reduced the neuroinflammation level in OE tissue. In addition, SFJDC increased p-mTOR and decreased p-AMPK, beclin1, LC3 and cleaved caspase-3 levels in the OE. CONCLUSIONS: In addition to antibacterial and antiviral activities, SFJDC has marked anti-inflammatory effects in AR mice. Its mechanism of action in the nasal cavity involves inhibition of upregulated anti-inflammatory cytokines, modulation of autophagy and apoptosis levels and regulation of autophagy through the AMPK/mTOR pathway in the OE tissue of AR mice. Hence, SFJDC is a promising drug for AR, and clinical trials should further validate the therapeutic impact of SFJDC on AR with olfactory dysfunction.

Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial.

Importance: Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. Objective: To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19-related OD. Design, Setting, and Participants: This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Interventions: Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19-related questions. Results: A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, -13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, -2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, -4% to 52%) in favor of theophylline. Conclusions and Relevance: This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19-related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. Trial Registration: ClinicalTrials.gov Identifier: NCT04789499.

Olfactory dysfunction in type II diabetes: Therapeutic options and lessons learned from other etiologies - A scoping review.

INTRODUCTION: Olfactory dysfunction (OD) is highly prevalent amongst type 2 diabetes mellitus (DM2) patients and has many associated health risks. For example, OD can lead to poor nutrition, safety issues related to diminished hazard detection, and increased mortality rates. While limited research exists about therapeutics for DM2-associated OD, recovery of olfactory function is better studied in other pathologic states. The objectives of this scoping review are to synthesize the existing data on interventions for DM2-associated OD and present the evidence for therapies that have been utilized for non-DM2-associated causes of OD. Additionally, the potential therapeutic opportunities for patients with DM2 are explored. METHODS: A scoping review was conducted with a medical librarian to identify studies investigating treatments of DM2-related OD. 6 databases were searched (Embase, CINAHL, the Cochrane Library, Google Scholar, OVID Medline, and Web of Science). Studies were eligible if the primary discussion involved treatment of olfactory deficits in the context of DM2. All publication dates were included, and studies published in languages other than English were excluded. RESULTS: 3631 articles were identified; 3 articles met inclusion criteria and underwent full text review. Hyperbaric oxygen (HBO), the DPP-4 inhibitor Linagliptin and the GLP-1 agonists Exenatide and Liraglutide are the only therapeutics that have been used in the context of DM2. Only HBO and GLP-1 agonists produced statistically significant improvements in olfactory identification. The literature regarding non-DM2-associated OD supports interventions such as olfactory training, dietary supplements, and intranasal insulin. Specifically, olfactory training was very effective in many contexts such as post-viral and traumatic OD while being affordable and non-invasive. CONCLUSION: This scoping review of olfactory rehabilitation options for DM2-induced OD demonstrates a paucity of prospective investigations of plausible therapeutics. Additionally, treatments for OD related to non-DM2-associated etiologies, such as olfactory training, are well-studied, efficacious, and should be investigated in the context of DM2. Future investigation has the potential to enhance the quality of clinical intervention for OD and improve short- and long-term outcomes for DM2 patients.

Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial.

BACKGROUND: Olfactory training is the only evidence-based treatment for post-viral olfactory dysfunction. Smell disorders after SARS-CoV-2 infection have been attributed to neuroinflammatory events within the olfactory bulb and the central nervous system. Therefore, targeting neuroinflammation is one potential strategy for promoting recovery from post-COVID-19 chronic olfactory dysfunction. Palmitoylethanolamide and luteolin (PEA-LUT) are candidate antiinflammatory/ neuroprotective agents. OBJECTIVE: To investigate recovery of olfactory function in patients treated with PEA-LUT oral supplements plus olfactory training versus olfactory training plus placebo. METHODS: Multicenter double-blinded randomized placebo-controlled clinical trial was held. Eligible subjects had prior COVID-19 and persistent olfactory impairment >6 months after follow-up SARS-CoV-2 negative testing, without prior history of olfactory dysfunction or other sinonasal disorders. Participants were randomized to daily oral supplementation with ultramicronized PEA-LUT 770 mg plus olfactory training (intervention group) or olfactory training with placebo (control). Sniffin' Sticks assessments were used to test the patients at baseline and 90 days. RESULTS: A total of 185 patients, including intervention (130) and control (55) were enrolled. The intervention group showed significantly greater improvement in olfactory threshold, discrimination, and identification scores compared to controls (p=0.0001). Overall, 92% of patients in the intervention group improved versus 42% of controls. Magnitude of recovery was significantly greater in the intervention group versus control (12.8 + 8.2 versus mean 3.2 + 3), with >10-fold higher prevalence of anosmia in control versus intervention groups at the 90-day endpoint. CONCLUSION: Among individuals with olfactory dysfunction post-COVID-19, combining PEA-LUT with olfactory training resulted in greater recovery of smell than olfactory training alone.

Intranasal photobiomodulation therapy for COVID-19-related olfactory dysfunction: A Brazilian multicenter case series.

Olfactory dysfunction is commonly seen in COVID-19 patients; however, little is known about the pathophysiology and management. The present study aimed to report a series of cases in which three protocols of intranasal photobiomodulation therapy (PBMT) were used for COVID-19-related olfactory dysfunction. Irrespective of the PBMT protocol, olfaction recovery was noted in all cases but with varying degrees of improvement. Although intranasal PBMT seems to be a promising therapeutic modality, more research is needed to better define effectiveness.

Interventions for the prevention of persistent post-COVID-19 olfactory dysfunction.

BACKGROUND: Loss of olfactory function is well recognised as a cardinal symptom of COVID-19 infection, and the ongoing pandemic has resulted in a large number of affected individuals with abnormalities in their sense of smell. For many, the condition is temporary and resolves within two to four weeks. However, in a significant minority the symptoms persist. At present, it is not known whether early intervention with any form of treatment (such as medication or olfactory training) can promote recovery and prevent persisting olfactory disturbance.  OBJECTIVES: To assess the effects (benefits and harms) of interventions that have been used, or proposed, to prevent persisting olfactory dysfunction due to COVID-19 infection. A secondary objective is to keep the evidence up-to-date, using a living systematic review approach.  SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane COVID-19 Study Register; Cochrane ENT Register; CENTRAL; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished studies. The date of the search was 16 December 2020. SELECTION CRITERIA: Randomised controlled trials including participants who had symptoms of olfactory disturbance following COVID-19 infection. Individuals who had symptoms for less than four weeks were included in this review. Studies compared any intervention with no treatment or placebo.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were the presence of normal olfactory function, serious adverse effects and change in sense of smell. Secondary outcomes were the prevalence of parosmia, change in sense of taste, disease-related quality of life and other adverse effects (including nosebleeds/bloody discharge). We used GRADE to assess the certainty of the evidence for each outcome.  MAIN RESULTS: We included one study of 100 participants, which compared an intranasal steroid spray to no intervention. Participants in both groups were also advised to undertake olfactory training for the duration of the trial. Data were identified for only two of the prespecified outcomes for this review, and no data were available for the primary outcome of serious adverse effects. Intranasal corticosteroids compared to no intervention (all using olfactory training) Presence of normal olfactory function after three weeks of treatment was self-assessed by the participants, using a visual analogue scale (range 0 to 10, higher scores = better). A score of 10 represented "completely normal smell sensation". The evidence is very uncertain about the effect of intranasal corticosteroids on self-rated recovery of sense of smell (estimated absolute effect 619 per 1000 compared to 520 per 1000, risk ratio (RR) 1.19, 95% confidence interval (CI) 0.85 to 1.68; 1 study; 100 participants; very low-certainty evidence).  Change in sense of smell was not reported, but the self-rated score for sense of smell was reported at the endpoint of the study with the same visual analogue scale (after three weeks of treatment). The median scores at endpoint were 10 (interquartile range (IQR) 9 to 10) for the group receiving intranasal corticosteroids, and 10 (IQR 5 to 10) for the group receiving no intervention (1 study; 100 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very limited evidence regarding the efficacy of different interventions at preventing persistent olfactory dysfunction following COVID-19 infection. However, we have identified a small number of additional ongoing studies in this area. As this is a living systematic review, the evidence will be updated regularly to incorporate new data from these, and other relevant studies, as they become available.  For this (first) version of the living review, we identified a single study of intranasal corticosteroids to include in this review, which provided data for only two of our prespecified outcomes. The evidence was of very low certainty, therefore we were unable to determine whether intranasal corticosteroids may have a beneficial or harmful effect.

Treatment of COVID-19-Related Olfactory Disorder Promoted by Kakkontokasenkyushin'i: A Case Series.

Olfactory disorders are one of the characteristic symptoms of the coronavirus disease of 2019 (COVID-19), which causes infection and inflammation of the upper and lower respiratory tract. To our knowledge, there are no treatments for COVID-19-related olfactory disorder. Here, we report five olfactory disorder cases in COVID-19, treated using the Japanese traditional (Kampo) medicine, kakkontokasenkyushin'i. We treated five patients with mild COVID-19 at an isolation facility using Kampo medicine, depending on their symptoms. Patients with the olfactory disorder presented with a blocked nose, nasal discharge or taste impairment. Physical examination using Kampo medicine showed similar findings, such as a red tongue with red spots and sublingual vein congestion, which presented as blood stasis and inflammation; thus, we prescribed the Kampo medicine, kakkontokasenkyushin'i. After administration, the numeric rating scale scores of the smell impairment improved within 3 days from 9 to 3 in case 1, from 10 to 0 in case 2, from 9 to 0 in case 3, from 5 to 0 in case 4, and from 9 to 0 within 5 days in case 5. Following the treatment, other common cold symptoms were also alleviated. Kakkontokasenkyushin'i can be used for treating nasal congestion, rhinitis, and inflammation in the nasal mucosa. The olfactory disorder in COVID-19 has been reportedly associated with inflammation and congestion, especially in the olfactory bulb and olfactory cleft. Kakkontokasenkyushin'i may be one of the treatment alternatives for the olfactory disorder with rhinitis in patients with COVID-19.

Taste and smell disturbances in cancer patients: a scoping review of available treatments.

PURPOSE: Taste and smell disturbances in patients affected by cancer are very common, but often under-recognized symptoms. If not addressed properly, they may impact nutritional status, food enjoyment, and quality of life. Treatment tools available for clinicians to manage chemosensory alterations are limited and are often based on personal clinical experiences. The aim of this study was to assess current oncological and palliative care literature through a scoping review, in order to identify available treatments for taste and smell alterations in cancer patients. METHODS: Medline, Embase, CINAHL, ProQuest Dissertations and Theses, and Google Scholar were searched from inception until January 2020, with subject headings relevant to the domains of chemosensory alterations, palliative, and cancer care. A total of 10,718 English and French language publications were reviewed, yielding 43 articles on the researched topic. RESULTS: The heterogeneity of selected articles led to difficulties in interpretation and analysis of the available evidence. Included publications differed in study design, population sample, anticancer treatments, and measures of assessment for taste and smell disturbances. A broad variety of treatment options were described including zinc and polaprezinc, radio-protectors, vitamins and supplements, anti-xerostomia agents, active swallowing exercises, nutritional interventions, delta-9-tetrahydrocannabinol, and photobiomodulation. CONCLUSION: This scoping review identifies the current state of knowledge regarding chemosensory alterations within supportive cancer care. Despite not reaching firm conclusions, this article offers therapeutic venues to further explore in larger and more methodologically sound studies.

Intranasal administration of white tea alleviates the olfactory function deficit induced by chronic unpredictable mild stress.

CONTEXT: White tea [Camellia sinensis (L) O.Ktze. (Theaceae)] is popular in Asia, but its benefits on olfactory injury are unknown. OBJECTIVE: The present study explores the effects of white tea on the olfactory injury caused by chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: C57BL/6J mice (WT) were exposed to CUMS. CUMS mice (CU) were intranasally treated with white tea extract [low tea (LT), 20 mg/kg; high tea (HT), 40 mg/kg] and fluoxetine (CF, 20 mg/kg) for 7 days. Several behavioural tests were conducted to assess depression and olfactory function. The transmission electron microscope (TEM) and semi-quantitative reverse transcription PCR were performed separately to observe the changes of related structures and genes transcription level. RESULTS: The depressive behaviours of the LT and HT mice were reversed. The latency time of the buried food pellet test decreased from 280 s (CU) to 130 s (HT), while the olfactory sensitivity and olfactory avoidance test showed that the olfactory behaviours disorder of LT and HT mice were alleviated. The white tea increased the A490 nm values of the cortisol treated cells from 0.15 to 1.4. Reduced mitochondrial and synaptic damage in the olfactory bulb (OB), enhanced expression of the brain-derived neurotrophic factor (BDNF) and olfactory marker protein (OMP) were observed in the LT and HT mice. CONCLUSIONS AND DISCUSSION: White tea has the potential in curing the olfactory deficiency related to chronic stress. It lays the foundation for the development of new and reliable drug to improve olfactory.

Letter to the editor: Study Summary - Randomized Control Trial of Omega-3 Fatty Acid Supplementation for the Treatment of COVID-19 Related Olfactory Dysfunction.

OBJECTIVES: To evaluate a therapeutic role for omega-3 fatty acid supplementation in the treatment of olfactory dysfunction associated with COVID-19 infection TRIAL DESIGN: Randomized, double-blinded, placebo-controlled trial PARTICIPANTS: Eligible patients are adults with self-reported new-onset olfactory dysfunction of any duration associated with laboratory-confirmed or clinically suspected COVID-19 patients. Exclusion criteria include patients with pre-existing olfactory dysfunction, history of chronic rhinosinusitis or history of sinus surgery, current use of nasal steroid sprays or omega-3 supplementation, fish allergy, or inability to provide informed consent for any reason. The trial is conducted at Mount Sinai Hospital INTERVENTION AND COMPARATOR: The intervention group will receive 2000 mg daily of omega-3 supplementation in the form of two "Fish Oil, Ultra Omega-3" capsules (product of Pharmavite®) daily. The comparator group will take 2 placebo capsules of identical size, shape, and odor daily for 6 weeks. MAIN OUTCOMES: Each subject will take a Brief Smell Identification Test at study enrolment and completion after 6 weeks. The primary outcome will be change in Brief Smell Identification Test over the 6-week period. RANDOMISATION: Patients will be randomized by the Investigational Drug Pharmacy at the Icahn School of Medicine at Sinai via a computer-generated sequence in a 1:1 allocation to treatment or control arms. BLINDING (MASKING): Both participants and researchers will be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): There will be 88 participants randomized to each group. A total of 176 participants will be randomized. TRIAL STATUS: Protocol Version 1, 8/3/2020 Recruitment is ongoing, started 8/5/2020 with estimated completion 11/30/2020. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov with Protocol Identifier: NCT04495816 . TRIAL REGISTRATION: ClinicalTrials.gov, NCT04495816 . Registered 3 August 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).

Recovery Over Time and Prognostic Factors in Treated Patients with Post-Infectious Olfactory Dysfunction: A Retrospective Study.

OBJECTIVES: The aims of the present study were to clarify the time-course of olfactory recovery and the prognostic factors in PIOD patients treated with Toki-shakuyaku-san (TSS). METHODS: A retrospective cohort study of patients with PIOD was conducted by reviewing patients' medical records. This study included patients who received TSS or a combination of TSS and zinc sulfate. Olfactory function was examined by T&T olfactometer at each 3-monthly follow-up visit. Patients with normal and mild olfactory dysfunction were excluded. Gender, age, treatment, duration of disease until the first visit and olfactory function scores of the T&T olfactometer at the first visit were analyzed as candidate clinical predictors of recovery. RESULTS: A total of 82 PIOD patients with ages ranging from 16 to 79 years were included. The mean duration of follow-up was 14.5 months (range 3-45 months). The number of patients with olfactory recovery increased for 24 months and the cumulative recovery rate was 77.3%. In about 60% of patients, olfactory recovery occurred within 6 months. Multivariate analysis showed that younger age (<65 years) and residual olfactory function were significantly associated with good olfactory recovery. CONCLUSIONS: We revealed recovery rates over time in patients with PIOD. The recovery of olfactory function often occurred during the early period (≤6 months). However, the number of patients with olfactory recovery increased for a long-term of 24 months after the first visit. Residual olfactory function and younger age were prognostic factors exactly. TSS may be a useful therapeutic agent for patients with PIOD. We believe that these results provide important information that is useful for counseling patients with PIOD.

Olfactory Loss Management in View of Avicenna: Focus on Neuroprotective Plants.

BACKGROUND: Loss of olfaction can cause noticeable reduction in general quality of life. Only a small portion of patients with olfactory loss respond to current medications. Thus, development of novel therapeutic strategies seems to be necessary. Looking into traditional medical knowledge can be of great value in addressing useful remedies. Traditional Persian Medicine (TPM) has been practiced in Persia for more than 2000 years. Avicenna is the most eminent Persian physician. OBJECTIVE: To survey Avicenna's views on etiology and management of olfactory loss and to search for relevant modern pharmacological data. METHODS: Avicenna's views on etiology and management (including suggested medicinal plants) of olfactory loss were obtained from "Canon of Medicine". In addition, a detailed search in ScienceDirect, PubMed, Scopus and Google Scholar databases was performed to elucidate relevant pharmacological actions and mechanisms of the plants and their major compounds with special focus on neuroprotective activity. RESULTS: Acorus calamus L., Allium cepa L., Allium sativum L., Aloe spp., Cinnamomum cassia (L.) J.Presl, Lavandula stoechas L., Mentha longifolia (L.) L., Nigella sativa L., Peganum harmala L., Piper nigrum L. and Zingiber officinale Roscoe were found to be the most emphatic plants for the treatment of olfactory loss. Pharmacological studies revealed biological activities including neuroprotective, anti-inflammatory, free radical scavenging activities and promoting endogenous antioxidant capacity for these plants and their major components. CONCLUSION: regarding the lack of effective treatments for recruiting normal smell in many cases, treatments suggested by Avicenna worth entering pharmacologic experiments and clinical trials.

[Clinical treatment effect of glucocorticoids and extract of ginkgo biloba on post-viral olfactory dysfunction].

Objective:To observe the effect of ginkgo biloba extraction combined with glucocorticoids on postviral olfactory dysfunction.Method:Forty-two patients were diagnosed as postviral olfactory dysfunction. All patients underwent olfactory test, including T&T test and Sniffin Sticks test before and after treatment. The treatment lasted up to 3 months based on effectiveness. The results of olfactory test were recorded every month.Result:Twenty patients received the treatment with prednisone acetate. T&T test showed that the effective and improvement rate of the treatment with prednisone acetate were 25.00%(5/20) and 45.00%(9/20),respectively; Sniffin Sticks test showed that the effective and improvement rate of the treatment were 20.00%(4/20)and 50.00%(10/20),respectively. Twenty-two patients received the treatment combined with extract of ginkgo biloba. T&T test showed that the effective and improvement rate of the treatment with prednisone acetate were 31.82%(7/22)and 50.00%(11/22),respectively; through Sniffin Sticks test showed that the effective and improvement rate of the treatment were 27.27%(6/22)and 54.55%(12/22),respectively.Conclusion:Olfactory function in patients with postviral olfactory dysfunction was improved with two therapy. There was no significant difference on effect between the two therapeutic groups, but the effect of combination of extract of ginkgo biloba was better than the effect of prednisone acetate. Prolong duration of treatment is help for the recovery of the olfaction.

Medical treatment of traumatic anosmia.

OBJECTIVES: To study the effects of zinc and steroid in the treatment of traumatic anosmia. STUDY DESIGN: A prospective, randomized study. SETTING: Academic medical center. SUBJECTS AND METHODS: Patients with a clear history of loss of smell after head injury and whose thresholds were -1 measured by the phenyl ethyl alcohol threshold test were included in this study from January 2010 to May 2013. They were randomly divided into 4 groups. Patients in group 1 were treated with zinc gluconate for a month and high-dose prednisolone with tapering for 2 weeks. Those in group 2 took only zinc gluconate, and those in group 3 took only prednisolone. Patients in group 4 did not take any medicine. All patients were followed up by phenyl ethyl alcohol threshold testing, and magnetic resonance imaging was performed to measure the volume of olfactory bulbs. RESULTS: Thirty-nine patients in group 1, 35 in group 2, 34 in group 3, and 37 in group 4 completed the study. The recovery of olfactory function was observed in 11 patients (28.2%) in group 1, in 9 (25.7%) in group 2, in 4 (11.8%) in group 3, and in 1 (2.7%) in group 4. The recovery rates of olfactory function of groups 1 and 2 were significantly higher than the recovery rate of group 4. The volume of olfactory bulbs was not significantly different between those with and without improved olfactory function. CONCLUSION: Our results show that zinc gluconate has a promising effect in treating traumatic anosmia.

The effect of a herbal combination of primrose, gentian root, vervain, elder flowers, and sorrel on olfactory function in patients with a sinonasal olfactory dysfunction.

Olfactory dysfunction is a common symptom in patients with inflammation of the nasal mucosa. Among numerous drugs, so far only the use of steroids has been shown to have a positive effect on olfactory function. Therefore the aim of the present study was to investigate whether patients with sinonasal disease would benefit in terms of olfactory function from oral treatment with a herbal drug (combination of primrose, gentian root, vervain, elder flowers, and sorrel: Sinupret(r)) which is commonly used in sinusitis. Olfactory function was tested using a standardised olfactory test kit (`sniffin` sticks`). The drug was applied in a double-blind fashion: after an initial therapy of 7 days of oral prednisolone for all participants with a sinonasal olfactory disease, participants were divided into a placebo- and a verum-group; tests were performed before and after treatment over a 2 months period. Statistical analysis did not reveal any major differences in olfactory function in relation to treatment. Considering that its benefit for the inflammatory component of sinusitis has been shown, the herbal drug may exhibit positive effects on olfactory function in a different setting, e.g., when applied without preceding administration of prednisolone, or when used in patients with certain degrees of rhinosinusitis.