Integrating the patient's voice into the research agenda for treatment of chemosensory disorders.

World-wide some 658 million people were infected with coronavirus disease 2019 (COVID-19) and millions suffer from chemosensory impairment associated with long COVID. Current treatments for taste and smell disorders are limited. Involving patients has the potential to catalyze the dynamic exchange and development of new ideas and approaches to facilitate biomedical research and therapeutics. We assessed patients' perceptions of the efficacy of treatments for chemosensory impairment using an online questionnaire completed by 5,815 people in the US Logistic regression determined variables predictive of reported treatment efficacy for patients aged 18 to 24, 25 to 39, 40 to 60, and 60+ yrs. who were treated with nasal steroids, oral steroids, zinc, nasal rinse, smell training, theophylline, platelet-rich plasma, and Omega 3. The most consistent predictor was age, with the majority of those 40 to 60 and 60+ reporting that nasal steroids, oral steroids, zinc, nasal rinse, and smell training were only slightly effective or not effective at all. Many of these treatment strategies target regeneration and immune response, processes compromised by age. Only those under 40 reported more than slight efficacy of steroids or smell training. Findings emphasize the need to include patients of all ages in clinical trials. Older adults with olfactory impairment are at increased risk for Alzheimer's disease (AD). We speculate that olfactory impairment associated with long COVID introduces the potential for a significant rise in AD. Long COVID-associated chemosensory impairment increases the urgency for translational and clinical research on novel treatment strategies. Suggestions for high-priority areas for epidemiological, basic, and clinical research on chemosensory impairment follow.

D2/D3 Receptor Agonism: Paving the Way for a New Therapeutic Target for Taste Disorders in Parkinson's Disease and Other Conditions?

Chemosensory (i.e., olfaction and taste) dysfunction is common in neurodegenerative (e.g., Parkinson's disease, Alzheimer's disease, and dementia), psychiatric (e.g., depression, bipolar disorders, other conditions), and postinfectious (i.e., long COVID) diseases and in the elderly. Despite its impact on patients' quality of life, no established treatment for taste disorders exists so far. A recent report on the effect of pramipexole, a D2/D3 agonist, on taste performance in healthy participants provides support for a new potential therapeutic target for taste dysfunction to be tested in future randomized, placebo-controlled, clinical trials across several populations reporting gustatory symptoms.

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.

A special symptom of olfactory dysfunction in coronavirus disease 2019: report of three cases.

Three patients of coronavirus disease (COVID-19) showed the symptoms of olfactory dysfunction. Clinical characteristics and treatment were retrospective analyzed. Olfactory disorders are uncommon symptoms of COVID-19 in China. Early diagnosis and intervention are keys to the recovery of olfactory disorders. Particular attention should be devoted to olfactory dysfunction.

Effect of Zinc Acetate Dihydrate (NobelzinR) Treatment on Anemia and Taste Disorders in Patients with Chronic Kidney Disease with Hypozincemia.

Some patients with chronic kidney disease (CKD) receiving hemodialysis develop erythropoietin-resistant anemia, possibly due to zinc deficiency. The frequency of zinc deficiency in CKD (stages 1-5 and 5D) and CKD improvement via zinc supplementation are not completely verified. Here 500 CKD patients (Stage 1/2, n=100; Stage 3, n=100; Stage 4, n=100, Stage n=5, 100; Stage 5D, n=100) will be recruited to determine the frequency of serum zinc deficiency at each CKD stage. Patients with serum zinc concentrations <80 µg/dL will be treated with zinc acetate dihydrate (NobelzinR) to evaluate its effects on hypozincemia, taste disturbances, and anemia.

Effect of a local anesthetic lozenge in relief of symptoms in burning mouth syndrome.

OBJECTIVE: Patients with burning mouth syndrome (BMS) often represent a clinical challenge as available agents for symptomatic treatment are few and often ineffective. The aim was to evaluate the effect of a bupivacaine lozenge on oral mucosal pain, xerostomia, and taste alterations in patients with BMS. METHODS: Eighteen patients (4 men and 14 women) aged 39-71 years with BMS were included in this randomized, double-blinded, placebo-controlled, crossover trial. Lozenges (containing bupivacaine or placebo) were administrated three times a day for 2 weeks for two separate treatment periods. Assessment of oral mucosal pain, xerostomia, and taste alterations was performed in a patient diary on a visual analog scale (ranging from 0 to 100 mm) before and after the lozenge was dissolved. RESULTS: The bupivacaine lozenge significantly reduced the burning oral pain (P < 0.001), increased the sense of taste disturbances (P < 0.001), and had no impact on xerostomia, when adjusted for the treatment period. CONCLUSIONS: Our results indicate that the bupivacaine lozenge offers a novel therapeutic modality to patients with BMS, although without alleviating effect on the associated symptoms, taste alterations, and xerostomia.

[The Effectiveness of Polaprezinc Preparation for Taste Alteration in Cancer Chemotherapy].

Taste alteration is an adverse effect of cancer chemotherapy that can cause a decrease in the nutritional status owing to appetite suppression. In most cases, taste alteration is attributed to zinc deficiency, which is treated using zinc-containing formulations, such as polaprezinc. Polaprezinc has commonly been administered to protect against taste alteration during the course of cancer chemotherapy, but its efficacy has not been fully evaluated. In addition, the background characteristics of the patients who are likely to experience taste alteration have not been fully investigated. Therefore, the effectiveness of zinccontaining formulations in the prevention of taste alteration was investigated retrospectively in our hospital. The objective of this study was to evaluate the presence of taste alteration and the effectiveness of polaprezinc administration in 136 female breast cancer patients who underwent FEC100 therapy between April 2011 and September 2014. We also investigated the relevance of the patient background factors in the occurrence of taste alteration(age, height, weight, body surface area, and levels of hemoglobin, serum iron, albumin, and total protein). Of 58 patients with taste alteration, 20 received polaprezinc, with the following outcomes: taste alteration improved in 70.0% of the patients, no change was observed in 25.0%, and the condition worsened in 5.0%. In a multiple regression analysis, the body surface area and decreased hemoglobin level were found to be significant independent factors that influence the development of taste alteration(p=0.003 and p=0.021, respectively). These results indicate that for patients who receive high doses of anticancer agents according to their body surface area and likelihood of anemia, such as that due to iron deficiency, early administration of zinc-containing formulations is anticipated to prevent taste alteration.

Zinc and Taste Disturbances in Older Adults: A Review of the Literature.

According to the National Health and Nutrition Examination Survey III, 35% to 45% of adults 60 years of age or older had zinc intakes below the estimated average requirement of 6.8 mg/day for elderly females and 9.4 mg/day for elderly males. Zinc deficiency may lead to loss of appetite, impaired immune function, weight loss, delayed healing of wounds, eye and skin lesions, and smell and taste disturbances. Older adults are especially affected by changes in taste sensations because of age-related gustatory dysfunction, use of multiple medications, increased frailty, and zinc deficiency. This article reviews the finding of clinical studies investigating the use of zinc supplementation for improvement with taste disturbances in older adults.

[The role of zinc in chronic kidney disease].

Renal anemia is one of the most important complication as a cause of cardiovascular event in patients with chronic kidney disease (CKD). The status of renal anemia has been ameliorated by using recombinant human erythropoietin (EPO), however, the EPO resistant anemia is sometimes seen in high stage CKD patients. Heavy metal deficiency including zinc deficiency is one of the cause of EPO resistant anemia. Recently, it is reported that zinc deficiency is seen in patients with CKD. In this article, we describe zinc deficiency in patients with CKD. The ability that zinc supplementation improves their anemia in CKD patients is also described.

[Time course of changes in gustatory function test results and subjective symptoms, and predictive factors for response in patients with taste disorder receiving 24-week zinc replacement treatment].

In a taste disorder, an agreement between patients' complaints and gustatory function test results is not necessarily found both at the initial hospital visit and during the course of treatment; therefore, it is difficult to assess treatment responses and review treatment strategies based on the assessed treatment responses. The present study investigated the time course of changes in disc gustometry results and subjective symptom scores measured at 4-week intervals in 44 patients with a taste disorder who were considered eligible for zinc replacement treatment and who received polaprezinc at a dose of 150 mg/day (equivalent to a 34 mg/day dose of zinc) for up to 24 weeks. The study also examined the potential differences in treatment outcomes according to the predictive factors for response such as patient background and assessed disc gustometry results during the course of treatment. Results indicated that disc gustometry results and subjective symptom scores showed different time courses of changes. The response rate as measured by disc gustometry was 47.7% at week 12 of treatment, and showed a subsequent slow increase to 56.8% at week 24. On the other hand, subjective symptom scores showed a time-proportional improvement up to week 24. Among the patients included in the present study, a clear difference was found according to the presence or absence of an improving trend as determined by disc gustometry at week 12 of treatment, although there were no differences in ultimate treatment responses, including categories of taste disorder, according to patient background. Patients showing a trend toward improvement had significantly better treatment responses in terms of both ultimate response rates and subjective symptom scores, whereas patients showing no trend toward improvement were less likely to respond to the subsequent 12-week continued treatment.

[The effect of zinc agent in 219 patients with zinc deficiency-inductive/ idiopathic taste disorder: a placebo controlled randomized study].

Diagnosis and treatment of taste disorders are challenging because the disorder can only be determined by the awareness of the patient. Hence, these disorders still require comprehensive evidence. We conducted a randomized, placebo-controlled double-blind study to investigate the effect of polaprezinc, a zinc-containing agent, in 219 patients with either zinc deficiency-inductive or an idiopathic taste, disorder. As a result, the zinc-treated arm experienced a statistically significant improvement against the placebo-treated arm in the perceptible threshold scores of the filter-paper disk method 8 weeks after the administration of the investigational drug. Moreover, the effect lasted for 4 weeks after discontinuation of the drug. However, the effective ratios based on the initial criteria were 55.6% in the treatment group and 43.2% in the placebo, where no statistical significance was recorded. Sex and degree of depression could be two of the potential factors to explain this discrepancy. Furthermore, the effect was not significant among male patients and patients with a high depression score based on the Self-rating Depression Scale (SDS) test. These results indicate that determining the symptom among such patients remains undisclosed. Whereas, in approximately 77%, or 168 patients with "normal" SDS scores and with completely impaired taste qualities, the ratio of effective cases reached 60.9% in the zinc-treated group, the ratio of the placebo-treated group reached 39.5%, resulting in a statistical significance. This may be partly because of a problem in the adaption of male subjects to the gustatory analyses, especially to the identification of saltiness and sourness. Care must also be taken regarding the depressive state of patients when diagnosing and treating taste disorders. Taste disorders caused by depression may not be cured by zinc supplementation due in part to the fact that the symptom is based on a mental issue, and due in part to the conservative responding bias generated by the depression itself, which may inhibit accurate and precise diagnosis of the disorder. In conclusion, administration of a zinc agent is effective for patients with taste disorders, provided selection of appropriate patients is performed, and that proper examination and evaluation are conducted. The present study also indicated that examining depressiveness based on the SDS scores and investigating disturbance of each taste quality using the filter-paper disk method are recommended for the diagnosis and determination of the treatment effect of a taste disorder.

[Clinical analysis of 1059 patients with taste disorders].

Taste disorders are caused by several factors, and there have been few reports concerning the clinical course of taste disorders. In this study, patients with taste disorders were classified into 10 groups according to causes, and they were retrospectively studied in terms of therapeutic effects. In total, 1059 patients (412 men and 647 women, mean age: 60.0 years) who complained of taste disorders were reviewed in our clinic. The patients were asked detailed questions about their history of symptoms, and their emotional status was assessed using a self-rating depression scale. In all subjects, taste functions were measured by electrogustometry (EGM) and filter paper disks (FPD). The grades of their symptoms were assessed with a visual analogue scale (VAS). In addition, the levels of serum iron, copper, and zinc were examined. The patients were treated with zinc sulfate, polaprezinc, iron preparation, herbal medicine, and minor tranquilizers according to the factors causing the taste disorders. The most frequent cause was idiopathic taste disorder (192 cases, 18.2%), the second was psychogenic (186 cases, 17.6%), and the third was drug-induced (179 cases, 16.9%). The recovery rate of the symptoms was 64/92 (70.2%) in post-common cold, 31/35 (88.6%) in iron deficiency, and 85/116 (73.3%) in zinc deficiency. In these groups, the rates of recoveries were better than in the other groups. The recovery period in drug-induced taste disorders was approximately twice as long as the recovery period in the other groups. In the patients who were able to start treatment within 6 months from the onset of taste disorder, the recovery rate was significantly higher and the therapeutic period was significantly shorter than in those who had the disorders for more than 6 months (p<0.05, respectively).

Evaluation of Chemotherapy-induced Dysgeusia in Patients With Gastrointestinal Cancer: A Pilot Study.

BACKGROUND/AIM: Dysgeusia, one of the adverse effects of cancer chemotherapy, and anorexia due to taste disorder can significantly impair the quality of life of patients. However, an evaluation method for dysgeusia has not yet been established. The present prospective study aimed to utilize a combination of subjective and objective assessment methods to evaluate dysgeusia in patients with gastrointestinal cancer initiating chemotherapy, to determine chemotherapeutic drugs and regimens causing dysgeusia, and to assess whether dysgeusia was associated with zinc deficiency. PATIENTS AND METHODS: A total of 21 patients with newly diagnosed gastrointestinal cancer were registered between August 2020 to March 2021. The following regimens were also included in the evaluation if the patients did not develop dysgeusia. A total 30 regimens were administered to the patients during the study period. A salt-impregnated test paper (Salsave®) was used as a subjective assessment, and the chemotherapy-induced taste alteration scale was used as an objective assessment. RESULTS: Based on physician interviews, dysgeusia was diagnosed in 8 of 21 patients (38%) treated with 8 of 30 regimens (27%). All regimens that resulted in dysgeusia contained platinum-based drugs. The patients who developed dysgeusia had higher controlling nutritional status scores at the start of chemotherapy compared to those who did not develop dysgeusia. In both subjective and objective assessments, the patients with dysgeusia performed significantly worse than those without dysgeusia. Six of the eight patients who developed dysgeusia were administered Novelzine, which did not improve the taste disorder despite the improvement of serum zinc levels. CONCLUSION: The combined approach using subjective and objective taste assessment methods was useful in assessing chemotherapy-induced dysgeusia. Mechanisms other than hypozincemia should be considered as contributors to taste disorders caused by platinum-based drugs.

Therapeutic supplementation with zinc in the management of COVID-19-related diarrhea and ageusia/dysgeusia: mechanisms and clues for a personalized dosage regimen.

Zinc supplementation is indicated for diarrhea and taste disorders, which are both features of COVID-19 . Nevertheless, this strategy has not been tested for the treatment of these secondary complications in the current pandemic. Through an updated review, a practical appraisal was considered as a means of providing a medical nexus of therapeutic zinc regimens as an adjunct in the management of COVID-19-related diarrhea and ageusia/dysgeusia. While diarrhea and taste disorders are consequences of COVID-19, zinc supplementation is useful for non-COVID-19 patients with these clinical problems. The overwhelming evidence for supplementing with zinc in diarrhea and pneumonia is associated with the treatment of children, while for taste disorders the use of supplementing with zinc is more examined in adults. Whereas COVID-19 is more prevalent in adults, precautions should be exercised not to translate the zinc dosage used for children with diarrhea and taste disorders into the current pandemic. Therapeutic doses of zinc used for adults (∼50-150 mg/day of elemental zinc) could be included in the treatment strategies for COVID-19, but this proposal should be examined through randomized studies.

Loss of taste responds to high-dose biotin treatment.

BACKGROUND AND OBJECTIVE: We saw 2 patients who lost their sense of taste, which was restored by pharmacologic doses of biotin. The key objective is to describe the 2 case reports and suggest a potential treatment for unexplained loss of taste. METHODS AND DESIGN: The first patient was a 67-year-old woman who lost her sense of taste taking Juvenon, a dietary herbal supplement containing acyl-L-carnitine, lipoic acid, calcium, phosphorus, and biotin 300 µg per day. The second patient was a 60-year-old man who lost his sense of taste after a sleeve gastrectomy for obesity. RESULTS: The first patient did not respond to 5 mg per day of biotin, but taste was restored with 10 mg of biotin per day. Biotin was prescribed based on information that lipoic acid bound to the biotin transporter. Baseline urine gave no evidence of a pre-existing biotin deficiency. The second patient did not have restoration of taste after taking biotin 5 mg per day for 7 weeks but did have taste restoration on biotin 20 mg per day. Neither subject had an abnormal biotinidase level. CONCLUSIONS: Further research into the relationship of biotin to taste is clearly indicated. Loss of taste was very distressing and significantly altered the quality of life for both patients. Since biotin up to 40 mg per day has been shown to be safe, a therapeutic trial of pharmacologic doses of biotin should be considered as a potentially curative treatment in patients who present with a loss of taste that has no obvious cause.

Evaluation of effects of chronic nasal steroid use on rhinological symptoms of COVID-19 with SNOT-22 questionnaire.

BACKGROUND: The benefits of corticosteroids for the treatment of COVID-19 infection are documented in the literature. The goal of the study is to compare the severity of rhinological symptoms of COVID-19 between patients with nasal steroid use (NSU) and the control group (CG) using the sino-nasal outcome test (SNOT-22) questionnaire. METHODS: A face-to-face survey was conducted at a second referral state hospital between. Patients with a complete recovery from COVID-19 were included in NSU and CG groups. Two subscales of the SNOT-22 were filled by the patients. The frequency and duration of smell and taste loss and SNOT-22 scores were compared between the two groups. RESULTS: Forty-seven patients were included in the study. Thirty-one patients were in CG and 16 patients in the NSU group. Twenty-four (51.1%) patients were females and 23 (48.9%) were males. The mean age was 41.4 ± 8.6 years. Olfactory dysfunction was detected in 12 (75%) patients in the NSU group, and 31 (93.3%) patients in the control group (CG). Gustatory dysfunction was seen in 10 (62.5%) patients in the NSU group and 24 (77.4%) patients NSU group. (p = 0.071, 0.279, respectively). The duration of the olfactory (6.6 ± 2.5 days) and gustatory dysfunction (6.1 ± 2.6 days) and the mean SNOT-22 total score (11.9 ± 1.6) was significantly lower in the NSU group (p < 0.001, CI 11.1-5.1, CI 9.9-4.6, CI 9.3-5.9, respectively). CONCLUSIONS: Although nasal steroid use does not prevent olfactory and gustatory dysfunction in COVID-19 patients, it may reduce the severity and duration of these symptoms.

Effects of polaprezinc on morphological change of the tongue in zinc-deficient rats.

OBJECTIVE: To examine the effects of polaprezinc on morphologic change of the tongue epithelium and on cell cycle regulation of taste bud cells by using zinc-deficient rats, an animal model of taste disturbance. METHODS: After 28 days of feeding with zinc-sufficient or -deficient diet, the rats fed a zinc-deficient diet were divided into four groups in which 0, 1, 3 and 10 mg/kg of polaprezinc were administered for 28 days with continuation of diet. Histopathological and morphological examinations of the tongue were carried out. RESULTS: Parakeratosis was observed in all rats receiving the zinc-deficient diet and 1 mg/kg polaprezinc but not in rats receiving 3 and 10 mg/kg polaprezinc. The ratio of keratinizing epithelium in the outer and inner circumference were significantly increased from 9.6% and 11.3%, respectively, in zinc-sufficient rats to 36.9% and 32.9%, respectively, in zinc-deficient rats (P<0.001 and <0.01). This increase was reversed to 13.7% and 12.3% in rats that received 3 and 10 mg/kg polaprezinc in the outer circumference, respectively. Same phenomenon was seen in the inner circumference part, 13.0% and 10.8% (P<0.01), respectively. In addition, proliferating cell nuclear antigen-positive cells in the taste bud were significantly decreased from 75.5% in zinc-sufficient rats to 32.2% in zinc-deficient rats (P<0.001). This decrease was reversed to 70.3%, 83.1% and 81.2% in rats that received 1, 3 and 10 mg/kg polaprezinc, respectively. CONCLUSION: Polaprezinc improves parakeratosis and decreases taste bud cell proliferation caused by zinc deficiency. These effects may be involved in mechanisms underlying improvement of taste disorders in animal models.

Aminofeel improves the sensitivity to taste in patients with HCV-infected liver disease.

BACKGROUND: Patients with chronic liver diseases have a taste disorder and altered zinc metabolism. We investigated the effects of a supplement enriched with branched-chain amino acids (BCAA) (Aminofeel) on sensitivity to different tastes in patients with hepatitis C virus (HCV) infected liver disease. MATERIAL/METHODS: Nine patients (mean age 63.3+/-9.1 years) with HCV-related liver diseases were identified and examined for sensitivity to different tastes. Eight patients had no awareness of taste disorders, and 3 patients had oral lichen planus. We examined 4 tastes (sweet, salty, sour, and bitter) using a Taste Disk and sensitivity to different tastes was rated on a 6-point scale (I, II, III, IV, V, and VI). Each patient was given one sachet of Aminofeel after breakfast and another at bedtime for 90 days. RESULTS: Only one patient was aware of a taste disorder before administration of Aminofeel, but 4 patients had decreased gustatory sensitivity in the sour taste test, and 2 had it in the bitter taste test. Sensitivity to sour tastes significantly increased after the administration of Aminofeel(R) (P=0.03). Sensitivity to sweet tastes increased after the administration of Aminofeel (P=0.06). Zinc value significantly increased after the administration of Aminofeel (P=0.02). CONCLUSIONS: Patients with HCV-infected liver disease have decreased sensitivity to different tastes and decreased zinc levels. Some patients were unaware that they had a taste disorder. Aminofeel improved sensitivity to different tastes and increased zinc values. Thus, Aminofeel is a useful therapeutic agent for taste disorders.

Prognostic factors of recovery with medication in patients with taste disorders.

OBJECTIVES: We aimed to elucidate the prognostic factors of the patients with taste disorders who were treated with popular and common medication in Japan. MATERIALS AND METHODS: A retrospective study on the medical charts of a total of 255 patients with taste disorders who were treated primarily with oral medication including a zinc agent. RESULTS: The factors below were significantly linked with poor prognosis: 1) male gender, 2) taste disorders that began 3 months before starting treatment and 3) a severe taste disorder grade at the initial visit. CONCLUSIONS: We have concluded that the prognosis for the patients with taste disorders who were treated by popular and standard medication therapy in Japan recently was significantly linked to gender, the period of 3 months before starting the treatment and the severity of the disorder at the time of diagnosis. In addition, we recognized some limitations we should resolve in further research including a method of measuring "umami" and so on. CLINICAL RELEVANCE: Better awareness of these factors should be clinically useful when we manage patients with taste disorders. Earlier treatment should be started to cure the symptoms.