Management of new onset loss of sense of smell during the COVID-19 pandemic - BRS Consensus Guidelines.

OBJECTIVES: The primary aim of the study is to provide recommendations for the investigation and management of patients with new onset loss of sense of smell during the COVID-19 pandemic. DESIGN: After undertaking a literature review, we used the RAND/UCLA methodology with a multi-step process to reach consensus about treatment options, onward referral, and imaging. SETTING AND PARTICIPANTS: An expert panel consisting of 15 members was assembled. A literature review was undertaken prior to the study and evidence was summarised for the panellists. MAIN OUTCOME MEASURES: The panel undertook a process of ranking and classifying appropriateness of different investigations and treatment options for new onset loss of sense of smell during the COVID-19 pandemic. Using a 9-point Likert scale, panellists scored whether a treatment was: Not recommended, optional, or recommended. Consensus was achieved when more than 70% of responses fell into the category defined by the mean. RESULTS: Consensus was reached on the majority of statements after 2 rounds of ranking. Disagreement meant no recommendation was made regarding one treatment, using Vitamin A drops. Alpha-lipoic acid was not recommended, olfactory training was recommended for all patients with persistent loss of sense of smell of more than 2 weeks duration, and oral steroids, steroid rinses, and omega 3 supplements may be considered on an individual basis. Recommendations regarding the need for referral and investigation have been made. CONCLUSION: This study identified the appropriateness of olfactory training, different medical treatment options, referral guidelines and imaging for patients with COVID-19-related loss of sense of smell. The guideline may evolve as our experience of COVID-19 develops.

Unexplained repeated pregnancy loss is associated with altered perceptual and brain responses to men's body-odor.

Mammalian olfaction and reproduction are tightly linked, a link less explored in humans. Here, we asked whether human unexplained repeated pregnancy loss (uRPL) is associated with altered olfaction, and particularly altered olfactory responses to body-odor. We found that whereas most women with uRPL could identify the body-odor of their spouse, most control women could not. Moreover, women with uRPL rated the perceptual attributes of men's body-odor differently from controls. These pronounced differences were accompanied by an only modest albeit significant advantage in ordinary, non-body-odor-related olfaction in uRPL. Next, using structural and functional brain imaging, we found that in comparison to controls, most women with uRPL had smaller olfactory bulbs, yet increased hypothalamic response in association with men's body-odor. These findings combine to suggest altered olfactory perceptual and brain responses in women experiencing uRPL, particularly in relation to men's body-odor. Whether this link has any causal aspects to it remains to be explored.

Remote psychophysical evaluation of olfactory and gustatory functions in early-stage coronavirus disease 2019 patients: the Bologna experience of 300 cases.

BACKGROUND: An objective evaluation of coronavirus disease 2019 in the first days of infection is almost impossible, as affected individuals are generally in home quarantine, and there is limited accessibility for the operator who should perform the test. To overcome this limitation, a recently validated psychophysical self-administered test was used, which can be performed remotely in the assessment of early-stage coronavirus disease 2019 patients. METHODS: Olfactory and gustatory functions were objectively assessed in 300 patients in the first 7 days from coronavirus disease 2019 symptom onset. RESULTS: Seventy per cent of the patients presented olfactory and/or gustatory disorders. The dysfunctions detected were mainly complete anosmia (47 per cent) or ageusia (38 per cent). A significant correlation was found between taste dysfunction and female gender (odds ratio = 1.936, p = 0.014) and fever (odds ratio = 2.132, p = 0.003). CONCLUSION: The psychophysical evaluation protocol proposed is an effective tool for the fast and objective evaluation of patients in the early stages of coronavirus disease 2019. Chemosensitive disorders have been confirmed to be frequent and early symptoms of the coronavirus infection, and, in a significant number of cases, they are the first or only manifestation of coronavirus disease 2019.

Herbal Drug EPs 7630 versus Amoxicillin in Patients with Uncomplicated Acute Bacterial Rhinosinusitis: A Randomized, Open-Label Study.

OBJECTIVE: Previous investigations suggest the use of extract from the root of Pelargonium sidoides (EPs 7630) for the therapy of uncomplicated acute upper airway inflammations, due to its strong antimicrobial and immunomodulatory effect. We aimed to compare clinical efficacy, safety and bactericidal effect of EPs 7630 and amoxicillin monotherapy in treatment of patients with mild to moderate acute bacterial rhinosinusitis (ABRS). METHODS: Fifty ABRS patients were divided into two groups by randomization. Group 1 (n = 25) received EPs 7630 tablets, 3 × 20 mg/day per os for 10 days. Group 2 (n = 25) received amoxicillin tablets 3 × 500 mg/day per os, for 10 days. We assessed total symptom score (TSS), individual symptom scores for each symptom (nasal obstruction, rhinorrhea, postnasal drip, facial pain/pressure, loss of the sense of smell), endoscopic findings, including total endoscopic score (TES) and individual endoscopic signs (mucosal edema, mucopurulent secretion), before and after treatment. Samples of discharge taken from the middle meatus of all patients were cultivated for bacteria before and after therapy. RESULTS: Higher absolute improvement after treatment was found for TSS, nasal obstruction, facial pain/pressure, impaired sense of smell, TES, mucosal edema and mucopurulent secretion in EPs 7630 group compared to amoxicillin group (P < .001 for all parameters). However, there were no differences in absolute improvement of rhinorrhea score and postnasal drip score between groups (P = .248; P = .679, respectively). Fewer types of bacteria grew on culture from middle meatal samples in EPs 7630 group compared to amoxicillin group. There were no reported adverse events from patients from either group. CONCLUSION: Our results demonstrated better clinical and antimicrobial efficacy of EPs 7630 than amoxicillin. EPs 7630 was shown as a potent agent and good alternative to antibiotic treatment of uncomplicated ABRS.

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.

Effect of lactoferrin on taste and smell abnormalities induced by chemotherapy: a proteome analysis.

Cancer patients receiving chemotherapy often experience taste and smell abnormalities (TSA). To date, the underlying molecular mechanisms of this frequent side-effect have not been determined and effective treatments are not available. This study assessed the feasibility of lactoferrin (LF) supplementation as a treatment for TSA and investigate the related mechanisms through salivary proteome analysis. Nineteen cancer patients with established TSA following chemotherapy administration were enrolled in this study. Cancer patients and additional 12 healthy subjects took LF supplements, 3 tablets per day (250 mg per tablet), for 30 days. Saliva was collected at three timepoints: baseline, 30-day LF supplementation, and 30-day post-LF supplementation. Patient's TSA level, salivary proteome, and salivary minerals at each LF treatment stage were analyzed. High TSA level was associated with high concentration of salivary Fe and loss of critical salivary immune proteins. LF supplementation significantly decreased the concentration of salivary Fe (P = 0.025), increased the abundance (P < 0.05) of salivary α-amylase and Zn-α-2-GP, and led to an overall increase of expression (≥2-fold changes) of immune proteins including immunoglobulin heavy chain, annexin A1, and proteinase inhibitor. Abundance of α-amylase and SPLUNC2 were further increased (P < 0.05) at 30-day post-LF supplementation in cancer patients. At the same time, total TSA score was significantly reduced (P < 0.001) in chemotherapy patients. This study demonstrated the feasibility of developing lactoferrin supplementation as a treatment to reduce TSA caused by chemotherapy and improve cancer patient's oral immunity.

Assessing pathophysiology of cancer anorexia.

PURPOSE OF REVIEW: Cancer anorexia is a negative prognostic factor and is broadly defined as the loss of the interest in food. However, multiple clinical domains contribute to the phenotype of cancer anorexia. The characterization of the clinical and molecular pathophysiology of cancer anorexia may enhance the efficacy of preventive and therapeutic strategies. RECENT FINDINGS: Clinical trials showed that cancer anorexia should be considered as an umbrella encompassing different signs and symptoms contributing to appetite disruption in cancer patients. Loss of appetite, early satiety, changes in taste and smell are determinants of cancer anorexia, whose presence should be assessed in cancer patients. Interestingly, neuronal correlates of cancer anorexia-related symptoms have been revealed by brain imaging techniques. SUMMARY: The pathophysiology of cancer anorexia is complex and involves different domains influencing eating behavior. Limiting the assessment of cancer anorexia to questions investigating changes in appetite may impede correct identification of the targets to address.

Intravenous olfactory test latency correlates with improvement in post-infectious olfactory dysfunction.

CONCLUSION: This cohort study showed that onset latency in the intravenous olfactory test (IVO) may help predict when olfaction in patients with post-infectious olfactory dysfunction (PIOD) improves. OBJECTIVES: To identify factors that predict the olfactory improvement period in patients with PIOD. METHODOLOGY/PRINCIPAL: All consecutive patients presenting with PIOD in 1994-2014 who were followed up for 2 years were identified retrospectively. The ability of demographic/clinical factors (age, sex, body mass index, presence/absence of allergic rhinitis, treatment/non-treatment with herbal medicines, patient dependence on herbal medicine treatment, presence/absence of diabetes mellitus, and smoking status) and olfactory test factors (response/no response and onset latency and duration in the IVO test, and detection and recognition scores on the T&T olfactory test) to predict the olfactory improvement period (defined respectively as the time from PIOD onset or olfactory testing to the first self-report of olfaction improvement) was analyzed by univariate and multivariate regression. RESULTS: Of the 187 PIOD patients, the prognostic ability of demographic/clinical factors was analyzed in 65. None predicted the olfactory improvement period. Of the 65 patients, 20 did not respond in the IVO test. In the remaining 45 patients, onset latency (but not the other olfactory test factors) was a significant prognosticator of olfactory improvement period (R2=0.24, p = 0.003).

The Nonmotor Features of Parkinson's Disease.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) were recognized by the great James Parkinson himself who mentioned symptoms such as sleep dysfunction, delirium, dementia, and dysautonomia, in his seminal 1817 essay, "An Essay on the Shaking Palsy" (Parkinson, 1817). In spite of the key impact of PD NMS on quality of life, there was little holistic research and awareness till the validation and use of comprehensive tools such as the NMS questionnaire, scale, and the revised version of the unified PD rating scale. Research studies using these tools highlighted the key impact of the burden of NMS on quality of life of PD patients and the need for NMS to be routinely assessed in clinic. We now define PD as a motor and nonmotor disorder, and the natural history includes a long prodromal phase of PD dominated by a range of NMS. The prodromal phase is the subject of much research particularly in relation to neuroprotection and identifying subjects at risk. Use of NMS tools has also validated burden grading of NMS with cutoff values, which can be used as outcome measure in clinical trials. Finally, the complex multineurotransmitter dysfunction that is seen in PD has been shown to manifest clinically as nonmotor subtypes. Recognition of such subtypes is likely to lead to the emergence of personalized and precision medicine in PD.

Metacognitive knowledge of olfactory dysfunction in Parkinson's disease.

It is well known that patients with Parkinson's Disease (PD) suffer from olfactory impairments, but it is not clear whether patients are aware of their level of deficit in olfactory functioning. Since PD is a neurodegenerative disorder and its progression may be correlated with olfactory loss (Ansari & Johnson, 1975; but see also Doty, Deems, & Stellar, 1988), it is possible that these patients would be subject to metacognitive errors of over-estimation of olfactory ability (White & Kurtz, 2003). Nineteen non-demented PD patients and 19 age-matched controls were each given an objective measure of olfactory identification (the UPSIT, Doty, Shaman, Kimmelman, & Dann, 1984) and a subjective measure involving a questionnaire that asked them to self-rate both their olfactory function generally and their ability to smell each of 20 odors, 12 of which were assessed on the UPSIT. All of the PD patients showed impaired olfactory ability, as did 7 of the controls, according to the UPSIT norms. Self-rated and performance-based olfactory ability scores were significantly correlated in controls (r=.49, p=.03) but not in patients with PD (r=.20, p=.39). When the 12 odors common to both the self-rated questionnaire and UPSIT were compared, PD patients were less accurate than controls (t(36)=-4.96, p<.01) at estimating their own ability and the number of over-estimation errors was significantly higher (tone-tailed(29)=1.80, p=.04) in PD patients than in the control group, showing less metacognitive awareness of their ability than controls. These results support the idea that olfactory metacognition is often impaired in PD, as well as in controls recruited for normosmic ability (Wehling, Nordin, Espeseth, Reinvang, & Lundervold, 2011), and indicate that people with PD generally exhibit over-estimation of their olfactory ability at a rate that is higher than controls. These findings imply that PD patients, unaware of their olfactory deficit, are at greater risk of harm normally detected through olfaction, such as smoke or spoiled foods.

Olfactory performance after crenotherapy in chronic rhinosinusitis in the elderly.

OBJECTIVE: To evaluate the effectiveness of crenotherapy on the olfactory performance of elderly patients with chronic rhinosinusitis (CRS). STUDY DESIGN: A longitudinal case-control study of a cohort of elderly patients affected by CRS and olfactory dysfunction assessed with the Sniffin' Sticks (Burghart Medical Technology, Wedel, Germany) (SS) olfactory test. METHODS: One hundred and thirty-seven elderly subjects with CRS were divided into two groups. The investigational arm (n = 69) underwent crenotherapy with hyperthermal water, rich in mineral salts, and the control group (n = 68) underwent NaCl 0.9% both for 12 days. At baseline and at 1 and 6 months after treatment, both groups underwent ear nose and throat assessment and SS. Self-report questionnaires were administered at baseline to evaluate the patients' own olfactory response, and after treatment to evaluate their degree tolerability. Olfactory performance was then evaluated in elderly subjects with hyposmia without CRS (n = 40) and in younger subjects with both hyposmia and CRS (n = 40). RESULTS: No adverse reactions were reported after crenotherapy. The SS total score showed that crenotherapy induced a statistically significant improvement in the olfactory function of both the elderly and the younger subjects with hyposmia and CRS. By contrast, no improvement was observed in the control arm and in the elderly with hyposmia without CRS. All subjects showed a good degree of tolerability. CONCLUSIONS: We demonstrated that crenotherapy effectively improves olfactory function in elderly patients with CRS. Finally, our study suggests that crenotherapy represents a safe therapeutic strategy for the treatment of CRS and olfactory dysfunction in the elderly.

Smell identification in individuals at clinical high risk for schizophrenia.

Smell identification deficits exist in schizophrenia, and may be associated with its negative symptoms. Less is known about smell identification and its clinical correlates in individuals at clinical high risk (CHR) for schizophrenia and related psychotic disorders. We examined smell identification, symptoms and IQ in 71 clinical high-risk (CHR) subjects and 36 healthy controls. Smell identification was assessed using both the 40-item University of Pennsylvania Smell Identification Test (UPSIT; Doty, R.L., Shaman, P., Kimmelman, C.P., Dann, M.S., 1984. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 94, 176-178) and its extracted 12-item Brief Smell Identification Test (Goudsmit, N., Coleman, E., Seckinger, R.A., Wolitzky, R., Stanford, A.D., Corcoran, C., Goetz, R.R., Malaspina, D., 2003. A brief smell identification test discriminates between deficit and non-deficit schizophrenia. Psychiatry Research 120, 155-164). Smell identification did not significantly differ between CHR subjects and controls. Among CHR subjects, smell identification did not predict schizophrenia (N=19; 27%) within 2 years, nor was it associated with negative or positive symptoms. This is the third prospective cohort study to examine smell identification in CHR subjects, and overall, findings are inconclusive, similar to what is found for other disorders in adolescents, such as autism spectrum, attention deficit and anxiety disorders. Smell identification deficit may not have clear utility as a marker of emergent schizophrenia and related psychotic disorders.

The fate of the inner nose: odor imagery in patients with olfactory loss.

Cerebral activations during olfactory mental imagery are fairly well investigated in healthy participants but little attention has been given to olfactory imagery in patients with olfactory loss. To explore whether olfactory loss leads to deficits in olfactory imagery, neural responses using functional magnetic resonance imaging (fMRI) and self-report measures were investigated in 16 participants with acquired olfactory loss and 19 control participants. Participants imagined both pleasant and unpleasant odors and their visual representations. Patients reported less vivid olfactory but not visual images than controls. Results from neuroimaging revealed that activation patterns differed between patients and controls. While the control group showed stronger activation in olfactory brain regions for unpleasant compared to pleasant odors, the patient group did not. Also, activation in critical areas for olfactory imagery was correlated with the duration of olfactory dysfunction, indicating that the longer the duration of dysfunction, the more the attentional resources were employed. This indicates that participants with olfactory loss have difficulties to perform olfactory imagery in the conventional way. Regular exposure to olfactory information may be necessary to maintain an olfactory imagery capacity.

Effectiveness of olfactory rehabilitation according to a structured protocol with potential of regaining pre-operative levels in laryngectomy patients using nasal airflow-inducing manoeuvre.

This pilot study aims to evaluate the effectiveness of the Nasal Airflow-Inducing Manoeuvre (NAIM) when employing a structured protocol as well as investigate if early rehabilitation has the potential to return olfaction to pre-operative levels in patients undergoing laryngectomy following laryngeal cancer. Prospective study of cases conducted during 1 year, 2009­2010, at the Department of Ear-, Nose and Throat at Sahlgrenska University Hospital, Gothenburg, Sweden. Ten patients with laryngeal cancer and about to undergo laryngectomy were identified, of which four were included in the study. The remaining six patients were unfit to participate (n = 4) or declined participation (n = 2). Testing was conducted pre- and post-operatively and at each NAIM training session. Patients received three initial NAIM sessions followed by reinforcement training at 3, 6 and 12 months. Measures included Scandinavian Odour-Identification Test (SOIT), a semi-structured interview and questionnaires including European Organisation for Research and Treatment of Cancer, QLQ-C30 and QLQ-H&N35. All patients were normosmic smellers according to SOIT at the study end-point. One patient reported higher SOIT scores at 12 months follow-up compared to pre-operatively. Remaining patients had scores close to that reported pre-operatively. Using subjective measures, olfaction improved in all patients with one patient's final score surpassing pre-operative scores. By implementing a structured protocol consisting of three training sessions early following laryngectomy with additional reinforcement sessions at 3, 6 and 12 months, NAIM is effective in terms of improving smelling ability. There also appears to be potential for restoring olfaction to a patient's pre-operative level as reflected by both olfactory testing and PRO instruments. However, larger studies are needed to further explore the findings highlighted by this study.

Neuroprotective and cognitive enhancing effects of a multi-targeted food intervention in an animal model of neurodegeneration and depression.

Rising neurodegenerative and depressive disease prevalence combined with the lack of effective pharmaceutical treatments and dangerous side effects, has created an urgent need for the development of effective therapies. Considering that these disorders are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological concepts. To that end, an experimental diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline was formulated. This diet was tested on the olfactory bulbectomized rat (OBX), an established animal model of depression and cognitive decline. The ingredients of the diet have been individually shown to attenuate glutamate excitoxicity, exert potent anti-oxidant/anti-inflammatory properties, and improve synaptogenesis; processes that all have been implicated in neurodegenerative diseases and in the cognitive deficits following OBX in rodents. Dietary treatment started 2 weeks before OBX surgery, continuing for 6 weeks in total. The diet attenuated OBX-induced cognitive and behavioral deficits, except long-term spatial memory. Ameliorating effects of the diet extended to the control animals. Furthermore, the experimental diet reduced hippocampal atrophy and decreased the peripheral immune activation in the OBX rats. The ameliorating effects of the diet on the OBX-induced changes were comparable to those of the NMDA receptor antagonist, memantine, a drug used for the management of Alzheimer's disease. This proof-of-concept study suggests that a diet, which simultaneously targets multiple disease etiologies, can prevent/impede the development of a neurodegenerative and depressive disorders and the concomitant cognitive deficits.

Anosmia does not impair the anxiolytic-like effect of lavender essential oil inhalation in mice.

AIM: The inhalation of Lavandula angustifolia (lavender) essential oil has anxiolytic-like effects in animal models and humans, but its mechanism of action is still not fully understood. The inhalation of essential oils can induce anxiolytic effects through the central nervous system (e.g., lung absorption and bloodstream transport) or stimulation of the olfactory system and secondary activation of brain regions. Thus, the main objective of the present study was to evaluate whether the perception of lavender essential oil aroma, when inhaled, is necessary to obtain its anxiolytic-like effects in mice tested in the marble-burying test. MAIN METHODS: Anosmia was induced by irrigating the nasal cavity with zinc gluconate+zinc acetate so that the mice could not detect odors in the olfactory discrimination test. The marble-burying test was used to evaluate the anxiolytic-like effects of inhaled lavender essential oil. KEY FINDINGS: Anosmia did not interfere with the anxiolytic-like effect of lavender essential oil inhalation in the marble-burying test at concentrations of 2.5% (number of marbles buried: vehicle, 4.7±1.0; zinc, 6.2±2.2; p>0.10) and 5% (number of marbles buried: vehicle, 3.4±0.8; zinc, 4.3±0.9; p>0.10). Lavender essential oil at a concentration of 0.5% was ineffective. SIGNIFICANCE: These results suggest that olfactory system activation is unlikely to participate in the anxiolytic-like effect of lavender essential oil inhalation.

The smell of Tokishakuyaku-san (TJ-23) induces generation of regulatory T cells and prolongation of survival of fully allogeneic cardiac grafts in mice.

Oral administration of Tokishakuyaku-san (TJ-23), a Japanese herbal medicine, induces prolongation of cardiac allograft survival and generates regulatory cells in mice. Because herbal medicines usually have unique odor, and because smell is supposed to modulate the immune system, we examined whether the odor of TJ-23 induced prolonged allograft survival and regulatory cell generation. Naïve CBA mice (H2(k)) and olfactory-dysfunctional CBA mice after a stereotaxic operation underwent transplantation of C57BL/6 (B6, H2(b)) hearts, receiving fumigated water only or TJ-23 until rejection. Untreated or treated with water fumigation CBA mice rejected B6 cardiac grafts acutely (median survival times [MSTs], 7 and 8.5 days). When CBA mice were treated with fumigation of TJ-23, allograft survival was significantly prolonged (MST, 48 days). Olfactory-dysfunctional CBA mice treated with fumigation of TJ-23 rejected grafts acutely (MST, 7 days). Treatment with fumigation of TJ-23 also suppressed splenocytes proliferation and interferon-γ production. Secondary CBA recipients of whole splenocytes or CD4(+) cells from primary TJ-23-treated CBA recipients of B6 cardiac allografts at 30 days after grafting showed prolonged survival of B6 hearts (MST, >60 days). Flow cytometry studies showed increased CD4(+)CD25(+)Foxp3(+) regulatory cells in recipients given fumigation of TJ-23. In conclusion naïve but not olfactory-dysfunctional CBA mice treated with fumigation of TJ-23 displayed prolonged survival of fully allogeneic cardiac allografts and generation of regulatory cells.