Trigeminal function in patients with COVID-associated olfactory loss.

PURPOSE: Olfactory dysfunction (OD) can be a long-term consequence of various viral infections, including COVID-19. Dysfunction includes hyposmia/anosmia and parosmia (odor distortions). Interactions of the virus with the olfactory nerve have been extensively researched, but little is known about the interactions of the intranasal trigeminal nerve system in modulating this sensory loss. METHODS: We investigated intranasal trigeminal function across COVID-19 OD patients with and without parosmia compared to normosmic controls, to determine whether (1) post-viral hyposmia and/or (2) post-viral hyposmia with parosmia is associated with altered trigeminal function. OD patients (n = 27) were tested for olfactory function using the extended Sniffin' Sticks olfactory test and for trigeminal function through three methods-odor lateralization, subjective ratings of nasal patency, and ammonium vapor pain intensity ratings. This group was subsequently compared to controls, normosmic subjects (n = 15). RESULTS: Our findings revealed that post-COVID OD patients without parosmia experienced decreased sensitivity in ammonium vapor pain intensity ratings and odor lateralization scores-but similar nasal patency ratings-compared to normosmic controls. There were no significant differences in trigeminal function between OD patients with and without parosmia. CONCLUSIONS: Based on our results, we conclude that the trigeminal nerve dysfunction may partially explain post-viral OD, but does not seem to be a major factor in the generation of parosmia pathophysiology.

Normative data for the lateralization task in the assessment of intranasal trigeminal function

AIM: To provide normative data for the lateralization task in the assessment of intranasal trigeminal function, as well as to investigate potential effects of age, sex and olfactory function. METHODS: The lateralization task using eucalyptus as target stimulus was performed to assess intranasal trigeminal function. Data were collected from: 360 healthy adult participants (mean age 37.5±17.4) for the 40-trial version; 284 participants (mean age 32.6±14.1) for the 20-trial version; and 418 participants (mean age 42.6±15.6) for the 10-trial version. The "Sniffin' Sticks" test was used to measure olfactory function. RESULTS: The mean scores were 35.46±4.50 for the 40-trial version, 15.64±3.65 for the 20-trial version, and 8.14±2.16 for the 10-trial version. In the reference group aged 18-25 years, the 10th percentiles were 33 for the 40-trial version, 11 for the 20-trial version, and 6 for the 10-trial version. Significant effects of age and odor discrimination score were observed on lateralization performance. CONCLUSIONS: We provide reference scores for the lateralization task, in large sample of healthy participants. Among the three examined tasks (40, 20 and 10), the 40-trial task yielded the most reliable information. For the 40-trial version, scores equal or higher to 33 points indicate a normal lateralization ability, whereas scores between 27 and 32 may warrant further assessment. Scores below 27 possibly point towards a decreased trigeminal function. The lateralization task serves as surrogate marker of intranasal trigeminal functions and further studies with pathological cases are needed to explore its clinical usefulness.

Objective nasal airflow measures in relation to subjective nasal obstruction, trigeminal function, and olfaction in patients with chronic rhinosinusitis.

BACKGROUND: This study aimed to determine how nasal airflow measures and trigeminal function vary among patients with chronic rhinosinusitis (CRS) versus healthy controls and whether these measures are correlated with subjective nasal obstruction (SNO), olfactory function, and CRS control. METHODOLOGY: Participants included CRS patients and healthy controls. After a structured medical history, nasal airflow (peak nasal inspiratory flow [PNIF]; active anterior rhinomanometry [AAR]), trigeminal function (trigeminal lateralization test, CO2 sensitivity), and olfactory "Sniffin's Sticks" odor identification test) tests were performed. SNO ratings were also obtained. RESULTS: Sixty-nine participants were included (37 men, 32 women, mean age 51 years). There was no significant difference for objective nasal airflow between patients and controls, but CRS patients had worse SNO, trigeminal function, and olfaction compared to controls. SNO, but not objective nasal airflow tests, was negatively correlated with CO2 sensitivity and odor identification. CONCLUSION: The perception of nasal obstruction does not only depend on nasal airflow, but may also be modulated by trigeminal function and other factors. Thus, the role of objective nasal airflow measures as a sole method of functional nasal obstruction assessment in CRS remains limited.

Taste loss in COVID-19 â€" psychophysical evidence supporting a low prevalence.

Much - possibly even too much - has been published about chemosensory dysfunction as a consequence of COVID-19. Studies have reported prevalence of taste loss in up to 89.9%, which is in a similar range as COVID-19 related smell loss. However, most of these publications rely solely on patients' self-reports. Only few studies used validated psychophysical tests to specifically address olfaction and gustation. Especially for gustation, it is evident that subjective reporting does not correlate well with more objective psychophysical findings, often leading to an overestimation of subjectively impaired taste.

Adherence to olfactory training improves orthonasal and retronasal olfaction in post-COVID-19 olfactory loss.

BACKGROUND: Olfactory loss (OL) has emerged as one of the most prevalent and debilitating symptoms of SARS-CoV-2 infection and long-COVID-19. The present prospective observational study aimed to evaluate the efficacy of olfactory training (OT) on orthonasal and retronasal olfactory function in a cohort of individuals with persistent post-COVID-19 OL. METHODOLOGY: Participants with post-COVID-19 olfactory impairment underwent 4 months of OT, self-assessing their smell perception and undergoing comprehensive psychophysical evaluation of orthonasal and retronasal olfaction at baseline and after training. Orthonasal olfactory function was assessed using the extended Sniffin' Sticks test battery. Retronasal olfactory function was tested with powdered aromas. RESULTS: Among 114 participants with post-COVID-19 olfactory loss, adherence to OT was 60%. In adherents, the average increase in composite TDI score was 6.0 points compared to 2.6 points in non-adherents. Fifty-seven percent of adherent participants achieved a clinically significant improvement in TDI score (≥5.5 points), compared to 22% of non-adherents. In retronasal olfactoryidentification, 56% of adherents achieved a clinically significant improvement (≥4 points), compared to 16% of non-adherents. CONCLUSION: Adherence to a 4-month OT regimen can yield clinically meaningful improvements in both orthonasal and retronasal olfactory function among individuals with persistent post-COVID-19 olfactory dysfunction.

Olfactory training in normosmic individuals: a randomised controlled trial.

BACKGROUND: Even if olfactory training (OT) is a well-established treatment for individuals with olfactory dysfunction, the effect on individuals with normosmia remains uncertain. In this randomised controlled trial, we explore how OT with different exposure lengths affect olfactory function in individuals with normosmia. METHODOLOGY: Two hundred normosmic individuals were randomly assigned to one of two intervention groups performing OT with different exposure lengths or to a control group. The OT groups did OT twice daily for three months, g four different odours (eucalyptus, lavender, mint, and lemon) for 10 seconds per bottle during either a total of 40 seconds (standard OT) or 4 minutes (extended OT), while the control group did not perform any OT. Olfactory function was assessed using a 48-item Sniffin Sticks test at baseline, after the intervention, and after one year. RESULTS: We found no significant effect of OT in either of the intervention groups on any aspect of olfaction after intervention or at follow-up. There was no association between sex, age, allergic rhinitis, education or olfactory scores at baseline, and changes in olfactory function after OT. The extended OT group performed significantly fewer training sessions compared to those in the standard OT group. CONCLUSIONS: OT had a limited effect on olfactory function in individuals with normosmia. Further, the superiority of a more extended OT is not supported by this study, and shorter training sessions seem to improve compliance with OT.

Patients with olfactory loss exhibit pronounced adaptation to chemosensory stimuli: an electrophysiological study.

BACKGROUND: Pronounced chemosensory adaptation affects many patients with olfactory loss. The study aimed to investigate adaptation to olfactory and trigeminal nasal stimuli in patients with olfactory loss in comparison to controls using electrophysiological measures. METHODOLOGY: Thirty-four patients with olfactory loss (mean age ± SD = 59 ± 16 years) and 17 healthy volunteers (mean age ± SD = 50 ± 14 years) were recruited. Sniffin’ sticks test was used for evaluation of olfactory function and EEG-derived chemosensory event-related potentials were recorded. Intranasal stimuli were presented using high-precision, computer-controlled stimulators based on the principles of air-dilution olfactometry. Data were analyzed in two different approaches according to the relatively short or long inter-stimulus interval. A decreased peak amplitude or a prolonged latency was considered as an expression of adaptation. RESULTS: The majority of participants (88%) responded reliably to chemosensory stimulation. Patients with olfactory loss exhibited pronounced olfactory and trigeminal adaptation within the long-term design, without such effects in healthy controls. Odor sensitivity correlated with both olfactory and trigeminal amplitude changes: the worse the olfactory sensitivity, the more pronounced chemosensory adaptation. CONCLUSIONS: The results help to explain the patients’ complaints in terms of the fast adaptation towards chemosensory stimuli, for example during eating and drinking. The differences in adaptation in patients with olfactory loss and healthy controls could serve as a clinical criterion to gauge olfactory dysfunction.

Variations of olfactory function with circadian timing and chronotype.

BACKGROUND: Cumulative animal studies have suggested that olfaction can be regulated by circadian clock. However, human studies on the topic are relatively limited. The present study thus aimed to investigate diurnal variation in olfaction in healthy adults while examining potential modulating factors. METHODS: We conducted four rounds of testing on 56 healthy adults (32 women) aged 31 ± 12 years, throughout a single day, during morning (8:00-10:00 h), noon (12:00-14:00 h), afternoon (16:00-18:00 h), and evening (20:00-22:00 h). At the first appointment, participants completed full olfactory function testing using the Sniffin’ Sticks, questionnaires on medical history, nasal symptoms, sleep quality, and chronotype, and were assessed for blood pressure, heart rate, peak nasal inspiratory flow (PNIF), attention level, and rated their smell ability, nasal patency, wakefulness, and concentration level using visual analog scale (VAS) ratings. Subsequent appointments measured olfactory threshold, attentional level, PNIF, blood pressure, heart rate and VAS ratings repeatedly. RESULTS: Olfactory threshold (OT) scores varied significantly between different times of the day, with the highest score in the evening and the lowest in the morning. Similar differences were also observed in PNIF, with the highest value in the evening and the lowest in the morning. However, there were no significant correlations between OT score and PNIF across all four-time testing, as well as between differences in [OT evening â€" OT morning] and [PNIF evening â€" PNIF morning]. Furthermore, a generalized linear mixed model indicated that the testing time of the morning, evening chronotype, self-reported body mass index (BMI), rated smell ability, and rated nasal patency significantly predicted the Sniffin' Sticks OT score. CONCLUSIONS: Olfactory function fluctuates throughout the waking hours of the day, with the highest olfactory sensitivity observed in the evening and the lowest in the morning. This pattern is also seen in nasal patency. However, it appears that the circadian changes of nasal airflow may not significantly depend on the circadian changes of the olfactory sensitivity. In addition, chronotype and BMI may regulate such olfactory-circadian variation. These findings provide important insights for future research on the accurate diagnosis and treatment of olfactory dysfunction.

Intranasal insulin's effects on the sense of smell.

Intranasal insulin (IN) administration is a promising way to deliver the peptide to the central nervous system (CNS), bypassing the blood-brain-barrier and gastrointestinal absorption inhibition. IN receptors are localized in the olfactory mucosa and the brain, mainly in the olfactory bulb, hypothalamus, hippocampus, amygdala, cerebral cortex, and cerebellum. The pleiotropic mechanism of insulin action is characterized by its anti-inflammatory properties, antithrombotic, vasodilatory, and antiapoptotic effects. It prevents energy failure and has regenerative properties, affects neuro-regeneration and counteracts insulin resistance. Hence, insulin has been suggested for various pathological states including neurocognitive disorders, obesity, and as a therapeutic option for smell loss. A sharply increased prevalence of olfactory dysfunction was observed due to the COVID-19 pandemic. The pandemic also emphasized the lack of therapeutic options for smell loss. Intranasal insulin administration has therefore been suggested to serve as potential treatment, influencing the regenerative capacities of the olfactory mucosa. This narrative review summarizes current knowledge on possible effects of intranasal insulin on the sense of smell.

Olfactory stimulation may modulate the sensation of nasal patency.

BACKGROUND: The sensation of nasal patency can be induced by inhaling menthol, which predominantly produces trigeminal stimulation. It remains unclear whether olfactory stimulation can also induce or modulate the sensation of nasal patency. METHODOLOGY: A total of 118 participants (normosmia: n=67, olfactory dysfunction: n=51) were exposed to four odors in a randomized order: 1) phenylethanol (PEA), 2) menthol, 3) a mixture of PEA and menthol, 4) nearly odorless propylene glycol. The odors were presented by nasal clips. After the nasal clip had been removed, the participants rated relative nasal patency (RNP) from - 50 to +50, and their peak nasal inspiratory flow (PNIF) was measured. Repeated measures analysis of variance was used to examine the difference of RNP and PNIF among the four conditions and the influence of olfactory function. RESULTS: The RNPs, other than PNIFs, differed between the four conditions. Menthol induced the highest RNP, followed by the mixed solution, PEA and the odorless condition. Normosmic participants, but not those with olfactory dysfunction, responded to PEA significantly higher than odorless condition with regard to RNP. The correlation analysis showed that the better the subjective or measured olfactory performance, the greater the PEA-induced sensation of nasal patency. CONCLUSIONS: A specific olfactory stimulant that selectively induces olfactory perception can also evoke and modulate the sensation of nasal patency. Hence, patients might benefit from exposing themselves to odors in order to relieve the annoying nasal obstruction.

Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative.

STATEMENT OF PROBLEM: Evaluating the effectiveness of the management of Olfactory Dysfunction (OD) has been limited by a paucity of high-quality randomised and/or controlled trials. A major barrier is heterogeneity of outcomes in such studies. Core outcome sets (COS) - standardized sets of outcomes that should be measured/reported as determined by consensus-would help overcome this problem and facilitate future meta-analyses and/or systematic reviews (SRs). We set out to develop a COS for interventions for patients with OD. METHODS: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed patients and healthcare practitioners to individually rate the outcomes in terms of importance on a 9-point Likert scale. RESULTS: After 2 rounds of the iterative eDelphi process, the initial outcomes were distilled down to a final COS including subjective questions (visual analogue scores, quantitative and qualitative), quality of life measures, psychophysical testing of smell, baseline psychophysical testing of taste, and presence of side effects along with the investigational medicine/device and patient's symptom log. CONCLUSIONS: Inclusion of these core outcomes in future trials will increase the value of research on clinical interventions for OD. We include recommendations regarding the outcomes that should be measured, although future work will be required to further develop and revalidate existing outcome measures.

Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency, and generalisability of work in this field.

Optimization of mRNA extraction from human nasal mucosa biopsies for gene expression profile analysis by qRT-PCR.

Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) is the gold-standard method for analyzing modifications in gene expression in cells and tissues. However, large quantities of high-quality RNA samples are needed for analyzing the expression of multiple genes from one human tissue sample. Here, we provide an optimized protocol for extracting large amounts of RNA from human nasal mucosal biopsies. The quality and quantity of samples were sufficient for qRT-PCR analyses of the expressions of various genes, in duplicate. In contrast to other protocols, we optimized RNA isolation to increase the amount from nasal biopsy samples for analyses of multiple genes. In most previous publications, expressions of only one or a few genes, including housekeeping genes, were analyzed because the amount of biological material was small. We were able to improve our protocol with respect to the yield and quality of RNA. This is likely to produce better results from molecular analyses of very small biopsy samples of human nasal mucosa.

Future therapeutic strategies for olfactory disorders: electrical stimulation, stem cell therapy, and transplantation of olfactory epithelium-an overview.

Olfactory disorders may be temporary or permanent and can have various causes. Currently, many COVID-19 patients report a reduced or complete loss of olfactory function. A wide range of treatment options have been investigated in the past, such as olfactory training, acupuncture, medical therapy, transcranial magnetic stimulation, or surgical excision of olfactory epithelium, e.g., in severe qualitative smell disorders. The development of a bioelectric nose, e.g., in connection with direct electrical stimulation or transplantation of olfactory epithelium or stem cells, represent treatment options of the future. The basis of these developments and the state of knowledge is discussed in the following work.

Olfactory Function and Olfactory Disorders. / Riechen und Riechstörungen.

The sense of smell is important. This became especially clear to patients with infection-related olfactory loss during the SARS-CoV-2 pandemic. We react, for example, to the body odors of other humans. The sense of smell warns us of danger, and it allows us to perceive flavors when eating and drinking. In essence, this means quality of life. Therefore, anosmia must be taken seriously. Although olfactory receptor neurons are characterized by regenerative capacity, anosmia is relatively common with about 5 % of anosmic people in the general population. Olfactory disorders are classified according to their causes (e. g., infections of the upper respiratory tract, traumatic brain injury, chronic rhinosinusitis, age) with the resulting different therapeutic options and prognoses. Thorough history taking is therefore important. A wide variety of tools are available for diagnosis, ranging from short screening tests and detailed multidimensional test procedures to electrophysiological and imaging methods. Thus, quantitative olfactory disorders are easily assessable and traceable. For qualitative olfactory disorders such as parosmia, however, no objectifying diagnostic procedures are currently available. Therapeutic options for olfactory disorders are limited. Nevertheless, there are effective options consisting of olfactory training as well as various additive drug therapies. The consultation and the competent discussion with the patients are of major importance.

Assessment of Taste Function.

Taste disorders, impacting well-being and physical health, can be caused by many etiologies including the use of medication. Recently, taste disturbance is also considered as one of the predominant symptoms of COVID-19 although its pathogenesis requires further research. Localized taste disorders may be overlooked considering that whole-mouth taste perception is insured through several mechanisms. Individuals often fail to discern taste from flavor, and interviews/surveys are insufficient to properly assess taste function. Hence, various taste assessment methods have been developed. Among them, psychophysical methods are most widely applied in a clinical context. Less-biased electrophysiological, imaging, or morphological methods are used to a much lesser degree. Overall, more research is needed in the field of taste.

Omega-3 supplementation in postviral olfactory dysfunction: a pilot study.

BACKGROUND: This study aimed to examine whether omega-3 supplementation would support olfactory recovery among postviral olfactory dysfunction patients. METHODOLOGY: Patients with postviral olfactory dysfunction were included in this non-blinded, prospective pilot study. Structured medical history was taken from the patients, including the following: age, sex, history of COVID-19 infection, and duration of symptoms. Patients were randomly assigned to receive olfactory training only (control group) versus olfactory training with omega-3 supplementation (treatment group). All patients exposed themselves twice a day to four odours (phenyl ethyl alcohol [rose], eucalyptol [eucalyptus], citronellal [lemon], and eugenol [cloves]). Olfactory function was measured before and after training using 'Sniffin' Sticks', comprised of tests for odour threshold, discrimination, and identification. The average interval between olfactory tests was 3 months. RESULTS: Fifty-eight patients were included in the study, 25 men and 33 women. Generally, an improvement in olfactory scores was observed. Compared to the control group, the improvement in odour thresholds was more pronounced in the omega-3 group. Age, sex, and duration of symptoms had no effect on olfactory scores among both control and treatment groups. CONCLUSION: Overall, the present results indicate that omega-3 supplementation may be an option for adjunct therapy with olfactory training in patients with postviral olfactory dysfunction.

Reliability and validity of a brief version of the Questionnaire of Olfactory Disorders (brief QOD) in patients with olfactory dysfunction.

BACKGROUND: The aim of this study was to determine the reliability and validity of the brief version of Questionnaire of Olfactory Disorders (brief QOD). METHODS: A total of 372 patients participated in this study. Olfactory function was examined using the Sniffin' Sticks test. The brief version of QOD, including 4 items concerning parosmia (QOD-P), 7 items concerning quality of life (QOD-QOL), and 3 visual analog scales to rate disease burden, awareness of the disorder and issues related to professional life (QOD-VAS), was used to assess subjective information on olfactory dysfunction. We evaluated the split-half reliability, internal consistency and validity of the brief QOD. RESULTS: The split-half reliability was 0.60 (QOD-P), 0.87 (QOD-QOL), and 0.66 (QOD-VAS), respectively. The Cronbach's coefficient was 0.63 (QOD-P), 0.87 (QOD-QOL), and 0.71 (QOD-VAS), respectively. Olfactory function was found to be associated with QOD-P, QOD-QOL and QOD-VAS. CONCLUSIONS: The brief QOD is a suitable scale for the assessment of subjective severity of olfactory dysfunction for purposes such as treatment counseling, disability assessment, treatment control, and research in patients with olfactory disorder.

Smell, taste and trigeminal function: similarities and differences between results from home tests and examinations in the clinic.

BACKGROUND: This study aimed to examine an easy-to-conduct home chemosensory test as a screening tool prior to clinical testing and to investigate the associations between home and clinical tests. METHODS: We examined 200 participants who performed a chemosensory test including subjective ratings as well as psychophysical smell, taste and trigeminal function tests at their homes. Following that, they were invited to the clinic for standardized testing using the Sniffin sticks test for assessment of olfactory function, taste sprays and strips for taste function, and a lateralization test for trigeminal function. RESULTS: The home smell test correlated well with the Sniffin sticks test. The home test had acceptable sensitivity for detecting smell loss (sensitivity of 67% at a specificity of 92%). The home test could distinguish between patients with olfactory loss and healthy controls. In contrast, the home tests for taste and trigeminal function did not provide valid results. When comparing home and clinical smell and taste tests older age and olfactory loss were the most influencing confounders in various models, while participants who had olfactory loss and admitted to drink alcohol regularly were more likely to have consistency between home and clinical smell measurements. CONCLUSIONS: Although the standardized psychophysical tests are valid and reliable and should be recommended, simple methods used at home could reflect the patients' information to some degree and provide useful data prior to clinical testing. The present home chemosensory test allows motivated individuals to screen their olfactory function in a simple way at home. Results from smell tests, but not from tests of taste or trigeminal function, obtained at home correlate with tests obtained at the clinic. Moreover, tests conducted at home or in the clinic have confounders that should be considered by researchers and clinicians.

Gendered differences in relative ACE2 expression in the nasal epithelium.

Gendered differences in relative ACE2 expression in the nasal epithelium.