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.

The role of peak nasal and oral inspiratory flow in the evaluation of patients with sleep-related breathing disorders.

BACKGROUND: Sleep-related breathing disorders (SRBD) are common reported disorders in the adult population. The nose plays an important role in the development of SRBD; thus, the measurement of nasal respiratory function remains an important step in the management of these patients. Peak nasal inspiratory flow (PNIF) is a useful tool to assess nasal airflow and it has recently been studied together with peak oral inspiratory flow (POIF). OBJECTIVE: The aim of the present study was to evaluate the role of PNIF and POIF in an adult population of patients affected by SRBD. METHODOLOGY: Seventy consecutive adult patients with SRBD were included in the present study. All patients were evaluated with home-based sleep studies (type III), PNIF, POIF, SNOT-22 questionnaire, Epworth Sleepiness Scale test and VAS for nasal obstruction. RESULTS: Although PNIF and POIF showed to correlate with each other, no correlations were observed between Apnea Hypopnea index (AHI) and PNIF, POIF or NPI (PNIF/POIF). A further analysis showed a marginal correlation between SNOT- 22 and AHI and between SNOT-22 and POIF. Furthermore, in a multivariate analysis, also POIF marginally correlated with some of the sleep- related SNOT-22 items. CONCLUSIONS: In the present study neither PNIF nor POIF were found to be associated with OSAS severity. However, POIF values correlated better than PNIF with sleep related symptoms suggesting that POIF could be a more useful parameter for upper airway assessment in patients with SRBD. In addition, a correlation between OSAS severity, in terms of AHI, and SNOT-22 total score has been reported.

Olfactory and rhinological evaluations in SARS-CoV-2 patients complaining of olfactory loss.

Since December 2019, a novel coronavirus SARS-CoV-2 (Covid-19) outbreak emerged in China and spread rapidly in several countries. As of April 5, 2020, 1.218.474 cases were confirmed with 65.884 deaths worldwide (1). The clinical manifestations of Covid-19 range from asymptomatic carrier status to severe pneumonia. In a study of 7,736 Covid-19 patients in China, of all the clinical symptoms, hyposmia was not reported in any patient(2). Anyway, it is now clear that olfactory dysfunction may also be present in these patients(3) as the only or prevalent manifestation(4).

European position paper on diagnostic tools in rhinology.

The accurate diagnosis of rhinologic disease depends on the clinical history, examination findings and, in many cases, further investigations. There are a wide variety of diagnostic tests available, the choice of which depends upon the condition being assessed. This position paper is intended to provide an up-to-date comprehensive description of the diagnostic tools available to rhinologists, allergists, general otolaryngologists and other physicians with an interest in sinonasal disease. The literature has been reviewed and evidence-based recommendations are included. The relevant history and examination techniques are described, including endoscopic assessment of the nose. General and disease-specific quality of life instruments are an important tool in assessing the impact of rhinologic disease and the response to treatment. Relevant blood tests are discussed, as well as the various methods of allergy testing. Techniques for collecting microbiological and tissue samples are described, as well as the use of more specialised tests such as nasal nitric oxide and those evaluating ciliary structure and function. Imaging techniques and their indications are included. Chemosensory (smell and taste) testing is explained, and the available techniques for objective measurement of nasal airflow and patency are reviewed. Prompt and accurate diagnosis allows appropriate management to be initiated; an understanding of the currently available diagnostic tools is a vital part of the assessment of rhinologic disease.

Nasal function before and after rapid maxillary expansion in children: A randomized, prospective, controlled study.

OBJECTIVES: Children can well detect and respond to odours in order to have information about food and environment. Rapid Maxillary Expansion seems to improve dental and skeletal crossbite and increase nasal patency correcting oral respiration in children. A previous pilot study suggested that Rapid Maxillary Expansion may lead to improved N-Butanol olfactory thresholds, and peak nasal inspiratory flow values (PNIF). The aim of the present study was to prospectively evaluate olfactory threshold, nasal flows and nasal resistances in children aged from 6 to 11 years before and after Rapid Maxillary Expansion, comparing treated children with a control group of similar age, growth stage (prepubertal) and transversal skeletal deficiency. METHODS: N-butanol olfactory thresholds, anterior active rhinomanometry (AAR) and PNIF were measured in 11 children (6-11 years) before (T0), immediately and 6 months after Rapid Maxillary Expansion application (T1 and T2 respectively), and in a control group of 11 children (6-11 years) whose members remained under observation for the period of the study. RESULTS: Considering the study group, PNIF values improved at T1 respect to the T0 values (p = 0.003), while T2 values were significantly higher than T0 ones (p = 0.0002). N-Butanol Olfactory Threshold significantly improved at each control (p = 0.01, p = 0,01 and p = 0.0003, for T1 vs T0, T2 vs T1, T2 vs T0 respectively). No differences on AAR values were found during the six months follow-up in this group. Considering the control group, no significant differences were found for any of the considered variables during the time of the study. Comparing the two groups, there was a significant increase of PNIF values in the study group compared to the control group (p = 0.003) at T1, which was even more evident six months after Rapid Maxillary Expansion (p = 0.0005). This improvement was not shown by AAR values. N-Butanol Olfactory Threshold showed a significant improvement at T2 respect to T1 (p = 0.002) and T0 (p = 0.0005). CONCLUSION: Rapid Maxillary Expansion seems to significantly improve the respiratory capacity of treated patients, at least in terms of PNIF, and their olfactory function, measured by N-Butanol Olfactory Threshold Test. Further studies should be performed to evaluate if also changes in nasal resistances, measured by AAR, could occur, maybe considering a larger group of subjects and possibly using 4-phase rhinomanometry in order to evaluate the effective resistances during the entire breath.

Influence of number of drugs on olfaction in the elderly.

BACKGROUND: The etiology of age-related olfactory loss is still unclear, but it has been claimed that polypharmacotherapy may contribute to olfactory dysfunction, particularly in the elderly, who are more likely to need multiple drugs. The present pilot study investigated the relationship between smell and the number and type of drugs taken in a group of elderly. METHODOLOGY: 50 elderly volunteers (over 64 years old) who were healthy from the sinonasal standpoint (SNOT-22 under 1) and had no cognitive impairments [Mini Mental State Examination (MMSE over 18) were administered the Screening 12 test and tested on their n-butanol olfactory threshold. Their olfactory performance was then connected with the number and type of drugs participants used. RESULTS: The mean age of the included volunteers was 74 plus/minus 7 years. No association emerged between odor identification and number of drugs taken. The number of drugs taken correlated directly with a worse olfactory threshold and with a worse MMSE score, meaning a worse cognitive status. Odor identification significantly worsened with age. Comparing those volunteers taking only one drug known to not influence olfaction with another sub-group of volunteers taking five or more drugs, it was evident that subjects taking only one drug scored significantly better in olfactory threshold test and MMSE, and marginally better in olfactory identification test. For what concerns the difference between male and female volunteers, no difference in olfactory test result was shown, both for threshold and identification. Univariate analysis showed a direct correlation between the consumption of calcium channel blockers, beta-blockers, acetylsalicylic acid and olfactory threshold, meaning a worse sense of smell. Acetylsalicylic acid also correlated inversely with odor identification, meaning again a worse sense of smell, and so did potassium-sparing diuretics. Multivariate analysis showed that MMSE scores correlated with a better sense of smell, that is a lower olfactory threshold, and that beta-blockers and acetylsalicylic acid negatively affected olfactory threshold, meaning a worse sense of smell. Acetylsalicylic acid also correlated inversely with odor identification, meaning again a worse sense of smell. CONCLUSIONS: The number of drugs taken demonstrated to be significantly correlated with a worse olfactory threshold and worse MMSE. Larger studies on elderly volunteers are needed to confirm these preliminary findings.

Comparison between unilateral PNIF and rhinomanometry in the evaluation of nasal cycle.

BACKGROUND: Human unilateral nasal airflow shows spontaneous changes over a period of hours due to the alternating congestion and decongestion of the venous sinuses within the nasal turbinates and nasal septum. The aim of the present study was to compare PNIF and unilateral PNIF with nasal resistances measured by means of AAR in the evaluation of the nasal cycle. METHODS: PNIF, unilateral PNIF and AAR measurements were randomly performed in 20 non-smokers, non-asthmatic volunteers, with a SNOT 22 score lower than 1. Nasal measurements were done four times in a single day at 08.30, 11.00, 13.30 and 16.00. The correlation between PNIF, unilateral PNIF and nasal resistances was studied. The pattern of nasal airflow for each subject was also analyzed. RESULTS: A significant negative correlation between PNIF-lPNIF-rPNIF and respectively AAR-lAAR-rAAR was found. Only 1 subject did not show nasal cycle, while all the rest were equally distributed between a reciprocal pattern of the nasal cycle, or an in-phase changes of the nasal cycle, both at PNIF and AAR. CONCLUSIONS: Nasal cycle can be easily assessed by means of PNIF. In fact, AAR and PNIF showed a reasonable correlation in the measurement of nasal cycle, although PNIF offered a lower variability. Reciprocal and in-phase patterns of the nasal cycle were equally distributed in our population.

Botulinum toxin therapy: functional silencing of salivary disorders.

Botulinum toxin (BTX) is a neurotoxic protein produced by Clostridium botulinum, an anaerobic bacterium. BTX therapy is a safe and effective treatment when used for functional silencing of the salivary glands in disorders such as sialoceles and salivary fistulae that may have a post-traumatic or post-operative origin. BTX injections can be considered in sialoceles and salivary fistulae after the failure of or together with conservative treatments (e.g. antibiotics, pressure dressings, or serial aspirations). BTX treatment has a promising role in chronic sialadenitis. BTX therapy is highly successful in the treatment of gustatory sweating (Frey's syndrome), and could be considered the gold standard treatment for this neurological disorder.

Left ventricular hypertrophy does not prevent heart failure in experimental hypertension.

BACKGROUND: Left ventricular hypertrophy (LVH) secondary to hypertension has been accepted to prevent heart failure (HF) while paradoxically increasing cardiovascular morbi-mortality. OBJECTIVES: To evaluate whether antihypertensive treatment inhibits LVH, restores beta-adrenergic response and affects myocardial oxidative metabolism. METHODS: Ninety spontaneously hypertensive rats (SHR) were distributed into groups and treated (mg/kg, p.o.) with: losartan 30 (L), hydralazine 11 (H), rosuvastatin 10 (R), carvedilol 20 (C). Hypertension control group comprised 18 normotensive rats (Wistar-Kyoto, WKY). Following euthanasia at 16months, contractility was measured in 50% of rats (Langendorff system) before and after isoproterenol (Iso) 10-9M, 10-7M and 10-5M stimulation. Left ventricular weight (LVW) was measured in the remaining hearts, and normalized by BW. Expression of thioredoxin 1 (Trx-1), peroxyredoxin 2 (Prx-2), glutaredoxin 3 (Grx-3), caspase-3 and brain natriuretic peptide (BNP) was determined. RESULTS: Systolic blood pressure (mmHg): 154±3 (L), 137±1 (H), 190±3 (R)*, 206±3 (SHR)*, 183±1 (C)**, and 141±1 (WKY) (*p<0.05 vs. L, H, WKY, **p<0.05 vs. L, H, WKY, SHR). LVW/BW was higher in SHR and R (p<0.05). Groups SHR, R and C evidenced baseline contractile depression. Response to Iso 10-5M was similar in WKY and L. Expression of Trx-1, Prx-2 and Grx-3 increased in C, H, R and L (p<0.01). CONCLUSIONS: Present findings argue against the traditional idea and support that LVH might not be required to prevent HF. Increased expression of thioredoxins by antihypertensive treatment might be involved in protection from HF.

Position paper on olfactory dysfunction.

Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: • Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. • Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. • Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. • Comprehensive chemosensory assessment should include gustatory screening. • Smell training can be helpful in patients with olfactory loss of several aetiologies. Conclusions: We hope the current manuscript 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.

Measurements of nasal airflow and patency: a critical review with emphasis on the use of peak nasal inspiratory flow in daily practice.

Objective measures can be used to assist the clinician to diagnose and treat nasal obstruction and also to quantify nasal obstruction in research. Objective measurements of nasal obstruction are as important as objective measurements of lung function. peak nasal inspiratory flow (PNIF), acoustic rhinometry (AR) and rhinomanometry (RM), with their specific peculiarity, assess different aspects of nasal obstruction. From the studies available in the literature, it seems that these methods roughly correlate with each other and that all of them can be alternatively utilized very well in research as well as in clinical practice. This review describes the various methods that can be used to measure nasal patency, airflow and resistance, mainly peak nasal inspiratory flow, rhinomanometry and acoustic rhinometry. PNIF has been demonstrated to be reproducible and as good an indication of objective nasal patency as formal rhinomanometry and has the advantage to be cheap, simple and suitable for serial measurements and for home use even in the paediatric population. PNIF normative data are available for children, adults and elderly subjects, and the availability of unilateral PNIF normal values allows evaluation of nasal sides separately. Just as in the lower airways, objective and subjective evaluation gives different information that together optimizes the diagnosis and the treatment of our patients. We argue that PNIF should be used regularly in every outpatient clinic that treats patients with nasal obstruction.

Position paper on olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript 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.

Brain anatomical substrates of mirror movements in Kallmann syndrome.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

The eminent anatomists who discovered the upper oesophageal sphincter.

OBJECTIVE: To discover the anatomist who first identified the upper oesophageal sphincter. METHOD: The authors searched dozens of antique anatomy textbooks kept in the old section of the 'Vincenzo Pinali' Medical Library of Padua University, looking for descriptions of the upper oesophageal sphincter. RESULTS: The oesophageal sphincter was drawn correctly only in 1601, by Julius Casserius, in the book De vocis auditusque organis historia anatomica… (which translates as 'An Anatomical History on the Organs of Voice and Hearing …'), and was properly described by Antonio Maria Valsalva in 1704 in the book De aure humana tractatus… ('Treatise on the Human Ear …'). CONCLUSION: Anatomists Casserius and Valsalva can be considered the discoverers of the 'oesophageal sphincter'.

N-butanol olfactory threshold and nasal patency before and after palatal expansion in children. A preliminary study.

OBJECTIVES: Olfaction is based on the function of the nasal olfactory receptors. Children can well detect and respond to odors in order to have information about food and environment. Rapid maxillary expansion seems to improve dental class and increase nasal patency correcting oral respiration in children. Nevertheless, there are no studies demonstrating that expansion in pediatric patients could influence olfactory sensitivity. The aim of this study was to evaluate olfactory threshold and nasal patency in children aged from 6 to 12 years before and after rapid maxillary expansion. METHOD: N-butanol olfactory thresholds, anterior active rhinomanometry, and peak nasal inspiratory flow were measured in 12 children (6-12 years) before (T0), 20 days (T1), and 6 months after rapid maxillary expansion application (T2). RESULTS: A significant lower olfactory threshold was found comparing T2 and T0 N-butanol olfactory threshold values (p=0.038). Peak nasal inspiratory flow showed a significant improvement both at T1 and T2, with respect to T0 values (p=0.043 and p=0.0001, respectively). T2 nasal resistances showed a trend towards a significant reduction when compared with T1 values (p=0.15). CONCLUSION: This pilot study suggested that rapid maxillary expansion may lead to improved N-butanol olfactory thresholds, at least 6 months after palatal expansion. Furthermore, rapid maxillary expansion seems to improve peak nasal inspiratory flow values, and finally although with lower sensitivity, reduce nasal resistances as measured by rhinomanometry.

Comparison between unilateral PNIF and rhinomanometry in healthy and obstructed noses.

AIMS: Peak Nasal Inspiratory Flow (PNIF) is an easy method to assess nasal patency. Normative unilateral PNIF data in adults have been proposed. The study purpose was to compare PNIF and unilateral PNIF values to total and unilateral nasal resistances measured by anterior active rhinomanometry (AAR) in subjects with and without nasal obstruction to see whether unilateral PNIFis sensitive to detect nasal obstruction. METHODS AND RESULTS: Measurements of PNIF, unilateral PNIF and AAR were performed in 125 volunteers. Seventy of them were healthy subjects not complaining of nasal symptoms and entered into the study as the'normal' group. The other group consisted of fifty-five symptomatic subjects.Data were analysed to show the correlation between PNIF, unilateral PNIF and nasal resistances. The ability of PNIF and AAR in predicting pathologies were compared by receiver operating characteristic (ROC) analysis indicating that PNIF and AAR have a similar and significant power to discriminate pathologic from healthy subjects. CONCLUSION: The measurement of unilateral PNIF could be a helpful method to support the diagnosis of nasal blockage also in those cases with single nostril obstruction, but, in cases of doubt, AAR should also be performed to improve diagnostic accuracy.

Case report of cholesteatoma recurrence with Bezold's abscess presenting as a deep neck infection.

Cervical masses are a common clinical finding, but differential diagnosis is often challenging. Acute neck swellings are often due to deep cervical space infections that have originated at oral or oropharyngeal sites. Deep neck infections originating elsewhere are not rare; however, they are difficult to diagnose, and their origins remain obscure in 20% of cases. Neck swellings that originate in the middle ear are very rare, with only a few reported in the scientific literature. Here we report an atypical case of Bezold's abscess caused by the recurrence of a middle ear cholesteatoma. In patients with neck swelling and a history of primary cholesteatoma of the middle ear, otolaryngologists should consider regional recurrence of disease a possibility even several years after the primary surgery.

The superior laryngeal nerve injury of a famous soprano, Amelita Galli-Curci.

The superior laryngeal nerve (SLN) has been attributed much less clinical significance than the recurrent laryngeal nerve. It has sometimes been described as the 'neglected' nerve in thyroid surgery, although injury to this nerve can cause significant disability. The external branch of the SLN is the only motor supply to the cricothyroid muscle, which increases the tension of the ipsilateral vocal fold during highfrequency phonation, particularly in women and voice professionals. Damage to this nerve can manifest as ipsilateral cricothyroid muscle paralysis, and clinical symptoms may include a hoarse, breathy voice, frequent throat clearing, vocal fatigue or diminished vocal frequency range, especially when rising pitch. SLN paralysis can be a significant issue for those whose careers depend largely on a full range of voice. The famous opera soprano, Amelita Galli-Curci, suffered SLN injury during thyroid surgery with distressing consequences.

Human olfactory sensitivity for bourgeonal and male infertility: a preliminary investigation.

Olfactory receptor (OR) expression is also present in the sperm cells and could mediate sperm chemotaxis. OR1D2 was the first OR expressed in the testis demonstrated to be involved in chemotaxis and to be expressed also in the nose with a similar behavior. Bourgeonal is the OR1D2 most potent known agonist. Infertility affects ~15 % of couples in western countries and sometimes it is unexplained. This pilot study compared the bourgeonal olfactory thresholds, the ability of sperm to sense the bourgeonal and the frequency of 13 single nucleotide polymorphisms (SNPs) of OR1D2 gene in nine males suffering of unexplained infertility with a control group of 15 healthy males. The mean olfactory threshold for bourgeonal was statistically different between the study group (10.5 ± 3.7; median 12.3) and the control group (14.0 ± 2.8; median 15.5) (p = 0.006). Statistical analysis showed a significantly higher percentage of spermatozoa that migrated toward the capillaries filled with bourgeonal in the control group compared to the study group (p < 0.0001). Sperm migration was equally inhibited in both groups of subjects when, together with bourgeonal, capillaries were filled with undecanal, a strong bourgeonal inhibitor (p = 0.42). The 13 SNPs of OR1D2 revealed a statistically significant difference for allele and genotype frequency of rs769423 in study group versus control group (p = 0.02). The present preliminary study seems to confirm the important role of OR1D2 both in nose and spermatozoa and may explain the idiopathic infertility of the study group. Further studies on larger series are mandatory to confirm our preliminary evidence.