Mood Impairment in Patients with Olfactory Loss Predicts a More Pronounced Recovery of Olfactory Function.

BACKGROUND: Here, we refer to our publication "Symptoms of depression change with olfactory function" [Sci Rep. 2022 Apr 5;12(1):5656]. OBJECTIVES: Depression decreases with olfactory improvement, but the question remains open of whether patients who indicate more suffering regarding mood impairment exhibit a different pattern of recovery from olfactory loss compared to those who suffer less. METHOD: In the course of an additional investigation of our previously published dataset, we established groups of participants (N = 171) with low (≤8 points on a depression [ADSL] scale; 47%; n = 45) and high (≥14 points on ADSL scale; 53%; n = 53) mood impairment. RESULTS: We found that the group that reported more sufferance on a depression [ADSL] scale improved more in change of olfactory function, and, more importantly, odor discrimination change over a period of an average of 11 months. CONCLUSION: Patients, who suffered more, as indicated by higher scores on ADSL scale, may have been more willing to commit to the study protocol, and thus their improvement was more notable.

Palmitoylethanolamide and Luteolin for Postinfectious Olfactory Disorders: How Clinically Meaningful Is Its Effect?

INTRODUCTION: The prevalence of post-viral olfactory dysfunction has increased significantly during the COVID-19 pandemic, posing a major challenge for patients and practitioners. While olfactory training (OT) is a common approach to therapy, there has been increasing interest in supplementing therapy with a combination of palmitoylethanolamide (PEA) and luteolin (LUT), which are known for their anti-inflammatory properties. In this study, their efficacy in the treatment of patients with olfactory loss following upper respiratory tract infections, mainly COVID-19, was investigated in an outpatient clinic. METHODS: Fifty patients with persistent olfactory dysfunction were randomized to two groups: one receiving OT and PEA-LUT, the other OT alone. Olfactory function was evaluated before and after treatment. RESULTS: The study group showed significant improvements in odor discrimination and overall olfactory function (TDI score) after treatment with PEA-LUT and OT, while the control group did not. However, when clinically meaningful improvements were considered, there was no significant difference between the groups. CONCLUSION: The present study suggests that while PEA-LUT may have the potential to improve olfactory function in post-viral dysfunction, the additional benefit over OT alone may be limited. These results contrast with some previous studies.

Loss of olfactory sensitivity is an early and reliable marker for COVID-19.

Detection of early and reliable symptoms is important in relation to limiting the spread of an infectious disease. For COVID-19, the most specific symptom is either losing or experiencing reduced olfactory functions. Anecdotal evidence suggests that olfactory dysfunction is also one of the earlier symptoms of COVID-19, but objective measures supporting this notion are currently missing. To determine whether olfactory loss is an early sign of COVID-19, we assessed available longitudinal data from a web-based interface enabling individuals to test their sense of smell by rating the intensity of selected household odors. Individuals continuously used the interface to assess their olfactory functions and at each login, in addition to odor ratings, recorded their symptoms and results from potential COVID-19 test. A total of 205 COVID-19-positive individuals and 156 pseudo-randomly matched control individuals lacking positive test provided longitudinal data which enabled us to assess olfactory functions in relation to their test result date. We found that odor intensity ratings started to decline in the COVID-19 group as early as 6 days prior to the test result date (±1.4 days). Symptoms, such as sore throat, aches, and runny nose appear around the same point in time; however, with a lower predictability of a COVID-19 diagnosis. Our results suggest that olfactory sensitivity loss is an early symptom but does not appear before other related COVID-19 symptoms. Olfactory loss is, however, more predictive of a COVID-19 diagnosis than other early symptoms.

Natural trajectory of recovery of COVID-19 associated olfactory loss.

IMPORTANCE: Prevalence of post-viral olfactory loss has increased dramatically due to the frequency and severity of olfactory dysfunction associated with infection by the SARS-CoV-2 virus. OBJECTIVE: To determine the trajectory of COVID-19 olfactory loss over a six-month period. A key secondary objective is to assess predictive factors associated with the recovery of olfaction. DESIGN: Longitudinal repeated-measures study that enrolled from May 5, 2020 to February 2, 2021, with the last date of data collection on June 15, 2021. SETTING: Barnes-Jewish HealthCare/Washington University School of Medicine facilities (Saint Louis, Missouri, USA). PARTICIPANTS: Individuals who tested positive for SARS-CoV-2 by real-time polymerase chain reaction on nasopharyngeal swab and indicated olfactory loss on COVID-19 screening questionnaire. Individuals were excluded if they had previously diagnosed history of olfactory loss, neurodegenerative disorders, <18 years of age, admitted to hospital service, unable to read, write, and understand English, or lacked computer or internet access. INTERVENTIONS/EXPOSURES: Watch and wait for spontaneous recovery. MAIN OUTCOME(S) AND MEASURE(S): Participants completed olfactory assessments every 30 days for six months. Each assessment consisted of the University of Pennsylvania Smell Identification Test (UPSIT), an objective "scratch-and-sniff" test, and Clinical Global Impressions (CGI), a subjective Likert rating scale. RESULTS: The mean age was 41 years old (SD = 16). 39 (80 %) were female and 42 (86 %) white. At baseline assessment of objective olfaction, 18 (36 %) participants had anosmia or severe hyposmia. Subjective, complete recovery at six months was 81 % (95 % CI 74 % to 88 %). Likelihood of recovery was associated with age <50 years (aHR = 8.1 (95 % CI 1.1 to 64.1)) and mild olfactory loss at baseline (UPSIT = 30-33 for males and 31-34 for females) (aHR 6.2 (95 % CI 1.2 to 33.0)). CONCLUSIONS AND RELEVANCE: The trajectory of olfactory recovery among adults with COVID-19 olfactory loss illustrated rapid recovery within 2-3 weeks of infection, and by six months 81 % had recovered based on self-report. Age <50 years old and mild severity of olfactory loss at baseline were associated with increased likelihood of recovery of olfaction. These findings can be used to inform shared decision-making with patients.

Olfactory Impairment and Close Social Relationships. A Narrative Review.

Olfactory impairment is one of the more unique symptoms of COVID-19 infection and has therefore enjoyed increased public attention in recent months. Olfactory impairment has various implications and consequences ranging from difficulty detecting dangerous pathogens to hindering social functioning and social behaviors. We provide an overview of how olfactory impairment can impact 3 types of close social relationships: family relationships, friendships, and romantic relationships. Evidence is divided into several categories representing potential mechanisms by which olfactory impairment can impact close social relationships: bonding disruptions, decreased social support, missed group-eating experiences, hygiene concerns, and altered sexual behaviors. We conclude with a discussion of emerging future research questions.

Sudden olfactory loss as an early marker of COVID-19: a nationwide Italian survey.

PURPOSE: The presence of many asymptomatic COVID-19 cases may increase the risks of disease dissemination, mainly for physicians. There are numerous reports on the frequent findings of sudden anosmia or hyposmia, before or at the same time of the typical COVID-19 symptoms onset. The aim of this study was to verify the association of olfactory impairment and COVID-19, providing a basis for subsequent research in the field of COVID-19 clinical heterogeneity. METHODS: We developed a 15-item online questionnaire on "Sudden Olfactory Loss (SOL) and COVID-19" that was administered during March 2020 to Italian general practitioners registered to a social media group. RESULTS: One hundred and eighty responses were received. SOL was identified as a significant sign of infection in COVID-19 patients, mainly aged between 30 and 40 years, even in the absence of other symptoms. SOL was present as an initial symptom in 46.7% of subjects, and in 16.7%, it was the only symptom. Among the COVID-19 confirmed cases, SOL occurred as the only symptom in 19.2% of patients. CONCLUSION: SOL could represent a possible early symptom in otherwise asymptomatic COVID-19 subjects. Subjects affected by SOL should be considered as potential COVID-19 cases. LEVEL OF EVIDENCE: 4.

Patient Experiences of Postinfectious Olfactory Dysfunction.

INTRODUCTION: To highlight the importance of the need for new treatment modalities, this study aimed to characterise the experience of patients with postinfectious olfactory dysfunction (PIOD) in terms of the treatment they received. METHODS: An online survey was hosted by the Norwich Clinical Trials Unit on the secure REDCap server. Members of the charity Fifth Sense (the UK charity that represents and supports people affected by smell and taste disorders) were invited to participate. RESULTS: There were 149 respondents, of whom 127 had identified themselves as having (or had) PIOD. The age range of respondents to the survey was 28-85 years, with a mean of 58 ± 12 years, with the duration of their disorder <5 years in 63% of cases. Respondents reported experiencing variable treatment with oral and/or intranasal steroids given typically (28%), often with no benefit, but with 50% receiving no treatment whatsoever; only 3% reported undertaking olfactory training. Over two-thirds of patients experience parosmia and, up to 5 years from the onset of the problem, were still actively seeking a solution. CONCLUSION: There appears to be a need to encourage greater use of guidelines for olfactory disorders amongst medical practitioners and also to develop more effective treatments for patients with PIOD, where there is clearly an unmet need.

Predictive Value of Sudden Olfactory Loss in the Diagnosis of COVID-19.

INTRODUCTION: Recent reports suggest that sudden smell loss might be a symptom of SARS-CoV-2 infection. The aim of this study was to investigate the frequency of olfactory loss in an outpatient population who presented to a coronavirus testing center during a 2-week period and to evaluate the diagnostic value of the symptom "sudden smell loss" for screening procedures. METHODS: In this cross-sectional controlled cohort study, 500 patients who presented with symptoms of a common cold to a corona testing center and fulfilled corona testing criteria completed a standardized diagnostic questionnaire which included the patients' main symptoms, time course, and an additional self-assessment of the patients' current smell, taste function, and nasal breathing compared to the level before the onset of symptoms. RESULTS: Out of the 500 patients, 69 presented with olfactory loss. Twenty-two of them subsequently tested positive for SARS-CoV-2. Only 12 out of the patients without olfactory loss tested positive, resulting in a frequency of 64.7% for the symptom "sudden smell loss" in COVID-19 patients. Compared to COVID-19 patients without smell loss, they were significantly younger and less severely affected. Changes in nasal airflow were significantly more pronounced in SARS-CoV-2 negative patients with olfactory complaints compared to the patients with smell loss who tested positive for SARS-CoV-2. By excluding patients with a blocked nose, the symptom "sudden smell loss" can be attested a high specificity (97%) and a sensitivity of 65% with a positive predictive value of 63% and negative predictive value of 97% for COVID-19. CONCLUSION: Considering the high frequency of smell loss in non-hospitalized COVID-19 patients, acute olfactory impairment should be recognized as an early symptom of the disease and should be tested for on a regular basis. In contrast to other acute viral smell impairment, COVID-19-associated smell loss seems to be only rarely accompanied by a severely blocked nose.

Olfactory loss is associated with reduced hippocampal activation in response to emotional pictures.

Emotional processing evolved within brain structures that were originally dedicated to olfactory function. Reduced olfactory function, absence of the olfactory bulb and the experimental removal of the olfactory bulb are associated with depressive behavior. Against this background, we hypothesized that olfactory dysfunction modifies the neural processing of non-olfactory emotion information. Using a functional magnetic resonance imaging design, we therefore tested whether people with and without impaired olfactory function differ in emotional perception and processing. Neural activity of 17 patients with acquired olfactory loss and 23 age- and sex-matched control participants were monitored in the MRI scanner, while they were presented with emotional and neutral pictures. Participants rated the valence and arousal for each picture after scanning. Patients showed reduced right hippocampal brain responses to emotional but not neutral pictures independent of their depressive symptoms. In addition, emotion-dependent activation in the hippocampus and insula was positively associated with the olfactory bulb (OB) volumes in healthy participants. Taken together, these findings suggest a disrupted neural processing of emotional pictures among patients with olfactory loss. This indicates a significant role of the neural olfactory trajectories for general emotion processing. Central emotion processing is reduced in olfactory disorders and relates to the OB volume in normosmic individuals.

Construction of an irreversible allergic rhinitis-induced olfactory loss mouse model.

Clinical data show that part of patients with sinonasal diseases suffered from olfactory dysfunction, especially with allergic rhinitis (AR) and chronic rhinosinusitis (CRS). However, the mechanisms responsible for AR-induced olfactory loss are still largely unknown. Because of the difficulty to obtain human olfactory mucosa, an AR-induced olfactory loss animal model needs to be constructed to clarify the mechanism. The AR mouse model was induced by intraperitoneal sensitizing with ovalbumin (OVA) followed by intranasal challenge lasted from 1 to 12 weeks. For groups with recovery, mice were housed for another 4-week long without any treatment after the last intranasal challenge. Olfactory function, olfactory receptor neurons (ORNs) density and leukocytes infiltration were examined at different time points. Olfactory loss occurs immediately after 1-week intranasal challenge and deteriorates almost to anosmia after 8th week, and after that olfactory loss become irreversible. Nasal inflammation induces significant infiltration of leukocytes into olfactory epithelium (OE), which negatively correlated with the density of ORNs and mouse olfaction in a time dependent manner. The neutrophilic subtype dominates in number amongst the total infiltrated leukocytes, indicating its pivotal role in nasal inflammation-induced olfactory dysfunction. In this study, we constructed a persistent AR-induced olfactory loss mouse model, losing the ability to recover from dysfunction if the disease duration more than eight weeks, which implies that timely treatments are necessary. Meanwhile, this mouse model could provide an easy and reliable system to clarify the mechanisms of AR-induced irreversible olfactory dysfunction.

Olfactory cleft evaluation: a predictor for olfactory function in smell-impaired patients?

OBJECTIVE: In this study, we introduce an extension of previous work by Soler et al. (Int Forum Allergy Rhinol 6(3):293-298, 2016) on a modified endoscopic scoring system of the Lund-Kennedy Score (focusing on the olfactory cleft) to evaluate its correlation with the olfactory function in patients with various smell disorders. STUDY DESIGN: A prospective cohort study. METHODS: Two-hundred and eighty-eight participants were included and categorized in five groups according to the cause of their olfactory disorder: (0) control, (1) idiopathic, (2) sino-nasal, (3) postinfectious and (4) post traumatic olfactory loss. Olfaction was evaluated using the "Sniffin' Sticks" test. The classical Lund-Kennedy scoring and a new olfactory cleft specific Lund-Kennedy scoring (OC-LK) were performed to evaluate mucosal changes. RESULTS: Significantly higher OC-LK scores on both sides were found in smell-impaired patients as compared to normosmic controls. When comparing the 4 groups, a significant difference of the OC-LK score were present between the sino-nasal and all other groups. Most importantly, significant negative correlations with strong effects were shown in the sino-nasal group between the OC-LK score and odor discrimination and odor identification. However, no such correlation emerged between the classical LK score and smell function. CONCLUSION: Olfactory cleft evaluation using the OC-LK score correlates with the olfactory function in patients with sino-nasal smell disorder. This diagnostic tool may reflect the underlying pathophysiological mechanism of sino-nasal smell loss, and therefore, should complement olfactory diagnostics in patients with sino-nasal smell disorder.

Cerebral metabolic changes related to clinical parameters in idiopathic anosmic patients during olfactory stimulation: a pilot investigation.

Idiopathic olfactory loss neural consequences have been studied especially by means of magnetic resonance imaging. Since other functional neuroimaging technique findings are lacking in the literature, present study used a validated 18F-2-fluoro-2-deoxy-D-glucose (FDG) functional positron emission tomography procedure under olfactory stimulation (OS) to assess brain changes in idiopathic anosmic patients (IAPs) in comparison with healthy subjects (HS). A voxel-based analysis between these groups was used to evaluate FDG uptake in the brain and perform a correlation analysis between metabolic responses and the Sniffin' stick test as well as intensity visuo-analogue scores and disease duration (DD). A significant relative decrease of glucose metabolism in the right and left frontal lobes, left insula, right parietal lobe, and left occipital, temporal and parietal lobes was found in IAPs during OS. The same condition resulted in a relative higher glucose metabolism in the right cerebellum in IAPs. Moreover, a negative correlation between DD and FDG uptake in the left temporo-parietal joint was found in IAPs. Such a correlation suggested a possible involvement of this area metabolic decrease in self-consciousness impairment, which is known to affect IAPs. Present preliminary functional results could be of interest to further deepen such neural impairments possibly useful for future perspective in pharmaceutical and rehabilitative protocols.

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.

Gray matter volume reduction of olfactory cortices in patients with idiopathic olfactory loss.

Idiopathic olfactory loss (IOL) is a common olfactory disorder. Little is known about the pathophysiology of this disease. Previous studies demonstrated decreased olfactory bulb (OB) volume in IOL patients when compared with controls. The aim of our study was to investigate structural brain alterations in areas beyond the OB. We acquired T1-weighted magnetic resonance images from 16 patients with IOL and from 16 age- and sex-matched controls on a 3T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. Psychophysical testing confirmed that patients had higher scores for Toyota and Takagi olfactometer and lower scores for Sniffin' Sticks olfactory test than controls (t = 46.9, P < 0.001 and t = 21.4, P < 0.001, respectively), consistent with olfactory dysfunction. There was a significant negative correlation between the 2 olfactory tests (r = -0.6, P = 0.01). In a volume of interest analysis including primary and secondary olfactory areas, we found patients with IOL to exhibit gray matter volume loss in the orbitofrontal cortex, anterior cingulate cortex, insular cortex, parahippocampal cortex, and the piriform cortex. The present study indicates that changes in the central brain structures proximal to the OB occur in IOL. Further investigations of this phenomenon may be helpful to elucidate the etiology of IOL.

Association Between Multisensory Impairment and Depression Among Older Adults: A Population-Based Analysis.

OBJECTIVE: In this study, we examine how impairments in vision, hearing, touch, and olfaction relate to depression in older adults, considering both individual and multisensory impairments (MSIs). STUDY DESIGN: Analysis of cross-sectional data from a longitudinal investigation involving black and white older adults aged 70 to 79 at enrollment. SETTING: We studied 1640 black and white participants in the Health ABC study using complete sensory evaluation data from years 3 to 5. METHODS: Our MSI assessment utilized data obtained for visual acuity, hearing perception, olfactory performance, and tactile function. We performed multivariable logistic regression analyses to examine the associations between the presence of individual and MSIs and depression which was defined as the presence of antidepressants prescribed for depression, or a Center for Epidemiological Studies Depression Scale score of greater than 10. RESULTS: We observed a possible dose-response relationship between the number of sensory impairments and depression. In adjusted models, when compared to no impairments, vision (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.09-1.93) and hearing impairments (OR = 1.49, 95% CI: 1.11-1.99) were significantly associated with depression, whereas olfaction (OR = 1.11, 95% CI: 0.83-1.47) and tactile impairments (OR = 1.28, 95% CI: 0.96-1.70) were not. Participants with 3 sensory impairments had a higher rate of depression (OR = 2.05, 95% CI: 1.22-3.54) compared to those without impairments, and this risk increased further for those with 4 sensory impairments (OR = 2.95, 95% CI: 1.48-5.88). CONCLUSION: The findings suggest that individuals with MSI represent a high-risk population for depression, warranting close monitoring to screen for depression. The study emphasizes the importance of considering multiple sensory impairments in the context of mental health and supports the early identification and monitoring of depression in this population.

Validity and reliability of the Questionnaire of Olfactory Disorders for Italian-speaking patients with olfactory dysfunction.

Objective: To translate and validate an Italian version of the Questionnaire of Olfactory Disorders (IT-QOD). Materials and methods: This is a prospective, multicentre study that involved patients with olfactory dysfunction (OD). Both cases and controls underwent administration of the IT-QOD, Sino-Nasal Outcome Test-22 (SNOT-22) and psychophysical evaluation of orthonasal and retronasal olfactory function. Results: The IT-QOD was administered to 96 patients and 38 controls. The Cronbach's alpha exceeded 0.90, indicating satisfactory internal consistency. The test-retest reliability was found to be high for both parosmia (rs = 0.944) and life quality (rs = 0.969). Patients with OD had significantly higher IT-QOD scores compared to healthy individuals (p < 0.001), indicating strong internal validity. The external validity was also satisfactory, as shown by the significant correlation with SNOT-22 (rs = -0.54) and the threshold, discrimination, and identification score (rs = -0.63). Conclusions: The IT-QOD was demonstrated to be reliable and valid to assess the impact of OD on the quality of life of Italian-speaking patients.

Parameter characteristics in intranasal drug delivery: A key to targeting medications to the olfactory airspace.

BACKGROUND: The nose is a viable pathway for topical drug delivery to the olfactory cleft for treatment of obstructive smell loss and nose-to-brain drug delivery. This study investigates how variations in nasal vestibule morphology influence intranasal spray drug transport to the olfactory cleft and olfactory roof/bulb regions. METHODS: The unilateral nasal vestibule morphology in three healthy subjects with healthy normal nasal anatomy was classified as Elongated (Subject DN001), Notched (Subject DN002), and Standard (Subject DN003). Computational fluid and particle dynamics modelling were used to simulate nasal airflow and drug particle transport to the olfactory cleft and olfactory roof/bulb regions in each subject-specific nasal cavity. To evaluate highest drug depositions in these regions, the particle transport simulations involved extensive parameter combination analyses: 6 inspiratory flow rates mimicking resting to sniffing (10-50 L/min); 5 spray release locations (Top, Bottom, Central, Lateral, and Medial); 5 head positions (Upright, Tilted Forward, Tilted Back, Supine, and Mygind); 3 particle velocities (1, 5, and 10 m/s); 350,000 µm-particles (1-100 µm) and 346,500 nanoparticles (10-990 nm). FINDINGS: Particle size groups with highest depositions in olfactory cleft: DN001 left = 28.4% at 11-20 µm, right = 75.3% at 6-10 µm; DN002 left = 16.8% at 1-5 µm, right = 45.3% at 30-40 nm; DN003 left = 29.1% at 21-30 µm, right = 15.9% at 6-10 µm. Highest depositions in olfactory roof/bulb: DN001 left = 6.5% at 11-20 µm, right = 26.4% at 11-20 µm; DN002 left = 3.6% at 1-5 µm, right = 2.6% at 1-5 µm; DN003 left = 2.8% at 21-30 µm, right = 1.7% at 31-40 µm. INTERPRETATION: DN001 (Elongated nasal vestibule) had the most deposition in the olfactory regions. Micron-particles size groups generally had better deposition in the olfactory regions.

Olfaction Now and in the Future in CRSwNP.

BACKGROUND: Chronic rhinosinusitis (CRS) is the leading cause of olfactory dysfunction in the general population. Olfactory dysfunction is more common in patients with CRS with nasal polyposis (CRSwNP) compared to those without polyps. PURPOSE: The present review aims to summarize the current literature on the mechanism behind olfactory dysfunction in CRSwNP and the impact of therapy on olfactory outcomes in this patient population. METHODS: A comprehensive review of the available literature on olfaction in CRSwNP was performed. We evaluated the most recent evidence from studies on the mechanisms behind smell loss in CRSwNP and the impact of medical and surgical therapy for CRS on olfactory outcomes. RESULTS: The mechanism behind olfactory dysfunction in CRSwNP is not completely understood, but evidence from clinical research and animal models suggests both an obstructive component causing conductive olfactory loss and an inflammatory response in the olfactory cleft leading to sensorineural olfactory loss. Oral steroids and endoscopic sinus surgery have both shown efficacy in improving olfactory outcomes in CRSwNP in the short term; however, the long-term response of these treatments remains uncertain. Newer targeted biologic therapies, such as dupilumab, have also shown remarkable and durable improvement in smell loss for CRSwNP patients. CONCLUSION: Olfactory dysfunction is highly prevalent in the CRSwNP population. Although significant advances have been made in our understanding of olfactory dysfunction in the setting of CRS, additional studies are needed to elucidate cellular and molecular changes mediated by type 2-mediated inflammation in the olfactory epithelium with potential downstream effects on the central olfactory system. Further identification of these underlying basic mechanisms will be vital for developing future therapies targeted to improve olfactory dysfunction in patients with CRSwNP.

Chronic interleukin-13 expression in mouse olfactory mucosa results in regional aneuronal epithelium.

BACKGROUND: Olfactory dysfunction is highly associated with chronic rhinosinusitis with nasal polyps (CRSwNP), and the severity of loss has been linked with biomarkers of type 2 inflammation. The ability of dupilumab to rapidly improve the sense of smell prior to improvement in polyp size suggests a direct role of IL-4/IL-13 receptor signaling in the olfactory epithelium (OE). METHODS: We created a transgenic mouse model in which IL-13 is inducibly expressed specifically within the OE. Gene expression analysis and immunohistology were utilized to characterize the effect of IL-13 on the structure of the OE. RESULTS: After induction of olfactory IL-13 expression, there is a time-dependent loss of neurons from OE regions, accompanied by a modest inflammatory infiltrate. Horizontal basal cells undergo morphologic changes consistent with activation and demonstrate proliferation. Mucus production and increased expression of eotaxins is observed, with marked expression of Ym2 by sustentacular cells. DISCUSSION: Chronic IL-13 exposure has several effects on the OE that are likely to affect function. The neuronal loss is in keeping with other models of allergic type 2 nasal inflammation. Future studies are needed to correlate cellular and molecular alterations in olfactory cell populations with findings in human CRSwNP, as well as to assess olfactory function in behavioral model systems.

The potential for clinical application of automatic quantification of olfactory bulb volume in MRI scans using convolutional neural networks.

The olfactory bulbs (OBs) play a key role in olfactory processing; their volume is important for diagnosis, prognosis and treatment of patients with olfactory loss. Until now, measurements of OB volumes have been limited to quantification of manually segmented OBs, which is a cumbersome task and makes evaluation of OB volumes in large scale clinical studies infeasible. Hence, the aim of this study was to evaluate the potential of our previously developed automatic OB segmentation method for application in clinical practice and to relate the results to clinical outcome measures. To evaluate utilization potential of the automatic segmentation method, three data sets containing MR scans of patients with olfactory loss were included. Dataset 1 (N = 66) and 3 (N = 181) were collected at the Smell and Taste Center in Ede (NL) on a 3 T scanner; dataset 2 (N = 42) was collected at the Smell and Taste Clinic in Dresden (DE) on a 1.5 T scanner. To define the reference standard, manual annotation of the OBs was performed in Dataset 1 and 2. OBs were segmented with a method that employs two consecutive convolutional neural networks (CNNs) that the first localize the OBs in an MRI scan and subsequently segment them. In Dataset 1 and 2, the method accurately segmented the OBs, resulting in a Dice coefficient above 0.7 and average symmetrical surface distance below 0.3 mm. Volumes determined from manual and automatic segmentations showed a strong correlation (Dataset 1: r = 0.79, p < 0.001; Dataset 2: r = 0.72, p = 0.004). In addition, the method was able to recognize the absence of an OB. In Dataset 3, OB volumes computed from automatic segmentations obtained with our method were related to clinical outcome measures, i.e. duration and etiology of olfactory loss, and olfactory ability. We found that OB volume was significantly related to age of the patient, duration and etiology of olfactory loss, and olfactory ability (F(5, 172) = 11.348, p < 0.001, R2 = 0.248). In conclusion, the results demonstrate that automatic segmentation of the OBs and subsequent computation of their volumes in MRI scans can be performed accurately and can be applied in clinical and research population studies. Automatic evaluation may lead to more insight in the role of OB volume in diagnosis, prognosis and treatment of olfactory loss.