Recovery from Covid-19 smell loss: Two-years of follow up.

OBJECTIVE: To report long-term patterns of recovery and non-recovery in a large nationwide cohort of subjects with COVID-19 associated smell loss. STUDY DESIGN: Prospectively, longitudinal questionnaires. SETTING: Web-based national survey. METHODS: A longitudinal survey of adults with COVID-19 and/or sudden change in smell or taste since January 1, 2020 was launched April 10, 2020. Participants were queried again in late May 2022 regarding recovery. Data from respondents with >2 years since loss were analyzed and compared to recovery status of those more recently effected. RESULTS: 1103 responded to the survey of whom 946 met inclusion criteria. Among the 267 respondents for whom at least 2 years of follow up was available, 38.2 % reported full recovery, 54.3 % partial, and 7.5 % no recovery. For the entire cohort (all with ≥3 months since smell loss), 38.7 % reported complete recovery, 51.0 % reported partial recovery (ranging from mild complaints to severe phantosmia or dysosmia), and 10.3 % reported no improvement at all. Complete recovery of smell function was significantly higher in those under 40 years old (45.6 % compared to 32.9 % in those over 40). CONCLUSION: Although the vast majority of subjects who do recover do so within the first 3 months, long-term spontaneous recovery can occur. Rates of recovery do not seem to differ depending on when during the pandemic the loss first occurred.

Predictors of smell recovery in a nationwide prospective cohort of patients with COVID-19.

OBJECTIVE: To determine which factors (demographic, symptoms, comorbidities, and treatments) are associated with recovery of smell in patients with COVID-19 associated olfactory loss. STUDY DESIGN: Prospective, longitudinal questionnaires. SETTING: National survey. METHODS: A longitudinal web-based nationwide survey of adults with COVID-19 associated smell and taste loss was launched April 10, 2020. After completing an initial entry survey, participants received detailed follow-up questionnaires 14 days, and 1, 3 and 6 months later. RESULTS: As of June 25, 2021, 798 participants met study inclusion criteria and completed 6-month questionnaires. Of demographic characteristics only age <40 years was positively associated with smell recovery (p < .003). Of symptoms, difficulty breathing was negatively associated with smell recovery (p < .004), and nasal congestion positively associated with smell recovery (p < .03). Of pre-existing comorbidities only previous head injury (p < .017) was negatively associated with smell recovery. None of the queried medications used to treat COVID were associated with better rates of smell recovery. CONCLUSIONS: Age <40 and presence of nasal congestion at time of COVID-19 infection were predictive of improved rates of smell recovery, while difficulty breathing at time of COVID-19 infection, and prior head trauma predicted worsened rates of recovery. Further study will be required to identify potential mechanisms for the other observed associations. Such information can be used by clinicians to counsel patients suffering COVID-19 associated smell loss as to prognosis for recovery.

Planar cell polarity defects and hearing loss in sperm-associated antigen 6 (Spag6)-deficient mice.

Spag6 encodes an axoneme central apparatus protein that is required for normal flagellar and cilia motility. Recent findings suggest that Spag6 also plays a role in ciliogenesis, orientation of cilia basal feet, and planar polarity. Sensory cells of the inner ear display unique structural features that underlie their mechanosensitivity. They represent a distinctive form of cellular polarity, known as planar cell polarity (PCP). However, a role for Spag6 in the inner ear has not yet been explored. In the present study, the function of Spag6 in the inner ear was examined using Spag6-deficient mice. Our results demonstrate hearing loss in the Spag6 mutants, associated with abnormalities in cellular patterning, cell shape, stereocilia bundles, and basal bodies, as well as abnormally distributed Frizzled class receptor 6 (FZD6), suggesting that Spag6 participates in PCP regulation. Moreover, we found that the subapical microtubule meshwork was disrupted. Our observations suggest new functions for Spag6 in hearing and PCP in the inner ear.

Wireless, intraoral hybrid electronics for real-time quantification of sodium intake toward hypertension management.

Recent wearable devices offer portable monitoring of biopotentials, heart rate, or physical activity, allowing for active management of human health and wellness. Such systems can be inserted in the oral cavity for measuring food intake in regard to controlling eating behavior, directly related to diseases such as hypertension, diabetes, and obesity. However, existing devices using plastic circuit boards and rigid sensors are not ideal for oral insertion. A user-comfortable system for the oral cavity requires an ultrathin, low-profile, and soft electronic platform along with miniaturized sensors. Here, we introduce a stretchable hybrid electronic system that has an exceptionally small form factor, enabling a long-range wireless monitoring of sodium intake. Computational study of flexible mechanics and soft materials provides fundamental aspects of key design factors for a tissue-friendly configuration, incorporating a stretchable circuit and sensor. Analytical calculation and experimental study enables reliable wireless circuitry that accommodates dynamic mechanical stress. Systematic in vitro modeling characterizes the functionality of a sodium sensor in the electronics. In vivo demonstration with human subjects captures the device feasibility for real-time quantification of sodium intake, which can be used to manage hypertension.

Quality of life and safety impact of COVID-19 associated smell and taste disturbances.

OBJECTIVE: The association between COVID-19 and chemosensory loss has garnered substantial attention, however to date little is known about the real-life consequences of impairment in this unique patient population. The aim of this study is to evaluate the quality of life (QOL) and personal safety deficits experienced by patients with COVID-19 infection. STUDY DESIGN: Prospective, longitudinal questionnaires. SETTING: National survey. METHODS: A longitudinal web-based nationwide survey of adults with COVID-19 and/or a sudden change in smell and taste was launched April 10, 2020. Previously published questions on chemosensory-related QOL and safety events were asked at the 6-month follow-up survey. RESULTS: As of February 10, 2021, 480 eligible respondents took the 6-month questionnaire, of whom 322 were COVID-19 positive. Impact on QOL was substantial with 96% of subjects reporting at least one of the defined deficits, and over 75% reporting at least 3 of these. "Reduced enjoyment of food" was the most common complaint (87%), while 43% of subjects self-reported depression. The prevalence of safety-related issues was common in this population, with over 57% reporting at least one, and 36% reporting 2 or more events. Of the events asked, the inability to smell smoke that others could perceive was the most common at 45%. CONCLUSIONS: COVID-19 associated chemosensory losses have a real and substantial impact on both quality of life and safety, beyond mere inconvenience. The high prevalence of these issues despite a relatively short period of olfactory deficit should alert clinicians to the serious risks to an already vulnerable patient population.

Subjective smell and taste changes during the COVID-19 pandemic: Short term recovery.

Since the COVID-19 pandemic began, many individuals have reported acute loss of smell and taste. In order to better characterize all patients with these symptoms, a longitudinal national survey was created. Since April 10, 2020, 549 completed the initial survey, with 295 completing 14-day, and 202 completing 1-month follow up surveys. At 1-month follow-up, 71.8% reported a return to "very good" or "good" smell, and 84.2% reported a return to "very good" or "good" taste. Chemosensory changes are a cardinal sign of COVID-19. Fortunately, our data, representing a large longitudinal study of patients experiencing smell and taste losses during the COVID-19 pandemic, indicates that the majority appear to recover within a month.

COVID-19-related chemosensory changes: Findings from a prospective national database.

Objective: The aim of this study was to review findings from a large prospective national database of chemosensory disturbances associated with coronavirus disease 2019 (COVID-19) infection. Data Sources: The Virginia Commonwealth University Smell and Taste Center national database of COVID-19 chemosensory disturbances. Methods: A series of online surveys, first opened on April 10, 2020, was made accessible nationwide to any adult with sudden chemosensory dysfunction since January 2020. Participants received subsequent follow-up surveys 14 days, 1 month, 3 months, and 6 months after enrollment. An additional survey was sent to all participants on May 28, 2022 to assess long-term outcomes. Information pertaining to demographics, symptoms, comorbidities, treatments, and life impact was collected. Results: Of 363 participants who reported complete smell recovery, 51.2% recovered within 1 month, 70% within 3 months, and 79% within 6 months, while 8.8% took over 1 year to completely recover. Among all participants, 7.5% had no smell recovery. Positive predictors of recovery included age <40, male gender, and the presence of nasal congestion. Negative predictors included difficulty breathing and prior head injury. Many participants reported a decrease in quality of life and the presence of potential safety hazards associated with decreased smell loss. Conclusions: Most subjects with COVID-19-related chemosensory dysfunction recover, with the majority noting complete recovery within weeks of infection. Those aged over 40 years and female gender were associated with lower rates of recovery. A considerable number of participants reported significant impact on quality of life and safety.

Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival.

Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.

Decreasing Incidence of Chemosensory Changes by COVID-19 Variant.

Anecdotal clinical observation suggests that rates of chemosensory dysfunction associated with COVID-19 infection may be decreasing. To investigate, the National COVID Cohort Collaborative database was queried for all patients with and without smell and taste loss within 2 weeks of COVID-19 diagnosis. Six-week periods of peak variant prevalence were selected by using CoVariants.org for analysis. Of 3,678,214 patients with COVID-19 in the database, 616,318 met inclusion criteria during the time intervals of interest, with 3431 having an associated smell or taste disturbance diagnosis. With the initial/untyped variant set as the baseline, the odds ratios for alpha, delta, and omicron (December 27, 2021-February 7, 2022) were 0.50 (95% CI, 0.45-0.55; P < .0001), 0.44 (95% CI, 0.41-0.48; P < .0001), and 0.17 (95% CI, 0.15-0.18; P < .0001), respectively. These data strongly support the clinical observation that patients infected with more recent variants are at a significantly lower risk of developing associated chemosensory loss.

COVID-19-Associated Chemosensory Loss Continues to Decline.

Chemosensory losses have long been considered a cardinal symptom of COVID-19 infection. Recent studies have shown changing symptom profiles with COVID-19, including decreasing incidence of olfactory losses. We accessed the National COVID Cohort Collaborative database to identify patients with and without smell and taste loss within 2 weeks of COVID-19 diagnosis. Peak prevalence time intervals for variants were determined from Covariants.org. Using rates of chemosensory loss during the peak time interval for "Untyped" variants as baseline (4/27/2020-6/18/2020), odds ratios for COVID-19-associated smell or taste disturbance fell for each of the Alpha (0.744), Delta (0.637), Omicron K (0.139), Omicron L (0.079), Omicron C (0.061), and Omicron B (0.070) peak intervals. These data suggest that during the recent Omicron waves and potentially moving forward, the presence or absence of smell and taste disturbances may no longer have predictive value in the diagnosis of COVID-19 infection.

International consensus statement on allergy and rhinology: Olfaction.

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.

Age-related changes in p2 odorant receptor mapping in the olfactory bulb.

The ability to identify odors is dependent on the spatial mapping of odorant receptors onto fixed positions within the olfactory bulb. In elderly adults, odor identification and discrimination is often impaired. The objective of this study was to determine if there are age-related changes in odorant receptor mapping. We studied 8 groups of mice ranging in age from 2 weeks to 2.5 years and mapped the projection of P2 odorant receptors onto targeted glomeruli within medial and lateral domains of the olfactory bulb. A total of 60 mice were used to measure the number of P2 glomeruli, bulb length, the position of each glomerulus, and the amount of P2 axons targeting each glomerulus. We found that over 70% of olfactory bulbs contained multiple P2 glomeruli, bulb length increased 42% between the ages of 2 and 13 weeks, and the position of P2 glomeruli shifted with bulb growth. In most cases, targeted glomeruli were either completely or partially filled with P2 axons. In some cases, targeting was diffuse, with glomeruli receiving only a few stray P2-labeled axons. The frequency of diffuse targeting was rare (<4%) in adult mice 3-6 months in age. However, significant increases in diffuse targeting were observed in older mice, reaching 10% at 1 year and 22% at 2 years of age. These findings suggest that odorant receptor mapping becomes more disrupted in old age and could account for impaired olfactory function in elderly adults.

Matrix metalloproteinase-9 and -2 expression in the olfactory bulb following methyl bromide gas exposure.

Matrix metalloproteinase-9 (MMP-9) and MMP-2 are important for recovery following direct traumatic injury within the central nervous system (CNS). However, most CNS injury models include both direct trauma and neuronal deafferentation. This limits the ability to determine if these MMPs are important to one or both components of injury. To establish if MMPs play a role in the deafferentation processes, we investigated MMP-9 and MMP-2 in the olfactory bulb following methyl bromide gas exposure. This injury model lesions neurons within the olfactory epithelium and thereby leads to deafferentation of the bulb without damaging it directly. We measured the response of MMP-9 and MMP-2 in the olfactory bulb from 1 to 60 days during neuronal deafferentation and recovery. MMP-9 increased rapidly on day 5 and remained elevated for 10 days. MMP-2 expression levels were low compared with MMP-9. Immunohistological staining performed on days 1, 5, and 10 revealed MMP-9 was localized to inflammatory cells within the olfactory nerve and glomerular layers. Our results demonstrate MMP-9 is present in inflammatory cells during deafferentation processes in the olfactory bulb. Although MMP-9 is elevated in other CNS injury models, this is the first report to demonstrate an increase in MMP-9 associated with neuronal deafferentation in the absence of direct trauma.

Subjective Changes in Smell and Taste During the COVID-19 Pandemic: A National Survey-Preliminary Results.

Since the COVID-19 pandemic began, many individuals have noted acute loss of smell and/or taste, although not all patients with these symptoms are tested for COVID-19. To better characterize all patients with these rare symptoms, a national survey was created. Over 13 days in April 2020, a total of 220 people completed the survey in its entirety, representing a wide geographic distribution across the United States. Of the 220 respondents, 93 (42%) were diagnosed with COVID-19, and 127 (58%) were not. A total of 37.7% of respondents reported changes in smell/taste as the initial or sole presentation of their condition. Most but not all patients had other symptoms suggestive of COVID-19 at the time of chemosensory loss. Despite its inclusion as a major symptom of COVID-19 by the CDC (Centers for Disease Control and Prevention), respondents with additional CDC-defined symptoms associated with COVID-19 were statistically more likely to be tested/diagnosed than those without.

Olfactory nerve recovery following mild and severe injury and the efficacy of dexamethasone treatment.

To investigate factors that influence the degree of neural regeneration and recovery, we studied 2 olfactory nerve injury models. Transection of the olfactory nerves along the surface of the olfactory bulb was performed in OMP-tau-lacZ mice using either a flexible Teflon blade (mild injury) or a stainless steel blade (severe injury). Histological assessment of recovery within the olfactory bulb was made at 5, 14, and 42 days after injury. We used X-gal staining to label the degenerating and regenerating olfactory nerve fibers and immunohistochemical staining to detect the presence of reactive astrocytes and macrophages. Areas of injury-associated tissue were significantly smaller in the mild injury model, and at 42 days, the regenerated nerves had reestablished connections to the glomerular layer of the bulb. With severe injury, there were larger areas of injury-associated tissue, more astrocytes and macrophages, and a decrease in regenerated nerve fibers. When dexamethasone (DXM) was injected after severe injury, there was a significant reduction in injury-associated tissue, better nerve recovery, and fewer astrocytes and macrophages. These results demonstrate that recovery in the olfactory system varies with the severity of injury and that DXM treatment may have therapeutic value by reducing injury-associated tissue and improving recovery outcome.

Etiology of subjective taste loss.

BACKGROUND: Taste complaints are commonly encountered in clinical practice. Although changes in taste function may arise from varied etiologies, numerous other factors may impact patients' taste perceptions, the most common of which is olfactory dysfunction. Thus, patients with taste complaints may or may not have measurable deficits in taste function. This poses a challenge to providers faced with evaluation of patients with taste disorders, and may delay diagnosis and management. METHODS: We retrospectively examined records of 1108 patients evaluated at the Virginia Commonwealth University Health System Smell and Taste Clinic and compared patients' subjective taste complaints with results of objective testing of the senses of taste and smell. RESULTS: A total of 358 patients had a subjective taste complaint and results from both gustatory and olfactory function tests. Patients were grouped by subjective complaint as "taste only" (n = 63) or "taste and smell" (n = 295). Of patients reporting a "taste-only" complaint, 25.4% had abnormal gustatory function, whereas 44.4% had abnormal olfactory function. For those reporting taste-and-smell complaints, only 9.5% had abnormal gustatory function, whereas 86.8% had abnormal olfactory function. CONCLUSION: This study supports the hypothesis that patients who present with a taste complaint are more likely to have an underlying olfactory than gustatory impairment. However, those with a taste-only complaint are more likely to have objective gustatory deficits than those with a taste-and-smell complaint. These findings may prove useful to healthcare providers who evaluate patients presenting with complaints of taste loss.

Peak in matrix metaloproteinases-2 levels observed during recovery from olfactory nerve injury.

Matrix metalloproteineases are associated with extracellular remodeling that occurs in injury and repair processes in the central nervous system (CNS). We examined the role of MMP-2 in a model of olfactory nerve injury and found that MMP-2 levels increased several hours following injury, peaked at day 7 and then decreased rapidly. We previously reported a rapid increase in MMP-9, within 5 h after nerve injury, corresponding to neuronal degeneration and increased glial activity. In this study, we show that MMP-2 peaks later than MMP-9, at the onset of neuronal regeneration and repair. Using MMP-9 knockout mice, we determined that the MMP-2 increase is independent of MMP-9. Our data suggest that MMP-2 and MMP-9 may play different roles in the injury and repair processes.

Head trauma and olfactory function.

Olfactory impairment is a well-established sequela of head injury. The presence and degree of olfactory dysfunction is dependent on severity of head trauma, duration of posttraumatic amnesia, injuries obtained, and as more recently established, age. Deficits in smell can be conductive or neurosensory, contingent on location of injury. The former may be amenable to medical or surgical treatment, whereas the majority of patients with neurosensory deficits will not recover. Many patients will not seek treatment for such deficits until days, weeks, or even months after the traumatic event due to focus on more pressing injuries. Evaluation should start with a comprehensive history and physical exam. Determination of the site of injury can be aided by CT and MRI scanning. Verification of the presence of olfactory deficit, and assessment of its severity requires objective olfactory testing, which can be accomplished with a number of methods. The prognosis of posttraumatic olfactory dysfunction is unfortunate, with approximately only one third improving. Emphasis must be placed on identification of reversible causes, such as nasal bone fractures, septal deviation, or mucosal edema/hematoma. Olfactory loss is often discounted as an annoyance, rather than a major health concern by both patients and many healthcare providers. Patients with olfactory impairment have diminished quality of life, decreased satisfaction with life, and increased risk for personal injury. Paramount to the management of these patients is counseling with regard to adoption of compensatory strategies to avoid safety risks and maximize quality of life. Practicing otolaryngologists should have a thorough understanding of the mechanisms of traumatic olfactory dysfunction in order to effectively diagnose, manage, and counsel affected patients.

Activation of the rat olfactory bulb by direct ventral stimulation after nerve transection.

BACKGROUND: The aim of this study was to demonstrate how direct electrical stimulation can activate the olfactory bulb after denervation of the olfactory nerve input. METHODS: Sprague-Dawley rats (n = 5) were anesthetized and olfactory bulbs exposed. Olfactory nerves were transected by passing a Teflon blade between the cribriform plate and ventral surface of the bulb. A cochlear implant electrode array was used to stimulate 6 different positions along the ventral surface of the olfactory bulb. Biphasic constant-current pulses were used (50-1000 µA, 50-1000 µs) to stimulate the bulb, and a 16-electrode paddle array was used to record localized negative field potential responses at the dorsal surface of the bulb. RESULTS: Localized negative field potentials were reliably obtained using biphasic, 500-µA, 200-µs pulses. A shift in stimulating position by 1 mm resulted in a significant change in the dorsal field potential. CONCLUSION: Direct stimulation of the deafferented olfactory bulb was effective in generating localized field potential responses. These findings support the potential use of direct electrical stimulation for the treatment of anosmia.

Cribriform plate width is highly variable within and between subjects.

OBJECTIVE: All successful endonasal surgery, including functional endoscopic sinus surgery (FESS), depends on knowledge of both anatomy and the specific variations that can occur between and within patients. Familiarity with these structures is a critical component in preventing complications from these procedures, and failure to understand subtle variation can have disastrous results. The aim of this study was to characterize the anatomical variations (if any) of the cribriform plate using a large cadaveric sample set. Better understanding of the disparities within and between patients may have important implications for surgical planning. METHODS: Whole human skull specimens (31 specimens, 62 sides) were examined to obtain dimensional measurements of the cribriform plate on the right and left sides. RESULTS: The average length of the cribriform plate was 21.28mm (range 15.25-27.73mm, SD 3.30mm). The average width of the cribriform plate (including the crista galli) was 4.53mm (range 1.75-8.03mm, SD 1.20mm). When comparing side differences in individual specimens, there was more variability between widths, relative standard deviation 26.4%, than between lengths, relative standard deviation 15.5%. CONCLUSION: There is a range of both length and width of the cribriform plate, between and within individuals. This is particularly true for width. In practice, this emphasizes the importance of pre-operative imaging and recognition of anatomic variability for sinus or anterior skull base procedure.