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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Spatial Mapping in the Rat Olfactory Bulb by Odor and Direct Electrical Stimulation.

OBJECTIVES: To directly measure the spatial mapping in the olfactory bulb by odor presentation and by direct electrical stimulation. STUDY DESIGN: Experimental (animal). SETTING: University research laboratory. SUBJECTS AND METHODS: Odor (n = 8) and electrical stimulation (n = 4) of the olfactory bulb in rats were used to demonstrate the spatial mapping of neural responses in the olfactory bulb. Both multiunit responses to odor stimulation and evoked potential responses to localized electrical stimulation were measured in different regions of the olfactory bulb. RESULTS: Responses that were recorded simultaneously from an array of 32 electrodes positioned at different locations within the olfactory bulb were mapped. Results show different spatial patterns of neural activity for different odors (odor maps). Direct stimulation of the olfactory bulb with electrical current pulses from electrodes positioned at different locations was also effective in generating spatial patterns of neural activity. CONCLUSION: These data suggest that by programming an array of stimulating electrodes, it should be possible to selectively activate different regions of the olfactory bulb, generating unique patterns of neural activity as seen in normal smell.

Posttraumatic olfactory dysfunction.

Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population.

Spag17 deficiency results in skeletal malformations and bone abnormalities.

Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area and the ratio of bone area to total area, leading to reductions in the ratio of marrow area/total area in the femur. Micro-CTs and von Kossa staining demonstrated increased mineral in the femur. Moreover, osteocalcin and osterix were more highly expressed in mutant mice than in wild-type mice femurs. These data suggest that femur bone shortening may be due to premature ossification. On the other hand, tibias appear to be shorter due to a delay in cartilage and bone development. Morphometric studies showed reduction in growth plate and bone formation. These defects did not affect bone mineralization, although the volume of primary bone and levels of osteocalcin and osterix were higher. Other skeletal malformations were observed including fused sternebrae, reduced mineralization in the skull, medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from knockout mice were shorter and fewer cells had primary cilia in comparison to cells from wild-type mice. In addition, Spag17 knockdown in wild-type MEFs by Spag17 siRNA duplex reproduced the shorter primary cilia phenotype. Our findings disclosed unexpected functions for Spag17 in the regulation of skeletal growth and mineralization, perhaps because of its role in primary cilia of chondrocytes and osteoblasts.

Pulmonary delivery of anorectic oxyntomodulin in rats: food intake suppression, reduced body weight gain and pharmacokinetics.

BACKGROUND: Oxyntomodulin (OXM1-37) is an anorectic gut-secreting peptide with a promise to treat obesity, but its needle-free delivery has yet to be successful. RESULTS: Pulmonary delivery of OXM1-37, but not its C-terminal octapeptides, caused dose-related, transient 4-6 h food intake suppression in rats. At 0.5 mg/kg, its 30-38% food intake suppression led to 46% reduction in body weight gain by day 8. Its lung absorption was fast, elevating the systemic level rapidly, yet the bioavailability was low at 13%. In the brain, twofold neuronal c-fos activation was seen in the hypothalamus arcuate nucleus and brainstem area postrema. CONCLUSION: Pulmonary delivery is a promising needle-free systemic delivery option for OXM1-37 to treat obesity, as enabling effective lung absorption and brain interaction.

Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat.

SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered.