Use of platelet-rich plasma for COVID-19-related olfactory loss: a randomized controlled trial.

INTRODUCTION: The current study evaluated the use of platelet-rich plasma (PRP), an autologous blood product with supraphysiologic concentrations of growth factors, in the treatment of prolonged coronavirus disease 2019 (COVID-19)-related smell loss. METHODS: This multi-institutional, randomized controlled trial recruited patients with COVID-19 who had objectively measured smell loss (University of Pennsylvania Smell Identification Test [UPSIT] ≤ 33) between 6 and 12 months. Patients were randomized to three intranasal injections of either PRP or sterile saline into their olfactory clefts. The primary outcome measure was change in Sniffin' Sticks score (threshold, discrimination, and identification [TDI]) from baseline. The secondary end point measures included responder rate (achievement of a clinically significant improvement, ≥5.5 points TDI), change in individual TDI olfaction scores, and change in subjective olfaction via a visual analog scale. RESULTS: A total of 35 patients were recruited and 26 completed the study. PRP treatment resulted in a 3.67-point (95% CI: 0.05-7.29, p = 0.047) greater improvement in olfaction compared with the placebo group at 3 months and a higher response rate (57.1% vs 8.3%, odds ratio 12.5 [95% exact bootstrap confidence interval, 2.2-116.7]). There was a greater improvement in smell discrimination following PRP treatment compared with placebo but no difference in smell identification or threshold. There was no difference in subjective scores between PRP and placebo. No adverse effects were reported. CONCLUSION: Olfactory function following COVID-19 can improve spontaneously after 6 months and can improve to a greater extent with PRP injection. These data build on the promise of PRP to be a safe potential treatment option for patients with COVID-19-related smell loss, and larger-powered studies will help further assess its efficacy.

Management of Post-Infectious Anosmia and Hyposmia: A Systematic Review.

BACKGROUND: Anosmia and hyposmia significantly affect patients' quality of life and have many etiologies, including trauma, inflammatory conditions including chronic rhinosinusitis, neoplasm, and viral infections, such as rhinovirus and SARS-CoV-2. OBJECTIVE: Our purpose was to establish whether a consensus exists regarding optimal management of olfactory dysfunction and to provide insight into the treatment of anosmia in the current climate of increased prevalence secondary to COVID-19. Thus, we aimed to systematically review the literature on the management of non-Chronic-rhinosinusitis- related anosmia/hyposmia. METHODS: PubMed, EMBASE, and Cochrane databases were searched for articles published since January 1990 using terms combined with Medical Subject Headings (MeSH). We included articles evaluating management of anosmia and hyposmia written in the English language, with original data, a minimum of 3 months of follow-up except for COVID-related studies, at least 2 patients, and well-defined and measurable outcomes. RESULTS: A total of 3013 unique titles were returned upon the initial search. Of these, 297 abstracts were examined, yielding 19 full texts meeting inclusion criteria (8 with level 1 evidence, 3 with level 2, 1 with level 3, and 7 with level 4). The studies included a total of 1522 subjects, with follow up ranging from 3 to 72 months, with an exception for COVID related studies. Endpoints were based on clinically significant improvements of olfactory functions as measured through validated smell tests. Treatments with the most robust data were intranasal corticosteroids and olfactory training. CONCLUSION: The literature on the treatment of anosmia and hyposmia includes randomized trials showing the efficacy of a few modalities. While further research is needed to expand therapeutic options for this debilitating condition, the current literature supports the use of olfactory training and topical corticosteroids.

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.

Smell and Taste Loss Associated with COVID-19 Infection.

OBJECTIVE: The aim of this study was to quantify the impact of COVID-19 on olfactory and gustatory function in US adults. METHODS: From the 2021 Adult National Health Interview Survey, demographic and survey-specific module data concerning COVID-19 diagnoses, testing and disease severity, and data quantifying disturbances and eventual recovery of smell and taste were extracted. Sample weights were applied to obtain nationally representative statistics. The overall rate of COVID-19 infection was determined, and those diagnosed with COVID-19 were analyzed with respect to disease severity, smell and taste disturbance, and respective recoveries. RESULTS: In 2021, 35.8 million or 14% of the adult population (95% CI 13.5-14.7%; mean age, 43.9 years; 53.8% female) had been diagnosed with COVID-19. Among those, 60.5% (58.6-62.5%) and 58.2% (56.2-60.1%) reported accompanying losses  in smell or taste, respectively; there was a significant association between overall COVID-19 symptom severity and smell (p < 0.001) and taste disturbance (p < 0.001). Following infection, 72.2% (69.9-74.3%), 24.1% (22.2-26.2%), and 3.7% (3.0-4.6%) of the patients experienced complete, partial, and no smell recovery, respectively. Recovery rates for gustatory function paralleled olfaction, with 76.8% (74.6-78.9%), 20.6% (18.7-22.7%), and 2.6 (1.9-3.4%) reporting complete, partial, and no recovery of taste, respectively. When sensory disturbance was present, severity of overall symptomatology was negatively associated with smell and taste recovery (p < 0.001 for each). CONCLUSION: The majority of adults infected with COVID-19 in 2021 experienced olfactory or gustatory dysfunction with a non-negligible population reporting incomplete or no near-term sensory recovery. Our results are useful for providers counseling patients and suggest that interventions lessening overall COVID-19 symptom burden may prevent prolonged sensory dysfunction. LEVEL OF EVIDENCE: IV. Laryngoscope, 2023.

Viral Shedding and Persistence of Anosmia and Ageusia in an Asymptomatic SARS-CoV-2 Infection.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in the region of Wuhan, China is responsible for the ongoing pandemic of coronavirus disease-19 (COVID-19) that has been a part of our life for almost three years now. Although there have been multiple reports of prolonged viral shedding in people with severe disease, viral shedding lasting for extended periods can occur in patients with less serious clinical insults or even asymptomatic individuals. Herein, we report a case of a female patient that, although otherwise asymptomatic, remained positive on nasopharyngeal viral testing for a prolonged period, alongside persisting complaints of anosmia and ageusia. The patient may well have been one of the first individuals to be infected in the Greek territory; we followed up on her long-term COVID sequelae from the time of proof of infection up until the present day.

Corticosteroid nasal irrigation as early treatment of olfactory dysfunction in COVID-19: A prospective randomised controlled trial.

OBJECTIVE: This study aimed to evaluate the efficacy of corticosteroid irrigation compared to saline to no nasal irrigation in COVID-19 patients with olfactory loss. DESIGN AND SETTING: A randomised controlled study was conducted at the Otolaryngology-Head & Neck Surgery Department, Ramathibodi Hospital, Faculty of Medicine, Mahidol University. PARTICIPANTS: Two hundred thirty-seven COVID-19 participants with a new-onset smell loss were recruited into the study. Two hundred twenty-two participants met the inclusion criteria and were randomised into three groups: corticosteroid irrigation, saline irrigation and no treatment. MAIN OUTCOME MEASURES: The primary outcome was the mean difference in the smell sensation score among the groups after treatment at 1, 2 and 6 weeks. The secondary outcomes measurements included (1) a self-rating quality of life (QOL)-related smell dysfunction score, (2) the change over time in smell sensation score and self-rating QOL-related smell dysfunction score and (3) the median time to complete recovery of smell loss. RESULTS: The mean differences in smell sensation scores among the three groups were not statistically significant at any follow-up period. The mean score of self-rating QOL-related smell dysfunction in the corticosteroid group was significantly better than the other groups at 1 week. The change of outcome scores showed significant improvement over time, regardless of the treatments. The median time to complete smell recovery was similar: 3 weeks. CONCLUSION: This study emphasised that corticosteroid nasal irrigation is not superior to saline or no nasal irrigation in restoring the sense of smell in COVID-19-associated olfactory 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.

Olfactory dysfunction in COVID-19: new insights into the underlying mechanisms.

The mechanisms of olfactory dysfunction in COVID-19 are still unclear. In this review, we examine potential mechanisms that may explain why the sense of smell is lost or altered. Among the current hypotheses, the most plausible is that death of infected support cells in the olfactory epithelium causes, besides altered composition of the mucus, retraction of the cilia on olfactory receptor neurons, possibly because of the lack of support cell-derived glucose in the mucus, which powers olfactory signal transduction within the cilia. This mechanism is consistent with the rapid loss of smell with COVID-19, and its rapid recovery after the regeneration of support cells. Host immune responses that cause downregulation of genes involved in olfactory signal transduction occur too late to trigger anosmia, but may contribute to the duration of the olfactory dysfunction.

Comparison of the Otolaryngological Symptoms of Laboratory-Confirmed and Clinically Diagnosed COVID-19 Patients.

Objectives: Our aim is to determine prevalence, severity, duration of otorhinolaryngologic symptoms related to coronavirus disease 2019 (COVID-19), and correlation between the test results obtained by oronasopharyngeal swab and the symptoms of these regions by evaluating differences in ear, nose, and throat (ENT) symptoms between laboratory-confirmed COVID-19 patients and clinically and computed tomography (CT)-diagnosed COVID-19 patients. Methods: The study enrolled patients with a positive polymerase chain reaction (PCR) test diagnosed with COVID-19 that grouped as PCR (+), and those with repeated negative PCR tests but COVID-19 Reporting and Data System (CO-RADS) chest CT findings with high (CO-RADS 5) or very high (CO-RADS 6) similarity to COVID-19 that grouped as PCR(-)/CT(+). Demographic features, general symptoms, and otorhinolaryngological symptoms and severity of disease were evaluated and compared. Results: The most common ENT symptoms in the PCR(+) group were loss of taste (n=77), loss of smell, and sore throat with respective frequencies of 34.5%, 31.8%, 26.0%, and in PCR(-) CT (+) group loss of taste, loss of smell, and sore throat with respective frequencies 24.6%, 21.1%, and 18.4%. ENT symptom rates were found higher in PCR (+) group (65.0%) according to PCR(-)/CT(+) group (49.1%) with statistically significant difference (p=0.008). Loss of smell rates were found higher in PCR (+) group according to PCR(-)/CT(+) group with statistically significant difference (p=0.037). Conclusion: Loss of smell and taste were most common ENT symptoms in laboratory-confirmed COVID-19 cases. The presence of COVID-19 should definitely be considered in patients presenting with sudden loss of smell or taste. In addition, loss of smell and otolaryngologic symptoms were more common in laboratory-confirmed COVID-19 according to clinically and computed tomograpy diagnosed COVID-19 cases. There can be a correlation between positive sample region and symptom region. Location of symptoms must be considered for decision of sampling location.

Acupuncture for olfactory dysfunction in infected COVID-19 patients: study protocol for a randomized, sham-controlled clinical trial

Objective Olfactory dysfunction (OD) is a common symptom of Corona Virus Disease 2019 (COVID-19). It is defined as the reduced or distorted ability to smell during sniffing (orthonasal olfaction) and represents one of the early symptoms in the clinical course of COVID-19 infection. A large online questionnaire-based survey has shown that some post-COVID-19 patients had no improvement 1 month after discharge from the hospital. Therefore, this clinical trial was designed to explore the efficacy of acupuncture for OD in COVID-19 infected patients and to determine whether acupuncture could have benefits over sham acupuncture for OD in post-COVID-19 patients. Methods This is a single-blind, randomized controlled, cross-over trial. We plan to recruit 40 post-COVID-19 patients with smell loss or smell distortions lasting for more than 1 month. Qualified patients will be randomly allocated to the intervention group (real acupuncture) or the control group (sham acupuncture) at a 1:1 ratio. Each patient will receive 8 sessions of treatment over 4 weeks (Cycle 1) and a 2-week follow-up. After the follow-up, the control group will be subjected to real acupuncture for another 4 weeks (Cycle 2), and the real acupuncture group will undergo the 4-week sham acupuncture. The primary outcomes will be the score changes on the questionnaire of olfactory functioning and olfaction-related quality of life at week 6, 8, 12, and 14 from the baseline. The secondary outcomes will be the changes in the olfactory test score at week 6 and 12 from the baseline measured by using the Traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC). Discussion The results of this trial will help to determine the effectiveness of acupuncture for OD in post-COVID-19 patients. This may provide a new treatment option for patients.

The prevalence of sensory changes in post-COVID syndrome: A systematic review and meta-analysis.

Post-COVID syndrome can be defined as symptoms of COVID-19 that persist for longer than 12 weeks, with several studies reporting persistent symptoms relating to the sensory organs (eyes, ears, and nose). The aim of this systematic review was to examine the prevalence of persistent anosmia, hyposmia, ageusia, and hypogeusia, as well as eye/vision and ear/hearing related long-COVID symptoms. Authors searched the electronic databases from inception to November 2021. Search terms included words related to long-COVID, smell, taste, eyes/vision, and ears/hearing, with all observational study designs being included. A random effects meta-analysis was undertaken, calculating the prevalence proportions of anosmia, hyposmia, ageusia, and hypogeusia, respectively. From the initial pool, 21 studies met the inclusion criteria (total n 4,707; median n per study 125; median age = 49.8; median percentage female = 59.2%) and 14 were included in the meta-analysis The prevalence of anosmia was 12.2% (95% CI 7.7-16.6%), hyposmia 29.9% (95% CI 19.9-40%), ageusia 11.7% (95% CI 6.1-17.3%), and hypogeusia 31.2% (95% 16.4-46.1%). Several eye/vision and ear/hearing symptoms were also reported. Considering that changes in the sensory organs are associated with decreases in quality of life, future research should examine the etiology behind the persistent symptoms. Systematic review registration: [www.crd.york.ac.uk/prospero], identifier [CRD42021292804].

Investigational drugs for the treatment of olfactory dysfunction.

INTRODUCTION: Olfactory dysfunction could be the sign of acquired or degenerative diseases. The loss of the sense can be caused by a damage in the nasal structure (olfactory epithelium) or a neuro inflammation/degeneration in the superior olfactory pathway. The understanding of the origin of the smell alteration would be desirable for appropriate management of the problem. Unfortunately, clinical investigations do not always allow to define the exact cause. AREAS COVERED: This review discusses the treatments available and their mechanism of action based on the administration methods; in fact, just looking at the results obtained by the researcher using topic versus systemic treatment, might be possible to speculate about the peripheral or central origin of the olfactory disorder. EXPERT OPINION: Because COVID-19 causes olfactory loss and several treatments (topical and systemic) have been tested in this disease, we have decided to use this model of acquired olfactory loss to discuss the different therapeutical option. The authors believe these treatments might be an option also for treating olfactory disease related to neurodegeneration.

COVID-19 infection related olfactory dysfunction in Saudi Arabia: Community-based study

Background: loss of smell is a common symptom of coronavirus infections. Studies have shown that patients following recovery from COVID-19 develop olfactory dysfunction which can persist for an extended period. The purpose of this study is to assess the long-term olfactory dysfunction and its associated factors in individuals with a history of infection COVID-19 infection, as well as the impact of olfactory dysfunction on quality of life in Saudi Arabia. Methods: A questionnaire based cross-sectional study was conducted targeting individuals with a history of COVID-19 infection. Results: A total of 174 participants were included in this study. The percentage of anosmia, hyposmia, parosmia, and phantosmia among the participants was 11.5%, 37.4%, 40.8%, and 33.3% respectively. Parosmia was significantly associated with olfactory training (P-value= 0.019). Olfactory training and age group from 46 to 55 years were showed significant association with phantosmia (ghost odors) (P-value= 0.008, 0.012) respectively. 28.7% of participants reported that their smell sense problems caused them to eat less than previously, and 21.8% reported that they ate out less. 13.8% stated that their smell sense issues have a negative impact on their daily social activities, and according to 5.2%, changes in the smell sense isolated them socially. Conclusion: Long-term olfactory dysfunction was shown to be common among individuals who had a history of COVID-19 infection. The quality of life of those who are affected by olfactory dysfunction is negatively impacted. Further research is recommended to understand the pathophysiology of anosmia, hyposmia, and phantosmia in COVID-19 patients.

Chemosensory loss in COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 virus quickly spread globally, infecting over half a billion individuals, and killing over 6 million*. One of the more unusual symptoms was patients' complaints of sudden loss of smell and/or taste, a symptom that has become more apparent as the virus mutated into different variants. Anosmia and ageusia, the loss of smell and taste, respectively, seem to be transient for some individuals, but for others persists even after recovery from the infection. Causes for COVID-19-associated chemosensory loss have undergone several hypotheses. These include non-functional or destroyed olfactory neurons and gustatory receptors or of their supporting cells, disruption of the signaling protein Neuropilin-1, and disruption in the interaction with semaphorins, key molecules in the gustatory and olfactory axon guidance. The current paper will review these hypotheses and chart out potential therapeutic avenues.

Depression Symptoms and Olfactory-related Quality of Life.

OBJECTIVES: Patients with olfactory dysfunction (OD) frequently report symptoms of depression. The objective of this study was to determine how clinical characteristics and olfactory-related quality of life (QoL) measures associate with the likelihood for major depressive disorders (MDDs). METHODS: A total of 192 OD patients were included. Olfactory function was measured using all three subtests of the Sniffn' Sticks test. Olfactory-related quality of life (QoL) was evaluated using the Questionnaires of Olfactory Dysfunction (QOD)-negative (NS) and -positive statement (PS). The likelihood for MDD was assessed using the Patients Health Questionnaire-2 (PHQ-2). Demographics and disease-specific variables (etiology and duration of OD) were collected. Univariate and multivariable analyses were used to associate disease-specific variables and the QOD with the outcome of the PHQ-2. Additionally, the predictive ability of the QOD-NS to predict depressive symptoms was calculated. RESULTS: In univariate analysis, COVID-19 related smell loss, the QOD-NS, and the QOD-PS were significantly associated with the PHQ-2. In multivariable analyses adjusting for QoL measures, the QOD-NS (ß = 0.532, p < 0.001) and sinonasal OD (compared with postinfectious OD) were significantly associated with the PHQ-2 (ß = 0.146, p = 0.047). When omitting QoL measures from multivariable analyses, only COVID-19 related OD (compared with postinfectious OD) was significantly associated with the PHQ-2 (ß = 0.287, p = 0.009). A QOD-NS score > 20.5 had 70.13% sensitivity and 76.32% specificity for detecting symptoms of depression. CONCLUSION: Our results suggest that COVID-19 related OD might be associated with a higher likelihood for MDD. Furthermore, we showed that the QOD-NS score might be helpful to predict symptoms of depression in OD patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1829-1834, 2022.

Identifying Olfactory Phenotypes to Differentiate Between COVID-19 Olfactory Dysfunction and Sinonasal Inflammatory Disease.

The objective of this study was to identify specific olfactory phenotypes-patterns of olfactory performance-across distinct cohorts with or without olfactory dysfunction (OD). Adult patients underwent testing via a novel olfactory testing methodology in 1 of 4 groups based on health status: sinonasal inflammatory condition (chronic rhinosinusitis or allergic rhinitis), ≥4 weeks of self-reported OD after resolved COVID-19 infection, Alzheimer's disease, and healthy control. Participants' scores for each scent were normalized on a scale of 0 to 1 relative to their worst and best scores. Agglomerative hierarchal cluster analysis was performed on normalized data for the COVID-19 and sinonasal cohorts. Resulting clusters from the penultimate merger revealed a sensitivity of 81% and specificity of 63% for the detection of patients with COVID-19. These results support that there are olfactory phenotypes that may discriminate COVID-19 OD from sinonasal inflammatory disease. These phenotypes will likely become increasingly leveraged in the workup and treatment of patients with OD.

Olfactory dysfunction as a post-infectious symptom of SARS-CoV-2 infection.

The unexpected onset smell and taste disability was being recognized as a COVID-19 related symptom. Loss of smell might occur alone or be followed by other COVID-19 symptoms, such as a dry cough, fever, headache, and shortness of breath. Other virus infections have been linked to anosmia (parainfluenza, rhinovirus, SARS, and others), affecting up to 20% of the adult population, which is much less common than SARS-CoV-2 infection. A hypothesis about the pathophysiology of post-infectious olfactory loss is that viruses could make an inflammatory response of the nasal mucosa or directly damage the olfactory neuroepithelium. However, in patients with COVID-19, loss of smell may occur without other rhino logic symptoms or suggestive nasal inflammation. According to evidence, anosmia-related SARS-CoV-2 could be a new viral syndrome unique to COVID-19. Furthermore, through experimental intranasal inoculation in mice, SARS-CoV-2 can be inoculated into the olfactory neural circuitry. This disease has not had the required focus, most likely because it is not life-threatening in and of itself. Though patients' quality of living is significantly reduced as their olfactory ability is lost, resulting in lowering and inadequate appetite, excessive or unbalanced food consumption, as well as an overall sense of insecurity. This review aims to give a quick overview of the latest epidemiological research, pathological mechanisms for the dysfunction of smell, and taste in patients infected with SARS-CoV-2. In addition, the initial diagnosis and treatment options for dysfunction are also discussed.