Prevalence and 24-month recovery of olfactory dysfunction in COVID-19 patients: A multicentre prospective study.

OBJECTIVE: To investigate the prevalence and recovery of olfactory dysfunction (OD) in COVID-19 patients 24 months after the infection. METHODS: From 22 March 2020 to 5 June 2022, 251 COVID-19 patients were followed in three European medical centres. Olfactory function was assessed with subjective patient-reported outcome questionnaires and odour identification tests at baseline, 6, 12, 18 and 24 months postinfection. The predictive values of epidemiological and clinical data were investigated with multivariate analysis. RESULTS: One hundred and seventy-one patients completed the evaluations. The odour identification test revealed that 123 patients (50.8%) had OD at baseline. The prevalence of persistent psychophysical abnormalities at 6, 12, 18 and 24 months post-COVID-19 was 24.2%, 17.9%, 5.8% and 2.9%, respectively (p = 0.001). Parosmia occurred in 40 patients (23.4%) and lasted 60 ± 119 days. At 2 years, 51 patients (29.8%) self reported that their olfaction was unnormalised. Older patients had better odour identification evaluations at baseline (p < 0.001) but those with OD reported lower odour identification test scores at the end of the follow-up. Parosmia occurred more frequently in young patients. The olfactory training was significantly associated with higher values of Sniffin' Sticks tests at 18 months postinfection (rs = 0.678; p < 0.001). CONCLUSION: Two years post-COVID-19, 29.8% of patients reported persistent OD, but only 2.9% had abnormal identification psychophysical evaluations.

[Interpretation of the 2021 American Academy of Allergy, Asthma and Immunology expert consensus on the treatment of postinfectious olfactory dysfunction].

Respiratory tract viruses are the second leading cause of olfactory dysfunction. Between 2019 to 2022, the world has been plagued by the problem of olfaction caused by the COVID-19. As we learn more about the impact of severe acute respiratory syndrome coronavirus 2（SARS-CoV-2）, with the recognition that olfactory dysfunction is a key symptom of this disease process, there is a greater need than ever for evidence-based management of postinfectious olfactory dysfunction（PIOD）. The Clinical Olfactory Working Group has proposed theconsensus on the roles of PIOD. This paper is the detailed interpretation of the consensus.

The Olfactory Dysfunction of COVID-19.

Until the coronavirus disease 2019 (COVID-19) pandemic, much of the scientific community and the general public lacked an appreciation of the impact of decreased smell function on everyday life, including the importance of this sensory system for safety, nutrition, and overall quality of life. It is now well established that the SARS-CoV-2 virus inflicts measurable but frequently reversible smell loss during its acute phase. Indeed, in many studies such loss is the most common symptom of COVID-19. Permanent or long-term deficits (i.e., deficits lasting over a year) may occur in up to 30% of those who have been infected, including the development of odor distortions (dysosmias; parosmias). This review presents up-to-date information on the epidemiology, severity, and pathophysiology of COVID-19-related smell dysfunction, including its association with psychological and neurological sequelae.

Olfactory dysfunction in patients with Wilson's Disease.

INTRODUCTION: Many neurodegenerative disorders are associated with olfactory dysfunction (OD), but little is known about OD in Wilson's Disease (WD). We evaluated olfactory function in patients with WD. MATERIAL AND METHODS: OD was examined in 68 patients with WD and 70 sex- and age-matched healthy controls using subjective testing with 'Sniffin Sticks'. Threshold discrimination identification (TDI) score and its three components (odour detection threshold, discrimination, and identification) were assessed. RESULTS: Compared to controls, patients with WD had a significantly weaker sense of smell in terms of TDI (p < 0.01), odour discrimination (p < 0.01), and identification (p < 0.01), but not in terms of odour detection threshold (p = 0.27). Patients with predominantly neurological symptoms were characterised by greater OD by TDI (p < 0.01), odour detection threshold (p = 0.01), and discrimination (p = 0.03). The presence of pathological lesions (p = 0.04) in brain magnetic resonance imaging and generalised brain atrophy (p = 0.02) predisposed to worse TDI. In the WD group, weak inverse correlations between age and TDI score (r = -0.27), odour detection threshold (r = -0.3), and discrimination (r = -0.3) were found. Male gender was a risk factor for abnormal TDI in both WD and controls (both p = 0.02). CONCLUSIONS: Patients with WD, particularly older individuals, more frequently had OD than healthy volunteers. Predominantly neurological symptoms, and the presence of typical brain MRI changes, predisposed patients with WD to smell disorders.

Olfactory Function and Olfactory Disorders. / Riechen und Riechstörungen.

The sense of smell is important. This became especially clear to patients with infection-related olfactory loss during the SARS-CoV-2 pandemic. We react, for example, to the body odors of other humans. The sense of smell warns us of danger, and it allows us to perceive flavors when eating and drinking. In essence, this means quality of life. Therefore, anosmia must be taken seriously. Although olfactory receptor neurons are characterized by regenerative capacity, anosmia is relatively common with about 5 % of anosmic people in the general population. Olfactory disorders are classified according to their causes (e. g., infections of the upper respiratory tract, traumatic brain injury, chronic rhinosinusitis, age) with the resulting different therapeutic options and prognoses. Thorough history taking is therefore important. A wide variety of tools are available for diagnosis, ranging from short screening tests and detailed multidimensional test procedures to electrophysiological and imaging methods. Thus, quantitative olfactory disorders are easily assessable and traceable. For qualitative olfactory disorders such as parosmia, however, no objectifying diagnostic procedures are currently available. Therapeutic options for olfactory disorders are limited. Nevertheless, there are effective options consisting of olfactory training as well as various additive drug therapies. The consultation and the competent discussion with the patients are of major importance.

Olfactory Dysfunction: Etiology, Diagnosis, and Treatment.

BACKGROUND: Disorders of the sense of smell have received greater attention because of the frequency with which they occur as a symptom of SARS-CoV-2 infection. Olfactory dysfunction can lead to profound reduction in quality of life and may arise from many different causes. METHODS: A selective literature review was conducted with consideration of the current version of the guideline issued by the Association of the Scientific Medical Societies in Germany. RESULTS: The cornerstones of diagnosis are the relevant medical history and psychophysical testing of olfactory function using standardized validated tests. Modern treatment strategies are oriented on the cause of the dysfunction. While treatment of the underlying inflammation takes precedence in patients with sinunasal dysosmia, olfactory training is the primary treatment option for other forms of the disorder. The prognosis is determined not only by the cause of the olfactory dysfunction and the patient's age, but also by the olfactory performance as measured at the time of diagnosis. CONCLUSION: Options for the treatment of olfactory dysfunction are available but limited, depending on the cause. It is therefore important to carry out a detailed diagnostic work-up and keep the patient informed of the expected course and prognosis.

SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice.

BACKGROUND: Depression and dysosmia have been regarded as primary neurological symptoms in COVID-19 patients, the mechanism of which remains unclear. Current studies have demonstrated that the SARS-CoV-2 envelope (E) protein is a pro-inflammatory factor sensed by Toll-like receptor 2 (TLR2), suggesting the pathological feature of E protein is independent of viral infection. In this study, we aim to ascertain the role of E protein in depression, dysosmia and associated neuroinflammation in the central nervous system (CNS). METHODS: Depression-like behaviors and olfactory function were observed in both female and male mice receiving intracisternal injection of E protein. Immunohistochemistry was applied in conjunction with RT-PCR to evaluate glial activation, blood-brain barrier status and mediators synthesis in the cortex, hippocampus and olfactory bulb. TLR2 was pharmacologically blocked to determine its role in E protein-related depression-like behaviors and dysosmia in mice. RESULTS: Intracisternal injection of E protein evoked depression-like behaviors and dysosmia in both female and male mice. Immunohistochemistry suggested that the E protein upregulated IBA1 and GFAP in the cortex, hippocampus and olfactory bulb, while ZO-1 was downregulated. Moreover, IL-1ß, TNF-α, IL-6, CCL2, MMP2 and CSF1 were upregulated in both cortex and hippocampus, whereas IL-1ß, IL-6 and CCL2 were upregulated in the olfactory bulb. Furtherly, inhibiting microglia, rather than astrocytes, alleviated depression-like behaviors and dysosmia induced by E protein. Finally, RT-PCR and immunohistochemistry suggested that TLR2 was upregulated in the cortex, hippocampus and olfactory bulb, the blocking of which mitigated depression-like behaviors and dysosmia induced by E protein. CONCLUSIONS: Our study demonstrates that envelope protein could directly induce depression-like behaviors, dysosmia, and obvious neuroinflammation in CNS. TLR2 mediated depression-like behaviors and dysosmia induced by envelope protein, which could serve as a promising therapeutic target for neurological manifestation in COVID-19 patients.

[Olfaction and respiratory viruses A relationship revealed by Covid-19]. / Odorat et virus respiratoires :une relation révélée par la Covid-19.

The sense of smell has been underestimated for a long time in humans. It has been brought to the fore by its sudden disappearance during the Covid-19 pandemic of which anosmia (complete loss of smell) is one of the major symptoms. However, respiratory viruses have long been associated with smell disorders, 25% of which are linked to a viral infection. Olfaction begins in the nose within the olfactory epithelium which has the particularity of containing neurons in direct contact with the environment. Several respiratory viruses are known for their replicative capacity within this epithelium. This is particularly the case for the flu virus (influenza) and bronchiolitis (respiratory syncytial virus) but their tropism for this tissue is much lower than SARS-CoV-2. The understanding of the SARS-CoV-2 pathophysiology in the nasal cavity makes it possible to reveal part of the links between viral infection and olfactory disorders.

Title: Odorat et virus respiratoires :une relation révélée par la Covid-19. Abstract: L'odorat, sens pendant longtemps sous-estimé chez l'homme, a été mis sur le devant de la scène par sa soudaine disparition, survenue pendant la pandémie de Covid-19, dont l'anosmie est un des symptômes majeurs. Pourtant, depuis longtemps, les virus respiratoires ont été associés aux troubles de l'odorat, dont 25 % seraient liés à une infection virale. L'olfaction débute dans le nez, au sein d'un épithélium olfactif qui a la particularité de contenir des neurones en contact direct avec l'environnement. Plusieurs virus respiratoires sont connus pour leur capacité réplicative au sein de cet épithélium. C'est notamment le cas du virus de la grippe (influenza) et du virus de la bronchiolite (VRS, pour virus respiratoire syncytial), mais leur tropisme pour ce tissu est bien moindre que celui du SARS-CoV-2. La physiopathologie de ce virus dans la cavité nasale a permis de commencer à comprendre les liens existant entre une infection virale et les troubles de l'olfaction.

Olfactory-related quality of life impacts psychological distress in people with COVID-19: The affective implications of olfactory dysfunctions.

BACKGROUND: Coronavirus disease 2019 (COVID-19) often causes chemosensory impairment, and olfactory dysfunctions may have negative consequences on psychological distress. This study aimed at assessing which dimension of perceived olfactory disfunctions (i.e., subjective olfactory capability, smell-related problems, or olfactory-related quality of life [QoL]) was most associated with psychological distress in people diagnosed with COVID-19. METHODS: 364 participants (65 men and 299 women) diagnosed with COVID-19 on average 7 months prior to the beginning of the study were recruited between June 5 and 21, 2021, to take part in an online cross-sectional survey. Participants answered questions on demographics, clinical factors, perceived olfactory functioning, and psychological distress. Hierarchical multiple linear regression analysis was conducted, assessing the role of demographics, clinical factors, and perceived olfactory functioning dimensions on psychological distress. RESULTS: More than half of the participants met the cut-off for all perceived olfactory dysfunctions scales and psychological distress. Being women, smoker, with comorbidities, and greater severity of COVID-19 symptoms were associated with higher scores on psychological distress. Among perceived olfactory functioning scales, only impairment in olfaction QoL was associated with psychological distress. LIMITATIONS: Limitations concerned the cross-sectional nature of the study and the unbalanced sample in terms of gender. CONCLUSIONS: The study confirmed the core intertwining between mood, perceived QoL, and olfactory functioning, showing how impairments in olfactory processing are strongly correlated with psychological distress through the impact they have on the perceived QoL.

Olfactory dysfunction in COVID-19: a marker of good prognosis?

INTRODUCTION: In May 2020, the World Health Organization recognized olfactory dysfunction as a COVID-19 symptom. The presence of hyposmia/anosmia may be a marker of good prognosis in COVID-19. OBJECTIVE: To associate the presence of olfaction disorder to the clinical condition severity in patients with COVID-19. METHODS: Individuals with the flu syndrome caused by SARS-CoV-2, diagnosed from March to June 2020, were recruited. They were divided into three groups: mild flu syndrome, severe flu syndrome (admitted to hospital wards) and critical illness (admitted to the ICU). Inpatients were interviewed by telephone contact after hospital discharge and their medical records were also evaluated regarding complementary test results. Outpatients answered an electronic questionnaire containing only clinical information. RESULTS: A total of 261 patients participated in the study: 23.75% with mild flu syndrome, 57.85% with severe flu syndrome and 18.40% with critical illness. A total of 66.28% patients with COVID-19 had olfaction disorders. In approximately 56.58% of the individuals the smell alterations lasted between 9 days and 2 months. There was a significantly higher proportion of individuals with olfactory dysfunction in the group with mild flu syndrome than in the severe flu syndrome group (mild × severe - p < 0.001; Odds Ratio = 4.63; 95% CI [1.87-10.86]). This relationship was also maintained between patients with mild flu syndrome and critically-ill patients (mild × critical - p <  0.001; Odds Ratio = 9.28; 95% CI [3.52-25.53]). CONCLUSION: Olfaction dysfunction was significantly more prevalent in patients with mild flu syndrome in COVID-19. It may be a predictor of a good prognosis for this infection. New population-based studies must be carried out to corroborate these findings.

Cognitive and functional connectivity impairment in post-COVID-19 olfactory dysfunction.

OBJECTIVES: To explore the neuropsychological profile and the integrity of the olfactory network in patients with COVID-19-related persistent olfactory dysfunction (OD). METHODS: Patients with persistent COVID-19-related OD underwent olfactory assessment with Sniffin' Sticks and neuropsychological evaluation. Additionally, both patients and a control group underwent brain MRI, including T1-weighted and resting-state functional MRI (rs-fMRI) sequences on a 3 T scanner. Morphometrical properties were evaluated in olfaction-associated regions; the rs-fMRI data were analysed using graph theory at the whole-brain level and within a standard parcellation of the olfactory functional network. All the MR-derived quantities were compared between the two groups and their correlation with clinical scores in patients were explored. RESULTS: We included 23 patients (mean age 37 ± 14 years, 12 females) with persistent (mean duration 11 ± 5 months, range 2-19 months) COVID-19-related OD (mean score 23.63 ± 5.32/48, hyposmia cut-off: 30.75) and 26 sex- and age-matched healthy controls. Applying population-derived cut-off values, the two cognitive domains mainly impaired were visuospatial memory and executive functions (17 % and 13 % of patients). Brain MRI did not show gross morphological abnormalities. The lateral orbital cortex, hippocampus, and amygdala volumes exhibited a reduction trend in patients, not significant after the correction for multiple comparisons. The olfactory bulb volumes did not differ between patients and controls. Graph analysis of the functional olfactory network showed altered global and local properties in the patients' group (n = 19, 4 excluded due to artifacts) compared to controls. Specifically, we detected a reduction in the global modularity coefficient, positively correlated with hyposmia severity, and an increase of the degree and strength of the right thalamus functional connections, negatively correlated with short-term verbal memory scores. DISCUSSION: Patients with persistent COVID-19-related OD showed an altered olfactory network connectivity correlated with hyposmia severity and neuropsychological performance. No significant morphological alterations were found in patients compared with controls.

Antibody response, associated symptoms and profile of patients presumably infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study.

BACKGROUND: Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and antibody response intensity associated with taste or smell disorders. METHODS: We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave. RESULTS: The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea. CONCLUSIONS: Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with an antibody response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.

Effectiveness and safety of PRP on persistent olfactory dysfunction related to COVID-19.

INTRODUCTION: Olfactory dysfunction (OD) is a well know symptom of coronavirus disease 2019 (COVID-19), accounting for 48 to 85% of patients. In 1 to 10% of cases, patients develop a chronic olfactory dysfunction (COD), lasting more than 6 months. Recently, platelet-rich plasma (PRP) was used in patients with non-COVID-19 COD and authors reported encouraging results. METHODS: In the present study, we investigated the usefulness and safety of PRP injection in 56 patients with COVID-19 COD by the Sniffing Stick test (TDI score) and a linker-scale from 0 (none) to 3 (strong) and we compare the result to a control group. RESULTS: At 1 month post-PRP injection, the mean TDI scores significantly improved by 6.7 points in the PRP group (p < 0,001), the mean self-assessment of improvement in smell function was 1.8 (mild-to-moderate) in the PRP group, which was significantly higher than the score (0.3) in the control group (p < 0,001). CONCLUSION: Our results showed that PRP in the olfactory cleft can increase the olfactory threshold 1 month after the injection. Moreover, our results suggest that timing of treatment may be an important factor and that PRP is a safe treatment, because no adverse effects were reported throughout the study. TRIAL REGISTRATION NUMBER: NCT05226546.

Efficacy of pentasodium diethylenetriamine pentaacetate in ameliorating anosmia post COVID-19.

BACKGROUND: COVID-19 has been frequently demonstrated to be associated with anosmia. Calcium cations are a mainstay in the transmission of odor. One of their documented effects is feedback inhibition. Thus, it has been advocated that reducing the free intranasal calcium cations using topical chelators such as pentasodium diethylenetriamine pentaacetate (DTPA) could lead to restoration of the olfactory function in patients with post-COVID-19 anosmia. METHODOLOGY: This is a randomized controlled trial that investigated the effect of DTPA on post-COVID-19 anosmia. A total of 66 adult patients who had confirmed COVID-19 with associated anosmia that continued beyond three months of being negative for SARS-CoV-2 infection. The included patients were randomly allocated to the control group that received 0.9 % sodium chloride-containing nasal spray or the interventional group that received 2 % DTPA-containing nasal spray at a 1:1 ratio. Before treatment and 30 days post-treatment, the patients' olfactory function was evaluated using Sniffin' Sticks, and quantitative estimation of the calcium cations in the nasal mucus was done using a carbon paste ion-selective electrode test. RESULTS: Patients in the DTPA-treated group significantly improved compared to the control group in recovery from functional anosmia to hyposmia. Additionally, they showed a significant post-treatment reduction in the calcium concentration compared to the control group. CONCLUSION: This study confirmed the efficacy of DTPA in treating post-COVID-19 anosmia.

Persistent olfactory dysfunction in mild COVID-19 patients: A descriptive study of the characteristics and association with other symptoms.

INTRODUCTION: Post-COVID olfactory dysfunction continues to be studied due to the controversy of the mechanisms involved. The aim was to investigate the olfactory dysfunctions in association with other post-COVID symptoms. MATERIAL AND METHODS: Observational, descriptive and single-center study. The patients had confirmed mild COVID-19 and subjective olfactory dysfunction of more than a month of evolution, which was assessed by Sniffin' Sticks Olfactory Test. RESULTS: A total of 86 patients participated. The mean age was 37.2 years (SD 9.82). 70.9% reported parosmia and 46.5% symptoms of brain fog. A pathological test result was obtained in 72.1% of the participants. The most failed pen was 11 (apple) in 76.7%. Anosmia of pen 15 (anise) was reported more frequently in 24.4% and cacosmia of pen 9 (garlic) in 27.9%. We observed a significant association between patients who reported parosmias and brain fog (RR 2.18; p=0.018), also between parosmia and phantosmia (RR 6.042; p<0.001). CONCLUSION: There is some pathological selectivity for certain test pens, a higher prevalence of cognitive symptoms and many patients with combined parosmia and brain fog.

Comparison of prevalence and evolution of COVID-19 olfactory disorders in patients infected by D614 (wild) and B.1.1.7. Alpha variant: a brief report.

OBJECTIVES: To investigate the prevalence and the evolution of olfactory disorders (OD) related to coronavirus disease 2019 (COVID-19) in patients infected during the first and the second European waves. METHODS: From March 2020 to October 2020, COVID-19 patients with OD were recruited and followed over the 12-month post-infection. The following data were collected: demographic, treatments, vaccination status, and olfactory function. Olfaction was assessed with the Olfactory Disorder Questionnaire (ODQ), and threshold, discrimination, and identification (TDI) test. Outcomes were compared between patients of the first wave (group 1: wild/D614G virus) and the second wave (group 2: B.1.1.7. Alpha variant) at 1-, 3- and 12-month post-infection. RESULTS: Sixty patients completed the evaluations accounting for 33 and 27 patients in group 1 and 2, respectively. The 1-month TDI score (23.7 ± 5.3) was significantly lower in group 2 compared to group 1 (29.8 ± 8.7; p = 0.017). Proportion of normosmic patients at 1-month post-infection was significantly higher in group 1 compared to group 2 (p = 0.009). TDI scores only significantly increased from 1- to 3-month post-infection in anosmic and hyposmic patients. Focusing on There was a negative association between the 1-month ODQ and the 1-month TDI (rs = - 0.493; p = 0.012). ODQ was a significant predictor of TDI scores at 3- and 12-month post-infection. The 12-month prevalence of parosmia was 60.6% in group 1 and 42.4% in group 2, respectively. There was no significant influence of oral corticosteroid treatment, adherence to an olfactory training and vaccination status on the olfactory outcomes. CONCLUSIONS: Patients of the second wave (Alpha B.1.1.7. variant) reported significant higher proportion of psychophysical test abnormalities at 1-month post-infection than patients infected during the first wave (D614G virus).

[The alleged mechanisms of olfactory disorders in the new coronavirus infection]. / Vozmozhnye mekhanizmy narushenii obonyaniya pri novoi koronavirusnoi infektsii.

In March 2020, the World Health Organization (WHO) announced the beginning of the COVID-19 pandemic, which continues to the present. A change in the sense of smell, up to the complete disappearance of odors, is regarded as one of the early symptoms of the disease. Sometimes anosmia was the only sign of infection of the patient. As is known, a disturbance of the sense of smell indicates a serious pathology of the brain, such as the consequences of traumatic brain injuries, strokes, Alzheimer's disease, Parkinson's disease, autoimmune diseases, a side-effect of drug therapy. The review is dedicated to the pathogenesis of anosmia in COVID-19. For a better understanding of the pathogenesis, the article presents a brief anatomy and physiology of the olfactory organ as well as the probable mechanisms of anosmia: encephalitis, inflammatory edema of the olfactory cleft, olfactory epithelium damage, apoptosis of bipolar neurons, damage of olfactory cell cilia and damage of olfactory bulbs. Because of the rapid accumulation of information on this topic, there is a need to structure, periodic systematization and presentation to a wide range of specialists.