Clinical and Imaging Evaluation of COVID-19-Related Olfactory Dysfunction.

BACKGROUND: Olfactory dysfunction has been reported in 47.85% of COVID patients. It can be broadly categorized into conductive or sensorineural olfactory loss. Conductive loss occurs due to impaired nasal air flow, while sensorineural loss implies dysfunction of the olfactory epithelium or central olfactory pathways. OBJECTIVES: The aim of this study was to analyze the clinical and imaging findings in patients with COVID-related olfactory dysfunction. Additionally, the study aimed to investigate the possible mechanisms of COVID-related olfactory dysfunction. METHODS: The study included 110 patients with post-COVID-19 olfactory dysfunction, and a control group of 50 COVID-negative subjects with normal olfactory function. Endoscopic nasal examination was performed for all participants with special focus on the olfactory cleft. Smell testing was performed for all participants by using a smell diskettes test. Olfactory pathway magnetic resonance imaging (MRI) was done to assess the condition of the olfactory cleft and the dimensions and volume of the olfactory bulb. RESULTS: Olfactory dysfunction was not associated with nasal symptoms in 51.8% of patients. MRI showed significantly increased olfactory bulb dimensions and volume competed to controls. Additionally, it revealed olfactory cleft edema in 57.3% of patients. On the other hand, radiological evidence of sinusitis was detected in only 15.5% of patients. CONCLUSION: The average olfactory bulb volumes were significantly higher in the patients' group compared to the control group, indicating significant edema and swelling in the olfactory bulb in patients with COVID-related olfactory dysfunction. Furthermore, in most patients, no sinonasal symptoms such as nasal congestion or rhinorrhea were reported, and similarly, no radiological evidence of sinusitis was detected. Consequently, the most probable mechanism of COVID-related olfactory dysfunction is sensorineural loss through virus spread and damage to the olfactory epithelium and pathways.

A comparative neuroimaging perspective of olfaction and higher-order olfactory processing: on health and disease.

Olfactory dysfunction is often the earliest indicator of disease in a range of neurological and psychiatric disorders. One tempting working hypothesis is that pathological changes in the peripheral olfactory system where the body is exposed to many adverse environmental stressors may have a causal role for the brain alteration. Whether and how the peripheral pathology spreads to more central brain regions may be effectively studied in rodent models, and there is successful precedence in experimental models for Parkinson's disease. It is of interest to study whether a similar mechanism may underlie the pathology of psychiatric illnesses, such as schizophrenia. However, direct comparison between rodent models and humans includes challenges under light of comparative neuroanatomy and experimental methodologies used in these two distinct species. We believe that neuroimaging modality that has been the main methodology of human brain studies may be a useful viewpoint to address and fill the knowledge gap between rodents and humans in this scientific question. Accordingly, in the present review article, we focus on brain imaging studies associated with olfaction in healthy humans and patients with neurological and psychiatric disorders, and if available those in rodents. We organize this review article at three levels: 1) olfactory bulb (OB) and peripheral structures of the olfactory system, 2) primary olfactory cortical and subcortical regions, and 3) associated higher-order cortical regions. This research area is still underdeveloped, and we acknowledge that further validation with independent cohorts may be needed for many studies presented here, in particular those with human subjects. Nevertheless, whether and how peripheral olfactory disturbance impacts brain function is becoming even a hotter topic in the ongoing COVID-19 pandemic, given the risk of long-term changes of mental status associated with olfactory infection of SARS-CoV-2. Together, in this review article, we introduce this underdeveloped but important research area focusing on its implications in neurological and psychiatric disorders, with several pioneered publications.

Changes in olfactory bulbus volume and olfactory sulcus depth in the chronic period after COVID-19 infection.

BACKGROUND: Although there are a limited number of studies investigating the changes in olfactory bulb volume (OBV) and olfactory sulcus depth (OSD) values in the acute and subacute periods after COVID-19 infection, there are no studies conducted in the chronic period. PURPOSE: The aim of this study is to reveal the changes in OBV and OSD after COVID-19 in the chronic period. MATERIAL AND METHODS: A total of 83 people were included in our study, including 42 normal healthy individuals (control group) and 41 patients with COVID-19 infection (10-12 months after infection). RESULTS: The COVID-19 group included 41 patients with the mean age 40.27 ± 14.5 years and the control group included 42 individuals with the mean age 40.27 ± 14.4. The mean OBV was 67.97 ± 14.27 mm3 in the COVID-19 group and 94.21 ± 7.56 mm3 in the control group. The mean OSD was 7.98 ± 0.37 mm in the COVID-19 group and 8.82 ± 0.74 mm in the control group. Left, right, and mean OBVs and OSD were significantly lower in patients with COVID- 19 than the control individuals (all p < .05). CONCLUSION: Our findings show that COVID-19 infection causes a significant decrease in the OBV and OSD measurements in the chronic period.

Peripheral and central smell regions in COVID-19 positive patients: an MRI evaluation.

BACKGROUND: Coronaviruses may lead to invasion of the central nervous system. PURPOSE: To investigate the effects of COVID-19 infection on smell using cranial magnetic resonance imaging (MRI). MATERIAL AND METHODS: Cranial MRI scans of 23 patients with COVID-19 (patient group [PG]) and 23 healthy controls (HCs) were evaluated. Peripheric (olfactory bulb [OB] volume and olfactory sulcus [OS] depth) and central (insular gyrus and corpus amygdala areas) smell regions were measured. RESULTS: Smell loss was present in nine patients (39.1%) in the PG. The means of the disease duration and antiviral treatment were 3.00 ± 2.35 and 5.65 ± 1.72 days, respectively. OB volumes of the PG were significantly lower than those of the HCs bilaterally. However, no significant differences were observed between the OS depth, insular gyrus, and corpus amygdala areas of both groups. The left corpus amygdala areas were both increased with the increased disease (P = 0.035, r = 0.442) and treatment durations (P = 0.037, r = 0.438). In the PG, longer treatment duration, increase in C-reactive protein (CRP), lymphocyte count decrease, and positive thoracic computed tomography (CT) involvement were related to OS depth decrease. Right corpus amygdala areas increased in patients with COVID-19 with increased D-dimer values, and thoracic CT involvement was detected. CONCLUSION: COVID-19 disease affects the peripheric smell region of OBs and does not affect the central smell regions of the insular gyrus and corpus amygdala areas. The importance of our study is to detect MRI findings in patients with COVID-19 leading to odor disorders. These findings may help in diagnosing the disease at an early stage.

Systemic inflammatory markers and psychophysical olfactory scores in coronavirus disease 2019 patients: is there any correlation?

OBJECTIVE: To analyse the correlations between olfactory psychophysical scores and the serum levels of D-dimer, C-reactive protein, ferritin, lactate dehydrogenase, procalcitonin and neutrophil-to-lymphocyte ratio in coronavirus disease 2019 patients. METHODS: Patients underwent psychophysical olfactory assessment with the Connecticut Chemosensory Clinical Research Center test, and determination of blood serum levels of the inflammatory markers D-dimer, C-reactive protein, ferritin, lactate dehydrogenase, procalcitonin and neutrophil-to-lymphocyte ratio within 10 days of the clinical onset of coronavirus disease 2019 and 60 days after. RESULTS: Seventy-seven patients were included in this study. D-dimer, procalcitonin, ferritin and neutrophil-to-lymphocyte ratio correlated significantly with severe coronavirus disease 2019. No significant correlations were found between baseline and 60-day Connecticut Chemosensory Clinical Research Center test scores and the inflammatory markers assessed. CONCLUSION: Olfactory disturbances appear to have little prognostic value in predicting the severity of coronavirus disease 2019 compared to D-dimer, ferritin, procalcitonin and neutrophil-to-lymphocyte ratio. The lack of correlation between the severity and duration of olfactory disturbances and serum levels of inflammatory markers seems to further suggest that the pathogenetic mechanisms underlying the loss of smell in coronavirus disease 2019 patients are related to local rather than systemic inflammatory factors.

Clinical Features of Olfactory Dysfunction in COVID-19 Patients.

BACKGROUND: The aim of this study was to evaluate the subjective and objective olfactory function in coronavirus disease 2019 (COVID-19) patients and the effect of olfactory training. METHODS: A prospective cohort study was performed in 53 patients who recovered from COVID-19 and visited our tertiary hospital. Subjective olfactory function was evaluated using the 11-point Likert scale (0-10) and the Korean version of the Questionnaire of Olfactory Disorders (QOD). Objective olfactory function was evaluated using Cross-Cultural Smell Identification Test (CC-SIT). Confirmed patients were followed up after 2 months of olfactory training. RESULTS: The median, interquartile range (Q1-Q3) score of subjective olfactory function significantly deteriorated in patients with olfactory dysfunction (OD) than in those without OD, even after 3 months of onset (11-point Likert scale, 8, 6-9 vs. 10, 10-10; short version of QOD-negative statements, 19, 16-21 vs. 21, 21-21; QOD-visual analogue scale, 7, 1-13 vs. 0, 0-0; all P < 0.001). However, the objective olfactory function was not significantly different between the two groups (median, interquartile range; 11, 9-11 vs. 11, 9-11, P = 0.887). The percentage of patients with objective hyposmia (CC-SIT ≤ 10) was also not significantly different (47.4% vs. 40%, P = 0.762). OD in COVID-19 was normalized after 2 months of olfactory training in 70% of patients even after 3 months of olfactory impairment. CONCLUSION: Although subjective olfactory function is significantly decreased in the OD group, the objective olfactory function was not significantly different. Moreover, olfactory training is effective in COVID-19 patients with OD.

COVID-19 and Parkinson's disease: Defects in neurogenesis as the potential cause of olfactory system impairments and anosmia.

Anosmia, a neuropathogenic condition of loss of smell, has been recognized as a key pathogenic hallmark of the current pandemic SARS-CoV-2 infection responsible for COVID-19. While the anosmia resulting from olfactory bulb (OB) pathology is the prominent clinical characteristic of Parkinson's disease (PD), SARS-CoV-2 infection has been predicted as a potential risk factor for developing Parkinsonism-related symptoms in a significant portion of COVID-19 patients and survivors. SARS-CoV-2 infection appears to alter the dopamine system and induce the loss of dopaminergic neurons that have been known to be the cause of PD. However, the underlying biological basis of anosmia and the potential link between COVID-19 and PD remains obscure. Ample experimental studies in rodents suggest that the occurrence of neural stem cell (NSC) mediated neurogenesis in the olfactory epithelium (OE) and OB is important for olfaction. Though the occurrence of neurogenesis in the human forebrain has been a subject of debate, considerable experimental evidence strongly supports the incidence of neurogenesis in the human OB in adulthood. To note, various viral infections and neuropathogenic conditions including PD with olfactory dysfunctions have been characterized by impaired neurogenesis in OB and OE. Therefore, this article describes and examines the recent reports on SARS-CoV-2 mediated OB dysfunctions and defects in the dopaminergic system responsible for PD. Further, the article emphasizes that COVID-19 and PD associated anosmia could result from the regenerative failure in the replenishment of the dopaminergic neurons in OB and olfactory sensory neurons in OE.

A systematic review and meta-analysis protocol examining the clinical characteristics and epidemiological features of olfactory dysfunction (OD) in coronavirus disease 2019 (COVID-19).

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has caused recurring and major outbreaks in multiple human populations around the world. The plethora of clinical presentations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described extensively, of which olfactory dysfunction (OD) was established as an important and common extrapulmonary manifestation of COVID-19 infection. The aim of this protocol is to conduct a systematic review and meta-analysis on peer-reviewed articles which described clinical data of OD in COVID-19 patients. METHODS: This research protocol has been prospectively registered with the Prospective Register of Systematic Reviews (PROSPERO; CRD42020196202). CINAHL, ClinicalTrials.gov, Cochrane Central, EMBASE, MEDLINE and PubMed, as well as Chinese medical databases China National Knowledge Infrastructure (CNKI), VIP and WANFANG, will be searched using keywords including 'COVID-19', 'coronavirus disease', '2019-nCoV', 'SARS-CoV-2', 'novel coronavirus', 'anosmia', 'hyposmia', 'loss of smell', and 'olfactory dysfunction'. Systematic review and meta-analysis will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Articles will be screened according to pre-specified inclusion and exclusion criteria to extract studies that include new clinical data investigating the effect of COVID-19 on olfactory dysfunction. Included articles will be reviewed in full; data including patient demographics, clinical characteristics of COVID-19-related OD, methods of olfactory assessment and relevant clinical outcomes will be extracted. Statistical analyses will be performed using the Comprehensive Meta-Analysis version 3. DISCUSSION: This systematic review and meta-analysis protocol will aim to collate and synthesise all available clinical evidence regarding COVID-19-related OD as an important neurosensory dysfunction of COVID-19 infection. A comprehensive search strategy and screening process will be conducted to incorporate broad clinical data for robust statistical analyses and representation. The outcome of the systematic review and meta-analysis will aim to improve our understanding of the symptomatology and clinical characteristics of COVID-19-related OD and identify knowledge gaps in its disease process, which will guide future research in this specific neurosensory defect. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42020196202.

Gaining Back What Is Lost: Recovering the Sense of Smell in Mild to Moderate Patients After COVID-19.

The purpose of our cohort study was to quantify olfactory deficits in Coronavirus disease 2019 (COVID-19) patients using Sniffin' Sticks and a pre-post design to evaluate olfactory recovery. Thirty adult patients with laboratory-confirmed mild to moderate forms of COVID-19 underwent a quantitative olfactory test performed with the Sniffin' Sticks test (SST; Burghardt, Wedel, Germany), considering olfactory threshold (T), odor discrimination (D), and odor identification (I). Results were presented as a composite TDI score (range 1-48) that used to define functional anosmia (TDI ≤ 16.5), hyposmia (16.5 < TDI < 30.5), or functionally normal ability to smell (TDI ≥ 30.5). Patients also self-evaluated their olfactory function by rating their ability to smell on a visual analogue scale (Visual Analog Scale rating) and answering a validated Italian questionnaire (Hyposmia Rating Scale). Patients were tested during hospitalization and about 2 months after symptoms onset. During the hospitalization, the overall TDI score indicated that our cohort had impairments in their olfactory ability (10% was diagnosed with anosmia and more than 50% were hyposmic). Almost all patients showed a significant improvement at around 1 month following the first test and for all the parts of the SST except for odor identification. None of the subjects at 1 month was still diagnosed with anosmia. We also quantified the improvement in the TDI score based on initial diagnosis. Anosmic subjects showed a greater improvement than hyposmic and normosmic subjects. In conclusion, within a month time window and 2 months after symptoms' onset, in our cohort of patients we observed a substantial improvement in the olfactory abilities.

Viral infection and smell loss: The case of COVID-19.

Olfactory disorders have been increasingly reported in individuals infected with SARS-CoV-2, the virus causing the coronavirus disease 2019 (COVID-19). Losing the sense of smell has a strong impact on the quality of life, since it may lead to malnutrition, weight loss, food poisoning, depression, and exposure to dangerous chemicals. Individuals who suffer from anosmia (inability to smell) also cannot sense the flavor of food, which is a combination of taste and smell. Interestingly, infected individuals have reported sudden loss of smell with no congested nose, as is frequently observed in common colds or other upper respiratory tract infections. These observations suggest that SARS-CoV-2 infection leads to olfactory loss through a distinct mechanism, which is still unclear. This article provides an overview of olfactory loss and the recent findings relating to COVID-19. Possible mechanisms of SARS-CoV-2-induced olfactory loss are also discussed.

A Systematic Review of the Neuropathologic Findings of Post-Viral Olfactory Dysfunction: Implications and Novel Insight for the COVID-19 Pandemic.

BACKGROUND: Post-viral olfactory dysfunction is a common cause of both short- and long-term smell alteration. The coronavirus pandemic further highlights the importance of post-viral olfactory dysfunction. Currently, a comprehensive review of the neural mechanism underpinning post-viral olfactory dysfunction is lacking. OBJECTIVES: To synthesize the existing primary literature related to olfactory dysfunction secondary to viral infection, detail the underlying pathophysiological mechanisms, highlight relevance for the current COVID-19 pandemic, and identify high impact areas of future research. METHODS: PubMed and Embase were searched to identify studies reporting primary scientific data on post-viral olfactory dysfunction. Results were supplemented by manual searches. Studies were categorized into animal and human studies for final analysis and summary. RESULTS: A total of 38 animal studies and 7 human studies met inclusion criteria and were analyzed. There was significant variability in study design, experimental model, and outcome measured. Viral effects on the olfactory system varies significantly based on viral substrain but generally include damage or alteration in components of the olfactory epithelium and/or the olfactory bulb. CONCLUSIONS: The mechanism of post-viral olfactory dysfunction is highly complex, virus-dependent, and involves a combination of insults at multiple levels of the olfactory pathway. This will have important implications for future diagnostic and therapeutic developments for patients infected with COVID-19.

Neurological injuries in COVID-19 patients: direct viral invasion or a bystander injury after infection of epithelial/endothelial cells.

A subset of patients with coronavirus 2 disease (COVID-19) experience neurological complications. These complications include loss of sense of taste and smell, stroke, delirium, and neuromuscular signs and symptoms. The etiological agent of COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), an RNA virus with a glycoprotein-studded viral envelope that uses ACE2 (angiotensin-converting enzyme 2) as a functional receptor for infecting the host cells. Thus, the interaction of the envelope spike proteins with ACE2 on host cells determines the tropism and virulence of SARS-CoV-2. Loss of sense of taste and smell is an initial symptom of COVID-19 because the virus enters the nasal and oral cavities first and the epithelial cells are the receptors for these senses. Stroke in COVID-19 patients is likely a consequence of coagulopathy and injury to cerebral vascular endothelial cells that cause thrombo-embolism and stroke. Delirium and encephalopathy in acute and post COVID-19 patients are likely multifactorial and secondary to hypoxia, metabolic abnormalities, and immunological abnormalities. Thus far, there is no clear evidence that coronaviruses cause inflammatory neuromuscular diseases via direct invasion of peripheral nerves or muscles or via molecular mimicry. It appears that most of neurologic complications in COVID-19 patients are indirect and as a result of a bystander injury to neurons.

Clinical and Radiological Evaluations of COVID-19 Patients With Anosmia: Preliminary Report.

OBJECTIVES/HYPOTHESIS: To investigate clinical and radiological features of olfactory clefts of patients with mild coronavirus disease 2019 (COVID-19). STUDY DESIGN: Prospective non controlled study. METHODS: Sixteen COVID-19 patients were recruited. The epidemiological and clinical data were extracted. Nasal complaints were assessed through the 22-item Sino-Nasal Outcome Test. Patients underwent psychophysical olfactory testing, olfactory cleft examination, and computed tomography (CT) scans. RESULTS: Sixteen anosmic patients were included. The mean Sniffin' Sticks score was 4.6 ± 1.7. The majority of patients had no endoscopical abnormality, with a mean olfactory cleft endoscopy score of 0.6 ± 0.9. The olfactory clefts were opacified in three patients on the CT scan. The mean radiological olfactory cleft score was 0.7 ± 0.8. There were no significant correlations between clinical, radiological, and psychophysical olfactory testing. CONCLUSIONS: The olfactory cleft of anosmic COVID-19 patients is free regarding endoscopic examination and imaging. The anosmia etiology is not related to edema of the olfactory cleft. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2526-2531, 2020.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

A COVID-19 patient with intense burning pain.

A woman in her forties with asthma and COPD was admitted to a general medical floor with respiratory symptoms, body aches, and anosmia. Reverse transcription polymerase chain reaction detected severe acute respiratory syndrome coronavirus-2. Admission labs, including biomarkers of the systemic immunological dysfunction seen in many cases of coronavirus disease 2019 (COVID-19), were within normal ranges. On the second day of admission, she developed neck and back pain that was constant, burning in quality, and exacerbated by light touch and heat. Wearing clothing caused pain and interfered with her sleep. The area was tender to light finger stroke. The patient was given acetaminophen, NSAIDs, and opioids with no relief of pain. However, gabapentin was effective. At follow-up 1 month later, her symptoms were improved and still relieved by gabapentin. Neuropathic pain was seen in over 2% of COVID-19 patients in one observational study. The pain seen in our case was bilateral, involved an area innervated by multiple levels of spinal nerves, and was limited to the back. While it is rare, a significant number of COVID-19 patients are afflicted by neuropathic pain, and our case illustrates that gabapentin may be effective.

Micronutrients as immunomodulatory tools for COVID-19 management.

COVID-19 rapidly turned to a global pandemic posing lethal threats to overwhelming health care capabilities, despite its relatively low mortality rate. The clinical respiratory symptoms include dry cough, fever, anosmia, breathing difficulties, and subsequent respiratory failure. No known cure is available for COVID-19. Apart from the anti-viral strategy, the supports of immune effectors and modulation of immunosuppressive mechanisms is the rationale immunomodulation approach in COVID-19 management. Diet and nutrition are essential for healthy immunity. However, a group of micronutrients plays a dominant role in immunomodulation. The deficiency of most nutrients increases the individual susceptibility to virus infection with a tendency for severe clinical presentation. Despite a shred of evidence, the supplementation of a single nutrient is not promising in the general population. Individuals at high-risk for specific nutrient deficiencies likely benefit from supplementation. The individual dietary and nutritional status assessments are critical for determining the comprehensive actions in COVID-19.

Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters.

Anosmia is one of the most prevalent symptoms of SARS-CoV-2 infection during the COVID-19 pandemic. However, the cellular mechanism behind the sudden loss of smell has not yet been investigated. The initial step of odour detection takes place in the pseudostratified olfactory epithelium (OE) mainly composed of olfactory sensory neurons surrounded by supporting cells known as sustentacular cells. The olfactory neurons project their axons to the olfactory bulb in the central nervous system offering a potential pathway for pathogens to enter the central nervous system by bypassing the blood brain barrier. In the present study, we explored the impact of SARS-CoV-2 infection on the olfactory system in golden Syrian hamsters. We observed massive damage of the OE as early as 2 days post nasal instillation of SARS-CoV-2, resulting in a major loss of cilia necessary for odour detection. These damages were associated with infection of a large proportion of sustentacular cells but not of olfactory neurons, and we did not detect any presence of the virus in the olfactory bulbs. We observed massive infiltration of immune cells in the OE and lamina propria of infected animals, which may contribute to the desquamation of the OE. The OE was partially restored 14 days post infection. Anosmia observed in COVID-19 patient is therefore likely to be linked to a massive and fast desquamation of the OE following sustentacular cells infection with SARS-CoV-2 and subsequent recruitment of immune cells in the OE and lamina propria.

Ageusia and anosmia, a common sign of COVID-19? A case series from four countries.

Over the course of the pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple new clinical manifestations, as the consequence of the tropism of the virus, have been recognized. That includes now the neurological manifestations and conditions, such as headache, encephalitis, as well as olfactory and taste disorders. We present a series of ten cases of RT-PCR-confirmed SARS-CoV-2-infected patients diagnosed with viral-associated olfactory and taste loss from four different countries.