The efficacy of intranasal insulin in the treatment of post viral persistent olfactory dysfunction: a systematic review.

While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID-19) olfactory dysfunction (OD), persistent COVID-19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling. COVID-19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID-19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti-viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann-Whitney tests with multi-comparison adjustment. Viral RNA was assessed through RT-PCR using the COVID-19 N2 primer. Thirty-five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non-COVID no OD). Significant differences in IFN-λ1 (p = 0.007) and IFN-γ (p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN-α2 levels were elevated in COVID OD versus no OD (p = 0.026). Mean IFN-γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non-COVID no OD (p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts. IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID-19 persistent OD compared to those with no OD and no prior history of COVID-19 infection.

BackgroundPatients with persistent COVID‐19 olfactory dysfunction (OD) commonly report parosmia. Understanding the impact of COVID‐19 OD and parosmia is critical to prioritizing research and interventions. In this study we investigate the impact of parosmia and other clinical and disease characteristics on health state utility values (HUVs) for those with persistent COVID‐19 OD.MethodsPatients with a history of COVID‐19 diagnosis and persistent OD were recruited from a tertiary medical center and a social media support forum for chemosensory dysfunction. Clinical characteristics and disease‐specific symptoms were obtained along with self‐reported history of smell function and presence of parosmia. HUVs were calculated using indirect (EuroQol 5‐Dimension [EQ‐5D]) and direct (VAS) measures.ResultsOur study included 286 subjects (75.52% women) with persistent COVID‐19–related OD. Results (mean ± standard deviation) of HUVs based on EQ‐5D and VAS were 0.81 ± 0.14 and 0.73 ± 0.21, respectively. Mean self‐reported smell function (on a 0‐10 scale) was 9.67 ± 1.25 pre–COVID‐19, 0.93 ± 2.34 at diagnosis, and 3.39 ± 2.32 at most current assessment. A total of 89.16% of the subjects reported parosmia and 24.13% sought medical care for anosmia. Seeing an MD for OD (p < 0.001), female gender (EQ‐5D only, p = 0.002), a history of chronic pain (p < 0.05) and depression/anxiety (EQ‐5D only, p < 0.001) predicted worse health. Parosmia and persistent symptoms, such as shortness of breath, were associated with lower EQ‐5D and VAS scores, but did not independently predict poorer health scores on multivariable analysis.ConclusionPersistent COVID‐19 OD results in health states comparable to other chronic diseases.

Olfactory dysfunction has emerged as a prominent symptom of COVID-19, persisting in a subset of patients even after recovery. This scoping review aims to explore the potential of intranasal insulin as a treatment modality for persistent post-COVID-19 olfactory dysfunction. A comprehensive literature search was conducted to gather relevant studies examining the role of intranasal insulin in treating olfactory dysfunction, particularly in post-COVID-19 cases. Studies were included investigating intranasal insulin's mechanisms, efficacy, safety, and clinical outcomes. The review synthesizes findings from various studies suggesting the therapeutic potential of intranasal insulin in improving olfactory function. Research highlights the influence of intranasal insulin on neuroprotection, neurogenesis, and synaptic plasticity within the olfactory system, providing insights into its mechanisms of action. Furthermore, preliminary clinical evidence suggests improvements in olfactory sensitivity and intensity following intranasal insulin administration in post-COVID-19 patients with persistent olfactory dysfunction. While initial findings are encouraging, further rigorous investigations, including clinical trials with larger cohorts, are essential to validate these observations, ascertain optimal dosage regimens, and establish the safety and efficacy of intranasal insulin. This review provides a foundation for future research directions aimed at harnessing the therapeutic potential of intranasal insulin in addressing olfactory dysfunction following COVID-19.

Olfactory dysfunction after COVID‐19: metanalysis reveals persistence in one-third of patients 6 months after initial infection

To evaluate the therapeutic efficacy of intranasal insulin for treating persistent and refractory olfactory dysfunction following viral infections. A comprehensive literature search was performed across PubMed, SCOPUS, Embase, Web of Science, Google Scholar, and the Cochrane Database, covering all indexed articles up to July 2025. Studies were included if they evaluated changes in olfactory scores in patients receiving intranasal insulin, either compared with a control group (placebo or no treatment) or between pre- and post-treatment measurements. Secondary outcomes, including serum glucose and insulin levels and the proportion of patients achieving significant olfactory recovery, were also assessed. Eight studies including 457 participants were reviewed. Intranasal insulin was generally associated with improvements in olfactory scores. Delivery via absorbable materials may enhance both threshold and discrimination outcomes, whereas self-administration showed minimal benefit. Some studies also reported higher rates of substantial olfactory recovery with absorbable material-based delivery. Combination therapy with intranasal insulin and budesonide was suggested to further improve threshold scores. Overall, treatment was well tolerated, with no major changes in serum glucose levels, though one study reported a mild hypoglycemic event. Current evidence suggests that intranasal insulin, particularly via absorbable material-based delivery, may offer therapeutic benefit for persistent post-viral olfactory dysfunction, with possible additional gains from corticosteroid coadministration. These findings remain preliminary and require confirmation in larger, well-controlled studies.

Persistent olfactory dysfunction was noted in many patients upon COVID-19 infection recovery. The research on its management has been very limited, especially among the Southeast Asian population. We aim to investigate the role of olfactory rehabilitation and topical corticosteroids among post-COVID-19 olfactory dysfunction patients in Sabah, Malaysia. Adult Malaysians with persistent olfactory dysfunction 1 month post-COVID-19 recovery without a prior history of olfactory dysfunction were recruited. In total, 31 patients with post-COVID olfactory dysfunction were randomly assigned into 3 groups via online randomizer. 10 patients were given an olfactory rehabilitation kit only (Group 1), another 10 received combination therapy (Momethasone furoate/olfactory rehabilitation kit) (Group 2); while 11 patients were given information related to post-viral olfactory dysfunction (Control). All groups were followed up for an average duration of 6 months. Olfactory function was evaluated by Top International Biotech Smell Identification Test (TIBSIT) scores and Olfactory Disorder Questionnaire (eODQ) before randomization, at 3 and 6 months after recruitment. The baseline characteristics of patients were similar in all groups. Generally, patients who received olfactory rehabilitation kit only, combination therapy and control all showed statistically significant improvement in TIBSIT scores after 6 months (p=0.011, p=0.001, p=0.002 respectively). It was noted that TIBSIT scores for combination therapy were statistically significantly higher than control (p=0.036) at 3 months. However, no statistically significant difference was shown at 6 months (p=0.085). As for the olfactory kit-only group, no statistically significant difference in TIBSIT scores at 3 months (p=0.973) and 6 months (p=0.387) were noted when compared to control. In terms of mean eODQ scores, statistically significant improvements were seen in all 3 groups (p=0.011, p=0.001, p=0.045). The data obtained showed no superiority of intervention for post-COVID olfactory dysfunction when compared to control.

Persistent olfactory dysfunction (OD) and cognitive impairment are among the most frequently reported sequelae of long term infection with SARS-CoV-2 (long COVID-19). However, the association between these conditions remains unclear. This study investigated the correlation between OD and cognitive impairment in patients recovering from COVID-19 to identify the implications for therapeutic and rehabilitation strategies. A cross-sectional study of adult patients diagnosed with long COVID was conducted at a healthcare centre in Brazil. Olfactory function was assessed using the Connecticut Chemosensory Clinical Research Centre (CCCRC) test, and cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA). Statistical analyses included odds ratios (OR) and linear regression to explore the association between OD severity and cognitive scores, adjusting for potential confounders such as age, sex, and comorbidities. A total of 241 patients (age: 48.60 ± 12.68 years; 73% female) were included. Cognitive impairment (MoCA < 23) was present in 64% of the participants. OD was identified in 92% of the patients and ranged from mild to anosmia. Linear regression analysis showed a weak yet statistically significant correlation between the CCCRC and MoCA scores (R = 0.14, p = 0.02). An OR of 2.87 (95% CI: 1.57-5.25, p = 0.00) indicated higher odds of cognitive impairment in patients with severe OD. This study supports the hypothesis that there is a weak yet significant association between OD and cognitive impairment in patients with long COVID. These findings underscore the importance of early screening for olfactory dysfunction as a potential marker of cognitive monitoring and the need for intervention in this population.

PurposeThis study investigated nasal cytological alterations in patients with persistent post-viral olfactory dysfunction. The primary objective was to evaluate the role of immune dysregulation and chronic local inflammation within the nasal mucosa in sustaining long-term olfactory impairment.MethodsAn observational case-control study was conducted at the Otorhinolaryngology Department of the University of Rome Tor Vergata. Thirty-six patients with persistent olfactory dysfunction were compared to two control groups: one comprised subjects recovered from SARS-CoV-2 infection without olfactory impairment, and the other included individuals without a history of COVID-19 or olfactory dysfunction. Psychophysical olfactory function was assessed using the TDI (Threshold, Discrimination, and Identification) test. Nasal cytology samples were obtained via nasal brushing at the level of the olfactory cleft and stained using the May-Grunwald-Giemsa technique. Cellular alterations were evaluated using a semiquantitative grading system.ResultsPatients with persistent olfactory dysfunction exhibited increased lymphocytes and neutrophils compared to both control groups, indicating ongoing local inflammation. Ciliocytophthoria was notably present in a significant portion of the olfactory dysfunction group, while absent or minimally present in controls. Eosinophils and mast cells were rare across all groups.ConclusionPersistent post-viral olfactory dysfunction is associated with sustained immune activation and epithelial damage localized to the olfactory cleft. Elevated lymphocytes, neutrophils, and ciliocytophthoria emphasize the role of chronic inflammation in the pathogenesis of prolonged olfactory deficits. These findings highlight the potential utility of targeted therapies to modulate immune responses and promote olfactory recovery in affected patients.

Determining the characteristics, type, and severity of olfactory dysfunction in patients with long COVID is important for the prognosis and potential treatment of the affected population. To describe the sociodemographic and clinical features of patients with long COVID who develop persistent olfactory dysfunction. This cross-sectional study, conducted at a rehabilitation center at a public university in the Amazon region of Brazil between September 9, 2020, and October 20, 2021, comprised 219 patients with long COVID and self-reported neurologic symptoms. Of these 219 patients, 139 received a diagnosis of chronic olfactory dysfunction, as confirmed by the Connecticut Chemosensory Clinical Research Center (CCCRC) test. Clinical diagnosis of long COVID. Electronic case report forms were prepared for the collection of sociodemographic and clinical data. Patients' sense of smell was evaluated via a CCCRC test, and the association of olfactory dysfunction with aspects of daily life was recorded using a questionnaire. Of the 219 patients included in the study, 164 (74.9%) were women, 194 (88.6%) were between 18 and 59 years of age (mean [SD] age, 43.2 [12.9] years), 206 (94.1%) had more than 9 years of education, and 115 (52.5%) had a monthly income of up to US $192.00. In the study group, 139 patients (63.5%) had some degree of olfactory dysfunction, whereas 80 patients (36.5%) had normosmia. Patients with olfactory dysfunction had a significantly longer duration of long COVID symptoms than those in the normosmia group (mean [SD], 242.7 [101.9] vs 221.0 [97.5] days; P = .01). Among patients with anosmia, there was a significant association between olfactory dysfunction and daily activities, especially in terms of impairment in hazard detection (21 of 31 patients [67.7%]), personal hygiene (21 of 31 patients [67.7%]), and food intake (21 of 31 patients [67.7%]). Univariable logistic regression analyses found that ageusia symptoms were associated with the occurrence of olfactory dysfunction (odds ratio [OR], 11.14 [95% CI, 4.76-26.07]; P < .001), whereas headache (OR, 0.41 [95% CI, 0.22-0.76]; P < .001) and sleep disorders (OR, 0.48 [95% CI, 0.26-0.92]; P = .02) showed an inverse association with the occurrence of olfactory dysfunction. Olfactory dysfunction is one of the most important long-term neurologic symptoms of COVID-19, with the highest prevalence seen among women, adults, and outpatients. Patients with olfactory dysfunction may experience persistent severe hyposmia or anosmia more than 1 year from the onset of symptoms, suggesting the possibility of the condition becoming a permanent sequela.

Olfactory dysfunction is a hallmark symptom of COVID-19 disease resulting from the SARS-CoV-2 virus. The cause of the sudden and usually temporary anosmia that most people suffer from COVID-19 is likely entirely peripheral-inflammation and other damage caused by the virus in the sensory epithelium inside the upper recesses of the nasal cavity can damage or prevent chemicals from properly activating the olfactory sensory neurons. However, persistent olfactory dysfunction from COVID-19, in the form of hyposmia and parosmia (decreased or altered smell) may affect as many as 15 million people worldwide. This epidemic of olfactory dysfunction is thus a continuing public health concern. Mounting evidence suggests that the SARS-CoV-2 virus itself or inflammation from the immune response in the nasal sensory epithelium may invade the olfactory bulb, likely via non-neuronal transmission. COVID-19-related long-term olfactory dysfunction and early damage to olfactory and limbic brain regions suggest a pattern of degeneration similar to that seen in early stages of Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Thus, long-term olfactory dysfunction coupled with cognitive and emotional disturbance from COVID-19 may be the first signs of delayed onset dementia from neurodegeneration. Few treatments are known to be effective to prevent further degeneration, but the first line of defense against degeneration may be olfactory and environmental enrichment. There is a pressing need for more research on treatments for olfactory dysfunction and longitudinal studies including cognitive and olfactory function from patients who have recovered from even mild COVID-19.NEW & NOTEWORTHY More than 15 million people worldwide experience persistent COVID-19 olfactory dysfunction, possibly caused by olfactory bulb damage. SARS-CoV-2 can cause inflammation and viral invasion of the olfactory bulb, initiating a cascade of degeneration similar to Alzheimer's disease and Lewy body disease. People who have had even mild cases of COVID-19 show signs of degeneration in cortical areas connected with the olfactory system. These data suggest a wave of post-COVID dementia in the coming decades.

BackgroundOlfactory dysfunction significantly impacts daily life, affecting safety, appetite, and sensory enjoyment. Olfactory receptor neurons (ORNs) are essential for odor detection, but environmental exposure can lead to dysfunction. Regeneration of these neurons is crucial for maintaining olfactory function, and elevated calcium levels in nasal mucus are linked to this dysfunction.ObjectiveThe study evaluated chitosan nasal gel for persistent olfactory dysfunction lasting over 6 months, focusing on ORNs regeneration and reduced calcium levels in nasal mucus.MethodsA randomized, double-blind trial included 215 participants with persistent olfactory dysfunction lasting over 6 months. Participants were divided into two groups: 116 received nasal chitosan gel, and 99 received a control sodium chloride gel. Over 3 months, 11 participants in the chitosan group and 9 in the control group were lost to follow-up. Olfactory function was assessed with the Sniffin' Sticks test, and calcium levels were measured before and after treatment.ResultsPatients treated with chitosan nasal gel showed an increased composite threshold, discrimination, identification (TDI) score, indicating improved olfactory function. Discrimination and identification scores improved, while threshold scores showed no significant change. Notably, while the total TDI score improved by 4.55 points, it did not reach the threshold for clinical significance (5.5 points). Furthermore, chitosan nasal gel significantly reduced calcium levels in nasal secretions compared to the control group. No improvement was observed in the placebo group, likely due to the strict inclusion criteria targeting individuals with treatment-resistant olfactory dysfunction persisting over 6 months.ConclusionThis small-scale pilot study highlights the potential of chitosan nasal gel to improve specific domains of olfactory dysfunction and reduce nasal calcium levels. However, further studies with larger sample sizes, diverse populations, and longer follow-up periods are required to confirm these preliminary findings.

Background Persistent olfactory dysfunction (OD) after long COVID-19 is an emerging global health concern. However, evidence-based therapies for persistent OD post-COVID-19 remain limited. This meta-analysis aims to assess the effectiveness of co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) combined with olfactory training (OT) for managing post-COVID-19 OD. Methods PubMed, Scopus, Web of Science, Embase, and Cochrane databases were systematically searched. Randomized clinical trials (RCTs) comparing um-PEA-LUT plus OT versus OT alone in treating post-COVID-19 OD were included. The primary outcome was the change in Sniffin’ Sticks test scores for Threshold, Discrimination, and Identification (TDI). Statistical analysis was performed using Review Manager software, and the results were presented as the mean difference (MD) with 95% confidence intervals (CI), employing a random-effect model. Results Four RCTs with a total of 367 patients were included in the meta-analysis. The combination of um-PEA-LUT and OT significantly improved the overall TDI score compared to OT alone (MD = 5.32, 95% CI [1.25, 9.39], p = 0.01). Significant heterogeneity in the TDI scores was identified but resolved through a sensitivity analysis, without affecting the significance of the results (MD = 6.86, 95% CI [2.82, 10.91], p = 0.0009). Conclusion The addition of um-PEA-LUT to OT resulted in significant improvements in the overall TDI score in patients with persistent post-COVID-19 OD. This finding offers a promising therapeutic option for managing this challenging condition. Disclosures All Authors: No reported disclosures

Introduction Persistent olfactory dysfunction was seen in many patients upon coronavirus disease 2019 (COVID-19) infection recovery. However, research on its management was very limited, especially among the Southeast Asian population. Objectives We aim to investigate the role of olfactory rehabilitation and topical corticosteroids among post-COVID-19 olfactory dysfunction patients in Malaysia, and at the same timeto determine factors leading to olfactory recovery post-COVID-19 infection. Methods Adult Malaysians with persistent olfactory dysfunction one month post-COVID-19 recovery were recruited. Thirty-one patients were randomly assigned into three groups with 10 patients being given olfactory training (Group 1), another 10 being given mometasone furoate nasal spray/olfactory training (Group 2), and 11 patients being assigned to the control group (Group 3). All groups were followed up for an average duration of six months. Olfactory function was evaluated by Top International Biotech Smell Identification Test (TIBSIT) scores and Olfactory Disorder Questionnaire (eODQ) prior to randomization, at three and six months after recruitment. Results The baseline characteristics of patients were similar in all groups. Generally, patients of all three groups showed a statistically significant improvement in the TIBSIT scores after six months. The TIBSIT scores for Group 2 were statistically significantly higher than the control at three months but not at six months. As for Group 1, no statistically significant differences in TIBSIT scores at both three and six months were noted when compared to control. Statistically significant improvements were seen in the eODQ scores in all three groups. Conclusion No superiority of intervention for post-COVID-19 olfactory dysfunction was seen compared to control.

Objectives: The study aimed to evaluate the effect of long-term olfactory training (OT) in patients with persistent olfactory dysfunction (OD) following coronavirus disease 2019 (COVID-19) infection. Patients and Methods: The study included patients who developed OD after COVID-19 infection between March 2021 and January 2022. Following the initial examination, olfactory Visual Analog Scale (VAS) scores were recorded before treatment and at 3, 6, and 12 months after treatment. Olfactory training was applied for a period of 12 months to all the patients diagnosed with persistent OD. The procedure was explained in a written document, and four intense smells (phenyl ethyl alcohol [rose], eucalyptol [eucalyptus], citronella [lemon], and eugenol [cloves]) in amber-colored jars were used. The OT scoring was interpreted as follows: 9-10 points, full recovery; 7-8 points, almost full recovery; 5-6 points, semi-recovery; 3-4 points, partial recovery; 1-2 points, no recovery. Kruskal-Wallis one-way analysis of variance was used to compare patients’ VAS scores, with post hoc analysis with Bonferroni correction. Results: Eighty-three patients (57 females, 26 males; mean age: 30.6±11.3 years; range, 17 to 62 years) were included in the analyses. The VAS score of all the patients was 0 before treatment. The mean VAS scores were 6.95±2.3 at three months, 7.59±2.13 at six months, and 7.96±1.97 at 12 months (p=0.0001). Full recovery of OD was obtained with OT in 41 (50%) patients, and one patient showed no recovery. Conclusion: Long-term OT is an effective treatment for persistent OD that developed after COVID-19 infection.

BackgroundMagnetic resonance imaging (MRI) is the gold standard in the etiological assessment of a persistent olfactory dysfunction (OD). While the utility of imaging in COVID‐19‐related OD has yet to be established, MRI is recommended in all patients with persistent OD. The high prevalence of the latter after SARS‐CoV‐2 infection means evaluating this strategy is an important public health matter.MethodsThe main objective was to examine the impact of systematic MRI on the management of patients with OD. All adult patients consulting for persistent OD (>2 months) after primary SARS‐COV‐2 infection (PCR) between March 2020 and December 2021 were included (n = 67). The secondary objective was to evaluate the relationship between the severity of the OD as measured by psychophysical testing (ETOC) and the volume of the olfactory bulb (OB) measured by MRI.ResultsAll patients underwent MRI, and none led to a change in diagnosis or treatment. Among them, 82% (55/67) were considered normal by the radiologist on initial interpretation. There were no significant differences (visual analysis or OB volume) between groups (mild, moderate, and severe hyposmia).ConclusionSystematic MRI may be unnecessary in patients whose persistent OD began soon (a few days) after confirmed SARS‐CoV‐2 infection.