Abstract
Olfactory dysfunction has emerged as a prominent symptom of post viral (COVID 19) rhinitis, persisting in a subset of patients even after recovery. Insulin (IN)receptors are found in the olfactory mucosa, and it has been noticed that IN treatment promotes olfactory sensory neuron regeneration, so it is included in the list of possible methods for treating olfactory impairment. To compare the effect of intranasal insulin films on improving post viral olfactory dysfunction in one group of patients and improving the prepared formulation by addition of another active ingredient (Budesonide) and study the percentage of recovery from this combination on another group of patients. The study included 250 patients of both sexes with post viral (COVID 19) olfactory dysfunction and divided into 2 groups Group A (n = 125 patients) received 100 IU of insulin combined with 10 mg budesonide and Group B (125 patients) received 100 IU of insulin only. Olfactory improvement in both groups after intranasal insulin fast dissolving film application were observed, olfactory scores were recorded in the group which received combined films containing Budesonide added to the insulin, signifying the important role of Budesonide together with insulin in improving Post viral olfactory dysfunction. Intranasal insulin therapy is a viable technique to treating post viral olfactory impairment since it improves both olfactory threshold and discrimination. Furthermore, combining Budesonide with insulin in the unique fast dissolving intranasal films produced significantly better results (p value < 0.001) in the therapy of post viral olfactory dysfunction.
Keywords: Budesonide, Intranasal insulin, Anosmia, COVID19
Introduction
Smell is a crucial sense for living a normal life and identifying dangerous odors that could risk one's life. Upper respiratory tract viral infections can produce variable degrees and durations of olfactory impairment or smell difficulties [1].
The anosmia prevalence is 70% among individuals with various virus infections such as rhinovirus, adenovirus, influenza and parainfluenza virus. The latest global coronavirus disease, COVID-19, is linked to SARS-CoV-2 (severe acute respiratory syndrome virus) [2].
At the start of the pandemic, anosmia was not anticipated to be a common COVID-19 side effect. Yet, as SARSCoV-2 disseminated over the world and the D614G variant (a mutation in the original Wuhan strain D614) arose, the incidence of anosmia among people diagnosed with the virus increased [3].
Numerous studies have investigated the impact of developing variants on anosmia incidence in COVID-19 patients. In accordance to a recently published review, the Omicron variant produces much less olfactory dysfunction (OD) than the other mutations by comparing data given on the impact of genetic variants on the development of anosmia [4, 5].
Furthermore, it has been claimed that minor spike mutations in the Alpha, Beta, and Delta variants alter the SARS-CoV-2 virus's ability to generate chemosensory abnormalities [6].
The pathophysiology of post-infectious anosmia in post COVID patients is unclear, but it is thought to involve olfactory neuroepithelium destruction or direct pathogen transmission to the brain through the olfactory nerve. Anosmia had approximately 62% prevalence in patients who tested positive for COVID19 [6, 7].
COVID-19 anosmia began as conductivity loss induced by regional inflammation in the OE was suggested as the etiology of anosmia in certain studies on COVID-19 patients. A conductive mechanism may also be suggested by the rapid onset of OD following SARS-CoV-2 infection. After SARS-CoV-2 attaches to cells and destroys multiple OE cell types, anosmia due to a sensorineural deficiency in COVID-19 may occur [8].
Our aim in this study is to compare the effect of intranasal insulin films on improving post viral (COVID19) olfactory dysfunction in one group of patients and improving the prepared formulation by addition of another active ingredient (Budesonide) and study the percentage of recovery from this combination on another group of patients.
Patients and Method
The current investigation was a prospective double blinded randomized clinical trial of 250 patients (sample size: phase 3 clinical trial) aged 18 to 70 years old of both sexes with post-COVID-19 olfactory dysfunction.
Inclusion Criteria
Adults aged 18 and up were included in the study if they were a confirmed case (positive PCR), recovered/discharged (2 negative PCR), suffering from abrupt recent anosmia or hyposmia with or without loss of taste, and were hospitalized or managed at home.
Exclusion Criteria
Patients with chronic sinusitis.
Patients’ nasal polyposis
Patients with history of nasal surgery, severe head trauma or any medical condition that may affect sense of smell.
Patients were Randomly Divided into 2 Groups Each Contains 125 Patients
Group A: 125 patients received 100 IU of insulin mixed with 10 mg budesonide in a fast-dissolving film administered intranasally in the olfactory cleft by nasal endoscope (4mm diameter, 0.30° nasal endoscope, KARL STORZ, Germany).
Group B: 125 patients were given 100 IU of insulin as a fast-dissolving film placed intranasally in the olfactory cleft by nasal endoscope, as indicated in Fig. 1.
Fig. 1.
Endoscopic application of the fast dissolving insulin film
Materials Include the Following
Insulin H Mix® (100 I.U./ml)
Hydroxypropyl methyl cellulose (HPMC)
Polyvinyl alcohol (PVA, m.wt. ca. 25,000)
Budesonide.
All reagents and chemicals were of analytical grade.
Phases of the Study
Phase 1: Insulin and budesonide compatibility was investigated using two experiments: temperature analysis (DSC) and UV spectroscopic analysis.
Phase 2: Formulation technique and examination of the films' physical, morphological, and releasing characteristics.
Phase 3: A randomized clinical trial assessing both groups clinical scent improvement.
Compatibility Studies
Spectroscopic Analysis
Using quartz cells with a path length of 10 mm, absorbance spectra covering the wavelength range of 200 to 1400 nm were anticipated using the UV-2600 series spectrometer (Agilent, Richardson, TX, USA), as illustrated in Fig. 2.
Fig. 2.
Differential Scanning Calorimetry (DSC)
Figure 3 depicts the DSC analysis of the crude drug (budesonide) and its physical mixing with equal amounts of insulin. Nitrogen gas was pushed out at a rate of 40 ml/min from 40 ml standard crucible aluminum pans with punctured lids containing 2–3 mg of sample material. The pans were heated at 5 °C each minute throughout a temperature range of 30–300 °C.
Fig. 3.
https://www.dksh.com/global-en/products/ins/ta-instruments-differential-scanning-calorimeters
Film Preparation and Characterization
The casting method was used to make insulin Budesonide fast-dissolving film formulations with the same HPMC/PVA ratio as in a prior work [9].
Film Physical Characterization
In the beginning, an attempt was made to physically characterize the resulting film compositions in order to study their appearance, content uniformity, thickness, and weight change. The appearance of the manufactured formulations was visually examined to determine the transparency of the films.[10]. To explore weight fluctuations, the average weight of five films was calculated [11]. The film's thickness was measured using a micrometer screw gauge [12].
Morphology of the Film Surface
An SEM (scanning electron microscopy) was applied to examine the morphology of insulin with budesonide film against plain film (Perkin Elmer, UK). A thin gold slip (150) was employed to shield a part of the film for two minutes at 0.3 atmospheric pressure while argon flowed through it.
Clinical Assessment
The clinical study was conducted according to The Code of Ethics of the World Medical Association for experiments involving humans. The study protocol was approved by Ethical Review Board of Faculty of medicine, Minia university, Minia, Egypt (ethical approval number is 12-183-2021 on (27/12/2021). The study was registered at Clinical Trials.gov ID: NCT05328414.
Two hundred and fifty patients with post-COVID olfactory loss, aged 18 to 70, participated in the study after providing informed consent and having an illness duration of more than two months. Each patient was checked by an ENT physician, who then performed an endoscopic examination of the nasal cavity.
From December 2021 to December 2023, all participants were invited to participate in a study that included two testing sessions each week for four weeks, totaling eight sessions at Minia University Hospital's ENT outpatient clinic. All patients were randomly assigned to one of two groups: Group A (n = 125), which included patients receiving both intranasal insulin and budesonide (56 men and 69 females), and Group B (n = 125), which included patients receiving only intranasal insulin (59 males and 66 females). Both groups had fast-dissolving film placed in the olfactory cleft using a 30o angle nasal endoscope. Up until week 4 following the initial intervention, these steps were performed twice weekly by a surgeon who was unaware of the treatment groups (8 visits). The patients were evaluated before and 30 min after the intervention using two validated measures. The tests include the olfactory discrimination test and the Sniffin's butanol threshold test. [13]
Regarding olfactory area safety, prior to the intervention, commencing with the second visit, all patients' local safety and adverse reactions to the intranasal application of combination insulin and budesonide in group A or insulin alone in group B were examined. The patient was asked about signs such as epistaxis, intranasal burning, or hypersecretions, and the olfactory region and surrounding nasal mucosa were endoscopically checked for evidence of mucosal congestion, mucosal atrophy, candida infection, or formula residues.
The raw materials used in both tests are widely used and well known by the different individuals in our country like starch, cinnamon, and coffee in our community without limitations except it is subjective.
Statistical Analysis
The one-way analysis of variance (ANOVA) test and student t-test were used in Graph Pad version 9 to conduct statistical analysis on the collected data, with a significant difference being considered if p ≤ 0.05.
Results
Clinical Assessment
As regards safety on olfactory region It is worth mentioning that there were no reported local side effects in both groups after administration of the intranasal fast dissolving films in all visits and Fig. 4 shows the endoscopic view of the olfactory cleft throughout the sessions of our intervention.
Fig. 4.
Normal appearance of the olfactory mucosa throughout the sessions of intervention
Descriptive Data
Table 1 shows that 125 (50%) patients received intranasal films containing a combination of Insulin and Budesonide while 125 (50%) patients received intranasal films containing only Insulin.
Table 1.
shows that 125 (50%) patients received intranasal films containing a combination of Insulin and Budesonide while 125 (50%) patients received intranasal films containing only Insulin
| Type of intervention | No | % |
|---|---|---|
| Group A: Insulin + Budesonide | 125 | 50 |
| Group B: Insulin | 125 | 50 |
Analyzed by independent sample t test
*Significant difference comparing between both groups at P value < 0.05
The number of patients is the same in each group.
Demographic Data of Both Groups
From the results shown in Table 2 we found that there was no statistically significant difference between the two study groups as regards age (P value = 0.9), sex (P value = 0.7), weight (P value = 0.9) and duration of anosmia (P value = 0.8).
Table 2.
demographic data of both groups
| Demographic data | Group A (insulin & steroid) 125 (50%) | Group B (insulin) 125 (50%) | p value |
|---|---|---|---|
| Age | |||
| Mean ± SD | 35.5 ± 14 | 35.4 ± 13.5 | 0.937 |
| Range | 16–72 | 17–73 | |
| Sex N (%) | |||
| Male | 56 (44.8%) | 59 (47.2%) | 0.703 |
| Female | 69 (55.2%) | 66 (52.8%) | |
| Weight | |||
| Mean ± SD | 76.6 ± 7.5 | 76.7 ± 7.74 | 0.932 |
| Range | 43–95 | 44–94 | |
| Duration of anosmia (by month) | |||
| Mean ± SD | 7.95 ± 6.72 | 8.13 ± 6.62 | 0.829 |
| Range | 1–24 | 1–24 | |
Analyzed by independent sample t test
*Significant difference comparing between both groups at P value < 0.05
There is no statistical difference between both groups (p > 0.05).
Butanol Threshold Test in Both Groups
Table 3 illustrating a significant difference between the magnitude of improvement between the two groups starting after the first session and denoting more improvement of olfaction in group A receiving combined Insulin and Budesonide than group B receiving only Insulin(p < 0.02).
Table 3.
Butanol Threshold test in both groups
| Butanol threshold test | Group A 125 (50%) | Group B 125 (50%) | p value | ||
|---|---|---|---|---|---|
| Mean ± SD | Range | Mean ± SD | Range | ||
| 1st session | 1 ± 0 | 1–1 | 1 ± 0 | 1–1 | > 0.99 |
| 2nd session | 1.61 ± 0.66 | 1–3 | 1.17 ± 0.37 | 1–2 | < 0.001* |
| 3rd session | 2.58 ± 1.08 | 1–5 | 1.94 ± 0.85 | 1–4 | < 0.001* |
| 4th session | 3.61 ± 1.56 | 1–7 | 2.98 ± 1.31 | 1–5 | 0.001* |
| 5th session | 4.49 ± 2.01 | 1–9 | 3.68 ± 1.48 | 2–6 | < 0.001* |
| 6th session | 5.23 ± 2.22 | 1–9 | 4.17 ± 1.77 | 2–7 | < 0.001* |
| 7th session | 5.67 ± 2.24 | 2–9 | 4.81 ± 2.13 | 3–8 | 0.002* |
| 8th session | 5.96 ± 2.28 | 2–9 | 5.08 ± 1.94 | 3–8 | < 0.001* |
Olfactory Discrimination Score in Both Groups
Table 4 shows the discrimination scores after each session for both groups and highlights statistically significant difference in discrimination scores between both study groups denoting higher discrimination scores in group A having intranasal films of Budesonide added to Insulin than group B receiving intranasal films of Insulin only (p > 0.02).
Table 4.
Olfactory discrimination score in both groups
| Identification test | Group A 125 (50%) | Group B 125 (50%) | p value | ||
|---|---|---|---|---|---|
| Mean ± SD | Range | Mean ± SD | Range | ||
| 1st session | 0.38 ± 0.48 | 0–1 | 0 ± 0.02 | 0–0.19 | < 0.001* |
| 2nd session | 1.24 ± 0.45 | 0–2 | 0.81 ± 0.38 | 0–1.03 | < 0.001* |
| 3rd session | 1.64 ± 0.66 | 1–3 | 1.10 ± 0.57 | 0–2 | < 0.001* |
| 4th session | 1.93 ± 0.76 | 1–3 | 1.59 ± 0.82 | 1–3 | 0.001* |
| 5th session | 2.21 ± 0.73 | 1–3 | 1.92 ± 0.75 | 1–3 | 0.002* |
| 6th session | 2.43 ± 0.63 | 1–3 | 2.01 ± 0.76 | 1–3 | < 0.001* |
| 7th session | 2.55 ± 0.56 | 1–3 | 2.09 ± 0.80 | 1–3 | < 0.001* |
| 8th session | 2.60 ± 0.55 | 1–3 | 2.10 ± 0.79 | 1–3 | < 0.001* |
Discussion
The pathophysiology of post-infectious anosmia in post COVID19 patients is unclear, but it is thought to involve olfactory neuroepithelium destruction or direct pathogen transmission to the brain through the olfactory nerve. Anosmia had approximately 62% prevalence in patients who tested positive for COVID19 [7].
COVID-19-induced anosmia was also associated with significant ethnic differences, with the prevalence being 3 folds higher in Caucasians than in Asians [14].
With the growing number of COVID-19 patients, the number of patients suffering from COVID-19-induced anosmia increased. COVID-19-induced anosmia will remain one of the most common disorders in otolaryngology for some period [15].
The natural course of post COVID olfactory dysfunction (PCOD) is spontaneous resolution by two weeks for 95% of patients, with mean recovery of 9 days [16, 17].
However, in some patients, persistent PCOD is a prevalent symptom, appearing in 75% of cases with persistent COVID symptoms. Risk factors for persistent PCOD include older age, diabetes mellitus, and longer duration of COVID-19 illness [18].
Our study showed olfactory improvement in both groups after intranasal insulin fast dissolving film application where much higher olfactory scores were recorded in the group which received combined films containing Budesonide added to the insulin, signifying the important role of Budesonide together with insulin in improving olfactory dysfunction post COVID-19.
Research by Boscolo-Rizzo et al. [19] discovered that up to 46% of cases of olfactory dysfunction (OD) persist over a 12-month period based on psychophysical olfactory evaluations [8].
According to several studies, hyposmia may result from a decrease in growth factor (GF) release since GFs stimulate the olfactory epithelium. The circumstances leading to GF-level decreases that may be accompanied with hyposmia were recently detailed in a study by Rezaeian 2018. Trace element and vitamin deficiencies, liver diseases, diabetes mellitus, metabolic syndrome, otolaryngologic and neurodegenerative problems are a few of these conditions, but they are not the only ones. Thus, increasing GF secretion may be a possibility for the treatment of hyposmia. Moreover, few studies have suggested that insulin raises GF levels [20].
Insulin signaling has been linked to olfaction directly through receptors present on mitral cells, and indirectly through its involvement in the regeneration of the olfactory mucosa or neural protection [21].
Our results were in line with Mohamad et al. [9], where patients were included in a randomized clinical trial comparing two groups each containing 20 patients. The intervention group received intranasal insulin films while the control group received plain films as a placebo. These intranasal films are made by the same authors and researchers of this thesis which is considered as an expansion and a next step after Mohamad et al. [9] clinical trial [9].
Results of our study coincided with Mohamad et al. [9] who found no significant differences between both groups before intervention as regards olfactory detection scores measured by butanol threshold test. When the average odor detection scores of the two groups were compared following treatment, it was discovered that the intervention group results were significantly greater than the placebo group results [9].
Daniel et al. [22] conducted a prospective study on 27 post COVID anosmic patients from January to May 2022. The olfactory assessment was carried out by Sniffin Sticks test. Gelfoam cottonoids moistened in 40 IU of NPH insulin were applied to the nasal roof of each nostril for 15 min during three sessions. Results showed that 93% of the sample improved. The mean TDI score at the beginning was 67%, and it increased to 83% at the end (p < 0.01) [22].
Mohamad et al. [11] performed a randomized clinical trial to evaluate the effect of insulin fast dissolving nasal films in improving health related quality of life (HRQOL). 40 post viral anosmic patients were included in the study and divided into intervention group receiving fast dissolving films containing insulin and a control group receiving intranasal placebo films. One intranasal film is administered in each nostril three times per week. The described Sniffin' Sticks test was utilized to investigate the quantitative performance of smell. After four weeks of therapy, the intervention group's quality of life in terms of physical, emotional, and social health was considerably (p-value < 0.0001) better than that of the control group [11].
Cherobin, et al. [23] conducted a prospective cohort study on 16 volunteers suffering from post-COVID anosmia. Two gelfoam® (absorbable gelatin sponge) pieces were placed into each olfactory cleft utilizing a Takahashi or bayonet forceps, a flashlight, a video endoscope, or a microscope. The pieces of the gelatin sponge are 1.0 cm by 1.5 cm in size. Twenty IU of neutral protamine Hagedorn (NPH) insulin were soaked in each. The gelatin sponge was allowed to dissolve naturally, and if it was still there the following visit, it was taken out before a fresh one was put in. For a month, the process was repeated twice a week, resulting in eight office visits. There were six (37.5%) males and ten (62.5%) females. The age range was 16 to 51 years old, with a mean of 32.1 years.
Conclusion
It is believed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages the olfactory neuroepithelium, resulting in post-coronavirus disease 2019 (COVID-19) olfactory dysfunction (PCOD)
Anosmia is thought to be present in 19–68% of patients and frequently occurs independently of coryzal symptoms. It frequently serves as the initial or only sign of COVID-19 disease.
For 95% of patients, PCOD naturally resolves on its own in two weeks, with a typical recovery time of nine days. On the other hand, in 75% of individuals with persistent COVID symptoms, persistent PCOD is a common symptom. Longer duration of COVID-19 disease, diabetes mellitus, and advanced age are risk factors for chronic PCOD.
Intranasal insulin treatment is a promising approach for treatment of post COVID-19 olfactory dysfunction by improving both the olfactory threshold reaching a mean of 5.0 after the end of sessions and olfactory discrimination reaching a mean of 2.1 at the end of sessions.
Adding Budesonide to insulin in the unique fast dissolving intranasal films yielded much more superior results in treatment of post COVID- 19 olfactory dysfunction with significant difference than the results of insulin alone as mean threshold reached 5.9 while the mean for discrimination test reached 2.6.
To summarize, Intranasal insulin therapy is a viable technique to treat post viral olfactory impairment since it improves both olfactory threshold and discrimination. Furthermore, combining Budesonide with insulin in the unique fast-dissolving intranasal films produced significantly better results in the therapy of post viral olfactory dysfunction.
Future Directions
As far as we know, our current study is the first study to be conducted for investigating the effect of combined intranasal insulin and budesonide for management of post COVID-19 anosmia. According to our outcome results, most of comparative parameters had guided us to ensure that our combined formulation can represent an encouraging approach therapeutic management of post COVID-19 olfactory dysfunction. However, due to limited research on this topic, we recommend further studies including larger populations in future.
Finding
Funding funded by personal efforts of the authors.
Declarations
Conflict of interest
Conflict of interest No.
Human or Animal Rights
Research involving human participants.
Informed consent
Informed consent was taken from each participant.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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