Abstract
There is no routinely determined treatment for olfactory dysfunction because of COVID-19. Saline irrigation and nasal corticosteroid treatments are safe and inexpensive methods, and have low side effects.In our study, we argue that saline nasal irrigation and topical corticosteroid treatment can be used in the treatment of patients with olfactory loss in all areas of rhinology. A total of 150 patients who admitted to our clinic with other symptoms or with only acute odor loss,diagnosed with COVID-19 with RT-PCR were divided into 3 equalgroups.Fiftypatients in Group 1 were not given any extra treatments. The other 50 patientsin Group 2 were given saline irrigation for treatment; and the 50 people in Group 3 were given both saline irrigation and nasal steroid sprayfor treatment. The “Subjective Olfactory Capability (SOC)” was used forolfactoryfunction evaluation of patients. Self-Rating Olfactory Score (SROS), and Olfactory Dysfunction Duration (ODD) were recorded on the 1st, 15th and 30th days. SROS of the group receiving NasalSaline + TriamcinoloneAcetonidetreatment on the 30thday was significantly higher thaninother groups(p−1–3 = 0.018,p2−3=0.033). Also, theODD wassignificantly reduced in this group compared to other groups(p−1–3=0.022,p2−3=0.028,). Topicaltriamcinolone treatmentwas found to be successful in the treatment of olfactory dysfunctiondue toCOVID-19. Nasal steroids, which are both inexpensive and have low side effect profiles,can be used safely in the treatment of patients with olfactory losses.
Keywords: COVID 19, Olfactory disorders, Steroid therapy, Olfactory test
Introduction
The new Coronavirus (COVID-19) is a serious infectious disease caused by SevereAcuteRespiratorySyndrome Coronavirus 2 (SARS- CoV-2) virus, which started in Hubei Province of China in 2019, and caused a pandemic all over the world in 2020 [1]. The diseasebegins with symptomssuch as fever, weakness, sore throat, cough, joint pains, diarrhea, loss of smell and taste, leading to respiratory failure and death with lung involvement. COVID-19 caused serious disruptions in healthcare systems all over the world. Approximately 90.000.000 newcases and 2.000.000 deaths were reported as of January 2021. For this reason, efforts to developnew vaccines and drugs to treatCOVID-19 are continuing very quickly. It was found that acute odor loss in COVID-19 can be an important symptom for the diagnosis of COVID-19. It was also determined that Angiotensin-Converting Enzyme-2 (ACE-2) and Transmembrane Serine Protease-2 (TMPRS2) receptors were present in the bronchial and respiratory epithelium, as well as in the olfactory epithelium with viral involvement in the disease. The disease also causes nasal inflammation, mucosal edema, and reduced airflow in olfactory cleft in the acute phase, like a classic upper respiratory tract disease. Loss of odor related to COVID-19 is often not a symptom that patients care about firstly;andtherefore, it is difficult to document and monitor these patientsbecausepatients without additional complaints are admitted to hospital later. Also, infection risks of patients and home quarantines prevent odor tests [2]. Although olfactory disorder is considered harmless for patients, a significant relation was foud in many studies between odor loss and 5years of mortality increase [3]. Infection is estimated to directly damage the olfactory cleft in viral olfactory dysfunction. In wider biopsy studies related toolfactoryepithelial, atypical findingssuch as metaplasia or neuroma formation were detected [4]. Increases were detected in bulb signalsin imaging studies performed with Magnetic Resonance Imaging (MRI) inPost-ViralOlfactoryDysfunction (PVOD) because of COVID-19 [5].
Olfactorydysfunction is a common disorder affecting more than 20% of general population. Among its causes, there are traumas, viral diseases or idiopathic causes. Post-Viral Olfactory Dysfunction (PVOD) is the most common form of it, and is seen in approximately 40% of population [5], impairing the quality of life in many patients, and leading toincreased morbidity rates. Spontaneous regression is very small in the majority of patients with olfactory dysfunction, and often a treatment modality is required. For this reason, many new treatments were identified in the past, including pharmacology agents, such as oral and nasal steroids, Platelet-Rich Plasma (PRP), Vitamin A, GinkgoBiloba, zinc sulfate, alpha lipoic acid, minocycline, theophylline, and minocycline [6]. However, despite all these agents, the treatment of olfactory dysfunction isstillquite limited. Topical steroid nasal irrigation and olfactory training are the best treatments proven so far [7, 8]. Nasal saline irrigation treatment can be used very successfully with high volume in chronic sinusitis [9]. Many studies were conducted on olfactory dysfunction in COVID-19. However, no successful treatmentswereperformed so far in Post-ViralOlfactoryDysfunction (PVOD) because of COVID-19 [10].Based ontheliteraturedata, we argue that nasal steroid and nasal saline irrigation treatment can be successful in the treatment of PVOD.
Materials and Methods
The study included 150 patients admitted to our hospital betweenNovember 2020andJanuary2021. The study was planned as a single-center randomized-controlled study. A total of 150 patients admitting to our clinic with other symptoms orwithonly acute odor loss, diagnosed with COVID-19 were divided into 3 equal groups (Group 1, 2, 3). The 50 patients in Group 1 were not given any extra treatment. Saline irrigation was applied for treatment to 50 people in Group 2 (hypertonic solution/10cc to each nose, twice a day/1month); and 50 people in Group 3 were given both saline irrigation (hypertonic solution/10cc per nose, twice a day/1month) and nasal steroid spray 2*2 puffs/each nose/TriamcinoloneAcetonide0.055%). The diagnosis of COVID-19 of patients was confirmed with the RT-PCR Test. The study was approved by the Ethics Committee ofAfyonkarahisarUniversity of Health Sciences,andwasconducted in line withthe PrinciplesofHelsinki Declaration. InformedConsentFormswere received from all patients.
The evaluation of patients was done with a wide-scope questionnaire that contained the characteristics of odor loss and other clinical findings. Evaluations were made on days 1, 15, and 30 with face-to-face interviews on the first day, andwithatelephone survey on the other days. Routine objective olfaction tests (e.g.,Sniffin’ Sticks Test, UPSIT, and CCRC) could not be usedto reduce infection of COVID-19and because patients were in quarantine. The “Subjective Olfactory Capability (SOC)” Method was used to evaluate the self-reported olfactory function and olfaction-related quality of life for evaluations [11, 12]. SOC was used face-to-face on the day that patients had COVID-19-related odor loss, and evaluations were repeated on the 15thand 30thdays of treatment. Olfactory functions were evaluated by using drinks with sharp smells (e.g., lemonade, coffee), nutrients (lemon, garlic), spices (mint, black pepper, thyme), and some cleaning agents (soap, bleach, menthol) to evaluate the odor separation of patients. The olfactory function was evaluated with self-scoring method. All patients were asked to evaluate olfactory function by giving a score of 1–10 (0 = no odor at all, and 10 = full odor) [12]. A form was created to include additional diseases, age and gender of patients in addition to the odor functions. The Self-rating olfactory scores and olfactory dysfunction severity scores collected on days 1, 15, and 30 were recorded.
Exclusion Criteria
Patients under the age of 18 and older than 65, those who had neurological and psychological diseases, those who had previous history of head traumas, and those who had metabolic diseases.
Statistical Analyses
SPSS for Windows version 20 (SPSS, Chicago, IL, USA) was used for statistical analyses. Continuous variables were calculated as Mean ± Standard Deviation (SD); and categorical variables were calculated as frequency (n) and percentage (%). One-Way ANOVA Test was used to compare the variables among the groups; andp < 0.05 was considered to be statistically significant.
Results
In terms of gender, there were 30 males (60%), 20 females (40%) in Group 1; Group 2 had 28 males (56%), 22 females (44%); and Group 3 had 26males (52%), and 24 females (48%). The groups were homogeneous in terms of gender. The mean age was 38.5 ± 10.5 (16–56) in Group 1, 39.2 ± 11.3 (18–61) in Group 2, and 39.2 ± 11.3 (18–61) in Group 3. The groups were homogeneous in terms of age. In terms of additional diseases, Group 1 had hypertension in 4 (8%) patients, Cardiac Disease in 10 (20%) patients, Diabetes Mellitus in 2 (4%) patients, asthma and COPD (Chronical Obstructive Pulmonary Disease) in 3 (6%) patients; Group 2 had hypertension in 8 (16%) patients, Cardiac Disease in 5 (10%) patients, Diabetes Mellitus in 4 (8%) patients, asthma and COPD (Chronical Obstructive Pulmonary Disease) in 1 (2%) patients; Group 3 had hypertension in 6 (12%) patients, Cardiac Disease in 4 (8%) patients, Diabetes Mellitus in 5 (10%) patients, asthma and COPD (Chronical Obstructive Pulmonary Disease) in 5 (10%) patients (Table 1).
Table 1.
Comparison of the demographic characteristics and clinical finding of the 3 groups
| Group 1 (Untreated) n = 50 | Group 2 (Intranasal saline irrigation therapy only) n = 50 | Group 3 (Intranasal saline and triamcinolone irrigation treatment) n = 50 | |
|---|---|---|---|
| Gender | |||
| Male | 30 (60%) | 28(56%) | 26(52%) |
| Female | 20(40%) | 22(44%) | 24 (48%) |
| Mean age | |||
38.5 ± 10.5 (16–56) | 39.2 ± 11.3 (18–61) | 37.2 ± 8.4 (22–57) | |
| Comorbidities | |||
| Hypertension | 4 (8%) | 8(16%) | 6(%12) |
| Cardiac disease | 10 (20%) | 5(10%) | 4(8%) |
Diabetes Mellitus | 2(4%) | 4(8%) | 5(10%) |
| Asthma/COPD | 3(6%) | 1(2%) | 5(%10) |
| ENT Symptoms accompanying the loss of smell | |||
| Rhinorrhea | 41(%82) | 45(%90) | 36(%72) |
| Nasal obstruction | 35(%70) | 42(%84) | 40(%80) |
| Sore throat | 48(%96) | 36(%72) | 32(%64) |
| Face pain | 25(%50) | 24(%48) | 26(%52) |
| Postnasal drip | 36(%72) | 35(%70) | 32(%64) |
| Headeche | 40(%80) | 42(%84) | 40(%80) |
| Ear pain | 15(%30) | 12(%24) | 10(%20) |
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Self-Rating Olfactory Score (SROS) was 3.1 ± 2.5 (0–6) before treatment in Group 1, 4.1 ± 2.6 (0–7), on day 15 after treatment, and 5.2 ± 2.3 (0–10) on day 30 after treatment. For Group 2, it was 2.8. ± 2.4 (0–5) before treatment, 4.8 ± 3.1 (1–8) on day 15 after treatment, and 6.1 ± 2.2 (3–10) on day 30 after treatment. For Group 3, it was 2.7 ± 3.3 (0–5) before treatment, 1 ± 2.5 (2–9) on day 15 after treatment, and 8.5 ± 3.2 (5–10) on day 30day after treatment. When Group 1 and 2 were compared in terms of SROS on day 30, no statistically significant differences weredetected(p1−2 = 0.22). When Group 1 and 3 were compared in terms of SROS on day 30, statistically significant differences were detected(p−1–3 = 0.018). When Group 2 and 3 were compared in terms of SROS on day 30, statistically significant differences were detected(p2−3 = 0.033) (Table 2, Fig.1).
Table 2.
Comparison of olfactory functions (Self-rating olfactory score) before and after treatment
| Before treatment SROS | 15th day SROS | 30th day SROS | P value | |
|---|---|---|---|---|
| Group 1 | 3.1 ± 2.5 (0–6) | 4.1 ± 2.6 (0–7) | 5.2 ± 2.3 (0–10) | |
| Group 2 | 2.8. ± 2.4 (0–5) | 4.8 ± 3,1 (1–8) | 6.1 ± 2.2 (3–10) | p1−2 = 0,22 |
| Group 3 | 2.7 ± 3.3 (0–5) | 6.1 ± 2.5 (2–9) | 8.5 ± 3.2 (5–10) | p−1–3 = 0,018 p2−3 = 0.033 |
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p values are shown in bold
(All values were calculated as mean ± standard deviation (SD), p1−2Group 1 vs. Group 2;
p1−3Group 1 vs. Group 3; p2−3 Group 2 vs. Group 3; SROS: Self-rating olfactory score)
Fig. 1.
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In terms of olfactory dysfunction duration, Group had 1:15.2 ± 2.3 (2–30) days, Group 2: 12.1 ± 2.2 (1–30) days; and Group 3: 5.6 ± 3.2 (1–30) days. When compared in statistical terms, Group 1 and 2 did not have significantdifferencesin terms of duration (p1−2 = 0.54). When Group 3 was compared with Group 1 and Group 2 in terms of duration, there were statistically significant differences (p−1–3 = 0.022, p2−3 = 0.028,respectively) (Table 3).
Table 3.
Comparison of olfactory dysfunction duration (days)
| Dsyfunction duration | P value | |
|---|---|---|
| Group 1 | 15.2 ± 2.3 (2–30) | – |
| Group 2 | 12.1 ± 2.2 (1–30) | p1−2 = 0,54 |
| Group 3 | 5.6 ± 3.2 (1–30) | p−1–3 = 0,022 p2–3 = 0.028 |
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p values are shown in bold
(All values were calculated as mean ± standard deviation (SD), p1−2Group 1 vs. Group 2;
p1−3Group 1 vs. Group 3; p2−3 Group 2 vs. Group 3)
As a result, day 30 SROS (Self-Rating Olfactory Score) of the group that received Nasal Saline + TriamcinoloneAcetonide treatment was significantly higher than other groups. Also,olfactorydysfunctionduration was significantly reduced compared to other groups.
For this reason, Nasal Saline + TriamcinoloneAcetonide treatment is successful in olfactory dysfunction treatmentdue toCOVID-19.
Discussion
New Coronavirus Disease (COVID-19) is a serious infectious disease that started in Wuhan, China in December 2019, and spread all over the world in 2020. It was declared to be a pandemic by the World Health Organization (WHO) because of the increasing number of patients. The disease begins with complaints such as fever, cough, sore throat, joint pains, and dyspnea.Olfactorydysfunction (e.g., anosmia, hyposmia) is a new markerwhich has been reported recently. In most patients, odor loss begins suddenly, and often also leads to tastedisorders. It was first reported in the UK and Iran in the world. British Association of Otorhinolaryngology and American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) recommended that symptoms of odor loss added to the list of screening tools for possible COVID-19 infections[13, 14]. Mechanisms such as direct olfactory bulb damage, olfactory epithelial involvement, orneurogenicinvolvement were mentioned in the olfactory disorder [15]. In a previous study, two key genes (i.e.ACE2 and TMPRSS2) were detected in the human and mice olfactory epithelium [16].
Olfactory dysfunction may occur due to post-infectious traumas orChronic Rhino-Sinusitis(CRS). Post-Viral Olfactory Dysfunction (PVOD) is the most common among these. Viral factors, such asEpstein-Barr Virus, Rhinovirus, Coronavirus, and Parainfluenza might cause PVOD. The novel coronavirus Severe Acute Respiratory Syndrome ((SARS)-CoV-2) is responsible for temporary or permanent loss of olfaction. It has been shown in recent studies that COVID-19-related olfactory dysfunction is not that different from other PVODpathophysiologies[10]. These patients complain about hyposmia,dysosmia, parosmia, and mostly anosmia. The number of patients with permanent olfactory losses is much higher than expected. In these patients, evidence-based treatment is not fully clear for the time being. Corticosteroids are used widely for treatment of olfactory losses, and the importance ofolfactorytraining is also remarkable in treatment. In the literature, there is no treatment modality reported for COVID-19-related PVOD so far. However, there are quite a lot of studies in the literature regarding the treatment of classical PVOD. Many of these studieswere conducted with systemic steroids. Agents such asprednisoloneandmethylprednisolonewere used in doses ranging from 2weeks to 1year in many studies in which systemic steroids were used, and most studies showed significant improvementsin TDI scores (Threshold, Discrimination, Identification) [17]. No significant results werereportedregarding the addition of Gingko Biloba to oral steroid and mometasonespray treatment [18].
In one ofthestudiesofHeilman et al., patients with odor loss were given local and systemic steroids, and although the systemic steroid olfactory corrected the functions, no significant effects were detected in local steroids [19]. In the study of Shu et al., it was shown that topical corticosteroid application with squirting system was more effective than spraying in maintaining olfactory healing with oral corticosteroid treatment [20]. It was reported in a review published in 2019 that the effectiveness of topical steroids was lowfor olfactory dysfunction, but oral steroids could be used at evidence Level 1 [8]. In an evidence-based review conductedbyHuraet al. both oral and topical steroids were recommended to treat PVOD, but it was also recommended that oral steroids used with caution because of their potential side effects [21]. InWhitcroftet al.’s study, it was reported that systemic steroids could not be used routinely in COVID-19-related olfactory dysfunction, and the use of nasal steroids was still discussed. Also, olfactory training, Vitamin A, zinc sulfate and systemicOmega-3 treatments were recommended as the standard treatment [22]. In our study, significant increases were detected in self-rating olfactory scores in patients who applied topical steroid irrigation with nasal saline compared to the control group. There werealso significant decreases in the duration ofolfactorydysfunction. Based on this outcome, we believe that topical steroid treatment can be used as a successful treatment modality in COVID-19-related olfactory dysfunction treatment. Also, the significantly low side effects compared to oral steroids constitute a reliable treatment option.
It was shown that nasal saline irrigation was ineffective in many studies conducted on nasal saline irrigation in patients with chronic rhino-sinusitis[23, 24]. In ameta-analysis; however, it was found that hypertonic salineirrigation was more effective in the treatment of chronic rhino-sinusitis compared to isotonic irrigation [25, 26]. In our study, it was found that there were no significant increases in self-rating olfactory scores in patients who did irrigation with nasal saline compared to the control group. Also, significant decreases were not detected in the duration of olfactory dysfunction.
The limitations of our study were our inability to performobjectiveolfactory tests because of COVID-19 infectionriskand quarantine periods.Also, the number of patients was relatively small, and the study had a single-centric design.
Conclusion
So far, there is no treatment employed as the gold standard for the treatment of olfactory dysfunction that occursdue toCOVID-19.As common cost-effective treatment agents,topical corticosteroidscan be used in most diseases of rhinology, especially in olfactory loss. It was proven in our study that nasal steroids can be used safely and therapeutically forthe treatment of the odor loss in Covid-19. Multi-centered studied with wider patientseriesare required to use steroids more widely in this disease.
Funding
The authors declared that this study has received no financial support.
Declarations
Conflict of interest
No conflict of interest was declared by the authors.
Ethical Approval
Ethics committee approvalwas receivedfromAfyonkarahisarHealtyScience University Clinical Research Ethic Committee.(05.03.2021–2021/2).
Informed Consent
Consent was obtained from of the patients.
Info
The English translation, editing and proofreading procedures of this article were carried out by “Academic Translation Services (www.tercumeakademik.com)”.
Footnotes
Publisher's Note
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