Treatments for Olfactory Dysfunction in COVID-19: A Systematic Review

Abstract Introduction  Olfactory dysfunction (OD) has emerged as a notable symptom among coronavirus disease 2019 (COVID-19) patients, with its prevalence varying among different populations. Recognizing the need to provide therapeutic solutions for these individuals, the present study seeks to comprehensively review the current evidence on potential underlying mechanisms and treatment modalities to manage OD in COVID-19 patients. Objective  To review the recent evidence on treatments for OD in COVID-19. From the beginning of the study until August 2nd, 2023, we conducted a systematic search on four electronic databases, PubMed, Scopus, Embase, and Web of Science, to find relevant publications. Data Synthesis  In the present study, 37 articles were selected for data extraction and included in the final review. The total number of patients was of 3,560 (2,098 female and 1,462 male subjects). The predominant disorders reported were hyposmia, anosmia, and parosmia. In most of the studies, the pre and postintervention assessments were the same, except for one study, in which the pre-intervention assessment of the disorder was through the SST, Sniffin' Sticks Test (SST), and the post-intervention assessment was through the Visual Analog Scale (VAS) and the 22-item Sinonasal Outcome Test (SNOT-22). The findings suggest olfactory training (OT), ivermectin, palmitoylethanolamide, luteolin, and systemic corticosteroids, in combination with topical corticosteroids, are potential therapies for COVID-19 patients with olfactory impairment. Conclusion  Although the review suggested several medications for OD treatment, further research must delve into the specific impact of OT, a non-pharmacological modality, regarding the mitigation of OD. By continuing to investigate and refine these therapeutic approaches, we can better support COVID-19 patients and improve their quality of life while navigating the challenges posed by OD.


Introduction
2][3] In most cases, olfactory dysfunction (OD) resolves after several weeks from the infection; nevertheless, it has been shown that nearly 20% of COVID-19 patients develop persistent OD, 4,5 which can have several detrimental impacts on human health, including, but not limited to, depression, social isolation, malnutrition, and death.0][11] Metabolic changes in core olfactory and high-order neocortical areas, 12 as well as hypometabolism in the bilateral parahippocampal and fusiform gyri and the left insula 13 of COVID-19 patients have been found, indicating that the virus may cause OD by involving the central nervous system (CNS).It has been hypothesized that molecular mechanisms may play a crucial role in the pathogenesis of OD, since there is a the prevalence of OD in COVID-19 patients varies among different populations, 14,15 and the Omicron variant was found to contribute to a lower OD prevalence compared with the Delta and Alpha variants, which was confirmed in two large cohort studies. 16,17here is an ongoing debate about the suitable pharmacotherapy for OD treatment.A few clinical trials have demonstrated the short-term beneficial effects of oral or topical corticosteroids; yet, to date, no large study has evaluated their safety and efficacy. 18Therefore, further studies with larger populations are warranted.Additionally, there is accumulated evidence in support of the fact that olfactory training (OT) can notably improve olfactory function and should be considered in new and existing COVID-19 patients. 19,20iven this context, in the present review, we discuss what is known regarding the molecular mechanisms involved in the pathogenesis of post-COVID-19 OD and examine the available treatment options for the management of OD as a complication of COVID-19.

Review of the Literature Information Sources and Search Strategies
We systematically searched four electronic databases (PubMed, Scopus, Embase, and Web of Science) to identify relevant articles published until to August 2nd, 2023.Systematic searches were conducted for relevant keywords in the titles and abstracts.Moreover, we examined the reference lists of the extracted articles to identify other relevant publications to review the subject.Supplementary Material 1 provides details of the search strategy.

Selection Process
The reference management tool EndNote X9 (Clarivate, London, United Kingdom) was used to import all search results and eliminate any duplicates.The titles and abstracts were independently screened by two authors.Then, two authors read the full text to evaluate them in light of the inclusion and exclusion criteria, with any discrepancies being settled by a third author.A summary of the study selection procedure is presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram 21 (►Fig.1).

Eligibility Criteria
All types of peer-reviewed original literature that addressed the molecular mechanisms behind post-COVID-19 OD and the available management options for the affected patients were included regardless of gender, nationality, race, religion, or publication date.Specific types of publications, namely case reports, editorials, letters, reviews, systematic reviews, and meta-analyses were excluded.Papers published in languages other than English were also excluded, as well as the studies whose full text could not be accessed.

Data Collection Process
The relevant information, including the first author's name, the year of publication, the country, age and gender of the patients, sample size, study type, disorder type, duration of the disorder, type of preintervention disorder assessment, type and duration of the intervention, improvement rate, type of postintervention disorder assessment, mechanism of treatment, and presence of other diseases were extracted by two authors for each selected study and presented in tables (►Table 1 and 2).The present report was formulated according to the PRISMA 2020 statement. 22

Risk of Bias Assessment
The revised Cochrane Risk of Bias Tool for Randomized Trials, version 2.0 (RoB 2), was used to assess the risk of bias of randomized controlled trials (RCTs). 23In addition, to assess observational studies (cohort and case-control studies) for potential biases, the Newcastle-Ottawa Scale (NOS) was Conclusion Although the review suggested several medications for OD treatment, further research must delve into the specific impact of OT, a non-pharmacological modality, regarding the mitigation of OD.By continuing to investigate and refine these therapeutic approaches, we can better support COVID-19 patients and improve their quality of life while navigating the challenges posed by OD.
employed. 24The risk-of-bias assessments were conducted independently by two authors.To achieve consensus, a third author was recruited to resolve any disagreements (►Table 3).
In the initial database search, 2,140 articles were retrieved, 595 of which were duplicates.The remaining 1,545 articles were screened considering the inclusion and exclusion, and ultimately 37 articles were selected for the final analysis and data extraction.►Fig. 1 illustrates the details of the article selection process.
In the present review, most of the studies were from Egypt (n ¼ 9), Italy (n ¼ 8) and the United States (n ¼ 4).Turkey, Germany, and the United Kingdom were represented by two studies each, and Greece, Spain, Iran, Belgium, Japan, Brazil, Iraq, The Netherlands, India, and France each contributed with one study.The total number of patients examined in these studies was of 3,560, (2,098 female and 1,462 male subjects) (►Table 1 and 2).
Regarding the types of disorders, most were issues related to hyposmia, anosmia, and parosmia.In most of the studies, the pre and post-intervention disorder assessments were the same, and were performed using the Visual Analogue Scale (VAS), the Sniffin' Sticks Test (SST), electroencephalography (EEG), the University of Pennsylvania Smell Identification Test (UPSIT), the Clinical Global Impressions-Improvement (CGI-I) scale, the Numerical Rating Scale (NRS), the Connecticut Chemosensory Clinical Research Center (CCCRC) test, among others, except for one study 25 in which the preintervention disorder assessment included the SST, and the postintervention disorder assessment was performed through the VAS and the 22-item Sinonasal Outcome Test (SNOT-22), and another study 26 in which the preintervention assessment was performed using the SST and, after the intervention, the Threshold, Discrimination, Identification (TDI) scores, Taste Strip Test (TST), the Olfactory Disorders Questionnaire (ODQ), and the self-reported VAS score.In the investigations, it was found that the average time for recovery of the sense of smell was longer in diabetic patients compared with non-diabetic ones. 27More details of this review are presented in ►Tables 1 and 2.
Among the pharmacological therapies, the combination of palmitoylethanolamide (PEA) and luteolin was the most common intervention evaluated in the included studies.Topical and systemic corticosteroids, local ivermectin, herbal remedies, platelet-rich plasma injection, zinc sulfate, theophylline, and omega-3 were the other interventions assessed in the studies.Treatments for Olfactory Dysfunction in COVID-19 Mehraeen et al.
Moreover, OT, which is described as exposure twice a day to a set of four odors, including rose, eucalyptus, lemon, and cloves, from media such as brown jars or markers, 28 was the most frequent non-pharmacological intervention applied in the included studies.

Discussion
The precise prevalence of OD caused by COVID-19 is difficult to establish; it depends on the severity of the disease, the geographic region, and the technique of measuring.Two      Treatments for Olfactory Dysfunction in COVID-19 Mehraeen et al. recent systematic reviews 29,30 have reported prevalence of loss of smell ranging from 43% to 62%.Additionally, data from sizable European cohorts 31,32 indicate prevalence rates between 50% to 85%.Based on the current evidence, Europe and North America are the regions with the highest prevalence rates.
There is still no clear understanding of how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes olfactory impairment. 4Numerous viruses produce conductive olfactory dysfunction, along with nasal congestion, inflammation, and rhinorrhea, which prevents individuals from detecting odors during the acute stage of the infection.These symptoms are less frequent in COVID-19 and, when they occur, they do not accurately reflect the level of olfactory impairment. 33The symptoms may also result from potential injury to or death of olfactory neurons or cells in the olfactory bulb; however, since most people who experience loss of smell due to COVID-19 recover quickly, this is less likely, because olfactory neurons lack angiotensinconverting enzyme 2 (ACE2) receptors, which enable viral entrance into cells.The ACE2 receptors and the supporting components for olfactory neurons 34 can be detected in the olfactory epithelium.Notably, the olfactory epithelium's sustentacular cells, which are essential for olfactory neuron functionality, can become infected, 35 suggesting that their inflammation and infection could adversely affect olfaction.Many people with COVID-19-related olfactory impairment only experience transient symptoms, and they quickly regain their normal sense of smell. 9,10Some studies have indicated full recovery within two to four weeks. 31,36However, for a subset of patients, olfactory issues persist even after other COVID-19 symptoms have resolved.According to data from the Global Consortium of Chemosensory Research, 37 up to 50.7% of people may continue to experience olfactory impairment 40 days after the initiation of COVID-19.Given the prevalence of infections (> 295 million infections worldwide as of December 2021) and the 5% to 7% of subjects who were found to be functionally anosmic 12 months after exposure, $ 15 million people could develop persistent anosmia, carrying a sizable burden of OD and a long-term disruption in quality of life. 36,38ighlighting the frequent remission of olfactory impairment within a month of the COVID-19 infection, we find it crucial to distinguish this in the evaluation of preventive and therapeutic strategies.Unlike previous systematic reviews composed mostly of RCTs, 29,39,40 the current review is more inclusive, encompassing three prospective or longitudinal cohort studies that track participants over time. 25,41,42n the present analysis, treatments such as topical and systemic corticosteroids, OT, local ivermectin, PEA, and luteolin seemed promising.4][45] Using PEA and luteolin, which are effective treatment options in two studies, 36,37 in combination with saline irrigation may help this situation progress faster, because the delivery of medication to the olfactory cleft may be increased compared with that of standard nasal spray administration, and this may be further enhanced by using particular head positions. 25,40uteolin and PEA may act to lessen nasal cavity inflammation and hasten the process of epithelium regeneration.The present review suggests that the exclusive use of systemic corticosteroids might mirror conditions such as diabetes mellitus and prolonging OD recovery.The underlying processes for these conditions seem interconnected, attributed to compromised immune cell function and diminished capacity to repair the olfactory epithelium. 27,46he findings of the present study suggest that the use of topical corticosteroids can expedite recovery from COVID-19induced OD within 2 to 4 weeks post-treatment.These findings are consistent with the theory that olfactory impairment in COVID-19 is primarily a result of an inflammatory process in the olfactory epithelium, in which intranasal corticosteroids might provide beneficial anti-inflammatory effects. 46Intranasal corticosteroids reduce local inflammation and may also improve olfaction by changing the activity of olfactory receptor neurons due to their effects on the sodium/potassium adenosine-triphosphatase Na þ /K þ -ATPase enzyme. 47It is interesting to note that two of the trials in the current study demonstrated that combining systemic steroids with OT was more beneficial than using systemic steroids alone. 32It should be mentioned that, despite the potential advantages of these pharmacotherapies, a recent position paper on OD 48 emphasizes the lack of high-level evidence to support any pharmacologic treatment in the management of OD.
Despite the comprehensive insight that the present review offers on OD treatment in COVID-19, some limitations should be considered in the interpretation of the results.First, the included studies used various techniques and medication treatments for olfactory rehabilitation, potentially leading to heterogeneous results; however, they are probably minimal, as the bulk of the research methods were comparable across the intervention and control groups, and the pre-and post-intervention treatments were identical, except for one study. 26here were also discrepancies in intervention timing, quantity, and dosage across trials.Large-sample RCTs and prospective cohort studies are essential to validate our findings.The reliability of our evidence is generally low, mainly due to the limited sample sizes in single studies and potential performance bias from a lack of participant blinding.
Our data are supported by anecdotal links between COVID-19-induced OD, inflammation in the olfactory cleft, and magnetic resonance imaging (MRI) evidence of viral infiltration into the olfactory bulb. 49,50We believe that by reducing mucosal inflammation and olfactory cleft blockages, nasal steroids can aid in olfactory rehabilitation.However, this remains a topic for debate.While combining saline irrigation with treatments like PEA and luteolin might accelerate recovery, OT remains a viable strategy, especially when paired with other therapies.

Final Comments
Coronavirus disease 2019 has been found to cause anosmia and hyposmia more frequently than other viral infections of the upper respiratory tract.This not only has emotional ramifications for patients but also reduces their ability to detect environmental dangers such as fires and gas leaks.Consequently, doctors must have effective treatments available for patients presenting with COVID-19-related olfactory impairments.For an enhanced quality of life, it is vital to devise strategies that can expedite the disease's resolution.The current research indicates that OT, ivermectin, PEA, luteolin, and systemic corticosteroids, when paired with topical corticosteroids, emerge as potential treatments for those suffering from olfactory deficits due to COVID-19.Future studies should particularly explore the efficacy of OT, a non-pharmacological intervention, in addressing this concern.
International Archives of Otorhinolaryngology © 2024.The Author(s).
Treatments for Olfactory Dysfunction in COVID- 19  Mehraeen et al.

Fig. 1
Fig. 1 Flow diagram of the current study.

Table 1
Description of the demographic information of patients International Archives of Otorhinolaryngology © 2024.The Author(s).

Table 2
Description of the findings reported in the eligible studies International Archives of Otorhinolaryngology © 2024.The Author(s).

Table 3
Risk of bias assessment according to the Newcastle-Ottawa Scale (NOS)