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Anosmia was a previously neglected symptom of coronavirus disease (COVID-19) [1,2]. In a study by Lechien et al. done in 2020, 86% of 2,500 patients with mild COVID-19 from 198 European hospitals who had anosmia recovered without any intervention within six months. When the olfactory dysfunction persists beyond 2 weeks, treatment maybe reasonable [3]. The efficacy of available treatments for patients with post COVID-19–related olfactory dysfunction was unknown. This treatment include olfactory training, corticosteroids and systemic omega-3 [4]. Studies have demonstrated improved olfaction in patients with post-COVID 19 olfactory dysfunction after training and administration of intranasal corticosteroid spray. The anti-inflammatory effect of steroid contributed to rapid improvement in olfaction. Hence, this study aims to evaluate the efficacy of topical corticosteroid nasal spray in COVID-19 patients with olfactory dysfunction.

Methods

Data sources and search strategy

Two reviewers independently identified eligible studies in the PubMed, Cochrane Central, and MEDLINE database in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. The following search terms were used: “steroid,” “nasal spray,” paired with “olfactory dysfunction” or “anosmia” and “COVID” with filters (1) humans, (2) aged >18 years, (3) English, and (4) randomized controlled trial (RCT) design. Searches for the studies published between December 2019 until July 2021 were conducted using subject heading terms, key words, titles and abstracts. All identified abstracts and studies were screened. In addition, we also hand-searched previous studies related to our subject.

Study Selection

Inclusion criteria were the following: 1) participants aged >18 years, who suffered from recent anosmia or hyposmia with or without ageusia, and was either hospitalized or managed at home; 2) confirmed case of COVID-19 infection based on a positive real-time reverse transcription-polymerase chain reaction (rRT-PCR); 3) Randomized clinical trials which include intranasal corticosteroid spray as part of the intervention group and 4) studies which include the Visual Analog Scale (VAS)-smell score to report the degree of anosmia after >3 weeks of intervention. Participants were excluded if: 1)they are pregnant and lactating, 2) with history of previous chronic rhinological pathologies, 3) on chronic corticosteroid for systemic disease treatment, 4) improved anosmia post-infection with COVID-19, and (5) did not complete the follow up period [5].

Data Extraction

Two investigators independently assessed the abstracts of articles from our initial search (n= 12) and determined their eligibility for inclusion based on the above-mentioned selection criteria. The following data were extracted: baseline characteristics, interventions, outcomes, and study design. The full-length articles of studies deemed potentially eligible were reviewed. Discrepancies in data extraction were arbitrated by the third party. We excluded 10 articles from the initial search because of conflict with the inclusion criteria.

Quality Assessment

The two reviewers evaluate the quality of included studies using 7 domains of the Cochrane risk-of-bias tool based on the following criteria: randomization sequence generation, concealment of randomization sequence, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Studies were classified as having a low,high, or unclear risk of bias for each item, based on Cochrane Handbook. Publication bias was assessed using a funnel plot.

Outcome Measures

The primary endpoint was the complete recovery of olfactory function after >3 weeks of intervention with the control group using VAS-smell score.

Statistical Analysis

The meta-analysis was performed with RevMan software version 5.4.1. Forest plot was generated for odds of complete recovery of smell, using the Peto fixed-effects model. The odds ratios (ORs) and 95% confidence intervals (CIs) served as a summary statistic. The statistically significant results were those with 95% CI that did not include 1. The heterogeneity test was completed using the χ2 -based Q test, and a P value 0.1 indicated a lack of heterogeneity. If heterogeneity was observed in the results, the degree of heterogeneity was determined using the I2 test (I2 = 0– 25%, no heterogeneity; I2 = 25–50%, moderate heterogeneity; I2 = 50–75%, substantial heterogeneity; and I2 = 75– 100%, extreme heterogeneity).

Results

Literature search

The literature search identified 4 records in PubMed, [7] records in Cochrane Central and 1 hand- searched record (Figure 1). Four unique and full text published articles remained after scrutiny for duplicates. The 2 studies were appropriate for a detailed analysis after a brief review of the abstract and manuscript. The 2 studies (Corticosteroid nasal spray for recovery of smell sensation in COVID- 19 patients: A randomized controlled trial; Mometasone furoate nasal spray in the treatment of patients with COVID-19 olfactory dysfunction: A randomized, double blind clinical trial) were included. Two articles were excluded because the end point of interest was not reported.

Figure 1: PRISMA flow chart depicting article selection process and final articles according to outcome of interest.

Characteristics of the Included Studies and Patients

The study characteristics of the two randomized controlled trials, representing 177 participants, were reported in Table 1. These randomized trials published between 2020 and 2021 had follow-ups between three to four weeks. In the two trials, mometasone intranasal spray was used as an intervention. Visual Analog Scale (VAS) smell score was utilized to assessed the perception of the individuals regarding their degree of anosmia/hyposmia. Visual Analog Scale (VAS) was graded from 0 to 10, with a score of zero denoting complete olfactory loss and a score of 10 indicating normal olfactory sensation. All patients had olfactory training. The olfactory training was done through sniffing various things for 20 seconds (i.e. rose, lemon, and clover) twice a day (Table 1).

Table 1: Summary Study Characteristics of Randomized Controlled Trials Included in the Meta- Analysis Assessing Complete Recovery of Olfactory Function in COVID-19 patients.

Quality of Studies

The quality assessment of the included studies was presented in Table 2. All studies were considered low risk for bias since they both mentioned the use of randomized allocation, and computer or network system method for group randomization. The allocation concealment method used by the studies were not mentioned and considered to have an unclear risk for bias [6]. All trials were double- blind, and the implementation of the blinding method could not be destroyed thus, the performance bias was considered to be low risk. The outcome indicator has an objective end point but the evaluation was done subjectively thus, the detection bias of the trials were of unclear risks. The rate of completion for all trials were >90% and missing data were thoroughly explained therefore, an incomplete outcome data for all trials were low risk for bias. The trials were not sponsored by pharmacists. They were also not involved in the data analysis thus their effect on the trial results were considered low risk for bias. In effect, all randomized clinical trials included in our study were deemed low risk for bias. (Table 2, Figure 2)

Table 2: Quality Scale Rating and Assessment of risk of bias of included randomized controlled trials.

Figure 2: Forest plot of included studies showing the effect of corticosteroid nasal spray plus olfactory training versus olfactory training in the recovery of OD in COVID-19 patients.

Corticosteroid effect in the recovery of olfactory function of COVID-19 patients

The forest plot of the studies in Peto Odds Ratio fixed-effects (n = 177) showed a point estimate of 0.48 with a wide confidence interval (0.26, 0.87) in favor of corticosteroid intervention. The individual point estimate also favored intervention with corticosteroids however, the confidence interval was wide (CI = 0.30, 1.47; 0.12, 0.76). The presence of heterogeneity in the study was non- significant (I2=39%).

Sensitivity analysis

The sensitivity analysis was not performed due to the limited number of studies and the rarity of the event.

Discussion

COVID-19 patients suffering from olfactory dysfunction can spontaneously recover from the disease within 15 to 20 days of the symptom onset. However for symptom persisting for more than two weeks, additional therapy can be considered. This meta-analysis is the first to summarize the evidence of corticosteroid nasal spray for COVID-19 olfactory dysfunction. With widespread anosmia or hyposmia following COVID-19 infection, this topic becomes increasingly relevant.4 A meta-analysis by Kattar et. al already showed clinical significant benefit of olfactory training in COVID-19 related olfactory dysfunction. To our knowledge, intranasal corticosteroids are not yet considered part of the recommendation in the treatment of COVID-19 olfactory dysfunction because of safety concerns and lacks of robust evidence.7 Some randomized clinical trials showed potential benefit of intranasal steroid therapy for olfactory dysfunction related with COVID-19 infection however, there exists not enough studies evaluating its safety. The potential benefit of corticosteroids as an addon therapy is due to its anti-inflammatory effect in the respiratory system nevertheless, current studies revealed conflicting results of its effect on post-COVID olfactory dysfunction. There was a randomized clinical trial done comparing the use of intranasal corticosteroid over olfactory training; results that intranasal corticosteroid offered no superior benefits over the olfactory training in post-COVID 19 patients with anosmia.5

On the other hand, some studies have demonstrated effect of intranasal corticosteroid in patients with COVID-related olfactory dysfunction. A pilot study with 72 COVID-19 patients reported the efficacy and safety of intranasal corticosteroids together with olfactory training. They concluded that the combination of intranasal corticosteroids and olfactory training are safe and can be of benefit in patients suffering from persistent olfactory dysfunction following COVID-19 infection [8]. A similar multi-center, randomized, casecontrol study involving 18 patients with COVID-19 was done which also conclude the effect of intranasal corticosteroids in the reduction of anosmia and severe hyposmia in patients with COVID-19 [9].

Limitations

The included studies have small sample size which could affect the overall result, often they show larger treatment effects than large ones.

Conclusion

Intranasal corticosteroid spray may be offered as add-on therapy to COVID-19 patients with olfactory dysfunction for 2 weeks or more in addition to olfactory training. However, additional studies are still needed to prove its efficacy as well as its safety

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