Treatment of COVID-19 Associated Olfactory Dysfunction: A Systematic Review

Abstract

Purpose of Review

COVID -19 associated olfactory dysfunction is widespread, yet effective treatment strategies remain unclear. This article aims to provide a comprehensive systematic review of therapeutic approaches and offers evidence-based recommendations for their clinical application.

Recent Findings

A living Cochrane review, with rigorous inclusion criteria, has so far included 2 studies with a low certainty of evidence.

Summary

In this systematic review we list clinical data of 36 randomised controlled trials (RCTs) and non-randomised studies published between Jan 1, 2020 and Nov 19, 2023 regarding treatment options for COVID-19 associated olfactory dysfunction. Nine treatment groups were analysed, including olfactory training, local and systemic corticosteroids, platelet-rich plasma (PRP), calcium chelators, vitamin supplements including palmitoylethanolamide with luteolin, insulin, gabapentin and cerebrolysin. Primary objective was the effect of the studied treatments on the delta olfactory function score (OFS) for objective/psychophysical testing. Treatments such as PRP and calcium chelators demonstrated significant improvements on OFS, whereas olfactory training and corticosteroids did not show notable efficacy for COVID-19 associated olfactory dysfunction.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11882-024-01182-6.

Introduction

Olfactory dysfunction (OD) is a common clinical symptom of COVID-19 with a prevalence of up to 77% [1–3]. The clinical course is usually short, but varies significantly. A meta-analysis from 2023 showed a prevalence of 31% at 6 months [4]. Despite the significant proportion of patients having persistent OD, there is still no clear recommendation on the most appropriate treatment for COVID-19 associated OD [5]. A living Cochrane review, with rigorous inclusion criteria (only RCTs), has so far included 2 studies with a low certainty of evidence. The studies evaluated systemic corticosteroids plus intranasal corticosteroid/mucolytic/decongestant and PEA-LUT with very limited evidence and no meaningful conclusions could be drawn [6]. Olfactory training (OT) is widely suggested as a first-line treatment for post-infectious olfactory dysfunction, including COVID-19-associated OD [7].

A recent meta-analysis by Delgado-Lima showed a statistically significant positive impact of olfactory training on the enhancement of all domains of olfactory function [8]. However, the precise mechanism by which olfactory training restores or improves olfactory function remains elusive. Furthermore, there is still discussion about the true efficacy of olfactory training, with some studies showing no additional benefit [9]. A systematic review of Pekala suggests that OT may represent a promising intervention for OD due to multiple etiologies, but several limitations of the included studies prevented them from making generalized recommendations [10]. Studies assessing the efficacy of olfactory training are often heterogeneous, lacking standardization in protocols. There are variations in the duration, frequency, and types of odors used in training, and many studies do not include a control group. These factors make it challenging to compare results across different studies.

Experimental data suggest that olfactory training may improve olfactory function, although the degree of improvement can vary. Current evidence indicates that olfactory training alone might have modest effects, but it remains a valuable part of a comprehensive approach to treating olfactory dysfunction [11, 12].

Opinions on the use of intranasal or oral corticosteroids, however, are controversial and should be considered on an individual basis [13–15]. And so far, there is no consensus about the use of other treatment options such as alpha-lipoic acid, vitamin A or omega-3 supplements, platelet-rich plasma or calcium chelators [5].

Long lasting OD can result in depression and cognitive impairment and has a significant negative impact on a person’s quality of life (QoL) [16, 17]. To adequately counsel and guide patients, a systematic review of the current evidence regarding treatment options in COVID-19 associated OD is essential. In this systematic review, our focus is to summarise all current clinical data on pharmacological and non-pharmacological treatments for COVID-19 associated OD.

Methods

Search Strategy and Selection Criteria

A systematic review was conducted, in accordance with the PRIMS guidelines, to explore treatment strategies for COVID-19 associated OD. In collaboration with biomedical reference librarians of the KU Leuven Libraries, we defined a search strategy based on a predefined population, intervention, comparator, outcome (PICO) model. The population of interest included patients with COVID-19 associated OD, experiencing OD for at least one month to account for the high rate of spontaneous recovery within the first month. The intervention included any therapeutic options for OD, with comparisons against placebo/sham procedures, alternative treatments or no treatment at all. The primary outcome measure was the change in olfactory function score (ΔOFS), subjectively and/or objectively (panel) after the treatment/intervention or placebo/sham/no treatment. Next, we formulated a search strategy based on relevant keywords (Supp. 1), searching through 7 databases (PubMed, Embase, Web of Science Core Collection, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, ICTRP and Europe PMC). Relevant reviews were filtered and scanned for additional references. Manuscripts in English, Dutch, Spanish and German from Jan 1, 2020 on were eligible for inclusion. The study protocol was published in the Prospero database (ID CRD42022300627). After publication of the protocol, we searched the databases on Nov 19, 2023. All manuscripts were exported to a reference manager, EndNote, and duplicates were removed. Manuscripts were then exported to Rayyan and two reviewers (SB and MM) screened titles and abstracts for eligibility. Conflicts were resolved by consensus. Next, full texts were assessed by two reviewers (SB and MM) according to the inclusion criteria. An electronic data collection form (Microsoft Excel) was filled in for all studies. Two reviewers (SB and MM) assessed risk of bias using the “Risk of Bias 2 (RoB2) tool” for randomised trials and the “Risk of Bias in Non-randomised Studies – of Interventions (ROBINS-I) tool” for non-randomised trials. Manuscripts were then sorted by intervention, study design and outcome parameters.

Outcome

Primary objective was the effect of the studied treatments on the recovery rate, OFS of COVID-19 associated OD and serious adverse events (Prospero database ID CRD42022300627). Only a few articles reported on the recovery rate, therefore, we focused on the OFS. ΔOFS was defined as the delta (Δ) of the pre- and posttreatment score of objective/psychophysical testing.

The most common objective function tests were TDI, UPSIT, BSIT and CCRC. The TDI (Threshold, Discrimination, and Identification) test evaluates olfactory function through three components: threshold (detecting the minimum concentration of an odour), discrimination (distinguishing between different odours), and identification (recognizing specific odours). Each component is scored from 0 to 16, resulting in a combined maximum score of 48 [18]. The UPSIT (University of Pennsylvania Smell Identification Test) is a standardized smell identification test consisting of 40 odorants embedded in a scratch-and-sniff booklet. Subjects scratch each odorant and select the correct identification from four multiple-choice options [19]. The BSIT (Brief Smell Identification Test) is a shorter version of the UPSIT, typically consisting of 12 odorants [20]. It follows the same scratch-and-sniff format and multiple-choice identification method. The CCCRC (Connecticut Chemosensory Clinical Research Center) assesses olfactory function through two components: threshold and identification from a list of options [21]. Secondary objective was the effect of the studied treatments on parosmia and the duration of COVID-19 associated OD. We also assessed serious adverse effects.

Data synthesis

A descriptive synthesis of the intervention effects of the selected studies was done. Study characteristics were summarised in a descriptive table and full text according to treatment modalities. Quantitative analysis was performed with RevMan if sufficient studies with consistency in reporting on OD were available and statistical heterogeneity was limited (I² < 50%). Continuous data were collected by mean difference (MD) with either 95% CIs or SDs. Taking different measurement tools for OD into account, the standardised MD (SMD) for the quantitative analysis was calculated. For studies that reported baseline and post-treatment OFS with standard deviations but did not specify the ΔOFS, we calculated the ΔOFS and its corresponding standard deviation. The study from D’Ascanio et al. and from Abu Shaby et al. did not provide a standard deviation for the OFS, so no proper analysis could be done with RevMan (Review Manager).

Results

Our database search resulted in a total of 26,719 studies (Fig. 1). After removing duplicates, 17085 articles were retained. Titles and abstracts were screened, resulting in 653 articles that were eligible for further screening. After full text screening, 35 articles were eligible for inclusion based on the predefined selection criteria. In addition, one article about COVID-19 associated OD was included from citation searching, resulting in 36 studies included for qualitative synthesis. The main reasons for exclusion were ineligible study designs, not meeting the inclusion criteria for the population or outcome (i.e. focus not on olfactory dysfunction but on other COVID-19 symptoms). In the following sections we provide a detailed overview of the current evidence regarding therapies for COVID-19 associated OD.

Fig. 1.

Prisma flow-chart (From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement an updated guideline for reporting systematic reviews. BMJ 2020;372:n71. https://doi.org/10.1136/bmj.n71)

Olfactory Training

Seven studies, five RCTs, and two non-randomised studies, have been published regarding OT for COVID-19 associated olfactory dysfunction (Table 1) [22–28]. Patients received OT with either the classical four scents or a modified training with eight scents. The duration of the therapy was 1.5 to 3 months, and the follow-up was 1–12 months. For the quantitative analysis, regarding the ΔOFS, we included 4 studies [24, 27–29]. Overall, the total effect across all studies indicates a standardized mean difference (SMD) of 0.05 (95% CI: -0.25 to 0.36), suggesting no significant overall impact of OT compared to control (p = 0.73) (Fig. 2). The analysis found no heterogeneity among the studies (I² = 0%).

Table 1.

Included studies olfactory training

Therapy	Reference	Study design	Samplesize	Intervention	Comparison	Outcomes	Parosmia assessment	Measurement tool/time	Results
Olfactory Training
	[26]	RCT	56	Oral Vitamin A (25,000 IU daily for 14 days)  +  Olfactory training (sniffing four odour each 20 s thrice daily for 4 weeks)	Olfactory training (sniffing four odour each 20 s thrice daily for 4 weeks) No treatment	Change in OFS, Change in OD classification	No	BTT, SIT, MRI, rs-fMRI at 0, 2, 4 weeks	Significant improvement in intervention group (BTT, SIT) No significant improvement in both control groups
	[24]	RCT	63	Olfactory training (sniffing four scents for 15 s each twice daily for 12 weeks)	No treatment	Change in OFS	No	BSIT, QoL at 0, 12 weeks, 1 year	No significant improvement
	[29]	RCT	50	Olfactory training (sniffing four scents for 10 s each twice daily for 12 weeks)	Placebo (sniffing odorless propylene glycol)	Final OFS	Yes	UPSIT, VAS-score, Parosmia assessment, QoL at 0, 12 weeks	No improvement of UPSIT Significant improvement of VAS, Parosmia and QoL
	[23]	RCT	80	Modified Olfactory training (sniffing eight scents for 15 s each twice daily for 12 weeks)	Olfactory training (sniffing four scents for 15 s each twice daily for 12 weeks)	Final OFS Change in OFS	No	UPSIT, VAS-score at 0, 4 weeks	No improvement between groups Significant improvement pre-, posttreatment both together
	[28]	NRS	67	Oral corticosteroids (Prednisolone 40 mg/daily for 5 days, then tapered down over 9 days)  +  Corticosteroid nasal spray (Betamethasone 0.1%, 2 drops/nostril twice daily for 2 weeks)  +  Olfactory training (idem as comparison group)	Olfactory training (sniffing four scents twice daily for 12 week) No treatment	Change in OFS	Yes	TDI, VAS-score at 0, 6 months	Significant improvement in intervention group and OT (TDI) Significant improvement in intervention group (VAS) No significant improvement between intervention group and OT
	[25]	NRS	75	Modified olfactory training (3 × sniffing 4 scents 10 s each for 5 min, twice a day for 12 weeks)	No Treatment	Final OFS	Yes	TDI, Parosmia assessment at 0, 3, 6, 9 months	Significant improvement of Parosmia and TDI
	[27]	NRS	69	PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 90 days)  +  Olfactory training (prior) (sniffing four scents 6 s each, three times daily for 6 min each session)	PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg twice daily for 90 days)  +  Olfactory training (naive) (same as intervention group) PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 90 days)	Final OFS, Change in OFS	Yes	Sniffin’ Sticks Score Identification, Parosmia VAS at 0, 30, 60, 90 days	Most significant improvement in PEA/Leotlin and OT group (prior) for Identification, Significant improvement of Parosmia in all groups at 90 days, between groups no difference

RCT randomised clincial trial, NRS non-randomised studies, OFS olfactory function sceore

Fig. 2.

Forest plot of the effect of (A) olfactory training, (B) intranasal corticosteroids (ICS) and (C) systemic corticosteroids (CS). The studies are categorized based on the duration of smell loss before the treatment, split into 3 subgroups: less than 3 months, between 3 to 6 months, and more than 6 months

In the subgroup analysis for OD duration of one to three months, the SMD was 0.10 (95% CI: -0.31 to 0.52) and for OD duration greater than six months, the SMD was 0.01 (95% CI: -0.47 to 0.45). Both analyses showed no significant differences (p = 0.62 and p = 0.97, respectively).

Intranasal Corticosteroids

We found six studies, five RCTs and one non-randomised study, involving the use of topical corticosteroids (Table 2) [30–35]. In most studies the patients received nasal corticosteroid sprays with a duration from two weeks to three months. Concomitant OT, in intervention and control group, was performed in four of the six studies.

Table 2.

Included studies corticosteroids

Therapy	Reference	Study design	Sample size	Intervention	Comparison	Outcomes	Parosmia assessment	Measurement tool/time	Results
Intranasal Coricosteroids
	[32]	RCT	123	Corticosteroid nasal irrigation (with budesonide (1 mg/2 ml) and 250 ml saline solution in a 20 ml syringe twice daily for 30 days)  +  Olfactory training (idem as in comparison group)	Nasal saline irrigation (saline solution in a 20 ml syringe twice daily for 30 days)  +  Olfactory training (idem as in intervention group)	Change in OFS Recovery rate	No	ODORATEST at 0, 30, 60 days and 8 months	No improvement compared to other group
	[34]	RCT	40	Corticosteroid injection (8 × Dexamethasone injection (8 mg) near the olfactory cleft over 2 months)	Saline injection (application idem as in intervention group)	Final OFS	No	QOD-NS at 0, 4 weeks	Significant improvement in both groups No significant improvement between groups
	[33]	RCT	20	Corticosteroid nasal spray (Mometasone furoate spray 2 puffs/nostril with 50 µg once daily for 3 weeks)  +  Olfactory training (idem as in comparison group)	Olfactory training (sniffing four scents for 10 s each twice daily for 3 weeks)	Final OFS	No	TDI, 20-item taste powder test at 0, 2, 3 months	Significant improvement in both groups No significant improvement between groups
	[30]	RCT	80	Corticosteroid nasal spray (Mometasone Furoate 0.05% 1 puff/nostril twice daily for 4 weeks)	Nasal saline irrigation (saline solution 1 puff/nostril twice daily for 4 weeks)	Final OFS Change in OFS, Change in OD classification	No	Iran-SIT, VAS-score at 0, 2, 4 weeks	Significant improvement in Final and Change in OFS No significant improvement in change in OD classification
	[31]	RCT	112	Corticosteroid nasal spray (Mometasone Furoate of 100 µg 2 puffs/nostril twice daily for 3 months)  +  Olfactory training (idem as in comparison group)	Olfactory training (sniffing three scents for 30 s each twice daily for 3 weeks)	Final OFS Change in OFS	No	TDI at 0, 3 months	Significant improvement in both groups (Final OFS), No significant improvement in Change in OFS No significant improvement between groups
				Intranasal Vitamin A&E  +  Olfactory training (idem as in comparison group)	Olfactory training (a sniffing session of 10 min twice daily for 30 days)			Sniffin’ Sticks Threshold, VAS-score at 0, 3 months	All significant improvement, with adjuvant therapy more No significant difference between the groups
	[35]	NRS	47	Corticosteroid nasal spray (Mometasone Furoate of 100 µg 2 puffs/nostril twice daily for 3 months)  +  Olfactory training (idem as in comparison group)		Change in OFS	No
				Corticosteroid nasal spray  +  Multivitamin supplement  +  Olfactory training (idem as in comparison group)
Oral Coricosteroid
	[37]	RCT	115	Oral corticosteroids (Prednisolone 40 mg once daily for 10 days)  +  Olfactory training (for 12 weeks)	Placebo (Matching Placobo pills for 10 days)  +  Olfactory training (idem)	Change in OFS Final OFS	No	TDI, VAS-score, ODQ at 0, 12 weeks	No improvement
	[36]	RCT	18	Oral corticosteroids (Prednisolone starting at a concentration of 1 mg/kg once daily with tapering for 15 days)  +  Nasal irrigation corticosteroid spray (Bethamethasone, Ambroxol and Rinazine for 15 days)	No treatment	Recovery rate, Change in OFS, Change in OD classification	No	CCCRC at 0, 20 and 40 days	Significant improvement at day 20 in intervention group, at day 40 in both groups
	[28]	NRS	67	Oral corticosteroids (Prednisolone 40 mg/daily for 5 days, then tapered down over 9 days)  +  Corticosteroid nasal spray (Betamethasone 0.1%, 2 drops/nostril twice daily for 2 weeks)  +  Olfactory training (idem as comparison group)	Olfactory training (sniffing four scents twice daily for 12 week) No treatment	Change in OFS	Yes	TDI, VAS-score at 0, 6 months	Significant improvement in intervention group and OT (TDI) Significant improvement in intervention group (VAS) No significant improvement between intervention group and OT
	[38]	NRS	72	Oral corticosteroids (Methylprednisolone 32 mg once daily for 10 days)  +  Olfactory training (idem as in comparison group)	Olfactory training (sniffing four scents for 10 s each twice daily for ten weeks)	Change in OFS	No	Sniffin’ Sticks battery test at 0 and 10 weeks	Significant improvement in intervention group No significant improvemnt in control group

RCT randomised clincial trial, NRS non-randomised studies, OFS olfactory function sceore

For the quantitative analysis we considered 3 studies, which evaluated the ΔOFS [30–32]. The overall pooled SMD across all subgroups is 0.41 [95% CI: -0.24, 1.07], indicating a non-significant trend, favouring the intervention group (Fig. 2). However, there is substantial heterogeneity (I² = 86%). While there might be a trend towards a benefit with intranasal corticosteroids, the effect is inconsistent and not statistically significant.

Oral Corticosteroids

Four studies, two RCTs and two non-randomised trials, described the effect of oral CS on olfactory function (Table 2) [28, 36–38]. Patients received either 32 mg, 40 mg or 1 mg/kg once daily for 10–15 days. Concomitant OT was performed in two studies, and concomitant corticosteroid nasal spray in one study. Follow-up was conducted from 10 weeks to 6 months.

All studies reported on the ΔOFS with a pooled SMD of 0.10 [95% CI: -0.19, 0.40], indicating no significant difference between the systemic CS and control groups. Subgroup analysis regarding OD duration also showed no significant difference (Fig. 2).

Platelet-Rich Plasma (PRP)

We found 5 studies, 3 RCTs and 2 non-randomised trials, examining the effect of platelet-rich plasma on olfactory dysfunction (Table 3) [39–43]. All 5 studies administered PRP injections into the olfactory cleft mucosa, ranging from one to three times. Control groups either received OT, placebo injection or no treatment at all. Four studies reported about the ΔOFS and were included in the quantitative analysis. The overall SMD favours PRP, with a pooled mean SMD of 1.81 [95% CI: 0.31, 3.31], indicating a statistically significant improvement for PRP treatment (p = 0.02) (Fig. 3. The heterogeneity is high (I² = 88%), suggesting substantial variability among the study results, therefore, the results should be interpreted with caution. Three studies reported about the outcome of parosmia [40, 42, 43]. These studies compared PRP injection to either a control group with pre-existing treatments for OD, including OT, intranasal corticosteroids, omega-3, vitamin B12, and zinc supplementation for 6 weeks, to a placebo group with saline injection into the olfactory cleft. Due to substantial differences in measured outcomes, no quantitative analysis was conducted. The study of El Naga and the study of Lechien reported a significant improvement, while the study of Yan showed no improvement at all [40, 42, 43]. PRP injection was generally well tolerated.

Table 3.

Included studies of other treatments

Therapy	Reference	Study design	Sample size	Intervention	Comparison	Outcomes	Parosmia assessment	Measurement tool/time	Results
Platelet-Rich Plasma
	[39]	RCT	32	PRP Injection (1 ml PRP into olfactory cleft once)	No treatment	Change in OFS	No	CCCRC at 0, 4 weeks	Significant improvement in intervention group
	[40]	RCT	35	PRP Injection (2 × 1 ml PRP into olfactory cleft submucosally at 2 sites three times)	Placebo (1 ml Saline injection into the olfactory cleft)	Change in OFS, Duration of OD	Yes	UPSIT, VAS-score at 0, 4 and 12 weeks	Significant improvement in both groups (VAS) Significant improvement in intervention group (TDI) No improvement of Parosmia
	[43]	RCT	60	PRP Injection (1 ml PRP into into the olfactory region approximately every 1 cm2 three times at three weeks intervals)	Pre-study treatment (olfactory training, topical corticosteroids, omega-three, vitamin B12, and zinc supplementation for 6 weeks)	Final OFS	Yes	Parosmia VAS at 0, 4 weeks after 3. Injection	More significant improvement in intervention group
	[42]	NRS	159	PRP Injection (bilateral 4 to 6 injections of 0.2 mL in the nasal septum of the olfactory cleft and medial part of the middle turbinate three times)  +  Olfactory training (sniffing four scents for 12 weeks)	Olfactory training (sniffing four scents for 12 weeks)	Final OFS	Yes	TDI, Olfactory Disorder Questionnaire (ODQ) at 0, 10 weeks	Significant improvement of TDI in both groups Significant improvement of Parosmia and ODQ in intervention group
	[41]	NRS	56	PRP Injection (1 ml PRP into each olfactory cleft submucosally)	Olfactory training (a sniffing session of 10 min twice daily for 30 days)	Change in OFS Final OFS	No	TDI, Likert-scale at 0, 4 weeks	Significant improvement of TDI and Likert-scale in intervention group
Vitamin supplement
	[48]	RCT	139	Oral Omega-3 Fish Oil (2,000 mg daily of O3FA supplementation twice daily for 6 weeks)	Placebo (placebo pill of identical size and shape twice daily for 6 weeks)	Final OFS, Change in OFS	No	BSIT, mQOD-NS at 0, 6 weeks, long-term	No significant improvement of BSIT in both groups Significant improvement of mQOD-NS in both groups
	[26]	RCT	56	Oral Vitamin A (25,000 IU daily for 14 days)  +  Olfactory training (sniffing four odour each 20 s thrice daily for 4 weeks)	Olfactory training (sniffing four odour each 20 s thrice daily for 4 weeks) No treatment	Change in OFS, Change in OD classification	No	BTT, SIT, MRI, rs-fMRI at 0, 2, 4 weeks	Significant improvement in intervention group (BTT, SIT) No significant improvement in both control groups
	[49]	RCT	128	Alpha-lipoic acid (600 mg/day for 12 weeks)  +  Olfactory training (sniffing four scents for 10 s each twice daily for 12 weeks)	Placebo (pills 600 mg/day for 12 weeks)  +  Olfactory training (idem as in intervention group)	Final OFS, Change in OFS, Change in OD classification	No	CCCRC, VAS-score at 0, 12 weeks	Significant improvement in both groups, but no difference between groups No improvement in Change in OD classification
				Vitamin A nasal drops (2drops 10.000 IU per each nostril once daily)
	[50]	NRS		Nasal theophylline (400 mg theophylline tablet diluted in 240 mL isotonic nasal saline, irrigation each nostril twice daily)	Nasal saline irrigation (Isotonic saline in each nostril twice daily for 1 month)	Recovery rate, OD duration	No	VAS-score at 0, 1, 2, 3, 4 weeks	No difference between groups at 4 weeks (recovery rate) Significant improvement in OD duration between groups
				Corticosteroid nasal spray (Mometasone Furoate of 100 µg 2 puffs/nostril twice daily for four weeks)
				Intranasal Vitamin A&E (solution of Vitamin A palmitate 15 000 UI/ml + Vitamin E acetate 20 mg/ml twice daily)  +  Olfactory training (idem as in comparison group)				Sniffin’ Sticks Threshold at 0, 3 months
	[35]	NRS	47	Corticosteroid nasal spray (50 μg mometasone twice daily)  +  Olfactory training (idem as in comparison group)	Olfactory training (sniffing four scents for 15 s each three times daily)	Change in OFS	No		All significant improvement, with adjuvant therapy more
				Corticosteroid nasal spray (50 μg mometasone twice daily)  +  Multivitamin supplement (0.2 mg of B1, 200 mg of B6 and 100 mg of B12 twice daily)  +  Olfactory training (idem as in comparison group)
PEA-LUT
	[54]	RCT	130	PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 90 days)  +  Olfactory training (idem as in comparison group)	Placebo (multivitamin, vitamin D 400 UI, and/or alpha-lipoic acid 120 mg daily for 90 days)  +  Olfactory training (sniffing four scents 20 s each, three times every day for 6 min each session)	Recovery rate, Final OFS	Yes	Sniffin’ Sticks identification, Parosmia questionnaire at 0, 90 days after treatment	No improvement of Parosmia Significant improvement of quantitative OD
	[53]	RCT	250	PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 90 days)  +  Olfactory training (idem as in comparison group) PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg twice daily for 90 days) PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 90 days)	Placebo (multivitamin, vitamin D 400 UI, and/or alpha-lipoic acid 120 mg daily for 90 days)  +  Olfactory training (sniffing four scents 20 s each, three times every day for 6 min each session)	Final OFS	No	Sniffin’ Sticks identification test at 0, 30, 60, 90 days	Significant improvement in all groups at 90 days Most significant improvement in PEA-LUT + OT group
	[52]	RCT	185	PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 90 days)  +  Olfactory training (idem as in comparison group)	Placebo (multivitamin, vitamin D 400 UI, and/or alpha-lipoic acid 120 mg daily for 90 days)  +  Olfactory training (sniffing four scents 6 s each, three times daily for 6 min each session for 90 days)	Finals OFS	No	TDI at 0, 90 days	Significant improvement in intervention group
	[51]	RCT	12	PEA/Luteolin supplement (PEA 700 mg and Luteolin 70 mg once daily for 30 days)  +  Olfactory training (idem as in comparison group)	Olfactory training (a sniffing session of 10 min twice daily for 30 days)	Final OFS	No	TDI at 0, 60 days	Significant improvement in intervention group No significant improvement in control group
Calcium chelators
	[44]	RCT	66	Pentasodium diethylenetriamine pentaacetate (Intranasal 2% DTPA-containing nasal spray, three times daily for 1 month)	Nasal saline spray (Intranasal 0.9% sodium chloride, three times daily for 1 month)	Final OFS, Change in OD classification	No	TDI at 0, 1 month	Significant improvement
	[47]	RCT	50	Ethylene diamine tetra acetic acid spray (Intranasal 1% EDTA in phosphate buffer solution, pH 7.5 three times daily for 3 month)  +  Olfactory training (same as comparison group)	Olfactory training (sniffing four scents daily for 3 months)	Change in OFS, Final OFS	No	TDI at 0, 3 month	Significant improvement in both groups, Intervention group more
	[46]	RCT	50	Sodium Gluconate spray (sodium gluconate in borate buffer solution, pH 8, three times daily for 1 month	Nasal saline spray (Intranasal 0.9% sodium chloride, three times daily for 1 month)	Final OFS, Change in OFS, Change in OD classification	No	TDI at 0, 1 month	Significant improvement
	[45]	RCT	64	Tetra sodium pyrophosphate spray (Intranasal 1% TSPP in borate buffer solution with a pH of 8, three times daily for 1 month)	Nasal saline spray (Intranasal 0.9% sodium chloride, three times daily for 1 month)	Final OFS, Change in OFS, Change in OD classification	No	TDI at 0, 1 month	Significant improvement
Insulin
	[55]	RCT	40	Insulin fast-dissolving film (application of insulin fast-dissolving film 100 units twice weekly for four weeks)	Placebo fast-dissolving film (application of placebo film twice weekly for four weeks)	Final OFS	No	Olfactory discrimination and threshold test at 0, 1, 2, 3, 4 weeks	Significant improvement
Gabapentin
	[56]	RCT	188	Oral Gabapentin (titrated to a maximum tolerable dose, maintained during an 8-week fixed-dose phase, then tapered off)	Placebo (same appearing pills)	Change in OFS	Yes	UPSIT, ODOR, NASAL-7, CGI-S, CGI-P at 0, 8, 12 weeks	No improvement
Cerebrolysin
	[57]	RCT	250	Cerebrolysin injection (5 ml/d x 5 day/week through intramuscular injection for ≥ 8–24 weeks)  +  Olfactory, gustatory training (idem as comparison group)	Olfactory, gustatory training (sniffing four scents for 20 s each twice daily for ≥ 8–24 weeks)	Final OFS, Recovery rate	Yes	SOIT, GRS, Flavor identification test, at 0, 8, 12, 18, 24 weeks	Significant improvement of Parosmia and SOIT

RCT randomised clincial trial, NRS non-randomised studies, OFS olfactory function sceore

Fig. 3.

Forest plot of the effect of (A) platelet-rich plasma (PRP), (B) palmitoylethanolamide and luteolin (PEA-LUT) and (C) calcium chelators

Calcium Chelators

In the past years 4 RCTs have been published regarding lowering the calcium level intranasally (Table 3) [44–47]. All studies were conducted by the same research group in Egypt. In each study, a different intranasal spray was used, all of which aimed to lower the calcium levels in the nose and enhance the sense of smell. The overall SMD favours the calcium chelators, with a pooled SMD of 0.75 [95% CI: 0.46, 1.04], indicating a statistically significant positive effect (p < 0.00001) (Fig. 3). The heterogeneity is low (I² = 12%), indicating that the results are relatively consistent across studies, which is not surprising since all the included studies were performed by the same team in Egypt. Each study individually demonstrates a positive effect, all favouring the calcium buffer intervention.

Vitamin Supplements

In this section, we included all studies using vitamin supplements, either orally or intranasally administered, to evaluate the effect on olfactory function. Five studies, three RCTs and two non-randomised trials, were included (Table 3) [26, 35, 48–50]. A 2023 RCT by Lerner involving 139 patients, examined the impact of oral omega-3 supplementation (“Omega-3 Fish Oil”) compared to placebo [48]. No significant improvement was observed on the final OFS between the two groups.

Another RCT by Chung in 2023 with 56 participants, evaluated the combination of oral vitamin A supplementation and OT [26]. This intervention led to significant improvements in the OFS scores within the treatment group, whereas no significant improvements were observed in the control group.

Figueiredo’s 2023 RCT, which included 128 participants, evaluated the effects of alpha-lipoic acid combined with OT compared to a placebo [49]. Both the intervention and placebo groups showed significant improvements in the OFS. However, there was no significant difference between the groups regarding changes in olfactory dysfunction classification.

A preprint study by Abu Shaby in 2023 used a non-randomized design to compare nasal theophylline to isotonic saline irrigation alone [50]. This study found a significant improvement in the VAS-score of OD in the theophylline group.

Finally, a 2022 non-randomized study by Sousa with 47 participants explored the use of mometasone nasal spray (50 µg twice daily) in combination with OT [35]. An additional group received a multivitamin supplement along with the nasal spray and training. Both groups demonstrated significant improvements.

Palmitoylethanolamide with Luteolin (PEA-LUT)

Four RCTs described the effect of PEA-LUT (Table 3) [51–54]. All studies were conducted by the same research group in Italy. The overall SMD is 0.97 [95% CI: -0.02, 1.95] and with very low heterogeneity among the studies (I² = 0%), indicating consistent results across studies. The individual SMDs range from 0.14 to 1.61, with Di Stadio (2023a) and Di Stadio (2023b) demonstrating the most positive effects. The analysis suggests that the PEA-LUT intervention may have a beneficial effect compared to the control; however, the overall effect is not statistically significant (p = 0.06) (Fig. 3).

Insulin

One RCT was published, involving 49 patients, describing local insulin application as a treatment for OD (Table 3) [55]. Twice a week for 4 weeks fast dissolving insulin was applied at the olfactory cleft. At the end of the therapy, a clinically significant improvement of OFS was seen. No serious adverse effects were mentioned.

Gabapentin

One RCT was identified that investigated the use of oral gabapentin as a treatment (Table 3) [56]. 188 patients were involved and received gabapentin titrated to a maximum tolerable dose, maintained during an 8-week fixed-dose phase, then tapered off. There were no serious adverse events, but some patients suffered of fatigue, dizziness, weight gain or brain fog. Overall, there was no clinical improvement in OFS nor parosmia.

Cerebrolysin

One RCT described the treatment effect of cerebrolysin on olfactory function (Table 3) [57]. This study included 250 patients receiving 5 ml cerebrolysin 5 days a week through intramuscular injection for ≥ 8–24 weeks. Intervention and control group performed both concomitant olfactory and gustatory training. At the end of the therapy, a clinically significant improvement of OFS and parosmia was measured. No serious adverse effects were described.

Discussion

In this systematic review, we present a structured overview of treatment options for COVID-19 associated olfactory dysfunction, analyzing various therapeutic strategies and their efficacy. To date, there is only one living systematic (Cochrane) review, which has included only two studies due to its rigorous inclusion criteria and exclusive focus on randomized controlled trials (RCTs) [58].

Our search yielded a total of 36 studies published between 2019 and 2023. We grouped these studies into 9 different treatment categories: OT, topical and systemic CS, PRP, calcium chelators, vitamin supplements, PEA-LUT, insulin, gabapentin and cerebrolysin. We included only studies with patients experiencing OD for at least one month to account for the high rate of spontaneous recovery within the first month [59]. Therefore, two studies were excluded because they recruited patients with OD lasting more than one month, but conducted olfactory function tests within two weeks of OD onset without subsequent testing after starting the treatment. This exclusion ensures that the included studies focus on patients with persistent OD, providing a more accurate assessment of treatment efficacy and size effect [60, 61].

A descriptive synthesis of the effects of the different intervention modalities was done, considering subjective and objective/psychophysical outcome parameters. For the quantitative analysis, however, we exclusively included studies with objective testing. While some studies demonstrate a significant association between subjective (VAS-score, Likert-scale) and objective olfactory function, others indicate a lack of correlation [62–64]. The discrepancy underscores the importance of conducting objective testing and reducing the potential biases and variabilities in subjective self-assessments. Due to the inclusion of objective testing studies only for quantitative OD, 2 studies were excluded.

OD significantly impacts quality of life, as it affects various daily activities and overall well-being.[65, 66]. However, QoL questionnaires, while valuable in assessing the broader impact of OD, do not directly measure olfactory function itself. Consequently, they were excluded from the quantitative analysis to ensure that the evaluation remained focused on direct, objective measures of olfactory function.

In the following section, we will focus on the three most significant treatment modalities, identified in our systematic review: olfactory training, corticosteroids, and PRP. These treatments have been more frequently and extensively studied, offering more substantial evidence of their efficacy in managing olfactory dysfunction.

Olfactory Training

OT, which typically involves regularly smelling specific scents, is widely suggested as a first-line treatment for post-infectious OD, including COVID-19 associated OD.

Aims to retrain the brain to accurately interpret the neurological signals generated when odorants are detected, which then travel through the olfactory nerve, olfactory bulb, and olfactory cortex [8].

The relatively low cost, the non-invasive nature and absence of associated complications, supports its use as first-line therapy. This therapy was firstly presented by Hummel et al., with a clinically significant improvement on olfaction in patients with post-infectious, post-traumatic, and idiopathic olfactory loss [67]. A meta-analysis of 2016 found benefit in the total TDI scores as well as odour identification and discrimination [10]. Further, functional magnetic resonance imaging (MRI) studies demonstrated alterations in connectivity among cortical olfactory networks after OT [68]. However, no control group was included in the latter study.

Pieniak et al. stated that OT can be considered as an established method for smell rehabilitation, supporting cognitive functions in both developmental and aging processes [69].

In our analysis, OT showed no significant overall impact compared to control groups. This suggests that, while OT is a widely recommended non-pharmacological intervention and considered as the standard of care for post-viral OD, its efficacy may not be as substantial in COVID-19 associated OD as previously thought. OT has been adopted as a foundational treatment in general otorhinolaryngology practices, even though the mechanisms of action are not well understood.

In addition, it is important to note that the duration of OT in the included studies ranged from one and a half to three months. This variability must be considered, as prior researches recommend a minimum training duration of three months to observe potential effects [8, 70]. Therefore, we can only conclude that short-term OT does not significantly improve OD.

Furthermore,while there is a slight numerical trend indicating better results for patients with a shorter duration of olfactory dysfunction (less than 3 months), the differences between the subgroups are minimal, and the confidence intervals overlap. This suggests that the duration of smell loss does not have a strong or significant effect. With such a small number of studies per subgroup, however, it’s difficult to draw conclusions about the impact of the duration of smell loss on the effectiveness of OT.

Corticosteroids

The use of topical corticosteroids carries some controversy. For instance, a systematic review highlighted that, while topical corticosteroids showed some potential in improving olfactory function, systemic corticosteroids did not demonstrate a significant benefit over placebo treatments in most studies reviewed [13]. However, another study showed no beneficial effect [71].Our results suggest that intranasal corticosteroids might provide some benefit for COVID-19-associated OD, although the evidence is not statistically significant. Furthermore, systemic corticosteroids do not appear to offer significant benefits for improving olfactory function, aligning with other research findings. It is important to note that our study did not consider different application methods, such as nasal irrigations, sprays or specific head positions, which could potentially influence the efficacy of the treatments. As Helman et al. stated in their systematic review on treatment strategies for post-viral OD, that studies that examined the efficacy of nasal corticosteroid spray should be interpreted with consideration of the administration method [72]. The administration of topical steroids via irrigations may increase delivery of medication to the olfactory cleft compared with standard nasal spray administration, and this effect may be augmented by using special head positions [73].

Despite the limited evidence on the efficacy of systemic corticosteroids for olfactory dysfunction, we must remain vigilant about their potentially severe adverse effects. The recent EAACI position paper on the benefits and harms of systemic steroids also reports the short- term effects of corticosteroids used in upper airway disease [74].

PRP

The growth factors in PRP, such as vascular endothelial growth factor and epidermal growth factor, contribute significantly to tissue regeneration and may play a role in olfactory recovery by promoting neurogenesis and modulating the inflammatory response [75]. A systematic review and meta-analysis examined the efficacy of PRP for treating persistent olfactory impairment, including post-COVID-19 and post-infectious cases [75]. The analysis revealed significant improvements in olfactory function. However, substantial inter-study heterogeneity was noted. Our findings suggest a statistically significant improvement in olfactory function with PRP treatment, aligning with studies that have reported beneficial outcomes. However, the substantial variability among studies highlights the need for standardized protocols and further large-scale RCTs to validate these results comprehensively.

The heterogeneity in some treatment outcomes complicates direct comparisons and limits definitive conclusions. Moreover, the inclusion of studies conducted by the same research teams could introduce bias, emphasizing the need for broader, multicentric trials.

Future research should, therefore, focus on two main areas to address the challenges in treating OD following COVID-19. First, standardizing treatment protocols and outcome assessments is essential to reduce heterogeneity and allow for more direct comparisons across studies. This standardization would facilitate the identification of the most effective interventions and ensure consistency in measuring their outcomes. Additionally, long-term studies are necessary to determine the long-term efficacy of various interventions.

Second, further research on the underlying pathophysiology of OD is important. A deeper understanding of the mechanisms by which SARS-CoV-2 causes OD could guide finding targeted treatment options [76, 77]. For instance, if scarring or fibrosis is identified as a key factor, then agents that inhibit fibrosis formation might be useful. Similarly, insights into the role of inflammation could lead to the use of anti-inflammatory drugs. By elucidating the pathophysiological mechanisms involved in COVID-19 associated OD, researchers can develop more effective and specific treatment strategies, ultimately improving the quality of life for those affected by this condition.

Nonetheless, in this systematic review, we have provided an overview of the most recently published studies regarding therapy options for COVID-19 associated OD. By highlighting the current state of research and the need for further studies, we aim to contribute to the ongoing efforts to find effective treatments for this challenging condition.

Conclusion

In conclusion, while several therapeutic options show promise for treating COVID-19-associated OD, the available evidence remains inconclusive. Olfactory training, intranasal corticosteroids, and PRP are potential interventions, but their efficacy varies. Calcium chelators and certain vitamin supplements offer hope, yet require further validation. Continued research is essential to establish clear, evidence-based guidelines for managing persistent OD in COVID-19 patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contribution

The pre-published protocol and the search strategy was developed by MC and A V. SB and MM screened titles and abstracts for eligibility. Full texts and risk of bias were also assessed by SB and MM according to the inclusion criteria. SB and MM wrote the main manuscript text, prepared the figures and tables. LVG served as the supervising professor, contributing to the overall guidance and coordination of the project and reviewed the manuscript.

Funding

Laura Van Gerven was supported by Research Foundation Flanders (FWO): Senior Clinical Investigator Fellowship 18B2222N.

Data Availability

Some Data are provided within the manuscript as supplementary information (search strategy).

Declarations

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing Interest

HippoDx (stocks and scientific advisory board), speakers fees from GSK.