Introduction

Post-coronavirus disease 2019 (COVID-19) olfactory dysfunction (PCOD) is thought to occur as a result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damaging the olfactory neuroepithelium [1, 2]. Several studies have hypothesized that this damage is mediated by viral invasion of ACEII and TMPRSS2 receptors on cells in the nasal and olfactory epithelium [3,4,5]. MRI studies have shown co-occurrence of transient olfactory bulb edema with PCOD, suggesting that an inflammatory response to this viral invasion may contribute to symptomatology as well [6].

Anosmia often represents the first or only symptom of COVID-19 disease, and it is estimated to be present in 19–68% of patients, often independently of coryzal symptoms [2, 7,8,9]. Any degree of olfactory dysfunction (OD) is estimated to be present in a larger majority, with up to 85–98% of patients affected in some studies [1, 2]. The natural course of PCOD is spontaneous resolution by two weeks for 95% of patients, with mean recovery of 9 days [9, 10]. However, in some patients, persistent PCOD is a prevalent symptom, appearing in 75% of cases with persistent COVID symptoms [11]. Risk factors for persistent PCOD include older age, diabetes mellitus, and longer duration of COVID-19 illness [9]. In light of the global prevalence of COVID-19, even a small proportion of patients with persistent PCOD likely numbers in the millions. Physicians face the challenge of managing an unprecedented number of patients with PCOD in the coming years.

The impacts of PCOD on quality of life are significant. PCOD reduces a person’s ability to enjoy foods and fragrances, recall olfaction-associated memories, and detect hazardous materials such as spoiled food and toxic fumes [12]. Furthermore, it is associated with a range of debilitating psychosocial effects, including depression, social isolation, impaired cognition, decreased nutrition, and earlier death [13•].

There is strong evidence supporting the use of olfactory training (OT) in the management of PCOD, with most studies demonstrating greater improvements in olfactory function (OF) with earlier initiation of therapy [13•, 14••]. However, there has been no consensus on appropriate pharmacotherapy for treatment of PCOD. Some limited randomized control trials have demonstrated benefit with short-term topical or oral corticosteroid use, but to date, there have been no large-scale trials investigating their efficacy [15,16,17,18]. Other therapies used in non-COVID-19 OD, such as theophylline, vitamin A, omega-3, or zinc, have been investigated but lack compelling evidence in favor of their use [19••].

The following studies employed a variety of olfactory tests to assess OF in response to treatment. Some studies used the Sniffin’ Sticks test, which uses felt-tip pens to present various concentrations of odorants to assess a subject’s odor threshold, discrimination, and identification. In this test, OF is measured using the threshold, discrimination, and identification (TDI) score [20]. The University of Pennsylvania Smell Identification Test (UPSIT) is another widely used, well-validated olfactory test, in which a subject is asked to identify 40 scratch-and-sniff odors in a test booklet [21]. Other tests include the objective Connecticut Chemosensory Clinical Research Center (CCCRC) test as described by Cain et al. [22] and the subjective Visual Analog Scale (VAS) as described by McCormack et al. [23]. In all of these tests, higher scores indicated better OF.

Treatment

Diet and Lifestyle

For patients with PCOD, counseling should be provided to maximize quality of life, nutrition, and safety. Patients should be strongly encouraged to ensure proper functioning of smoke and natural gas detectors to facilitate early detection of warning smells [24], class 2A]. They should also be advised to exercise caution in food safety by monitoring food expiration dates as well as to monitor overall nutritional intake [24], class 2A]. In active smokers, smoking cessation has been suggested to improve olfactory symptoms in patients with post-infectious olfactory disorders (PIOD) [19••], class 2A]. Traditional Chinese acupuncture has also been studied in limited low-level studies (1 level 3 study; 1 level 4 study), showing clinically significant improvements in TDI and UPSIT scores among a small group of patients with minimal treatment-related risk [13•], class 4].

Patients with OD have also demonstrated higher rates of depression than normosmic patients, suggesting a need for early recognition, screening, and intervention including referral to mental health services when appropriate [24], class 2A].

First-Line Therapy

Olfactory Training

The therapy for treatment of PCOD with the greatest evidentiary support is olfactory training (OT). OT is a non-pharmacologic treatment option involving repeated odor exposure, with promising outcomes for treatment of PVOD [Table 1]. The mechanism of action for this therapy is largely hypothetical but is thought to be related to regeneration of olfactory receptor neurons and/or improved higher order processing of olfactory information [25], level 4]. A position paper by Hummel et al. recommended OT in patients with olfactory loss of several etiologies, given the demonstrated benefits seen in several studies [26], level 5].

Table 1 Studies comparing effectiveness of olfactory training
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Classical OT protocols include twice-daily exposure to a set of 4 intense odors, including rose, eucalyptus, lemon, and cloves over a period of 12 weeks [20], level 2B]. In the morning and evening, patients smell each odorant for 10 s, rotating through all 4 odors to finish the set. Since the inception of OT, modified OT protocols have allowed patients to purchase their own essentials oils with varying odor concentrations and combinations, which have been shown to increase patient compliance and adherence while still achieving clinically significant improvements in olfactory function [14••], level 2A; 28, level 2B]. Modified OT protocols have tested a wider variety of odors and longer durations of therapy with improved outcomes [14••], level 2A; 25, level 4]. Conversely, therapy durations of less than 12 weeks may be ineffective [17], level 2B].

Denis et al. described a trial wherein 548 participants underwent olfactory training with concurrent visual depictions of the scents. After 4 weeks, 64% of patients reported improved symptoms [27], level 1B]. Though this study was limited by the lack of a control cohort, the results demonstrated that a large proportion of patients experienced clinically significant benefit from OT. Several meta-analyses published by Hura et al., Kattar et al., and Addison et al. all came to similar conclusions, as evidenced in Table 1 [13•], level 1A; 14••, level 2A; 19••, level 2A]. Hura et al. reviewed 10 studies, including 5 randomized controlled trials (RCTs), which demonstrated that OT resulted in improved TDI and UPSIT scores, concluding that a minimum of 12 weeks of therapy was recommended for treatment of PVOD [13•], level 1A]. Addison et al. reviewed 40 studies – of which 11 were RCTs – and published similar findings, demonstrating that long-term OT (> 32 weeks) with high-concentration odorants conferred significant benefit for patients with generalized anosmia [19••], level 2A]. Kattar et al. reviewed 4 studies including 2 RCTs, concluding that there was a threefold greater chance of achieving a clinically significant improvement in TDI scores among patients undergoing OT compared to controls. This finding also held true after accounting for variability in OT protocols. Additionally, this systematic review found that longer duration of OT (up to 56 weeks) along with earlier initiation of OT following symptoms (< 12 months) was associated with greater improvements in olfactory function [14••], level 2A]. Kattar et al., however, acknowledged the current limitations to OT, including a lack of consensus regarding optimal duration of therapy, dependence on high patient compliance, and need for long durations of treatment to achieve therapeutic effect.

Nevertheless, given its limited harm profile, relatively low cost, and evidence of effectiveness, patients should begin OT as soon as possible following symptoms of PCOD and continue therapy for a minimum of 12 weeks [19••, 29], level 2A].

Pharmacologic Treatment

While most cases of PCOD resolve spontaneously within 2 weeks, cases that persist beyond this timepoint may require pharmacologic intervention. Recent MRI studies have demonstrated inflammatory changes in the olfactory clefts of COVID-19 patients with anosmia compared to healthy controls, suggesting a possible role for anti-inflammatory agents such as intranasal corticosteroid sprays and oral corticosteroids [25], level 4]. A position paper by Hummel et al. recommended use of systemic and/or topical steroids in patients with olfactory dysfunction secondary to chronic rhinosinusitis and other inflammatory conditions, also suggesting a role for steroid treatments for PCOD [26], level 5].

Intranasal Corticosteroid Sprays

There is conflicting evidence regarding the efficacy of intranasal corticosteroid sprays (ICS), with some RCTs showing no benefit [18], level 2B], and others demonstrating improvement in olfaction scores following short-term courses of ICS therapy [16, 30], level 2B] [Table 2].

Table 2 Studies comparing effectiveness of intranasal corticosteroid sprays
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In one of the few RCTs published studying PCOD patients, Abdelalim et al. [18], level 1B] performed a study of 50 individuals who underwent daily mometasone furoate nasal sprays in combination with OT for 3 weeks, compared to 50 patients who underwent OT alone. Patients who underwent added MFNS therapy experienced no significant benefit over OT alone, as measured by smell scores, duration of anosmia, and recovery rates. However, the time since onset of OD symptoms was not standardized among the patients of this study. Given that patients experience variable recovery depending on the time of therapy initiation after infection, this study does not exclude the possibility of a subset of patients that, when treated early in their clinical course, might benefit from ICS.

Several consensus statements have recommended ICS for patients with PCOD symptoms lasting longer than 2 weeks [15, level 5; 19••, level 2A]. Hopkins et al. reported the consensus statement of the British Rhinological Society, integrating information from a literature review of post infectious olfactory dysfunction graded by 15 experts [15], level 5]. Multiple studies reviewed by Hopkins et al. demonstrated no additive benefit to topical steroids when used in combination with oral steroids. However, another retrospective study cited by Hopkins et al. noted combination of ICS with olfactory training was more therapeutic than olfactory training alone. Ultimately, Hopkins et al. recommended ICS for PCOD symptoms persisting past 2 weeks [19••], level 2A].

Interestingly, one study reported by Hopkins et al. demonstrated a benefit with budesonide irrigations, leading the authors to suggest that sufficient contact of areas of inflammation was necessary to achieve therapeutic effect [19••], level 2A]. In a similar vein, some authors have suggested that nasal irrigation, rather than sprays, may be more effective at treating PCOD due to increased penetration to the olfactory cleft [31], level 2B]. To this end, some have suggested the use of the Kaiteki position, wherein patients lay on their side with the head tilted and chin lifted at a 20 to 40 degree angle, such that nasal drops may reach the olfactory cleft [32], level 4].

Addison et al. reported on the consensus statement of the Clinical Olfactory Working Group based on 15 articles evaluating management of post-infectious olfactory dysfunction [19••], level 2A]. This group concluded that, though direct evidence of the utility of ICS was limited, the relative risk of ICS was low enough such that a trial of ICS was advisable for most patients. Like the studies analyzed by Hopkins et al., many of the papers analyzed by Addison et al. tested the efficacy of ICS in combination with other therapies. As such, there has been limited evidence of the use of ICS alone. Importantly, Addison et al. concurred with Hopkins et al. in concluding that effective delivery of topical corticosteroids could play a limiting factor in the efficacy of ICS and suggested that patients might benefit from usage of the Kaiteki position [19••], level 2A].

A systematic review by Hura et al. included three studies that looked into the utility of topical corticosteroid sprays, of which one was a RCT performed by Blomqvist et al. in 2003 among patients with post-viral olfactory dysfunction [13•], level 1A]. In this RCT, 23 patients were treated with a 10-day course of ICS and oral corticosteroids (OCS), after which they were randomized to continued ICS, placebo, or control groups. The study demonstrated no differences in outcome in olfactory function at 6 months among the three groups, suggesting limited benefit in chronic use of ICS. However, in two other case series analyzed by Hura et al., topical application of corticosteroids was investigated and found to cause some improvement in olfactory dysfunction. Though this effect was only seen in a subset of patients (25–58%), Hura et al. concluded that the limited side effects of topical corticosteroids and the possibility of therapeutic effect made ICS preferable to oral corticosteroids for many patients [13•], level 1A].

In summary, though the evidence to support use of ICS in PCOD patients is mixed both in strength and applicability to post-SARS-CoV2 patients, the side effect profile of this therapy is limited; as such, for most patients, the potential benefits likely outweigh the risks for a short-term trial. Drug information for intranasal corticosteroids is provided in Table 3.

Table 3 Drug information for intranasal corticosteroids
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Oral Corticosteroids

There is limited evidence to support the use of oral corticosteroids (OCS) in PCOD [Table 4]. Consensus statements published by Hopkins et al. and Addison et al. advised that, though OCS have evidence of effectiveness, they have a limited role in routine clinical management of PCOD due to their extended side effect profile [15], level 5; 19••, level 2A]. One retrospective study analyzed by Addison et al. was performed on patients with any cause of olfactory dysfunction and showed the combination of OCS + ICS or OCS alone was more effective at treating PCOD than ICS alone [19••], level 2A]. The consensus statement released by Addison et al. also discussed an RCT in which patients with post-infectious olfactory dysfunction were initially treated with oral prednisolone before transitioning to ICS. This investigation found that the initial course of oral steroids was effective at reducing PCOD symptoms, while the subsequent course of topical steroids conferred no additional advantage [19••], level 2A]. Another study included by Addison et al. showed an oral methylprednisolone taper was able to improve olfactory dysfunction of all etiologies [19••], level 2A]. However, these studies were all limited by lack of specificity to PCOD. Moreover, several studies reported by Addison et al. were performed on patient populations with olfactory dysfunction of non-infectious origins and thus cannot be readily generalizable to the PCOD patient set. Both consensus statements published by Addison et al. and Hopkins et al. agreed that, due to the multi-system nature of SARS-CoV2, multidimensional risk benefit analysis should occur before initiation of oral steroid therapy. However, Hopkins et al. stated that a short trial of oral corticosteroids could be appropriate in the scenario where olfactory dysfunction is the only symptom of SARS-CoV2 [19••], level 2A].

Table 4 Studies comparing effectiveness of systemic corticosteroids
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Several studies exist examining the effect of oral steroids more specifically in PCOD patients. A non-randomized controlled trial by Le Bon et al. [17], level 2B] showed greater improvements in olfactory scores among PCOD patients undergoing OCS and olfactory training (OT), compared to OT alone. However, this trial studied 27 patients, of which only 9 were treated with oral corticosteroids, thereby limiting its statistical power. Vaira et al. reported on a non-randomized control trial testing the efficacy of the combination of systemic prednisone and ICS in patients with PCOD persisting longer than 30 days. This study found significant improvement at 40 days of treatment, suggesting that long-term courses of OCS and intranasal steroid irrigation could prove useful for refractory cases [8], level 2B].

Hura et al. aggregated six studies of OCS to show that patients experienced quantifiable improvement in olfaction, but concluded that consideration of OCS was patient- and situation-dependent, given the broad side effect profile [13•], level 3A]. Similarly, Addison et al. stated that while OCS had some evidence of clinical utility, clinicians were divided on its routine use in a PCOD setting; the authors suggested the alternative of a short 3–4-day course of OCS to trial therapy responsiveness before beginning a more prolonged course [19••], level 2A].

Ultimately, though the side effect profile limits its applicability, evidence suggests OCS may be an effective option in some patients with persistent PCOD symptoms. Furthermore, several trials in the literature suggest the combination of OCS and ICS may prove useful for refractory cases of olfactory dysfunction. Drug information for oral corticosteroids is provided in Table 5.

Table 5 Drug information for oral corticosteroids
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