key: cord-0800093-49thwas4
authors: Wu, Tara J.; Yu, Alice C.; Lee, Jivianne T.
title: Management of post-COVID-19 olfactory dysfunction
date: 2022-01-04
journal: Curr Treat Options Allergy
DOI: 10.1007/s40521-021-00297-9
sha: 9d86b6170d32423b5edcaa295759058738de37a4
doc_id: 800093
cord_uid: 49thwas4

PURPOSE OF REVIEW: Olfactory dysfunction is a frequent complication of SARS-CoV-2 infection. This review presents the current literature regarding the management of post-COVID-19 olfactory dysfunction (PCOD). RECENT FINDINGS: A systematic review of the literature using the PubMed/MEDLINE, EMBASE, and Cochrane databases for the following keywords, “Covid-19,” “SARS-CoV-2,” “anosmia,” “olfactory,” “treatment,” and “management” was performed. While most cases of post-COVID-19 olfactory dysfunction resolve spontaneously within 2 weeks of symptom onset, patients with symptoms that persist past 2 weeks require medical management. The intervention with the greatest degree of supporting evidence is olfactory training, wherein patients are repeatedly exposed to potent olfactory stimuli. To date, no large-scale randomized clinical trials exist that examine the efficacy of pharmacologic therapies for PCOD. Limited clinical trials and prospective controlled trials suggest intranasal corticosteroids and oral corticosteroids may alleviate symptoms. SUMMARY: Olfactory training should be initiated as soon as possible for patients with PCOD. Patients may benefit from a limited intranasal or oral corticosteroid course. Further research on effective pharmacologic therapies for PCOD is required to manage the growing number of patients with this condition.

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, wellvalidated 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.

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) [ 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].

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].

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 [ 

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].

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 ].

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 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 .

There is limited evidence to support the use of oral corticosteroids (OCS) in PCOD [ Table 4 ] although there was no control group and the increase in TDI score failed to reach the minimal clinically importance difference -Short-term OCS (~ 2 weeks with taper) are an option in select patients with PVOD, after consideration of the potential risks of oral steroids in the setting of medical comorbidities 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 .

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Anosmia in COVID-19: a bumpy road to establishing a cellular mechanism

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This is a meta-analysis of 4 studies, including 2 RCTs, investigating OT outcomes in PVOD, demonstrating a 3-fold greater odds of a clinically significant improvement in olfactory func

Management of new onset loss of sense of smell during the COVID-19 pandemic-BRS Consensus Guidelines

Objective evaluation of anosmia and ageusia in COVID-19 patients: single-center experience on 72 cases

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This is a metaanalysis of 40 studies, including 11 RCTs investigating PVOD, which showed mild benefit with use of ICS and OCS and significant benefit with OT

Effects of olfactory training in patients with olfactory loss

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Position paper on olfactory dysfunction

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Randomized controlled trial demonstrating cost-effective method of olfactory training in clinical practice: essential oils at uncontrolled concentration

Systemic corticosteroids in coronavirus disease 2019 (COVID-19)-related smell dysfunction: an international view

The outcome of fluticasone nasal spray on anosmia and triamcinolone oral paste in dysgeusia in COVID-19 patients

Budesonide irrigation with olfactory training improves outcomes compared with olfactory training alone in patients with olfactory loss

The administration of nasal drops in the "Kaiteki" position allows for delivery of the drug to the olfactory cleft: a pilot study in healthy subjects

The authors declare no competing interests.

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