Since the early reports of coronavirus disease 2019 (COVID-19), various authors have pointed out the high prevalence of hyposmia or anosmia during the course of the infection. Although olfactory impairment is well known in (viral) upper airway infections, it rapidly became obvious that olfactory impairment potentially leading to lasting olfactory loss is among the frequent initial symptoms of COVID-19. This Paradigms and Perspectives article provides an overview of the prevalence of COVID-19–related olfactory dysfunction (OD), its time course and potential pathophysiology, and the treatment options available.
Prevalence of COVID-19–induced OD
The range of the prevalence of COVID-19–associated OD (5%-98%)1 is wide compared with the general prevalence of OD, which ranges between 1.5% and 25%.2 The reasons for this wide variation in prevalence are different constellations of patient age and sex in each sample, and in particular, differences in OD assessment. In this regard, in September 2020 the pooled prevalence estimate of COVID-19–associated OD was reported to be 44% (95% CI = 32%-57%) based on subjective ratings and 77% (95% CI = 61%-89%) based on psychophysical olfactory testing (Fig 1 ). Finally, the prevalence is expected to be higher when the study sample consists mainly of patients who are aware of their OD than in studies based on a more random sample. A higher prevalence of COVID-19–associated OD is found in younger individuals and in patients with mild forms of COVID-19 than in patients with more severe cases. However, OD might become less noticeable or important with increasing disease severity. Some studies indicate a higher prevalence of OD among women. Another influencing factor seems to be ethnicity, as the prevalence was reported to be higher in White individuals than in Asian individuals.3 The virus variant is also highly related to the risk of OD, with the highest odds ratio for the alpha variant (50% [45%-55%]) compared with those for the delta variant (44% [41%-48%]) and the omicron variant (17% [15%-18%]).4 , 5 This may be explained by the difference in the variants' ability to damage the olfactory mucosa (see later). Whether virus variant also influences the severity and time course of cases of COVID-19–associated OD is under discussion.
Fig 1.
Summary of the pathophysiology, prevalence, time course, and treatment options in COVID-19–induced OD. MRI, Magnetic resonance imaging. Figure adapted in part from Doty RL. OD in COVID-19: Pathology and long-term implications for brain health. Trends Mol Med 2022;28:781-94.
The frequency and severity of COVID-19–associated OD depend on the duration of disease. At the 2-year follow-up, an altered sense of smell or taste was reported in 11.7% of patients (9.2% of those showed an improvement and 2.5% had unchanged symptoms).6
Mechanisms of COVID-19–induced OD
Damage to the olfactory system might occur on different levels (peripheral or central). In contrast to other respiratory viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seems to cause significantly less conductive smell loss due to rhinorrhea or mucosal edema. On the other hand, central dysfunction resulting from direct passage of the virus through the cribriform plate to the olfactory bulb or even higher central nervous structures is unlikely.7
Growing evidence suggests that SARS-CoV-2 causes OD through damage to the olfactory mucosa itself (Fig 1). The cellular entry is dependent on the angiotensin-converting enzyme 2 (ACE-2) receptor and the transmembrane protease serine subtype 2 (TMPRSS2). However, sustentacular cells, supporting cells with glia-like properties and not olfactory receptor neurons (ORNs) coexpress these essential entry mediators.7 Accordingly, ORNs are not or not very susceptible to infection by SARS-CoV-2. Even if ORNs are sporadically infected, this can hardly be associated with the frequent clinical finding of a pronounced smell loss. However, the damage of sustentacular cells may lead to secondary ORN damage, causing transient OD or lasting olfactory loss due to temporary functional damage or neuronal death with consecutive, slow replacement of ORNs from globose basal cells. Moreover, SARS-CoV-2 may lead to a non–cell-autonomous and persistent downregulation of olfactory signaling genes within ORNs.8 These lesions go along with inflammation of the olfactory mucosa; previous studies showed an invasion of leukocytes and a high level of inflammatory cytokines in the olfactory epithelium. A further release of proteases may lead to the destruction of the epithelium and also to a loss of noninfected ORNs.5
Time course of OD in COVID-19
Long-term prospective follow-up studies using questionnaires and/or psychophysical olfactory tests are sparse, and there is limited information regarding risk or protecting factors for long-term damage, improvement, or recovery of the chemosensory system. The self-reported recovery rate varies from 32% to 95%.5 , 9 Improvement seems to depend on the initial severity of OD, with poorer performance in anosmic patients and better prognosis in younger patients.10 Some 50% of the affected population recover within weeks. Although the proportion of patients who reach a plateau (with a defect healing) and the proportion of patients in whom improvement results in complete recovery are uncertain, approximately 5% of the patients still report OD 6 months after developing COVID-19.9 A significant symptom during the course of COVID-19 is parosmia (distorted olfactory sensations). It occurs in nearly 50% of patients; it is most frequently reported by younger and female patients, typically occurs within a few months after the infection, and can have significant effects on quality of life. Although it often resolves over periods of 1 to 2 years, its exact time course and the predictors associated with its resolution remain unclear.10
Treatment options for COVID-19–induced OD
Even when assuming that only a small percentage of patients who have had COVID-19 exhibit lasting olfactory loss, the numbers of those affected are large. There is general agreement that “olfactory training” should be recommended.2 It has been shown to support the recovery of olfactory function based on effects at the level of the olfactory mucosa, olfactory bulb, connectivity of the central nervous olfactory network, and cognitive factors.2 Hence, if postinfectious OD lasts longer, “olfactory training” should be attempted (twice daily sessions consisting of smelling 4 odors for 30 seconds each [eg, rose, eucalyptus, lemon, clove]).
Other potentially promising therapeutic options include the administration of platelet-rich plasma, topical vitamin A, oral omega-3 acid or palmitoylethanolamid, and luteolin (Fig 1).2 Systemic and/or topically applied corticosteroids have also been tried with limited success. There are other studies on various treatment options for COVID-19–associated olfactory loss, including acupuncture, or topical Na chelators.2 However, as with OD in general, the evidence-based treatment options are limited.
Conclusion
Olfactory impairment is a frequent and early symptom of COVID-19, although the latest omicron variant has a weaker potential to induce OD. The data on prevalence and time course of COVID-19–induced OD vary according to the method of testing, study population, and trial design. Damage of the olfactory mucosa appears to be the underlying pathophysiology, with supporting cells being the main suggested target for SARS-CoV2 infections. OD improves over time in the majority of cases, and patients with less severe OD seem to have a good prognosis. However, a significant number of patients exhibit long-lasting olfactory impairment. Olfactory training should be recommended to improve olfactory performance in patients with COVID-19–associated OD.
Footnotes
Disclosure of potential conflict of interest: In the past 5 years, M. Laudien has engaged in cooperation with Olympus Deutschland GmbH, Olympus Europa SE and Co KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, GlaxoSmithKline GmbH and Co KG, and the John Grube Foundation. B. A. Stuck has received research grants, reimbursement of travel expenses, and speaking fees from GlaxoSmithKlinie GmbH and Co KG, Merck, and Sanofi; in addition, his department has received financial support for meetings or symposia from Bristol-Myers Squibb, Merck, Neuwirth Medical Products, ALK, Sanofi, Pohl-Boskamp, MSD, and Takeda. In the past 5 years, T. Hummel has engaged in cooperation with Sony (Stuttgart, Germany), Smell and Taste Lab (Geneva, Switzerland), Takasago (Paris, France), aspUraclip (Berlin, Germany), Baia Foods (Madrid, Spain), Bayer (Berlin, Germany), Procter and Gamble (London, United Kingdom) Burghart (Wedel, Germany), and Primavera (Oy-Mittelberg, Germany). The rest of the authors declare that they have no relevant conflicts of interest.
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