Current treatments for smell impairment

There are multiple aetiologies for smell impairment, with the most common being post-infectious olfactory dysfunction, particularly virally mediated upper respiratory tract infections.^{Reference Hummel, Whitcroft, Andrews, Altundag, Cinghi and Costanzo32} Recent systematic reviews have found that olfactory function in patients with post-viral olfactory dysfunction improved with olfactory training.^{Reference Hopkins, Alanin, Philpott, Harries, Whitcroft and Qureishi12,Reference Kattar, Do, Unis, Migneron, Thomas and McCoul33,Reference Yuan, Huang, Wei and Wu34} This is supported by previous studies which found olfactory training to be effective for olfactory dysfunction associated with a broad range of aetiologies,^{Reference Pekala, Chandra and Turner35,Reference Sorokowska, Drechsler, Karwowski and Hummel36} although some studies have shown it is less efficacious for post-traumatic olfactory dysfunction,^{Reference Jiang, Twu and Liang37} idiopathic olfactory dysfunction^{Reference Liu, Pellegrino, Sabha, Altundag, Damm and Poletti38} and olfactory dysfunction related to Parkinson's disease.^{Reference Haehner, Tosch, Wolz, Klingelhoefer, Fauser and Storch39} Nonetheless, the studies included in systematic reviews often lack control groups or a double-blinded study design.^{Reference Turner40}

Apart from olfactory training, there have been suggestions that topical steroids, oral steroids, vitamin or zinc supplements, and sodium citrate, can be used to treat smell impairment.^{Reference Hummel, Whitcroft, Andrews, Altundag, Cinghi and Costanzo32} However, all of these treatments lack robust evidence, and there is a potential risk of harm with steroids.^{Reference Whitcroft and Hummel41}

There are also reports of spontaneous resolution of symptoms, with certain factors being found to improve chances of this, such as younger age, being female, a higher olfactory function baseline, and not smoking.^{Reference Hähner, Hummel and Stuck42}

The most recent British Rhinological Society consensus guidelines recommend olfactory training for patients with Covid-19-related anosmia persistent for more than two weeks, with oral steroids, topical steroids and omega 3 supplements considered on an individual basis.^{Reference Hopkins, Alanin, Philpott, Harries, Whitcroft and Qureishi12}

Possible mechanisms of vitamin D improving olfactory function

This review has identified three studies that show a significant association between vitamin D deficiency and smell impairment,^{Reference Bigman23,Reference Kim, Oh, Park, Youn, Kim and Jang25,Reference Shin, Ha, Kim, Yon, Lee and Sim26} alongside three studies which revealed that correcting vitamin D deficiency can lead to significant improvements in smell impairment.^{Reference Ibrahim and Elnimeiri27–Reference Baki, Yıldız and Gündoğar29} There has not been a proven explanation for this relationship between vitamin D and olfactory function, although several possible mechanisms have been proposed.

As mentioned, vitamin D is known to have a neuroprotective effect.^{Reference Kalueff and Tuohimaa18,Reference Xu, Baylink, Chen, Reeves, Xiao and Lacy19} With the discovery that rat olfactory systems contain widespread vitamin D receptors, vitamin D could be neuroprotective against degenerative processes in the olfactory system.^{Reference Glaser, Veenstra, Jirikowski and Prüfer17} This is especially relevant for patients with Parkinson's disease related olfactory dysfunction, or idiopathic olfactory dysfunction which is more prevalent in older age groups.

One of the four cardinal symptoms of chronic rhinosinusitis is the reduction or loss of sense of smell. Low-grade chronic inflammation may lead to smell impairment, either through conductive or sensorineural mechanisms.^{Reference Guilemany, García-Piñero, Alobid, Cardelus, Centellas and Bartra43} Apart from neuroprotective effects, vitamin D has also been shown to have anti-inflammatory effects, by suppressing the release of pro-inflammatory cytokines such as interleukin (IL)-2, IL-6 and IL-12, and tumour necrosis factor alpha, the levels of which have been proven to be directly related to coronavirus outcome.^{Reference Xu, Baylink, Chen, Reeves, Xiao and Lacy19,Reference Vabret, Britton, Gruber, Hegde, Kim and Kuksin44} Vitamin D exerts important regulatory functions on both innate and adaptive immunity, by inducing the differentiation of macrophages and exerting direct antibacterial and antiviral actions.^{Reference Xu, Baylink, Chen, Reeves, Xiao and Lacy19} These anti-inflammatory effects of vitamin D may provide a possible explanation as to how it can improve olfactory function.

Vitamin D deficiency

Vitamin D deficiency, defined as a serum 25(OH)D level of less than 30 ng/ml, is estimated to have a worldwide prevalence of 1 billion people.^{Reference Nair and Maseeh45} A national survey in 2017 by Public Health England revealed the prevalence rate to be about 24.0 per cent in men and 21.7 per cent in women aged 19–64 years, in the UK.⁴⁶ Vitamin D deficiency was found to be more prevalent in winter and spring, in the northern part of the UK, and amongst non-white ethnic groups.^{Reference Lin, Smeeth, Langan and Warren-Gash47}

Studies in our review demonstrated an association between vitamin D deficiency and smell impairment;^{Reference Bigman23–Reference Shin, Ha, Kim, Yon, Lee and Sim26} therefore, patients presenting with smell impairment may have unidentified vitamin D deficiency, which is not routinely screened for. It may be prudent to measure the serum 25(OH)D levels in patients presenting with smell impairment, as treatment with vitamin D supplements can be easily achieved.

With vitamin D being shown to be important for preventing osteoporosis, cardiovascular diseases, type 1 diabetes, autoimmune diseases and some cancers,^{Reference Holick48} the recommendation from Public Health England to take vitamin D supplements between winter and spring may well be sound advice.⁴⁹ Studies have shown that patients who take vitamin D supplements have a lower risk of developing vitamin D deficiency.^{46,Reference Lin, Smeeth, Langan and Warren-Gash47} Interestingly, certain studies have shown that diseases such as inflammatory bowel disease which affect nutrient absorption are associated with smell impairment.^{Reference Steinbach, Reindl, Dempfle, Schuster, Wolf and Hundt50,Reference Sollai, Melis, Mastinu, Paduano, Chicco and Magri51} These patients may well be vitamin D deficient, and it would be beneficial to measure their serum 25(OH)D levels and provide vitamin D supplements as necessary.

Studies on vitamin D as treatment for smell impairment

In conducting this literature review, it was apparent there were no robust, large-scale, blinded, placebo-controlled trials investigating the use of vitamin D to treat smell impairment. Of three studies included in this review, two were case reports,^{Reference Ibrahim and Elnimeiri27,Reference Kruse and Cambron28} which were level 5 in terms of hierarchy of evidence. Additionally, they did not use any objective olfactory test to measure olfactory function, instead relying on the subjective improvement reported by the patients themselves. Baki and colleagues’ study utilised an objective measuring tool for olfactory function and ensured the serum 25(OH)D levels were taken with a standardised method; however, this study was not blinded, and there was no placebo-controlled group to determine whether vitamin D was the causative factor leading to improvements in olfactory function scores.^{Reference Baki, Yıldız and Gündoğar29}

Studies on vitamin D deficiency and smell impairment association

Bigman's cross-sectional study involved a robust statistical analysis, employing multivariate analyses, and adjusting covariates to form ideal weighted logistic regression models, to investigate the relationships between the outcomes and each covariate studied.^{Reference Bigman23} It also included a large population group, standardised the method of measuring serum 25(OH)D levels, and measured olfactory function using the validated Pocket Smell Test.^{Reference Rawal, Hoffman, Honda, Huedo-Medina and Duffy52} They also ensured their study sample had appropriate exclusion criteria.

Catton and Gardner's study did not investigate the association between vitamin D deficiency and smell impairment; rather, it examined whether there was a significant difference in vitamin D between groups that experienced either rapid (28 days or fewer) or prolonged (more than 28 days) recovery of Covid-19-induced smell loss, for which they found none.^{Reference Catton and Gardner24} Their study utilised statistical methods that only included binary variables, and were not able to adjust for confounding factors. Additionally, they relied on self-reports of olfactory function, with patients rating the severity of smell loss on an 11-point scale (with possible responses ranging from 0 to 10), making the data less reliable.

Shin and colleagues adjusted for confounding factors in their statistical analysis, and determined that low serum 25(OH)D levels were significantly associated with low olfactory threshold scores, independent of age, sex, secondary smoking, BMI score, nasal obstruction, aeroallergen sensitisation and nasal obstruction.^{Reference Shin, Ha, Kim, Yon, Lee and Sim26} By using the Sniffin’ Sticks test, the authors were able to obtain objective measurements for olfactory impairment. One limitation, however, was that their study only included children. Kim and colleagues also adjusted for other variables when performing their statistical analysis; however, their study had a small sample size, lacked a control group, and focused on patients with Parkinson's disease.^{Reference Kim, Oh, Park, Youn, Kim and Jang25}

Overall, the studies included were cross-sectional surveys, which increases the risk of selection bias and/or recall bias.^{Reference Bigman23,Reference Catton and Gardner24,Reference Shin, Ha, Kim, Yon, Lee and Sim26} Studies with a large sample size, and which include comparison with a control group, will be able to increase the validity of the association identified by these studies.