Introduction
Smell impairment ranges from a decreased sense of smell (hyposmia) to a complete loss of smell (anosmia). Smell impairment can also be qualitative, whereby patients have distorted perceptions of smell (parosmia), or olfactory hallucinations (phantosmia). A large cross-sectional study conducted in the USA in 2016 found an estimated prevalence of 13.5 per cent for smell impairment (spectrum of hyposmia to anosmia) in people aged 40 years or older.Reference Liu, Zong, Doty and Sun1 This progressively worsens with age, with smell and taste impairment affecting more than 50 per cent of individuals aged over 65 years, and 60–80 per cent of individuals aged over 80 years old.Reference Attems, Walker and Jellinger2 Anosmia has been associated with increased five-year mortality rates in older adults.Reference Pinto, Wroblewski, Kern, Schumm and McClintock3 In addition, studies have shown that smell impairment significantly affects quality of life with regard to eating habits and nutritional intake, leading to depression.Reference Hummel and Nordin4–Reference Miwa, Furukawa, Tsuhatani, Costanzo, DiNardo and Reiter6
One of the recognised symptoms of coronavirus disease 2019 (Covid-19) is sudden-onset anosmia.7 Various theories of pathogenesis have been proposed for this, such as damage to olfactory sensory neurons or the olfactory centre in the brain, nasal obstruction, or inflammation-related olfactory epithelium dysfunction.Reference Mutiawati, Fahriani, Mamada, Fajar, Frediansyah and Maliga8 Studies showed that Covid-19 patients have high recovery rates for smell impairment, with approximately 2 per cent having persisting symptoms after one year.Reference Renaud, Thibault, Le Normand, Mcdonald, Gallix and Debry9,Reference Hopkins and Kelly10 Nonetheless, with the high incidence of Covid-19 globally (584 million cases as of August 2022), there are a significant number of individuals who may have persistent olfactory dysfunction, with an estimated 11.6 million people affected.11 Many studies have investigated treatments for Covid-19-related anosmia, including olfactory training, intranasal and systemic corticosteroids, oral theophylline, vitamin A and omega 3 supplements, or sodium citrate, as summarised in the British Rhinological Society Consensus Guidelines published by Hopkins et al. in 2020.Reference Hopkins, Alanin, Philpott, Harries, Whitcroft and Qureishi12,Reference Karamali, Elliott and Hopkins13 However, further evaluation is required before recommendations on their use can be made.Reference Karamali, Elliott and Hopkins13 It would therefore be useful to identify further potential treatments for smell impairment.
Vitamin D acts as a neurosteroid hormone involved in brain homeostasis.Reference Nimitphong and Holick14 Studies have shown that it binds to vitamin D receptors, which are widely disseminated in the brain of rats, suggesting multiple functional properties of vitamin D in the central nervous system, including the olfactory system.Reference Prüfer, Veenstra, Jirikowski and Kumar15–Reference Glaser, Veenstra, Jirikowski and Prüfer17 Vitamin D has been shown to have neuroprotective and immunomodulating effects through several mechanisms, including the regulation of neurotrophins and stimulation of neurotrophic factors.Reference Kalueff and Tuohimaa18,Reference Xu, Baylink, Chen, Reeves, Xiao and Lacy19 A vitamin D deficiency has been shown to be associated with neurological dysfunction,Reference Kalueff and Tuohimaa18 with hypoacusis demonstrated in mice with defective vitamin D receptors.Reference Kalueff, Loseva, Haapasalo, Rantala, Keranen and Lou20
This systematic study aimed to identify any association of vitamin D deficiency with smell impairment, and to review existing literature on the efficacy of vitamin D for the treatment of smell impairment.
Materials and methods
Literature search strategy
This review was carried out using structured methods recommended by Tawfik et al.Reference Tawfik, Dila, Mohamed, Tam, Kien and Ahmed21 The Population, Intervention, Comparison, Outcome (‘PICO’) tool was utilised to develop our literature search strategy.Reference Richardson, Wilson, Nishikawa and Hayward22
A literature search was conducted across four databases: PubMed/Medline, Cochrane Database of Systematic Reviews, ScienceDirect and ProQuest. The following search strategy was used across all databases, for studies published between the years 2000 and 2022: ‘(vitamin D) AND (anosmia OR hyposmia OR olfactory function)’.
Inclusion and exclusion criteria
Studies investigating the use of vitamin D for the treatment of hyposmia or anosmia, and any association between vitamin D and smell impairment, were included. Studies that investigated other nasal symptoms, such as congestion, discharge or obstruction, were excluded. Abstracts, conference titles, books, letters to editors, and articles not written in English language were excluded. All articles were screened by two independent reviewers, and the results were compared.
Data extraction
The data extraction process of the included articles was carried out by two authors (WWA and ETG). Extracted data included the year, country and design of each study, sample size, treatment regimen, follow-up period, olfactory test used, and findings. The extracted data were then compared and summarised in tables.
Results
Literature search results
The results of the literature search are shown in Fig. 1.
Figure 1. Preferred Reporting Items for Systematic reviews and Meta-Analyses (‘PRISMA’) flowchart, showing the article selection process for this review.
After abstract screening, 15 articles remained. Seventeen full-text articles were reviewed independently by two authors (WWA and ETG); these included 2 additional articles identified from the 15 articles. Nine articles were excluded as they were deemed irrelevant, and one article had no full text. Thus, a total of seven articles were ultimately included in this review.
Vitamin D deficiency and smell impairment association
Four studies that investigated the association between vitamin D deficiency and smell impairmentReference Bigman23–Reference Shin, Ha, Kim, Yon, Lee and Sim26 were included, with details summarised in Table 1. Three studies found a significant relationship between vitamin D deficiency and smell impairment, and these three studies all utilised objective olfactory tests to evaluate the olfactory function of their study participants.Reference Bigman23,Reference Kim, Oh, Park, Youn, Kim and Jang25,Reference Shin, Ha, Kim, Yon, Lee and Sim26 Bigman's study revealed a significant relationship between vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) level of less than 20 ng/ml) and smell impairment (p = 0.038).Reference Bigman23 It also found a greater prevalence of smell impairment with increased age (p < 0.001) and with decreased vitamin D levels (p < 0.001).Reference Bigman23 Shin and colleagues’ study investigated 518 children (mean age, 11.45 years), and found vitamin D deficiency (serum 25(OH)D level of less than 20 ng/ml) to be significantly associated with smell impairment, independent of aeroallergen sensitisation, nasal obstruction and the presence of allergic rhinitis (p = 0.009).Reference Shin, Ha, Kim, Yon, Lee and Sim26 Kim and colleagues’ study investigated patients with Parkinson's disease, and found significant correlations between serum 25(OH)D levels and the sum olfactory identification score, in addition to an independent association between 25(OH)D levels and olfactory identification test scores after adjusting for other variables such as age, gender, body mass index (BMI) and disease duration.Reference Kim, Oh, Park, Youn, Kim and Jang25
Table 1. Summary of four articles investigating vitamin D deficiency and smell impairment
NHANES = National Health and Nutrition Examination Survey; Covid-19 = coronavirus disease 2019; PD = Parkinson's disease; 25(OH)D = 25-hydroxyvitamin D
Catton and Gardner's study investigated patients with Covid-19-induced smell loss; in their study, vitamin D did not significantly influence the smell loss recovery period, which was classified as rapid (28 days or fewer) or prolonged (more than 28 days), with a follow-up period of 120 days.Reference Catton and Gardner24 Their study used a patient survey to collect data on patients’ olfactory function (p = 0.27).Reference Catton and Gardner24
Vitamin D to treat smell impairment
We identified three articles that investigated the use of vitamin D as a treatment for smell impairment;Reference Ibrahim and Elnimeiri27–Reference Baki, Yıldız and Gündoğar29 their extracted data are shown in Table 2. These included a case report,Reference Ibrahim and Elnimeiri27 a case seriesReference Kruse and Cambron28 and a cohort study.Reference Baki, Yıldız and Gündoğar29
Table 2. Summary of three articles investigating vitamin D as treatment for smell impairment
FU = follow-up; wks = weeks; mths = months; n/a = not applicable; 25(OH)D = 25-hydroxyvitamin D; CCCRC = Connecticut Chemosensory Clinical Research Center
All the cases from the case report and case series (total patients n = 3) demonstrated complete resolution of smell impairment after vitamin D deficiency was treated with vitamin D supplements.Reference Ibrahim and Elnimeiri27,Reference Kruse and Cambron28 One of the patients had a relapse of smell impairment once she stopped taking vitamin D supplements and had low serum 25(OH)D levels on a repeat blood test.Reference Kruse and Cambron28 Unfortunately, these two papers did not utilise any objective olfactory test, and the improvement in symptoms was based on a subjective evaluation as reported by patients themselves. The authors also did not investigate other confounding factors that may have resulted in symptom resolution.
The cohort study, by Baki et al.,Reference Baki, Yıldız and Gündoğar29 which comprised 182 patients and used the validated Connecticut Chemosensory Clinical Research Center olfactory testReference Veyseller, Ozucer, Karaaltin, Yildirim, Degirmenci and Aksoy30 as an outcome measure, revealed a significant difference in olfactory test scores between pre-replacement and post-replacement groups (p < 0.001), implying improved olfactory function with vitamin D supplementation. The median value of serum 25(OH)D was 11.8 ng/ml in the pre-replacement group and 42.8 ng/ml in the post-replacement group, which also represented a significant difference (p < 0.001).Reference Baki, Yıldız and Gündoğar29
The studies generally utilised Institute of Medicine criteria, defining vitamin D deficiency as a serum 25(OH)D level of less than 20 ng/ml, vitamin D insufficiency as a 25(OH)D level of 20–30 ng/ml and vitamin D sufficiency as a 25(OH)D level of more than 30 ng/ml.31
Discussion
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 dysfunctionReference 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.
Conclusion
This review identified limited studies showing the efficacy of using vitamin D to treat smell impairment, alongside the association of vitamin D deficiency and smell impairment. Nonetheless, as vitamin D supplementation is relatively low-cost, can be easily measured and has other proven benefits when the deficit is corrected, the authors would recommend its use. Further large-scale studies, including randomised, controlled trials, should be carried out to investigate the efficacy of using vitamin D for the treatment of anosmia, for the benefit of patients suffering from smell impairment.
Competing interests
None declared.
