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Introduction

Allergic rhinitis is an inflammatory disease of the nasal mucosa mainly mediated by immunoglobulin E, caused by exposure to allergens and characterized by the presence of one or more of the following symptoms: nasal itching, rhinorrhea, nasal obstruction, and sneezing. With a great impact on both health and quality of life deterioration, as well as on productivity, involving high costs. [1] Its worldwide prevalence has increased over the last 30 years, currently reported at 15-25%. [2]

Vitamin D3 or cholecalciferol is the main dietary source of vitamin D and it is present mostly in foods of animal origin, nevertheless, around 80% of vitamin D3 is produced endogenously in the skin from 7- dehydrocholesterol by the action of UV light. Cholecalciferol and ergocalciferol (vitamin D2), undergo 25-hydroxylation in liver to 25(OH)D (calcidiol), the major circulating form. Then it is converted in kidneys through 1-alpha-hydroxylation to its most active form, 1,25(OH)2D (calcitriol). In the innate immune system, 1,25-OH-D increases chemotaxis, autophagy, phagolysosome fusion, defensin and cathelicidin production by macrophages, monocytes and keratinocytes. In the adaptive immune system, it causes inhibition of the production of proinflammatory cytokines. In monocytes and macrophages, it decreases the expression of major histocompatibility complex class II (MHC II) molecules, CD80/86, decreasing antigen presentation. In dendritic cells, it inhibits the production of IL-12 and IL-23 and stimulates the production of IL-10. It modulates the response of T lymphocytes, decreasing their proliferation, inducing apoptosis of autoreactive lymphocytes, and increasing regulatory T lymphocytes, FoxP3 and cytotoxic T lymphocyte antigen (CTLA 4). (Figure 1) [3-6]

The prevalence of vitamin D deficiency in children and adults has increased exponentially in recent years, making it a global epidemic, related to overweight, sedentary lifestyles, decreased intake, gastrointestinal diseases, deficient absorption, renal and hepatic pathologies. Guidelines published by the Endocrine Society on vitamin D defined vitamin D deficiency as 1,25-OH-D <20 ng/mL, insufficiency as 21-29 ng/mL, and suffi-ciency as at least 30 ng/mL for maximum skeletal muscle health. [7] In Europe, it is estimated that more than 40% of the population has deficiency, 13% being severe. In the U.S. population aged 1 to 21 years, 61% had insufficiency and 9% deficiency. In Mexico, the prevalence of deficiency and insufficiency in children is 16% and 23% respectively, while in the adult population, deficiency was 9.8% and insufficiency 20%. [8]

There is currently no international consensus on the supplementation of this vitamin. The dose of 25 mcg (1000 IU) increases the serum level of 1,25-OH-D by an average of 15 to 25 nmol/L. [9] According to the Endocrine Society, the daily dose of 10,000 IU of vitamin D should not be exceeded; even with this dose, no adverse reactions occurred in healthy adults. [10] Cholecalciferol supplementation has been shown in several studies to have a positive impact on the clinical outcome of the patient. A study in Australia showed that low vitamin D levels at age 6 years were predictive of increased risk of asthma and sensitization to aeroallergens at age 14 years. [11] It has been reported that low levels of vitamin D correlated with severity of allergic rhinitis, and after supplementation there was a decrease in the TNSS score, an improvement attributed to the immunomodulatory effects of vitamin D. [12] Our group has previously reported that vitamin D supplementation, in patients with allergic rhinitis, with 6000 IU weekly for adults and 5000 IU weekly for children improves symptomatology. However, it does not demonstrate an increase in serum 25-OH-D concentrations. [13]

The aim of this study was to evaluate the efficacy of supplementation with 5000 units of cholecalciferol in patients with allergic rhinitis and insufficiency or deficiency of Vitamin D, to describe the relationship between the severity of allergic rhinitis symptoms and vitamin D levels after it's supplementation. In addition, the safety of this intervention was evaluated by assesing possible adverse effects related to vitamin D and by monitoring its serum levels.

Materials and Methods

Randomized, double-blind, placebo-controlled, experimental study involving pa-tients aged 10 to 40 years who attended the Allergy and Clinical Immunology service of the University Hospital of Puebla, Mexico, during the period from October 2020 to July 2021, with a diagnosis of allergic rhinitis, confirmed by skin tests or specific serum IgE. Patients with pathologies that alter the metabolism, absorption or excretion of cholecal-ciferol, patients pregnant or breastfeeding, and patients under treatment with cortico-steroids, antiepileptic drugs and vitamin D supplements in the previous 3 months were excluded from the study.

Patients were randomly divided into two groups in a double-blind design. Randomization sequence was created using Excel for Microsoft 365, participants were randomly assigned to 1 of 2 treatment groups (active or placebo). The placebo group received pharmacological treatment (fluticasone furoate 27.5 mcg once a day for two months), subcutaneous immunotherapy and placebo. On the other hand, patients in the active group received the same dose of fluticasone furoate, subcutaneous immunotherapy and cholecalciferol 5000 IU or 714 IU/day for 8 weeks

Severity of allergic rhinitis symptoms was assessed at study entry, 30 days, and 60 days later using the TNSS. 25(OH)D levels were quantified at baseline and at the end of the study by particle chemiluminescent immunoassay with ARCHITECT i1000SR equipment.

During follow-up, the presence of symptoms and signs of adverse effects of vitamin D supplementation was questioned at one month of follow-up and at the end of supplementation

Statistical analysis

Data were collected and organized in Microsoft Excel. Descriptive summary statistics were used by determining averages, percentages, and frequencies. A comparison of two averages was considered with a bilateral hypothesis, 95% confidence level, and an expected loss ratio of 20%. Statistical analysis of the data was performed with the IBM® SPSS® Statistics 28 program by means of a comparison of means using Student's t-test considering a significance value < 0.05.

All procedures during the present study were performed in accordance with the ethical norms, the Regulations of the General Law of Health, on Health Research and the Declaration of Helsinki. All participants expressed their authorization through informed consent and assent.

Results

Thirty-six patients with allergic rhinitis and vitamin D deficiency and insufficiency were included. The experimental group, which received vitamin D3, included 19 patients (52.78%),10 males and 9 females aged 10-40 years (SD 12.2). The control group included 17 patients (47.25%), 8 men and 9 women between 13 and 40 years of age (SD 9.6). When comparing both groups with respect to gender and age, no statistically significant differences were found between them (p> 0.05).

Serum 25(OH)D levels

The mean value of serum 25(OH)D levels at baseline in the placebo group was 20.32 ng/ml and in the active group 18.10 ng/ml. At 8 weeks of follow-up, the placebo group presented a mean vitamin D level of 21.38 ng/ml even with deficiency and in the active group it was 44.94 ng/ml reaching sufficiency. A statistically significant difference was shown between the initial value and at 8 weeks after treatment, with a mean increase of 26.83. (p=<0.05). (Figure 2) Within the active group, patients between 10 and 20 years old presented a mean serum 25(OH)D elevation of 34.6 ng/ml, while in the 20 to 40 years old age group the mean was 19.7ng/ml.

Severity of symptoms

The mean nasal symptom score (TNSS) at baseline was 6.47 in the placebo group and 7.16 in the active group. Consequently, no significant differences were observed between the two groups with respect to this variable (p= 0.277). The improvement in mean TNSS at the end of the study was lower in the placebo group (6.47 to 3.94) than the active group (7.16 to 2.58) and this difference between groups was statistically significant p<0.029

Safety of supplementation with cholecalciferol

None of the participants presented toxicity levels (> 150 ng/ml) or adverse events related to cholecalciferol supplementation, therein the risk of total adverse events was not increased in vitamin D supplemented arm compared with placebo.

Discussion

In recent years, multiple investigations have been performed analyzing the relationship between serum vitamin D value and the incidence and severity of allergic diseases.

There are multiple clinical trials evaluating the effects of cholecalciferol supple-mentation and correction of cholecalciferol levels with doses ranging from 800 IU to 7000 IU daily, showing efficacy and safety at low doses (800-1000 IU). [14-22]. However, the safety and incidence of adverse effects associated with it are rarely analyzed.

In the present study, the efficacy and safety of vitamin D supplementation in children older than 10 years old and adults with 5,000 units daily for 60 days was analyzed, none of the participants presented adverse events associated with the supplementation, in addition, at the end of the study, there was highly significant improvement in the total nasal symptom score in the active group compared to the placebo group, all participants within the active group, significantly decreased their symptoms and reached sufficiency levels with the mentioned dose without presenting toxicity levels (> 150 ng/ml). These results agree with the proposal of Khan et al., that a daily dose of 4000 to 5000 IU of vitamin D2 or vitamin D3 per day is required to reach levels of 40 to 60 ng/ml 23, and similarly with the safety studies of Bischoff-Ferrari et al. where there were no adverse reactions associated with intakes of up to 50,000 IU per day. [24-26]. Another study previously conducted at the University Hospital of Puebla, proved the clinical efficacy of supplementation with 5000 IU weekly for children and 6000 IU for adults for 8 weeks, however no significant sufficiency levels were achieved in the experimental group [13].

Bakhshaee et al. demonstrated that supplementation with 50,000 IU cholecalciferol every week for 2 months in patients with AR and vitamin D deficiency resulted in a significant difference between the initial and final nasal symptom severity score measured by TNSS (P = 0.007). [27]. Other placebo-controlled studies have used lower doses of cholecalciferol, 1000 IU daily, in shorter periods of time, 21 and 30 days, obtaining the same reduction in the total score of nasal symptoms (P < 0.05). [28, 29]. Patients aged 10 to 20 years’ old who received vitamin D supplementation showed an elevation of serum levels 1.75 times higher than patients aged 20 to 40 years old, which is consistent with that described in studies of fixed-dose supplementation in children and adults, where the elevation of serum levels is more significant in children and the elderly. [3, 30].

Conclusion

This study supports the evidence about the association between vitamin D deficiency and allergic rhinitis. Results shown here, remark the importance of assessing vitamin D levels in allergic rhinitis patients, to provide vitamin D supplementation along with standard treatment in deficient subjects. Funding: This research received no external funding

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of Hospital Universitario de Puebla. Informed consent was obtained from all subjects involved in the study.

Conflicts of Interest: The authors declare no conflict of interest.