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Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies

Respiratory Research volume 25, Article number: 344 (2024) Cite this article

Abstract

Background

Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma.

Methods

A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies.

Results

We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (β (95% CI)= − 0.33 (–0.65 to − 0.01); I2 = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D.

Conclusion

Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations.

Introduction

Asthma is a chronic respiratory disease characterized by bronchial hyperreactivity and inflammation leading to preventable symptoms and exacerbations [1, 2]. In 2019, approximately 262 million people were affected by asthma, resulting in 455,000 deaths [3]. Asthma is characterized by chronic inflammation that is mediated, in many patients, by T helper 2 (Th2) cytokines, which can enhance the infiltration of inflammatory cells into the airways, activate resident immune cells, and trigger the release of inflammatory mediators [4]. Inflammatory biomarkers measured in sputum and serum can be used in disease management, prognosis, and therapeutic adjustment [5]. Key biomarkers include pro-inflammatory markers of Th2 inflammation, often measured in clinical practice and research in asthma patients, such as immunoglobulin E (IgE) [5,6,7], eosinophils [5, 8, 9], fractional exhaled nitric oxide (FeNO) [5, 10], interleukin (IL)-4, and IL-5 [11], as well as non-Th2 pro-inflammatory biomarkers, including neutrophils [12, 13], C-reactive protein (CRP) [14, 15], tumor necrosis factor α (TNF-α) [16], and interferon gamma (IFN-γ) [17]. Additionally, several anti-inflammatory biomarkers, including regulatory T cells (Tregs) [18, 19], the antimicrobial peptide cathelicidin (LL-37) [20], and IL-10 [11], have also been studied in patients with asthma.

Vitamin D deficiency and insufficiency represent a global public health problem affecting individuals of all ages, with more than one billion children and adults at risk worldwide [21, 22]. The Institute of Medicine (IOM) classifies vitamin D deficiency and insufficiency as a serum 25-hydroxyvitamin D (25(OH)D) concentration less than 30 nmol/L and less than 50 nmol/L, respectively [23]. In patients with asthma, a lower level of serum 25(OH)D has been associated with a greater risk of hospital admissions, emergency department visits, exacerbations, and use of rescue oral corticosteroids (OCS) for asthma [24, 25]. Several extraosseous anti-inflammatory and immunomodulatory effects of vitamin D have been demonstrated through in vivo studies using animal models, as well as through in vitro cell cultures [26]. Perhaps even more convincing is the evidence from meta-analyses of randomized controlled trials (RCTs), which report an increase in the levels of anti-inflammatory cytokines, such as IL-10, in both children and adults with asthma after vitamin D supplementation with doses ranging from 800 to 400,000 IU over periods of 6 weeks to 12 months [27]. However, the relationship between inflammatory biomarkers and vitamin D status, as assessed by 25(OH)D—the most reliable indicator of vitamin D levels in the human body, influenced not only by vitamin D supplementation but also by factors such as diet, sunlight exposure, and genetic predisposition [28]—is not yet clear. Indeed, numerous observational epidemiological studies conducted in children and adults with asthma have reported an inverse association between serum 25(OH)D levels and pro-inflammatory Th2 [29,30,31,32,33,34,35,36] and non-Th2 [36,37,38,39,40] biomarkers, as well as a positive association with anti-inflammatory biomarkers [40, 41]. However, there is significant heterogeneity and inconsistency in these findings. Notably, some studies suggest a different direction of the association between 25(OH)D and these inflammatory biomarkers in asthma [36, 42,43,44], while others have failed to demonstrate any significant association at all [29, 36, 39, 45,46,47,48,49,50]. Given these discrepancies, a comprehensive review is crucial.

This systematic review aimed to synthesize the current evidence on the association between vitamin D status (25(OH)D) and inflammatory biomarkers in children and adults with asthma.

Materials and methods

The research protocol (#CRD42022365666) was registered in the International Prospective Register of Systematic Reviews (PROSPERO). We conducted this systematic review and meta-analysis in accordance with guidelines specified by the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement [51].

Search strategy

A comprehensive search for relevant articles published up to November 24, 2022, was conducted by a trained librarian (PD) in six databases, namely PubMed, Medline, All EBM (evidence-based medicine), Embase, CINAHL (cumulative index to nursing and allied health literature), and Web of Science. The complete search strategy, including Medical Subject Headings (MESH) terms and keywords used for each database, is detailed in Additional file 1: Method S1. We also conducted a manual search of the bibliography of the selected articles to identify additional relevant studies.

Selection criteria

The population of interest consists of individuals diagnosed with asthma of any age (children and adults), sex, or ethnicity. Studies were eligible if they were RCTs, pre-post intervention studies, or observational studies (cohorts, case‒control, or cross-sectional designs) investigating the association between vitamin D status (25(OH)D) and inflammatory biomarkers in patients with asthma. The exposure of interest was vitamin D status, either reported as (i) continuous 25(OH)D serum levels or (ii) categorical variable based on definitions (e.g., deficiency, insufficiency, or sufficiency) used by included studies. Outcomes of interest were all inflammatory biomarkers that were reported in included studies, grouped as follows: (i) pro-inflammatory biomarkers of Th2 inflammation (i.e., IgE, eosinophils, FeNO, Eosinophil Cationic Protein [ECP], IL-4, IL-5, IL-13, and IL-33); (ii) pro-inflammatory biomarkers of non-Th2 inflammation (i.e., IL-1, IL-2, IL-3, IL-6, IL-8, IL-9, IL-12, IL-17, IL-31, CRP, Hs-CRP [high-sensitivity C-reactive protein], TNF-α, IFN-γ, interferon gamma-induced protein 10 (IP-10), neutrophils, and polymorphonuclear [PMN] cells); (iii) anti-inflammatory biomarkers (i.e., Tregs, IL-10, LL-37, transforming growth factor-beta 1 [TGF-β1], and adiponectin); and (iv) non-specific biomarkers (i.e., leucocytes, lymphocytes, platelets, Th1/Th2 ratio, hemoglobin, IgG, IgM, IgA, leptin, and resistin).

We did not consider the following designs: animal models, in vitro studies, narrative and systematic reviews, opinion papers, case reports, or abstract and conference papers. We also excluded studies involving mother‒child pairs where vitamin D levels were measured in either the mother or the umbilical cord blood at or before delivery and where inflammatory biomarkers were assessed in the children. Additionally, we did not include interventional studies where patients received any kind of supplementation other than vitamin D (e.g., anti-IgE therapy) or were exposed to vitamin D alongside other vitamins or mineral supplements, except for standard asthma therapy. This exclusion criterion was applicable to interventional studies in which the inflammatory biomarker was not assessed at baseline before supplementation, but only at the endpoint or as a change from baseline. This approach was taken to avoid confounding effects of other immunomodulatory interventions on inflammatory biomarkers and to ensure that our analysis focused solely on the relationship between 25(OH)D and inflammatory biomarkers.

Study selection and data extraction

Two reviewers (AEA and HD) independently screened all titles and abstracts and then reviewed the full texts of those studies deemed relevant. The following information was extracted independently using a predesigned form: study design, location, sample size, study population characteristics (number, age, and % male), vitamin D status, inflammatory biomarker results, main statistical analysis methods, and, if applicable, adjustment variables included in statistical models. When multivariable models were presented, we extracted the results from the model with the best fit, including adjustment for relevant variables. All conflicts between reviewers related to study selection and data extraction were resolved by discussion; the input of a third independent reviewer (FMD) was solicited in cases of disagreement. Covidence systematic review software (2023, Veritas Health Innovation, Melbourne, Australia) was used to manage and streamline the process.

Quality assessment

Two independent reviewers (AEA and HD) evaluated the methodological quality of included studies using the standardized critical appraisal checklist designed by the American Academy of Nutrition and Dietetics [52] which comprises ten validity questions related to study design, addressing aspects such as the research question, study population, sampling, intervention or exposure, outcome measurements, statistical analysis, and interpretation of findings. This tool offers a meticulous and rigorous approach to ensure objectivity, transparency, and reproducibility, demonstrating higher inter-observer agreement compared to the Cochrane risk-of-bias tool [53]. It is also specifically adapted to nutrition-related topics, with a comprehensive focus on nutritional interventions and exposures, making it particularly useful and relevant for our research question [54]. Reviewers assessed each study individually and determined its quality as high, moderate (neutral), or low risk of bias. Any disagreement regarding the methodological quality of a study was resolved by reaching a consensus or by consulting a third reviewer (FMD).

Qualitative and quantitative analysis

The results were presented both narratively and in tabulated form. A meta-analysis was planned only in studies that used multivariate analysis to adjust for potential confounding factors or imbalances between groups, when the following criteria were met: (i) at least two studies measured the same inflammatory biomarker from the same body fluid using identical parametrization (i.e., continuous or categorical variable); (ii) adjusted β coefficients from multivariable linear regression and standard errors (SE) or 95% confidence intervals (CI) reported for inflammatory biomarkers analysed as a continuous variable; (iii) adjusted odds ratios (OR) from multivariable logistic regression and SEs or 95% CIs reported for inflammatory biomarkers analysed as a categorical variable; and (iv) rated as being at low risk of bias. For inflammatory biomarkers measured at different time points, we only considered the baseline time point. All 95% confidence intervals (CIs) were converted in SEs to facilitate the calculation of the pooled associations. Heterogeneity was assumed if I² was greater than 50% and the P value was less than 0.1 [55]. Adjusted estimates were combined using the inverse variance method with fixed-effects model when I² was less than 50%; else, a random-effects model was used. To explore the source of heterogeneity, we planned to conduct subgroup analyses on study design (cohort, case‒control, vs. cross-sectional studies), patient age (children vs. adults), and baseline 25(OH)D levels (< 50 nmol/L vs. ≥ 50 nmol/L). A sensitivity analysis was planned after excluding studies with asymmetric data distribution, where the conversion of the 95% CI into SE was imprecise. The analysis was performed using R software, version 2023.09.1 + 494.

When meta-analyses for a given biomarker could not be conducted (i.e., not meeting our stated criteria for aggregation), the following complementary approach was used: for each inflammatory biomarker, we counted the number of studies reporting a significant negative, positive, or no statistically significant association, considering the results from all studies, irrespective of the risk of bias, and then focusing only on studies at low risk of bias.

Results

Search results

The literature search yielded a total of 4,236 publications. After removing 1,891 duplicate records, the remaining 2,345 citations were screened by their title and abstracts, 164 articles were selected for full-text assessment. Subsequently, 93 studies were excluded for various reasons, such as not assessing the association between 25(OH)D and inflammatory biomarkers (59 studies), not focusing on asthma (14 studies), and lacking relevant outcomes (3 studies). Finally, 71 studies were included in the review (Fig. 1).

Fig. 1
figure 1

Selection process for eligible studies from all identified citations

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Study characteristics

Seventy-one eligible studies evaluated the association between vitamin D status and inflammatory biomarkers based on measurements taken at a single point in time at the start of the study. These included 3 interventional studies: 2 RCTs [38, 45] and 1 crossover trial [56], as well as 68 observational studies, namely: 8 cohort studies [29, 30, 44, 46, 57,58,59,60], 10 case-control studies [31, 39, 40, 42, 47, 61,62,63,64,65], and 50 cross-sectional studies [32,33,34,35,36,37, 41, 43, 48,49,50, 66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104] (Table 1). Turkey contributed 11 studies (15.5%), followed by Egypt (8 studies, 11.3%) and Iran (5 studies, 7.0%). Other notable contributing countries were China, Poland, and United States (4 studies each, 5.6%). Most studies were published in the past 6 years (Fig. 2A). They were conducted predominantly in children (N = 50), with the remaining focusing on adults (N = 18) or both pediatric and adult patients (N = 3), with ages ranging from 0 to 80 years (Fig. 2B). The sample sizes of included studies varied widely, ranging from 13 to 847 individuals; collectively, these studies involved 7,787 participants (Fig. 2C). Vitamin D status (25(OH)D) was measured in all included studies, with a reported mean or median baseline values generally above 25 nmol/L, ranging from 29.5 nmol/L [92] to 131.0 nmol/L [80] with the exception of two studies in which lower values were observed: one study with a median (interquartile range) of 18.5 nmol/L (10.0, 26.0) in a group of individuals with uncontrolled asthma [66], and another study showing a mean ± standard deviation of 20.6 ± 2.0 nmol/L in a group of children [79]. In the remaining 16 studies [30, 32, 35, 39, 41, 43, 50, 64, 73, 88,89,90, 97, 102,103,104], the mean or median baseline 25(OH)D was not reported. As for vitamin D status categories, most studies (N = 34) adopted the following classification: deficiency (< or ≤ 50 nmol/L), insufficiency (50–75 nmol/L), and sufficiency (> or ≥ 75 nmol/L). Two studies used an alternative classification namely, deficiency (< or ≤ 25 nmol/L), insufficiency (25–50 nmol/L), and sufficiency (> or ≥ 50 nmol/L) [60, 96]. Ten studies adopted a dichotomic classification; 6 studies defining deficiency (< 50 nmol/L) and sufficiency (> or ≥ 50 nmol/L) [38, 45, 84, 86,87,88], whereas four studies defined deficiency or insufficiency as values < 75 nmol/L and sufficiency as values > or ≥ 75 nmol/L [34, 48, 49, 63]. Finally, thirteen studies adopted various other classifications, while eight studies not using any specific classification criteria [33, 41, 57, 70, 85, 93, 102, 103].

Fig. 2
figure 2

Overview of some study characteristics of the studies included in the systematic review. (A) Number of studies based on the year of publication; (B) Percentage (count) of studies by population type; (C) Descriptive statistics on sample size grouped by type of population; (D) Number of studies according to the type of statistical analysis carried out and the type of population; (E) Number of studies according to type of biomarkers. (F) Percentage (count) of studies reporting at least one, in any of the four categories of biomarkers, stratified by the risk of bias; Note: Inflammatory biomarkers were separately examined within the same article. Abbreviations: Max, Maximum; Min, Minimum; Th2, T Helper 2

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Statistical analysis and adjustment variables

Of 71 studies, only 14 (19.7%) conducted a multivariate analysis for at least one inflammatory biomarker, adjusting for potential confounders such as age, sex, body mass index, ethnicity, inhaled corticosteroids, season/month of blood collection, sun exposure, vitamin D supplementation, vitamin D binding protein level, socioeconomic status, smoking status, alcohol consumption, upper respiratory tract infections, pulmonary function, and/or asthma status [29,30,31,32, 34, 46, 57, 66, 73, 83, 86, 89, 95, 103]. Other univariate statistical analyses were also utilized, mainly the Pearson and Spearman correlation coefficients (r/ρ) (45 studies), univariate linear regression (4 studies), Student’s t test (6 studies), Mann‒Whitney U test (6 studies), analysis of variance (ANOVA) (10 studies), Kruskal‒Wallis test (5 studies) and chi-square or Fisher test (4 studies) (Fig. 2D).

Study quality assessment

Eight (3 cohort, 1 case‒control, and 4 cross-sectional) studies (11.3%) were rated at low risk of bias. These studies’ methodology was strengthened by their use of multiple regression models to adjust for confounding variables. Conversely, 13 (1 case‒control and 12 cross-sectional) studies (18.3%) were rated as having a high risk of bias; and the remining 50 (70.4%), at a moderate (neutral) risk of bias. Factors limiting the methodological quality of these studies included insufficient reporting of study inclusion & exclusion criteria and/or of data collection methods, lack of adjustment for confounders, no/limited discussion about biases and limitations, and unclear declarations of conflicts of interest. The methodological quality of included studies is detailed in Additional file 2: Table S1.

Th2 pro-inflammatory biomarkers

Most (58 of 71 (81.7%)) studies assessed the association between vitamin D status and at least one Th2 pro-inflammatory biomarker (Fig. 2E). We distinguished 44 studies on serum IgE, 28 on eosinophils (26 on blood and 2 on sputum), 13 on FeNO, three each on IL-13 (two in serum, one in bronchoalveolar lavage) and IL-33 (one in serum, one in plasma, and one in nasopharyngeal fluid), two each on serum IL-4 and ECP, and one on serum IL-5. These included 1 RCT, 5 cohort studies, 6 case‒control studies, and 46 cross-sectional studies [29,30,31,32,33,34,35,36,37, 41,42,43,44,45,46,47,48,49, 59, 61, 62, 64, 67,68,69,70,71,72,73,74,75,76,77,78,79, 81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102, 104]. Regardless of the risk of bias, the interventional study (1 RCT) did not detect a significant association between 25(OH)D and Th2 pro-inflammatory biomarkers. In observational studies, most comparisons (N = 58) also failed to detect significant associations. However, among those with statistically significant results, most indicated a negative association between 25(OH)D and Th2 pro-inflammatory biomarkers (N = 31), while a few (N = 6) revealed a positive association (Fig. 3A; Table 1). Only 7 (12.1%) of the 58 studies on Th2 pro-inflammatory biomarkers were rated as having a low risk of bias and focused on serum IgE, blood and sputum eosinophils, FeNO, and interleukins [29, 31, 32, 46, 73, 86, 95] (Fig. 2F).

Fig. 3
figure 3

Summary of the type of association for inflammatory biomarkers explored in 71 included studies. (A) Th2 pro-inflammatory biomarkers (N = 58 studies). (B) Non-Th2 pro-inflammatory biomarkers (N = 18 studies). (C) Anti-inflammatory biomarkers (N = 16 studies). (D) Non-specific biomarkers (N = 10 studies). Abbreviations: CRP, C-reactive protein; ECP, Eosinophil Cationic Protein; FeNO, Fractional exhaled nitric oxide; Hs-CRP, High-sensitivity C-reactive protein; IFN-γ, Interferon gamma; Ig, Immunoglobulin; IL, Interleukin; IP-10, Interferon gamma-induced protein 10; LL-37, Cathelicidin; N, Number of total studies; PMN, Polymorphonuclear; TGF-β1, Transforming growth factor-beta 1; Th, T helper ; TNF-α, Tumor necrosis factor α; Tregs, Regulatory T cells

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Serum IgE

Six (13.6%) studies on serum IgE were rated at low risk of bias [29, 31, 32, 46, 73, 95]; all were conducted in children. Study sample sizes varied from 30 [29] to 616 [32] participants; their mean baseline 25(OH)D levels ranged from 44.9 nmol/L [31] to 64.2 nmol/L [29]. Due to discrepancies in the parameterization of vitamin D and inflammatory biomarkers (i.e., continuous vs. categorical variables with different cut-off values), and the lack of reporting values on association estimates or 95% confidence intervals (CIs) for certain biomarkers [46, 73], our quantitative meta-analysis aggregated four of six low-risk studies [29, 31, 32, 95]. Using the random-effects model, the pooled estimate showed a significant negative association (β (95% CI) = − 0.33 (–0.65 to − 0.01); I2 = 88%; P < 0.01; N = 4 studies) with significant heterogeneity (Fig. 4). The association was affected by: (i) study design, with a stronger correlation between 25(OH)D and serum IgE in the cohort study and cross-sectional studies, than in the case-control study (Fig. 5A) and (ii) baseline vitamin D levels, with a stronger association in studies with mean baseline 25(OH)D ≥ 50 nmol/L or unknown, than in those with vitamin D insufficiency (Fig. 5B). Subgroup analyses based on patient age could not be conducted, as all included studies pertained to children. A sensitivity analysis that included the three studies with symmetrically distributed data confirmed the inverse association between 25(OH)D and IgE but failed to reach statistical significance (β (95% CI) = − 0.19 (–0.52 to 0.13); I2 = 60%; P = 0.08; N = 3 studies) (Fig. 5C). Of note, two small low-risk studies (one cohort and one cross-sectional) that reported their results narratively could not be aggregated in the meta-analysis [46, 73]; they mentioned no statistically significant association between 25(OH)D levels and serum IgE levels. In summary, focusing only on studies at low risk of bias on serum IgE, three reported a statistically significant negative association, while one large study and two small studies (that did not provide numerical values) concluded to no statistically significant association between 25(OH)D and serum IgE levels (Fig. 6A).

Fig. 4
figure 4

Forest plots for the association between vitamin D status (25(OH)D) (ng/mL) and serum IgE (IU/mL). Each study β is presented as a small vertical line with 95% CIs (horizontal lines). The weight of each study in the overall estimate is depicted graphically as the shaded box around each β estimate and numerically in the right-hand column. The pooled β and 95% CI, calculated with the random-effects model, are depicted by a lozenge. Heterogeneity was quantified by I2. Abbreviations: β: Linear coefficient of regression; CI: confidence intervals; IgE: immunoglobulin E; 25(OH)D, 25-Hydroxyvitamin D

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Fig. 5
figure 5

Forest plots for the association between vitamin D status (25(OH)D) (ng/mL) and serum IgE (IU/mL). (A) Adjusted β by study design. (B) Adjusted β by baseline 25(OH)D. (C) Adjusted β in sensitivity analysis after excluding studies with an asymmetric distribution of data. Each study β is presented as a small vertical line with 95% CIs (horizontal lines). The weight of each study in the overall estimate is depicted graphically as the shaded box around each β estimate and numerically in the right-hand column. The pooled β and 95% CI, calculated with the random-effects model, are depicted by a lozenge. Heterogeneity was quantified by I2. Abbreviations: β: Linear coefficient of regression; CI: confidence intervals; IgE: immunoglobulin E; 25(OH)D, 25-Hydroxyvitamin D

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Fig. 6
figure 6

Summary of the type of association for inflammatory biomarkers explored in low-risk bias studies. (A) Pro-inflammatory biomarkers (Th2 inflammation) (N = 7). (B) Pro-inflammatory biomarkers (non-Th2 inflammation) (N = 2). (C) Anti-inflammatory biomarkers (N = 2). Abbreviations: FeNO, Fractional exhaled nitric oxide; IFN-γ, Interferon gamma; Ig, Immunoglobulin; IL, Interleukin; IP-10, Interferon gamma-induced protein 10; LL-37, Cathelicidin; N, Number of total studies; TGF-β1, Transforming growth factor-beta 1; Tregs, Regulatory T cells

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Table 1 Characteristics and results of studies on vitamin D status and inflammatory biomarkers in asthma patients
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Blood and sputum eosinophils

Only three (11.5%) studies, all reporting blood eosinophils, were rated at low risk of bias [29, 32, 46] but aggregation of these studies was not feasible. A large cross-sectional study demonstrated a statistically significant negative association in 616 children whose baseline 25(OH)D levels ranged from 31.2 to 245.2 nmol/L (β (95% CI) = − 0.26 (− 0.48 to − 0.05)) [32]. One small cohort study reported no statistically significant association between 25(OH)D levels and blood eosinophils in 67 children, with a mean baseline 25(OH)D level of 53.1 nmol/L [46]. Another small cohort study found no statistically significant association in 30 children with a mean baseline 25(OH)D level of 64.2 nmol/L (r = 0.009; p value = 0.923) [29]. Regarding sputum eosinophils, only one cross-sectional study at low risk of bias was identified, involving 297 adults; no significant group difference in sputum eosinophil (%) (β (95% CI) = 1.03 (0.58 to 1.84)) was observed between individuals with 25(OH)D levels < 50 nmol/L vs. ≥50 nmol/L [86]. In summary, one large study at low risk of bias reported a negative association between 25(OH)D and serum eosinophils, whereas two small studies failed to identify a significant association; no statistically significant association with sputum eosinophils was noted in a large adult study.

FeNO

We identified three (23.1%) cross-sectional studies at low risk of bias that evaluated the association between vitamin D status and FeNO. Two of them reported mean 25(OH)D levels greater than 50 nmol/L [86, 95], while other failed to comment on baseline values [73]. No meta-analysis was feasible. One pediatric study of 86 children narratively mentioned the absence of a statistically significant association [73]. Another study involving 413 children, presented no statistically significant association (β (95% CI = − 0.007 (− 0.036 to 0.002)) [95]. The third study in 297 adults comparing FeNO across various serum 25(OH)D levels found no statistically significant differences (< 25 nmol/L (β (95% CI) = 1.04 (0.80 to 1.35)); 25-49.9 nmol/L (β (95% CI) = 1.10 (0.90 to 1.34)); 50-74.9 nmol/L (β (95% CI) = 1.13 (0.91 to 1.40)), compared to 25(OH)D ≥ 75 nmol/L serving as the reference category [86]. In conclusion, no statistically significant associations between FeNO and 25(OH)D were reported in two adult and one pediatric studies at low risk of bias.

Interleukins

We identified one small cohort study at low risk of bias investigating the association between 25(OH)D and two serum interleukins in 30 children with a baseline 25(OH)D level of 64.2 nmol/L [29]; no statistically significant association between 25(OH)D levels and serum IL-4 (β (95% CI) = − 0.10 (–0.80 to 0.46)) or serum IL-13 (r = 0.128; p = 0.099) was observed [29].

Non-Th2 pro-inflammatory biomarkers

Eighteen (25.4%) of 71 studies explored the association between pro-inflammatory biomarkers of non-Th2 inflammation and vitamin D, namely 2 RCTs, 2 cohort studies, 4 case‒control studies, and 10 cross-sectional studies [29, 36,37,38,39,40,41, 45, 57, 62, 63, 71, 74, 80, 83, 88, 100, 103]. We identified seven studies testing serum Hs-CRP/CRP, five exploring IL-17 in the serum (N = 3), plasma (N = 1), and airway lavage (N = 1), four tested serum (N = 3) and plasma (N = 1) IL-6, three on blood neutrophils, two each on serum TNF-α, IL-2, and IL-12, and one each on serum IL-3, IL-8, IL-9, IL-1, IFN-γ, IP-10, PMN cells and plasma IL-31. Irrespective of the risk of bias, in interventional studies, 1 RCT did not detect a significant association between 25(OH)D and non-Th2 pro-inflammatory biomarkers, while another detected a negative association. In observational studies, the majority (N = 17) of comparisons did not find any statistically significant association. However, some comparisons (N = 9) showed a negative association between 25(OH)D and non-Th2 pro-inflammatory biomarkers, while the remainder (N = 5) indicated a positive association (Fig. 3B; Table 1). Only two (11.1%) of these 18 studies on non-Th2 pro-inflammatory biomarkers were rated as having a low risk of bias [29, 57].

These studies evaluated the association between 25(OH)D and serum IP-10, IL-2, IL-12, and/or IFN-γ levels [29, 57]. One cohort study was conducted in 63 children with a median baseline 25(OH)D levels of 32.4 nmol/L in the acute asthma group and 61.1 nmol/L in the controlled asthma group; it demonstrated no significant association with serum IP-10 levels (β (95% CI): 1.70 (− 2.6 to 6.0)) [57]. Another cohort study involving 30 children with a baseline 25(OH)D level of 64.2 nmol/L also showed no statistically significant associations between 25(OH)D and serum IL-2 (r = − 0.226; p = 0.072), serum IL-12 (r = 0.151; p = 0.099), or serum IFN-γ (r = − 0.195; p = 0.064) levels [29]. Overall, in the two small studies at low risk of bias, no meta-analysis was feasible, and no statistically significant associations were observed (Fig. 6B).

Anti-inflammatory biomarkers

Sixteen studies investigated the association between vitamin D status and anti-inflammatory biomarkers. These included 2 RCTs, 6 cohort studies, 2 case‒control studies, and 6 cross-sectional studies [29, 30, 34, 36, 38, 40, 41, 46, 50, 56, 58, 60, 63, 66, 72, 87]. Overall, seven studies examined the association between 25(OH)D and IL-10 in the serum (N = 5), plasma (N = 1) and bronchial lavage (N = 1). Five studies examined LL-37 measured in serum or plasma (two each) and one in nasal secretions; four focused on blood Treg cells, and one on serum TGF-β. When considering all studies irrespective of the risk of bias, and for interventional studies (2 RCTs), no statistically significant associations between serum 25(OH)D and anti-inflammatory biomarkers were detected. For observational studies, most comparisons (N = 8) reported a statistically significant positive association between serum 25(OH)D and anti-inflammatory biomarkers. This was closely followed by no significant association in 7 comparisons, and a negative association in the remaining 2 comparisons (Fig. 3C; Table 1). Only two studies on anti-inflammatory biomarkers were rated as having a low risk of bias [29, 46].

These studies evaluated the association between 25(OH)D and serum LL-37, blood Treg cells, and/or serum TGF-β. Both cohort studies were conducted in children with mean baseline 25(OH)D levels > 50 nmol/L [29, 46]. One small study (N = 67) demonstrated a statistically significant negative association between 25(OH)D levels and serum LL-37 (β (95% CI) = − 0.018 (–0.032 to − 0.003)) [46]. The other study found no statistically significant association between 25(OH)D levels and Treg cells (β (95% CI) = 0.41 (0.23 to 0.50), IL-10 (r = − 0.099; p = 0.283), or TGF-β (r = − 0.170; p = 0.064) [29] (Fig. 6C).

Non-specific biomarkers

Ten of 71 (14.1%) studies evaluated the association between vitamin D status and non-specific biomarkers that are neither pro- nor anti-inflammatory (1 cohort study, 3 case‒control studies, and 6 cross-sectional studies) [37, 40, 50, 58, 64, 65, 72, 80, 88, 91]. No study was rated at being at a low risk of bias. Overall, the majority (N = 11) of investigations reported no statistically significant association with non-specific biomarkers; a minority of comparisons (N = 6) observed a statistically significant negative association, and one, a positive association with these biomarkers (Fig. 3D; Table 1).

Discussion

This review summarizes 71 studies exploring the association between serum vitamin D status (25(OH)D) and inflammatory biomarkers in patients with asthma. Of these, only eight studies (11.3%) were rated at a low risk of bias and served as the main basis for our conclusions. A meta-analysis of 4 studies was possible for a single biomarker—a Th2 pro-inflammatory type—showing a statistically significant negative association between serum 25(OH)D levels and serum IgE levels. In the small number of remaining studies at low risk of bias, the diversity of biomarkers studied, the variety of metrics used, and incomplete reporting prevented the quantitative aggregation of data. The reporting of the studies’ direction of associations within the context of a narrative review provided some information. However, the inability to take into consideration the precision of results—that is, to distinguish between evidence of no effect and no evidence of effect due to insufficient power in many studies—made it challenging to draw firm conclusions about the true association between 25(OH)D serum levels and most biomarkers.

For Th2 pro-inflammatory biomarkers, our meta-analysis of four studies at low risk of bias revealed that for every 2.5 nmol/L (1 ng/mL) increase in 25(OH)D levels, serum IgE decreased by about 0.33 IU/mL. As subgroup analyses highlighted a stronger association in children with 25(OH)D levels above 50 nmol/L or unknown than others, the linearity of the association remains to be established across the whole spectrum of 25(OH)D levels. The two remaining small studies at low risk of bias that narratively reported no significant association, failed to provide numerical values of the effect’s magnitude or precision, thus preventing any worthwhile contribution to the conclusions. We were unable to find previous reviews examining the association between 25(OH)D levels and IgE, confirming a gap in the literature that our review begins to address. However, our results align with other observational studies involving patients with inflammatory diseases that have reported a negative association between 25(OH)D and serum IgE, although without adjusting for potential confounders. Indeed, in children with gastrointestinal food allergies and atopic dermatitis, an inverse correlation between vitamin D and IgE levels was noted, with correlation coefficients ranging from − 0.4 to −0.5 [105, 106]. As for eosinophils, although two small studies that could not be aggregated failed to identify a significant association, possibly due to lack of power, we identified one large study that found a statistically significant negative association between blood eosinophils and serum 25(OH)D; whereas the magnitude of the effect corresponded to a weak association, the lower limit (more negative) of the confidence interval indicated a moderate effect size. This observed negative association is supported by the results of a study conducted in children with gastrointestinal food allergy, where children with low 25(OH)D (< 75 nmol/L) had persistent blood eosinophilia compared to those with higher 25(O)HD (≥ 75 nmol/L) (56% vs. 25%, P < 0.05) [105]. No significant associations with other Th2 pro-inflammatory biomarkers, including FeNO, were observed, and we could not find any previous reviews examining the association between 25(OH)D levels and those biomarkers. Collectively, our analysis suggests a negative association between serum 25(OH)D and serum IgE, and possibly with blood eosinophils; no apparent association with FeNO; and insufficient data to conclude on other Th2 biomarkers in asthma.

When examining evidence from systematic reviews of vitamin D supplementation trials on Th2 inflammatory biomarkers, the findings do not suggest a causal relationship for the negative association between 25(OH)D and Th2 inflammatory biomarkers, that is, a significant decrease in these biomarkers following supplementation. Our 2024 systematic review and meta-analysis of 13 intervention studies—testing vitamin D supplementation (cholecalciferol, calcidiol, and calcitriol) doses ranging from 800 to 400,000 IU over periods of 6 weeks to 12 months—revealed no significant group difference at study endpoint compared to placebo, in serum IgE levels (4 RCTs, Mean difference [MD] [95% CI]: 0.06 [-0.13, 0.26] IU/mL), blood eosinophils (3 RCTs, MD [95% CI]: − 0.02 [-0.11, 0.07] 103/µL), FeNO (3 RCTs, MD [95% CI]: -4.10 [-10.95, 2.75] ppb), or other Th2 interleukins namely serum [107], sputum [108], exhaled breath condensate IL-4 [109], and sputum IL-13 [108], among 1459 adults and children with asthma [27]. Our later findings are concordant with previous systematic reviews and meta-analyses of RCTs that included the same or fewer trials testing the impact of supplementation [110,111,112]. Due to insufficient reporting, we were unable to aggregate data to examine whether, compared to placebo, vitamin D supplementation was associated with significant within-patient decrease from baseline in Th2 biomarkers. However, a significant decrease in serum IL-13 was observed in 86 adult patients supplemented with a daily dose of calcitriol for 6 months [113]. Indeed, included most supplementation trials did not adjust for baseline values of biomarkers and potential confounders, nor did they report the within-patient change in biomarkers between groups. Consequently, it remains unclear whether the observed inverse cross-sectional association between 25(OH)D and serum IgE (and potentially blood eosinophils) in this review reflects a direct effect of vitamin D deficiency, an indirect effect through other mediators, or a spurious association.

As for non-Th2 pro-inflammation, studies at low risk of bias identified in this review did not find a statistically significant association between 25(OH)D levels and a variety of biomarkers, namely IP-10, IL-2, IL-12, or IFN-γ. No study at low risk of bias was identified for non-specific biomarkers, making it impossible to generate hypotheses. Additionally, no prior systematic reviews have been found on the association between 25(OH)D and either non-Th2 pro-inflammation or non-specific biomarkers in other inflammatory conditions. In a supplementation trial, no significant difference was observed at the 12-month endpoint in sputum IL-2 and IFN-γ levels in 250 adults supplemented bi-monthly with 120,000 IU of cholecalciferol compared to a placebo [108]. The paucity of studies at low risk of bias, including supplemental trials, prevent any firm conclusion regarding a potential association between vitamin D level or supplementation and non-Th2 pro-inflammatory biomarkers.

Regarding anti-inflammatory biomarkers, the only one (small) study at low risk of bias reported a statistically significant negative association between 25(OH)D levels and serum LL-37 in children, suggesting less antimicrobial activity in those with higher 25(OH)D levels; no statistically significant associations were found for IL-10, Treg cells, or TGF-β. Of note, a supplemental trial alluded to the opposite conclusion. Indeed, in 86 adults with asthma, supplementation with calcitriol for 6 months resulted in a significantly greater increase in sputum LL-37 and serum IFN-γ compared to the placebo group [113], suggesting more antimicrobial activity with greater 25(OH)D levels. This is in concordance with a study in primary cultures of normal human and cystic fibrosis bronchial epithelial cells, which showed that vitamin D up-regulates cathelicidin expression and enhances antimicrobial activity in both settings [114]. Overall, the evidence from our studies at low risk of bias and supplementation trials suggests that 25(OH)D levels are possibly associated with LL-37, but the direction of effect needs to be clarified.

Our findings revealed a negative association with IgE, and possibly with blood eosinophils and LL-37, consistent with recent mechanistic reviews. These reviews indicate that vitamin D reduces levels of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α [115, 116]. Moreover, evidence suggests that vitamin D influences B lymphocytes by inhibiting their differentiation, limiting their proliferation, and decreasing immunoglobulin production such as IgE, while also boosting IL-10 production, thereby exerting an additional regulatory effect [115, 116]. It is important to note the dual role of LL-37, which can exhibit both pro- and anti-inflammatory effects, either directly stimulating inflammatory cells or modulating the cellular response to specific cytokines or signals, which potentially explain the divergent findings. Remarkably, it can rapidly transition from an anti-inflammatory to a pro-inflammatory state under certain conditions [117, 118]. Our findings underscore the multifaceted role of vitamin D in modulating immune responses, highlighting its potential as a crucial regulator of both innate and adaptive immunity. Yet, the paucity of high-quality in vivo data prevents any firm conclusion about this validity of these purported mechanisms of action in asthma patients.

Strengths and limitations

Our systematic review has several strengths and limitations. First, our study was comprehensive, as evidenced by our broad literature search across several databases, the incorporation of various study designs, adult and pediatric populations, and a wide range of inflammatory biomarkers. Whereas the variability in the populations studied, in age, comorbidities, vitamin D status categories, and asthma control status contributed to significant heterogeneity, it also increased the generalisability of our findings. We adhered to well-defined inclusion and exclusion criteria, independent quality assessment using a validated tool, systematic and rigorous approach to data extraction and assessment of analytic methods and focused our conclusions on studies at low risk of bias. However, the large body of evidence is weakened by the small number of studies at low risk of bias (e.g., no, or inadequate adjustment for confounding, incomplete reporting of study selection criteria and/or of data collection methods, use of various metrics that prevented aggregation). Whereas this review included intervention supplementation trials, most of them reported the 25(OH)D and biomarkers at baseline and not over time. Consequently, the cross-sectional association between 25(OH)D levels and some inflammatory biomarkers observed in this review, do not imply causation as they could be due to type 1 error or reverse causality. Indeed, we cannot rule out the possibility that uncontrolled asthma might be independently associated with both a rise in Th2 biomarkers and reduced 25(OH)D, if the later acts as an acute phase response to inflammation [119] or if uncontrolled disease is associated with reduced sun exposure [120, 121] and thus vitamin D synthesis [122]. Consequently, monitoring these biomarkers in the context of interventional vitamin D supplementation trial are crucial for tracking temporal changes and establishing support for or against a cause-and-effect relationship. Also, complete reporting of studies with high methodological quality, featuring larger sample sizes, robust designs, precise measurements, and strategies to minimize bias and reduced imprecision (e.g., by treating 25(OH)D levels as a continuous variable) are essential to better address the questions. This approach would facilitate the pooling of data for future meta-analyses, thereby offering more comprehensive insight into the in vivo mechanism of action of vitamin D in asthma patients by clarifying the direction, magnitude, and precision of associations.

Conclusion

Most of the published evidence regarding the association between 25(OH)D and inflammatory biomarkers is at significant (high or moderate) risk of bias, resulting in a paucity of methodologically strong studies on which to base firm conclusions. Studies at low-risk of bias suggest a negative, but not robust, association between vitamin D status and serum IgE levels, a probably negative association with blood eosinophils and serum LL-37; collectively alluding to an immunomodulatory effect of vitamin D. Future interventional and longitudinal studies, adjusting for confounders, should examine the association over time between serum 25(OH)D levels and inflammatory biomarkers, to clarify our observations. Understanding this relationship is crucial for developing targeted interventions and clinical guidelines aimed at optimizing vitamin D levels to manage inflammation in asthma patients effectively.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

25(OH):

25-hydroxyvitamin D

EBM:

Evidence-Based Medicine

ANOVA:

Analysis of variance

CINAHL:

Cumulative Index to Nursing and Allied Health Literature

CRP:

C-reactive protein

ECP:

Eosinophil Cationic Protein

FeNO:

Fractional exhaled nitric oxide

Hs-CRP:

High-sensitivity C-reactive protein

IFN-γ:

Interferon gamma

Ig:

Immunoglobulin

IL:

Interleukin

IP-10:

Interferon gamma-induced protein 10

IOM:

Institute of Medicine

LL-37:

Cathelicidin

MESH:

Medical Subject Headings

OCS:

Oral corticosteroids

PMN:

Polymorphonuclear

PRISMA:

Preferred Reporting Items for Systematic Review and Meta-analysis

PROSPERO:

International Prospective Register of Systematic Reviews

RCTs:

Randomized controlled trials

TGF-β1:

Transforming growth factor-beta 1

Th:

T helper

TNF-α:

Tumor necrosis factorα

Tregs T:

Regulatory T cells

References

  1. Reddel HK, Levy ML. The GINA Asthma strategy report: what’s new for primary care? NPJ Prim care Respiratory Med. 2015;25(1):1–4.

  2. Gras D, Bourdin A, Chanez P, Vachier I. médecine/sciences. 2011;27:959–65. dans l’asthme.

    Article  PubMed  Google Scholar 

  3. (WHO) WHO. Chronic respiratory diseases: asthma 2023 [ https://www.who.int/news-room/questions-and-answers/item/chronic-respiratory-diseases-asthma

  4. Hamid Q, Tulic M. Immunobiology of asthma. Annu Rev Physiol. 2009;71:489–507.

    Article  CAS  PubMed  Google Scholar 

  5. Szefler SJ, Wenzel S, Brown R, Erzurum SC, Fahy JV, Hamilton RG, et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol. 2012;129(3 Suppl):S9–23.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Froidure A, Mouthuy J, Durham SR, Chanez P, Sibille Y, Pilette C. Asthma phenotypes and IgE responses. Eur Respir J. 2016;47(1):304–19.

    Article  CAS  PubMed  Google Scholar 

  7. Ahmad Al Obaidi AH, Mohamed Al Samarai AG, Yahya Al Samarai AK, Al Janabi JM. The predictive value of IgE as biomarker in asthma. J Asthma. 2008;45(8):654–63.

    Article  CAS  PubMed  Google Scholar 

  8. Bousquet J, Chanez P, Lacoste JY, Barnéon G, Ghavanian N, Enander I, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990;323(15):1033–9.

    Article  CAS  PubMed  Google Scholar 

  9. Chu HW, Martin RJ. Are eosinophils still important in asthma? Clin Exp Allergy. 2001;31(4):525–8.

    Article  CAS  PubMed  Google Scholar 

  10. Sandrini A, Taylor DR, Thomas PS, Yates DH. Fractional exhaled nitric oxide in asthma: an update. Respirology. 2010;15(1):57–70.

    Article  PubMed  Google Scholar 

  11. Kips J. Cytokines in asthma. Eur Respir J. 2001;18(34 suppl):s24–33.

    Article  Google Scholar 

  12. The ENFUMOSA cross-. Sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for understanding mechanisms of severe asthma. Eur Respir J. 2003;22(3):470–7.

    Article  Google Scholar 

  13. Sampson AP. The role of eosinophils and neutrophils in inflammation. Clin Exp Allergy. 2000;30(Suppl 1):22–7.

    Article  PubMed  Google Scholar 

  14. Takemura M, Matsumoto H, Niimi A, Ueda T, Matsuoka H, Yamaguchi M, et al. High sensitivity C-reactive protein in asthma. Eur Respir J. 2006;27(5):908–12.

    Article  CAS  PubMed  Google Scholar 

  15. Fujita M, Ueki S, Ito W, Chiba T, Takeda M, Saito N, et al. C-reactive protein levels in the serum of asthmatic patients. Ann Allergy Asthma Immunol. 2007;99(1):48–53.

    Article  CAS  PubMed  Google Scholar 

  16. Berry M, Brightling C, Pavord I, Wardlaw AJ. TNF-α in asthma. Curr Opin Pharmacol. 2007;7(3):279–82.

    Article  CAS  PubMed  Google Scholar 

  17. Kumar RK, Webb DC, Herbert C, Foster PS. Interferon-γ as a possible target in chronic asthma. Inflamm Allergy-Drug Targets (Formerly Curr Drug Targets-Inflammation Allergy)(Discontinued). 2006;5(4):253–6.

    CAS  Google Scholar 

  18. Singh R, Alape D, de Lima A, Ascanio J, Majid A, Gangadharan SP. Regulatory T cells in respiratory health and diseases. Pulmonary Medicine. 2019;2019.

  19. Hinks TS, Zhou X, Staples KJ, Dimitrov BD, Manta A, Petrossian T, et al. Innate and adaptive T cells in asthmatic patients: relationship to severity and disease mechanisms. J Allergy Clin Immunol. 2015;136(2):323–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xiao W, Hsu Y-P, Ishizaka A, Kirikae T, Moss RB. Sputum cathelicidin, urokinase plasminogen activation system components, and cytokines discriminate cystic fibrosis, COPD, and asthma inflammation. Chest. 2005;128(4):2316–26.

    Article  CAS  PubMed  Google Scholar 

  21. Holick MF, Vitamin D, Deficiency. N Engl J Med. 2007;357(3):266–81.

    Article  CAS  PubMed  Google Scholar 

  22. Holick MF. Health benefits of vitamin D and sunlight: a D-bate. Nat Reviews Endocrinol. 2011;7(2):73–5.

    Article  CAS  Google Scholar 

  23. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Committee to review dietary reference intakes for vitamin D and calcium. Food and Nutrition Board; 2011.

  24. Ali NS, Nanji K. A review on the role of vitamin D in Asthma. Cureus. 2017;9(5):e1288–e.

    PubMed  PubMed Central  Google Scholar 

  25. Brehm J, Schuemann B, Fuhlbrigge A, Hollis B, Strunk R, Zeiger R, et al. Childhood Asthma Management Program Research Group Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126(1):52–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Guillot X, Semerano L, Saidenberg-Kermanac’h N, Falgarone G, Boissier M-C. Vitamin D and inflammation. Joint Bone Spine. 2010;77(6):552–7.

    Article  CAS  PubMed  Google Scholar 

  27. El Abd A, Dasari H, Dodin P, Trottier H, Ducharme FM. The effects of vitamin D supplementation on inflammatory biomarkers in patients with asthma: a systematic review and meta-analysis of randomized controlled trials. Front Immunol. 2024;15.

  28. Wagner D, Hanwell HE, Vieth R. An evaluation of automated methods for measurement of serum 25-hydroxyvitamin D. Clin Biochem. 2009;42(15):1549–56.

    Article  CAS  PubMed  Google Scholar 

  29. Batmaz SB, Arıkoğlu T, Tamer L, Eskandari G, Kuyucu S. Seasonal variation of asthma control, lung function tests and allergic inflammation in relation to vitamin D levels: a prospective annual study. Postepy Dermatol Alergol. 2018;35(1):99–105.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Goleva E, Searing DA, Jackson LP, Richers BN, Leung DY. Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma. J Allergy Clin Immunol. 2012;129(5):1243–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nasiri Kalmarzi R, Zamani A, Fathallahpour A, Ghaderi E, Rahehagh R, Kooti W. The relationship between serum levels of vitamin D with asthma and its symptom severity: a case-control study. Allergol Immunopathol (Madr). 2016;44(6):547–55.

    Article  PubMed  Google Scholar 

  32. Brehm JM, Celedón JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009;179(9):765–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Al-Thagfan SS, Alolayan SO, Ahmed S, Emara MM, Awadallah MF. Impacts of deficiency in vitamin D derivatives on disease severity in adult bronchial asthma patients. Pulm Pharmacol Ther. 2021;70:102073.

    Article  CAS  PubMed  Google Scholar 

  34. Korn S, Hübner M, Jung M, Blettner M, Buhl R. Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. Respir Res. 2013;14(1):25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Samaha HMS, Elsaid AR, NasrEldin E. Vitamin D and markers of airway inflammation in asthma. Egypt J Chest Dis Tuberculosis. 2015;64(4):779–83.

    Article  Google Scholar 

  36. Kuti BP, Kuti DK. Relationship between serum 25-hydroxyvitamin D and inflammatory cytokines in Nigerian children with asthma. J Asthma. 2021;58(5):604–13.

    Article  CAS  PubMed  Google Scholar 

  37. Wang S, Pan Y, Zhang Z. Relationship between 25-hydroxyvitamin D levels and inflammatory factors in children with asthma attack. Exp Ther Med. 2018;15(6):4743–8.

    PubMed  PubMed Central  Google Scholar 

  38. Shabana MA, Esawy MM, Ismail NA, Said AM. Predictive role of IL-17A/IL-10 ratio in persistent asthmatic patients on vitamin D supplement. Immunobiology. 2019;224(6):721–7.

    Article  CAS  PubMed  Google Scholar 

  39. Pervaiz S, Farooq MB, Shaheen T, Javed N, Javaid A, Azhar A. Association of serum Vitamin D levels with serum pro-inflammatory mediators in asthmatic children. Pakistan J Med Health Sci. 2019;13(3):985–6.

    Google Scholar 

  40. Maalmi H, Berraïes A, Tangour E, Ammar J, Abid H, Hamzaoui K, et al. The impact of vitamin D deficiency on immune T cells in asthmatic children: a case-control study. J Asthma Allergy. 2012;5:11–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gupta A, Dimeloe S, Richards DF, Chambers ES, Black C, Urry Z, et al. Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma. Thorax. 2014;69(6):508–15.

    Article  PubMed  Google Scholar 

  42. Ehlayel MS, Bener A, Sabbah A. Is high prevalence of vitamin D deficiency evidence for asthma and allergy risks? Eur Ann Allergy Clin Immunol. 2011;43(3):81–8.

    CAS  PubMed  Google Scholar 

  43. Beyhan-Sagmen S, Baykan O, Balcan B, Ceyhan B. Association between Severe Vitamin D Deficiency, lung function and Asthma Control. Arch Bronconeumol. 2017;53(4):186–91.

    Article  PubMed  Google Scholar 

  44. Haag P, Sharma H, Rauh M, Zimmermann T, Vuorinen T, Papadopoulos NG, et al. Soluble ST2 regulation by rhinovirus and 25(OH)-vitamin D3 in the blood of asthmatic children. Clin Exp Immunol. 2018;193(2):207–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kerley CP, Hutchinson K, Cormican L, Faul J, Greally P, Coghlan D, et al. Vitamin D3 for uncontrolled childhood asthma: a pilot study. Pediatr Allergy Immunol. 2016;27(4):404–12.

    Article  PubMed  Google Scholar 

  46. Arikoglu T, Kuyucu S, Karaismailoglu E, Batmaz SB, Balci S. The association of vitamin D, cathelicidin, and vitamin D binding protein with acute asthma attacks in children. Allergy Asthma Proc. 2015;36(4):51 – 8.

  47. Kilic M, Ecin S, Taskin E, Sen A, Kara M. The Vitamin D Receptor Gene Polymorphisms in Asthmatic children: a case-control study. Pediatr Allergy Immunol Pulmonol. 2019;32(2):63–9.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Adam-Bonci TI, Cherecheș-Panța P, Bonci EA, Man SC, Cutaș-Benedec A, Drugan T, et al. Suboptimal serum 25-Hydroxy-vitamin D is Associated with a history of recent Disease Exacerbation in Pediatric patients with bronchial asthma or asthma-suggestive recurrent wheezing. Int J Environ Res Public Health. 2020;17:18.

    Article  Google Scholar 

  49. Brehm JM, Acosta-Pérez E, Klei L, Roeder K, Barmada M, Boutaoui N, et al. Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children. Am J Respir Crit Care Med. 2012;186(2):140–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Al-Attas OS, Al-Daghri NM, Yakout SM, Alnaami AM, Wani K, Alokail MS. Differences in adipokines among healthy and asthmatic children. Int J Clin Exp Pathol. 2017;10(2):2149–55.

    CAS  Google Scholar 

  51. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006–12.

    Article  PubMed  Google Scholar 

  52. Dietetics AoNa. Quality Criteria Checklist: Primary Research in Evidence Analysis Manual: Steps in the Academy Evidence Analysis Process. 2012 [ https://www.andeal.org/files/Docs/2012_Jan_EA_Manual.pdf

  53. Handu D. Comparison of the Academy of Nutrition and Dietetics updated Quality Criteria Checklist and Cochrane’s ROB 2.0 as risk of bias tools. London, UK: Cochrane Database of Systematic Reviews; Cochrane Library; 2018. p. 9.

    Google Scholar 

  54. Handu D, Moloney L, Wolfram T, Ziegler P, Acosta A, Steiber A. Academy of Nutrition and Dietetics methodology for conducting systematic reviews for the evidence analysis Library. J Acad Nutr Dietetics. 2016;116(2):311–8.

    Article  Google Scholar 

  55. Deeks JJ, Altman HJ, Higgins JPTTJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions Cochrane 2023.

  56. Thijs W, Janssen K, van Schadewijk AM, Papapoulos SE, le Cessie S, Middeldorp S, et al. Nasal levels of antimicrobial peptides in allergic asthma patients and healthy controls: differences and effect of a short 1,25(OH)2 vitamin D3 treatment. PLoS ONE. 2015;10(11):e0140986.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Arikoglu T, Akyilmaz E, Yildirim DD, Batmaz SB, Ulger ST, Aslan G, et al. The relation of innate and adaptive immunity with viral-induced acute asthma attacks: focusing on IP-10 and cathelicidin. Allergol Immunopathol (Madr). 2017;45(2):160–8.

    Article  CAS  PubMed  Google Scholar 

  58. Bantulà M, Tubita V, Roca-Ferrer J, Mullol J, Valero A, Bobolea I et al. Weight loss and vitamin D improve hyporesponsiveness to corticosteroids in obese asthma. J Investig Allergol Clin Immunol. 2022:0.

  59. Bose S, Breysse PN, McCormack MC, Hansel NN, Rusher RR, Matsui E, et al. Outdoor exposure and vitamin D levels in urban children with asthma. Nutr J. 2013;12:81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hebbar KB, Wittkamp M, Alvarez JA, McCracken CE, Tangpricha V. Vitamin D Deficiency in Pediatric critical illness. J Clin Transl Endocrinol. 2014;1(4):170–5.

    PubMed  PubMed Central  Google Scholar 

  61. Ahmed AE, Hassan MH, Toghan R, Rashwan NI. Analysis of 25-hydroxy cholecalciferol, immunoglobulin E, and vitamin D receptor single nucleotide polymorphisms (Apa1, Taq1, and Bsm1), among sample of Egyptian children with bronchial asthma: a case-control study. Pediatr Pulmonol. 2020;55(6):1349–58.

    Article  PubMed  Google Scholar 

  62. Al-Athari AJH, Aldhalmi AK, Al-Hindy HAAM. Association of High-Sensitivity C-Reactive Protein and Vitamin D with Bronchial Asthma. Open Access Macedonian J Med Sci 2022;Part B 10:931–6.

  63. Albanna EA, Salah KM, Ahmed HS. Effects of vitamin D and the antimicrobial peptide in asthma. Egypt J Pediatr Allergy Immunol (The). 2012;10(2).

  64. Mohammadzadeh I, Darvish S, Qujeq D, Hajiahmadi M, Vaghari-Tabari M. Association of serum 25-OH vitamin D₃ with serum IgE and the Pediatric Asthma Severity Score in patients with pediatric asthma. Allergy Asthma Proc. 2020;41(2):126 – 33.

  65. Wawrzyniak A, Lipińska-Opałka A, Zdanowski R, Lewicki S, Murawski P, Kalicki B. Evaluation of selected immunological parameters and the concentration of vitamin D in children with asthma. Case-control study. Cent Eur J Immunol. 2017;42(1):101–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Aldubi HM, Alissa EM, Kamfar HZ, Gaber O, Marzouki ZM. Bronchial asthma and hypovitaminosis D in Saudi children. Asia Pac Allergy. 2015;5(2):103–13.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Alyasin S, Momen T, Kashef S, Alipour A, Amin R. The relationship between serum 25 hydroxy vitamin d levels and asthma in children. Allergy Asthma Immunol Res. 2011;3(4):251–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alzughaibi MA, Abdalhadi NA, Shumran AM, Al-Hindy HAAM, Al-Dahmoshi HOM, Al-Khafaji NSK, et al. The Association of Serum 1, 25-Dihydroxy vitamin D2 status with asthma in a comparative study of Iraqi adults. Biochem Cell Archives. 2022;22(1 Part–1):1267–72.

    Google Scholar 

  69. Amorim C, Oliveira JM, Rodrigues A, Furlanetto KC, Pitta F. Vitamin D: association with eosinophil counts and IgE levels in children with asthma. J Bras Pneumol. 2020;47(1):e20200279.

    PubMed  Google Scholar 

  70. Beigh AH, Rasool R, Masoodi M, Qureshi T, Qadri Q, Shah ZA. Influence of single gene variants of FOXP3 on allergic asthma predisposition. Gene. 2020;763:145073.

    Article  CAS  PubMed  Google Scholar 

  71. Bonanno A, Gangemi S, La Grutta S, Malizia V, Riccobono L, Colombo P, et al. 25-Hydroxyvitamin D, IL-31, and IL-33 in children with allergic disease of the airways. Mediators Inflamm. 2014;2014:520241.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chary AV, Hemalatha R, Murali MV, Jayaprakash D, Kumar BD. Association of T-regulatory cells and CD23/CD21 expression with vitamin D in children with asthma. Ann Allergy Asthma Immunol. 2016;116(5):447–e542.

    Article  CAS  PubMed  Google Scholar 

  73. Checkley W, Robinson CL, Baumann LM, Hansel NN, Romero KM, Pollard SL, et al. 25-hydroxy vitamin D levels are associated with childhood asthma in a population-based study in Peru. Clin Exp Allergy. 2015;45(1):273–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dabbah H, Bar Yoseph R, Livnat G, Hakim F, Bentur L. Bronchial reactivity, inflammatory and allergic parameters, and Vitamin D Levels in children with asthma. Respir Care. 2015;60(8):1157–63.

    Article  PubMed  Google Scholar 

  75. Dajic K, Stojkovic N, Novkovic L, Vujic A, Stojkovic A. Dependence of the allergic status markers on the level of vitamin D in the serum. Srp Arh Celok Lek. 2019;147(9–10):560–6.

    Article  Google Scholar 

  76. Dogru M, Kirmizibekmez H, Mutlu RGY, Aktas A, Ozturkmen S. Clinical effects of vitamin D in children with asthma. Int Arch Allergy Immunol. 2014;164(4):319–25.

    Article  CAS  PubMed  Google Scholar 

  77. Ebrahimi M, Rahafard S, Aghapour SA. Evaluation of the relationship between Vitamin D Level and allergic indicators in patients with Asthma referred to Gorgan Asthma and Allergy Clinic. Int J Pediatrics-Mashhad. 2021;9(12):14981–7.

    CAS  Google Scholar 

  78. Elnady HG, Fouda EM, Elsheikh OM, ElAlameey IR, Elshafie AI, Sherif LS, et al. Serum vitamin D level as a predictor of bronchial asthma in Egyptian children. J Arab Soc Med Res. 2013;8(2):67–73.

    Article  Google Scholar 

  79. El-Said N, Wadoud NRA, Mohamed NAE-G, Gamil H, Rafea AS, Helmy F, CHEMICAL SCIENCES. The relationship of vitamin D in Egyptian asthmatics. Volume 7. RESEARCH JOURNAL OF PHARMACEUTICAL BIOLOGICAL AND; 2016. pp. 43–50. 5.

  80. Hakamifard A, Fatemi MR, Maghami-Mehr A. Relationship between severity of asthma attacks and vitamin D levels in children. J Med Sci (Taiwan). 2020;40(1):17–23.

    Article  Google Scholar 

  81. Hamed HM, Yamamah GAN, Ibrahim NAEA, Elhelaly NEM, Wadalla EA, Shahat MM. Assessment of vitamin D and iron levels in childhood asthma. Int J Pharm Clin Res. 2016;8(10):1407–13.

    Google Scholar 

  82. Havan M, Razi CH, Bulus AD, Köksal AO, Andıran N. Effects of 25 hydroxy vitamin D levels on the severity and asthma control in school age asthma patients. Arch Argent Pediatr. 2017;115(4):336–42.

    PubMed  Google Scholar 

  83. Hutchinson K, Kerley C, Cormican L, Rochev Y, Faul J. The Association between 25 hydroxyvitamin D and airway obstruction in Asthma. Ir Med J. 2016;109(3):371.

    CAS  PubMed  Google Scholar 

  84. Hutchinson K, Kerley CP, Faul J, Greally P, Coghlan D, Louw M, et al. Vitamin D receptor variants and uncontrolled asthma. Eur Ann Allergy Clin Immunol. 2018;50(3):108–16.

    Article  CAS  PubMed  Google Scholar 

  85. Janeva-Jovanovska E, Dokic D, Jovkovska-Kaeva B, Breskovska G, Goseva Z, Minov J, et al. Relationship between vitamin D, inflammation and lung function in patients with severe uncontrolled asthma. Open Access Maced J Med Sci. 2017;5(7):899–903.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Jolliffe DA, Kilpin K, MacLaughlin BD, Greiller CL, Hooper RL, Barnes NC, et al. Prevalence, determinants and clinical correlates of vitamin D deficiency in adults with inhaled corticosteroid-treated asthma in London, UK. J Steroid Biochem Mol Biol. 2018;175:88–96.

    Article  CAS  PubMed  Google Scholar 

  87. Kalicki B, Wawrzyniak A, Lipińska-Opałka A, Lewicki S, Zdanowski R. Influence of Vitamin D and cotinine on T-Regulatory cells and asthma severity in children. Adv Exp Med Biol. 2017;1021:27–36.

    Article  CAS  PubMed  Google Scholar 

  88. Lan N, Luo G, Yang X, Cheng Y, Zhang Y, Wang X, et al. 25-Hydroxyvitamin D3-deficiency enhances oxidative stress and corticosteroid resistance in severe asthma exacerbation. PLoS ONE. 2014;9(11):e111599.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Li F, Peng M, Jiang L, Sun Q, Zhang K, Lian F, et al. Vitamin D deficiency is associated with decreased lung function in Chinese adults with asthma. Respiration. 2011;81(6):469–75.

    Article  CAS  PubMed  Google Scholar 

  90. Montero-Arias F, Sedó-Mejía G, Ramos-Esquivel A. Vitamin d insufficiency and asthma severity in adults from costa Rica. Allergy Asthma Immunol Res. 2013;5(5):283–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Osman NS, Mohammad HA, Metwalley KA, Embaby M, ElMelegy TT. Vitamin D level in preschool children with recurrent wheezy chest, and its relation to the severity of the wheezing episodes. Egypt J Pediatr Allergy Immunol. 2019;17(1):21–9.

    Article  Google Scholar 

  92. Ozdogan S, Sari G, Aktan IH, Aydin B, Irmak C, Cavdar S. Vitamin D status, lung function and atopy in children with asthma. J Coll Physicians Surg Pak. 2017;27(5):292–5.

    PubMed  Google Scholar 

  93. Ozkars MY, Keskin O, Almacioglu M, Kucukosmanoglu E, Keskin M, Balci O. The relationship between serum vitamin D level and asthma. North Clin Istanb. 2019;6(4):334–40.

    PubMed  PubMed Central  Google Scholar 

  94. Ozturk Thomas G, Tutar E, Tokuc G, Oktem S. 25-hydroxy vitamin D levels in Pediatric Asthma patients and its link with Asthma Severity. Cureus. 2019;11(3):e4302.

    PubMed  PubMed Central  Google Scholar 

  95. Pollard SL, Lima JJ, Romero K, Tarazona-Meza C, Mougey E, Tomaino K, et al. Associations between serum 25(OH)D concentrations and prevalent asthma among children living in communities with differing levels of urbanization: a cross-sectional study. Asthma Res Pract. 2017;3:5.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Protsiuk TL, Herasymova YV, Protsiuk LO, Surkova NM. The course of bronchial asthma associated with metabolic syndrome in children with different phenotypes depending on vitamin D-3 level. Pathologia. 2018(1):68–72.

  97. Santos H, Silva SSE, Paula E, Pereira-Ferrari L, Mikami L, Riedi CA, et al. VITAMIN D RECEPTOR GENE MUTATIONS AND VITAMIN D SERUM LEVELS IN ASTHMATIC CHILDREN. Rev Paul Pediatr. 2018;36(3):269–74.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol. 2010;125(5):995–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Solidoro P, Bellocchia M, Aredano I, Mattei A, Pivetta E, Patrucco F et al. Asthmatic patients with vitamin D Deficiency have decreased exacerbations after vitamin replacement. Nutrients. 2017;9(11).

  100. Odrowąż-Sypniewska G, Fulgheri G, Siódmiak J, Krintus M, Kuligowska-Prusińska M, Jaszowska I, et al. 25-hydroxyvitamin D insufficiency in children with newly diagnosed asthma. Med Res J. 2014;2(3):93–7.

    Google Scholar 

  101. Tamašauskienė L, Gasiūnienė E, Lavinskienė S, Sakalauskas R, Šitkauskienė B. Evaluation of vitamin D levels in allergic and non-allergic asthma. Med (Kaunas). 2015;51(6):321–7.

    Google Scholar 

  102. Wytrychowski K, Kumorek M, Hans-Wytrychowska A, Radzik-Zajac J, Obojski A. The relationship between elevated body mass index, exhaled nitric oxide, vitamin d serum concentration, and asthma control: a cross-sectional pilot study. Family Med Prim Care Rev. 2020;22(2):171–8.

    Article  Google Scholar 

  103. Yang F, Sun MZ, Sun C, Li JG, Yang XN, Bi CL, et al. Associations of C-reactive protein with 25-hydroxyvitamin D in 24 specific diseases: a cross-sectional study from NHANES. Sci Rep. 2020;10(1):9.

    Google Scholar 

  104. Yousif SO, Muhsin JM. Serum Vitamin-D levels in bronchial asthmatic patients in Baghdad City. Indian J Public Health Res Dev. 2019;10(8):2212–7.

    Article  Google Scholar 

  105. Guo H, Zheng Y, Cai X, Yang H, Zhang Y, Hao L, et al. Correlation between serum vitamin D status and immunological changes in children affected by gastrointestinal food allergy. Allergol Immunopathol. 2018;46(1):39–44.

    Article  CAS  Google Scholar 

  106. Ibrahim HM, El-Taieb MA, Hassan MH, Mohamed AAE, Kotop EA, Abd-Ellah OH, et al. Relations between vitamin D3, total and specific IgE for house dust mites in atopic dermatitis patients. Sci Rep. 2020;10(1):21000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dodamani MH, Muthu V, Thakur R, Pal A, Sehgal IS, Dhooria S, et al. A randomised trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Mycoses. 2019;62(4):320–7.

    Article  CAS  PubMed  Google Scholar 

  108. Martineau AR, MacLaughlin BD, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax. 2015;70(5):451–7.

    Article  PubMed  Google Scholar 

  109. Bar Yoseph R, Livnat G, Schnapp Z, Hakim F, Dabbah H, Goldbart A, et al. The effect of vitamin D on airway reactivity and inflammation in asthmatic children: a double-blind placebo‐controlled trial. Pediatr Pulmonol. 2015;50(8):747–53.

    Article  PubMed  Google Scholar 

  110. Williamson A, Martineau AR, Sheikh A, Jolliffe D, Griffiths CJ. Vitamin D for the management of asthma. Cochrane Database Syst Reviews. 2023(2).

  111. Wang M, Liu M, Wang C, Xiao Y, An T, Zou M, et al. Association between vitamin D status and asthma control: a meta-analysis of randomized trials. Respir Med. 2019;150:85–94.

    Article  PubMed  Google Scholar 

  112. Luo J, Liu D, Liu CT. Can vitamin D supplementation in addition to Asthma controllers improve clinical outcomes in patients with asthma? A Meta-analysis. Med (Baltim). 2015;94(50):e2185.

    Article  CAS  Google Scholar 

  113. Ramos-Martínez E, López-Vancell MR, Fernández de Córdova-Aguirre JC, Rojas-Serrano J, Chavarría A, Velasco-Medina A, et al. Reduction of respiratory infections in asthma patients supplemented with vitamin D is related to increased serum IL-10 and IFNγ levels and cathelicidin expression. Cytokine. 2018;108:239–46.

    Article  PubMed  Google Scholar 

  114. Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1, 25-dihydroxyvitamin D3. J Cyst Fibros. 2007;6(6):403–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ao T, Kikuta J, Ishii M. The effects of vitamin D on immune system and inflammatory diseases. Biomolecules. 2021;11(11):1624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Martens P-J, Gysemans C, Verstuyf A, Mathieu C. Vitamin D’s effect on Immune function. Nutrients. 2020;12(5):1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Brown KL, Poon GF, Birkenhead D, Pena OM, Falsafi R, Dahlgren C, et al. Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses. J Immunol. 2011;186(9):5497–505.

    Article  CAS  PubMed  Google Scholar 

  118. Koro C, Hellvard A, Delaleu N, Binder V, Scavenius C, Bergum B, et al. Carbamylated LL-37 as a modulator of the immune response. Innate Immun. 2016;22(3):218–29.

    Article  CAS  PubMed  Google Scholar 

  119. Silva MC, Furlanetto TW. Does serum 25-hydroxyvitamin D decrease during acute-phase response? A systematic review. Nutr Res. 2015;35(2):91–6.

    Article  CAS  PubMed  Google Scholar 

  120. Panagiotou M, Koulouris NG, Rovina N. Physical activity: a missing link in Asthma Care. J Clin Med. 2020;9(3).

  121. van ‘t Hul AJ, Frouws S, van den Akker E, van Lummel R, Starrenburg-Razenberg A, van Bruggen A, et al. Decreased physical activity in adults with bronchial asthma. Respir Med. 2016;114:72–7.

    Article  PubMed  Google Scholar 

  122. Bouillon R, De Groot LJ, Jameson JL, Vitamin. D: from photosynthesis, metabolism, and action to clinical applications. 2001.

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Acknowledgements

The authors thank Wael Abdelmageed for his assistance with article selection.

Funding

AEA holds a PhD scholarship from the CHU Sainte-Justine Foundation and from the Quebec Research Fund - Health (FRQS) (333208). Partial funding for a PhD was also provided to AEA by a grant from the Canadian Institutes of Health Research (CIHR) (153252) awarded to FMD.

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  1. Sainte-Justine University Health Center, Research Center, Montreal, Quebec, Canada

    Asmae El Abd, Harika Dasari, Philippe Dodin, Helen Trottier & Francine M. Ducharme

  2. Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, Quebec, Canada

    Asmae El Abd, Helen Trottier & Francine M. Ducharme

  3. Department of Pediatrics, Faculty of Medicine, University of Montreal, Sainte-Justine Hospital, Montreal, Quebec, Canada

    Francine M. Ducharme

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  1. Asmae El Abd
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Contributions

AEA revised the literature search strategy; performed the article selection, data extraction, and quality assessment of the included studies; prepared the narrative and quantitative analysis; and wrote the article. HD performed article selection and data extraction and carried out the quality assessment of the included studies. PD formulated the literature search strategy and identified the relevant articles. HT and FMD supervised the conduct of this review from inception to analysis and revised and edited the manuscript. All authors reviewed the manuscript.

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Correspondence to Asmae El Abd.

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Competing interests

FMD has received unrestricted research funds from Jamieson and GSK, as well as investigator-initiated research funds from Covis Pharma, the Banque Scotia Foundation, GlaxoSmithKline, and MEDteq in partnership with Thorasys, Inc. FMD has received an honorarium for consultancy work from INESSS, Astra Zeneca, Covis Pharma, Ontario Lung Association, Sanofi, and Teva. FMD has also been on the advisory board for Sanofi and has received honoraria as an invited speaker from the Association des Médecins omnipraticiens du Richelieu Saint-Laurent, Covis Pharma, Réseau québécois d’éducation en santé respiratoire (RQESR), Sanofi-Regeneron, Thorasys Inc., and Trudell Medical International. HT reported receiving occasional lecture fees from Merck and unrestricted grants from ViiV Healthcare. All the other co-authors declare that they have no competing interests.

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El Abd, A., Dasari, H., Dodin, P. et al. Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies. Respir Res 25, 344 (2024). https://doi.org/10.1186/s12931-024-02967-z

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Respiratory Research

ISSN: 1465-993X

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