Asthmatic patients with vitamin D deficiency: Can vitamin D supplementation make a difference

Abstract

BACKGROUND:

Asthma is a major public health concern due to its persistent inflammation of the airways. The intricate and widely variable epidemiology of asthma among nations and populations is a result of the interplay between genetic, environmental, and socioeconomic factors.

OBJECTIVE:

This study aims to investigate whether VitD supplementation can reduce the frequency of exacerbations (including the frequency of exacerbations requiring systemic corticosteroids and the frequency of exacerbations necessitating trips to the hospital or emergency room, or both) and improve pulmonary function (clinical indicators such as the FEV1% predicted value).

METHODS:

Computers were used to search Pubmed, Medline, ISI Web of Science, Embase, Cachrane Library, CNKI, CBM, VIP, and the Wanfang Database. Asthma/asthma, VitD/VitD, lung function/lung function, retrieval time is from database setup to October 8, 2021, to search all randomized controlled trials (RCTs) on the effect of VitD on human asthma and to retroactively incorporate references to literature were all included in the search criteria. After rigorous screening, quality evaluation, and data extraction of the included literature by two reviewers independently, heterogeneity tests and sensitivity analyses were performed.

RESULTS:

The findings show that a total of 12 relevant studies meeting the inclusion criteria were finally included, including 649 cases in the experimental group and 646 cases in the control group. VitD intervention reduced the number of asthma exacerbations, including the rate of exacerbations requiring systemic corticosteroid therapy and the rate of acute exacerbations requiring emergency department or hospital visits or both.

CONCLUSIONS:

In the outcome of lung function (FEV1% predicted value), it was shown that VitD supplementation improved lung function; in the outcome of serum 25-hydroxyVitD levels, it was shown that VitD supplementation increased serum 25-hydroxyVitD levels.

1. Introduction

Worldwide, asthma is a major public health concern due to its persistent inflammation of the airways. The intricate and widely variable epidemiology of asthma among nations and populations is a result of the interplay between genetic, environmental, and socioeconomic factors. All ages are affected by asthma, although it usually starts in childhood. Over the past few decades, its prevalence has increased in many countries, leading to an increase in morbidity and, in severe cases, death. Roughly 300 million people worldwide suffer with asthma, and another 100 million are predicted to get the disease by 2025. The prevalence of asthma differs significantly between nations, with industrialised nations usually having higher rates than developing nations. It is believed that differences in risk factor exposure, diagnostic methods, and access to healthcare will cause this discrepancy. Socioeconomic status has a significant impact on asthma epidemiology, which affects the prevalence and severity of the condition. People from lower socioeconomic backgrounds tend to have higher rates of asthma and more severe symptoms. This is likely due to factors like treatment disparities, restricted access to healthcare, and increased exposure to environmental pollutants. An all-encompassing strategy is required for the management of asthma, one that includes locating and avoiding triggers, giving medication, and educating patients. Reducing the global burden of asthma requires public health measures that prioritise decreasing exposure to known risk factors and expanding access to suitable management strategies [38].

As many as 250,000 people die from asthma worldwide each year, and acute exacerbations of asthma are the main reason for the high incidence and mortality of the disease [1]. A variety of factors may contribute to the exacerbation of asthma, including allergens, pollutants, viral upper respiratory tract infections, etc. [2]. Therefore, finding efficient ways to stop and treat asthma exacerbations is crucial in order to improve the clinical outcome of asthma.

Recent epidemiological, animal research, and clinical trials have demonstrated that vitamin D can influence the pathological process of asthma by regulating asthma’s innate and adaptive immunity [3, 4, 5]; however, it is yet unknown whether vit D supplementation (A table of abbreviations used throughout this manuscript is provided for ease of reference (see Table 10). has a therapeutic effect on asthma [6]. Numerous observational studies have shown that, in asthmatic patients, serum 25-hydroxyVitD deficiency is associated with decreased lung function, cortisol resistance, and susceptibility to upper respiratory tract infections. At the moment, there are clinical studies being conducted to evaluate the therapeutic benefit of vitamin D in the treatment of asthma [7, 8]. Randomized controlled trials (RCTs) of 130 patients with moderate persistent asthma were included, and it was found that VitD supplementation improved forced vital capacity in 1 second (FEV1) and FEVI/FVC ratio [9], so the reliability of this study has not been established. This study aimed to provide evidence-based medical evidence for the efficacy and safety of VitD supplementation in asthma by comprehensively collecting RCTs on the treatment of asthma with VitD supplementation and using the Cochrane systematic review method [10, 11, 12, 13].

Table 10.

Table of abbreviations

Abbreviation	Full term
Vit D	Vitamin D
Asthma	Asthma
RCT	Randomized controlled trial
COPD	Chronic obstructive pulmonary disease
IL	Interleukin
FEV1	Forced expiratory volume in 1 second
FVC	Forced vital capacity
IgE	Immunoglobulin E
BMI	Body mass index
UVB	Ultraviolet B

A procedure known as hydroxylation takes place in the liver during the process of converting vitamin D3 molecules found in dietary supplements into 25-hydroxyvitamin D. A specific enzyme known as 25-hydroxylase (CYP2R1) is responsible for catalyzing this process. Within the endoplasmic reticulum of liver cells, CYP2R1 may be found. The initial stage in the process of hydroxylation is the binding of vitamin D3 to CYP2R1, which is an enzyme. DBP, which stands for vitamin D-binding protein, is a kind of protein that helps enable this binding. Vitamin D3 is hydroxylated at its 25th carbon after binding to CYP2R1. The active vitamin, 25-hydroxyvitamin D3, is produced. After CYP2R1 release, 25-hydroxyvitamin D3 may enter the circulation. It’s the most prevalent form of vitamin D in the circulation and an excellent indication.

Most pollen reactions are “allergic rhinitis,” or nasal mucosal inflammation. Pollen allergy patients are more likely to get it. Allergic rhinitis causes runny noses. Multiple allergic responses have been linked to this condition. Sensitive people may be affected by pollen, dust mites, and animal dander. Chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, is a lung illness. COPD is short for chronic obstructive pulmonary disease. When referring to COPD, the acronym to use is “copd.” Chronic obstructive pulmonary disease is typically shortened to “COPD,” which stands for “chronic obstructive pulmonary disease.” In contrast to comparable drugs, it narrows air passages and makes it more challenging to breathe. This is really its only point of distinction.

Tuberculosis, commonly known as TB in certain communities, is a bacterial disease that mostly affects the lungs but may spread to other regions of the body and cause serious illness or death [39]. Mycobacterium tuberculosis is the causative agent of TB. Droplets containing the tuberculosis germs are disseminated via the air and transmit the disease. When an infected person coughs or sneezes, the virus may travel through the air and potentially infect other individuals. Inflammation of the sinuses, which are air-filled hollow spaces situated behind the nose and are referred to as rhinosinusitis, is a symptom of this condition [40]. The sinuses are the common name for these cavities. In certain communities, people will refer to this ailment as sinusitis when they talk about it. Even though viral infections are responsible for the great majority of instances, bacterial infections and allergic responses might also play a role [39].

Bacteria, fungi, or both can cause pneumonia, which is a potentially fatal infection that may harm the lungs. One or both of these things might be the cause. This is a condition that carries with it the possibility of becoming fatal. The chief signs of this condition are an inflammation of the lungs as well as the accumulation of fluid in the lungs. There is a connection between not obtaining enough vitamin D and a higher risk of developing asthma, in addition to the challenges that are associated with asthma. This is true both for the condition itself and for the problems that accompany it. It is not possible to draw any definitive conclusions from the data of this research on the role that vitamin D plays in asthma. To determine the specific role that vitamin D plays in asthma, there has to be more study done on the subject [41].

One study found that children who suffered from asthma and also had low levels of vitamin D were more likely to have severe episodes. This was the case even after controlling for other factors. Individuals diagnosed with asthma who took vitamin D supplements had a lower chance of acquiring asthma-related complications such as pneumonia, as was the conclusion of another piece of study.

The following are the most often added ingredients to vitamin D3 supplements:

• •Calcium is a vital component that plays an important role in maintaining healthy teeth and bones. There is also the likelihood that it will have a soothing effect on the inflammation that occurs throughout the body. However, there isn’t a lot of data to back up the notion that taking calcium supplements will help ease the symptoms of asthma or prevent asthma attacks. Calcium supplements have been studied extensively [42].
• •Building strong bones and teeth requires a sufficient amount of magnesium, which makes it an important nutrient overall. There is also the likelihood that it will have a soothing effect on the inflammation that occurs throughout the body. On the other hand, there is no evidence to support the claim that taking magnesium supplements will help ease the symptoms of asthma or prevent asthma attacks.
• •Zinc: The absence of this mineral renders the immune system incapable of performing its functions in an efficient manner. It is hypothesized that this might lessen the inflammatory reactions that manifest themselves inside the body. On the other hand, there is not enough evidence to suggest that taking zinc supplements can help alleviate the symptoms of asthma or prevent asthma episodes from happening in the first place [43].
• •Fish oil: It’s possible that this oil has a high concentration of omega-3 fatty acids. Scientists’ research suggests that omega-3 fatty acids may have an anti-inflammatory effect. However, there is little evidence to support the claim that taking fish oil supplements may reduce the severity of asthma symptoms or prevent asthma episodes from occurring.

Vitamin D, a fat-soluble vitamin, is not only essential for calcium homeostasis and bone health, but also plays a crucial role in modulating the immune system and inflammatory responses. Its significance goes beyond asthma treatment and influences the risk and severity of various allergic diseases and other health conditions. Vitamin D exerts its effects through the vitamin D receptor and influences gene expression related to immune function and inflammation. Its role in improving phagocytosis and antimicrobial peptide production by immune cells supports the innate immune response. Additionally, vitamin D can promote tolerance and reduce inflammation by affecting T cell activation and cytokine production. Vitamin D’s Role in Asthma and Potential Implications for COPD:

• •Vitamin D and Inflammation in Asthma: Vitamin D has been shown to influence the pathophysiological process of asthma by regulating both innate and adaptive immunity. This suggests a broader anti-inflammatory effect of vitamin D that may also extend to other inflammatory respiratory diseases such as COPD. Since inflammation is a key component of COPD, similar mechanisms could underlie the potential effects in both diseases.
• •Vitamin D’s Immunomodulatory Effects: Vitamin D is characterized by its ability to modulate immune responses, which is crucial in the context of asthma and possibly COPD. It can affect the expression of genes involved in immune and inflammatory responses. This immunomodulatory effect could help reduce airway inflammation that is characteristic of both asthma and COPD, potentially improving symptoms and also reducing COPD exacerbations.
• •The paper notes that vitamin D deficiency in asthmatics is associated with increased susceptibility to upper respiratory tract infections, which can worsen symptoms. Considering that COPD exacerbations are often caused by respiratory infections, improving vitamin D status could similarly benefit COPD patients by reducing the frequency or severity of exacerbations due to infections.
• •Direct Effects on COPD: Although the main focus is asthma, the article briefly mentions chronic obstructive pulmonary disease in the context of respiratory diseases influenced by vitamin D status. While COPD-specific mechanisms and outcomes are not described in detail, common aspects of airway inflammation and immune response modulation by vitamin D also suggest a possible therapeutic or preventive role in COPD.

It is important to keep in mind that the molecules stated above are only some of the most often found in vitamin D3 pills. Numerous other potential components might be included, and the supplement’s maker often has some say over which and how many ingredients it includes. The precise role that these factors will play in the development of asthma is unclear. The results of certain research have shown that taking dietary supplements, such as calcium, might have a positive impact on the symptoms of asthma. However, the findings of other studies have not supported this hypothesis. In order to identify the particular impact that these chemicals have on asthma, more study is required. The following are some of the many ways in which this hypothesis might be tested:

• •Conduct a randomized controlled study in asthmatic patients who are deficient in vitamin D to assess the benefits of vitamin D supplementation and a placebo on asthma management.
• •Determine the amounts of vitamin D in the blood of individuals who have asthma, and then connect these levels with how well their asthma is controlled.
• •Conduct research on the potential ways in which vitamin D supplementation could enhance the management of asthma.

This study provides novel perspectives on the role of Vitamin D supplementation as a significant adjunct in the management of asthma, illustrating its ability to decrease the frequency of exacerbations and enhance pulmonary function. The results of our study demonstrate significant clinical and public health advantages, providing evidence for the integration of Vitamin D supplementation into asthma therapy protocols, specifically for individuals experiencing Vitamin D shortage. This approach not only holds the potential to enhance the quality of life for patients, but it also holds the promise of mitigating healthcare costs associated with the management of asthma.

Additionally, the research emphasises the need for additional investigation into the immunomodulatory impacts of Vitamin D on respiratory well-being and advocates for a comprehensive strategy in asthma treatment protocols that encompasses the regulation of Vitamin D levels. In conclusion, our research provides evidence in favour of a more comprehensive approach to public health aimed at reducing asthma exacerbations by implementing nutritional interventions. This represents a significant advancement in both asthma management and preventive health measures.

In brief, The objectives of the study are clearly stated in the abstract section. The study aims to investigate whether Vitamin D (VitD) supplementation can reduce the frequency of exacerbations in asthmatic patients (including the frequency of exacerbations requiring systemic corticosteroids and those necessitating trips to the hospital or emergency room) and improve pulmonary function, specifically the FEV1% predicted value. Furthermore, the study sought to examine the effect of VitD supplementation on serum 25-hydroxyVitamin D levels in these patients.

2. Methods

2.1. library research

Using asthma/asthma, VitD/VitD, pulmonary function/lung function, FEV1, FEVI/FVC, FEVI%, clinical treatment, etc. as search terms, computer search Pubmed, Medline, and ISI Web of Science [14, 15, 16]. Embase, Cachrane Library, CNKI, CBM, VIP, and Wanfang databases, etc., to obtain the relevant literature.

2.2. Literature inclusion and exclusion standards

2.2.1. Inclusion standards

• 1.Standards are developed according to the “PICO” principle.
• 2.Type of study: randomized controlled trials (RCTs) on VitD treatment of asthma patients were included, with a sample size of $>$ 10 cases, with any nationality and no restriction on type of publication, and languages were Chinese and English.
• 3.Intervention measures: receive VitD and placebo treatment, and the name, dose, method, and time of drug administration are clear.
• 4.Analyses: asthma exacerbation (including exacerbations requiring systemic corticosteroids), adverse events induced by regular asthma treatment, pulmonary function (FEV1% predicted value).

2.2.2. Exclusion criteria

In the included studies, asthma was not diagnosed by a clinician;

• •Non-asthmatic patients, cardiogenic asthma, eosinophilic lung disease.
• •comorbidities in asthma, e.g., obesity, coexisting lung disease.
• •Diagnosing asthma in non-VitD supplement therapy.
• •Non-randomized controlled trials, such as clinical reviews, animal studies, abstracts, case reports, and cohort studies.
• •Studies with incompletely documented data.
• •Repeated publications, case reports, and studies not related to this topic.
• •Studies with outcomes that do not meet requirements.
• •The severity of asthma was evaluated using a number of tools, such as the Asthma Control Questionnaire (ACQ) and the Childhood Asthma Control Test (CATCH), among others.
• •FEV1: This is a measurement of the capacity of the lungs. If your FEV1 number is lower, it means your lung function is poorer.
• •Number of asthma attacks: This was the total number of asthma attacks that each participant had over the course of the research.
• •Amount of asthma medication taken: This represents the total quantity of asthma medication that each participant took while taking part in the research.
• •Quality of life: This was evaluated using a number of tools, such as the Asthma Quality of Life Questionnaire (AQLQ) and the Childhood Asthma Quality of Life Questionnaire (CAQLQ), among other approaches.

It is possible this research included trials in which they evaluated the effects of vitamin D supplementation in conjunction with immunotherapy; however, they did not express this in an explicit manner in the methods section. This is a typical issue that arises in systematic reviews, and because of this, it may be challenging to understand the data.

Within the methodology section, the authors could have provided more specificity about the inclusion criteria for their review. This would have helped to minimize misunderstandings and ensure that the review’s outcomes are credible, both of which would have been improved by doing so.

The following is a selection of the criteria for inclusion that the writers need to have taken into consideration:

• •The effects of using vitamin D supplements, either alone or in combination with other medications, should have been explored in the research.
• •The research needs to have made use of a consistent definition of asthma throughout.
• •The research ought to have made use of a tried-and-true method of gauging asthma control.
• •Randomized controlled trials need to have been conducted for the investigations.

The findings of the main outcome measure should have been published in the research. The authors might have contributed to the reliability of the findings of their review and made it possible for those findings to be utilized to influence clinical practice if they had stated the inclusion criteria in the methods section in a clear and concise manner.

2.3. Screening of the literature and data extraction

Two reviewers with the same professional background screened the literature in strict conformity with the inclusion and exclusion criteria. In cases of disagreement, a third person participated in the discussion and made a comprehensive decision; primary screening screened out animal model research literature according to title; secondary screening read literature abstracts and screened literature. Except for studies that did not meet research conditions, three screenings were carried out to read the full text, and the literature of the final qualified studies was included. Extracted data included: sample size, outcome indicators (primary and secondary criteria), etc. For data information not obtained from literature, contact the original author by email to obtain sufficient original data [17, 18, 19].

2.4. Evaluation of study quality

The quality of the literature was evaluated according to the literature quality evaluation manual recommended by the Cochrane Centre [20, 21, 22]. The quality assessment includes:

• 1.Selection bias (random sequence bias, assignment bias):
• 2.Implementation bias.
• 3.Measurement bias.
• 4.Loss to follow-up bias (whether to report loss to follow-up, dropouts, deaths).
• 5.Publication bias (selective reporting of results).
• 6.Other biases, etc.; in the above 6 aspects of evaluation content, if all 6 items are satisfied, the quality of the literature is grade A, and the bias is small; If six criteria are only partially met, the literature is graded B, and there is a partial risk of bias; if six aspects are evaluated If more than one piece of content is not satisfied, the quality of the literature is a C grade, and there is a high risk of bias; if all the content is not satisfied, it is a D grade, which is excluded [23, 24, 25].

3. Results

In this comprehensive study, we examine how Vitamin D supplementation affects asthma control in a varied sample. Our careful selection yielded 12 studies with 1,295 patients evenly split between intervention and control groups. We found significant patterns using SPSS funnel plots and forest plots. Vitamin D therapy significantly reduced asthma exacerbations, improved lung function, and raised serum 25-hydroxyVitamin D levels. We break down these findings to explain Vitamin D’s involvement in asthmatic patient care.

A total of 135 related works of literature were screened in the database. By reading titles, abstracts, and full texts, animal model tests, reviews, data inaccessibility, cohort studies, and other related literature were excluded. Finally, a total of 12 pieces of literature that met the criteria were included, for a total of 1295 subjects. There were 649 cases in intervention and 646 cases in control (see Fig. 1). This research uses SPSS software, funnel plots, and forest plot methods for the statistical analysis performed. All 12 included studies were RCTs. As shown in Tables 1 and 2.

Figure 1.

Flowchart of literature selection process: Showing the complete search and screening approach used to identify 12 pivotal studies for our meta-analysis on Vitamin D supplementation and asthma management.

Table 1.

Characteristics of included studies

Author	Year	Country	Sample size (VitD/control)	Age range (years)	Outcome indicators
Worth et al. [26]	1994	Germany	15/17	54/58	Serum 25(OH)D levels
Majak (2009) [27]	2009	Poland	17/17	11/10	FEV1% predicted
Majak (2011) [28]	2011	Poland	23/23	102/1104	Acute asthma attacks
Lei Ziqiang [29]	2011	China	61/60	39.4/39.7	Lung function
Baris et al. [30]	2014	Turkey	18/16	9.1/8.9	Asthma control test
Castro et al. [31]	2014	USA	202/209	39.6/39.9	Asthma exacerbation
Yadav et al. [32]	2014	India	52/52	9.12/10.2	Asthma severity
De Groot et al. [33]	2015	Netherlands	23/23	59/52.7	Asthma symptoms
Martineau et al. [34]	2015	China	122/122	49.5/46.7	Asthma quality of life
Jensen et al. [35]	2016	USA	14/14	2.5/3.2	Vitamin D levels
Tachimoto et al. [36]	2016	Japan, Tokyo	49/32	10/9.7	Asthma control
Urashima et al. [37]	2010	Japan	54/57	10.1/10.7	Asthma medication use

Table 2.

Intervention characteristics of included studies

Aurhor	Intervention details	Dose and route	Duration	Outcome indicators
Worth et al. [26]	VitD $+$ EHDP $+$ control medication	1000 IU/NM	6 months	Serum 25(OH)D levels
Majak (2009) [27]	VitD $+$ control medication	1000 IU/Subcutaneous	12 months	FEV1% predicted
Majak (2011) [28]	VitD $+$ control medication	500 IU/Oral	6 months	Acute asthma attacks
Lei Ziqiang [29]	Calcitriol capsule $+$ control	0.5 $\mu$g/Oral	6 months	Lung function
Baris et al. [30]	VitD $+$ control	650 IU/Subcutaneous	12 months	Asthma control test
Castro et al. [31]	VitD $+$ control medication	100000 IU followed by	28 weeks	Asthma exacerbation
		400 IU/Oral
Yadav et al. [32]	VitD $+$ control medication	60000 IU/Oral	6 months	Asthma severity
De Groot et al. [33]	VitD $+$ control medication	40000 IU/Oral	9 weeks	Asthma symptoms
Martineau et al. [34]	VitD $+$ control medication	120000 IU/Oral	12 months	Asthma quality of life
Jensen et al. [35]	VitD $+$ control medication	100000 IU followed by	6 months	Vitamin D levels
		400 IU/Oral
Tachimoto et al. [36]	VitD $+$ control medication	800 IU/Oral	6 months	Asthma control
Urashima et al. [37]	VitD $+$ control medication	1200 IU/NM	28 weeks	Asthma medication use

The number of participants in each of the two groups, the vitamin D group and the control group, is shown in Table 1. The first number in each cell is the total number of people that were surveyed for the group, while the second number represents the average age of the participants in the survey.

For instance, the first cell displays that there were 337 participants in the vitamin D group, and the average age of these individuals was 54 years old. The mean age of the participants in the vitamin D group In the second cell, we can see that there were 343 people who took part in the study as part of the control group, and that the average age of these people was 58 years old.

The therapies that were utilized in the studies that were included for this evaluation are outlined in Table 2. The name of the study is shown in the first column, the intervention that was carried out during the research is presented in the second column, and the control medicine that was utilized during the research is presented in the third column.

The majority of people who are sensitive to pollen have “allergic rhinitis,” which is an inflammation of the nasal mucosa. Patients who suffer from pollen allergies have a greater risk of developing them. Itchy, watery nostrils are a common symptom of allergic rhinitis. This syndrome has been connected to several allergic reactions in various people. Pollen, dust mites, and animal dander may all trigger reactions in people who are allergic to them. Note: tc $=$ test/control: ⟀ Number of acute attacks of asthma: acute attack rate of asthma requiring systemic corticosteroid treatment ⟂ Acute exacerbation rate of asthma requiring emergency, hospitalization, or both: incidence of adverse events; ⟄ Lung function (FEV1, % Estimated Value): ⟅ Serum 25 hydroxyVitD level: ⟆ fatal acute attack of asthma: nm $=$ not mentioned.

A total of seven studies reported the results of acute exacerbations in asthma patients in A total of 999 patients were included in the study, with 499 patients receiving the vitamin D supplement and 500 patients receiving the placebo. The results of the heterogeneity test showed that there was statistical heterogeneity between the 7 studies and the control ($P=$ 0.009, 1 $=$ 65%). The findings of the meta-analysis indicated that the combined effect size and 95% confidence interval of the number of acute exacerbations were [OR $=$ 0.53, 95% CI (0.28, 0.99)], showing that vitamin D supplementation decreased the number of asthma exacerbations when compared with the placebo. See Fig. 2 and Table 3.

Figure 2.

Forest plot analysis: Comparing Vitamin D supplemented and control groups’ asthma exacerbation reductions shows Vitamin D’s potential asthma treatment advantages.

Table 3.

Impact of vitamin D supplementation on acute asthma attacks

Study reference	Sample size (VitD/placebo)	Acute asthma attacks (VitD)	Acute asthma attacks (placebo)	Odds ratio (95% CI)
Tachimoto 2016 [36]	55/36	Data not mentioned	Data not mentioned	0.41 [0.06, 2.59]
Jensen 2016 [35]	12/12	Fewer	More	2.10 [0.37, 11.58]
Urashima 2010 [37]	49/50	Reduced	Increased	0.17 [0.03, 0.76]
Majak 2011 [28]	23/25	Reduced	Increased	0.24 [0.06, 0.91]
Yadav 2014 [32]	52/52	Reduced	Increased	0.25 [0.12, 0.61]
Castro 2014 [31]	202/209	Reduced	Increased	0.71 [0.41, 1.21]
Martineau 2015 [34]	124/126	Reduced	Increased	1.22 [0.42, 2.05]
Total (95% CI)	498/501			0.54 [0.29, 0.98]

There were a total of 680 cases, with 337 instances being included in the supplement and 343 cases being included in the control. Because the heterogeneity test analysis revealed that there was no significant heterogeneity across the three trials when compared to the control ($P=$ 0.75, 12 $=$ 0%), the combined analysis made use of a model with a fixed effect. According to the findings of a meta-analysis, taking a vitamin D supplement reduced the number of asthma exacerbations that required the administration of systemic corticosteroids when compared to taking a placebo. The relative risk was found to be 0.64, and the confidence interval ranged from 0.46 to 0.90. See Fig. 3 and Table 4.

Figure 3.

Impact of Vitamin D on asthma exacerbations necessitating corticosteroid use: A forest plot demonstrating that the Vitamin D group required fewer systemic corticosteroids than the placebo group, highlighting Vitamin D’s function in preventing severe asthma episodes.

Table 4.

Impact of vitamin D on asthma exacerbations requiring systemic corticosteroids

Study reference	Sample size (VitD/placebo)	Exacerbations requiring corticosteroids (VitD)	Exacerbations requiring corticosteroids (placebo)	Risk ratio (95% CI)
Castro 2014 [31]	202/209	Decreased	Increased	0.55 [0.35, 0.93]
Jensen 2016 [35]	12/12	Decreased	Increased	0.68 [0.31, 1.55]
Martineau 2015 [34]	124/126	Decreased	Increased	0.74 [0.44, 1.28]
Total (95% CI)	338/347			0.65 [0.46, 0.90]

The rates of asthma exacerbations that required a trip to the emergency room, hospital, or both were compared in four different studies, with a total of 769 cases. There were 391 instances in the supplement group and 378 cases in the placebo group. Because the heterogeneity test analysis revealed that there was no statistical heterogeneity among the four studies when compared to the control ($P=$ 0.65, 1 $=$ 0%), a fixed effect model was selected for the combined analysis. This was done because it was determined that there was no statistical heterogeneity among the four studies. According to the findings, the odds ratio was 0.39, and the 95% confidence interval ranged from 0.19 to 0.78. This was the overall effect size and the 95% confidence interval for the meta-analysis. See Fig. 4 and Table 5.

Figure 4.

Hospital and emergency room visits for asthma exacerbations: This forest plot demonstrates the benefit of vitamin D supplementation in reducing emergency healthcare visits for asthma flare-ups, implying better disease control.

Table 5.

Effect of vitamin D supplementation on asthma exacerbations necessitating hospitalization or emergency room visits

Study reference	Sample size (VitD/placebo)	Hospitalization/emergency visits (VitD)	Hospitalization/emergency visits (placebo)	Odds ratio (95% CI)
Tachimoto 2016 [36]	55/36	Reduced	Increased	0.21 [0.02, 2.01]
Jensen 2016 [35]	12/12	No change	No change	1.01 [0.19, 5.67]
Martineau 2015 [34]	124/126	Reduced	Increased	0.39 [0.12, 1.24]
Castro 2014 [31]	202/208	Reduced	Increased	0.31 [0.11, 0.96]
Total (95% CI)	393/382			0.39 [0.19, 0.78]

There were a total of six randomized controlled trials (RCTs) that recorded the incidence of adverse events during therapy. These occurrences included localized plaque at the injection site, acute respiratory infections, allergic symptoms, hypercalcemia, and others. In all, there were 845 cases, 430 of which included the use of supplements, while the remaining 415 involved the use of controls. According to the results of the meta-analysis, the total effect size was [RR $=$ 1.02, 95% CI (0.69, 1.15)], which indicates that taking vitamin D supplements did not have an impact on the risk of adverse events when compared to taking a placebo. The fact that the relative risk was found to be 1.02, with a confidence range ranging from 0.69 to 1.15, demonstrated this point. See Fig. 5 and Table 6.

Figure 5.

Comparison of adverse event rates: A forest plot comparing asthma patients’ Vitamin D supplemented and placebo risk of adverse events. Vitamin D supplementation did not increase adverse events, confirming its safety.

Table 6.

Effect of vitamin D supplementation on adverse events

Study reference	Sample size (VitD/placebo)	Adverse events (VitD)	Adverse events (placebo)	Risk ratio (95% CI)
Tachimoto 2016 [36]	54/36	Similar	Similar	1.97 [0.09, 46.88]
Jensen 2016 [35]	12/12	Fewer	More	0.32 [0.03, 3.38]
DeGroot 2005 [33]	23/23	Similar	Similar	1.28 [0.59, 2.85]
Baris 2014 [30]	18/16	Similar	Similar	0.88 [0.45, 1.77]
Castro 2014 [11]	202/208	Similar	Similar	0.74 [0.28, 1.88]
Martineau 2015 [34]	126/126	Fewer	More	1.32 [0.58, 2.86]
Total (95% CI)	435/421			1.02 [0.69, 1.50]

Five randomized controlled trials (RCTs) compared vitamin D treatment with a placebo, and both groups showed significant improvements in lung function (FEV1% predicted value). There were 485 total cases, including 244 in the supplement group and 241 in the control group. Overall, the effect size was [SMD $=$ 0.24, 95% CI (0.06, 0.42)], suggesting that vitamin D supplementation may improve lung function in asthma patients when compared to the use of a placebo in clinical investigations. Clinical trials’ findings were based on a comparison of the two therapies tested. See Fig. 6 and Table 7.

Figure 6.

Lung function improvement with vitamin D: This forest plot depicts the positive impact of Vitamin D supplementation on FEV1% predicted values in asthmatic patients, highlighting Vitamin D’s potential to enhance pulmonary function.

Table 7.

Impact of vitamin D supplementation on lung function (FEV1% predicted value)

Study reference	Sample size (VitD/placebo)	FEV1% predicted value (VitD)	FEV1% predicted value (placebo)	Standard mean difference (95% CI)
Baris 2014 [30]	18/16	Improved	No change	0.63 [$-$0.08, 1.32]
De Groot 2005 [33]	23/22	Improved	Slight improvement	0.22 [$-$0.38, 0.82]
Majak 2009 [27]	17/19	Improved	No change	0.33 [$-$0.34, 0.99]
Martineau 2015 [34]	126/127	Significant improvement	Slight improvement	0.08 [$-$0.17, 0.31]
Lei Ziqiang 2011 [29]	63/62	Improved	Less improvement	0.48 [0.12, 0.84]
Total (95% CI)	247/246			0.25 [0.12, 0.84]

There were a total of 6 randomized controlled trials that documented the impact of blood 25-hydroxyvitamin D levels in vitamin D supplementation and control, and there were a total of 893 cases, with 446 instances in the supplement group and 447 cases in the control group. According to a heterogeneity test analysis that revealed statistical heterogeneity among 6 studies ($P=$ 0.0005, 1 $=$ 73%), the serum 25-light VitD changes at 2-month and 12-month follow-up points in VitD-supplemented and placebo-supplemented, respectively, were 0.54 (95% CI: 0.28, 0.79) and 1.03 (95% CI: 0.78, 1.28) respectively. This implies that, in comparison to taking a placebo, taking a vitamin D supplement may boost blood levels of the 25-light-base vitamin. See Fig. 7 and Table 8.

Figure 7.

Serum 25-hydroxyVitamin D levels post-supplementation: Shows that Vitamin D treatment significantly raises serum 25-hydroxyVitamin D levels compared to placebo, demonstrating its efficacy in optimising serum levels.

Table 8.

Effect of vitamin D supplementation on serum 25-hydroxyvitamin D levels

Study reference	Sample size (VitD/placebo)	Serum 25(OH)D level (VitD)	Serum 25(OH)D level (placebo)	Mean difference (95% CI)
Martineau 2015 [34]	126/126	Significantly increased	No significant change	$+$30.5 nmol/L [15.8, 45.2]
Majak 2009 [27]	17/18	Increased	No significant change	$+$20.3 nmol/L [10.1, 30.5]
Lei Ziqiang 2011 [29]	63/62	Increased	No significant change	$+$25.4 nmol/L [20.2, 30.6]
Worth 1994 [26]	15/17	Significantly increased	No significant change	$+$28.7 nmol/L [18.9, 38.5]
Total (95% CI)	221/223			$+$26.2 nmol/L [21.4, 31.0]

Table 9.

Impact of vitamin D supplementation on fatal asthma attacks

Study reference	Sample size (VitD/placebo)	Fatal asthma attacks (VitD)	Fatal asthma attacks (placebo)	Risk difference (95% CI)
Castro 2014 [11]	202/208	0	0	0.00 [$-$0.01, 0.01]
Jensen 2016 [35]	12/12	0	0	0.00 [$-$0.15, 0.16]
Majak 2009 [27]	17/17	0	0	0.00 [$-$0.11, 0.11]
Majak 2011 [28]	25/25	0	0	0.00 [$-$0.09, 0.09]
Martineau 2015 [34]	126/126	0	0	0.00 [0.01, 0.01]
Tachimoto 2016 [36]	55/36	0	0	0.00 [$-$0.04, 0.04]
Total (95% CI)	437/424			0.00 [$-$0.02, 0.02]

The recent work [14, 16, 21, 22, 23, 25] reported the occurrence of fatal asthma attacks in VitD supplementation and placebo control, with a total of 853 cases, 433 cases in supplement, and 420 cases in control. The total effect size and 95% confidence interval for the meta-analysis were [RD $=$ 0.00, 95% CI ($-$0.01, 0.01)] according to the results. See Fig. 8 and Table 8.

Figure 8.

Analysis of fatal asthma attacks: A forest plot comparing fatal asthma attack rates in Vitamin D and placebo groups, demonstrating Vitamin D supplementation’s safety in severe asthma outcomes.

The funnel plot approach was used for the analysis, with the cumulative effect size serving as the abscissa and the standard error of the natural logarithm serving as the ordinate. This was done in order to completely represent publication bias in the literature that was included. Because of the limitations of observation indicators in each research project, the funnel plot was only used to analyze the number of acute asthma episodes, serum 25-hydroxyVitD, pulmonary function (FEV1) (% expected value), and the incidence of adverse events. The four samples (Sample 1–Sample 4) considered refer to the four grades, i.e., Grade A, Grade B, Grade C, and Grade D, respectively. The results showed that the funnel plot was basically symmetrical, and there is a slight deviation, but the effect on the combined effect size can be ignored, indicating that the possibility of publication bias is small and the results are more reliable (Figs 9 and 10).

Figure 9.

Publication bias in studies on acute asthma attacks: A funnel plot of studies on Vitamin D and acute asthma attacks shows a symmetrical distribution, suggesting negligible publication bias.

Figure 10.

Effect of Vitamin D on FEV1 (% predicted value) – A meta-analysis funnel chart: This funnel graphic shows consistent findings and little publication bias in Vitamin D research on FEV1.

4. Discussion

Beyond allergies, vitamin D deficiency is associated with an increased risk of respiratory diseases, including COPD, and susceptibility to infections, particularly of the upper respiratory tract. These infections are crucial in the context of asthma because they can trigger exacerbations. Some studies suggest that vitamin D supplementation may reduce the frequency or severity of respiratory infections and may benefit COPD patients by modulating airway inflammation. Clinical trials and observational studies have provided conflicting results on the association between vitamin D levels and allergic and respiratory outcomes. While some research demonstrates the positive effects of vitamin D supplementation in reducing the occurrence or managing the severity of allergies and respiratory diseases, others have found limited or no effects. These discrepancies highlight the complexity of vitamin D’s role in human health and the need for well-designed studies to elucidate its effects. Research on the health benefits of vitamin D is characterized by varying study designs, dosages, and population characteristics. The optimal vitamin D level for preventing or treating allergies and other diseases is still unclear, highlighting the need for more targeted research

This study methodically evaluates the effect of Vitamin D (VitD) supplementation on asthma management, with a focus on reducing the frequency of exacerbations and improving pulmonary function. By combining data from 12 rigorously selected randomized controlled trials (RCTs), the study provides a critical assessment of VitD’s ability to reduce asthma exacerbations, as evidenced by lower systemic corticosteroid requirements and emergency department visits or hospital admissions. Furthermore, the study provides persuasive evidence that VitD supplementation improves lung function, as seen by improvements in the FEV1% predicted value and significant increases in serum 25-hydroxyVitD levels.

The findings highlight VitD’s vital function in modifying immunological responses and reducing inflammation in the respiratory system, both of which are important in the pathophysiology of asthma. The potential of VitD supplementation as an adjuvant therapy in asthma management is especially important for individuals with diagnosed VitD deficiencies, implying a new channel for therapeutic intervention aimed at improving clinical outcomes in this patient population.

Despite these hopeful findings, the study admits inherent limitations, such as the possibility of publication bias and the concentration solely on English and Chinese literature, which may limit the data’ generalizability. The need for larger-scale, multicenter trials to substantiate the observed effects of VitD supplementation in varied asthma populations is emphasized, indicating a future direction for study in this field.

In brief, this study provides valuable insights into the therapeutic efficacy of Vitamin D supplementation in the management of asthma. It emphasises the need for a complete approach that incorporates the evaluation of Vitamin D levels as a regular component of clinical care. Further research is necessary to elucidate the mechanisms through which Vitamin D influences the pathophysiology of asthma and to create specific recommendations for the administration of Vitamin D in asthma treatment protocols.

5. Conclusion

In conclusion, this comprehensive meta-analysis provides compelling evidence that vitamin D supplementation plays an important role in asthma management, with a marked reduction in asthma exacerbations, including those requiring systemic corticosteroids and emergency hospital visits. Furthermore, it shows a significant increase in lung function among asthmatic patients. Notably, the increase in blood 25-hydroxyvitamin D levels after vitamin D intervention supports the biological plausibility and efficacy of vitamin D supplementation in this group. These findings, together with a positive safety profile shown by the absence of substantial adverse events associated with vitamin D administration, imply that vitamin D could be an effective supplementary therapy in asthma control. Future study should focus on determining the appropriate dose and duration of vitamin D treatment, as well as.

5.1. Future work

Building on the abundant proof that Vitamin D supplementation can greatly enhance asthma management, future research should concentrate on optimising dosage and duration, determining the effect of genetic variants, and investigating interactions with other medications. Investigating Vitamin D’s effect on asthma-related comorbid diseases may lead to a more comprehensive approach to patient therapy. Additionally, incorporating these findings into public health policy, particularly in areas with high rates of Vitamin D insufficiency, could have a significant impact on asthma prevalence and management at the community level. Such endeavours have the potential to improve personalized asthma care by making medications more effective, targeted, and widely available.

5.2. Research limitations

The following are this paper’s limitations: ⟀ Only English and Chinese literature are included, and some data is not available, and the included literature may be incomplete. ⟁ Some potential confounding factors have not been adjusted, the relevant evidence level is not high, and there may be a certain selection bias. ⟂ Inclusion: the literature has a small sample size, and publication bias can be present; ⟃ The toxicity of high-dose VD supplementation was not evaluated. As a low-cost, low-risk prevention or treatment method, VD control is expected to become the primary prevention of human asthma. Current research shows that VD may have positive effects on asthmatic humans. Future randomized controlled trials need large samples. A multicenter, long-term study to evaluate the efficacy of vitamin D intake in asthma.

Author contributions

Conceptualization, H.N. and H.H.; methodology, G.Z.; software, Z.Z.; validation, X.L.; formal analysis, H.H.; investigation, Z.Z. and G.Z.; resources, H.H.; data curation, H.N. and X.L.; writing-original draft preparation, Z.Z.; writ-ing-review and editing, H.N.; visualization, H.H.; supervision, X.L. and G.Z.; project administration, H.N., H.H. and G.Z. All authors have read and agreed to the published version of the manuscript.

Data availability

The data used to support the findings of this study are included in the article.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.