Vitamin D and Its Association with Severity and Control of Childhood Bronchial Asthma

Abstract

Background: 

Bronchial asthma is a common disease in childhood. Vitamin D deficiency is a common unidentified nutritional deficiency. In spite of high prevalence, an association between the two has not been well understood.

Objectives: 

Our study aimed to determine serum Vitamin D levels among asthmatic children and its association with clinical severity and level of control.

Methods: 

A hospital-based cross-sectional study was conducted from 2017 to 2019 where 64 recurrent wheezers, classified into 6–15 years and the under 5 wheezers as per Global Initiative for Asthma guidelines, were included. The group of asthmatic children was comparable with respect to their demographic profiles with good adherence and proper inhaler use. Serum Vitamin D levels were estimated using an enzyme-linked immunosorbent assay and classified using the US Endocrine Society classification. Association between Vitamin D status and outcome variables was analyzed using Chi-square test, Fisher’s exact test, unpaired t-test, and ANOVA.

Results: 

Among the 64 wheezers, 29 (45.3%) had intermittent symptoms and 35 (54.7%) had persistent symptoms. Mean Vitamin D levels in the entire study population were in deficiency range (18.96 ng/ml ± 2.23). Persistent asthmatics had significantly lower Vitamin D levels (13.75 ng/ml) as compared to intermittent asthmatics (28.52 ng/ml). Those asthmatics who had hypovitaminosis D had higher rates of hospitalization (P = 0.048), increased use of rescue medications (P = 0.008), and poor symptom control (P = 0.001).

Conclusions: 

Asthmatic children had a higher incidence of reduced Vitamin D levels showing a statistically significant association. There is also a significant association between Vitamin D level and poor symptom control, hospitalization for exacerbations, and requirement of rescue medication in asthmatic children.

INTRODUCTION

Bronchial asthma is common in childhood with prevalence in India varying from 5% to 23%.^[1] Vitamin D is produced from sunlight; however, sun-enriched tropical countries have a high incidence of Vitamin D deficiency due to inadequate diet, cultural factors, etc.^[2,3] Studies show that Vitamin D reduces intercurrent childhood respiratory tract infections, hospitalizations for asthma,^[3] and also the risk of allergy in the offspring of pregnant women.^[4] As there is scant literature in this area, this study aimed to find out the incidence of Vitamin D deficiency among childhood asthmatics and correlate Vitamin D level with asthma severity and control.

MATERIALS AND METHODS

Study design

The study was designed as a cross-sectional study.

Study setting

This study was conducted at the tertiary medical college hospitals in coastal Karnataka.

Study population

Sixty-four clinically diagnosed cases of recurrent childhood wheezing were included in the study. The children were subclassified into childhood asthmatics above 6 years of age and under 5 wheezers in those below 5 years of age as per the Global Initiative for Asthma (GINA) guidelines.

Inclusion criteria

All children between 3 and 15 years of age who had recurrent wheezing episodes (>4 wheezing episodes/year and wheezing apart from viral infections) were included in the study. All the children were included only after ascertaining proper inhaler use and medication adherence.

Exclusion criteria

1. Children receiving Vitamin D supplements 1 month prior to enrollment
2. Those with other chronic pulmonary conditions (tuberculosis, bronchiectasis, bronchopulmonary dysplasia, and cystic fibrosis)
3. Children who were obese according to the WHO body mass index (BMI) charts
4. Children who had other familial, psychological issues that could confound the asthma control and inhaler use
5. Children <3 years were not included as it is difficult to clinically diagnose and classify bronchial asthma in them.

Study duration

The study was conducted over a 2-year period from October 2017 to September 2019.

Sample size calculation

Sample size of 178 was initially considered as per the study by Litonjua et al.^[5] In this study, the prevalence of hypovitaminosis D in bronchial asthma in pediatric age group was 35%. Hence our sample size was calculated using this value along with 95% confidence limits, 80% power and a relative precision of 20% (N = Zα² pq/d² = 178). Applying the formula for finite population, n = n0/(1 + n0/N) where N = 100 (as per available hospital records), the final sample size to be enrolled was calculated as 64.

Sampling technique

Convenient consecutive sampling was done as the children who satisfied the inclusion criteria visited the hospital and whose parents consented to participate in the study. Children were recruited after obtaining Institutional Ethics Committee approval (IEC KMC MLR 10-19/181) and informed consent/assent from parents/children. All necessary details, namely sociodemographic profile, gender, age at disease onset, symptom control, use of rescue medications, and requirement for hospitalizations were recorded on semi-structured pro forma.

Details of asthma symptoms and terms used

1. Classification of asthma – Done as per the European Respiratory Society
1. Intermittent asthma was said when the child had episodic viral wheeze (wheezing primarily during viral infections and fine in between episodes)
2. Persistent asthma was said when the child had multi-trigger wheezing (wheezing both before and after discrete episodes and in routine activities)
2. Level of control: Done as per the GINA guidelines [Table A]
3. Assessment of severity was also done by the frequency of hospitalizations as confounding factors such as proper inhaler use and medication adherence were ascertained before prospectively including them in the study.

Table A: GINA Guidelines for symptom control^{[ 2 ]}

Investigation collection details

Blood sample (2 ml) was collected from each child under aseptic precautions, serum was extracted and stored at minus 20° centigrade, and estimation of 25-hydroxyvitamin D was done using an enzyme-linked immunosorbent assay kit which is the facility available at the laboratory of the tertiary medical college hospital. The kits were standardized and used as per standards of the National Accreditation Board for Testing and Calibration Laboratories (NABL)-accredited laboratory of the college.

The study subjects were grouped into three categories based on the levels of Vitamin D as per the US Endocrine Society Classification:

• Vitamin D deficient (<20 ng/ml)
• Vitamin D insufficient (20–30 ng/ml)
• Vitamin D sufficient (>30 ng/ml).

Data analysis was done using IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp. Basic sociodemographic data of the study participants were expressed in terms of frequency and percentage for categorical variables and means with standard deviation for continuous variables. Serum Vitamin D was expressed as mean with standard deviation. Association between serum Vitamin D level and important exposure variables (asthma control and asthma severity and use of rescue medication) was tested using Chi-square test, Fisher’s exact test, unpaired t-test, and analysis of variants (P value was considered statistically significant if found <0.05 and as highly significant if found <0.01).

RESULTS

Sixty-four children with bronchial asthma were enrolled in the study. The baseline characteristics of the study population and the respective Vitamin D levels are shown in Table 1. There was no significant statistical association between age, gender, place of residence or BMI, and Vitamin D status in asthmatic children, and the groups were uniform as per demographic and clinical profile.

Table 1: Sociodemographic variables of the study population and the distribution of Vitamin D levels in the study population (n=64)

Out of 64 children, 29 children had intermittent asthma, 22 had mild persistent symptoms, and 13 had moderate persistent asthma. Out of these, 35 were on regular inhaled corticosteroids (intermittent asthmatic children were on rescue inhaled steroids/leukotriene receptor antagonists). The mean Vitamin D level in the entire study population (n = 64) was 18.56 ng/ml ± 2.23, which was found to be in the deficiency range. Fifty-two children had a mean Vitamin D level of 13.76 ng/ml ± 3.3, showing hypovitaminosis D. Twelve children had Vitamin D levels which were normal with a mean of 39.36 ng/ml ± 2.4. Among those with hypovitaminosis D, 40 (62.5%) had deficiency with a mean Vitamin D level of 10.61 ng/ml and 12 (18.7%) had insufficiency with a mean of 24.30 ng/ml.

Asthma symptom control was assessed using frequency of daytime symptoms, nocturnal symptoms, and hospitalization rates and correlated with Vitamin D values. Activity limitation as a marker for symptom control could not be assessed as all children who were brought to the hospital had activity limitation during the exacerbation, hence the frequency of hospitalization was taken as the other parameter for severity. Forty-one children were well controlled and 23 partially controlled according to the symptom checklist. We did not have any uncontrolled asthmatic children in our study population. Among those with well-controlled symptoms (n = 41), 13 had persistent asthma. Twenty-two out of 23 asthmatics whose symptoms were partially controlled had persistent asthma in our study population. The mean Vitamin D value in the intermittent asthma group was 28.52 ng/ml as compared to lower values of 14.4 ng/ml and 12.5 ng/ml in the mild intermittent and moderate persistent groups, respectively. Vitamin D deficient/insufficient group had significantly higher rates of daytime exacerbations (>2 in 1 week) (P = 0.012) and higher incidence of nocturnal symptoms (>3/month) with 30.8% in hypovitaminosis D group having these features as against none in the sufficient group (P = 0.037). Those asthmatics who had hypovitaminosis D had higher hospitalization rates (>4/year) as compared to those who had normal levels of Vitamin D (P = 0.044) [Table 2]. Symptoms were better controlled in children with normal Vitamin D levels compared to those with hypovitaminosis D (deficiency/insufficiency) on application of Student’s t-test. The results were found to be statistically significant having P = 0.001 [Table 3].

Table 2: Vitamin D levels and frequency of exacerbations, nocturnal symptoms, and hospitalization (n=64)

Table 3: Vitamin D levels and level of control and use of rescue medications among bronchial asthma cases (n=64)

In our study population, 27 among 40 Vitamin D deficient and 7 among 12 insufficient children had persistent asthma. Seventeen in former group and two in latter group required rescue medications (more than twice per week) for control of symptoms. However, only one out of 12 Vitamin D sufficient asthmatics required such rescue medications [Table 2]. Upon estimation, those who needed rescue medications had mean Vitamin D levels in deficiency range as compared to those who did not need rescue medications, for whom, the Vitamin D levels was in the insufficiency range [Table 3]. Analysis revealed a statistically significant association between serum Vitamin D levels and need for rescue medications (more than twice per week), having P = 0.008.

DISCUSSION

Worldwide, bronchial asthma is a leading cause of childhood morbidity. In spite of being a tropical country, Vitamin D deficiency/insufficiency is prevalent among Indian population in all age groups and both sexes. As Vitamin D has a role as an immunomodulator as well as in respiratory infections, a probable association between bronchial asthma and Vitamin D deficiency or insufficiency has been postulated. Available data are insufficient to draw conclusions about the association of the nutrient with clinical spectrum of the disease.^[6–9] Systematic reviews and meta-analyses have also concurred that the details of association between Vitamin D and asthma control are unclear and there are no such studies from India, hence this study was planned.^[10]

At the outset in our study, the issue of confounders was addressed. Modifiable factors such as inhaler technique and adherence to medication affect the level of control and severity of childhood asthma, hence these factors were obviated by ensuring that our study population had good adherence, follow-up, and correct inhaler technique. The exposure to sunlight and dietary factors that also affect the level of Vitamin D was also considered, and in our study population, all the children are from the same region where the exposure to sunlight in school hours is the same and dietary patterns are constant among the families from our district.

Hypovitaminosis D either deficiency or insufficiency was seen in 81% of the childhood wheezers in our study. In a case–control study among African-American asthmatics 6–20 years of age, the prevalence was found to be 86% and the median Vitamin D level in these asthmatics was 18.5 ng/ml, significantly lower than nonasthmatic controls (40.4 ng/ml).^[10] Davoodi et al.^[11] reported that 68.1% of asthmatics have hypovitaminosis D in the Middle East region. Even in tropical countries blessed with plenty of sunlight, a high incidence of Vitamin D deficiency has been reported, which is similar to what has been found in our study as well as other studies in the Middle East and can be attributed to low dietary intake, indoor stay, and changing lifestyle.^[12]

The present study showed that children with hypovitaminosis D had more severe asthma with partial symptom control. Childhood Asthma Management Programme (CAMP)^[13] cohort study of 1,024 children revealed increased risk of severe asthma exacerbations when there was associated hypovitaminosis D. In this study adjustment for age, body mass index, gender and baseline asthma severity was done. Our study also supports similar findings as the children were comparable in the characteristics listed above.

Higher hospitalization rates among those with hypovitaminosis D compared to the Vitamin D sufficient group were found in the present study (P = 0.044). Vitamin D has been reported to have immunomodulatory effects in respiratory tract infections,^[14] hence we concluded that this could explain the increased exacerbations requiring hospitalizations in our hypovitaminosis group. Brehm et al.^[15] reported, among 616 asthmatic children aged 6–14 years, that a unit increase in the levels of Vitamin D was associated with reduced events of hospitalization as well as reduced requirement of anti-inflammatory medications, which is probably due to both the effects of Vitamin D, as an immunomodulator and as an anti-inflammatory agent in asthma. The present study found that Vitamin D sufficient group had remarkably better symptom control as compared to the deficient and insufficient groups as per the GINA symptom control checklist. Another finding that was evident in the present study was that the use of rescue medications (more than twice per week) was significantly high among the deficient/insufficient group as against the sufficient group. In concordance with our study, Litonjua^[5]et al have reported an association between hypovitaminosis D and increased rates of hospitalization and emergency department visits among asthmatic children and concluded that vitamin D deficiency was one of the strongest predictors of asthma. These studies have been done in the temperate climates in North America, and despite our country being in the tropics and our district being on the sea coast in the southern part of India, which is sun replete, these findings were noted even in our nation that needs to be addressed for better asthma follow-up care in children.

Limitations

One of the limitations of our study was that the study did not include a treatment limb where supplementation of Vitamin D and subsequent better symptom control could be assessed and the association proven. We also did not analyze the dosage of inhaled corticosteroids as primary caregivers did not accompany the child each time and did not get their inhaler prescriptions during review visits.

CONCLUSIONS

There is high incidence of hypovitaminosis D among our study population and shows an inverse correlation with symptom control and severity of childhood bronchial asthma. The group of children with sufficient Vitamin D had better symptom control as compared to the deficient/insufficient groups. The Vitamin D deficient/insufficient group had higher rates of hospitalization and use of rescue medications (more than twice per week) compared to the sufficient group, hence Vitamin D status can serve as an important modifiable factor in the control of bronchial asthma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.