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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 31  |  Issue : 2  |  Page : 76-82

Factors influencing age of onset of wheezing among children with recurrent wheezing and the association of Vitamin D status with atopic manifestations


1 Department of Pediatrics, Sardar Vallabhbhai Patel Post Graduate Institute of Paediatrics, SCB Medical College, Cuttack, India
2 Department of Pediatrics, KIMS, Bhubaneswar, Odisha, India

Date of Web Publication29-Sep-2017

Correspondence Address:
Bijay Kumar Meher
C/455, Sector-6, CDA, Cuttack - 753 014, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijaai.ijaai_29_17

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  Abstract 

Background: Onset of wheezing before 3 years of age is concerning due to its potential for the development of asthma. Different risk factors, atopic manifestations, and Vitamin D deficiency are attributed to it.
Aims: The aim of this study is to assess the factors influencing the age of wheezing onset among children with early-onset recurrent wheezing and the association of Vitamin D status with different atopic manifestations.
Subjects And Methods: This cross-sectional observational study included 141 children aged from 1 month to 14 years with recurrent wheezing. Onset of wheezing after 36 months was excluded from the study. Different risk factors and atopic manifestations were recorded, and Vitamin D levels were measured. Descriptive analysis, independent t-test, analysis of variance, and regression analysis were done using SPSS version 24.0.
Results: Of 141 children, 65 (46.0%) had onset of wheezing at <1 year of age. Children with onset of wheezing <1 year had early age of presentation (29.38 ± 29.35 vs. 46.25 ± 27.77 months) were predominately male (52.1% vs. 47.9%) and had a low birth weight (2688.46 ± 608.84 vs. 2904.61 ± 510.96 g) and high Vitamin D level (22.01 ± 12.63 vs. 16.65 ± 9.05 ng/mL; P < 0.05). In the regression analysis, birth weight, family with >1 sibling, and atopic dermatitis had regression coefficients of 0.393 (P < 0.01), 4.525 (P < 0.01), and −2.970, respectively (P > 0.05).
Conclusions: Children with onset of wheezing before 1 year were predominantly male and had a lower birth weight. Vitamin D deficiency does not hasten the onset of wheezing; however, a low birth weight and associated atopic dermatitis hasten the onset of wheezing, and being part of a family with >1 sibling delays onset.

Keywords: Asthma, respiratory sounds, risk factor, Vitamin D, wheezing


How to cite this article:
Meher BK, Pradhan DD, Pradeep S, Das L, Beriha SS, Panigrahi S. Factors influencing age of onset of wheezing among children with recurrent wheezing and the association of Vitamin D status with atopic manifestations. Indian J Allergy Asthma Immunol 2017;31:76-82

How to cite this URL:
Meher BK, Pradhan DD, Pradeep S, Das L, Beriha SS, Panigrahi S. Factors influencing age of onset of wheezing among children with recurrent wheezing and the association of Vitamin D status with atopic manifestations. Indian J Allergy Asthma Immunol [serial online] 2017 [cited 2019 Nov 22];31:76-82. Available from: http://www.ijaai.in/text.asp?2017/31/2/76/215836




  Introduction Top


Wheezing is a very common respiratory problem during childhood and a worthy cause of morbidity and mortality worldwide.[1] A wheeze is defined as a continuous high-pitched sound emitting from the chest during expiration, which lasts for >250 ms.[2] Recurrent wheezing is defined as three or more episodes of parentally reported wheezing over a 12-month period.[3] Epidemiological studies have reported that one-third of all children experience wheezing at least once in their first 3 years of life; between 10% and 80.3% of infants experience at least one episode of wheezing during their 1st year of life.[3],[4],[5],[6]

In India, the prevalence of wheezing is 6.2% in schoolchildren aged 6–7 years.[7] It is thought that genetic and individual immunologic features along with environmental factors may be responsible for childhood temporal patterns of wheezing.[8] It has recently been reported that the frequency of asthma has increased, which is suggested to be due to changes in environmental factors, Western lifestyle, and eating habits.[9] Different risk factors are attributed to the development of recurrent wheezing and asthma, including family history, pollution, hygienic conditions, birth weight, and smoking in the family. Other atopic manifestations such as allergic rhinitis, urticaria, and atopic dermatitis are also associated with this condition.

Although there are many risk factors for the development of recurrent wheezing,[10] an emerging risk factor of particular interest is the Vitamin D status.[11] In the Childhood Asthma Management Program, children with low baseline 25-hydroxyvitamin D [25(OH)D] levels (<75 nmol/L) were more likely to have a severe asthma exacerbation over a 4-month period.[12],[13] There is evidence to suggest that an enhanced risk of childhood wheezing is associated with low levels of maternal intake of Vitamin D during pregnancy and lower levels of 25(OH) D in the umbilical cord blood.[14],[15] Various interventional trials support these associations by establishing a lower occurrence of respiratory tract infections in children undergoing Vitamin D supplementation;[16],[17] therefore, the lower the amount of Vitamin D, the higher the risk for wheezing.

The present study aimed to examine the risk factors associated with recurrent wheezing in children with age of onset <3 years of age to include the factors influencing the age of wheezing onset and the association of Vitamin D status with different atopic manifestations.


  Subjects and Methods Top


Study design

This cross-sectional observational study was conducted in the outpatient department of a tertiary care hospital. As there are no ethical issues related to the study, approval was not obtained from the Institutional Ethical Committee. Informed consent was obtained from the parents before enrolling children into the study.

Participants

Children aged between 1 month and 14 years who presented to the outpatient department with a history of recurrent episodes (>3) of respiratory symptoms such as wheezing, shortness of breath, chest tightness, and cough were included in the study. Children with the onset of wheezing occurring after 36 months of age were excluded from the study. Seriously ill children requiring hospitalization, those diagnosed with Vitamin D deficiency/rickets, and children with nephrotic syndrome were excluded from the study.

Data collection

The variables recorded for all patients included age of presentation, age of onset of wheezing, sex, current weight, birth weight, family history of atopy and asthma, smoking in the family, number of siblings at home, and if living near an industrial area (suggestive of air pollution). In addition, the duration of exclusive breastfeeding, age of introduction to cow's milk and Vitamin D supplementation or multivitamin supplementation, and levels of sun exposure (approximate duration of direct sunlight exposure from 10 am to 3 pm)[18] were recorded. The features of atopy, such as atopic dermatitis, allergic rhinitis, urticaria, and requirement of inhaled steroids to control for wheezing, were assessed from the given history and previous health records.

Laboratory procedures

Blood was collected and an estimation of 25(OH)D levels was recorded using a sandwich enzyme-linked immunoassay method. Additional tests required for the treatment of wheezing and its associated conditions, including chest radiography, blood count analysis, and C-reactive protein test, were carried out per the physician's recommendation and hospital protocol. Management of the patient was performed by treating physicians who were blinded to the study results.

Sample size

Since proportions of different characteristics of the population with wheezing were to be estimated, the minimum sample size, n, was computed as 119 using the formula for estimation of proportion: , where is the value of the standard normal variant for 1−∝/2 level of significance, P is the anticipated population proportion (taken as 50%), and d is the absolute precession required on either side of the population (taken as 9% point). We have used a sample size of 141.

Statistical analysis

The cross-tabulation procedure along with the independent Chi-square test was used to find an association between categorical variables. The independent sample t-test was used to compare means of two groups, and analysis of variance (ANOVA) was used to compare means among more than two groups. Stepwise backward regression analysis was performed to determine the influence of 16 predictor variables on the dependent variable, i.e., onset of wheezing. Since some predictive variables were categorical in nature, they were converted into dummy variables. If the categorical variables were at two levels, then each one of them was converted into one dummy variable (presence, 1; absence, 0). If the categorical variables had more than two levels, then they were converted into the number of the level minus one number of the dummy variables. Predictive variables were Vitamin D level, exclusive breastfeeding in months, birth weight in grams, family history of atopy ( first degree and second degree), industrial habitat, family structure (>1 sibling or no sibling), smoking in the family, early cow's milk supplementation, associated atopic conditions (atopic dermatitis, allergic rhinitis, or urticaria), adequate sunlight exposure, Vitamin D supplementation, and multivitamin supplementation.

In this method, all the selected 16 variables were entered into the model initially. Regression analysis was rerun by following the stepwise method of model selection. This was done to include the most useful variables in the model and to address any problem of collinearity.[19] Regression analysis was performed using IBM Corporation may be replaced with IBM SPSS Statistics for Windows, IBM Corporation Released 2016, Marketed by SPSS South Asia Pvt. Ltd. Values are presented a mean ± standard deviation unless otherwise stated.


  Results Top


[Table 1] shows the baseline characteristics of children with early-onset recurrent wheezing. The mean age of presentation was 38.48 ± 29.63 months with a male predominance (68.1%). A family history of atopy in a first- and second-degree relative was found in 40 (28.4%) and 49 (34.8%) children, respectively. An industrial habitat suggestive of pollution was true for 12 (8.5%) and smoking in the family was seen in 23 (16.3%) children. Sixty-three (44.7%) children lived in a family with <2 siblings, 52 (36.9%) were from a family with 1 sibling, and 26 (18.4%) were from a family with no siblings. Exclusive breastfeeding for <6 months occurred in 36 (25.5%) children, and cow's milk was introduced before 1 year in 28 (19.9%) children. Sun exposure (<30 min of direct sunlight exposure between 10 am to 3 pm) was inadequate in 91 (64.5%) children, and 89 (63.1%) children were Vitamin D deficient with a mean Vitamin D level of 19.12 ± 11.14 ng/mL.
Table 1: Baseline characteristics of patients with early-onset recurrent wheezing (n=141)

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[Table 2] compares the different parameters in the study cohort with the age of onset of wheezing (>1 year and <1 year). The following parameters had no significant effect on the age of onset of wheezing: a family history of atopy, industrial habitat, family structure, smoking in the family, duration of exclusive breastfeeding, early introduction of cow's milk, and adequacy of sun exposure (P > 0.05). Children with onset of wheezing <1 year had a significantly earlier age of presentation (<1 year, 29.38 ± 29.35 vs. >1 year, 46.25 ± 27.77 months; P = 0.001), were predominantly male (<1 year, 52.1% vs. >1 year, 47.9%; P = 0.037), had a lower birth weight (<1 year, 2688.46 ± 608.84 g vs. >1 year, 2904.61 ± 510.96 g; P = 0.023), and had a higher Vitamin D level (<1 year, 22.01 ± 12.63 ng/mL vs. >1 year, 16.65 ± 9.05 ng/mL; P = 0.004).
Table 2: Comparison of parameters in patients with recurrent wheezing with a different age of onset (n=141)

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[Table 3] shows the association of different atopic manifestations with early-onset recurrent wheezing and the association with Vitamin D status. In this cohort of early-onset recurrent wheezing, atopic dermatitis, allergic rhinitis, and urticaria were seen in 48 (34%), 107 (75.8%), and 12 (8.5%) children, respectively. The onset of wheezing occurred in 65 (46.0%) children before 1 year of age; the mean age of onset was 13.73 ± 10.15 months. In addition, 53 (27.5%) children needed inhaled steroid therapy to control the wheezing. There was no significant difference in atopic dermatitis, allergic rhinitis, and urticaria in children with a differing Vitamin D status (deficient, insufficient, and sufficient); however, the mean age of wheezing onset was significantly higher in the Vitamin D deficient group than in the Vitamin D sufficient group (15.11 ± 10.35 vs. 9.04 ± 9.25 months; P = 0.021). The requirement for steroid use was higher in the Vitamin D deficient group than in the Vitamin D sufficient group, but this was statistically insignificant (P > 0.05).
Table 3: Association of the serum Vitamin D level and atopy in children with early-onset recurrent wheezing (n=141)

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In the regression analysis, the final model was achieved at the 14th step; the model is presented in [Table 4] and [Table 5]. The ANOVA gave a significant value for the F statistic (P = 0.000). The regression sum of square was significant. Three variables were finally retained in the stepwise backward regression analysis. The constant term was 7.064 (P = 0.000). Birth weight had a regression coefficient of 0.393 (P = 0.000). This implied that a one-unit change in birth weight would bring about a 0.393 increment in the onset of wheezing, meaning that a low birth weight contributes to the early onset of wheezing and a higher birth weight delayed the onset of wheezing. Family structure (>1 sibling) had a coefficient of 4.525 (P = 0.000). This implied that being part of a family with >1 sibling had a positive impact; it is associated with a delay in the onset of wheezing. Atopic dermatitis had a regression coefficient of −2.970 (P = 0.078), implying that it is associated with an early onset of wheezing; however, this did not reach significance.
Table 4: Results of analysis of variance and model summary of regression analysis

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Table 5: Regression coefficients for predictors of age of onset of wheezing

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  Discussion Top


In the present study, we found different risk factors of varying proportion in our study cohort of early-onset recurrent wheezing. Sixty-five (46.0%) children had onset of wheezing before 1 year of age and had a significantly early age of presentation, male predominance, low birth weight, and high Vitamin D level. However, in the regression analysis, we found that low birth weight and associated atopic dermatitis were factors that hasten the onset of wheezing.

In our study population, we found that children from a family with <1 sibling developed the onset of wheezing later, which is similar to the results of previous studies where it was hypothesized that as the family size decreases, exposure to infections and microbial agents also decreases, leading to an increase in asthma and allergies.[20],[21] Similarly, a study by Martinez et al. also reported that exposure to older siblings protected against asthma.[3]

Our results indicated that a family history of atopy in a first- or second-degree relative was found in 63.2% of children. Similarly, using a validated questionnaire administered to parents, Bessa et al. reported that risk factors for wheezing in children between 12 and 15 months of age were a family history of asthma (odds ratio = 2.12; 95% confidence interval: 1.76–2.54).[22] In addition, in our study cohort, there were 12 (8.5%) children living in an industrial habitat, indicating air pollution as a risk factor for wheezing. This finding is similar to that in a previous study by Cara et al. who suggested industrial air pollution to be the main risk factor for wheezing during the 1st years of life in children of Călăraşi, Romania, a natural experiment was used to study the relationship between the occurrence of wheezing in children aged 0–2 years and the change in industrial pollution from the factory.[23] In addition, de Sousa et al., in a case–control study that used a multiple analysis model, reported that exposure to environmental smoke remained as a risk factor for the development of wheezing.[24]

In a study by Martinez et al., maternal asthma, maternal smoking, rhinitis apart from colds, eczema during the 1st year of life, male sex, and a Hispanic ethnic background were all reported to be independently associated with persistent wheezing. Exposure to older siblings, domestic animals, endotoxins, and attendance to day care were all factors found to protect against asthma.[3] Reis et al. also reported, in a community-based study, that maternal atopic-related disease was independently associated with recurrent wheezing; however, a smoker at home and low birth weight were independently associated with occasional wheezing.[25] Bozaykut et al. evaluated the risk factors for recurrent wheezing in 500 patients diagnosed as having acute bronchiolitis in a prospective study, and they found that male sex, a low birth weight (<2500 g), a low gestational age (<37 weeks), breastfeeding for <6 months, congenital heart disease, a family history of atopy, asthma, smoking exposure, and stove warming were indicated as significant risk factors for recurrent wheezing.[26] In our study, male sex, a low birth weight, and Vitamin D status were found to be associated with the age of onset of wheezing. We found no significant difference in number of children developing wheezing <1 year of age with a family history of atopy and smoking in family. However, Pellegrini-Belinchón et al. reported that infants presenting with eczema and with a mother who had been diagnosed as having asthma, smoked during the third trimester of pregnancy, and did not consume a Mediterranean diet during pregnancy were found to have a probability of 79.7% of developing recurrent wheezing during the 1st year of life.[27]

The literature regarding the relationship between infant feeding practices and the development of childhood asthma and allergic wheezing is conflicting. In this study cohort, 25.5% of children were exclusively breastfed for <6 months, and 19.9% were introduced to cow's milk before 1 year of age. In addition, we did not find a significant difference between the age of onset of wheezing and the duration of breastfeeding. In agreement, several published larger studies have shown no significant relationship between feeding history and asthma;[28],[29],[30] however, other studies have reported a protective effect of breastfeeding for asthma in 6-year-old children.[31] A study by Wright et al. reported the relationship between recurrent wheezing and breastfeeding to be age dependent; in the first 2 years of life, exclusive breastfeeding was associated with significantly lower rates of recurrent wheezing, whereas at the age of 6 years, exclusive breastfeeding was unrelated to the prevalence of recurrent wheezing.[32] Patra et al. also reported that children with wheezing were more likely to not be exclusively breastfed.[33]

Insufficient levels of Vitamin D were observed in 80.14% of the children in this study, which is higher than previously reported in a group of patients aged 0–18 years with asthma, atopic dermatitis, and/or food allergy (48%).[34] Uysalol et al. reported Vitamin D levels to be significantly lower in children with recurrent wheezing than in patients with nonrecurrent wheezing; the postulated serum levels of Vitamin D were used as a routine biomarker for determination of asthma risk in patients with recurrent wheezing.[35] The levels of Vitamin D deficiency observed in the children with recurrent wheezing in this study were comparable to those in a study by Özaydın et al.[36] Demirel et al. also reported that the serum 25(OH) D levels in children with wheezing aged 1–3 years were significantly lower than in those without wheezing.[37] Furthermore, Stenberg Hammar et al. studied 130 children with acute wheezing aged from 6 months to 4 years and found Vitamin D insufficiency (<30 ng/mL) to be associated with acute wheezing; however, no association was found between Vitamin D insufficiency and atopy.[38] Prasad et al. studied the association of Vitamin D deficiency with recurrent wheezing in Indian children <3 years of age and found that each 10 ng/mL decrease in the Vitamin D level was associated with a 7.25% increase in the risk of wheezing.[39] Ozdemir et al. studied the Vitamin D status in infants with recurrent wheezing in those with a positive and negative asthma predictive index and found decreased levels of Vitamin D and a higher Vitamin D deficiency in both phenotypes compared to the control group.[40] This is comparable to findings of the levels of Vitamin D in our study group.

A potential limitation of our study was that we did not compare the risk factors in the study participants with those in a control group. Furthermore, not all risk factors associated with recurrent wheezing were considered in the study. Further study that measures the Vitamin D level at the time of onset of wheezing and prospectively follows it for an objective evaluation of the recurrence of wheezing may need to be conducted. Another limitation is that although we performed regression analysis, the R-square value was 0.174, which implies that only 17.4% variation in the onset of variation is explained by this model. This is not a standard for accepting the model. However, the significance of the F statistics and significance of B values provide adequate rational to conduct further research with an improved design, for example, a larger sample size, adequate representation of low birth weight babies, and objective evaluation of hygienic conditions.

Children who develop wheezing <1 year of age have a significantly earlier age of presentation with a male predominance and lower birth weight. Vitamin D deficiency does not hasten the onset of wheezing; however, a low birth weight and associated atopic dermatitis hasten the onset of wheezing, and being part of a family with >1 sibling is associated with a delay in the onset of wheezing.


  Conclusions Top


Children who develop wheezing <1 year of age have a significantly earlier age of presentation with a male predominance and lower birth weight. Vitamin D deficiency does not hasten the onset of wheezing; however, a low birth weight and associated atopic dermatitis hasten the onset of wheezing, and being part of a family with >1 sibling is associated with a delay in the onset of wheezing.

Acknowledgment

We thank Prof. N. Mohanty and Prof. Anil Kumar Mohanty for allowing us to perform the study and guiding and constantly inspiring us in this work; Dr. Bijayaabhusan Nanda, Deputy Director, Regional Institute of Planning, Applied Economics and Statistics, Odisha, for providing statistical guidance; and Francis Satapathy for his help in drafting the manuscript. We would also like to thank Editage (www.editage.com) for English language editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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