Habib, S., Salman, G. (2020). Vitamin D Status in Children with Recurrent Wheeze. , 38(1), 29-36. doi: 10.33762/mjbu.2020.127089.1014
Sawsan Habib; Ghufran Salman. "Vitamin D Status in Children with Recurrent Wheeze". , 38, 1, 2020, 29-36. doi: 10.33762/mjbu.2020.127089.1014
Habib, S., Salman, G. (2020). 'Vitamin D Status in Children with Recurrent Wheeze', , 38(1), pp. 29-36. doi: 10.33762/mjbu.2020.127089.1014
Habib, S., Salman, G. Vitamin D Status in Children with Recurrent Wheeze. , 2020; 38(1): 29-36. doi: 10.33762/mjbu.2020.127089.1014

Vitamin D Status in Children with Recurrent Wheeze

The Medical Journal of Basrah University
Article 4, Volume 38, Issue 1, 2020, Pages 29-36    PDF (468.67 K)
Document Type: Research Paper
DOI: 10.33762/mjbu.2020.127089.1014
Authors
Sawsan Habib* 1; Ghufran Salman2
1University of Basrah
2Misan Health Directorate / Al-Zahrawi hospital
Abstract
Background it has been shown that low serum 25-hydroxyvitamin D concentration was associated with a higher risk of upper and lower respiratory infections in children
Aim to evaluate vitamin D concentration and selected biochemical markers in infants and children with recurrent wheeze.
Methods a case-control study has been carried out to measure serum vitamin D concentration; on 33 patients with recurrent wheeze, their ages ranged from 4-60 months; over the period from the1stof March 2014 to the end of June 2014.
Forty-two age and sex matched healthy children were selected as control group. List of investigation was measured by spectrophotometer as serum calcium, phosphorus, alkaline phosphatase and 25-OH vitamin.
Result
Frequency of breast feeding in the first two years of life was low in wheezy children and significantly shorter duration of breast feeding less than 4 months in wheezy children than control group, P value 0.01.
Vitamin D concentration was significantly low in children with recurrent wheeze than the control group; (21.69 ng/ml, 39.36 ng/ml) respectively with p-value 0.000
The severity of vitamin D deficiency was significant in children with recurrent wheeze, severe deficiency of vitamin D There is no significant relation observed between mean Vitamin D concentration and selected variables of infants and children with wheeze (p value >0.05)
Conclusion vitamin D supplementation may be considered in infants and children with recurrent wheeze.
Keywords
Vitamin D,,; ,،,؛recurrent wheeze,,; ,،,؛children
Full Text

Introduction

There are many studies highlighting associations between childhood asthma and vitamin D deficiency. The hypothesis is that vitamin D could have a central role in these pathological situations and that it may represent a novel preventive and/or therapeutic strategy. 1 Meta-analysis data of published clinical trials concluded that vitamin D supplementation decreased the risk of asthma exacerbations in those with 25OHD levels less than 10ng/ml. The evidence suggests that there is a protective effect of higher vitamin D level primary prevention of asthma and itsexacerbations. 2 Almost all cells in the body possess vitamin D receptors, including cells of the immune system. This has fueled more research and hypotheses that vitamin D may be integral to immune system regulatory functions. Vitamin D deficiency can affect Th1 and Th2 cytokines, which may also contribute to the development of atopy. 3 Vitamin D, can modulate the innate and adaptive immune responses; 1, 25-Dihydroxyvitamin D stimulates innate (macrophage) immunity by enhancing bacterial killing but it also modulates adaptive (lymphocyte) immunity to minimize inflammation and autoimmune disease. 4 During a bacterial infection, macrophages acquire the capacity to convert circulating 25 vitamin D into 1, 25 OH vitamin D, which is a direct inducer of the expression of genes encoding for antimicrobial peptides and cathlicid in antimicrobial peptide in particular. This peptide is central in host defense against respiratory tract pathogens. 5 Deficiency in vitamin D is associated with increased autoimmunity as well as an increased susceptibility to infection. Many studies in adults and children found a higher prevalence of vitamin D deficiency in asthmatics than in the normal population; in addition, low vitamin D levels are associated with increasing severity of asthma and impaired pulmonary function. Patients with vitamin D deficiency have shown to have increased airway hyper-responsiveness and increased corticosteroid requirements. 6

Subjects and Methods

A Case-control study has been carried out to measure serum level of vitamin D; 33 infants and children with recurrent wheeze (more than 3 attacks) 7 , 8 who were admitted to Basra Maternity and Children Hospital and Basra teaching Hospital or those who visit pediatric emergency room, their ages ranged from 4-60 months; over the period from the 1st of March to the end of June 2014 were included. Forty-two infants and children visiting AL-Razi primary health care center for routine checkup and vaccination were age and sex matched as control group.

Exclusion criteria including history of:

1. Congenital heart diseases, chronic lung disease, immunodeficiency, neurologic or metabolic disease.

2. Prematurity with or without admission to neonatal care unit

3. Vitamin D supplements for the last 3 weeks. 9

4. Steroids treatment for previous one month. 10

Especial Questionnaire was designed for the purpose of the study. An informed consent was obtained from the parents for recruitment in the study. All patients underwent general and systemic examination, and anthropometric measurements were assessed and applied to appropriate charts. 11

Laboratory Data

Blood samples (3 milliliters) from recruited subjects were collected using, Clot Activator with Gel Tube. A List of investigations was measured by spectrophotometer for the patients and control group: Serum calcium (Ca), phosphorus (Ph), Alkaline Phosphatase. Serum 25-OH Vitamin Dmeasurement by Euroimmun25-OH Vitamin D by ELISA kitEuroimmun AG, Seekamp 31,23560 lübeck, Germany. 12

Reference values 13

Severe deficiency ( 20

Data were analyzed using SPSS version 18

Results

A total of 75 infants and children, their ages ranged from 4-60 months are included in this study; 33 infants and children with history of wheeze; more than three attacks, their mean age is 16 monthswith standard error 2.5; 17(51. 5%) are males, and 16(48.5%) are females. The control group includes 42 healthy children, 22(52.4) are males and 20(47.6) are females, their mean age is19.21with standard error 2.1

Selected characteristics of patients with wheeze and control group

High frequency of breast feeding reported in the control group than children with recurrent wheeze, (38.1%,27.3%) respectively but statistically non-significant result, with significantly shorter duration of breast feeding less than 4 months in wheezy children than control group (39.1%,5.6%) respectively p value 0.01. There is no significant difference in children with recurrent wheeze and control group regarding history of atopy (48.5%, 33.3%) with significant family history of allergic rhinitis and conjunctivitis (48.5%, 39.3%) in wheezy children than control group (14.3%,7.1%) respectively as shown in (Table -1)

VariablesWheezy groupControl groupP value
No.%No.%
Feeding history in 1st two years Breast 9 27.3 16 38.1 0.225
Bottle 10 30.3 6 14.3
Mixed 14 42.4 20 47.6
Duration of breast feeding (months) < 4m 9 39.1 2 5.6 0.01
4-12m 10 43.5 14 38.9
> 12m 4 17.4 20 55.5
History of child atopy (atopic dermatitis) Positive 16 48.5 14 33.3 0.137
Negative 17 51.5 28 66.7
Positive family history of atopy Atopic dermatitis 14 42.4 7 16.7 0.13
Allergic Rhinitis 16 48.5 6 14.3 0.001
Allergic conjunctivitis 13 39.4 3 7.1 0.02  
Asthma 23 69.7 16 38.1 0.06
Table 1. Selected characteristics of wheezy children and control groups

Biochemical parameters

(Table-2), shows that children and infants with recurrent wheeze have lower serum vitamin D level (21.69 ng/ml) than the control group (39.36ng/ml) with statistically significant result (p-value 0.000),while mean serum calcium, phosphorus and alkaline phosphatase levels shows no significant difference.

VariablePatientsControlP-value
Mean ± SD
Vitamin D (ng/ml) 21.69 ± 2.04 1.23 ± 0.48 0.000
Calcium (mg/dl) 8.5 ± 1.2 1.23 ± 0.48 0.261
Phosphorus (mmol/l) 1.23 ± 0.48 1.23 ± 0.48 0.534
Table 2. Biochemical parameters in patients and control

Vitamin D status

Higher frequency of vitamin D deficiency; severe deficiency (12.1%) deficient (12.1%) and insufficiency (21.3%) recorded in children with recurrent wheeze than control group (4%); as well as sufficient level of vitamin D >20 ng/ml was recorded with higher frequency in control group than children with wheeze (97.6%,54.5%) respectively with statistically significant result (P-value 0.001). (Table-3)

VariableSevere deficiency < 5ng/mlDeficient < 15 ng/mlInsufficient 15-20 ng/mlSufficient>20 ng/mlP value
Patients 4(12.1%) 4(12.1%) 7(21.3%) 18(54.5%) 0.001
Control 0(0%) 0(0%) 1(2.4%) 41(97.6%)
Table 3. Vitamin D status in patients and control group

Vitamin D and selected characteristics of patients with wheezes

(Table-4), shows no significant relation observed between mean Vitamin D level and selected variables of studied infants and children with recurrent wheeze; as age, sex, feeding history, history of atopy (p value > 0.0

VariablesVitamin D Mean (SE)P-value
Age(months) 4m-12m 24.1(2.6) 0.198
> 12m-24m 19.5(5.2)
24m-60m 17.2(2.6)
Sex Male 20(2.1) 0.095
Female 22.4(3.5)
Frequency of wheezing attacks ≤ 3 times 24.5(3.4) 0.297
4-6 times 25.4(9.4)
> 6 times 18.6(2.5)
Feeding history in 1st 2 years Breast 17.3(2.8) 0.074
bottle 22.6(4.8)
Mixed 23.8(2.7)
Duration of breast feeding (months) < 4m 22.7(3.1) 0.934
4-12m 20.8(3.8)
> 12 16.2(5.9)
History of child a topy Positive 24.2(3.1) 0.321
Negative 19.3(2.5)
Positive family history of atopy Atopic dermatitis 24.5(3.8) 0.355
Allergic rhinitis 23.4(3.6)
Allergic conjunctivitis 19.3(3.6)
Asthma 22.2(2.5)
Table 4. Vitamin D in relation to selected characteristics of patients

Discussion

The effects of vitamin D deficiency in pediatrics have become increasingly apparent and extend beyond skeletal health. Vitamin D modifies airway inflammation and appears to be important in building immunity against respiratory infections, so is potentially beneficial in asthma. 14 The present study reveals that; the frequency and duration of breast feeding was reported less in wheezy child than control group, this is in consistent with Silvers et al 15 , and Sonnenschein-van et al 16 studies respectively. It is possible that the effect of breastfeeding on early wheeze reflects protection against respiratory infection, the predominant trigger of wheezing in early childhood. 17 , 18 Much attention has focused on the strong association between atopic tendency and childhood wheezing. 19 Current study shows no significant difference of atopic tendency in children with recurrent wheeze and control group; similar result was concluded by Linneberg, et al study in Denmark. 20 They found most risk factors had opposite direction of their effects on wheeze and atopic dermatitis. For example, breast-feeding was associated with a decreased risk of wheezing but an increased risk of atopy. Hence, these findings support the hypothesis that wheeze and atopic dermatitis have a different etiology. In contrast to a study carried out in Hong Kong by Wang SS etal 21 who concludes that vitamin D deficiency is associated with childhood atopic dermatitis. There was no significant difference regarding family history of atopic dermatitis and asthma among wheezy children and control group in contrast to a study carried out in Italy by Esposito, et al 22 , a family history of atopy was significantly frequent among children with wheeze than the controls as well as in UK study bySherriff et al 23 ; atopy and a family history of asthma emerged as the main predictors of wheeze that developed after 6 months of age. In this study there is significant family history of allergic rhinitis and conjunctivitis in wheezy children ,these finding is inconsistent with other study in Singapore done byTan TN et al 24 , also a study done by Bessa etal inBrazil, 25 demonstrated a statistically significant association between wheeze and family history of rhinitis. Vitamin D level is significantly lower in children with recurrent wheeze than control group as well as vitamin D status as severe deficiency, deficiency, and insufficiency significantly recorded in children with recurrent wheeze. This is in consistent to a study carried out by Dogru, etal 26 and in Sweden by Stenberg et al 27 who shows that preschool children admitted to hospital with acute wheeze had significantly lower levels of vitamin D than children with no wheeze in an age-matched control group. In the current study the mean serum calcium, phosphorus and alkaline phosphatase levels shows no statistically significant difference between patients and control group. These results are in accordance with Smith, et al 28 in England. Vitamin D stimulates protein synthesis, such as filaggrin, that is necessary for stratum corneum barrier formation. Therefore, vitamin D deficiency might exacerbate atopic dermatitis via disturbed epidermal barrier function and immunologic dysregulation, with subsequent impaired defense against infections. 29 In this study history of atopic dermatitis in wheezy children with low vitamin D is not significant. A study in Australiaby Allen, et al. 30 also did not find significant association between eczema and low serum 25(OH) D levels. While Lee et al, in Korea found an inverse correlation between serum concentration of vitamin D and severity of the disease in children with atopic dermatitis associated with food allergy. 31 We conclude that vitamin D supplementation may be considered in infants and children with recurrent wheeze.

References

  1. Bozzetto S, Carraro S, Giordano G, Boner A, Baraldi E. Asthma, allergy, and respiratory infections: the vitamin D hypothesis.Allergy. 2012 Jan;67(1):10-7
  2. Litonjua AA. Vitamin D and childhood asthma: causation and contribution to disease activity. Curr Opin Allergy Clin Immunol. 2019; 19(2):126-131. doi:10.1097/ACI.0000000000000509
  3. Staeva-Vieira TP, Freedman LP. 1, 25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 level during in vitro polarization of primary murine CD4+ T cells. Journal of immunology (Baltimore, Md.: 1950) 2002; 168: 1181–1189. [PubMed] [Google Scholar]
  4. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008; 4:80–90.
  5. White JH. Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. J Steroid Biochem Mol Biol 2010; 121:234–238.
  6. Krobtrakulchai W, Praikanahok J, Visitsunthorn N, Vichyanond P, Manonukul K, Pratumvinit B et al . The effect of vitamin d status on pediatric asthma at a university hospital, Thailand.Allergy Asthma Immunol Res. 2013 Sep; 5(5):289-94.                        
  7. Özaydın E, Bütün MF, Cakır BC, Köse G. The association between vitamin D status and recurrent wheezing. Indian J Pediatr.2013 Nov; 80(11):907-10. 
  8. Bozaykut A, Paketci A, Sezer RG, Paketci C. Evaluation of risk factors for recurrent wheezing episodes. J Clin Med Res. 2013 Oct;5(5):395-400
  9. Wootton A. Improving the Measurement of 25-hydroxyvitaminD.Clin Biochem Rev. Feb 2005; 26(1): 33–36.                                        
  10. Skversky AL, Kumar J, Abramowitz MK, Kaskel FJ, Melamed ML. Association of glucocorticoid use and low 25-hydroxyvitamin D levels: results from the National Health and Nutrition Examination Survey (NHANES): 2001-2006. J Clin Endocrinol Metab. 2011 Dec; 96(12):3838-45.      
  11. http://www.WHO.int/nutgrowthdb/about/introduction/en/index5.html.
  12. https://www.euroimmun.com/documents/Indications/Antigen-detection/Bone-metabolism/Vitamin-D/EQ_6411_D_UK_A.pdf
  13. Razazizan N. comparison of hydroxyl vitamin d, calcium, alkaline phosphatase in epileptic and non-epileptic children. Acta Neurologica Taiwanica 2013; 7:112-116.
  14. Bantz SK, Zhu Z, Zheng T. The Role of Vitamin D in Pediatric Asthma. Ann Pediatr Child Health. 2015; 3(1):1032.
  15. Silvers KM, Frampton CM, Wickens K, Pattemore PK, Ingham T, Fishwick D et al . Breastfeeding Protects against Current Asthma up to 6 Years of Age.See comment in PubMed Commons belowJ Pediatr. 2012 Jun;160(6):991
  16. Sonnenschein-van der Voort AM, Jaddoe VW, van der Valk RJ, Willemsen SP, Hofman A, Moll HA, de Jongste JC, Duijts L. Duration and exclusiveness of breastfeeding and childhood asthma-related symptoms.Eur Respir J. 2012 Jan; 39(1):81-9.
  17. Matheson MC, Allen KJ, Tang ML. Understanding the evidence for and against the role of breastfeeding in allergy prevention. Clin Exp Allergy. 2012 Jun; 42(6):827-51.
  18. Gerhart KD, Stern DA, Guerra S, et al. Protective effect of breastfeeding on recurrent cough in adulthood. Thorax 2018; 73:833-839.
  19. Holt PG. Key factors in the development of asthma: atopy.Am J Respir Crit Care Med. 2000 Mar; 161(3): 172-5.
  20. Linneberg A, Simonsen JB, Petersen J, Stensballe LG, Benn CS. Differential effects of risk factors on infant wheeze and atopic dermatitis emphasize a different etiology.See comment in PubMed Commons belowJ Allergy Clin Immunol. 2006 Jan; 117(1):184-9.
  21. Wang SS, Hon KL, Kong AP, Pong HN, Wong GW, Leung TF. Vitamin D deficiency is associated with diagnosis and severity of childhood atopic dermatitis. Pediatr Allergy Immunol. 2014; 25(1):30-35. doi:10.1111/pai.12167
  22. Esposito S, Ierardi V, Daleno C, Scala A, Terranova L, Tagliabue C et al. Genetic polymorphisms and risk of recurrent wheezing in pediatric age. BMC Pulm Med. 2014 Oct 18; 14:162.
  23. Sherriff A, Peters TJ, Henderson J, Strachan D,ALSPAC Study Team. Avon Longitudinal Study of Parents and Children. Risk factor associations with wheezing patterns in children followed longitudinally from birth to 3(1/2) years. Int J Epidemiol. 2001 Dec; 30(6):1473-84.
  24. Tan TN, Lim DL, Lee BW, Van Bever HP.Prevalence of allergy-related symptoms in Singaporean children in the second year of life. Pediatr Allergy Immunol. 2005 Mar; 16(2):151-6.
  25. Bessa OA, Leite ÁJ, Solé D, Mallol J. Prevalence and risk factors associated with wheezing in the first year of life. J Pediatr (Rio J). 2014 Mar-Apr; 90(2):190-6.
  26. Dogru M, Seren LP. Serum 25-hydroxyvitamin D levels in children with recurrent wheezing and relation to the phenotypes and frequency of wheezing. EurAnn Allergy Clin Immunol.2017; 49(6):257-262.doi:10.23822/EurAnnACI.1764-1489.14
  27. Stenberg Hammar K, Hedlin G, Konradsen JR, Nordlund B, Kull I, Giske CG et al. Subnormal levels of vitamin D are associated with acute wheeze in young children. Acta Paediatr. 2014 Aug; 103(8):856-61.
  28. Smith GR, Collinson PO, Kiely PD. Diagnosing hypovitaminosis D: serum measurements of calcium, phosphate, and alkaline phosphatase are unreliable, even in the presence of secondary hyperparathyroidism. J Rheumatol. 2005 Apr; 32(4):684-689.
  29. Weiland SK, Hüsing A, Strachan DP, Rzehak P, Pearce N. ISAAC Phase One Study Group. Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occup Environ Med. 2004 Jul; 61(7): 609–615.
  30. Allen KJ, Koplin JJ, Ponsonby AL, Gurrin LC, Wake M, Vuillermin Pet al. Vitamin D insufficiency is associated with challenge-proven food allergy in infants. J Allergy Clin Immunol 2013: 131: 1109–1116.
  31. Lee SA, Hong SN, Kim HJ, Lee SH, Yum HY. Correlation between serum vitamin D level and the severity of atopic dermatitis associated with food sensitization. Allergy Asthma Immunol Res. 2013; 5:207–210.
References
  1. Bozzetto S, Carraro S, Giordano G, Boner A, Baraldi E. Asthma, allergy, and respiratory infections: the vitamin D hypothesis.Allergy. 2012 Jan;67(1):10-7
  2. Litonjua AA. Vitamin D and childhood asthma: causation and contribution to disease activity. Curr Opin Allergy Clin Immunol. 2019; 19(2):126-131. doi:10.1097/ACI.0000000000000509
  3. Staeva-Vieira TP, Freedman LP. 1, 25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 level during in vitro polarization of primary murine CD4+ T cells. Journal of immunology (Baltimore, Md.: 1950) 2002; 168: 1181–1189. [PubMed] [Google Scholar]
  4. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008; 4:80–90.
  5. White JH. Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. J Steroid Biochem Mol Biol 2010; 121:234–238.
  6. Krobtrakulchai W, Praikanahok J, Visitsunthorn N, Vichyanond P, Manonukul K, Pratumvinit B et al . The effect of vitamin d status on pediatric asthma at a university hospital, Thailand.Allergy Asthma Immunol Res. 2013 Sep; 5(5):289-94.                        
  7. Özaydın E, Bütün MF, Cakır BC, Köse G. The association between vitamin D status and recurrent wheezing. Indian J Pediatr.2013 Nov; 80(11):907-10. 
  8. Bozaykut A, Paketci A, Sezer RG, Paketci C. Evaluation of risk factors for recurrent wheezing episodes. J Clin Med Res. 2013 Oct;5(5):395-400
  9. Wootton A. Improving the Measurement of 25-hydroxyvitaminD.Clin Biochem Rev. Feb 2005; 26(1): 33–36.                                        
  10. Skversky AL, Kumar J, Abramowitz MK, Kaskel FJ, Melamed ML. Association of glucocorticoid use and low 25-hydroxyvitamin D levels: results from the National Health and Nutrition Examination Survey (NHANES): 2001-2006. J Clin Endocrinol Metab. 2011 Dec; 96(12):3838-45.      
  11. http://www.WHO.int/nutgrowthdb/about/introduction/en/index5.html.
  12. https://www.euroimmun.com/documents/Indications/Antigen-detection/Bone-metabolism/Vitamin-D/EQ_6411_D_UK_A.pdf
  13. Razazizan N. comparison of hydroxyl vitamin d, calcium, alkaline phosphatase in epileptic and non-epileptic children. Acta Neurologica Taiwanica 2013; 7:112-116.
  14. Bantz SK, Zhu Z, Zheng T. The Role of Vitamin D in Pediatric Asthma. Ann Pediatr Child Health. 2015; 3(1):1032.
  15. Silvers KM, Frampton CM, Wickens K, Pattemore PK, Ingham T, Fishwick D et al . Breastfeeding Protects against Current Asthma up to 6 Years of Age.See comment in PubMed Commons belowJ Pediatr. 2012 Jun;160(6):991
  16. Sonnenschein-van der Voort AM, Jaddoe VW, van der Valk RJ, Willemsen SP, Hofman A, Moll HA, de Jongste JC, Duijts L. Duration and exclusiveness of breastfeeding and childhood asthma-related symptoms.Eur Respir J. 2012 Jan; 39(1):81-9.
  17. Matheson MC, Allen KJ, Tang ML. Understanding the evidence for and against the role of breastfeeding in allergy prevention. Clin Exp Allergy. 2012 Jun; 42(6):827-51.
  18. Gerhart KD, Stern DA, Guerra S, et al. Protective effect of breastfeeding on recurrent cough in adulthood. Thorax 2018; 73:833-839.
  19. Holt PG. Key factors in the development of asthma: atopy.Am J Respir Crit Care Med. 2000 Mar; 161(3): 172-5.
  20. Linneberg A, Simonsen JB, Petersen J, Stensballe LG, Benn CS. Differential effects of risk factors on infant wheeze and atopic dermatitis emphasize a different etiology.See comment in PubMed Commons belowJ Allergy Clin Immunol. 2006 Jan; 117(1):184-9.
  21. Wang SS, Hon KL, Kong AP, Pong HN, Wong GW, Leung TF. Vitamin D deficiency is associated with diagnosis and severity of childhood atopic dermatitis. Pediatr Allergy Immunol. 2014; 25(1):30-35. doi:10.1111/pai.12167
  22. Esposito S, Ierardi V, Daleno C, Scala A, Terranova L, Tagliabue C et al. Genetic polymorphisms and risk of recurrent wheezing in pediatric age. BMC Pulm Med. 2014 Oct 18; 14:162.
  23. Sherriff A, Peters TJ, Henderson J, Strachan D,ALSPAC Study Team. Avon Longitudinal Study of Parents and Children. Risk factor associations with wheezing patterns in children followed longitudinally from birth to 3(1/2) years. Int J Epidemiol. 2001 Dec; 30(6):1473-84.
  24. Tan TN, Lim DL, Lee BW, Van Bever HP.Prevalence of allergy-related symptoms in Singaporean children in the second year of life. Pediatr Allergy Immunol. 2005 Mar; 16(2):151-6.
  25. Bessa OA, Leite ÁJ, Solé D, Mallol J. Prevalence and risk factors associated with wheezing in the first year of life. J Pediatr (Rio J). 2014 Mar-Apr; 90(2):190-6.
  26. Dogru M, Seren LP. Serum 25-hydroxyvitamin D levels in children with recurrent wheezing and relation to the phenotypes and frequency of wheezing. EurAnn Allergy Clin Immunol.2017; 49(6):257-262.doi:10.23822/EurAnnACI.1764-1489.14
  27. Stenberg Hammar K, Hedlin G, Konradsen JR, Nordlund B, Kull I, Giske CG et al. Subnormal levels of vitamin D are associated with acute wheeze in young children. Acta Paediatr. 2014 Aug; 103(8):856-61.
  28. Smith GR, Collinson PO, Kiely PD. Diagnosing hypovitaminosis D: serum measurements of calcium, phosphate, and alkaline phosphatase are unreliable, even in the presence of secondary hyperparathyroidism. J Rheumatol. 2005 Apr; 32(4):684-689.
  29. Weiland SK, Hüsing A, Strachan DP, Rzehak P, Pearce N. ISAAC Phase One Study Group. Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occup Environ Med. 2004 Jul; 61(7): 609–615.
  30. Allen KJ, Koplin JJ, Ponsonby AL, Gurrin LC, Wake M, Vuillermin Pet al. Vitamin D insufficiency is associated with challenge-proven food allergy in infants. J Allergy Clin Immunol 2013: 131: 1109–1116.
  31. Lee SA, Hong SN, Kim HJ, Lee SH, Yum HY. Correlation between serum vitamin D level and the severity of atopic dermatitis associated with food sensitization. Allergy Asthma Immunol Res. 2013; 5:207–210.
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