Asthma’s Perfect Storm

Bacteria, vitamin D, stress, and inflammation

By Matthew Baral, ND

Printer Friendly PagePrinter Friendly Page

This paper is part of the September 2016 Pediatrics Special Issue. Read the entire issue or download it.

Integrative Pediatrics Special Issue


Asthma affects approximately 24 million Americans, and 6.3 million of those are under 18 years of age. The reliance on asthma medication as the only treatment for this widespread condition has had virtually no effect on asthma rates, which have continually increased since the 1980s. It is therefore imperative that the medical community at large start to commit to prevention as an equally important measure when considering asthma as a condition. A holistic perspective should take into account all the factors affecting asthma prevalence and expose the connections between them. 


Asthma is one of the most common chronic diseases in childhood, second only to dental caries.1 Like many chronic conditions seen in both children and adults, asthma may be preventable and treatable with lifestyle changes and environmental improvements. Historically, the predominant medical approach to asthma management has been through the use of medications such as corticosteroids, beta-agonists, leukotriene modifiers, anticholinergics, mast-cell stabilizers, methylxanthines, and anti-IgE monoclonal antibodies.2 These medications are unquestionably effective at curbing or eliminating the symptoms of asthma and saving lives. So effective, in fact, that little else has the same immediate treatment response. That consequently lessens the perceived need for preventive and nutritional maintenance measures. However, asthma medications are not without adverse effects. Associations between decreased bone mineral density and exposure to inhaled corticosteroids (ICS) have been reported.3-5 Most recently, ICS use for more than 6 months before 6 years of age proved to be a significant risk factor for decreased bone mineral density.6 Monoclonal antibody treatments, used in patients with severe and/or steroid-resistant asthma, have concerning adverse effects as well, including increased risk of cardiovascular and cerebrovascular events.7,8 Regardless, the FDA has approved 2 new monoclonal antibody treatments in the past year, one of which lists anaphylaxis and cancer as potential adverse effects.9,10 The leukotriene inhibitor montelukast has also been linked to neuropsychiatric events, including suicide and depression,11 although there may be contributing factors to this risk, which will be discussed later in this paper.
Ignoring the research on potential roots of inflammation and aggravation of symptoms in asthmatic patients may be detrimental to the efforts of the National Heart, Lung, and Blood Institute’s National Asthma Education and Prevention Program (NAEP). Remarkably, since its creation in 1991 there has not been a decline in emergency room visits, hospitalizations, or deaths in children with asthma.12,13 Despite the fact that asthma deaths overall have decreased,14 a trending increase in deaths due to asthma in children aged 0 to 4 years was seen from 1999 to 2009,14 implying that additional measures must be considered in the standards of asthma care. Additionally, asthma prevalence in children also trended upward in this same time period, plateauing after 2009 and followed by a modest decline in 2013 to 8.3%; however, the rate rose again to 8.6% in 2014.15,16
Parents are often told that their children will likely grow out of asthma, but according to a recent study by Andersson and colleagues, this may occur in only 21% of patients; women, severe asthmatics, and those with animal allergies have the lowest remission rates.17 Thus, since the majority of asthma patients do not have full resolution in their lifetime, more focus should be on preventive measures that are simple and noninvasive. Evidence shows that the most opportune times for preventive treatments are the prenatal and perinatal periods, through modification of diet and lifestyle factors. 

The Microbiome

The microbiome has received considerable attention in medical communities in recent years, reflected by a large volume of published research on the subject. The intestinal flora plays a substantial role in directing immune system development in infants, including but not limited to improved thymus development and antibody response to vaccination.18 The intestinal milieu is an integral factor in asthma development through several mechanisms, including mucosal immunity,19 production of immunoglobulins E (IgE) and A (IgA),20 and modulation of allergic reactions to antigens.21 Lactic acid–forming bacteria specifically induce production of interluekin-10 (IL-10),22 an anti-inflammatory mediator, illustrating their role in asthma prevention. Interestingly, this is also a mechanism of corticosteroid therapy for alleviating asthma symptoms.23,24
Disrupting the internal microbial environment of pregnant women often results in increased asthma risk in their offspring. A study of 39,907 mothers in China revealed that treatment of mothers with either penicillin or chloramphenicol during pregnancy was associated with childhood asthma in their children, especially if treatment occurred during the first trimester.25 Metsala in Sweden showed that prenatal cephalosporin exposure, as well as infant exposure during the first year to cephalosporins, sulfonamides, trimethoprim, macrolides, and amoxicillin, was associated with an increased risk of asthma.26 Postnatal antibiotic exposure in infants seems to have similar effects in other areas of atopy; in a Swedish birth cohort of 4,051 children, antibiotic intake in the first year of life increased allergic rhinitis risk, while living on a farm decreased the risk.27 These findings are consistent with the hygiene hypothesis. However, another recent study questioned whether some of the data supporting the hygiene hypothesis is due to reverse causation. The correlation of asthma and antibiotic use during fetal and early life was only shown when antibiotics were used for respiratory infections and not for urinary tract or skin infections.28 Frequent respiratory infections are a known risk factor for asthma development. An earlier large meta-analysis of 21 research articles showed that probiotic administration during fetal and early life did not decrease asthma risk but did decrease atopic sensitization risk and total IgE levels in children.29 It is important to note here that studies showing an insignificant influence of probiotics on the development of asthma or atopy may be due to the limitations of investigating single-strain effects; measuring total microbial diversity and quantity seems to be a more reliable technique for determining the influence of the microbiome on the development of atopy.30,31

Vitamin D: Prenatal and Postnatal

Like the microbiome, vitamin D has garnered consideration for its role in many conditions that have inflammation as a vital part of their pathophysiology. Vitamin D deficiency [defined as 25-hydroxyvitamin D (25-OH vitamin D) level <20 ng/mL] during pregnancy can have significant inverse effects on asthma development and lung function.32 A 2014 study by Zosky showed that prenatal deficiency of vitamin D was related to increased asthma incidence at 6 years of age in boys, while girls showed a decrease in forced expiratory volume (FEV). When data was collected again at 14 years, girls whose mothers were vitamin D–deficient in pregnancy had adversely impacted FEV1/FVC (forced vital capacity) ratios. This pattern reflects existing data on asthma rates by gender, which show that males younger than 18 years have a 16% higher asthma rate than females the same age.33 Interestingly, several studies show gender differences with respect to lung development and asthma. In animal models, males have a stronger immune response when exposed to allergens, with higher rates of both eosinophil and neutrophil production compared to females.34 In humans and animals, there are also gender disparities in lung surfactant production, occurring earlier in female neonates than male.35 Vitamin D is intricately involved with maturation of the surfactant system.36 These influences of prenatal deficiency on asthma and lung function may be strongest if the mother is deficient between 16 and 20 weeks gestation, a time period when the majority of lung cell differentiation occurs.37 Furthermore, concerns have been expressed over earlier findings that supplementation in late pregnancy may increase childhood asthma and eczema risk,38 but more recent research did not demonstrate any significant associations with development of any atopic conditions, including asthma.39
After birth, vitamin D supplementation in the infant can also play a critical role in asthma prevention and treatment. In the first in vivo study on vitamin D and its relationship to lung function and structural changes, Gupta et al discovered that children with moderate and steroid-resistant asthma were affected significantly by their vitamin D levels; asthma exacerbations and steroid use were inversely related to vitamin D serum concentrations.40 Airway smooth muscle mass was also increased with lower vitamin D levels, but only in the steroid-resistant asthmatics in that study. This increase in mass may be a result of chronic inflammation, a phenomenon also seen in those with chronic allergic rhinitis and subsequent turbinate hypertrophy. Gupta et al additionally reported a direct relationship between vitamin D levels and positive performance on the Asthma Control Test, a self-administered tool for identifying patients 4 to 11 years old with poorly controlled asthma.41 Reverse causation should also be considered; multiple studies show that vitamin D levels can be depressed as a result of systemic inflammation for up to 3 months afterwards.42-44
In 2008, the American Academy of Pediatrics (AAP) published guidelines for infant vitamin D intake at 400 IU daily,45 in order to maintain 25-OH vitamin D levels >20 ng/mL.46 However, the recommended daily intake for infants of 400 IU as stated in 2011 by the Institute of Medicine reveals that this would maintain a 25-OH vitamin D level of only 16 to 20 ng/mL.47 Considering that levels less than 20 ng/mL represent deficiency, and 20 to 32 ng/mL represents insufficiency,48-50 these recommendations will likely be inadequate for achieving necessary concentrations for many people. The AAP recommendations for breast-fed infants include continuation of supplementation unless an infant is additionally consuming at least 1 liter per day of vitamin D-fortified formula or 1 quart per day of fortified whole milk.47 Concerns expressed about vitamin D toxicity may be overestimated, as daily supplementation in infants up to 1,600 IU per day does not appear to result in hypercalcemia.51-54 The standard recommendation for vitamin D intake during pregnancy is 400 to 600 IU per day. However, in the first study that tested the current prenatal upper limit of 4,000 IU per day, this dose produced sufficient levels in both the mother and neonate without any adverse effects, while the standard recommendation of 400 to 600 IU per day did not.55 Therefore, this author proposes that vitamin D intake guidelines should be revisited, at least for pregnant and breast-feeding women as well as infants. 
Inverse relationships have been reported between vitamin D concentration and IgE levels, eosinophil count, hospitalizations for asthma, lung function, and use of asthma medications such as ICS and leukotriene inhibitors.56-58 Furthermore, Goleva et al found inverse relationships between vitamin D levels and both ICS use and IgE levels in asthma.59 Searing et al had similar findings and also discovered that vitamin D in vitro increased corticosteroid effectiveness, evidenced by enhanced IL-10 production by CD4+ T cells.60 Previously, Xystrakis et al found that CD4+ T cells of steroid-resistant asthmatics were unresponsive to dexamethasone by not producing IL-10, whereas cells from steroid-sensitive asthmatics did produce IL-10. Subsequently adding vitamin D to these steroid-resistant cells enhanced dexamethasone effectiveness by increasing IL-10 production to levels seen in steroid-sensitive cells.61 It has been postulated that corticosteroid upregulation of renal 25-hydroxyvitamin D(3)-24-hydroxylase activity, which degrades vitamin D metabolites, is the mechanism responsible for reduced vitamin D levels in patients taking ICS.62,63 Vitamin D supplementation also attenuated the severity of atopic dermatitis, often a precursor to asthma, by regulating the balance of type 1 and type 2 T helper (Th1 and Th2) cells,64 which is skewed in asthmatics as well.

Dietary Avoidance

The effect of maternal diet during breast-feeding on atopic development has been extensively studied, with conflicting results. A study of primarily atopic mothers found that maternal cow’s milk avoidance while breast-feeding may increase risk of cow’s milk allergy in the infant.65 Avoidance in study participants resulted in lower cow’s milk-specific IgA in their breast milk. Subsequently, those infants who did develop cow’s milk allergy had much lower casein-specific IgA compared to control infants, as well as lower beta-lactoglobulin–specific and casein-specific IgG4 levels. The researchers demonstrated that breast milk low in cow’s milk–specific IgA reduced the antigen trafficking in vitro. The presence of secretory IgA would otherwise decrease this trafficking and therefore reduce immune system exposure to those allergens at the mucosal barrier.66 Considering that most of the mothers and siblings of the infants in this study were atopic, more research is needed to determine whether these findings are applicable to the general population. Other research has confirmed that limiting the diet of a pregnant mother or breast-feeding mother as well as the infant may not decrease risk of atopy or food-related allergies such as wheat and egg.67,68

Emotions and Asthma 

The emotional link to asthma exists on several levels. Consistent feelings of shortness of breath or even the anticipation of an exacerbation can induce anxiety and depression, 2 commonly occurring comorbidities found in asthmatics as well as patients with chronic disease.69,70 To compound this scenario, chronic stress is a known precursor to decreased lung function as well as the fraction of exhaled nitric oxide, a marker for airway inflammation.71,72 As mentioned previously, asthma treatments such as montelukast may increase the risk for depression, but this may not be solely due to medication effects. Systemic inflammation can induce depression,73,74 and those with major depressive disorder show elevations in pro-inflammatory cytokines such as IL-6 and inflammatory marker C-reactive protein not due to another existing condition.75,76 Interluekin-6 and tumor necrosis factor (TNF)-alpha are commonly elevated in asthmatics and are also associated with symptoms of depression.77,78 This association may be explained through several factors; TNF-alpha can affect serotonin metabolism by activating indoleamine 2,3-dioxygenase, leading to a peripheral tryptophan depletion, therefore supplementation may be of benefit. IL-1, IL-6, and TNF-alpha, pro-inflammatory mediators abundant in asthmatics, can stimulate hypothalamic-pituitary-adrenal (HPA) axis activity, as does acute stress.79,80 Conversely, an overactive HPA axis may be due to reduced sensitivity to endogenous (cortisol) and exogenous corticosteroids and thus the negative feedback they provide. One of the consequences of this blunted immune-suppressive action is higher TNF-alpha production demonstrated in asthma patients.81,82 This decreased response to corticosteroids has been identified in depressed patients as well.83-85 

Oxidative Stress 

Increased oxidative stress plays a significant role and is a common finding in asthma.86 In fact, exhaled volatile organic compounds (VOCs), a marker of lipid peroxidation induced by reactive oxygen species, can help predict asthma exacerbations in children.87,88 During the inflammatory process, immune cells release reactive oxygen species that further increase the inflammatory response.89,90 In animal models exposed to allergens, S-adenosylmethionine treatment decreased airway inflammation through suppression of pro-inflammatory cytokines, likely by reducing oxidative stress through its participation in the methylation cycle.91 Relatedly, reduced eosinophil methylation activity was seen in asthma patients with high IgE levels, and to a lesser extent asthmatics without elevated IgE levels, when compared to controls.92 Another consideration is that reactive oxygen species can impair mitochondrial function, which can further reduce their ability to prevent oxidative stress, leading to airway inflammation, smooth muscle remodeling, and increased smooth muscle mass93 seen in both chronic obstructive pulmonary disease (COPD) and asthma.94,95 Other findings show that asthma symptoms were inversely related to serum selenium concentrations and directly associated with glutathione reductase activity in men.96 Guo et al additionally found that an antioxidant vitamin supplement can also attenuate oxidative stress and hence improve asthma control scores.97


The existing volume of research on many aspects of asthma pathogenesis exposes the obvious connections between them. The use of pharmaceutical medication as the only approach to treat asthma has revealed that it is simply not sustainable. Without considering the measures stated here, we can expect asthma rates to remain unchanged or, more likely, to increase. Nevertheless, it is clear that asthma medications are necessary for the safe treatment of patients with asthma. However, stressing the importance of diet, vitamin D supplementation, the microbiome, and emotions in all stages of life could diminish the tempest that is asthma and potentiate the change all physicians hope to see for this condition.

About the Author

Matthew Baral, ND, received his naturopathic medical degree from Bastyr University, Kenmore, Washington, in 2000. He is chair of the Department of Pediatric Medicine at the Southwest College of Naturopathic Medicine and Health Sciences (SCNM), Tempe, Arizona, where he teaches pediatrics in the classroom and supervises student clinicians on clinical rotations. Baral designed the first naturopathic pediatric residency program in naturopathic medicine and serves as its director at SCNM. He is also the founding and current president of the Pediatric Association of Naturopathic Physicians.


  1. American Academy of Pediatric Dentistry. Early Childhood Caries. American Academy of Pediatric Dentistry website. Accessed August 15, 2016.
  2. National Asthma Education and Prevention Program. Expert Panel Report (EPR-3): Guidelines for the Diagnosis and Management of Asthma Guidelines for the Diagnosis and Management of Asthma. J Allergy Clin Immunol. 2007;120(5 Suppl):S94-S138.
  3. Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green P, Strunk RC, CAMP Research Group. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood asthma management program (CAMP) study. Pediatrics. 2008;122:53-61.
  4. Allen HD, Thong IG, Clifton-Bligh P, Holmes S, Nery L, Wilson KB. Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma. Pediatr Pulmonol. 2000;29:188-193.
  5. Turpeinen M, Pelkonen AS, Nikander K, et al. Bone mineral density in children treated with daily or periodical inhaled budesonide: the Helsinki early intervention childhood asthma study. Pediatr Res. 2010;68:169-173.
  6. Sidoroff VH, Ylinen MK, Kröger LM, Kröger HP, Korppi MO. Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood wheezing. Pediatr Pulmonol. 2015;50(1):1-7.
  7. FDA Drug Safety Communication: FDA approves label changes for asthma drug Xolair (omalizumab), including describing slightly higher risk of heart and brain adverse events. Baltimore, MD: Johns Hopkins Office of Communications and Public Affairs; September 26, 2014. Accessed August 15, 2016.
  8. American Academy of Pediatrics. FDA warns of increased risks of asthma drug Xolair. AAP News. Published September 26, 2014. Accessed August 15, 2016.
  9. FDA approves Nucala to treat severe asthma [news release]. Baltimore, MD: Johns Hopkins Office of Communications and Public Affairs; November 4, 2015. Accessed August 15, 2016.
  10. FDA approves Cinqair to treat severe asthma [news release]. Baltimore, MD: Johns Hopkins Office of Communications and Public Affairs; March 23, 2016. Accessed August 15, 2006.
  11. Food and Drug Administration Office of Pediatric Therapeutics and Division of Pediatric and Maternal Health. Neuropsychiatric events linked to asthma medication. AAP News. 2015;36(4):18.
  12. Weinberger M. Seventeen years of asthma guidelines: why hasn't the outcome improved for children? J Pediatr. 2009;154(6):786-788. 
  13. Akinbami LJ. The State of Childhood Asthma, United States, 1980-2005. Hyattsville, MD: National Center for Health Statistics. Advance Data from Vital and Health Statistics. 2006;381. Available at Accessed August 16, 2016.
  14. American Lung Association Epidemiology and Statistics Unit, Research and Health Education Division. Trends in Asthma Morbidity and Mortality. Published September, 2012. Accessed August 15, 2016.
  15. Akinbami LJ, Simon AE, Rossen LM. Changing Trends in Asthma Prevalence Among Children. Pediatrics. 2016;137(1).
  16. Centers for Disease Control and Prevention. Most Recent Asthma Data. Updated March, 2016. Accessed August 15, 2016.
  17. Andersson M, Hedman L, Bjerg A, Forsberg B, Lundbäck B, Rönmark E. Remission and persistence of asthma followed from 7 to 19 years of age. Pediatrics. 2013;132:e435-e442.
  18. Huda MN, Lewis Z2, Kalanetra KM, et al. Stool microbiota and vaccine responses of infants. Pediatrics. 2014;134(2):e362-372. 
  19. Glück U, Gebbers JO. Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and beta-hemolytic streptococci). Am J Clin Nutr. 2003;77(2):517-520.
  20. Erickson KL, Hubbard NE. Probiotic immunomodulation in health and disease. J Nutr. 2000;130(2S Suppl):403S-409S.
  21. Matsuzaki T, Chin J. Modulating immune responses with probiotic bacteria. Immunol Cell Biol. 2000;78(1):67-73.
  22. Miettinen M, Vuopio-Varkila J, Varkila K. Production of human tumor necrosis factor alpha, interleukin-6, and interleukin-10 is induced by lactic acid bacteria. Infect Immun. 1996;64(12):5403-5405.
  23. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med. 2003;139(5 Pt 1):359-370.
  24. Umland SP, Schleimer RP, Johnston SL. Review of the molecular and cellular mechanisms of action of glucocorticoids for use in asthma. Pulm Pharmacol Ther. 2002;15(1):35-50.
  25. Chu S, Yu H, Chen Y, Chen Q, Wang B, Zhang J. Periconceptional and gestational exposure to antibiotics and childhood asthma. PLoS One. 2015;10(10):e0140443. 
  26. Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post-natal exposure to antibiotics and risk of asthma in childhood. Clin Exp Allergy. 2015;45(1):137-145. 
  27. Alm B, Goksör E, Pettersson R, et al. Antibiotics in the first week of life is a risk factor for allergic rhinitis at school age. Pediatr Allergy Immunol. 2014;25(5):468-472. 
  28. Örtqvist AK, Lundholm C, Kieler H, et al. Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis. BMJ. 2014;349:g6979. 
  29. Elazab N, Mendy A, Gasana J, Vieira ER, Quizon A, Forno E. Probiotic administration in early life, atopy, and asthma: a meta-analysis of clinical trials. Pediatrics. 2013;132(3):e666-e676. 
  30. Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy. 2014;44(6):842-850.
  31. Karvonen AM, Hyvärinen A, Rintala H, et al. Quantity and diversity of environmental microbial exposure and development of asthma: a birth cohort study. Allergy. 2014;69(8):1092-1101.
  32. Zosky GR, Berry LJ, Elliot JG, James AL, Gorman S, Hart PH. Vitamin D deficiency causes deficits in lung function and alters lung structure. Am J Respir Crit Care Med. 2011;183(10):1336-1343.
  33. American Lung Association. Trends in asthma morbidity and mortality, September 2012.
  34. Gorman S, Weeden CE, Tan DHW, et al. Reversible control by vitamin D of granulocytes and bacteria in the lungs of mice: an ovalbumin- induced model of allergic airway disease. PLoS One. 2013;8:e67823.
  35. Carey MA, Card JW, Voltz JW, et al. It’s all about sex: gender, lung development and lung disease. Trends Endocrinol Metab. 2007;18:308–313.
  36. Nguyen M, Trubert CL, Rizk-Rabin M, et al.1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase. J Steroid Biochem Mol Biol. 2004;89-90:93–97.
  37. Merkus PJ, ten Have-Opbroek AA, Quanjer PH. Human lung growth: a review. Pediatr Pulmonol. 1996;21(6):383-397.
  38. Gale CR, Robinson SM, Harvey NC, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr. 2008;62(1):68–77. 
  39. Pike KC, Inskip HM, Robinson S, et al. Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes. Thorax. 2012;67(11):950-956.
  40. Gupta A, Sjoukes A, Richards D, et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011;184(12):1342-1349. 
  41. Liu AH, Zeiger R, Sorkness C, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol. 2007;119(4):817-825. 
  42. Reid D, Toole BJ, Knox S, et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr. 2011;93:1006-1011.
  43. Louw JA, Werbeck A, Louw ME, et al. Blood vitamin concentrations during the acute-phase response. Crit Care Med. 1992;20:934-941.
  44. Waldron JL, Ashby HL, Cornes MP, et al. Vitamin D: a negative acute phase reactant. J Clin Pathol. 2013;66(7):620-622. 
  45. Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142-1152. 
  46. Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. High dose vitamin D3 supplementation in a cohort of breast- feeding mothers and their infants: a six-month follow-up pilot study. Breastfeed Med. 2006;1(2):59-70. 
  47. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Washington, DC: The National Academies Press; 2001. 
  48. Hathcock JN, Shao A, Vieth R, Heaney RP. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85(1):6-18.
  49. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
  50. Hollis BW, Wagner CL, Drezner MK, Binkley NC. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007;103(3-5):631-634.
  51. Grant CC, Stewart AW, Scragg R et al. Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatrics. 2014;133(1):e143-153.
  52. Gallo S, Comeau K, Vanstone C, et al. Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. JAMA. 2013;309(17):1785-1792.
  53. Holmlund-Suila E, Viljakainen H, Hytinantti T, Lamberg-Allardt C, Andersson S, Mäkitie O. High-dose vitamin D intervention in infants—effects on vitamin D status, calcium homeostasis, and bone strength. J Clin Endocrinol Metab. 2012;97(11):4139-4147. 
  54. Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW. Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol Metab. 2013;98(6):2337-2346.
  55. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-2357. 
  56. Wu AC, Tantisira K, Li L, Fuhlbrigge AL, Weiss ST, Litonjua A. Effect of vitamin D and inhaled corticosteroid treatment on lung function in children. Am J Respir Crit Care Med. 2012;186(6):508-513. 
  57. Brehm JM, Celedon JC, Soto-Quiros ME, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009;179:765-771. 
  58. Brehm JM, Schuemann B, Fuhlbrigge AL et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126:52-58.
  59. Goleva E, Searing DA, Jackson LP, Richers BN, Leung DY. Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma. J Allergy Clin Immunol. 2012;129(5):1243-1251. 
  60. Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol. 2010;125(5):995-1000. 
  61. Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116(1):146-155. 
  62. Dhawan P, Christakos S. Novel regulation of 25-hydroxyvitamin D3 24-hydroxylase (24(OH)ase) transcription by glucocorticoids: cooperative effects of the glucocorticoid receptor, C/EBP beta, and the Vitamin D receptor in 24(OH)ase transcription. J Cell Biochem. 2010;110(6):1314-1323.
  63. Akeno N, Matsunuma A, Maeda T, Kawane T, Horiuchi N. Regulation of vitamin D-1 alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney. J Endocrinol. 2000;164(3):339-348.
  64. Di Filippo P, Scaparrotta A, Rapino D, et al. Vitamin D supplementation modulates the immune system and improves atopic dermatitis in children. Int Arch Allergy Immunol. 2015;166(2):91-96. 
  65. Järvinen KM, Westfall JE, Seppo MS, et al. Role of maternal elimination diets and human milk IgA in development of cow’s milk allergy in the infants. Clin Exp Allergy. 2014;44(1): 69-78. 
  66. Renz H, Brandtzaeg P, Hornef M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol. 201;12(1):9-23. 
  67. Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: a randomized controlled trial. J Allergy Clin Immunol. 2013;132(2):387-392.
  68. Greer FR, Sicherer SH, Burks AW; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183-191.
  69. Ciprandi G, Schiavetti I, Rindone E, Ricciardolo FL. The impact of anxiety and depression on outpatients with asthma. Ann Allergy Asthma Immunol. 2015;115(5):408-414.
  70. Ferro MA. Major depressive disorder, suicidal behaviour, bipolar disorder, and generalised anxiety disorder among emerging adults with and without chronic health conditions. Epidemiol Psychiatr Sci. 2015;8:1-13. 
  71. Ritz T, Ayala ES, Trueba AF, Vance CD, Auchus RJ. Acute stress-induced increases in exhaled nitric oxide in asthma and their association with endogenous cortisol. Am J Respir Crit Care Med. 2011;183(1):26-30.
  72. Kullowatz A, Rosenfield D, Dahme B, Magnussen H, Kanniess F, Ritz T. Stress effects on lung function in asthma are mediated by changes in airway inflammation. Psychosom Med. 2008;70(4):468-475.
  73. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24-31. 
  74. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009;66(5):407-414.
  75. Zorrilla EP, Luborsky L, Mckay JR, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15(3):199-226.
  76. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol. 2002;90(12):1279-1283.
  77. Bluthé RM, Pawlowski M, Suarez S, et al. Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice. Psychoneuroendocrinology. 1994;19(2):197-207.
  78. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol. 2002;5(4):375-388.
  79. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21:55-89.
  80. Whelan R, Kim C, Chen M, Leiter J, Grunstein MM, Hakonarson H. Role and regulation of interleukin-1 molecules in pro-asthmatic sensitised airway smooth muscle. Eur Respir J. 2004;24(4):559-567.
  81. Rosenkranz MA, Busse WW, Johnstone T, et al. Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci USA. 2005;102(37):13319-13324.
  82. Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci USA. 2001;98(12):6865-6870. 
  83. Owens MJ, Nemeroff CB. The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies. Ciba Found Symp. 1993;172:296-308; discussion 308-316.
  84. Nemeroff CB. The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry. 1996;1(4):336-342.
  85. Gold PW, Goodwin FK, Chrousos GP. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (1). N Engl J Med. 1988;319(6):348-353.
  86. Reddy PH. Mitochondrial dysfunction and oxidative stress in asthma: implications for mitochondria- targeted antioxidant therapeutics. Pharmaceuticals. 2011;4:429-456.
  87. Robroeks CM, van Berkel JJ, Jöbsis Q, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013;42(1):98-106. 
  88. Van Berkel JJ, Dallinga JW, Moller GM, et al. Development of accurate classification method based on the analysis of volatile organic compounds from human exhaled air. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;861:101–107. 
  89. Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118:3546-3556.
  90. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. 2006;111:476-494.
  91. Yoon SY, Hong GH, Kwon HS, et al. S-adenosylmethionine reduces airway inflammation and fibrosis in a murine model of chronic severe asthma via suppression of oxidative stress. Exp Mol Med. 2016;48(6):e236. 
  92. Liang L, Willis-Owen SA, Laprise C, et al. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature. 2015;520(7549):670-674.
  93. Foong RE, Zosky GR. Vitamin D deficiency and the lung: disease initiator or disease modifier? Nutrients. 2013;5(8):2880-2900. 
  94. Wiegman CH, Michaeloudes C, Haji G, et al. Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2015;136(3):769-780.
  95. Trian T, Benard G, Begueret H, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med. 2007;204(13):3173-3181.
  96. Malling TH, Sigsgaard T, Andersen HR, et al. Differences in associations between markers of antioxidative defense and asthma are sex specific. Gend Med. 2010;7(2):115-124. 
  97. Guo CH, Liu PJ, Lin KP, Chen PC. Nutritional supplement therapy improves oxidative stress, immune response, pulmonary function, and quality of life in allergic asthma patients: an open-label pilot study. Altern Med Rev. 2012;17(1):42-56.