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Evidence for the Role of Inadequate Vitamin D in Asthma Severity Among Children
Abstract
Asthma is the most common chronic pediatric medical condition in the United States and accounts for significant morbidity, particularly among minority and disadvantaged populations. Hypovitaminosis D is also highly prevalent throughout the developed world, and many of the risk factors for hypovitaminosis D and asthma are the same. Several recent observational studies have documented a correlation between asthma severity and vitamin D levels; however, there is no strong evidence for causality yet. Until trials of vitamin D supplementation among children with asthma are performed, the role of low levels of vitamin D in causing asthma morbidity will remain unclear.
... In addition, vitamin D level is determined by sex, age, area of residence, skin pigmentation, obesity and dietary habits [3][4][5]. In some studies, it is stated that asthmatic children were allowed to spent less time outdoors and feed less with vitamin D enriched foods with the belief that seasonal weather changes and vitamin D enriched foods triggered asthma attacks [6][7][8]. ...
... It is reported that relatively less incidence of asthma exacerbation is observed in asthmatic children taking vitamin D supplements [16]. Various review articles have suggested a strong link between vitamin D levels and asthma severity, although the causality has not been proven [7,17,18]. The high prevalence of vitamin D insufficiency observed in dark-skinned people of certain races living in the Northern hemisphere may suggest a relationship between vitamin D level and asthma severity [6,11,12,14]. ...
Epidemiological studies show that vitamin D deficiency and insufficiency are common worldwide and associated with many diseases including asthma. Our aim was to evaluate vitamin D insufficiency and its clinical consequences.
This cross-sectional study was carried out on 170 children consisted of 85 who were asthmatic and 85 who were not, aged 2 to 14 years in Tekirdag, Turkey, from September 2009 to May 2010. Children's basal serum D vitamin levels were determined, and their eating habits, vitamin D intake, exposure to sunlight and use of health services during the previous year were investigated. The severity of asthma and levels of asthma control were assessed according to the Global Initiative for Asthma guidelines.
The difference between mean vitamin D levels in the asthmatic group (mean +/- SD) 16.6 +/- 8.5 ng/mL and the healthy control group (mean +/- SD) 28.2 +/- 19.5 ng/mL was found to be statistically significant (p < 0.001). Children in the asthma group had less exposure to sunlight and ate a diet less rich in vitamin D (p < 0.001). A significant difference was observed between the groups regarding the frequency of respiratory tract infections leading to emergency unit admissions and number of hospitalizations (p < 0.001). It was also shown that a decrease in vitamin D level increased the severity of asthma (p < 0.001) and decreased the frequency of controlled asthma (p = 0.010).
This study has demonstrated the correlation between plasma 25 (OH) D levels and childhood asthma. Evidently, this relationship being influenced by multiple factors other than vitamin D, further studies should be conducted to explore the interrelation between all such factors.
... Observational studies [5][6][7] and a randomized trial [8] have suggested that vitamin D could have a role in asthma management. ...
Background . We assessed vitamin D intakes and serum 25(OH) vitamin D levels in pediatric asthma patients on moderate-to-high dose inhaled steroids and compared them to published findings of healthy children in our city. Methods . Parents and/or patients were interviewed to estimate the children’s vitamin D intakes from foods and supplements (using an adapted validated food frequency questionnaire) and asthma duration and management. Vitamin D status: serum 25-hyroxy vitamin D (25(OH)D) was obtained from the medical records. Results . Vitamin D intakes from food and supplements of the asthma patients ( n=20 , 742 ± 185 IU/day) were significantly higher compared to healthy Canadian children ( n=1442 , 229 ± 121 IU/day). Despite higher vitamin D intakes, the children had nonsignificantly lower serum 25(OH) vitamin D levels compared to the comparison group. Serum 25(OH)D levels increased by 3.6 nmol/L with each 100 IU of vitamin D intake (95% Confidence interval = 2.0–4.0, R2 = 0.931, and p=0.001 ). Conclusion . Since adequate vitamin D status in asthma patients is necessary to support bone mineral accretion, it is important to achieve adequate vitamin D status by checking serum 25(OH)D status and supplement accordingly.
... Plusieurs études très récemment publiées suggèrent un impact de l'insuffisance en vitamine D sur la sévérité et le niveau de contrôle de l'asthme aussi bien chez l'enfant que chez l'adulte [6,7]. ...
... Клинические работы почти однозначно свидетельствуют, что VD является фактором, защищающим от астмы. Показано, что уровни VD в сыворотке крови обратно коррелируют с заболеваемостью БА как у младенцев и детей [20,51,58,78,79,92,131,144,156,307], так и у взрослых [197], положительно коррелируют с показателем ОФВ-1, сниженным при БА [20,197], отрицательно коррелируют с процентом эозинофилов и общим содержанием IgE в крови детей с бронхиальной астмой [20,41,204], хотя в одной работе зависимость между уровнями VD с одной стороны и уровнями IgD и IgE с другой была охарактеризована как нелинейная [162]. ...
Besides the well-known effects upon bone metabolism, vitamin D (VD) plays important roles in many other processes in the body, including immune regulation. VD action is carried out through its cellular membrane receptor, which is expressed in a variety of human organs and tissues, e.g., most cells of immune system, as well as epithelial cells lining the mucous membranes. The cell-membrane bound VD receptor is transferred to the cytoplasm, to form a functional complex with vitamin A and its receptor. This complex provides either inhibiting, or enhancing effect upon transcription of hundreds genes in the nuclear DNA, including those that regulate cell growth, differentiation, apoptosis, thus preventing malignancy and angiogenesis. The following effects of VD are supposed with respect to immune system: VD inhibits antigen presentation by dendritic cells, supresses Th1-cell differentiation and the production of Th1-cytokines, shifts the balance of Th1/Th2 cell responses towards the Th2 response, exerts inhibitory effect upon Th17 cells, promotes Treg cell development, and increases their activity. In addition, VD boosts production of «endogenous antibiotics» that may provide powerful effects upon Gram-positive and Gram-negative bacteria, fungi and viruses. Therefore, VD seems quite important for prevention of autoimmune and atopic diseases: multiple sclerosis, rheumatoid arthritis, type 1 diabetes, Crohn’s disease, ulcerative colitis, development of asthma in children and chronic obstructive pulmonary disease. VD protects from a wide range of infections, including tuberculosis, leprosy and respiratory infections, and prevents the development of several tumors. Almost half the population of different countries has a VD hypovitaminosis, often hidden and undiagnosed, and this can be a leading cause of weakened immunity and increased morbidity. The diagnostics of VD hypovitaminosis, prevention and treatment of hypovitaminosis should be among the most important healthcare tasks in Russia.
... Unlike the rather controversial experimental and genetic data, the related clinical works show almost unequivocally that VD is a protective factor against asthma. A big cluster of clinical studies has shown that serum VD level are inversely correlated with the incidence of asthma or wheezing, at least in infants and children [181,188,[205][206][207][208][209][210][211][212]. Similar observations were made in adults [213]. ...
This paper reviews the recent data on the role of vitamin D (VD) in the genesis of various immunological disorders. It inhibits immune reactions in general, but it enhances the transcription of 'endogenous antibiotics' such as cathelicidin and defensins. VD inhibits the genesis of both Th1- and Th2-cell mediated diseases. The pleiotropic character VD-induced effects are due to the altered transcription of hundreds of genes. VD supplementation in most related studies reduced the prevalence of asthma. Th1-dependent autoimmune diseases (e.g., multiple sclerosis, Type 1 diabetes, Crohn's disease, rheumatoid arthritis and so on) are also inhibited by VD due to inhibition of antigen presentation, reduced polarization of Th0 cells to Th1 cells and reduced production of cytokines from the latter cells. VD seems to also be a useful adjunct in the prevention of allograft rejection. Last but not least, VD supplementation may be useful in the prevention or adjunct treatment of chronic obstructive pulmonary disease.
The relationship between serum vitamin D levels and atopy is an up to date topic. Most studies, particularly transversal and observational studies, demonstrate that there is a relationship between vitamin D deficiency and symptoms of atopy (rhinitis, asthma, atopic dermatitis, food allergies). Vitamin D deficiency is more frequently observed in atopic children than in controls in the general population. Vitamin D could play a major role in the genesis of allergies because of its multiple extra- osseous effects, particularly on natural and acquired immunity. Variations in exposure to UV- B radiation leading to differences in vitamin D synthesis could explain the North- South gradient described in epidemiological studies for most symptoms of atopy. The same theory could explain the significant excess in food allergies observed in children born during the cold season in both hemispheres. In some studies, prescription of vitamin D to patients with deficiencies improved their symptoms, i.e. better control of asthma, improvement in atopic dermatitis scores. The demonstration that the vitamin D status of pregnant women has an effect on the later development of allergic or infectious diseases (bronchiolitis, tuberculosis) in their children further accentuated the importance of the relationship between vitamin D, atopy and immunity. Large, prospective studies are currently underway to define the precise nature of this relationship and its practical clinical impact.
The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.
To establish the relationship between vitamin D serum levels, pulmonary function, and asthma control in children.
We studied the relationship between 25-hydroxy cholecalciferol [25(OH)D] concentrations and baseline spirometry and levels of asthma control, assessed according to Global Initiative for Asthma guidelines and the Childhood Asthma Control Test, in 75 children with asthma (age range 5-11 years; 43 males) in a cross-sectional study carried out during the winter and early spring.
Only 9.4% of our children had a sufficient serum 25(OH)D (at least 30 to 40 ng/mL). A significant positive correlation was found between forced vital capacity percent predicted and serum 25(OH)D (r = 0.25, P = .040). This was true also for forced expiratory volume in 1 second, even though it was not statistically significant (r = 0.16, P = .157). Subjects with well-controlled asthma had higher serum levels of 25(OH)D than children with partially controlled or non-controlled asthma, with values of (median [Q1; Q3]) 22.2 (16.3; 25.4), 17.8 (11.8; 22.1) and 18.1 (15.0; 18.5), respectively (P = .023). Furthermore, a positive correlation was found between 25(OH)D and the Childhood Asthma Control Test (r = 0.28; P = .011).
Our results indicate that hypovitaminosis D is frequent in children with asthma living in a Mediterranean country. In those children, lower levels of vitamin D are associated with reduced asthma control.
The goal of this study was to examine the prevalence of vitamin D insufficiency and deficiency among urban African-American (AA) youth with asthma compared with control subjects without asthma.
A cross-sectional case-control study was conducted at an urban pediatric medical center. Total 25-hydroxyvitamin D insufficiency (<30 ng/mL) and deficiency (<20 ng/mL) were assessed in urban self-reported AA patients, aged 6 to 20 years, with (n = 92) and without (n = 21) physician-diagnosed asthma.
Blood samples were available for 85 (92%) cases. The prevalence of vitamin D insufficiency and deficiency were significantly greater among cases than control subjects (73/85 [86%] vs 4/21 [19%], adjusted odds ratio = 42 [95% confidence interval: 4.4 to 399] for insufficiency and 46/85 [54%] vs 1/21 [5%], adjusted odds ratio = 20 [95% confidence interval: 1.4 to 272] for deficiency).
Most of this sample of urban AA youth with persistent asthma were vitamin D deficient or insufficient. Given the emerging associations between low vitamin D levels and asthma, strong consideration should be given to routine vitamin D testing in urban AA youth, particularly those with asthma.
To our knowledge, no rigorously designed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza.
We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren.
From December 2008 through March 2009, we conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D(3) supplements (1200 IU/d) with placebo in schoolchildren. The primary outcome was the incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen.
Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D(3) group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3) compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006).
This study suggests that vitamin D(3) supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren. This trial was registered at https://center.umin.ac.jp as UMIN000001373.
The effects of vitamin D on bone metabolism and calcium homeostasis have long been recognized. Emerging evidence has implicated vitamin D as a critical regulator of immunity, playing a role in both the innate and cell-mediated immune systems. Vitamin D deficiency has been found to be associated with several immune-mediated diseases, susceptibility to infection and cancer. Recently, there has been increasing interest in the possible link between vitamin D and asthma. Further elucidation of the role of vitamin D in lung development and immune system function may hold profound implications for the prevention and treatment of asthma.
To determine the prevalence of 25-hydroxyvitamin D (25[OH]D) deficiency and associations between 25(OH)D deficiency and cardiovascular risk factors in children and adolescents.
With a nationally representative sample of children aged 1 to 21 years in the National Health and Nutrition Examination Survey 2001-2004 (n = 6275), we measured serum 25(OH)D deficiency and insufficiency (25[OH]D <15 ng/mL and 15-29 ng/mL, respectively) and cardiovascular risk factors.
Overall, 9% of the pediatric population, representing 7.6 million US children and adolescents, were 25(OH)D deficient and 61%, representing 50.8 million US children and adolescents, were 25(OH)D insufficient. Only 4% had taken 400 IU of vitamin D per day for the past 30 days. After multivariable adjustment, those who were older (odds ratio [OR]: 1.16 [95% confidence interval (CI): 1.12 to 1.20] per year of age), girls (OR: 1.9 [1.6 to 2.4]), non-Hispanic black (OR: 21.9 [13.4 to 35.7]) or Mexican-American (OR: 3.5 [1.9 to 6.4]) compared with non-Hispanic white, obese (OR: 1.9 [1.5 to 2.5]), and those who drank milk less than once a week (OR: 2.9 [2.1 to 3.9]) or used >4 hours of television, video, or computers per day (OR: 1.6 [1.1 to 2.3]) were more likely to be 25(OH)D deficient. Those who used vitamin D supplementation were less likely (OR: 0.4 [0.2 to 0.8]) to be 25(OH)D deficient. Also, after multivariable adjustment, 25(OH)D deficiency was associated with elevated parathyroid hormone levels (OR: 3.6; [1.8 to 7.1]), higher systolic blood pressure (OR: 2.24 mmHg [0.98 to 3.50 mmHg]), and lower serum calcium (OR: -0.10 mg/dL [-0.15 to -0.04 mg/dL]) and high-density lipoprotein cholesterol (OR: -3.03 mg/dL [-5.02 to -1.04]) levels compared with those with 25(OH)D levels > or =30 ng/mL.
25(OH)D deficiency is common in the general US pediatric population and is associated with adverse cardiovascular risks.
Recent studies suggest a role for vitamin D in innate immunity, including the prevention of respiratory tract infections (RTIs). We hypothesize that serum 25-hydroxyvitamin D (25[OH]D) levels are inversely associated with self-reported recent upper RTI (URTI).
We performed a secondary analysis of the Third National Health and Nutrition Examination Survey, a probability survey of the US population conducted between 1988 and 1994. We examined the association between 25(OH)D level and recent URTI in 18 883 participants 12 years and older. The analysis adjusted for demographics and clinical factors (season, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease).
The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles per liter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidence interval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI was reported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% with levels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more (P < .001). Even after adjusting for demographic and clinical characteristics, lower 25(OH)D levels were independently associated with recent URTI (compared with 25[OH]D levels of > or =30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for <10 ng/mL and 1.24; 1.07-1.43 for 10 to <30 ng/mL). The association between 25(OH)D level and URTI seemed to be stronger in individuals with asthma and chronic obstructive pulmonary disease (OR, 5.67 and 2.26, respectively).
Serum 25(OH)D levels are inversely associated with recent URTI. This association may be stronger in those with respiratory tract diseases. Randomized controlled trials are warranted to explore the effects of vitamin D supplementation on RTI.
Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.
To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood. Methods: We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses.
Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log(10) unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004-0.71; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.18; 95% CI, 0.05-0.67; P = 0.01), and increased airway responsiveness (a < or =8.58-mumol provocative dose of methacholine producing a 20% fall in baseline FEV(1) [OR, 0.15; 95% CI, 0.024-0.97; P = 0.05]).
Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.
To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community.
Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses.
108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire.
Southampton and surrounding community.
Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions.
Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 l/min. The most commonly identified virus type was rhinovirus.
This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.
Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome
7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing
two genes. One of these coded for an orphan G protein–coupled receptor named GPRA (G protein–coupled receptor for asthma susceptibility),
which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals.
In three cohorts from Finland and Canada, single nucleotide polymorphism–tagged haplotypes associated with high serum immunoglobulin
E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these
data implicate GPRA in the pathogenesis of atopy and asthma.
Although research has shown that early life exposure to household endotoxin protects against development of allergies, studies are less clear on the relationship between household endotoxin exposure and prevalence of wheezing and asthma. We assayed 2,552 house dust samples in a representative nationwide sam- ple to explore relationships between endotoxin exposures and risk factors for asthma, asthma symptoms, and medication use.
House dust was vacuum-sampled from five locations within homes and assayed for endotoxin. Health, demographic, and housing information was assessed through questionnaire and on-site evaluation of 2,456 residents of 831 homes selected to represent the demographics of the United States.
Endotoxin concentration (EU/mg) and load (EU/m(2)) were highly correlated (r = 0.73-0.79). Geometric mean endotoxin concentrations were as follows (in EU/mg): bedroom floors, 35.3 (5th-95th percentile, 5.0-260); bedding, 18.7 (2.0-142); family room floors, 63.9 (11.5-331); sofas, 44.8 (6.4-240); and kitchen floors, 80.5 (9.8-512). Multivariate analysis demonstrated significant relationships between increasing endotoxin levels and diagnosed asthma, asthma symptoms in the past year, current use of asthma medications, and wheezing among residents of the homes. These relationships were strongest for bedroom floor and bedding dust and were observed in adults only. Modeling the joint effect of bedding and bedroom floor endotoxin on recent asthma symptoms yielded an adjusted odds ratio of 2.83 (95% confidence interval, 1.01-7.87). When stratified by allergy status, allergic subjects with higher endotoxin exposure were no more likely to have diagnosed asthma or asthma symptoms than nonallergic subjects.
This study demonstrates that household endotoxin exposure is a significant risk factor for increased asthma prevalence.
The authors investigated the relation between ambient concentrations of five of the Environmental Protection Agency's criteria pollutants and asthma exacerbations (daily symptoms and use of rescue inhalers) among 990 children in eight North American cities during the 22-month prerandomization phase (November 1993-September 1995) of the Childhood Asthma Management Program. Short-term effects of carbon monoxide, nitrogen dioxide, particulate matter less than 10 mum in aerodynamic diameter (PM10), sulfur dioxide, and warm-season ozone were examined in both one-pollutant and two-pollutant models, using lags of up to 2 days. Lags in carbon monoxide and nitrogen dioxide were positively associated with both measures of asthma exacerbation, and the 3-day moving sum of sulfur dioxide levels was marginally related to asthma symptoms. PM10 and ozone were unrelated to exacerbations. The strongest effects tended to be seen with 2-day lags, where a 1-parts-per-million change in carbon monoxide and a 20-parts-per-billion change in nitrogen dioxide were associated with symptom odds ratios of 1.08 (95% confidence interval (CI): 1.02, 1.15) and 1.09 (95% CI: 1.03, 1.15), respectively, and with rate ratios for rescue inhaler use of 1.06 (95% CI: 1.01, 1.10) and 1.05 (95% CI: 1.01, 1.09), respectively. The authors believe that the observed carbon monoxide and nitrogen dioxide associations can probably be attributed to mobile-source emissions, though more research is required.
Although involuntary exposure to maternal smoking during the in utero period and to secondhand smoke are associated with occurrence of childhood asthma, few studies have investigated the role of active cigarette smoking on asthma onset during adolescence.
To determine whether regular smoking is associated with the new onset of asthma during adolescence.
We conducted a prospective cohort study among 2,609 children with no lifetime history of asthma or wheezing who were recruited from fourth- and seventh-grade classrooms and followed annually in schools in 12 southern California communities. Regular smoking was defined as smoking at least seven cigarettes per day on average over the week before and 300 cigarettes in the year before each annual interview. Incident asthma was defined using new cases of physician-diagnosed asthma.
Regular smoking was associated with increased risk of new-onset asthma. Children who reported smoking 300 or more cigarettes per year had a relative risk (RR) of 3.9 (95% confidence interval [95% CI], 1.7-8.5) for new-onset asthma compared with nonsmokers. The increased risk from regular smoking was greater in nonallergic than in allergic children. Regular smokers who were exposed to maternal smoking during gestation had the largest risk from active smoking (RR, 8.8; 95% CI, 3.2-24.0).
Regular smoking increased risk for asthma among adolescents, especially for nonallergic adolescents and those exposed to maternal smoking during the in utero period.
Role of vitamin D deficiency in allergic and autoimmune diseases
Asthma is occurring in epidemic proportions with more than 300 million affected subjects worldwide. In almost all cases the disease has its onset in early childhood, with 80–90% of all cases initially being diagnosed before the age of 6 years.1,2
It was not always so. In the early 1970s the prevalences of asthma and allergy were roughly half of what they are today, and although the onset of the asthma epidemic started insidiously and cannot be precisely documented, it has several interesting and important features that have defied a unified explanation until now. There is clearly a North/South equatorial gradient with Western industrialised countries furthest away from the equator (New Zealand, Australia, the UK) having the highest prevalence worldwide. There is also a clear urban/rural gradient among poorer Third World countries, and a First (industrialised) World/Third World gradient with the lowest asthma prevalence occurring in rural areas in Third World societies. A very important feature of the epidemic is that it is not only asthma that has increased. A host of other autoimmune diseases—such as multiple sclerosis, type 1 diabetes and Crohn’s disease—have all increased dramatically as well.3 So it is not just Th2 diseases like asthma, allergic rhinitis, eczema and food allergy that have increased, but also Th1 autoimmune diseases. Less directly connected to the epidemic is the seasonal gradient in incidence with a peak in the late winter/early spring. Finally, in the USA the asthma epidemic seems worse among the urban poor, particularly among minorities (African-Americans and Puerto Ricans).
One of the theories to explain these disparate epidemiological findings is the hygiene hypothesis, which posits that the decrease in early childhood infections leads to “missing immune deviation” …
To review the current literature on vitamin D and asthma, discussing the possible roles of vitamin D on asthma pathogenesis and the potential consequences of vitamin D deficiency.
PubMed database was searched from 1950 to 2009. Keywords used included asthma, vitamin D, inflammation, airway smooth muscle and cytokines.
Articles were selected based on relevance to the subject.
Vitamin D deficiency has been associated with epidemiologic patterns observed in the asthma epidemic. Vitamin D deficiency is more common with obesity, African American ethnicity, and westernization of countries with higher-risk populations for asthma. Evidence suggests that vitamin D deficiency is associated with increased airway hyperresponsiveness, lower pulmonary functions, worse asthma control, and possibly steroid resistance. Lung epithelial cells express high baseline levels of 1alpha-hydroxylase. This allows the conversion of inactive calcidiol to active calcitriol locally within the lung. Calcitriol has been shown to inhibit the synthesis and release of certain cytokines, such as RANTES, platelet-derived growth factor, and matrix metalloproteinases, from bronchial smooth muscle cells, thereby leading to decreased lung inflammation and smooth muscle cell proliferation. Vitamin D also increases synthesis of interleukin 10 by CD4+CD25+Foxp3+ T-regulatory cells and dendritic cells, while concurrently inhibiting dendritic cell activation by downregulating expression of costimulatory molecules CD40 and CD80/86. Vitamin D is also capable of inducing the expression of several anti-infective molecules, such as cathelicidin. Thus, vitamin D has a number of biologic effects that are likely important in regulating key mechanisms in asthma.
We hypothesize that vitamin D supplementation may lead to improved asthma control by inhibiting the influx of inflammatory cytokines in the lung and increasing the secretion of interleukin 10 by T-regulatory cells and dendritic cells.
Asthma exacerbations, most often caused by respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status might play a role in preventing asthma exacerbations.
We sought to assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations.
We measured 25-hydroxyvitamin D levels in sera collected from 1024 children with mild-to-moderate persistent asthma at the time of enrollment in a multicenter clinical trial of children randomized to receive budesonide, nedocromil, or placebo (as-needed beta-agonists): the Childhood Asthma Management Program. Using multivariable modeling, we examined the relationship between baseline vitamin D levels and the odds of any hospitalization or emergency department visit over the 4 years of the trial.
Thirty-five percent of all subjects were vitamin D insufficient, as defined by a level of 30 ng/mL or less 25-hydroxyvitamin D. Mean vitamin D levels were lowest in African American subjects and highest in white subjects. After adjusting for age, sex, body mass index, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or emergency department visit (odds ratio, 1.5; 95% CI, 1.1-1.9; P = .01).
Vitamin D insufficiency is common in this population of North American children with mild-to-moderate persistent asthma and is associated with higher odds of severe exacerbation over a 4-year period.
There is little knowledge about clinical variables associated with vitamin D (VitD) insufficiency in asthmatic children.
We sought to investigate disease variables associated with VitD insufficiency in patients with childhood asthma and interaction of VitD with corticosteroid-mediated anti-inflammatory responses.
We analyzed 25-hydroxyvitamin D serum levels in 100 asthmatic children to investigate relationships between 25-hydroxyvitamin D levels and patients' characteristics. We determined VitD's effects on dexamethasone (DEX) induction of mitogen-activated protein kinase phosphatase 1 and IL-10 in PBMCs.
The median 25-hydroxyvitamin D serum level was 31 ng/mL. Forty-seven percent of subjects had VitD levels in the insufficient range (<30 ng/mL), whereas 17% were VitD deficient (<20 ng/mL). Log(10) IgE (P = .01, rho = -0.25) and the number of positive aeroallergen skin prick test responses (P = .02, rho = -0.23) showed a significant inverse correlation with VitD levels, whereas FEV(1) percent predicted (P = .004, rho = 0.34) and FEV(1)/forced vital capacity ratio (P = .01, rho = 0.30) showed a significant positive correlation with VitD levels. The use of inhaled steroids (P = .0475), use of oral steroids (P = .02), and total steroid dose (P = .001) all showed significant inverse correlations with VitD levels. The amount of mitogen-activated protein kinase phosphatase 1 and IL10 mRNA induced by VitD plus DEX was significantly greater than that induced by DEX alone (P < .01). In an experimental model of steroid resistance in which DEX alone did not inhibit T-cell proliferation, addition of VitD to DEX resulted in significant dose-dependent suppression of cell proliferation.
Corticosteroid use and worsening airflow limitation are associated with lower VitD serum levels in asthmatic patients. VitD enhances glucocorticoid action in PBMCs from asthmatic patients and enhances the immunosuppressive function of DEX in vitro.
Single-center studies suggest [corrected] that hypovitaminosis D is widespread. Our objective was to determine the serum levels of 25-hydroxyvitamin D (25[OH]D) in a nationally representative sample of U.S. [corrected] children ages 1-11 [corrected] years.
Data were obtained from the 2001-2006 National Health and Nutrition Examination Survey (NHANES). [corrected] Serum 25(OH)D levels was [corrected] determined by radioimmunoassay and categorized as <25 nmol/L, [corrected] <50 nmol/L, [corrected] and <75 nmol/L. National estimates were obtained by using assigned patient visit weights and reported with 95% confidence intervals (95% CI). [corrected]
During [corrected] 2001-2006, the mean serum 25(OH)D level for U.S. children ages 1 to 11 years was 68 nmol/L (95% CI, [corrected] 66-70). Children ages 6-11 [corrected] years had lower mean levels of 25(OH)D (66 nmol/L 95% CI, [corrected] 64-68) compared to [corrected] children ages 1-5 [corrected] years (70 nmol/L 95% [corrected] CI, 68-73). [corrected] Overall, the prevalence of <25 nmol/L [corrected] was 1% (95% CI, 0.7-1.4), <50 nmol/L was 18% (95% CI, [corrected] 16-21), and <75 nmol/L was 69% (95% CI, [corrected] 65-73). The prevalence of [corrected] 25(OH)D [corrected] <75 nmol/L was higher among ages [corrected] 6-11 [corrected] years (73%) compared to ages [corrected] 1-5 [corrected] years (63%); females [corrected] (71%) compared to males [corrected] (67%); and non-Hispanic black (92%) and Hispanic (80%) [corrected] compared to [corrected] non-Hispanic whites [corrected] (59%).
Based on [corrected] a nationally representative sample of U.S. children aged 1-11 [corrected] years, millions of children may have suboptimal levels of 25(OH)D, especially non-Hispanic black and Hispanic children. More data in children are needed not only to understand better the health implications of specific serum levels of 25(OH)D but also to determine the appropriate vitamin D supplement requirements for children.
Virus-induced wheezing in infancy is a risk factor for asthma, and recent studies have highlighted the role of rhinoviruses in causing acute illnesses and as a possible contributing factor to chronic asthma.
Human rhinoviruses (HRVs) have long been known as the most common cause of common cold in infants and children. Recent developments in molecular diagnostics have led to the discovery of new viruses and have also provided data to implicate HRV as an important cause of lower respiratory infections and acute virus-induced wheezing in preschool children. In addition, HRV-induced wheezing episodes appear to identify children who are at increased risk for the subsequent development of childhood asthma.
Collectively, these findings raise the possibility that lower respiratory infections with pathogens such as HRV and respiratory syncytial virus could participate in the causation of asthma, especially in children with suboptimal antiviral defenses. A variety of experimental models and clinical studies have been used to identify possible mechanisms related to the infection and the ensuing host response that could disturb normal lung and immunologic development to promote asthma. Defining these relationships could lead to new therapeutic and preventive approaches to common forms of childhood asthma.
Vitamin D deficiency has been rediscovered as a public-health problem worldwide. It has been postulated that vitamin D deficiency may explain a portion of the asthma epidemic. The purpose of this review is to present the evidence for a role of vitamin D in asthma.
Both animal models and studies in human fetal tissues show that vitamin D plays a role in fetal lung growth and maturation. Epidemiologic studies have also suggested that higher prenatal vitamin D intakes have a protective role against wheezing illnesses in young children. Vitamin D may protect against wheezing illnesses through its role in upregulating antimicrobial proteins or through its multiple immune effects. In addition, vitamin D may play a therapeutic role in steroid resistant asthmatics, and lower vitamin D levels have recently been associated with higher risks for asthma exacerbations.
Improving vitamin D status holds promise in primary prevention of asthma, in decreasing exacerbations of disease, and in treating steroid resistance. However, the appropriate level of circulating vitamin D for optimal immune functioning remains unclear. Because vitamin D deficiency is prevalent even in sun-replete areas, clinical trials are needed to definitively answer questions about the role of vitamin D in asthma.
Over the past decade, interest has grown in the role of vitamin D in many nonskeletal medical conditions, including respiratory infection. Emerging evidence indicates that vitamin D-mediated innate immunity, particularly through enhanced expression of the human cathelicidin antimicrobial peptide (hCAP-18), is important in host defenses against respiratory tract pathogens. Observational studies suggest that vitamin D deficiency increases risk of respiratory infections. This increased risk may contribute to incident wheezing illness in children and adults and cause asthma exacerbations. Although unproven, the increased risk of specific respiratory infections in susceptible hosts may contribute to some cases of incident asthma. Vitamin D also modulates regulatory T-cell function and interleukin-10 production, which may increase the therapeutic response to glucocorticoids in steroid-resistant asthma. Future laboratory, epidemiologic, and randomized interventional studies are needed to better understand vitamin D's effects on respiratory infection and asthma.
A close relation between asthma and allergic rhinitis has been reported by several epidemiological and clinical studies. However, the nature of this relation remains unclear. We used the follow-up data from the European Community Respiratory Health Survey to investigate the onset of asthma in patients with allergic and non-allergic rhinitis during an 8.8-year period.
We did a longitudinal population-based study, which included 29 centres (14 countries) mostly in western Europe. Frequency of asthma was studied in 6461 participants, aged 20-44 years, without asthma at baseline. Incident asthma was defined as reporting ever having had asthma confirmed by a physician between the two surveys. Atopy was defined as a positive skin-prick test to mites, cat, Alternaria, Cladosporium, grass, birch, Parietaria, olive, or ragweed. Participants were classified into four groups at baseline: controls (no atopy, no rhinitis; n=3163), atopy only (atopy, no rhinitis; n=704), non-allergic rhinitis (rhinitis, no atopy; n=1377), and allergic rhinitis (atopy+rhinitis; n=1217). Cox proportional hazards models were used to study asthma onset in the four groups.
The 8.8-year cumulative incidence of asthma was 2.2% (140 events), and was different in the four groups (1.1% (36), 1.9% (13), 3.1% (42), and 4.0% (49), respectively; p<0.0001). After controlling for country, sex, baseline age, body-mass index, forced expiratory volume in 1 s (FEV(1)), log total IgE, family history of asthma, and smoking, the adjusted relative risk for asthma was 1.63 (95% CI 0.82-3.24) for atopy only, 2.71 (1.64-4.46) for non-allergic rhinitis, and 3.53 (2.11-5.91) for allergic rhinitis. Only allergic rhinitis with sensitisation to mite was associated with increased risk of asthma independently of other allergens (2.79 [1.57-4.96]).
Rhinitis, even in the absence of atopy, is a powerful predictor of adult-onset asthma.
To describe the incidence and prognosis of wheezing illness from birth to age 33 and the relation of incidence to perinatal, medical, social, environmental, and lifestyle factors.
Prospective longitudinal study.
England, Scotland and Wales.
18,559 people born on 3-9 March 1958. 5801 (31%) contributed information at ages 7, 11, 16, 23, and 33 years. Attrition bias was evaluated using information on 14, 571 (79%) subjects.
History of asthma, wheezy bronchitis, or wheezing obtained from interview with subjects' parents at ages 7, 11, and 16 and reported at interview by subjects at ages 23 and 33.
The cumulative incidence of wheezing illness was 18% by age 7, 24% by age 16, and 43% by age 33. Incidence during childhood was strongly and independently associated with pneumonia, hay fever, and eczema. There were weaker independent associations with male sex, third trimester antepartum haemorrhage, whooping cough, recurrent abdominal pain, and migraine. Incidence from age 17 to 33 was associated strongly with active cigarette smoking and a history of hay fever. There were weaker independent associations with female sex, maternal albuminuria during pregnancy, and histories of eczema and migraine. Maternal smoking during pregnancy was weakly and inconsistently related to childhood wheezing but was a stronger and significant independent predictor of incidence after age 16. Among 880 subjects who developed asthma or wheezy bronchitis from birth to age 7, 50% had attacks in the previous year at age 7; 18% at 11, 10% at 16, 10% at 23, and 27% at 33. Relapse at 33 after prolonged remission of childhood wheezing was more common among current smokers and atopic subjects.
Atopy and active cigarette smoking are major influences on the incidence and recurrence of wheezing during adulthood.
Although vitamin D deficiency has been documented as a frequent problem in studies of young adults, elderly persons, and children in other countries, there are limited data on the prevalence of this nutritional deficiency among healthy US teenagers.
To determine the prevalence of vitamin D deficiency in healthy adolescents presenting for primary care.
A cross-sectional clinic-based sample.
An urban hospital in Boston.
Three hundred seven adolescents recruited at an annual physical examination to undergo a blood test and nutritional and activity assessments.
Serum levels of 25-hydroxyvitamin D (25OHD) and parathyroid hormone, anthropometric data, nutritional intake, and weekly physical activity and lifestyle variables that were potential risk factors for hypovitaminosis D.
Seventy-four patients (24.1%) were vitamin D deficient (serum 25OHD level, </=15 ng/mL [</=37.5 nmol/L]), of whom 14 (4.6%) were severely vitamin D deficient (25OHD level, </=8 ng/mL [</=20 nmol/L]). By using a broader definition (25OHD level, </=20 ng/mL [</=50 nmol/L]), 129 patients (42.0%) were vitamin D insufficient. Serum 25OHD levels were inversely correlated with parathyroid hormone levels (r = -0.29), and were 24% lower during winter compared with summer. In a final multivariate model, season, ethnicity, milk and juice consumption, body mass index, and physical activity were significant independent predictors of hypovitaminosis D.
Vitamin D deficiency was present in many US adolescents in this urban clinic-based sample. The prevalence was highest in African American teenagers and during winter, although the problem seems to be common across sex, season, and ethnicity.
The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.
In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular
bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here
that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1–hydroxylase
genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had
low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link
between TLRs and vitamin D–mediated innate immunity and suggest that differences in ability of human populations to produce
vitamin D may contribute to susceptibility to microbial infection.
The percentage of asthma cases attributable to atopy is the subject of debate.
The objectives were to estimate the percentage of asthma cases in the US population attributable to atopy and to examine associations between allergen-specific skin tests and asthma.
Data were obtained from the Third National Health and Nutrition Examination Survey, in which subjects age 6 to 59 years were skin tested with 10 allergens. Atopy was defined as at least 1 positive allergen-specific test. Doctor-diagnosed current asthma was assessed by questionnaire.
In the United States, 56.3% of the asthma cases were attributable to atopy, and that percentage was greater among males than females, among persons in the highest education category than in lower education categories, and among persons living in highly populated metropolitan areas than in all other areas. Each allergen-specific test was strongly associated with asthma before adjustment (odds ratios varied from 2.1 to 4.5); however, after adjustment by all the allergens, only tests to cat, Alternaria, white oak, and perennial rye were independently associated with asthma. Perennial rye was inversely associated with asthma. Of the 10 allergens, a positive response to cat accounted for the highest percentage of asthma cases (29.3%).
About half of the current asthma cases in the US population represented by the Third National Health and Nutrition Examination Survey were attributable to atopy. Some allergen-specific skin tests were not independently associated with asthma.
If atopy could be prevented or reversed, or its effect on asthma blocked, then a large percentage of asthma cases in the US population could be prevented.
In the 1960s, the prevalence of asthma and allergic diseases began to increase worldwide. Currently, the burden of the disease is more than 300 million people affected. We hypothesize that as populations grow more prosperous, more time is spent indoors, and there is less exposure to sunlight, leading to decreased cutaneous vitamin D production. Coupled with inadequate intake from foods and supplements, this then leads to vitamin D deficiency, particularly in pregnant women, resulting in more asthma and allergy in their offspring. Vitamin D has been linked to immune system and lung development in utero, and our epidemiologic studies show that higher vitamin D intake by pregnant mothers reduces asthma risk by as much as 40% in children 3 to 5 years old. Vitamin D deficiency has been associated with obesity, African American race (particularly in urban, inner-city settings), and recent immigrants to westernized countries, thus reflecting the epidemiologic patterns observed in the asthma epidemic. Providing adequate vitamin D supplementation in pregnancy may lead to significant decreases in asthma incidence in young children.