The association between vitamin D status and the rate of exacerbations requiring oral corticosteroids in preschool children with recurrent wheezing
2014; Elsevier BV; Volume: 133; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2014.02.024
ISSN1097-6825
AutoresAvraham Beigelman, Robert S. Zeiger, David T. Mauger, Robert C. Strunk, Daniel J. Jackson, Fernando D. Martínez, Wayne J. Morgan, Ronina Covar, Stanley J. Szefler, Lynn M. Taussig, Leonard B. Bacharier,
Tópico(s)Child Nutrition and Water Access
ResumoPreschool children with recurrent yet intermittent wheezing experience substantial disease morbidity that is primarily related to acute and often severe exacerbations.1Bacharier L.B. Guilbert T.W. Diagnosis and management of early asthma in preschool-aged children.J Allergy Clin Immunol. 2012; 130 (quiz 97-8): 287-296Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Recent epidemiologic data suggest that vitamin D status may modulate the risk of these wheezing exacerbations because vitamin D levels are inversely associated with adverse asthma-related outcomes among older children and adolescents.2Hollams E.M. Vitamin D and atopy and asthma phenotypes in children.Curr Opin Allergy Clin Immunol. 2012; 12: 228-234Crossref PubMed Scopus (34) Google Scholar, 3Litonjua A.A. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma.Curr Opin Allergy Clin Immunol. 2012; 12: 179-185Crossref PubMed Scopus (97) Google Scholar To the best of our knowledge, no study has evaluated whether vitamin D deficiency during early life is a risk factor for exacerbation of wheezing episodes among preschool children who have already developed the recurrent wheezing phenotype. We conducted this post hoc analysis to investigate whether deficient serum vitamin D levels were associated with an increase in the rate of wheezing exacerbations requiring oral corticosteroids (OCS) among a well-defined cohort of preschool children with severe intermittent wheezing participating in the Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddler (MIST) clinical trial of the Childhood Asthma Research and Education Network.4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google ScholarA detailed description of the MIST trial,4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar study population, clinical outcome measurements, vitamin D measurements, analysis plan, sample size, and power calculations is given in this article's Methods section in the Online Repository at www.jacionline.org.Briefly, MIST4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar was a 1-year multicenter, double-blind, randomized trial comparing daily low-dose budesonide inhalation suspension to intermittent high-dose budesonide starting at the early signs of respiratory tract illness (RTI) for the prevention of severe respiratory exacerbations requiring OCS. Participants were children aged 12 to 53 months with a history of recurrent severe wheezing. All participants had risk factors for future asthma, as evidenced by a positive modified Asthma Predictive Index.5Guilbert T.W. Morgan W.J. Krawiec M. Lemanske Jr., R.F. Sorkness C. Szefler S.J. et al.The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.Control Clin Trials. 2004; 25: 286-310Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Institutional review boards at all participating centers approved the MIST protocol, and parents provided written informed consent. The primary outcome measure of MIST, as well as this post hoc analysis, was the rate of severe respiratory exacerbations, requiring OCS (prednisolone), over the 1-year study period,4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar which did not differ between the daily low-dose and intermittent high-dose regimens of inhaled budesonide.4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google ScholarThere is a lack of consensus as to the optimal levels of 25-hydroxyvitamin D (25-OH-VitD) to define vitamin D status for conditions other than for the maintenance of bone health, for which The Institute of Medicine recommends a serum 25-OH-VitD level of at least 20 ng/mL.6Ross A.C. Manson J.E. Abrams S.A. Aloia J.F. Brannon P.M. Clinton S.K. et al.The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.J Clin Endocrinol Metab. 2011; 96: 53-58Crossref PubMed Scopus (866) Google Scholar Moreover, there is a lack of consensus concerning the normal or optimal vitamin D serum levels in various ethnic groups because it was recently reported that compared with whites, black adults had lower total serum vitamin D levels, but these black subjects had similar estimated concentrations of bioavailable vitamin D resulting from lower levels of vitamin D–binding protein.7Powe C.E. Evans M.K. Wenger J. Zonderman A.B. Berg A.H. Nalls M. et al.Vitamin D-binding protein and vitamin D status of black Americans and white Americans.N Engl J Med. 2013; 369: 1991-2000Crossref PubMed Scopus (791) Google Scholar Previous asthma studies have detected associations between vitamin D levels and asthma outcomes using different serum vitamin D cutoff levels among older children.2Hollams E.M. Vitamin D and atopy and asthma phenotypes in children.Curr Opin Allergy Clin Immunol. 2012; 12: 228-234Crossref PubMed Scopus (34) Google Scholar, 3Litonjua A.A. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma.Curr Opin Allergy Clin Immunol. 2012; 12: 179-185Crossref PubMed Scopus (97) Google Scholar Because of these uncertainties in defining the appropriate vitamin D cutoffs for respiratory health, the lack of consensus concerning the normal vitamin D serum levels in various ethnic groups, and the absence of previous studies that investigated the relationships between serum vitamin D levels and asthma-related outcomes in preschool children, our primary analysis considered 25-OH-VitD level as a continuous variable, whereas secondary analyses were performed using 25-OH-VitD as a dichotomous variable, with a 25-OH-VitD cutoff of 20 ng/mL.Baseline serum vitamin D levels were measured in 264 (95%) of the 278 children enrolled in the MIST trial. The mean age of the patients was 35 ± 11 months, 70% of the participants were males, and 62% were white (Table I). The median (Q1-Q3) 25-OH-VitD level was 33.5 ng/mL (26.4-43.7). Eighteen participants (7%) had 25-OH-VitD levels below 20 ng/mL (ie, vitamin D deficiency). Vitamin D–deficient participants were more often non-white (72% vs 36%; P = .002) and reported tobacco smoke exposure (72% vs 41%; P = .010) compared with the nondeficient participants (Table I). Vitamin D deficiency was more common in samples obtained in winter and fall seasons, although these differences were only marginally significant (Table I).Table IBaseline characteristics of study populationCharacteristicAll participants (n = 264)Participants with baseline serum 25-OH-VitD level of <20 ng/mL (n = 18)Participants with baseline serum 25-OH-VitD level of ≥20 ng/mL (n = 246)P valueYounger children (12-32 mo)∗Data are expressed as number (%).120 (45.5)7 (38.9)113 (45.9).56Sex: male∗Data are expressed as number (%).184 (69.7)13 (72.2)171 (69.5).81Race (white)∗Data are expressed as number (%).163 (61.7)5 (27.8)158 (64.2)<.01Height (cm)94.2 ± 8.993.4 ± 8.994.3 ± 9.75Weight (kg)15.3 ± 3.115.1 ± 3.315.3 ± 3.1.60Physician diagnosis of asthma∗Data are expressed as number (%).188 (71.2)15 (83.3)173 (70.3).24Rate of wheezing episodes per child in the past year6.6 ± 5.46.1 ± 2.66.7 ± 5.6.95Rate of urgent/ED visits per child in the past year4.9 ± 4.26.3 ± 4.54.8 ± 4.2.08Hospitalization in the past year∗Data are expressed as number (%).50 (18.9)5 (27.8)45 (18.3).32Tobacco smoke exposure∗Data are expressed as number (%).113 (43.3)13 (72.2)100 (41.2).01Any asthma controller use in the past year∗Data are expressed as number (%).184 (69.7)13 (72.2)171 (69.5).81Received OCS in the past year∗Data are expressed as number (%).199 (75.4)12 (66.7)187 (76).37≥1 positive food skin test result∗Data are expressed as number (%).95 (36.5)9 (52.9)86 (35.4).15≥1 positive aeroallergen skin test result∗Data are expressed as number (%).153 (58.4)13 (72.2)140 (57.4).22≥1 positive aeroallergen skin test result to outdoor allergen∗Data are expressed as number (%).120 (45.5)10 (55.6)110 (44.7).38≥1 positive aeroallergen skin test result to indoor allergen∗Data are expressed as number (%).98 (37.1)6 (33.3)92 (37.4).73Serum IgE (kU/L), median (Q1-Q3)58.8 (21.5-183.7)82.5 (39.1-343.2)55.3 (20.2-166.8).06Percent eosinophil in CBC, median (Q1-Q3)3.1 (2-6)3 (2-8)3.1 (2-6).61Child ever had eczema∗Data are expressed as number (%).141 (53.4)12 (66.7)129 (52.4).24Presence of allergic rhinitis∗Data are expressed as number (%).101 (38.3)9 (50)92 (37.4).29Parental history of asthma∗Data are expressed as number (%).160 (63.5)15 (83.3)145 (62).07Feno (ppb), median (Q1-Q3)8.6 (5.7-14)6.3 (3.9-19.5)8.6 (5.7-14).54Percent episode-free days66.9 ± 29.677.3 ± 22.566.2 ± 29.9.16Randomized to intermittent treatment arm∗Data are expressed as number (%).132 (50)12 (66.7)120 (48.8).14Family keep a cat or a dog∗Data are expressed as number (%).121 (45.8)5 (27.8)116 (47.2).11Season during which serum was obtained (season at enrollment)∗Data are expressed as number (%). Winter (December-February)57 (22)6 (33)51 (21).05 Spring (March-May)76 (29)2 (11)74 (30) Summer (June-August)66 (25)2 (11)64 (26) Fall (September-November)65 (25)8 (44)57 (23)Sites∗Data are expressed as number (%). Albuquerque, NM10 (4)2 (11)8 (3).02 Denver, Colo43 (16)1 (6)42 (17) Madison, Wis35 (13)0 (0)35 (13) San Diego, Calif40 (15)1 (6)39 (16) St Louis, Mo74 (28)10 (56)64 (26) Tucson, Ariz62 (23)4 (22)58 (24)Data are expressed as mean ± SE, except as noted.CBC, Complete blood cell count; ED, emergency department; Feno, fraction of exhaled nitric oxide.∗ Data are expressed as number (%). Open table in a new tab 25-OH-VitD level (as a continuous variable) at the time of study randomization was not associated with the rate of exacerbations requiring OCS therapy over the 1-year trial (pseudo r2 = 0.006; P = .65).Vitamin D–deficient participants had a significantly higher mean rate of exacerbations requiring OCS compared with nondeficient participants (1.46 vs 0.93 exacerbations/child-year, P = .035; rate ratio, 1.56; 95% CI, 1.03-2.37). Because of the relatively small number of participants with vitamin D deficiency, adjustment for covariates that significantly differed between the vitamin D–deficient and nondeficient groups was performed for each covariate one at a time (one model included adjustment for race and an additional model included adjustment for tobacco smoke exposure) rather than simultaneously. The rate ratio for OCS treatment remained significant after adjustment for race and smoke exposure (Table II). Multiple secondary outcomes did not differ between participants with vitamin D levels of less than 20 ng/mL and participants with vitamin D levels of 20 ng/mL or more (see Table E1 in this article's Online Repository at www.jacionline.org): the rate of RTIs, the rate of RTIs in which a viral etiology was detected by multiplex PCR in the nasal samples obtained during the acute episode (viral RTIs), the rates of emergency department or urgent care visits, and the proportion of episode-free days over the 12-month trial, defined as days without any respiratory symptoms and without use of albuterol. We did not detect interactions between MIST study treatment assignment or race and vitamin D deficiency status on the rate of exacerbations (P = .3 and .6, respectively). Stratification by race showed that both white and non-white participants who were deficient in vitamin D had numerically higher mean rates of exacerbations requiring OCS compared with nondeficient children; however, this difference was statistically significant only among non-whites (see Table E2 in this article's Online Repository at www.jacionline.org). The lack of statistical significance in the rate of exacerbations among white subjects is most likely a reflection of reduced statistical power to detect such a difference among white subjects, only 5 of whom were deficient in vitamin D. However, we cannot definitively exclude a differential effect of vitamin D deficiency on the basis of race because low serum vitamin D levels among black and white subjects might have different clinical significance resulting from different levels of vitamin D–binding proteins among these 2 ethnic groups.7Powe C.E. Evans M.K. Wenger J. Zonderman A.B. Berg A.H. Nalls M. et al.Vitamin D-binding protein and vitamin D status of black Americans and white Americans.N Engl J Med. 2013; 369: 1991-2000Crossref PubMed Scopus (791) Google ScholarTable IIRate ratios (95% CIs) of exacerbations requiring OCS among the children with 25-OH-VitD levels of less than 20 ng/mL relative to children with 25-OH-VitD levels of 20 ng/mL or moreRate ratioRate ratio∗The rate ratio represents the ratio between the rate of exacerbations requiring OCS among the vitamin D–deficient group and the rate of exacerbations requiring OCS among the nondeficient group. of exacerbations requiring OCS95% CIP valueUnadjusted1.561.03-2.37.035Adjusted for Race1.681.09-2.58.019 Tobacco smoke exposure1.571.02-2.40.038∗ The rate ratio represents the ratio between the rate of exacerbations requiring OCS among the vitamin D–deficient group and the rate of exacerbations requiring OCS among the nondeficient group. Open table in a new tab To the best of our knowledge, this is the first study to demonstrate an association between vitamin D deficiency and significant exacerbations among preschool children with severe but intermittent wheezing, corroborating the findings of increased asthma morbidity among vitamin D–deficient school-age children and adolescents with persistent asthma.2Hollams E.M. Vitamin D and atopy and asthma phenotypes in children.Curr Opin Allergy Clin Immunol. 2012; 12: 228-234Crossref PubMed Scopus (34) Google Scholar, 3Litonjua A.A. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma.Curr Opin Allergy Clin Immunol. 2012; 12: 179-185Crossref PubMed Scopus (97) Google Scholar Our findings demonstrate that the relationship between significant exacerbations and vitamin D status was evident when a level of 20 ng/mL of 25-OH-VitD was used as the cutoff, whereas no association was demonstrated using 25-OH-VitD as a continuous measure, suggesting a threshold effect of vitamin D level on the outcome of exacerbations in this age group in which serum vitamin D levels of at least 20 ng/mL may be adequate to attenuate the risk of exacerbations, while higher levels may not provide any additional benefits.Vitamin D deficiency in the United States was reported to be less common among young children than among older children and adolescents.8Kumar J. Muntner P. Kaskel F.J. Hailpern S.M. Melamed M.L. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001-2004.Pediatrics. 2009; 124: e362-e370Crossref PubMed Scopus (474) Google Scholar Accordingly, the prevalence of vitamin D deficiency in our study was only slightly lower than the 12% prevalence reported among 2 independent cohorts of preschool children in North America: 380 children in the United States9Gordon C.M. Feldman H.A. Sinclair L. Williams A.L. Kleinman P.K. Perez-Rossello J. et al.Prevalence of vitamin D deficiency among healthy infants and toddlers.Arch Pediatr Adolesc Med. 2008; 162: 505-512Crossref PubMed Scopus (300) Google Scholar and 508 children in Canada.10El Hayek J. Pham T.T. Finch S. Hazell T.J. Jean-Philippe S. Vanstone C.A. et al.Vitamin D status in Montreal preschoolers is satisfactory despite low vitamin D intake.J Nutr. 2013; 143: 154-160Crossref PubMed Scopus (36) Google Scholar Lower prevalence of vitamin D deficiency among toddlers in North America might be related to routine vitamin D supplementation among this age group and/or to the presence of vitamin D supplements in dairy products. Our study also revealed a substantially higher prevalence of vitamin D deficiency among non-whites, which is in agreement with the epidemiology of vitamin D deficiency.3Litonjua A.A. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma.Curr Opin Allergy Clin Immunol. 2012; 12: 179-185Crossref PubMed Scopus (97) Google Scholar However, a recent report has questioned the clinical significance of low total serum vitamin D levels among black adults.7Powe C.E. Evans M.K. Wenger J. Zonderman A.B. Berg A.H. Nalls M. et al.Vitamin D-binding protein and vitamin D status of black Americans and white Americans.N Engl J Med. 2013; 369: 1991-2000Crossref PubMed Scopus (791) Google ScholarOur study has the advantages of using a well-characterized cohort of preschool children with severe intermittent wheezing and positive modified Asthma Predictive Index, and of a direct measurement of vitamin D status in participants at study inception as opposed to previous studies that have estimated early life vitamin D status indirectly by measuring maternal serum or cord blood vitamin D levels.11Camargo Jr., C.A. Ingham T. Wickens K. Thadhani R. Silvers K.M. Epton M.J. et al.Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.Pediatrics. 2011; 127: e180-e187Crossref PubMed Scopus (406) Google Scholar, 12Morales E. Romieu I. Guerra S. Ballester F. Rebagliato M. Vioque J. et al.Maternal vitamin D status in pregnancy and risk of lower respiratory tract infections, wheezing, and asthma in offspring.Epidemiology. 2012; 23: 64-71Crossref PubMed Scopus (138) Google Scholar, 13Pike K.C. Inskip H.M. Robinson S. Lucas J.S. Cooper C. Harvey N.C. et al.Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes.Thorax. 2012; 67: 950-956Crossref PubMed Scopus (89) Google Scholar These previous studies yielded conflicting results regarding the association between maternal vitamin D status and the development of the wheezing phenotype during early life.11Camargo Jr., C.A. Ingham T. Wickens K. Thadhani R. Silvers K.M. Epton M.J. et al.Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.Pediatrics. 2011; 127: e180-e187Crossref PubMed Scopus (406) Google Scholar, 12Morales E. Romieu I. Guerra S. Ballester F. Rebagliato M. Vioque J. et al.Maternal vitamin D status in pregnancy and risk of lower respiratory tract infections, wheezing, and asthma in offspring.Epidemiology. 2012; 23: 64-71Crossref PubMed Scopus (138) Google Scholar, 13Pike K.C. Inskip H.M. Robinson S. Lucas J.S. Cooper C. Harvey N.C. et al.Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes.Thorax. 2012; 67: 950-956Crossref PubMed Scopus (89) Google Scholar Some study limitations exist. Because vitamin D deficiency was relatively infrequent in the MIST trial, we adjusted for the most relevant potential confounders (race and tobacco smoke exposure) one at a time using separate models rather than analyzing both confounders simultaneously in a single, unstable model. The low number of vitamin D–deficient participants at each Childhood Asthma Research and Education center precluded adjustment for study center because of multivariate model instability. Therefore, although unlikely, we cannot definitively exclude residual bias that contributes to the detection of a higher rate of exacerbations among the vitamin D–deficient children. Because our primary outcome was the rate of exacerbations assessed over the year of the study, which exposed all participants to seasonal variations in vitamin D levels, we did not adjust the rate of severe exacerbation by season at enrollment despite marginally significant variability in the prevalence of vitamin D deficiency by season of enrolment. Finally, on the basis of the cross-sectional nature of this analysis, we cannot determine whether the relationship between vitamin D deficiency and exacerbations noted in this study is causal, nor can we exclude the possible contributions of other factors, such as diet, activity, or other environmental exposures.In summary, vitamin D deficiency in preschool children with severe intermittent wheezing treated with inhaled corticosteroid therapy was associated with a higher rate of exacerbations requiring OCS. While the association between vitamin D deficiency and exacerbations was statistically significant only among non-white children, the relevance of these ethnic differences remains uncertain because the use of a single reference value to discriminate vitamin D deficiency in white and black subjects may be inappropriate.7Powe C.E. Evans M.K. Wenger J. Zonderman A.B. Berg A.H. Nalls M. et al.Vitamin D-binding protein and vitamin D status of black Americans and white Americans.N Engl J Med. 2013; 369: 1991-2000Crossref PubMed Scopus (791) Google Scholar The association between vitamin D levels and the risk of exacerbations was significant only among children with serum 25-OH-VitD levels of less than 20 ng/mL, suggesting that future studies of vitamin D supplementation as an intervention for the prevention of wheezing episodes might need to focus on this subgroup of children. Preschool children with recurrent yet intermittent wheezing experience substantial disease morbidity that is primarily related to acute and often severe exacerbations.1Bacharier L.B. Guilbert T.W. Diagnosis and management of early asthma in preschool-aged children.J Allergy Clin Immunol. 2012; 130 (quiz 97-8): 287-296Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Recent epidemiologic data suggest that vitamin D status may modulate the risk of these wheezing exacerbations because vitamin D levels are inversely associated with adverse asthma-related outcomes among older children and adolescents.2Hollams E.M. Vitamin D and atopy and asthma phenotypes in children.Curr Opin Allergy Clin Immunol. 2012; 12: 228-234Crossref PubMed Scopus (34) Google Scholar, 3Litonjua A.A. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma.Curr Opin Allergy Clin Immunol. 2012; 12: 179-185Crossref PubMed Scopus (97) Google Scholar To the best of our knowledge, no study has evaluated whether vitamin D deficiency during early life is a risk factor for exacerbation of wheezing episodes among preschool children who have already developed the recurrent wheezing phenotype. We conducted this post hoc analysis to investigate whether deficient serum vitamin D levels were associated with an increase in the rate of wheezing exacerbations requiring oral corticosteroids (OCS) among a well-defined cohort of preschool children with severe intermittent wheezing participating in the Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddler (MIST) clinical trial of the Childhood Asthma Research and Education Network.4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar A detailed description of the MIST trial,4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar study population, clinical outcome measurements, vitamin D measurements, analysis plan, sample size, and power calculations is given in this article's Methods section in the Online Repository at www.jacionline.org. Briefly, MIST4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar was a 1-year multicenter, double-blind, randomized trial comparing daily low-dose budesonide inhalation suspension to intermittent high-dose budesonide starting at the early signs of respiratory tract illness (RTI) for the prevention of severe respiratory exacerbations requiring OCS. Participants were children aged 12 to 53 months with a history of recurrent severe wheezing. All participants had risk factors for future asthma, as evidenced by a positive modified Asthma Predictive Index.5Guilbert T.W. Morgan W.J. Krawiec M. Lemanske Jr., R.F. Sorkness C. Szefler S.J. et al.The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.Control Clin Trials. 2004; 25: 286-310Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Institutional review boards at all participating centers approved the MIST protocol, and parents provided written informed consent. The primary outcome measure of MIST, as well as this post hoc analysis, was the rate of severe respiratory exacerbations, requiring OCS (prednisolone), over the 1-year study period,4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar which did not differ between the daily low-dose and intermittent high-dose regimens of inhaled budesonide.4Zeiger R.S. Mauger D. Bacharier L.B. Guilbert T.W. Martinez F.D. Lemanske Jr., R.F. et al.Daily or intermittent budesonide in preschool children with recurrent wheezing.N Engl J Med. 2011; 365: 1990-2001Crossref PubMed Google Scholar There is a lack of consensus as to the optimal levels of 25-hydroxyvitamin D (25-OH-VitD) to define vitamin D status for conditions other than for the maintenance of bone health, for which The Institute of Medicine recommends a serum 25-OH-VitD level of at least 20 ng/mL.6Ross A.C. Manson J.E. Abrams S.A. Aloia J.F. Brannon P.M. Clinton S.K. et al.The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.J Clin Endocrinol Metab. 2011; 96: 53-58Crossref PubMed Scopus (866) Google Scholar Moreover, there is a lack of consensus concerning the normal or optimal vitamin D serum levels in various ethnic groups because it was recently reported that compared with whites, black adults had lower total serum vitamin D levels, but these black subjects had similar estimated concentrations of bioavailable vitamin D resulting from lower levels of vitamin D–binding protein.7Powe C.E. Evans M.K. Wenger J. Zonderman A.B. Berg A.H. Nalls M. et al.Vitamin D-binding protein and vitamin D status of black Americans and white Americans.N Engl J Med. 2013; 369: 1991-2000Crossref PubMed Scopus (791) Google Scholar Previous asthma studies have detected associations between vitamin D levels and asthma outcomes using different serum vitamin D cutoff levels among older children.2Hollams E.M. Vitamin D and atopy and asthma phenotypes in children.Curr Opin Allergy Clin Immunol. 2012; 12: 228-234Crossref PubMed Scopus (34) Google Scholar, 3Litonjua A.A. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma.Curr Opin Allergy Clin Immunol. 2012; 12: 179-185Crossref PubMed Scopus (97) Google Scholar Because of these uncertainties in defining the appropriate vitamin D cutoffs for respiratory health, the lack of consensus concerning the normal vitamin D serum levels in various ethnic groups, and the absence of previous studies that investigated the relationships between serum vitamin D levels and asthma-related outcomes in preschool children, our primary analysis considered 25-OH-VitD level as a continuous variable, whereas secondary analyses were performed using 25-OH-VitD as a dichotomous variable, with a 25-OH-VitD cutoff of 20 ng/mL. Baseline serum vitamin D levels were measured in 264 (95%) of the 278 children enrolled in the MIST trial. The mean age of the patients was 35 ± 11 months, 70% of the participants were males, and 62% were white (Table I). The median (Q1-Q3) 25-OH-VitD level was 33.5 ng/mL (26.4-43.7). Eighteen participants (7%) had 25-OH-VitD levels below 20 ng/mL (ie, vitamin D deficiency). Vitamin D–deficient participants were more often non-white (72% vs 36%; P = .002) and reported tobacco smoke exposure (72% vs 41%; P = .010) compared with the nondeficient participants (Table I). Vitamin D deficiency was more common in samples obtained in winter and fall seasons, although these differences were only marginally significant (Table I). Data are expressed as mean ± SE, except as noted. CBC, Complete blood cell count; ED, emergency department; Feno, fraction of exhaled nitric oxide. 25-OH-VitD level (as a continuous variable) at the time of study randomization was not associated with the rate of exacerbations requiring OCS therapy over the 1-year trial (pseudo r2 = 0.006; P = .65). Vitamin D–deficient participants had a significantly higher mean rate of exacerbations requiring OCS compared with nondeficient participants (1.46 vs 0.93 exacerbations/child-year, P = .035; rate ratio, 1.56; 95% CI, 1.03-2.37). Because of the relatively small number of participants with vitamin D deficiency, adjustment for covariates that significantly differed between the vitamin D–deficien
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