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Suggested Publications
Vitamin D and wheezing in childhood
The article WAidid suggests this week, "Prenatal vs Infant Vitamin D Supplementation and the Risk of Wheezing in Childhood", was published last month on JAMA and tackles the issue of vitamin D supplementation related benefits. SUMMARYAlthough the association of vitamin D with respiratory disease has been observed for more than 100 years, the potential benefits of vitamin D for the prevention of respiratory tract disease, including wheezing disorders, continue to be investigated in many observational and epidemiologic studies. Most cell nuclei in the human body have a vitamin D receptor, through which vitamin D may affect gene transcription. 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), the hormonal metabolite of vitamin D, regulates, directly or indirectly, approximately 2000 genes, such as the ones inhibiting cellular proliferation, differentiation, and angiogenesis, the ones inducing apoptosis, and the ones which upregulate antiinflammatory pathways and downregulate molecules, that activate immune and inflammatory cells. Although these known actions suggest potential pathways for the interaction of vitamin D and respiratory disease, a recent review concluded that there are few suitable clinical trials to support the beneficial effect of vitamin D supplementation on respiratory disease. The D-Wheeze study reported by Hibbs and colleagues is now one of these supporting studies, that attempts to fill this important evidence gap. D-Wheeze was a multicenter, double-blind, randomized clinical trial, that enrolled 300 black preterm infants, born between 28 weeks and less than 37 weeks’ gestation, who were randomized into 1 of 2 different postnatal vitamin D supplementation strategies. No attempt was made to standardize the feeding protocol within or across centers. An oral supplement of 400 IU/d of vitamin D was started after birth, when oral feedings were tolerated. When infants achieved a daily oral intake of 200 IU of vitamin D from the feedings of vitamin D–fortified human milk or infant formula, they were randomized to 1 of 2 groups. The sustained group continued the daily supplement of 400 IU of vitamin D, whereas the diet-limited group was maintained only on the vitamin D, that was present in the formula or human milk feedings. The protocol was continued until 6 months of age, adjusted for prematurity. The incidence of recurrent wheezing at 12 months occurred in 31.1% in the sustained group and 41.8% in the diet-limited group (absolute risk difference, −10.7%; relative risk, 0.66), a clinically significant difference. Regardless of feeding group, at 3 months, only a few of the 272 infants measured had a serum 25-hydroxyvitamin D (25[OH]D) level less than 20 ng/mL. No infant’s serum 25(OH)D level exceeded 80 ng/mL.The authors underlined that the results of D-Wheeze should not be used to support vitamin D intakes that exceed 1000 IU/d in preterm infants, and that the vitamin D intakes studied are relevant also to infants who are not black or premature.The results of this study complement and contrast with 2 previous studies in JAMA, that examined the effects of prenatal supplementation of vitamin D on recurrent wheezing or asthma among infants followed up until 3 years of age, which reported a slightly reduction in persistent or recurrent wheezing, without statistically significance.In addition to the time of supplementation, the prenatal and postnatal supplementation trials differed in the populations enrolled. Therefore, the authors highlighted that the role of prenatal vs early-life supplementation, and in which populations, remains unclear, and that further follow-up studies of the infants in all 3 trials will be needed to determine whether the effects of prenatal or postnatal supplements of vitamin D on respiratory disease in infants are sustained. AUTHOR: Frank R. Greer
The D-Wheeze randomized clinical trial
The article WAidid suggests this week, "Effect of Vitamin D Supplementation on Recurrent Wheezing in Black Infants Who Were Born Preterm. The D-Wheeze Randomized Clinical Trial", was published last May on JAMA and aims at assessing the effectiveness of 2 vitamin D dosing strategies in preventing recurrent wheezing. SUMMARYWheezing is a common complication of prematurity. Early environmental and iatrogenic exposures may perturb the development of the lung, airway, or immune system and lead to recurrent wheezing. Substantial evidence suggests vitamin D is important in multiple pathways relevant to the development of wheezing in young children, including regulating inflammation, response to pathogens, lung and airway development, and propensity to allergic disease. Preterm infants may be particularly vulnerable to any positive and negative effects of vitamin D. Black infants experience higher rates of both prematurity and prematurity-associated wheezing. The authors reported the results of the Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy (D-Wheeze) Study. It was a masked placebo-controlled randomized clinical trial of the effectiveness of 2 vitamin D supplementation strategies in black infants born at 280/7 to 366/7 weeks’ gestational age (GA). Patients were enrolled between January 2013 and January 2016. Infants were randomized to receive 400 IU of cholecalciferol daily until 6 months’ adjusted age (sustained group) or until they were taking at least 200 IU/d of vitamin D from formula or human milk fortifier (diet-limited group). Infants were eligible for enrollment if they were 280/7 to 366/7 weeks’ GA at birth, the family identified the child as black or African American, they received 28 days or less of supplemental oxygen, were admitted to a participating nursery as a neonate, were 406/7 weeks’ adjusted GA or younger at enrollment, and lived within a predefined geographic area at each site.Out of 1481 eligible infants, 300 were enrolled; of them, 18 withdrew from the study and 1 died while cosleeping.Recurrent wheezing was experienced by 42 of 135 (31.1%) in the sustained supplementation group compared with 56 of 134 (41.8%) in the diet-limited supplementation group in the primary unadjusted analysis (P = 0.02). A planned model of recurrent wheezing, adjusted for different variables, showed that recurrent wheezing was significantly decreased in the sustained supplementation group (P = 0.005).No significant differences between groups were seen in total medically attended illnesses or markers of allergy or bone health. The Asthma Predictive Index was positive for 15 of 140 (10.7%) and 19 of 137 (13.9%) infants in the sustained and diet-limited groups, respectively (difference, −3.2%). Emergency department visits for a respiratory cause were experienced by 75 of 141 (53.2%) in the sustained group and 69 of 137 (50.4%) in the diet-limited group (difference, 2.8%). There was also not a significant difference in respiratory hospitalizations. No participants had a tibial speed of sound measurement more than 2 SDs below the mean. Cases of elevated calcium and alkaline phosphatase levels were generally transient and did not differ between treatment groups. A significant decrease was seen in the sustained group at some, but not all, points for wheezing, respiratory medication use, and hospitalization.There were no statistically significant differences between the groups in the number of infants experiencing any adverse events or serious adverse events. Upper and lower respiratory tract infections were among the most commonly reported adverse events. No adverse events were attributed to vitamin D treatment or deficiency. No infants were diagnosed as having rickets. Median achieved circulating 25(OH)D concentrations were greater than 30 ng/mL at follow-up.The authors concluded that sustained supplementation with vitamin D, compared with diet-limited supplementation, resulted in a reduced risk of recurrent wheezing by 12 months’ adjusted age. Neither group demonstrated superiority in terms of bone health or allergic disease. The authors also highlighted that their study suggested a benefit of sustained supplementation with 400 IU/d with regard to recurrent wheezing, without an increase in allergy or eczema. The mechanisms of such an effect are still unknown, but could potentially include developmental alterations in the airway or immune system, or acute alterations in inflammation or response to infection, so the authors claimed the need of future research to better understand the mechanisms and longer-term effects of vitamin D supplementation on wheezing in children born preterm. AUTHORS: Hibbs A .M., Ross K., Kerns L. A., Wagner C., Fuloria M., Groh-Wargo S., Zimmerman T., Minich N., Tatsuoka C.
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