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Friday 6 July 2018
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.

Wheezing 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.