Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease

Abstract

In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

ViDAS trial schema. FENO, fractional exhaled NO; PFT, pulmonary function tests.

Figure 2.

ViDAS participant flow diagram.

Figure 3.

Annual rates of respiratory events by treatment group. Data are shown in a Tukey box plot. The horizontal line in the box represents the median. The bottom and top of the box indicate the first and third quartiles; the upper whisker shows the largest value from the top of the box that is no further than 1.5 times the interquartile range (IQR), the lower whisker shows the smallest value from the bottom of the box to within 1.5 times the IQR, and data beyond the ends of the whiskers are displayed as points. The mean (♦; ± standard error of the mean [SEM]) annual rates of respiratory events at baseline, intervention year 1, and intervention year 2 were 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 and 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37, respectively, for monthly standard-dose and high-dose oral vitamin D3. The rates did not differ significantly between the groups (P = .24), but they decreased significantly during year 2 in both groups (P = .0005).

Figure 4.

Mean serum 25-hydroxyvitamin D concentrations by treatment group. The mean serum 25-OHD concentrations of the groups receiving standard-dose (12 000 IU/mo) and high-dose (100 000 IU/mo) vitamin D3 did not differ statistically at baseline and rose to plateau at different levels at 3-4 months; overall mean concentration during the 2-year treatment period was significantly higher in the high-dose group (36.1 ng/mL) compared with the standard-dose group (19.1 ng/mL; P < .001). Error bars indicate SEM.