Iron supplementation does not worsen respiratory health or alter the sputum microbiome in cystic fibrosis

Abstract

Background: Iron supplementation for hypoferremic anemia could potentiate bacterial growth in the cystic fibrosis (CF) lung, but clinical trials testing this hypothesis are lacking.

Methods: Twenty-two adults with CF and hypoferremic anemia participated in a randomized, double-blind, placebo-controlled, crossover trial of ferrous sulfate 325mg daily for 6weeks. Iron-related hematologic parameters, anthropometric data, sputum iron, Akron Pulmonary Exacerbation Score (PES), and the sputum microbiome were serially assessed. Fixed-effect models were used to describe how ferrous sulfate affected these variables.

Results: Ferrous sulfate increased serum iron by 22.3% and transferrin saturation (TSAT) by 26.8% from baseline (p<0.05) but did not affect hemoglobin, sputum iron, Akron PES, and the sputum microbiome.

Conclusions: Low-dose ferrous sulfate improved hypoferremia without correcting anemia after 6weeks. We did not observe significant effects on sputum iron, Akron PES, and the sputum microbiome. Although we did not identify untoward health effects of iron supplementation, a larger blinded randomized controlled trial would be needed to fully demonstrate safety.

Keywords: Anemia; Cystic fibrosis; Hepcidin-25; Hypoferremia; Iron; Microbiome.

Figure 1

Diagram of enrollment, allocation, follow-up, and analysis of subjects.

Figure 2

Treatment Related Differences in Serum Iron and TSAT. Bars and whiskers denote mean differences from baseline and (standard error), respectively. After 6 weeks, serum iron increased by 13.7 (5.9) µg/dl for ferrous sulfate but fell by 4.2 (5.7) µg/dl for placebo. TSAT increased 4.7 (1.5) % for ferrous sulfate and fell by 1.8 (1.7) % for placebo. * p <0.05 for comparison of ferrous sulfate to placebo.

Figure 3

Relationship Between Akron PES and Serum Hepcidin-25 in CF. The fixed-effect model for serum hepcidin-25 revealed that every ng/ml increase in serum hepcidin-25 above baseline was associated with a 0.04 (0.01) point increase in Akron PES above baseline (p <0.05). 95% confidence intervals for the slope of this relationship intersect PES = 5 at 35 ng/ml and 115 ng/ml for hepcidin-25.

Figure 4

Sputum Microbiome is Unaltered by Iron Supplementation. The CF sputum microbiome is unaltered by iron supplementation. A) Relative abundance of P.a. as calculated by deep sequencing (P.a. reads/Total reads) for sputum samples obtained from 21 subjects while on or off iron supplementation. Sputum from week 6 of Arm 1 and Arm 2 were compared and analyzed for difference by paired Student’s t-test. Each symbol indicates an individual sputum sample. Horizontal line indicates the mean and error bars indicate the standard deviation. There is no significant difference in P.a. relative abundance in subjects on or off iron supplementation (p >0.05). B) Simpson Diversity Index (SDI) for sputum samples obtained while on or off iron supplementation for the same samples and by the same method described in panel A. There is no significant difference in Simpson Diversity index in subjects on or off iron supplementation (p >0.05).