Chest
Volume 142, Issue 5, November 2012, Pages 1259-1266
Journal home page for Chest

Original Research
Cystic Fibrosis
Effect of Azithromycin on Systemic Markers of Inflammation in Patients With Cystic Fibrosis Uninfected With Pseudomonas aeruginosa

https://doi.org/10.1378/chest.12-0628Get rights and content

Background

While the mechanism of action by which azithromycin exerts positive effects in patients with cystic fibrosis remains unclear, evidence suggests that azithromycin may act as an immunomodulatory agent. We examined changes in systemic inflammatory markers in a double-blind, randomized, controlled trial of oral azithromycin in patients 6-18 years of age with cystic fibrosis who were uninfected with Pseudomonas aeruginosa.

Methods

WBC counts and differential, serum myeloperoxidase (MPO), high-sensitivity C reactive protein (hsCRP), intracellular adhesion molecule 1, IL-6, calprotectin, serum amyloid A (SAA), and granulocyte colony-stimulating factor (G-CSF) were measured at baseline and after 28 and 168 days of treatment in patients receiving either oral azithromycin or placebo.

Results

Inflammatory markers were similar in both groups at baseline. HsCRP, MPO, SAA, calprotectin, and the absolute neutrophil count (ANC) significantly decreased from baseline to day 28 in the azithromycin group compared with the placebo group (P < .05). This treatment effect was sustained at day 168 for ANC, calprotectin, and SAA (P < .05). Changes in hsCRP, calprotectin, and SAA at day 28 were negatively correlated with changes in FEV1 (L) and FEV1 (% predicted), as well as both absolute and relative changes in weight (P < .05). Except for weight (%), the associations remained significant for calprotectin; FEV1(L) and weight (%) remained significantly correlated with the 168-day change in hsCRP. The 168-day change in ANC was significantly correlated with changes in lung function, but not in weight; the change in G-CSF was significantly correlated with the change in weight (%) only.

Conclusions

In patients not infected with P aeruginosa, oral azithromycin significantly reduced neutrophil counts and serum inflammatory markers within 28 days of initiating treatment.

Trial registry

ClinicalTrials.gov; No.: NCT00431964; URL: www.clinicaltrials.gov

Section snippets

Materials and Methods

Details of the AZ0004 study have been described elsewhere.18 The trial was conducted at 31 Cystic Fibrosis Foundation-accredited care centers in the United States and at nine Canadian Cystic Fibrosis Foundation-accredited care centers coordinated by the CF Therapeutics Development Network Coordinating Center located in Seattle, Washington. Respective institutional review boards and ethics committees at each center approved the study and each participant and/or their parent voluntarily

Results

Of the 324 participants screened for the AZ0004 study, 260 (80%) were randomized and treated; 131 were randomized to azithromycin and 129 to placebo.18 Of the 260 participants, all had inflammatory marker laboratory results for MPO, hsCRP, ICAM-1, IL-6, G-CSF, calprotectin, SAA, and ANC, but a small fraction of test results could not be used due to hemolysis. Baseline characteristics were similar between treatment groups, including baseline weight (kg and percentile), lung function (FEV1 L and

Discussion

To the best of our knowledge, this is the first large study to assess the utility of a panel of systemic inflammatory markers in an interventional trial of patients with CF who have preserved lung function. Patients treated with azithromycin exhibited significant reductions in inflammatory markers after 4 weeks that persisted (albeit to a lesser degree) to week 24. Reduction in inflammatory markers were correlated to improvements in lung function and weight gain, providing indirect evidence

Acknowledgments

Author contributions: Dr Ratjen is the guarantor of the manuscript and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Ratgen: contributed to conception and design of the study; data acquisition, analysis, and interpretation; writing or revising the final manuscript for important intellectual content; and approval of the final manuscript; and served as principal author.

Dr Saiman: contributed to conception and design of the study; data acquisition,

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    Funding/Support: This research was funded by the Cystic Fibrosis Foundation, and grants from the National Institutes of Health/National Heart, Lung and Blood Institute [Grant 1 U01 HL081335-01] and National Center for Research Resources [Grant 1 UL1 RR025780].

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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