Effect of Treatment of Cystic Fibrosis Pulmonary Exacerbations on Systemic Inflammation

Abstract

Rationale: In cystic fibrosis (CF), pulmonary exacerbations present an opportunity to define the effect of antibiotic therapy on systemic measures of inflammation.Objectives: Investigate whether plasma inflammatory proteins demonstrate and predict a clinical response to antibiotic therapy and determine which proteins are associated with measures of clinical improvement.Methods: In this multicenter study, a panel of 15 plasma proteins was measured at the onset and end of treatment for pulmonary exacerbation and at a clinically stable visit in patients with CF who were 10 years of age or older.Measurements and Main Results: Significant reductions in 10 plasma proteins were observed in 103 patients who had paired blood collections during antibiotic treatment for pulmonary exacerbations. Plasma C-reactive protein, serum amyloid A, calprotectin, and neutrophil elastase antiprotease complexes correlated most strongly with clinical measures at exacerbation onset. Reductions in C-reactive protein, serum amyloid A, IL-1ra, and haptoglobin were most associated with improvements in lung function with antibiotic therapy. Having higher IL-6, IL-8, and a 1 -antitrypsin (a1AT) levels at exacerbation onset were associated with an increased risk of being a nonresponder (i.e., failing to recover to baseline FEV 1 ). Baseline IL-8, neutrophil elastase antiprotease complexes, and a1AT along with changes in several plasma proteins with antibiotic treatment, in combination with FEV 1 at exacerbation onset, were predictive of being a treatment responder. Conclusions:Circulating inflammatory proteins demonstrate and predict a response to treatment of CF pulmonary exacerbations. A systemic biomarker panel could speed up drug discovery, leading to a quicker, more efficient drug development process for the CF community.

Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis

“…Patients with CF 10 years and older being started on two or more intravenous antibiotics for a clinically diagnosed PEx using criteria outlined by a CFF Consensus Conference20 were eligible to enrol in the observational study conducted at six adult and paediatric CF centres between 2007 and 2010 21. Study protocol encouraged at least 10 days of antibiotic administration and mucus clearance in accordance with CF Care Guidelines,13 but all other treating factors, including location, concomitant administration of inhaled or oral antibiotics or systemic steroids, were at physician's discretion.…”

Biomarkers for cystic fibrosis drug development

“…Circulating biomarkers have consistently changed more than sputum markers of inflammation with exacerbation treatment (91, 96, 105), suggesting that systemic inflammatory measures may be more sensitive in short term interventional studies focused on mitigating exacerbations. Based on results from a multicenter exacerbation study (106), serum C reactive protein (CRP), serum amyloid A (SAA) and calprotectin declined during azithromycin treatment in a CF interventional trial (107). These reductions correlated with improvements in lung function and weight gain, providing indirect evidence that the changes were associated with clinically meaningful outcomes.…”

Cystic Fibrosis

“…In a multicenter study measuring a panel of plasma proteins at onset of a pulmonary exacerbation and following treatment with IV antibiotics, significant reductions in 10 of 15 proteins were observed 75 . Baseline measurements of IL-8, NE-protease complexes and alpha-1-antitrypsin, when combined with changes in protein markers and lung function, predicted a better treatment response, suggesting that a panel of circulating markers may be useful clinically and for future therapeutic trials.…”