Candidate Markers Associated with the Probability of Future Pulmonary Exacerbations in Cystic Fibrosis Patients

Gabriella Wojewodka,Danuta Radzioch,Joanie Bernier,Jim Gruber,Dao Nguyen,Julie Bérubé,Juan B De Sanctis,Simon Rousseau,Heather G Ahlgren,Larry C Lands,Jennifer Landry,Elias Matouk,Andrea Benedetti,Erich Gulbins

doi:10.1371/journal.pone.0088567

Abstract

IntroductionPulmonary exacerbations (PEs) cause significant morbidity and can severely impact disease progression in cystic fibrosis (CF) lung disease, especially in patients who suffer from recurrent PEs. The assessments able to predict a future PE or a recurrent PE are limited. We hypothesized that combining clinical, molecular and patient reported data could identify patients who are at risk of PE.MethodsWe prospectively followed a cohort of 53 adult CF patients for 24 months. Baseline values for spirometry, clinical status using the Matouk Disease Score, quality of life (QOL), inflammatory markers (C-reactive protein (CRP), interleukins (IL)-1β, -6, -8, -10, macrophage inflammatory protein (MIP)-1β, tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF)), polyunsaturated fatty acids and lipid peroxidation in blood plasma were collected for all patients during periods of stable disease, and patients were monitored for PE requiring PO/IV antibiotic treatment. Additionally, we closely followed 13 patients during PEs collecting longitudinal data on changes in markers from baseline values. We assessed whether any markers were predictors of future PE at baseline and after antibiotic treatment.ResultsOut of 53 patients, 37 experienced PEs during our study period. At baseline, we found that low lung function, clinical scoring and QOL values were associated with increased risk of PE events. PEs were associated with increased inflammatory markers at Day 1, and these biomarkers improved with treatment. The imbalance in arachidonic acid and docosahexaenoic acid levels improved with treatment which coincided with reductions in lipid peroxidation. High levels of inflammatory markers CRP and IL-8 were associated with an early re-exacerbation.ConclusionOur results demonstrate that worse clinical and QOL assessments during stable disease are potential markers associated with a higher risk of future PEs, while higher levels of inflammatory markers at the end of antibiotic treatment may be associated with early re-exacerbation.

Highlights

Pulmonary exacerbations (PEs) cause significant morbidity and can severely impact disease progression in cystic fibrosis (CF) lung disease, especially in patients who suffer from recurrent PEs
CF patients that experienced at least one PE (‘‘PE group’’) had lower lung function, weight, body mass index (BMI) and Matouk Disease Score compared to the patients who did not have a PE (‘‘no PE group’’) (Table 1)
Consistent with previously reported data from our group and other investigators[24,25,26] there was a lipid imbalance in polyunsaturated fatty acids (PUFA) with high arachidonic acid (AA) levels and low docosahexaenoic acid (DHA) levels CF patients compared to healthy controls (HC)

Summary

Introduction

Pulmonary exacerbations (PEs) cause significant morbidity and can severely impact disease progression in cystic fibrosis (CF) lung disease, especially in patients who suffer from recurrent PEs. The assessments able to predict a future PE or a recurrent PE are limited. Cystic fibrosis (CF) patients often suffer acute exacerbations of their pulmonary symptoms, necessitating more aggressive treatment. Pulmonary exacerbations (PEs) are major events contributing to the morbidity and progression of CF lung disease. Given the substantial morbidity and mortality associated with PEs, there is an urgent need to identify patients at risk of PE, recurrent PEs. Improving the clinicians’ ability to stratify patients based on their risk to develop PEs will allow for more effective prevention The standard criteria used to monitor PEs are mainly focused on lung function indicators such as FEV1% which are mostly reflective of disease severity and not necessarily disease activity[6]. Newly developed diaries are being validated for the purpose of early intervention to quickly reduce the development of a full and vigorous inflammatory response and to shorten and reduce the severity of PE with the hope of preventing the development of irreversible lung damage[7]

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Discussion

Conclusion