The effect of treatment of cystic fibrosis pulmonary exacerbations on airways and systemic inflammation

Downey, D.G.; Brockbank, Simon; Martin, S. Lorraine; Ennis, Madeleine; Elborn, J. Stuart

doi:10.1002/ppul.20646

Cited by 51 publications

(48 citation statements)

References 28 publications

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“…In the study from Horsley and colleagues (20), in which both sputum and blood were collected to track changes during CF pulmonary exacerbations, the most significant changes in inflammation were observed in serum rather than sputum. Similarly, data from another study examining the effects of CF pulmonary exacerbation treatment on both systemic and airway inflammation demonstrated a reduction in systemic inflammation after intravenous antibiotics but a persistent inflammatory response in the airways (35). These data suggest that systemic measures of inflammation may be more useful than sputum markers in short-term interventional studies, particularly ones that investigate exacerbation therapies.…”

Section: O2 Saturationmentioning

confidence: 87%

Effect of Treatment of Cystic Fibrosis Pulmonary Exacerbations on Systemic Inflammation

et al. 2015

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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.

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Section: O2 Saturationmentioning

confidence: 87%

Effect of Treatment of Cystic Fibrosis Pulmonary Exacerbations on Systemic Inflammation

et al. 2015

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“…Although many markers of airway inflammation can be detected in the sputum, multiple previous studies (particularly of this size) have not been able to detect changes in sputum concentrations of inflammatory markers associated with the treatment of an acute pulmonary exacerbation (33)(34)(35)(36)(37)(38). Thus, to directly compare identified changes in PBMC expression with specific inflammatory markers in the sputum, sputum markers of inflammation were not analyzed as a part of this study..…”

Section: Discussionmentioning

confidence: 99%

Circulating RNA Transcripts Identify Therapeutic Response in Cystic Fibrosis Lung Disease

Saavedra¹,

Hughes²,

Sanders³

et al. 2008

Am J Respir Crit Care Med

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Rationale: Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in cystic fibrosis (CF) lung disease. Although the standard assessment of pulmonary treatment response is FEV 1 , a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits the testing of proposed therapeutics. Objectives: We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation using a model by which RNA transcripts could increase the predictive value of spirometry. Methods: Peripheral blood mononuclear cells were isolated from 10 patients with CF and acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed that 10 genes significantly changed with treatment when compared with matched non-CF and control subjects with stable CF to establish baseline transcript abundance. Peripheral blood mononuclear cell RNA transcripts were prospectively validated, using real-time polymerase chain reaction amplification, in an independent cohort of acutely ill patients with CF (n 5 14). Patients who responded to therapy were analyzed using general estimating equations and multiple logistic regression, such that changes in FEV 1 % predicted were regressed with transcript changes. Measurements and Main Results: Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of a therapeutic response beyond that of FEV 1 alone (P , 0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV 1 . Conclusions: Circulating mononuclear cell transcripts characterize a response to the treatment of pulmonary exacerbations. Even in small patient cohorts, changes in gene expression in conjunction with FEV 1 may enhance current outcomes measures for treatment response.

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“…In CF patients, a limited number of studies have been performed involving a broad range of CF subjects (discussed further later). In particular, the assessment of induced sputum has proven helpful in studying the effect of antibiotic treatment [20][21][22]86]. The value of induced sputum in studying more subtle effects of anti-inflammatory therapies remains unclear as no study of anti-inflammatory drugs published to date using outcome measures obtained from induced sputum has convincingly demonstrated an effect.…”

Section: Bronchoalveolar Lavagementioning

confidence: 99%

“…Other outcome measures, such as exacerbation rate or quality of life, might additionally help in the monitoring of CF patients' lung disease, and should be considered when performing clinical studies. Inflammatory outcome markers in blood, sputum or urine have been shown to be especially helpful in the assessment of antibiotic treatment [20][21][22].…”

mentioning

confidence: 99%

Inhibition of airway proteases in cystic fibrosis lung disease

Griese¹,

Kappler²,

Gaggar³

et al. 2008

Eur Respir J

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Progressive lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients.CF lung disease is characterised by endobronchial inflammation sustained by bacterial infections and an ongoing accumulation of airway neutrophils. Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment.Among various proteases released by airway cells, elastase is considered to play the major role in CF lung disease. Based on this concept, several therapeutic approaches have been developed to inhibit free elastolytic activity, including small synthetic chemical compounds, semi-synthetic inhibitors and natural inhibitors of free elastase.The present review summarises and discusses the pathophysiological rationales, methodological requirements and clinical implications of inhibition of airway proteases in cystic fibrosis lung disease.

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The effect of treatment of cystic fibrosis pulmonary exacerbations on airways and systemic inflammation

Cited by 51 publications

References 28 publications

Effect of Treatment of Cystic Fibrosis Pulmonary Exacerbations on Systemic Inflammation

Effect of Treatment of Cystic Fibrosis Pulmonary Exacerbations on Systemic Inflammation

Circulating RNA Transcripts Identify Therapeutic Response in Cystic Fibrosis Lung Disease

Inhibition of airway proteases in cystic fibrosis lung disease

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