Dataset Information

Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis.

ABSTRACT:

Rationale

Progressive lung function decline is a defining feature of cystic fibrosis (CF). Because airway inflammation plays a central role in CF lung disease, inflammatory biomarkers that can be used to monitor disease activity would be valuable.

Objectives

Examine longitudinal relationships between sputum biomarkers and lung function.

Methods

In this prospective, longitudinal cohort study, sputum induction was performed annually over 3 years in 35 children with CF. Sputum was assayed for mediators related to proteolysis and a panel of inflammatory cytokines.

Measurements and main results

Sputum neutrophil elastase, tissue inhibitor of metalloproteinase-1, and TNF-α increased over time, whereas neutrophil elastase antiprotease complexes (NEAPCs) and secretory leukoprotease inhibitor (SLPI) significantly decreased over time. Higher detectable baseline neutrophil elastase was associated with more rapid lung function decline. Similar results for neutrophil elastase were observed in a validation cohort. When categorizing subjects as "rapid" or "slow" decliners, logistic regression demonstrated that the initial measurement of neutrophil elastase had the highest individual predictive value for subsequent lung function decline, whereas neutrophil elastase, IL-8, and IL-6 had the highest combined predictive value. Lung function decline was associated with increases in neutrophil counts, neutrophil elastase, and IL-1β and declines in NEAPCs and SLPI.

Conclusions

In children with CF, a single determination of sputum biomarkers, particularly neutrophil elastase, has predictive value for subsequent lung function decline, and longitudinal changes in sputum inflammatory biomarkers are related to lung function changes. Based on our results, sputum neutrophil elastase was the most informative biomarker to monitor disease activity.

SUBMITTER: Sagel SD

PROVIDER: S-EPMC3530222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF).MethodsRate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006-2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6-12 (children), 13-17 (adolescents), 18-24 (young adults), and ≥ 25 years (adults)] were performed.ResultsThe estimated annualized rate of ppFEV1 decline was - 0.70 percentage points per year (95% CI -1.09, -0.30) in the F/RF (all) cohort (N = 1242) versus -1.91 percentage points per year (95% CI -2.01, -1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from -0.30 to -1.38. In the F/RF (excluding R117H) cohort, the rate of decline was -1.05 percentage points per year (95% CI -1.51, -0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults].ConclusionProgressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.

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