Scott D. Sagel

Primary ciliary dyskinesia (PCD) is a rare genetic disease characterized by abnormal ciliary structure and function leading to impaired mucociliary clearance and chronic progressive sinopulmonary disease. Upper and lower respiratory tract manifestations are cardinal features of PCD. This review summarizes the current state of knowledge of respiratory tract disease in individuals with PCD and highlights the challenges in identifying and quantifying lung disease in very young children with PCD. No specific therapies are available to correct ciliary dysfunction in PCD. Treatment is not evidence based, and recommendations are largely extrapolated from cystic fibrosis and other conditions with impaired mucociliary clearance. There is a pressing need to develop and validate outcome measures, including patient-reported outcomes, that could be used to evaluate potential therapies in PCD. This review concludes with recommendations for clinical endpoints and outcome measures and a prioritized list of treatments to study in PCD clinical trials.

Antimicrobial proteins are important in lung defense and are potential therapeutic agents in chronic airways infection such as seen in cystic fibrosis (CF). In preparation for future clinical studies, we sought (1) to determine levels of three antimicrobial proteins [lactoferrin, lysozyme, and secretory leukoprotease inhibitor (SLPI)] in the CF airway and (2) to examine the relationships between these antimicrobial proteins and airway inflammation and infection. We examined bronchoalveolar lavage fluid (BALF) from 45 individuals with CF and 23 disease control individuals. Airway inflammation was measured through BALF neutrophil counts and neutrophil elastase activity. Infection was assessed through quantitative counts of CF‐related bacterial pathogens. BALF lysozyme activity and lactoferrin levels were elevated in individuals with CF compared to controls whereas SLPI levels were not different between the groups. Among the CF subjects, lysozyme activity and lactoferrin increased with age while SLPI decreased with age. Lysozyme activity and lactoferrin concentrations correlated positively with neutrophil counts but not with bacterial colony counts. SLPI levels were inversely related to both neutrophil counts and bacterial colony counts. This study provides information concerning the levels of antimicrobial proteins present in the CF airway that are relevant to future clinical trials of these compounds and demonstrates clear relationships between antimicrobial protein‐specific levels and airway inflammation and infection. Pediatr Pulmonol. 2009; 44:402–409.

Pulmonary biomarkers are being used more frequently to monitor disease activity and evaluate response to treatment in individuals with cystic fibrosis (CF). This article summarizes the current state of knowledge of biomarkers of inflammation relevant to CF lung disease, and the tools to measure inflammation, with specific emphasis on sputum. Sputum is a rich, noninvasive source of biomarkers of inflammation and infection. Sputum induction, through the inhalation of hypertonic saline, has expanded the possibilities for monitoring airway inflammation and infection, especially in individuals who do not routinely expectorate sputum. We critically examine the existing data supporting the validity of sputum biomarkers in CF, with an eye toward their application as surrogate endpoints or outcome measures in CF clinical trials. Further validation studies are needed regarding the variability of inflammatory biomarker measurements, and to evaluate how these biomarkers relate to disease severity, and to longitudinal changes in lung function and other clinical endpoints. We highlight the need to incorporate sputum collection, by induction if necessary, and measurement of sputum biomarkers into routine CF clinical care. In the future, pulmonary biomarkers will likely be useful in predicting disease progression, indicating the onset and resolution of a pulmonary exacerbation, and assessing response to current therapies or candidate therapeutics.

Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in causing airway damage in chronic inflammatory lung diseases, including cystic fibrosis (CF). Our primary objective was to examine the relationship between matrix metalloproteinase‐9 (MMP‐9) and pulmonary function, as measured by forced expiratory volume in 1 sec (FEV₁), in children with CF. We measured MMP‐9 and its natural tissue inhibitor of metalloproteinase‐1 (TIMP‐1) in induced sputum from 18 clinically stable CF children with normal to mildly abnormal lung function and 7 healthy control children. Measures of airway inflammation from induced sputum included cell counts and differentials, interleukin‐8 (IL‐8), neutrophil elastase, MMP‐9, and TIMP‐1. Infection was assessed through quantitative bacterial counts. Induced sputum levels of MMP‐9 and TIMP‐1 were significantly increased in children with CF compared with healthy controls. Also, the MMP‐9/TIMP‐1 molar ratio was higher in the CF group. Among CF children, there was a significant inverse relationship between MMP‐9 and FEV₁. In addition, sputum MMP‐9 and TIMP‐1 concentrations significantly correlated with total white cells and neutrophils, IL‐8, and neutrophil elastase. Neither MMP‐9 nor TIMP‐1 correlated with airway infection. We conclude that clinically stable CF children with normal to mildly abnormal lung function have an increased burden of MMP‐9 in their airways. The observed relationships of MMP‐9 with lung function and other measures of airway inflammation suggest that this enzyme may be a useful marker of airway injury and airflow obstruction in persons with CF. Pediatr Pulmonol. 2005; 39:224–232.

Airway inflammation plays a central role in the lung disease of cystic fibrosis (CF). Biomarkers of inflammation may be useful for monitoring disease progression and evaluating response to therapy. Much of our knowledge of the chronic inflammatory process in the CF airway derives from studies of bronchoscopy and bronchoalveolar lavage. A number of noninvasive approaches have been recently developed to more readily assess airway inflammation including sputum induction, collection of exhaled air, analysis of systemic markers of inflammation, and computed tomography imaging. While measurements of biomarkers of inflammation continue to advance our understanding of the underlying disease process, there is as yet no established role for these markers in clinical practice. This review summarizes the current state of knowledge of various inflammatory markers relevant to CF lung disease, with an eye towards application as surrogate outcome measures in CF clinical trials. It is hoped that biomarkers obtained by noninvasive means will be useful in determining specific pathways of injury (ie, oxidative or proteolytic) in individual persons with CF and in assessing response to antiinflammatory treatments.

In cystic fibrosis (CF), chronic airway infection and neutrophil-dominated airway inflammation lead to progressive lung disease. Cytokines play an important role in the inflammatory response. Evidence suggests that cytokine production is altered or dysregulated in CF. Moreover, polymorphisms in cytokines may be linked to disease severity by acting as modifier genes. This article reviews the current state of knowledge regarding individual cytokines and CF lung disease, with an eye towards the possibility that cytokines may be used as outcome measures in clinical trials in CF. In addition, cytokines may eventually serve as targets for novel anti-inflammatory therapies in CF.