Sputum Biomarkers of Inflammation in Cystic Fibrosis Lung Disease

Abstract

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.

Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways

“…Sputum induction is a minimally invasive procedure was shown by several independent groups to faithfully reflect CF inflammatory lung disease (reviewed in ref. 10). Because our study focused on characterizing baseline functional and signaling profiles of CF neutrophils, we sought to prevent any artefactual ex vivo activation of these cells, as detailed in the online supplement, and excluded any culture, expansion, or stimulation.…”

“…We compared neutrophils from induced sputum, a well standardized procedure that yields cells from conducting airways (10), where CF symptoms are the most manifest, to their blood counterparts. We combined multiparametric profiling (11) of functional properties (lipid raft and degranulation markers, immune receptors) and intracellular phosphoepitopes (total phosphotyrosine levels, intermediate kinases, and final effectors that reflect key signaling pathways).…”

Lung Transplantation for Cystic Fibrosis

“…For example, biomarkers of inflammation (IL-2; IL-6; IL-8; IL-10; TGF-b, etc.) in the sera or sputa of patients with CF awaiting transplant may better predict which patients are most likely to deteriorate more rapidly, providing impetus for earlier transplantation (151)(152)(153). The same inflammatory biomarkers post-transplant may influence choices for immunsuppressive regimens, need for invasive studies such as bronchoalveolar lavage and transbronchial biopsy, or antimicrobial treatment.…”

Sputum Tobramycin Concentrations in Cystic Fibrosis Patients with Repeated Administration of Inhaled Tobramycin

“…(15,16) Sputum induction offers high recovery rates of bacterial pathogens, inflammatory cells, and proinflammatory cytokines. (16)(17)(18) Although to our knowledge it has never been utilized to assess airway drug concentrations, sputum induction has the potential to offer a safe, noninvasive alternative to BAL in pre-expectorating young CF patients, and may allow measurement of antibiotic concentrations more directly at the site of infection than ES.…”