Bronchoalveolar Lavage as a Tool to Predict, Diagnose and Understand Bronchiolitis Obliterans Syndrome

Abstract

Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past twenty years, numerous studies have evaluated the BAL cellular composition, cytokine profiles, and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins, and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment, and standardization of BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.

Sequential Bronchoalveolar Lavages Reflect Distinct Pulmonary Compartments: Clinical and Research Implications in Lung Transplantation

“…BAL cells and proteins have long been studied in the context of pulmonary diseases. In lung transplantation, in particular, BAL parameters have been shown to correlate with allograft dysfunction [7]. However, concerns exist regarding the lack of standardization of BAL techniques, which hinders the potential clinical utility of measured BAL components and limits comparison and The results of this study demonstrate reproducible differences between sequential fractions of BAL.…”

“…Examination of the cellular composition and protein constituents in the BAL provides a unique window into the microenvironment of the lung. In lung transplantation, BAL proteins have been proposed as potential biomarkers of acute rejection [3][4][5][6] and chronic lung allograft dysfunction (CLAD) [7]. However, small sample sizes, lack of control for potential confounders and lack of standardization related to BAL collection and handling have all been proposed as sources of variability between studies [7,8].…”

“…Standardization of BAL collection and processing is essential to enable sharing of data across collaborative research networks and to maximize their utility. The purpose of this study was to determine whether there are systematic differences between sequential BAL fractions in lung transplant patients, with a focus on cellular composition and proteins that have previously been shown to correlate with clinical outcomes in lung transplant recipients, including lymphocytes [10], neutrophils [7,10], Surfactant Protein-D (SP-D) [11], Club Cell Secretory Protein (CCSP) [12,13], CXCL10 [7], IL-10 [14], CCL2 [7], CCL5 [7], VEGF-C [15], RAGE [16], CXCL9 [7], CXCL1 [17], IL-17A [18], IL-21 [19], PDGF [20][21][22] and GCSF [23].…”

Evaluation of nasal fluid β-defensin 2 levels in children with allergic rhinitis

“…In addition, it has been reported that defensin levels were increased in bronchoalveolar lavage fluids in many inflammatory lung diseases including cystic fibrosis, pneumonia, tuberculosis, and bronchiolitis obliterans (18)(19)(20)(21)(22). On the other hand, exposure of airway epithelium to Th2 cytokines including interleukin 4 and 13 significantly reduces BD-2 mRNA synthesis (23).…”

Chronic lung allograft dysfunction phenotypes and treatment

“…Given the heterogeneous nature of CLAD, it comes to no surprise that at this moment, there are no universally applied biomarkers for BOS diagnosis. Broncho-alveolar lavage (BAL) analysis may provide insights in the lung micro-environment (27). Using BAL, the first important markers for BOS came to light, which included neutrophils and markers of neutrophil activation (CXL-8, MMP-9) (28).…”