Bronchial inflammation biomarker patterns link humoral immunodeficiency with bronchiectasis‐related small airway dysfunction

Abstract

Background The progression of chronic destructive lung disease in patients with humoral immunodeficiency (ID) and concomitant development of bronchiectasis is difficult to prevent. Lung function tests in these patients typically show bronchial obstruction of the small airways in combination with increased air trapping in the distal airways, which is consistent with small airway dysfunction. Objective The objective was to assess the grade of chronic lower airway inflammation and small airway dysfunction from induced sputum and the corresponding local pro‐inflammatory mediator pattern to discriminate patients affected by bronchiectasis‐related Small Airway Dysfunction (SAD). Methods In a prospective design, 22 patients with ID (14 CVID, 3 XLA, 3 hyper‐IgM syndrome, 1 hyper‐IgE syndrome and low IgG levels due to treatment with rituximab and 1 SCID after BMT and persistent humoral defect) and 21 healthy controls were examined. Lung function, Fraction Expiratory Nitric Oxide (FeNO) and pro‐inflammatory cytokine levels were compared in subsets of patients with (ID + BE) and without bronchiectasis (ID) pre‐stratified using high‐resolution computed tomography (HRCT) scans and control subjects. Results Analysis of induced sputum showed significantly increased total cell counts and severe neutrophilic inflammation in ID. The concomitant SAD revealed higher total cell numbers compared to ID. Bronchial inflammation in ID is clearly mirrored by pro‐inflammatory mediators IL‐1β, IL‐6 and CXCL‐8, whilst TNF‐α revealed a correlation with lung function parameters altered in the context of bronchiectasis‐related Small Airway Dysfunction. Conclusions In spite of immunoglobulin substitution, bronchial inflammation was dominated by neutrophils and was highly increased in patients with ID + BE. Notably, the pro‐inflammatory cytokines in patients with ID were significantly increased in induced sputum. The context‐dependent cytokine pattern in relation to the presence of concomitant bronchiectasis associated with SAD in ID patients could be helpful in delimiting ID patient subgroups and individualizing therapeutic approaches.

Bronchiectasis and obstructive lung diseases in primary antibody deficiencies and beyond: update on management and pathomechanisms

“…Zissler et al examined prospectively local pro-inflammatory markers at gene expression and protein secretion levels in induced sputum of 22 patients and 21 healthy controls. Bronchiectasis-related airway dysfunction was associated with elevated levels of IL-1beta, IL-6, CXCL-8 and TNF-alpha as well as higher overall cell load with an increased percentage of neutrophils [18 ▪ ].…”

CXC Chemokines in the Pathogenesis of Pulmonary Disease and Pharmacological Relevance

“…The level of the chemokine in sputum was directly correlated with neutrophils, the severity of bronchiectasis, and the frequency of exacerbations [ 104 ]. In a prospective study to evaluate the pattern and role of inflammatory mediators in bronchiectasis-related small airway dysfunction (SAD) in patients with humoral immunodeficiency, severe neutrophilic inflammation was evident in induced sputum and bronchial inflammation was paralleled by proinflammatory mediators CXCL-8 and IL-1 β [ 105 ].…”

Biomarkers of airway inflammation and immunotherapy

“…Unfortunately, immune deficiencies are generally under‐diagnosed, leading to advanced lung damage prior to diagnosis and treatment in some cases. Zissler et al aimed to assess the grade of chronic lower airway inflammation with small airway dysfunction using induced sputum samples 7 . The study included 22 patients with different types of immune deficiency (14 CVID, 3 X‐linked agammaglobulinaemia, 3 hyper‐IgM syndrome, 1 hyper‐IgE syndrome along with low IgG levels due to rituximab treatment and 1 severe combined immune deficiency following bone marrow transplant and persistent humoral defect), along with 21 healthy controls.…”