Elsevier

Cytokine

Volume 73, Issue 1, May 2015, Pages 156-162
Cytokine

Airway inflammation in children and adolescents with bronchiolitis obliterans

https://doi.org/10.1016/j.cyto.2014.10.026Get rights and content

Highlights

  • First sputum analysis from patients with BO originating in childhood.

  • Monitoring of bronchial inflammation from induced sputum.

  • Analysis of sputum samples by cell count, qRT-PCR and CBA.

Abstract

Background

Airway inflammation plays a major role in the progression of chronic lung diseases. The features of airway inflammation are not well defined among patients with cases of bronchiolitis obliterans (BO) that began in childhood.

Objectives

To investigate the sputum cell and cytokine profiles of stable cases of BO regarding lung function and the involvement of small airway disease (SAD).

Methods

Twenty patients with BO (median age = 14.5, range = 7–23 years) and 22 healthy controls (median age = 16.5 years, range = 7–24 years) were investigated. Lung function parameters and bronchial reversibility testing as well as sputum cell and cytokine profiles (IL-1β, IL-6, IL-8, TNF-α, IL-5, IFN-γ, and NFκB regulation) were analysed using quantitative RT-PCR and cytometric bead assay (CBA) in induced sputum.

Results

Patients with BO had significantly lower lung function values, including FVC, forced expiratory volume (FEV1), the Tiffeneau index (FEV1/VC), and MEF25, but increased functional residual capacity (RV/TLC) values. Bronchial reversibility was found in five patients (25%). Moreover, airway inflammation (as indicated by total cells, neutrophils, IL-1β, IL-6, IL-8, TNF-α, and NFκB) was significantly increased among patients with BO compared with controls.

Conclusions

BO is predominantly a neutrophilic disease of the small bronchioles featuring elevated levels of pro-inflammatory cytokines leading to tissue remodelling and fibrosis of the small airways. Future therapies for patients with BO should more efficiently target the small airways.

Introduction

Bronchiolitis obliterans (BO) is a rare, chronic, inflammatory and fibrosing lung disease. In children, it typically begins with an injury of the bronchiolar epithelium followed by an inflammatory reaction that progresses towards airway obliteration as the repair process of restoring the epithelium and microvasculature to its previous state, is severely altered [1]. Inflammatory cells and mesenchymal structures can be found in the lumen, the wall and around the bronchiole sparing other parenchymal structures [2].

This severe injury to the lower respiratory tract can be caused by either common pathogens (adenovirus, influenza, measles, respiratory syncytial virus, or Mycoplasma pneumonia) or by lung, and bone marrow transplantation. Rare causes of bronchiolitis include drugs, collagen vascular disease, graft versus host disease, and chronic occult aspiration [3], [4], [5]. The aetiology is used for clinical classification schemes and is important to guide the investigator to the diagnosis when tachypnoea, wheezing, and hypoxaemia persist for at least 2 months after a causative event [1]. Still the gold standard for diagnosing and classification of BO is the histopathology, as it shows an improved correlation with radiological manifestations, the natural history of the disease and the response to therapy [5]. BO can be classified histopathologically i.e. as cellular BO, bronchiolitis with intraluminal polyps, constrictive bronchiolitis and peribronchiolar fibrosis. Due to its invasive nature this procedure cannot be performed routinely. Thus, many experts define BO using clinical course, lung function (hyperinflation and obstruction) [6], [7], and characteristic CT findings (mosaic attenuation pattern with ground glass opacities and central bronchiectasis) [6], [8] especially in patients with post-infectious BO as these patients often show a mild clinical course.

The pathologic processes of BO are poorly understood. BO might be caused by a progressive inflammatory response with elements of tissue remodelling, fibrosis of the small airways, airway obstruction, and reduced expiratory flow rates that can eventually lead to death from respiratory failure. Although the importance of inflammation in the pathophysiology of BO is intriguing, few studies have measured airway inflammation among patients with cases of BO that began in childhood [9], [10]. A study of bronchoalveolar lavage (BAL) samples found increased levels of pulmonary neutrophils, IL-8, and CD8+T lymphocytes, all of which might play a role in the pathogenesis of post-infectious BO [9]. These findings resemble BO after lung transplantation, where several BAL parameters, including neutrophil count and IL-8 levels, were associated with small airway disease (SAD) [11].

Early closure of the small airways due to neutrophilic inflammation is reflected by lung function tests that reveal peripheral airway obstruction, raised RV/TLC, or both in diseases such as cystic fibrosis and chronic obstructive bronchitis [12], [13]. CT scans and lung biopsies have confirmed the central role of small airways in BO [8], [14]. Thus, whether we can more precisely define SAD among patients with stable BO is relevant and should be investigated. To our knowledge, the inflammatory pattern present in induced sputum specimens from patients with BO originating from childhood has not been elucidated. The aim of this study was to investigate sputum cell and cytokine profiles in stable BO in relation to lung function and involvement of small airway disease (SAD).

Section snippets

Patients

Patients with BO were recruited from the outpatient clinic of the paediatric pneumology of the Goethe-University, Frankfurt, Germany. Initially, an electronic chart review of 2006–2011 was performed. A diagnosis of BO in children older than 6 years was found in 36 of the 6,924 records. In 24 of these 36 patients, the diagnosis was confirmed using patient history, lung function data, and CT scans. In 6 patients the diagnosis was confirmed by histopathology. All 24 patients with BO were invited to

Study population

The median age of the 22 control participants was 16.5 (range = 7.8–24.5 years); they were well matched for age with the patients with BO (median age = 14.5, range = 7–23 years). Further clinical characteristics of the two study populations are summarised in Table 1.

Lung function testing

Patients and controls were compared in means of lung function and bronchodilator reversibility. As shown in Fig. 1, FVC, FEV1, and MEF25 were significantly lower but RV/TLC was higher among patients with BO compared with the control group,

Discussion

Distinct inflammatory profiles have emerged as an important area of investigation that advances the understanding of on-going inflammation and remodelling in airway diseases such as cystic fibrosis (CF) and asthma [20], [21]. Airway inflammation in asthma is usually characterised as an eosinophilic, TH-2 driven inflammation [17], [22]. CF is associated with an exuberant pro-inflammatory state primarily driven by IL-8 and neutrophils, which leads to a decline in lung function, tissue

Acknowledgement

A grant from the Starke Lunge Foundation supported this study.

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