Airway inflammation in children and adolescents with bronchiolitis obliterans
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.
References (40)
- et al.
Bronchiolitis obliterans in the 1990s in Korea and the United States
Chest
(2001) - et al.
Bronchoalveolar cellularity and interleukin-8 levels in measles bronchiolitis obliterans
Chest
(2007) - et al.
Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome
Am J Transplant
(2013) - et al.
Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis
Clin Chest Med
(1993) - et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method
Methods
(2001) - et al.
Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function
Cytokine
(2010) - et al.
IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies
J Allergy Clin Immunol
(2012) Bronchiolitis obliterans in children: a ghostly journey to the origin
Allergol Immunopathol (Madr)
(2011)- et al.
Oxidative stress and nutritional intakes in lung patients with bronchiolitis obliterans syndrome
Transplant. Proc.
(2009) - et al.
Increased oxidative stress in children with post infectious Bronchiolitis Obliterans
Allergol Immunopathol (Madr)
(2011)
Alveolar neutrophilia is a predictor for the bronchiolitis obliterans syndrome, and increases with degree of severity
Transpl Immunol
Distinct intracellular signaling pathways control the synthesis of IL-8 and RANTES in TLR1/TLR2, TLR3 or NOD1 activated human airway epithelial cells
Cell Signal
Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation
Biol Blood Marrow Transplant
Exhaled nitric oxide in pulmonary diseases: a comprehensive review
Chest
Usefulness of exhaled nitric oxide to guide risk stratification for bronchiolitis obliterans syndrome after lung transplantation
Am J Transplant
Exhaled nitric oxide in diagnosis of bronchiolitis obliterans syndrome in lung transplant recipients: possible limitations
Am J Transplant
Acute bronchodilator responsiveness in bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation
Chest
Bronchiolitis obliterans in children
Pediatr Pulmonol
Persistent adenoviral infection and chronic obstructive bronchitis in children: is there a link?
Pediatr Pulmonol
Insights into post-infectious bronchiolitis obliterans in children
Thorax
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