Introduction
Bronchiolitis obliterans (BO) is an inflammatory disease of the small airways that is caused by an insult to the lower respiratory tract. The presence of inflammation and fibrosis of the terminal and respiratory bronchioles leads to a narrowing or full obliteration of the airway lumen, and subsequently to the chronic obstruction of airflow. BO is characterized by the presence of intraluminal granulation tissue in the airways or peribronchial fibrosis and lumen narrowing, resulting in scarring and obstruction (1).
BO is diagnosed according to a variety of factors, including the history of insult to the lower respiratory tract (usually caused by infection), persistent symptoms that do not respond to the administration of bronchodilators for two weeks, computed tomographic (CT) findings and the exclusion of other diseases (2). However, BO is often undiagnosed or misdiagnosed as other childhood lung diseases, such as wheezing syndromes.
Epidemiological factors, treatment and disease prognosis should be clearly defined in order to reduce the morbidity and mortality rates of the disease. The aim of the present study was to describe the clinical and radiological findings, and the treatment protocols, during the follow-up of patients with BO in the Pediatric Department of the Second Hospital of Tianjin Medical University (Tianjin, China).
Increasing evidence has demonstrated that macrolide antibiotics exert immune-modifying properties, in addition to their role as antimicrobials (3). Azithromycin has been reported to be effective for long-term use in the treatment of several chronic conditions, including mycobacterial diseases, cystic fibrosis and asthma (4). A previous study demonstrated that following three months of treatment with azithromycin, airway neutrophilia was shown to decrease in patients with BO syndrome (BOS) that had undergone a lung transplantation (5). Therefore, long-term low-dose azithromycin therapy may offer a novel, safe therapy for patients with BOS who have undergone a lung transplantation. To the best of our knowledge, the present study was the first long-term study investigating azithromycin treatment for patients with post-infectious BO (PIBO).
Discussion
BO is a chronic obstruction of the airflow associated with inflammatory lesions of the small airways (1). The condition is divided into two types depending on the basis of the histological features, namely proliferative bronchiolitis and obstructive or constrictive bronchiolitis. The latter form is predominant (7). Constrictive bronchiolitis has a range of morphological abnormalities, from bronchiolar to peribronchiolar inflammation, and the condition can lead to complete obstruction of the bronchioles through submucosal fibrosis (8).
The clinical manifestations of BO are usually continuous or repeated coughing and wheezing, and a poor exercise tolerance. Distinguishing BO from ordinary bronchiolitis or viral pneumonia through observation of the symptoms is challenging; however, delaying treatment may result in aggravated respiratory tract infections or even mortality due to respiratory failure in a period of one to two years (2).
BO has a number of causes, including infection, connective tissue disorders, bone marrow or lung transplantation and severe mucocutaneous allergic disorders, such as Stevens-Johnson syndrome, or the inhalation of toxic substances (9–11). BO following a severe infectious lung disease is the most common form reported in children (12). The causal agents of BO include adenovirus, influenza virus, measles virus and Mycoplasma pneumoniae (13). Adenovirus is the leading infectious cause of BO worldwide (14). In the present study, 37.5% of patients (6/16) were infected with adenovirus. An additional major infectious agent is Mycoplasma pneumoniae, which accounted for 37.5% of patients in the present study. The increased percentage of cases with Mycoplasma pneumoniae as a causal agent may be associated with the increased incidence of Mycoplasma pneumonia in China.
Respiratory signs and symptoms of acute viral bronchiolitis disappear within a few days. Therefore, in children with acute lower respiratory tract infections, BO must be considered if wheezing and respiratory distress do not resolve within the expected time frame, particularly in those with severe adenovirus infections. Further diagnosis is imperative (15).
With regard to diagnosis, PIBO has no specific signs and symptoms. Ideally, the diagnosis requires histopathological confirmation; however, the irregular distribution of the lesions results in sample collection being challenging (16). Therefore, clinical and imaging criteria are combined with laboratory tests for agent identification and to eliminate other forms of chronic lung disease. Imaging techniques, particularly HRCT, play an important role in the diagnosis of PIBO (17,18). A number of characteristics are observed on PIBO-positive HRCT scans, including patchy ground-glass opacity, air retention, bronchial wall thickening, bronchiectasis, mosaic perfusion and a unilateral hyperlucent lung (19). Air retention syndrome has the highest sensitivity and accuracy in the diagnosis of BO. Leung et al (20) reported that the sensitivity of air retention syndrome in HRCT was 91%, with a specificity of 80% and an accuracy of 86%. The expiratory phase of respiration is important in diagnosing air retention, particularly in less severe cases where the inspiratory phase may miss or underestimate this important characteristic (21). Acquiring scans of the two respiratory phases may be a challenge in uncooperative pediatric patients; therefore, more attention should be paid to ground-glass opacity features. In the current study, the HRCT results from 10 patients revealed ground-glass opacity.
In the study by Colom and Teper (22), the following scoring method was proposed: Typical medical history (4 points); adenovirus infection (3 points) and HRCT showing mosaic perfusion syndrome (4 points). A score of >7 points indicated a diagnosis of BO, with a specificity of 100% and a sensitivity of 67%.
PIBO is a rare disease, which has limited the opportunity for proper randomized clinical trials focused on its treatment; thus, therapeutic decisions are empirically based (23,24). The drug treatments for PIBO include: i) Oral or inhaled corticosteroids aimed at reducing the inflammatory component; ii) hydroxychloroquine and high-dose pulses of methylprednisolone for treating severe or prolonged obstruction; iii) short and long-acting bronchodilators or inhaled anticholinergic agents for cases of symptomatic wheezing; and iv) antibiotics, orally or intravenously administered, for the treatment of patients with frequent infections (25).
Oxygen supplementation may also be used in addition to drug treatment, particularly during the first few years of the disease. In the majority of cases, subsequent clinical improvement leads to the complete weaning off of oxygen. The requirement for supplemental oxygen at night is a concern; however, only in severe cases have patients demonstrated significant desaturation during sleep (26).
Although inflammation plays a prominent role in the pathogenesis of BO, the use of corticosteroid drug treatment remains controversial due to the side effects. Certain studies have suggested that steroids may slow down the progression of bronchiole fibrosis (27). In the current study, the patients were administered an initial dose of prednisone of 1 mg/kg/day. The dose was gradually reduced after 3 months, with the overall course duration varying between 6 and 27 months, or longer. A previous study used steroid therapy, for a period ranging between 1 and 60 months, in children receiving different BO treatments, including bronchodilators, azithromycin and oxygen therapy (28). Among these patients, >80% exhibited rapid improvement in disease symptoms when medicated using steroids.
Azithromycin is a macrolide antibiotic that has been demonstrated in prospective, double-blind, placebo-controlled trials to be effective for the treatment of diffuse panbronchiolitis and cystic fibrosis. The efficacy of azithromycin has been hypothesized to be a result of its anti-inflammatory effects (29).
In addition, a previous study in patients with BOS following a lung transplant have demonstrated an improvement in the forced expiratory volume in 1 sec following a prolonged course of oral azithromycin (250 mg three times per week) (30). Although no previous studies have been performed with azithromycin in children with PIBO, oral azithromycin should be considered as a therapeutic option for these patients due to the efficacy demonstrated in the present study.
In conclusion, the results of the current study indicate that a typical clinical history and patchy ground-glass opacity features on HRCT scans can be used as screening indices to predict BO development. Steroid therapy is the cornerstone of BO treatment; however, azithromycin is also indispensable in the treatment of this disease.